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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY



Sexta-feira, 30.01.15

POTENTIAL DRUG FOR DEADLY BRAIN CANCER

A*STAR SCIENTISTS DISCOVER POTENTIAL DRUG FOR DEADLY BRAIN CANCER

This discovery can potentially prevent the progression and relapse of deadly brain tumours

 

  1.         A*STAR scientists have identified a biomarker of the most lethal form of brain tumours in adults − glioblastoma multiforme[1]. The scientists found that by targeting this biomarker and depleting it with a potential drug, they were able to prevent the progression and relapse of the brain tumour. 
  2. This research was conducted by scientists at A*STAR’s Institute of Medical Biology led by Dr Prabha Sampath, Principal Investigator, in collaboration with A*STAR’s Bioinformatics Institute (BII), and clinical collaborators from Medical University of Graz, Austria, and National University of Singapore. The research findings were published on Aug 23 in the scientific journal, Cell Reports from Cell Press.
  3. The scientists found that the biomarker, miR-138, is highly expressed in cancer stem cells compared to normal neural stem cells. They thus carried out in vitro experiments to deplete miR-138 in these cancer stem cells with a potential drug, antimiR-138, to observe the effect. They found that when miR-138 is depleted, the cancer cells are completely destroyed. This is an important breakthrough as current therapies such as gamma radiation and surgical methods proved to be inadequate in treating these brain tumours, which tend to re-grow from cancer stem cells and become extremely lethal.
  4.         Dr Sampath said, “In this study we have identified a master regulator, miR-138, which is essential for the progression and relapse of a deadly form of brain cancer. By targeting this regulator we can effectively prevent the recurrence of this lethal form of cancer. This promising finding will pave the way for the development of a novel therapy to successfully treat the aggressive forms of brain cancer.”
  5. Studies were also done in mice to determine whether antimiR-138 could effectively inhibit the growth of tumours. These experiments were conducted with a control drug as well, revealing that tumours continued to be present when mice were injected with the control, while injection with the antimiR-138 showed no tumour growth after nine months.
  6. Dr Alan Colman, Executive Director of Singapore Stem Cell Consortium and a Principal Investigator at IMB said, “Malignant gliomas are a particularly devastating and lethal form of human brain cancer. As with a growing number of other cancers, evidence is accumulating that the persistence and chemo-resistance of this cancer is due to the presence of glioma stem cells (GSCs).  In this exciting publication, Sampath and colleagues indicate that in the tumours, these GSCs express the microRNA-138 (miR-138) and that the targeted elimination of this RNA markedly reduced the growth and survival of GSCs in cell culture.  This work highlights the possible significance of miR-138 as a prognostic biomarker and also suggests miR-138 synthesis as a target for therapeutic intervention.”
  7. Prof Sir David Lane, Chief Scientist at A*STAR, added, “These findings will facilitate the translation of basic research into clinical applications such as targeted drug design to treat brain cancer. This is an excellent example of how A*STAR’s impactful research can be applied to develop treatments for diseases like cancer.”
  8. Dr Sampath was a recipient of the A*STAR Investigatorship Award in 2007, a prestigious research award designed to attract the most promising young researchers from around the world to do independent research at A*STAR.

________________________________________________________________

 

Notes for Editor:

The research findings described in this media release can be found in the 23 August online issue of Cell Press under the title, “Targeting Glioma Stem Cells by Functional Inhibition of a Prosurvival OncomiR-138 in Malignant Gliomas” by Xin Hui Derryn Chan1,*, Srikanth Nama1,*, Felicia Gopal1, Pamela Rizk1, Srinivas Ramasamy1,Gopinath Sundaram1, Ghim Siong Ow2, Ivshina Anna Vladimirovna2, Vivek Tanavde2, Johannes Haybaeck3,Vladimir Kuznetsov2, and Prabha Sampath1,4,#

 

1Institute of Medical Biology, Agency for Science Technology and Research, Singapore 138648, Singapore

 

2Bioinformatics Institute, Agency for Science Technology and Research, Singapore 138671, Singapore

 

3Department of Neuropathology, Medical University of Graz, 8036 Graz, Austria

 

4Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore

 

*These authors contributed equally to this work.

#Correspondence should be addressed to: Prabha Sampath (prabha.sampath@imb.a-star.edu.sg)

 

Prabha Sampath

Institute of Medical Biology (IMB)

Agency for Science, Technology and Research (A*STAR)

8A Biomedical Grove, IMMUNOS Building #06-06

BIOPOLIS, 138648, Singapore

Tel: (65) 64070171

Email: prabha.sampath@imb.a-star.edu.sg

________________________________________________________________

 

AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH (A*STAR)

For media queries and clarifications, please contact:

 

Vithya Selvam (Ms)

Senior Officer, Corporate Communications

Agency for Science, Technology and Research

Tel: (+65) 6826 6291

Email: vithya_selvam@a-star.edu.sg

 

About the Institute of Medical Biology (IMB)

IMB is one of the Biomedical Sciences Institutes of the Agency for Science, Technology and Research (A*STAR). It was formed in 2007, the 7th and youngest of the BMRC Research Institutes, with a mission to study mechanisms of human disease in order to discover new and effective therapeutic strategies for improved quality of life. From 2011, IMB also hosts the inter-research institute Skin Biology Cluster platform.

IMB has 20 research teams of international excellence in stem cells, genetic diseases, cancer and skin and epithelial biology, and works closely with clinical collaborators to target the challenging interface between basic science and clinical medicine. Its growing portfolio of strategic research topics is targeted at translational research on the mechanisms of human diseases, with a cell-to-tissue emphasis that can help identify new therapeutic strategies for disease amelioration, cure and eradication.

For more information about IMB, please visit www.imb.a-star.edu.sg.

 

About the Agency for Science, Technology and Research (A*STAR)

The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences and physical sciences and engineering research institutes, and six consortia & centres, located in Biopolis and Fusionopolis as well as their immediate vicinity.

A*STAR supports Singapore's key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, and with other local and international partners.

For more information about A*STAR, please visit www.a-star.edu.sg.

 

[1] This form of brain tumour comprises 60% of the estimated 17 000 primary brain tumours diagnosed in the United States each year (http://emedicine.medscape.com/article/283252-overview)and patients diagnosed typically do not live longer than 12 to 14 months.

Related Documents

IMB press release on brain cancer.pdf [217.7 KB]

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por cyto às 02:23

Sexta-feira, 30.01.15

Hyperbaric oxygen (HBO) treatment

Hyperbaric oxygen (HBO) treatment

Hyperbaric oxygen treatment (HBO) is sometimes used to treat severe side effects of cancer treatment. This information describes HBO, how it’s given and some of its possible side effects.

You will see your doctor regularly while you have this treatment so they can monitor its effects. This information should help you to discuss any queries about your treatment and its side effects with your doctor or specialist nurse.

Hyperbaric oxygen treatment (HBO) involves providing the body with extra oxygen. 'Hyper' means increased and 'baric' relates to pressure. Oxygen is one of the gases in the air, and it’s essential for life. In HBO treatment, people breathe in pure (100%) oxygen. This is done by sitting in a chamber known as a hyperbaric oxygen chamber and using a mask or hood.

What HBO treatment is used for

HBO treatment can help in a number of different situations where body tissues have suffered from a decrease in oxygen levels. These include:

  • decompression illness ('the bends')
  • severe carbon monoxide poisoning
  • smoke inhalation
  • chronic wounds and some infections
  • wound healing after reconstructive surgery
  • radiation necrosis (body tissue dying off after radiotherapy treatment)
  • acute blood loss where a blood transfusion is not possible (for example, for Jehovah's Witnesses)
  • sports injuries
  • diabetic foot ulcers.

 

 

How HBO treatment works

Oxygen is carried around the body by the blood. Breathing in 100% (pure) oxygen under increased pressure, called HBO, allows extra oxygen to be taken up by the bloodstream and dissolved at a far greater rate. This extra oxygen can help where healing is slowed down by infection or where blood supply is limited by damage to the tissues.

 

HBO treatment:

  • assists healing by raising tissue oxygen levels to normal in areas where they are reduced through illness or injury
  • encourages new blood vessels to grow and carry additional blood
  • increases the ability of the body’s defence mechanisms to fight infection and kill bacteria
  • helps reduce any swelling that may occur around the area.

 

HBO treatment for people with cancer

The most common use of HBO is in treating the side effects of radiotherapy|. Other uses are being investigated.

 

HBO treatment for radiotherapy side effects: Radiotherapy| can cause changes in the oxygen supply to tissues in the treated area. This is because radiotherapy affects normal cells and blood vessels as well as cancer cells.

The small blood vessels in the treated area can be damaged by radiotherapy, causing less blood to be supplied to that area. When this happens, it becomes more difficult for essential oxygen and nutrients to reach the tissues.

Over a period of time, the affected tissues may become fragile and start to break down. They may form areas of open sores (ulceration) and rarely, some tissues may eventually die off completely (radiation necrosis). These radiation injuries can occur very slowly over a number of months or even years.

HBO treatment for radiation injuries works by increasing the oxygen supply to damaged tissue. This encourages new blood vessels to grow and the tissues to heal.

 

Research has shown that HBO treatment may help treat the following:

 

Chronic radiation cystitis

Radiotherapy is used as a treatment for some types of pelvic cancer. Sometimes, treatment can lead to chronic cystitis (inflammation of the bladder). Symptoms include needing to pass urine frequently, pain when passing urine and blood in the urine (haematuria). These problems can occur months or years after treatment. Symptoms can be persistent and range from moderate to severe. HBO treatment may help to relieve these symptoms when other forms of treatment have been tried without success.

 

 

Osteoradionecrosis

Radiotherapy is often used for cancers in the head and neck|. The tissues around this area are fragile and may break down after radiotherapy, particularly if surgery| has been carried out previously. Rarely, the bone itself can be affected by radiotherapy and start to break down and die. This is known as osteoradionecrosis. Osteoradionecrosis can also happen when radiotherapy is given to other areas of the body, such as the chest or pelvis.

research study| called HOPON (hyperbaric oxygen therapy to prevent osteoradionecrosis) is finding out if giving HBO to people with head and neck cancer after radiotherapy prevents damage to the jaw bone.

When the damage has occurred, treatment for osteoradionecrosis includes antibiotics, ‘washing out’ the area with salt water (saline irrigation), and sometimes surgery to remove some or all of the affected bone. Although HBO treatment cannot restore the dead bone, increased oxygen can help the tissues around the area to heal by encouraging blood vessels to grow.

HBO treatment can also be given before reconstructive surgery to help healing, prevent infection and encourage blood vessels to grow and form new bone.

If wounds or tissue are infected, treatment usually consists of medicines or surgery as well as HBO treatment.

 

Tooth removal

Having a tooth removed shortly before, during or after radiotherapy to the mouth and jaw area may increase the risk of osteoradionecrosis. This is because of the reduced oxygen supply to the healing area. HBO treatment can be given to help prevent this, if used both before and after the tooth extraction, and to stimulate the healing process.

Chronic radiation effects on the bowel

Radiotherapy can be given for bowel cancer|. The bowel is very sensitive and, although rare, long-term symptoms due to radiation damage can occur. These include pain, bleeding and irregular bowel habits. If these symptoms don't improve following treatments such as anti-inflammatory medicines; HBO treatment may be helpful.

A research study called HOT II is trying to find out if HBO helps people who have developed bowel complications as a result of radiotherapy to the pelvis. This trial is now closed to new recruits.

How HBO treatment is given

Your hospital specialist can advise you whether HBO treatment is appropriate in your situation. They may refer you for HBO treatment if you have long-term side effects from radiotherapy treatment that have not responded to standard treatments.

There are a number of places where HBO treatment is given. Your doctor will be able to tell you your nearest centre for treatment. Some people may have to travel some distance.

Before having HBO treatment you will be examined by a doctor to make sure that you are fit enough to have it. HBO treatment is suitable for most people. It is given inside a chamber, so if you have a fear of enclosed spaces (claustrophobia), you may need medicines to help calm you.

If you smoke, you'll be asked to stop smoking before and during treatment as this is likely to affect the level of oxygen in your body.

Treatment is usually painless and is carried out in simple chambers. There are two types of chamber: a monoplace chamber and a multiplace chamber:

Monoplace chambers

These are designed to treat one person at a time and treatment involves lying on a 2.1m (7ft) padded stretcher that slides into a clear plastic tube (chamber) about 60cm (2ft) wide. Once you are inside, the door is closed and the chamber is pressurised with Oxygen. You will be able to see and talk to a member of staff at all times during the treatment.

 

Multiplace chambers

These are designed to fit and treat up to 12 people at a time, and are more commonly used than monoplace chambers. These chambers are quite large and you will be able to walk about inside. Once you are sitting or lying inside the chamber, the doors will be closed and air is blown into the chamber to increase the pressure. You will hear a sound similar to that in an aircraft as the air begins to circulate.

In both monoplace and multiplace chambers it is necessary to 'clear' your ears as soon as the pressure begins to increase. You will be shown how to do this. Clearing your ears helps to equalise the pressure in them and prevent any pain in your eardrum.

When the pressure reaches the correct level, you will be asked to put on either a mask or a clear hood to receive 100% oxygen. Monoplace chambers are pressurised using 100% oxygen, so you don’t need to wear a mask or hood. You will be able to relax, read, or listen to music and you can talk to staff who are operating the chamber if you need anything.

Near the end of the treatment the pressure in the chamber is slowly decreased. You may feel 'popping' in your ears during this time. After the decompression phase you can leave the chamber.

The length of each treatment varies depending on what you are being treated for. It can last anywhere from 60–90 minutes at a time. Treatments are usually repeated over a number of days, or several weeks. The entire course should be completed for maximum benefit.

Treatment sessions are likely to be postponed if you have a severe cold or flu, runny nose, vomiting or are generally feeling unwell. You should let your nurse or doctor know if you have any of these symptoms before starting a treatment session.

Possible side effects of HBO treatment

HBO treatment is very safe with few side effects. These are usually minor and short-lived. If you notice any other problems which you think may be due to the treatment, discuss them with your nurse or doctor.

Blurred vision

This can occur after having multiple treatments and is due to the development of short sightedness (myopia). It usually comes on gradually and then gets better slowly when treatment ends. Temporary use of glasses or a change in prescription may be helpful, but the blurred vision only lasts a few weeks at most.

 

Light-headedness

Some people feel light-headed after treatment. This only lasts for a few minutes.

 

Fatigue

Tiredness| is a side effect that can be more of a problem if you have treatment more than once a day. The effect usually wears off after a few days once the treatment sessions are finished.

Less common side effects

Ear problems

Although rare, damage to the eardrum can occur due to the change in pressure. Before treatment you will be shown how to equalise the pressure in your ears, which can help to prevent any ear problems.

 

Sinuses

The change in pressure may cause discomfort if you have congested sinuses, leading to headaches or facial pain.

Usually this can be controlled with decongestant medicine, but occasionally HBO therapy needs to be stopped.

 

Research into HBO treatment

Research has shown that HBO may be helpful when used alongside cancer treatments. HBO treatment may:

  • Reduce cancer growth.
  • Improve the delivery of chemotherapy drugs to a tumour.
  • Result in an increase in the body's own stem cells. These are blood cells at the earliest stage of development in the bone marrow. Because HBO treatment can increase stem cells it may have a role in stem cell transplantation – a treatment sometimes used in haematological (blood) cancers.

References

This information has been compiled using a number of reliable sources, including:

  • Mechem CC, Manaker S.  Hyperbaric oxygen therapy. (accessed October 2012).
  • Oliai C, et al. Hyperbaric oxygen therapy for radiation-induced cystitis and proctitis. International Journal of Radiation Oncology *Biology* Physics. 2012. Nov 1;84(3):733-40. Epub 2012 Mar 21.
  • Ritchie K, et al. The clinical and cost effectiveness of hyperbaric oxygen therapy. HTA programme: HTA systematic review 2. 2008.
  • Bennett MH, et al. Hyperbaric oxygen therapy for late radiation tissue injury (Review). The Cochrane Library. 2012.  

Content last reviewed: 1 January 2013 Next planned review: 2015

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por cyto às 02:21

Sexta-feira, 30.01.15

Cryosurgery in Cancer Treatment

Cryosurgery in Cancer Treatment (Fact Sheet)

What is cryosurgery?

Cryosurgery (also called cryotherapy) is the use of extreme cold produced by liquid nitrogen (or argon gas) to destroy abnormal tissue. Cryosurgery is used to treat external tumors, such as those on the skin. For external tumors, liquid nitrogen is applied directly to the cancer cells with a cotton swab or spraying device.

Cryosurgery is also used to treat tumors inside the body (internal tumors and tumors in the bone). For internal tumors, liquid nitrogen or argon gas is circulated through a hollow instrument called a cryoprobe, which is placed in contact with the tumor. The doctor uses ultrasound or MRI to guide the cryoprobe and monitor the freezing of the cells, thus limiting damage to nearby healthy tissue. (In ultrasound, sound waves are bounced off organs and other tissues to create a picture called a sonogram.) A ball of ice crystals forms around the probe, freezing nearby cells. Sometimes more than one probe is used to deliver the liquid nitrogen to various parts of the tumor. The probes may be put into the tumor during surgery or through the skin (percutaneously). After cryosurgery, the frozen tissue thaws and is either naturally absorbed by the body (for internal tumors), or it dissolves and forms a scab (for external tumors).

What types of cancer can be treated with cryosurgery?

Cryosurgery is used to treat several types of cancer, and some precancerous or noncancerous conditions. In addition to prostate and liver tumors, cryosurgery can be an effective treatment for the following:

  • Retinoblastoma (a childhood cancer that affects the retina of the eye). Doctors have found that cryosurgery is most effective when the tumor is small and only in certain parts of the retina.
  • Early-stage skin cancers (both basal cell and squamous cell carcinomas).
  • Precancerous skin growths known as actinic keratosis.
  • Precancerous conditions of the cervix known as cervical intraepithelial neoplasia (abnormal cell changes in the cervix that can develop into cervical cancer).

Cryosurgery is also used to treat some types of low-grade cancerous and noncancerous tumors of the bone. It may reduce the risk of joint damage when compared with more extensive surgery, and help lessen the need for amputation. The treatment is also used to treat AIDS-related Kaposi sarcoma when the skin lesions are small and localized.

Researchers are evaluating cryosurgery as a treatment for a number of cancers, including breast, colon, and kidney cancer. They are also exploring cryotherapy in combination with other cancer treatments, such as hormone therapy, chemotherapy, radiation therapy, or surgery.

In what situations can cryosurgery be used to treat prostate cancer? What are the side effects?

Cryosurgery can be used to treat men who have early-stage prostate cancer that is confined to the prostate gland. It is less well established than standard prostatectomy and various types of radiation therapy. Long-term outcomes are not known. Because it is effective only in small areas, cryosurgery is not used to treat prostate cancer that has spread outside the gland, or to distant parts of the body.

Some advantages of cryosurgery are that the procedure can be repeated, and it can be used to treat men who cannot have surgery or radiation therapy because of their age or other medical problems.

Cryosurgery for the prostate gland can cause side effects. These side effects may occur more often in men who have had radiation to the prostate.

  • Cryosurgery may obstruct urine flow or cause incontinence (lack of control over urine flow); often, these side effects are temporary.
  • Many men become impotent (loss of sexual function).
  • In some cases, the surgery has caused injury to the rectum.

In what situations can cryosurgery be used to treat primary liver cancer or liver metastases (cancer that has spread to the liver from another part of the body)? What are the side effects?

Cryosurgery may be used to treat primary liver cancer that has not spread. It is used especially if surgery is not possible due to factors such as other medical conditions. The treatment also may be used for cancer that has spread to the liver from another site (such as the colon or rectum). In some cases, chemotherapy and/or radiation therapy may be given before or after cryosurgery. Cryosurgery in the liver may cause damage to the bile ducts and/or major blood vessels, which can lead to hemorrhage (heavy bleeding) or infection.

Does cryosurgery have any complications or side effects?

Cryosurgery does have side effects, although they may be less severe than those associated with surgery or radiation therapy. The effects depend on the location of the tumor. Cryosurgery for cervical intraepithelial neoplasia has not been shown to affect a woman's fertility, but it can cause cramping, pain, or bleeding. When used to treat skin cancer (including Kaposi sarcoma), cryosurgery may cause scarring and swelling; if nerves are damaged, loss of sensation may occur, and, rarely, it may cause a loss of pigmentation and loss of hair in the treated area. When used to treat tumors of the bone, cryosurgery may lead to the destruction of nearby bone tissue and result in fractures, but these effects may not be seen for some time after the initial treatment and can often be delayed with other treatments. In rare cases, cryosurgery may interact badly with certain types of chemotherapy. Although the side effects of cryosurgery may be less severe than those associated with conventional surgery or radiation, more studies are needed to determine the long-term effects.

What are the advantages of cryosurgery?

Cryosurgery offers advantages over other methods of cancer treatment. It is less invasive than surgery, involving only a small incision or insertion of the cryoprobe through the skin. Consequently, pain, bleeding, and other complications of surgery are minimized. Cryosurgery is less expensive than other treatments and requires shorter recovery time and a shorter hospital stay, or no hospital stay at all. Sometimes cryosurgery can be done using only local anesthesia.

Because physicians can focus cryosurgical treatment on a limited area, they can avoid the destruction of nearby healthy tissue. The treatment can be safely repeated and may be used along with standard treatments such as surgery, chemotherapy, hormone therapy, and radiation. Cryosurgery may offer an option for treating cancers that are considered inoperable or that do not respond to standard treatments. Furthermore, it can be used for patients who are not good candidates for conventional surgery because of their age or other medical conditions.

What are the disadvantages of cryosurgery?

The major disadvantage of cryosurgery is the uncertainty surrounding its long-term effectiveness. While cryosurgery may be effective in treating tumors the physician can see by using imaging tests (tests that produce pictures of areas inside the body), it can miss microscopic cancer spread. Furthermore, because the effectiveness of the technique is still being assessed, insurance coverage issues may arise.

What does the future hold for cryosurgery?

Additional studies are needed to determine the effectiveness of cryosurgery in controlling cancer and improving survival. Data from these studies will allow physicians to compare cryosurgery with standard treatment options such as surgery, chemotherapy, and radiation. Moreover, physicians continue to examine the possibility of using cryosurgery in combination with other treatments.

Where is cryosurgery currently available?

Cryosurgery is widely available in gynecologists' offices for the treatment of cervical neoplasias. A limited number of hospitals and cancer centers throughout the country currently have skilled doctors and the necessary technology to perform cryosurgery for other noncancerous, precancerous, and cancerous conditions. Individuals can consult with their doctors or contact hospitals and cancer centers in their area to find out where cryosurgery is being used.

Source: National Cancer Institute

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por cyto às 02:18

Sexta-feira, 30.01.15

Why is there concern that cell phones may cause cancer or other health problems?

Cell Phones and Cancer Risk (Fact Sheet)

Why is there concern that cell phones may cause cancer or other health problems?

There are three main reasons why people are concerned that cell phones (also known as “wireless” or “mobile” telephones) might have the potential to cause certain types of cancer or other health problems:

  • Cell phones emit radiofrequency energy (radio waves), a form of non-ionizing radiation. Tissues nearest to where the phone is held can absorb this energy.
  • The number of cell phone users has increased rapidly. As of 2010, there were more than 303 million subscribers to cell phone service in the United States, according to the Cellular Telecommunications and Internet Association. This is a nearly threefold increase from the 110 million users in 2000. Globally, the number of cell phone subscriptions is estimated by the International Telecommunications Union to be 5 billion.
  • Over time, the number of cell phone calls per day, the length of each call, and the amount of time people use cell phones, have increased. Cell phone technology has also undergone substantial changes.

What is radiofrequency energy and how does it affect the body?

Radiofrequency energy is a form of electromagnetic radiation. Electromagnetic radiation can be categorized into two types: ionizing (e.g., x-rays, radon, and cosmic rays) and non-ionizing (e.g., radiofrequency and extremely low-frequency or power frequency).

Exposure to ionizing radiation, such as from radiation therapy, is known to increase the risk of cancer. However, although many studies have examined the potential health effects of non-ionizing radiation from radar, microwave ovens, and other sources, there is currently no consistent evidence that non-ionizing radiation increases cancer risk (1).

The only known biological effect of radiofrequency energy is heating. The ability of microwave ovens to heat food is one example of this effect of radiofrequency energy. Radiofrequency exposure from cell phone use does cause heating; however, it is not sufficient to measurably increase body temperature.

A recent study showed that when people used a cell phone for 50 minutes, brain tissues on the same side of the head as the phone's antenna metabolized more glucose than did tissues on the opposite side of the brain (2). The researchers noted that the results are preliminary, and possible health outcomes from this increase in glucose metabolism are still unknown.

How is radiofrequency energy exposure measured in epidemiologic studies?

Levels of radiofrequency exposure are indirectly estimated using information from interviews or questionnaires. These measures include the following:

  • How “regularly” study participants use cell phones (the minimum number of calls per week or month)
  • The age and the year when study participants first used a cell phone and the age and the year of last use (allows calculation of the duration of use and time since the start of use)
  • The average number of cell phone calls per day, week, or month (frequency)
  • The average length of a typical cell phone call
  • The total hours of lifetime use, calculated from the length of typical call times, the frequency of use, and the duration of use

What has research shown about the possible cancer-causing effects of radiofrequency energy?

Although there have been some concerns that radiofrequency energy from cell phones held closely to the head may affect the brain and other tissues, to date there is no evidence from studies of cells, animals, or humans that radiofrequency energy can cause cancer.

It is generally accepted that damage to DNA is necessary for cancer to develop. However, radiofrequency energy, unlike ionizing radiation, does not cause DNA damage in cells, and it has not been found to cause cancer in animals or to enhance the cancer-causing effects of known chemical carcinogens in animals (3–5).

Researchers have carried out several types of epidemiologic studies to investigate the possibility of a relationship between cell phone use and the risk of malignant (cancerous) brain tumors, such as gliomas, as well as benign (noncancerous) tumors, such as acoustic neuromas (tumors in the cells of the nerve responsible for hearing), most meningiomas (tumors in the meninges, membranes that cover and protect the brain and spinal cord), and parotid gland tumors (tumors in the salivary glands) (6).

In one type of study, called a case-control study, cell phone use is compared between people with these types of tumors and people without them. In another type of study, called a cohort study, a large group of people is followed over time and the rate of these tumors in people who did and didn't use cell phones is compared. Cancer incidence data can also be analyzed over time to see if the rates of cancer changed in large populations during the time that cell phone use increased dramatically. The results of these studies have generally not provided clear evidence of a relationship between cell phone use and cancer, but there have been some statistically significant findings in certain subgroups of people.

Findings from specific research studies are summarized below:

  • The Interphone Study, conducted by a consortium of researchers from 13 countries, is the largest health-related case-control study of use of cell phones and head and neck tumors. Most published analyses from this study have shown no statistically significant increases in brain or central nervous system cancers related to higher amounts of cell phone use. One recent analysis showed a statistically significant, albeit modest, increase in the risk of glioma among the small proportion of study participants who spent the most total time on cell phone calls. However, the researchers considered this finding inconclusive because they felt that the amount of use reported by some respondents was unlikely and because the participants who reported lower levels of use appeared to have a slightly reduced risk of brain cancer compared with people who did not use cell phones regularly (7–9). Another recent study from the group found no relationship between brain tumor locations and regions of the brain that were exposed to the highest level of radiofrequency energy from cell phones (10).
  • A cohort study in Denmark linked billing information from more than 358,000 cell phone subscribers with brain tumor incidence data from the Danish Cancer Registry. The analyses found no association between cell phone use and the incidence of glioma, meningioma, or acoustic neuroma, even among people who had been cell phone subscribers for 13 or more years (11–13).
  • The prospective Million Women Study in the United Kingdom found that self-reported cell phone use was not associated with an increased risk of glioma, meningioma, or non-central nervous system tumors. The researchers did find that the use of cell phones for more than 5 years was associated with an increased risk of acoustic neuroma, and that the risk of acoustic neuroma increased with increasing duration of cell phone use (14). However, the incidence of these tumors among men and women in the United Kingdom did not increase during 1998 to 2008, even though cell phone use increased dramatically over that decade (14).
  • An early case-control study in the United States was unable to demonstrate a relationship between cell phone use and glioma or meningioma (15).
  • Some case-control studies in Sweden found statistically significant trends of increasing brain cancer risk for the total amount of cell phone use and the years of use among people who began using cell phones before age 20 (16). However, another large, case-control study in Sweden did not find an increased risk of brain cancer among people between the ages of 20 and 69 (17). In addition, the international CEFALO study, which compared children who were diagnosed with brain cancer between ages 7 and 19 with similar children who were not, found no relationship between their cell phone use and risk for brain cancer (18).
  • NCI's Surveillance, Epidemiology, and End Results (SEER) Program, which tracks cancer incidence in the United States over time, found no increase in the incidence of brain or other central nervous system cancers between 1987 and 2007, despite the dramatic increase in cell phone use in this country during that time (19, 20). Similarly, incidence data from Denmark, Finland, Norway, and Sweden for the period 1974–2008 revealed no increase in age-adjusted incidence of brain tumors (21, 22). A 2012 study by NCI researchers, which compared observed glioma incidence rates in SEER with projected rates based on risks observed in the Interphone study (8), found that the projected rates were consistent with observed U.S. rates. The researchers also compared the SEER rates with projected rates based on a Swedish study published in 2011 (16). They determined that the projected rates were at least 40 percent higher than, and incompatible with, the actual U.S. rates.
  • Studies of workers exposed to radiofrequency energy have shown no evidence of increased risk of brain tumors among U.S. Navy electronics technicians, aviation technicians, or fire control technicians, those working in an electromagnetic pulse test program, plastic-ware workers, cellular phone manufacturing workers, or Navy personnel with a high probability of exposure to radar (6). 

Why are the findings from different studies of cell phone use and cancer risk inconsistent?

A limited number of studies have shown some evidence of statistical association of cell phone use and brain tumor risks, but most studies have found no association. Reasons for these discrepancies include the following:

  • Recall bias, which may happen when a study collects data about prior habits and exposures using questionnaires administered after disease has been diagnosed in some of the study participants. It is possible that study participants who have brain tumors may remember their cell phone use differently than individuals without brain tumors. Many epidemiologic studies of cell phone use and brain cancer risk lack verifiable data about the total amount of cell phone use over time. In addition, people who develop a brain tumor may have a tendency to recall using their cell phone mostly on the same side of their head where the tumor was found, regardless of whether they actually used their phone on that side of their head a lot or only a little.
  • Inaccurate reporting, which may happen when people say that something has happened more or less often than it actually did. People may not remember how much they used cell phones in a given time period.
  • Morbidity and mortality among study participants who have brain cancer. Gliomas are particularly difficult to study, for example, because of their high death rate and the short survival of people who develop these tumors. Patients who survive initial treatment are often impaired, which may affect their responses to questions. Furthermore, for people who have died, next-of-kin are often less familiar with the cell phone use patterns of their deceased family member and may not accurately describe their patterns of use to an interviewer.
  • Participation bias, which can happen when people who are diagnosed with brain tumors are more likely than healthy people (known as controls) to enroll in a research study. Also, controls who did not or rarely used cell phones were less likely to participate in the Interphone study than controls who used cell phones regularly. For example, the Interphone study reported participation rates of 78 percent for meningioma patients (range 56–92 percent for the individual studies), 64 percent for the glioma patients (range 36–92 percent), and 53 percent for control subjects (range 42–74 percent) (9). One series of Swedish studies reported participation rates of 85 percent in people with brain cancer and 84 percent in control subjects (17).
  • Changing technology and methods of use. Older studies evaluated radiofrequency energy exposure from analog cell phones. However, most cell phones today use digital technology, which operates at a different frequency and a lower power level than analog phones. Digital cell phones have been in use for more than a decade in the United States, and cellular technology continues to change (6). Texting, for example, has become a popular way of using a cell phone to communicate that does not require bringing the phone close to the head. Furthermore, the use of hands-free technology, such as wired and wireless headsets, is increasing and may decrease radiofrequency energy exposure to the head and brain.

What do expert organizations conclude?

The International Agency for Research on Cancer Exit Disclaimer (IARC), a component of the World Health Organization, has recently classified radiofrequency fields as “possibly carcinogenic to humans,” based on limited evidence from human studies, limited evidence from studies of radiofrequency energy and cancer in rodents, and weak mechanistic evidence (from studies of genotoxicity, effects on immune system function, gene and protein expression, cell signaling, oxidative stress, and apoptosis, along with studies of the possible effects of radiofrequency energy on the blood-brain barrier).

The American Cancer Society Exit Disclaimer (ACS) states that the IARC classification means that there could be some risk associated with cancer, but the evidence is not strong enough to be considered causal and needs to be investigated further. Individuals who are concerned about radiofrequency exposure can limit their exposure, including using an ear piece and limiting cell phone use, particularly among children.

The National Institute of Environmental Health Sciences (NIEHS) states that the weight of the current scientific evidence has not conclusively linked cell phone use with any adverse health problems, but more research is needed.

The U.S. Food and Drug Administration (FDA), which is responsible for regulating the safety of machines and devices that emit radiation (including cell phones), notes that studies reporting biological changes associated with radiofrequency energy have failed to be replicated and that the majority of human epidemiologic studies have failed to show a relationship between exposure to radiofrequency energy from cell phones and health problems.

The U.S. Centers for Disease Control and Prevention (CDC) states that, although some studies have raised concerns about the possible risks of cell phone use, scientific research as a whole does not support a statistically significant association between cell phone use and health effects.

The Federal Communications Commission (FCC) concludes that there is no scientific evidence that proves that wireless phone use can lead to cancer or to other health problems, including headaches, dizziness, or memory loss.

What studies are under way that will help further our understanding of the health effects of cell phone use?

A large prospective cohort study of cell phone use and its possible long-term health effects was launched in Europe in March 2010. This study, known as COSMOS Exit Disclaimer, has enrolled approximately 290,000 cell phone users aged 18 years or older to date and will follow them for 20 to 30 years.

Participants in COSMOS will complete a questionnaire about their health, lifestyle, and current and past cell phone use. This information will be supplemented with information from health records and cell phone records.

The challenge of this ambitious study is to continue following the participants for a range of health effects over many decades. Researchers will need to determine whether participants who leave are somehow different from those who remain throughout the follow-up period.

Another study already under way is a case-control study called Mobi-Kids Exit Disclaimer, which will include 2000 young people (aged 10-24 years) with newly diagnosed brain tumors and 4000 healthy young people. The goal of the study is to learn more about risk factors for childhood brain tumors. Results are expected in 2016.

Although recall bias is minimized in studies that link participants to their cell phone records, such studies face other problems. For example, it is impossible to know who is using the listed cell phone or whether that individual also places calls using other cell phones. To a lesser extent, it is not clear whether multiple users of a single phone will be represented on a single phone company account.

The NIEHS, which is part of the National Institutes of Health, is carrying out a study of risks related to exposure to radiofrequency energy (the type used in cell phones) in highly specialized labs that can specify and control sources of radiation and measure their effects on rodents. 

Do children have a higher risk of developing cancer due to cell phone use than adults?

In theory, children have the potential to be at greater risk than adults for developing brain cancer from cell phones. Their nervous systems are still developing and therefore more vulnerable to factors that may cause cancer. Their heads are smaller than those of adults and therefore have a greater proportional exposure to the field of radiofrequency radiation that is emitted by cell phones. And children have the potential of accumulating more years of cell phone exposure than adults do.

So far, the data from studies in children with cancer do not support this theory. The first published analysis came from a large case-control study called CEFALO, which was conducted in Denmark, Sweden, Norway, and Switzerland. The study included children who were diagnosed with brain tumors between 2004 and 2008, when their ages ranged from 7 to 19. Researchers did not find an association between cell phone use and brain tumor risk in this group of children. However, they noted that their results did not rule out the possibility of a slight increase in brain cancer risk among children who use cell phones, and that data gathered through prospective studies and objective measurements, rather than participant surveys and recollections, will be key in clarifying whether there is an increased risk (19).

Researchers from the Centre for Research in Environmental Epidemiology in Spain are conducting another international study—Mobi-Kids Exit Disclaimer—to evaluate the risk associated with new communications technologies (including cell phones) and other environmental factors in young people newly diagnosed with brain tumors at ages 10 to 24 years.

What can cell phone users do to reduce their exposure to radiofrequency energy?

The FDA and FCC have suggested some steps that concerned cell phone users can take to reduce their exposure to radiofrequency energy (1, 23):

  • Reserve the use of cell phones for shorter conversations or for times when a landline phone is not available.
  • Use a hands-free device, which places more distance between the phone and the head of the user.

Hands-free kits reduce the amount of radiofrequency energy exposure to the head because the antenna, which is the source of energy, is not placed against the head.

Where can I find more information about radiofrequency energy from my cell phone?

The FCC provides information about the specific absorption rate (SAR) of cell phones produced and marketed within the last 1 to 2 years. The SAR corresponds with the relative amount of radiofrequency energy absorbed by the head of a cell phone user (24). Consumers can access this information using the phone's FCC ID number, which is usually located on the case of the phone, and the FCC's ID search form.

What are other sources of radiofrequency energy?

The most common exposures to radiofrequency energy are from telecommunications devices and equipment (1). In the United States, cell phones currently operate in a frequency range of about 1,800 to 2,200 megahertz (MHz) (6). In this range, the electromagnetic radiation produced is in the form of non-ionizing radiofrequency energy.

Cordless phones (phones that have a base unit connected to the telephone wiring in a house) often operate at radio frequencies similar to those of cell phones; however, since cordless phones have a limited range and require a nearby base, their signals are generally much less powerful than those of cell phones.

Among other radiofrequency energy sources, AM/FM radios and VHF/UHF televisions operate at lower radio frequencies than cell phones, whereas sources such as radar, satellite stations, magnetic resonance imaging (MRI) devices, industrial equipment, and microwave ovens operate at somewhat higher radio frequencies (1).

How common is brain cancer? Has the incidence of brain cancer changed over time?

Brain cancer incidence and mortality (death) rates have changed little in the past decade. In the United States, 23,130 new diagnoses and 14,080 deaths from brain cancer are estimated for 2013.

The 5-year relative survival for brain cancers diagnosed from 2003 through 2009 was 35 percent (25). This is the percentage of people diagnosed with brain cancer who will still be alive 5 years after diagnosis compared with the survival of a person of the same age and sex who does not have cancer.

The risk of developing brain cancer increases with age. From 2006 through 2010, there were fewer than 5 brain cancer cases for every 100,000 people in the United States under age 65, compared with approximately 19 cases for every 100,000 people in the United States who were ages 65 or older (25).

Selected References

  1. U.S. Food and Drug Administration (2009). Radiation-Emitting Products: Reducing Exposure: Hands-free Kits and Other Accessories. Silver Spring, MD. Retrieved June 18, 2012.
  2. Volkow ND, Tomasi D, Wang GJ, et al. Effects of cell phone radiofrequency signal exposure on brain glucose metabolism. JAMA 2011; 305(8):808–813.
  3. Hirose H, Suhara T, Kaji N, et al. Mobile phone base station radiation does not affect neoplastic transformation in BALB/3T3 cells. Bioelectromagnetics 2008; 29(1):55–64.
  4. Oberto G, Rolfo K, Yu P, et al. Carcinogenicity study of 217 Hz pulsed 900 MHz electromagnetic fields in Pim1 transgenic mice. Radiation Research 2007; 168(3):316–326.
  5. Zook BC, Simmens SJ. The effects of pulsed 860 MHz radiofrequency radiation on the promotion of neurogenic tumors in rats. Radiation Research 2006; 165(5):608–615.
  6. Ahlbom A, Green A, Kheifets L, et al. Epidemiology of health effects of radiofrequency exposure. Environmental Health Perspectives 2004; 112(17):1741–1754.
  7. Cardis E, Richardson L, Deltour I, et al. The INTERPHONE study: design, epidemiological methods, and description of the study population. European Journal of Epidemiology 2007; 22(9):647–664.
  8. International Agency for Research on Cancer (2008). INTERPHONE Study: latest results update—8 October 2008 Exit Disclaimer. Lyon, France. Retrieved June 18, 2012.
  9. The INTERPHONE Study Group. Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case-control study. International Journal of Epidemiology 2010; 39(3):675–694.
  10. Larjavaara S, Schüz J, Swerdlow A, et al. Location of gliomas in relation to mobile telephone use: a case-case and case-specular analysis. American Journal of Epidemiology 2011; 174(1):2–11.
  11. Johansen C, Boice J Jr, McLaughlin J, Olsen J. Cellular telephones and cancer: a nationwide cohort study in Denmark. Journal of the National Cancer Institute 2001; 93(3):203–207.
  12. Schüz J, Jacobsen R, Olsen JH, et al. Cellular telephone use and cancer risk: update of a nationwide Danish cohort. Journal of the National Cancer Institute 2006; 98(23):1707–1713.
  13. Frei P, Poulsen AH, Johansen C, et al. Use of mobile phones and risk of brain tumours: update of Danish cohort study. British Medical Journal 2011; 343:d6387.
  14. Benson VS, Pirie K, Schüz J, et al. Mobile phone use and risk of brain neoplasms and other cancers: Prospective study. International Journal of Epidemiology 2013; First published online: May 8, 2013. doi:10.1093/ije/dyt072 Exit Disclaimer
  15. Muscat JE, Malkin MG, Thompson S, et al. Handheld cellular telephone use and risk of brain cancer. JAMA 2000; 284(23):3001–3007.
  16. Hardell L, Carlberg M, Hansson Mild K. Pooled analysis of case-control studies on malignant brain tumours and the use of mobile and cordless phones including living and deceased subjects. International Journal of Oncology 2011; 38(5):1465–1474.
  17. Lönn S, Ahlbom A, Hall P, Feychting M. Long-term mobile phone use and brain tumor risk. American Journal of Epidemiology 2005; 161(6):526–535.
  18. Aydin D, Feychting M, Schüz J, et al. Mobile phone use and brain tumors in children and adolescents: a multicenter case-control study. Journal of the National Cancer Institute 2011; 103(16):1264–1276.
  19. Inskip PD, Hoover RN, Devesa SS. Brain cancer incidence trends in relation to cellular telephone use in the United States. Neuro-Oncology 2010; 12(11):1147–1151.
  20. Little MP, Rajaraman P, Curtis RE, et al. Mobile phone use and glioma risk: comparison of epidemiological study results with incidence trends in the United States. British Medical Journal 2012; 344:e1147.
  21. Deltour I, Johansen C, Auvinen A, et al. Time trends in brain tumor incidence rates in Denmark, Finland, Norway, and Sweden, 1974–2003. Journal of the National Cancer Institute 2009; 101(24):1721–1724.
  22. Deltour I, Auvinen A, Feychting M, et al. Mobile phone use and incidence of glioma in the Nordic countries 1979–2008: consistency check. Epidemiology 2012; 23(2):301–307.
  23. U.S. Federal Communications Commission (2010). Wireless. Washington, D.C. Retrieved June 18, 2012.
  24. U.S. Federal Communications Commission. (n.d.). FCC Encyclopedia: Specific Absorption Rate (SAR) for Cellular Telephones. Retrieved June 18, 2012.
  25. Howlader N, Noone AM, Krapcho M, et al. (eds.). (2013) SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute. Retrieved June 24, 2013.

Source: National Cancer Institute 

 

Autoria e outros dados (tags, etc)

por cyto às 02:15

Sexta-feira, 30.01.15

Cell Phones and Cancer Risk

Cell Phones and Cancer Risk

Key Points

  • Cell phones emit radiofrequency energy, a form of non-ionizing electromagnetic radiation, which can be absorbed by tissues closest to where the phone is held.
  • The amount of radiofrequency energy a cell phone user is exposed to depends on the technology of the phone, the distance between the phone’s antenna and the user, the extent and type of use, and the user’s distance from cell phone towers.
  • Studies thus far have not shown a consistent link between cell phone use and cancers of the brain, nerves, or other tissues of the head or neck. More research is needed because cell phone technology and how people use cell phones have been changing rapidly.
  • Why is there concern that cell phones may cause cancer or other health problems?

 

There are three main reasons why people are concerned that cell phones (also known as “wireless” or “mobile” telephones) might have the potential to cause certain types of cancer or other health problems:

      • Cell phones emit radiofrequency energy (radio waves), a form of non-ionizing radiation. Tissues nearest to where the phone is held can absorb this energy.
      • The number of cell phone users has increased rapidly. As of 2010, there were more than 303 million subscribers to cell phone service in the United States, according to the Cellular Telecommunications and Internet Association. This is a nearly threefold increase from the 110 million users in 2000. Globally, the number of cell phone subscriptions is estimated by the International Telecommunications Union to be 5 billion.
      • Over time, the number of cell phone calls per day, the length of each call, and the amount of time people use cell phones have increased. Cell phone technology has also undergone substantial changes.
      •  
  • What is radiofrequency energy and how does it affect the body?

 

Radiofrequency energy is a form of electromagnetic radiation. Electromagnetic radiation can be categorized into two types: ionizing (e.g., x-rays, radon, and cosmic rays) and non-ionizing (e.g., radiofrequency and extremely low-frequency or power frequency).

Exposure to ionizing radiation, such as from radiation therapy, is known to increase the risk of cancer. However, although many studies have examined the potential health effects of non-ionizing radiation from radar, microwave ovens, and other sources, there is currently no consistent evidence that non-ionizing radiation increases cancer risk (1).

The only known biological effect of radiofrequency energy is heating. The ability of microwave ovens to heat food is one example of this effect of radiofrequency energy. Radiofrequency exposure from cell phone use does cause heating; however, it is not sufficient to measurably increase body temperature.

A recent study showed that when people used a cell phone for 50 minutes, brain tissues on the same side of the head as the phone’s antenna metabolized more glucose than did tissues on the opposite side of the brain (2). The researchers noted that the results are preliminary, and possible health outcomes from this increase in glucose metabolism are still unknown.

  • How is radiofrequency energy exposure measured in epidemiologic studies?

 

Levels of radiofrequency exposure are indirectly estimated using information from interviews or questionnaires. These measures include the following:

      • How “regularly” study participants use cell phones (the minimum number of calls per week or month)
      • The age and the year when study participants first used a cell phone and the age and the year of last use (allows calculation of the duration of use and time since the start of use)
      • The average number of cell phone calls per day, week, or month (frequency)
      • The average length of a typical cell phone call
      • The total hours of lifetime use, calculated from the length of typical call times, the frequency of use, and the duration of use
  • What has research shown about the possible cancer-causing effects of radiofrequency energy?

 

Although there have been some concerns that radiofrequency energy from cell phones held closely to the head may affect the brain and other tissues, to date there is no evidence from studies of cells, animals, or humans that radiofrequency energy can cause cancer.

It is generally accepted that damage to DNA is necessary for cancer to develop. However, radiofrequency energy, unlike ionizing radiation, does not cause DNA damage in cells, and it has not been found to cause cancer in animals or to enhance the cancer-causing effects of known chemical carcinogens in animals (35).

Researchers have carried out several types of epidemiologic studies to investigate the possibility of a relationship between cell phone use and the risk of malignant (cancerous) brain tumors, such as gliomas, as well as benign (noncancerous) tumors, such as acoustic neuromas (tumors in the cells of the nerve responsible for hearing), most meningiomas (tumors in the meninges, membranes that cover and protect the brain and spinal cord), and parotid gland tumors (tumors in the salivary glands) (6).

In one type of study, called a case-control study, cell phone use is compared between people with these types of tumors and people without them. In another type of study, called a cohort study, a large group of people is followed over time and the rate of these tumors in people who did and didn’t use cell phones is compared. Cancer incidence data can also be analyzed over time to see if the rates of cancer changed in large populations during the time that cell phone use increased dramatically. The results of these studies have generally not provided clear evidence of a relationship between cell phone use and cancer, but there have been some statistically significant findings in certain subgroups of people.

Findings from specific research studies are summarized below:

      • The Interphone Study, conducted by a consortium of researchers from 13 countries, is the largest health-related case-control study of use of cell phones and head and neck tumors. Most published analyses from this study have shown no statistically significant increases in brain or central nervous system cancers related to higher amounts of cell phone use. One recent analysis showed a statistically significant, albeit modest, increase in the risk of glioma among the small proportion of study participants who spent the most total time on cell phone calls. However, the researchers considered this finding inconclusive because they felt that the amount of use reported by some respondents was unlikely and because the participants who reported lower levels of use appeared to have a slightly reduced risk of brain cancer compared with people who did not use cell phones regularly (79).
      • Another recent study from the group found no relationship between brain tumor locations and regions of the brain that were exposed to the highest level of radiofrequency energy from cell phones (10).
      • A cohort study in Denmark linked billing information from more than 358,000 cell phone subscribers with brain tumor incidence data from the Danish Cancer Registry. The analyses found no association between cell phone use and the incidence of glioma, meningioma, or acoustic neuroma, even among people who had been cell phone subscribers for 13 or more years (1113).
      • The prospective Million Women Study in the United Kingdom found that self-reported cell phone use was not associated with an increased risk of glioma, meningioma, or non-central nervous system tumors. The researchers did find that the use of cell phones for more than 5 years was associated with an increased risk of acoustic neuroma, and that the risk of acoustic neuroma increased with increasing duration of cell phone use (14). However, the incidence of these tumors among men and women in the United Kingdom did not increase during 1998 to 2008, even though cell phone use increased dramatically over that decade (14).
      • An early case-control study in the United States was unable to demonstrate a relationship between cell phone use and glioma or meningioma (15).
      • Some case-control studies in Sweden found statistically significant trends of increasing brain cancer risk for the total amount of cell phone use and the years of use among people who began using cell phones before age 20 (16). However, another large, case-control study in Sweden did not find an increased risk of brain cancer among people between the ages of 20 and 69 (17). In addition, the international CEFALO study, which compared children who were diagnosed with brain cancer between ages 7 and 19 with similar children who were not, found no relationship between their cell phone use and risk for brain cancer (18).
      • NCI's Surveillance, Epidemiology, and End Results (SEER) Program, which tracks cancer incidence in the United States over time, found no increase in the incidence of brain or other central nervous system cancers between 1987 and 2007, despite the dramatic increase in cell phone use in this country during that time (19, 20). Similarly, incidence data from Denmark, Finland, Norway, and Sweden for the period 1974–2008 revealed no increase in age-adjusted incidence of brain tumors (21, 22). A 2012 study by NCI researchers, which compared observed glioma incidence rates in SEER with projected rates based on risks observed in the Interphone study (8), found that the projected rates were consistent with observed U.S. rates. The researchers also compared the SEER rates with projected rates based on a Swedish study published in 2011 (16). They determined that the projected rates were at least 40 percent higher than, and incompatible with, the actual U.S. rates.
      • Studies of workers exposed to radiofrequency energy have shown no evidence of increased risk of brain tumors among U.S. Navy electronics technicians, aviation technicians, or fire control technicians, those working in an electromagnetic pulse test program, plastic-ware workers, cellular phone manufacturing workers, or Navy personnel with a high probability of exposure to radar (6).
      •  
  • Why are the findings from different studies of cell phone use and cancer risk inconsistent?

 

A limited number of studies have shown some evidence of statistical association of cell phone use and brain tumor risks, but most studies have found no association. Reasons for these discrepancies include the following:

      • Recall bias, which may happen when a study collects data about prior habits and exposures using questionnaires administered after disease has been diagnosed in some of the study participants. It is possible that study participants who have brain tumors may remember their cell phone use differently than individuals without brain tumors. Many epidemiologic studies of cell phone use and brain cancer risk lack verifiable data about the total amount of cell phone use over time. In addition, people who develop a brain tumor may have a tendency to recall using their cell phone mostly on the same side of their head where the tumor was found, regardless of whether they actually used their phone on that side of their head a lot or only a little.
      • Inaccurate reporting, which may happen when people say that something has happened more or less often than it actually did. People may not remember how much they used cell phones in a given time period.
      • Morbidity and mortality among study participants who have brain cancer. Gliomas are particularly difficult to study, for example, because of their high death rate and the short survival of people who develop these tumors. Patients who survive initial treatment are often impaired, which may affect their responses to questions. Furthermore, for people who have died, next-of-kin are often less familiar with the cell phone use patterns of their deceased family member and may not accurately describe their patterns of use to an interviewer.
      • Participation bias, which can happen when people who are diagnosed with brain tumors are more likely than healthy people (known as controls) to enroll in a research study. Also, controls who did not or rarely used cell phones were less likely to participate in the Interphone study than controls who used cell phones regularly. For example, the Interphone study reported participation rates of 78 percent for meningioma patients (range 56–92 percent for the individual studies), 64 percent for the glioma patients (range 36–92 percent), and 53 percent for control subjects (range 42–74 percent) (9).
      • One series of Swedish studies reported participation rates of 85 percent in people with brain cancer and 84 percent in control subjects (17).
      • Changing technology and methods of use. Older studies evaluated radiofrequency energy exposure from analog cell phones. However, most cell phones today use digital technology, which operates at a different frequency and a lower power level than analog phones. Digital cell phones have been in use for more than a decade in the United States, and cellular technology continues to change (6). Texting, for example, has become a popular way of using a cell phone to communicate that does not require bringing the phone close to the head. Furthermore, the use of hands-free technology, such as wired and wireless headsets, is increasing and may decrease radiofrequency energy exposure to the head and brain.
      •  
  • What do expert organizations conclude?

 

The International Agency for Research on Cancer (IARC), a component of the World Health Organization, has recently classified radiofrequency fields as “possibly carcinogenic to humans,” based on limited evidence from human studies, limited evidence from studies of radiofrequency energy and cancer in rodents, and weak mechanistic evidence (from studies of genotoxicity, effects on immune system function, gene and protein expression, cell signaling, oxidative stress, and apoptosis, along with studies of the possible effects of radiofrequency energy on the blood-brain barrier).

The American Cancer Society (ACS) states that the IARC classification means that there could be some risk associated with cancer, but the evidence is not strong enough to be considered causal and needs to be investigated further. Individuals who are concerned about radiofrequency exposure can limit their exposure, including using an ear piece and limiting cell phone use, particularly among children.

The National Institute of Environmental Health Sciences (NIEHS) states that the weight of the current scientific evidence has not conclusively linked cell phone use with any adverse health problems, but more research is needed.

The U.S. Food and Drug Administration (FDA), which is responsible for regulating the safety of machines and devices that emit radiation (including cell phones), notes that studies reporting biological changes associated with radiofrequency energy have failed to be replicated and that the majority of human epidemiologic studies have failed to show a relationship between exposure to radiofrequency energy from cell phones and health problems.

The U.S. Centers for Disease Control and Prevention (CDC) states that, although some studies have raised concerns about the possible risks of cell phone use, scientific research as a whole does not support a statistically significant association between cell phone use and health effects.

The Federal Communications Commission (FCC) concludes that there is no scientific evidence that proves that wireless phone use can lead to cancer or to other health problems, including headaches, dizziness, or memory loss.

  • What studies are under way that will help further our understanding of the health effects of cell phone use?

 

A large prospective cohort study of cell phone use and its possible long-term health effects was launched in Europe in March 2010. This study, known as COSMOS , has enrolled approximately 290,000 cell phone users aged 18 years or older to date and will follow them for 20 to 30 years.

Participants in COSMOS will complete a questionnaire about their health, lifestyle, and current and past cell phone use. This information will be supplemented with information from health records and cell phone records.

The challenge of this ambitious study is to continue following the participants for a range of health effects over many decades. Researchers will need to determine whether participants who leave are somehow different from those who remain throughout the follow-up period.

Another study already under way is a case-control study called Mobi-Kids , which will include 2000 young people (aged 10-24 years) with newly diagnosed brain tumors and 4000 healthy young people. The goal of the study is to learn more about risk factors for childhood brain tumors. Results are expected in 2016.

Although recall bias is minimized in studies that link participants to their cell phone records, such studies face other problems. For example, it is impossible to know who is using the listed cell phone or whether that individual also places calls using other cell phones. To a lesser extent, it is not clear whether multiple users of a single phone will be represented on a single phone company account.

The NIEHS, which is part of the National Institutes of Health, is carrying out a study of risks related to exposure to radiofrequency energy (the type used in cell phones) in highly specialized labs that can specify and control sources of radiation and measure their effects on rodents.

  • Do children have a higher risk of developing cancer due to cell phone use than adults?

 

In theory, children have the potential to be at greater risk than adults for developing brain cancer from cell phones. Their nervous systems are still developing and therefore more vulnerable to factors that may cause cancer. Their heads are smaller than those of adults and therefore have a greater proportional exposure to the field of radiofrequency radiation that is emitted by cell phones. And children have the potential of accumulating more years of cell phone exposure than adults do.

So far, the data from studies in children with cancer do not support this theory. The first published analysis came from a large case-control study called CEFALO, which was conducted in Denmark, Sweden, Norway, and Switzerland. The study included children who were diagnosed with brain tumors between 2004 and 2008, when their ages ranged from 7 to 19. Researchers did not find an association between cell phone use and brain tumor risk in this group of children. However, they noted that their results did not rule out the possibility of a slight increase in brain cancer risk among children who use cell phones, and that data gathered through prospective studies and objective measurements, rather than participant surveys and recollections, will be key in clarifying whether there is an increased risk (19).

Researchers from the Centre for Research in Environmental Epidemiology in Spain are conducting another international study—Mobi-Kids —to evaluate the risk associated with new communications technologies (including cell phones) and other environmental factors in young people newly diagnosed with brain tumors at ages 10 to 24 years. 

  • What can cell phone users do to reduce their exposure to radiofrequency energy?

 

The FDA and FCC have suggested some steps that concerned cell phone users can take to reduce their exposure to radiofrequency energy (1, 23):

    • Reserve the use of cell phones for shorter conversations or for times when a landline phone is not available.
    • Use a hands-free device, which places more distance between the phone and the head of the user.

Hands-free kits reduce the amount of radiofrequency energy exposure to the head because the antenna, which is the source of energy, is not placed against the head.

  • Where can I find more information about radiofrequency energy from my cell phone?

 

The FCC provides information about the specific absorption rate (SAR) of cell phones produced and marketed within the last 1 to 2 years. The SAR corresponds with the relative amount of radiofrequency energy absorbed by the head of a cell phone user (24). Consumers can access this information using the phone’s FCC ID number, which is usually located on the case of the phone, and the FCC’s ID search form.

 

  • What are other sources of radiofrequency energy?

 

The most common exposures to radiofrequency energy are from telecommunications devices and equipment (1). In the United States, cell phones currently operate in a frequency range of about 1,800 to 2,200 megahertz (MHz) (6). In this range, the electromagnetic radiation produced is in the form of non-ionizing radiofrequency energy.

Cordless phones (phones that have a base unit connected to the telephone wiring in a house) often operate at radio frequencies similar to those of cell phones; however, since cordless phones have a limited range and require a nearby base, their signals are generally much less powerful than those of cell phones.

Among other radiofrequency energy sources, AM/FM radios and VHF/UHF televisions operate at lower radio frequencies than cell phones, whereas sources such as radar, satellite stations, magnetic resonance imaging (MRI) devices, industrial equipment, and microwave ovens operate at somewhat higher radio frequencies (1).

  • How common is brain cancer? Has the incidence of brain cancer changed over time?

 

Brain cancer incidence and mortality (death) rates have changed little in the past decade. In the United States, 23,130 new diagnoses and 14,080 deaths from brain cancer are estimated for 2013.

The 5-year relative survival for brain cancers diagnosed from 2003 through 2009 was 35 percent (25). This is the percentage of people diagnosed with brain cancer who will still be alive 5 years after diagnosis compared with the survival of a person of the same age and sex who does not have cancer.

The risk of developing brain cancer increases with age. From 2006 through 2010, there were fewer than 5 brain cancer cases for every 100,000 people in the United States under age 65, compared with approximately 19 cases for every 100,000 people in the United States who were ages 65 or older (25).

Selected References

  1. U.S. Food and Drug Administration (2009). Radiation-Emitting Products: Reducing Exposure: Hands-free Kits and Other Accessories. Silver Spring, MD. Retrieved June 18, 2012.
  2. Volkow ND, Tomasi D, Wang GJ, et al. Effects of cell phone radiofrequency signal exposure on brain glucose metabolism. JAMA 2011; 305(8):808–813. [PubMed Abstract]
  3. Hirose H, Suhara T, Kaji N, et al. Mobile phone base station radiation does not affect neoplastic transformation in BALB/3T3 cells. Bioelectromagnetics 2008; 29(1):55–64. [PubMed Abstract]
  4. Oberto G, Rolfo K, Yu P, et al. Carcinogenicity study of 217 Hz pulsed 900 MHz electromagnetic fields in Pim1 transgenic mice. Radiation Research 2007; 168(3):316–326. [PubMed Abstract]
  5. Zook BC, Simmens SJ. The effects of pulsed 860 MHz radiofrequency radiation on the promotion of neurogenic tumors in rats. Radiation Research 2006; 165(5):608–615. [PubMed Abstract]
  6. Ahlbom A, Green A, Kheifets L, et al. Epidemiology of health effects of radiofrequency exposure. Environmental Health Perspectives 2004; 112(17):1741–1754. [PubMed Abstract]
  7. Cardis E, Richardson L, Deltour I, et al. The INTERPHONE study: design, epidemiological methods, and description of the study population. European Journal of Epidemiology 2007; 22(9):647–664. [PubMed Abstract]
  8. International Agency for Research on Cancer (2008). INTERPHONE Study: latest results update—8 October 2008 . Lyon, France. Retrieved June 18, 2012.
  9. The INTERPHONE Study Group. Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case-control study. International Journal of Epidemiology 2010; 39(3):675–694. [PubMed Abstract]
  10. Larjavaara S, Schüz J, Swerdlow A, et al. Location of gliomas in relation to mobile telephone use: a case-case and case-specular analysis. American Journal of Epidemiology 2011; 174(1):2–11. [PubMed Abstract]
  11. Johansen C, Boice J Jr, McLaughlin J, Olsen J. Cellular telephones and cancer: a nationwide cohort study in Denmark. Journal of the National Cancer Institute 2001; 93(3):203–207. [PubMed Abstract]
  12. Schüz J, Jacobsen R, Olsen JH, et al. Cellular telephone use and cancer risk: update of a nationwide Danish cohort. Journal of the National Cancer Institute 2006; 98(23):1707–1713. [PubMed Abstract]
  13. Frei P, Poulsen AH, Johansen C, et al. Use of mobile phones and risk of brain tumours: update of Danish cohort study. British Medical Journal 2011; 343:d6387. [PubMed Abstract]
  14. Benson VS, Pirie K, Schüz J, et al. Mobile phone use and risk of brain neoplasms and other cancers: Prospective study. International Journal of Epidemiology 2013; First published online: May 8, 2013. doi:10.1093/ije/dyt072
  15. Muscat JE, Malkin MG, Thompson S, et al. Handheld cellular telephone use and risk of brain cancer. JAMA 2000; 284(23):3001–3007. [PubMed Abstract]
  16. Hardell L, Carlberg M, Hansson Mild K. Pooled analysis of case-control studies on malignant brain tumours and the use of mobile and cordless phones including living and deceased subjects. International Journal of Oncology 2011; 38(5):1465–1474. [PubMed Abstract]
  17. Lönn S, Ahlbom A, Hall P, Feychting M. Long-term mobile phone use and brain tumor risk. American Journal of Epidemiology 2005; 161(6):526–535. [PubMed Abstract]
  18. Aydin D, Feychting M, Schüz J, et al. Mobile phone use and brain tumors in children and adolescents: a multicenter case-control study. Journal of the National Cancer Institute 2011; 103(16):1264–1276. [PubMed Abstract]
  19. Inskip PD, Hoover RN, Devesa SS. Brain cancer incidence trends in relation to cellular telephone use in the United States. Neuro-Oncology 2010; 12(11):1147–1151. [PubMed Abstract]
  20. Little MP, Rajaraman P, Curtis RE, et al. Mobile phone use and glioma risk: comparison of epidemiological study results with incidence trends in the United States. British Medical Journal 2012; 344:e1147.

[PubMed Abstract]

  1. Deltour I, Johansen C, Auvinen A, et al. Time trends in brain tumor incidence rates in Denmark, Finland, Norway, and Sweden, 1974–2003. Journal of the National Cancer Institute 2009; 101(24):1721–1724. [PubMed Abstract]
  2. Deltour I, Auvinen A, Feychting M, et al. Mobile phone use and incidence of glioma in the Nordic countries 1979–2008: consistency check. Epidemiology 2012; 23(2):301–307.

[PubMed Abstract]

  1. U.S. Federal Communications Commission (2010). Wireless. Washington, D.C. Retrieved June 18, 2012.
  2. U.S. Federal Communications Commission. (n.d.). FCC Encyclopedia: Specific Absorption Rate (SAR) for Cellular Telephones. Retrieved June 18, 2012.
  3. Howlader N, Noone AM, Krapcho M, et al. (eds.). (2013) SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute. Retrieved June 24, 2013.

Related Resources

This text may be reproduced or reused freely. Please credit the National Cancer Institute as the source. Any graphics may be owned by the artist or publisher who created them, and permission may be needed for their reuse.

Autoria e outros dados (tags, etc)

por cyto às 02:02

Sexta-feira, 30.01.15

Biological Therapies for Cancer

Biological Therapies for Cancer

Key Points

  • Biological therapy uses living organisms, substances derived from living organisms, or synthetic versions of such substances to treat cancer.
  • Some types of biological therapy exploit the immune system’s natural ability to detect and kill cancer cells, whereas other types target cancer cells directly.
  • Biological therapies include monoclonal antibodies, cytokines, therapeutic vaccines, the bacterium bacillus Calmette-Guérin, cancer-killing viruses, gene therapy, and adoptive T-cell transfer.
  • The side effects of biological therapies can differ by treatment type, but reactions at the site of administration are fairly common with these treatments.
  1. What is biological therapy?

Biological therapy involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Some biological therapies for cancer use vaccines or bacteria to stimulate the body’s immune system to act against cancer cells. These types of biological therapy, which are sometimes referred to collectively as “immunotherapy” or “biological response modifier therapy,” do not target cancer cells directly. Other biological therapies, such as antibodies or segments of genetic material (RNA or DNA), do target cancer cells directly. Biological therapies that interfere with specific molecules involved in tumor growth and progression are also referred to as targeted therapies. (For more information, see Targeted Cancer Therapies.)

For patients with cancer, biological therapies may be used to treat the cancer itself or the side effects of other cancer treatments. Although many forms of biological therapy have been approved by the U.S. Food and Drug Administration (FDA), others remain experimental and are available to cancer patients principally through participation in clinical trials (research studies involving people).

  1. What is the immune system and what role does it have in biological therapy for cancer?

The immune system is a complex network of organs, tissues, and specialized cells. It recognizes and destroys foreign invaders, such as bacteria or viruses, as well as some damaged, diseased, or abnormal cells in the body, including cancer cells. An immune response is triggered when the immune system encounters a substance, called an antigen, it recognizes as “foreign.”

White blood cells are the primary players in immune system responses. Some white blood cells, including macrophages and natural killer cells, patrol the body, seeking out foreign invaders and diseased, damaged, or dead cells. These white blood cells provide a general—or nonspecific—level of immune protection.

Other white blood cells, including cytotoxic T cells and B cells, act against specific targets. Cytotoxic T cells release chemicals that can directly destroy microbes or abnormal cells. B cells make antibodies that latch onto foreign intruders or abnormal cells and tag them for destruction by another component of the immune system. Still other white blood cells, including dendritic cells, play supporting roles to ensure that cytotoxic T cells and B cells do their jobs effectively.

It is generally believed that the immune system’s natural capacity to detect and destroy abnormal cells prevents the development of many cancers. Nevertheless, some cancer cells are able to evade detection by using one or more strategies. For example, cancer cells can undergo genetic changes that lead to the loss of cancer-associated antigens, making them less “visible” to the immune system. They may also use several different mechanisms to suppress immune responses or to avoid being killed by cytotoxic T cells (1).

The goal of immunotherapy for cancer is to overcome these barriers to an effective anticancer immune response. These biological therapies restore or increase the activities of specific immune-system components or counteract immunosuppressive signals produced by cancer cells.

  1. What are monoclonal antibodies, and how are they used in cancer treatment?

Monoclonal antibodies, or MAbs, are laboratory-produced antibodies that bind to specific antigens expressed by cancer cells, such as a protein that is present on the surface of cancer cells but is absent from (or expressed at lower levels by) normal cells.

To create MAbs, researchers inject mice with an antigen from human cancer cells. They then harvest the antibody-producing cells from the mice and individually fuse them with a myeloma cell (cancerous B cell) to produce a fusion cell known as a hybridoma. Each hybridoma then divides to produce identical daughter cells or clones—hence the term “monoclonal”—and antibodies secreted by different clones are tested to identify the antibodies that bind most strongly to the antigen. Large quantities of antibodies can be produced by these immortal hybridoma cells. Because mouse antibodies can themselves elicit an immune response in humans, which would reduce their effectiveness, mouse antibodies are often “humanized” by replacing as much of the mouse portion of the antibody as possible with human portions. This is done through genetic engineering.

Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs “coat” the cancer cell surface, triggering its destruction by the immune system. FDA-approved MAbs of this type include rituximab, which targets the CD20 antigen found on non-Hodgkin lymphoma cells, and alemtuzumab, which targets the CD52 antigen found on B-cell chronic lymphocytic leukemia (CLL) cells. Rituximab may also trigger cell death (apoptosis) directly.

Another group of MAbs stimulates an anticancer immune response by binding to receptors on the surface of immune cells and inhibiting signals that prevent immune cells from attacking the body’s own tissues, including cancer cells. One such MAb, ipilimumab, has been approved by the FDA for treatment of metastatic melanoma, and others are being investigated in clinical studies (2).

Other MAbs interfere with the action of proteins that are necessary for tumor growth. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels.

Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.

Another group of cancer therapeutic MAbs are the immunoconjugates. These MAbs, which are sometimes called immunotoxins or antibody-drug conjugates, consist of an antibody attached to a cell-killing substance, such as a plant or bacterial toxin, a chemotherapy drug, or a radioactive molecule. The antibody latches onto its specific antigen on the surface of a cancer cell, and the cell-killing substance is taken up by the cell. FDA-approved conjugated MAbs that work this way include 90Y-ibritumomab tiuxetan, which targets the CD20 antigen to deliver radioactive yttrium-90 to B-cell non-Hodgkin lymphoma cells; 131I-tositumomab, which targets the CD20 antigen to deliver radioactive iodine-131 to non-Hodgkin lymphoma cells; and ado-trastuzumab emtansine, which targets the HER-2 molecule to deliver the drug DM1, which inhibits cell proliferation, to HER-2 expressing metastatic breast cancer cells.

  1. What are cytokines, and how are they used in cancer treatment?

Cytokines are signaling proteins that are produced by white blood cells. They help mediate and regulate immune responses, inflammation, and hematopoiesis (new blood cell formation). Two types of cytokines are used to treat patients with cancer: interferons (INFs) and interleukins (ILs). A third type, called hematopoietic growth factors, is used to counteract some of the side effects of certain chemotherapy regimens.

Researchers have found that one type of INF, INF-alfa, can enhance a patient’s immune response to cancer cells by activating certain white blood cells, such as natural killer cells and dendritic cells (3). INF-alfa may also inhibit the growth of cancer cells or promote their death (4,5). INF-alfa has been approved for the treatment of melanoma, Kaposi sarcoma, and several hematologic cancers.

Like INFs, ILs play important roles in the body’s normal immune response and in the immune system’s ability to respond to cancer. Researchers have identified more than a dozen distinct ILs, including IL-2, which is also called T-cell growth factor. IL-2 is naturally produced by activated T cells. It increases the proliferation of white blood cells, including cytotoxic T cells and natural killer cells, leading to an enhanced anticancer immune response (6). IL-2 also facilitates the production of antibodies by B cells to further target cancer cells. Aldesleukin, IL-2 that is made in a laboratory, has been approved for the treatment of metastatic kidney cancer and metastatic melanoma. Researchers are currently investigating whether combining Aldesleukin treatment with other types of biological therapies may enhance its anticancer effects.

Hematopoietic growth factors are a special class of naturally occurring cytokines. All blood cells arise from hematopoietic stem cells in the bone marrow. Because chemotherapy drugs target proliferating cells, including normal blood stem cells, chemotherapy depletes these stem cells and the blood cells that they produce. Loss of red blood cells, which transport oxygen and nutrients throughout the body, can cause anemia. A decrease in platelets, which are responsible for blood clotting, often leads to abnormal bleeding. Finally, lower white blood cell counts leave chemotherapy patients vulnerable to infections.

Several growth factors that promote the growth of these various blood cell populations have been approved for clinical use. Erythropoietin stimulates red blood cell formation, and IL-11 increases platelet production. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) both increase the number of white blood cells, reducing the risk of infections. Treatment with these factors allows patients to continue chemotherapy regimens that might otherwise be stopped temporarily or modified to reduce the drug doses because of low blood cell numbers.

G-CSF and GM-CSF can also enhance the immune system’s specific anticancer responses by increasing the number of cancer-fighting T cells. Thus, GM-CSF and G-CSF are used in combination with other biological therapies to strengthen anticancer immune responses.

 

 

  1. What are cancer treatment vaccines?

Cancer treatment vaccines are designed to treat cancers that have already developed rather than to prevent them in the first place. Cancer treatment vaccines contain cancer-associated antigens to enhance the immune system’s response to a patient’s tumor cells. The cancer-associated antigens can be proteins or another type of molecule found on the surface of or inside cancer cells that can stimulate B cells or killer T cells to attack them.

Some vaccines that are under development target antigens that are found on or in many types of cancer cells. These types of cancer vaccines are being tested in clinical trials in patients with a variety of cancers, including prostate, colorectal, lung, breast, and thyroid cancers. Other cancer vaccines target antigens that are unique to a specific cancer type (7-14). Still other vaccines are designed against an antigen specific to one patient’s tumor and need to be customized for each patient. The one cancer treatment vaccine that has received FDA approval, sipuleucel-T, is this type of vaccine.

Because of the limited toxicity seen with cancer vaccines, they are also being tested in clinical trials in combination with other forms of therapy, such as hormonal therapy, chemotherapy, radiation therapy, and targeted therapies. (For more information see Cancer Vaccines.)

  1. What is bacillus Calmette-Guérin therapy?

Bacillus Calmette-Guérin (BCG) was the first biological therapy to be approved by the FDA. It is a weakened form of a live tuberculosis bacterium that does not cause disease in humans. It was first used medically as a vaccine against tuberculosis. When inserted directly into the bladder with a catheter, BCG stimulates a general immune response that is directed not only against the foreign bacterium itself but also against bladder cancer cells. How and why BCG exerts this anticancer effect is not well understood, but the efficacy of the treatment is well documented. Approximately 70 percent of patients with early-stage bladder cancer experience a remission after BCG therapy (15).

BCG is also being studied in the treatment of other types of cancer (16-18).

  1. What is oncolytic virus therapy?

Oncolytic virus therapy is an experimental form of biological therapy that involves the direct destruction of cancer cells. Oncolytic viruses infect both cancer and normal cells, but they have little effect on normal cells. In contrast, they readily replicate, or reproduce, inside cancer cells and ultimately cause the cancer cells to die. Some viruses, such as reovirus, Newcastle disease virus, and mumps virus, are naturally oncolytic, whereas others, including measles virus, adenovirus, and vaccinia virus, can be adapted or modified to replicate efficiently only in cancer cells. In addition, oncolytic viruses can be genetically engineered to preferentially infect and replicate in cancer cells that produce a specific cancer-associated antigen, such as EGFR or HER-2 (19).

One of the challenges in using oncolytic viruses is that they may themselves be destroyed by the patient’s immune system before they have a chance to attack the cancer. Researchers have developed several strategies to overcome this challenge, such as administering a combination of immune-suppressing chemotherapy drugs like cyclophosphamide along with the virus or “cloaking” the virus within a protective envelope. But an immune reaction in the patient may actually have benefits: although it may hamper oncolytic virus therapy at the time of viral delivery, it may enhance cancer cell destruction after the virus has infected the tumor cells (20-23).

No oncolytic virus has been approved for use in the United States, although H101, a modified form of adenovirus, was approved in China in 2006 for the treatment of patients with head and neck cancer. Several oncolytic viruses are currently being tested in clinical trials. Researchers are also investigating whether oncolytic viruses can be combined with other types of cancer therapies or can be used to sensitize patients’ tumors to additional therapy.

  1. What is gene therapy?

Still an experimental form of treatment, gene therapy attempts to introduce genetic material (DNA or RNA) into living cells. Gene therapy is being studied in clinical trials for many types of cancer.

In general, genetic material cannot be inserted directly into a person's cells. Instead, it is delivered to the cells using a carrier, or “vector.” The vectors most commonly used in gene therapy are viruses, because they have the unique ability to recognize certain cells and insert genetic material into them. Scientists alter these viruses to make them more safe for humans (e.g., by inactivating genes that enable them to reproduce or cause disease) and/or to improve their ability to recognize and enter the target cell. A variety of liposomes (fatty particles) and nanoparticles are also being used as gene therapy vectors, and scientists are investigating methods of targeting these vectors to specific cell types.

Researchers are studying several methods for treating cancer with gene therapy.

-Some approaches target cancer cells, to destroy them or prevent their growth. -Others target healthy cells to enhance their ability to fight cancer.

-In some cases, researchers remove cells from the patient, treat the cells with the vector in the laboratory, and return the cells to the patient. In others, the vector is given directly to the patient.

-Some gene therapy approaches being studied are described below.

 

-.Replacing an altered tumor suppressor gene that produces a nonfunctional protein (or no protein) with a normal version of the gene. Because tumor suppressor genes (e.g., TP53) play a role in preventing cancer, restoring the normal function of these genes may inhibit cancer growth or promote cancer regression.

-.Introducing genetic material to block the expression of an oncogene whose product promotes tumor growth. Short RNA or DNA molecules with sequences complementary to the gene’s messenger RNA (mRNA) can be packaged into vectors or given to cells directly. These short molecules, called oligonucleotides, can bind to the target mRNA, preventing its translation into protein or even causing its degradation.

-.Improving a patient's immune response to cancer. In one approach, gene therapy is used to introduce cytokine-producing genes into cancer cells to stimulate the immune response to the tumor.

-.Inserting genes into cancer cells to make them more sensitive to chemotherapy, radiation therapy, or other treatments

-.Inserting genes into healthy blood-forming stem cells to make them more resistant to the side effects of cancer treatments, such as high doses of anticancer drugs

-.Introducing “suicide genes” into a patient's cancer cells. A suicide gene is a gene whose product is able to activate a “pro-drug” (an inactive form of a toxic drug), causing the toxic drug to be produced only in cancer cells in patients given the pro-drug. Normal cells, which do not express the suicide genes, are not affected by the pro-drug.

-.Inserting genes to prevent cancer cells from developing new blood vessels (angiogenesis)

Proposed gene therapy clinical trials, or protocols, must be approved by at least two review boards at the researchers’ institution before they can be conducted. Gene therapy protocols must also be approved by the FDA, which regulates all gene therapy products. In addition, gene therapy trials that are funded by the National Institutes of Health must be registered with the NIH Recombinant DNA Advisory Committee.

  1. What is adoptive T-cell transfer therapy?

Adoptive cell transfer is an experimental anticancer therapy that attempts to enhance the natural cancer-fighting ability of a patient’s T cells. In one form of this therapy, researchers first harvest cytotoxic T cells that have invaded a patient’s tumor. They then identify the cells with the greatest antitumor activity and grow large populations of those cells in a laboratory. The patients are then treated to deplete their immune cells, and the laboratory-grown T cells are infused into the patients.

In another, more recently developed form of this therapy, which is also a kind of gene therapy, researchers isolate T cells from a small sample of the patient’s blood. They genetically modify the cells by inserting the gene for a receptor that recognizes an antigen specific to the patient’s cancer cells and grow large numbers of these modified cells in culture. The genetically modified cells are then infused into patients whose immune cells have been depleted. The receptor expressed by the modified T cells allows these cells to attach to antigens on the surface of the tumor cells, which activates the T cells to attack and kill the tumor cells.

Adoptive T-cell transfer was first studied for the treatment of metastatic melanoma because melanomas often cause a substantial immune response, with many tumor-invading cytotoxic T cells. Adoptive cell transfer with genetically modified T cells is also being investigated as a treatment for other solid tumors, as well as for hematologic cancers (24-29).

  1. What are the side effects of biological therapies?

The side effects associated with various biological therapies can differ by treatment type. However, pain, swelling, soreness, redness, itchiness, and rash at the site of infusion or injection are fairly common with these treatments.

Less common but more serious side effects tend to be more specific to one or a few types of biological therapy. For example, therapies intended to prompt an immune response against cancer can cause an array of flu-like symptoms, including fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint aches, fatigue, headache, occasional breathing difficulties, and lowered or heightened blood pressure. Biological therapies that provoke an immune system response also pose a risk of severe or even fatal hypersensitivity (allergic) reactions.

Potential serious side effects of specific biological therapies are as follows:

MAbs

Flu-like symptoms, Severe allergic reaction, Lowered blood counts, Changes in blood chemistry, Organ damage (usually to heart, lungs, kidneys, liver or brain).

Cytokines (interferons, interleukins, hematopoietic growth factors)

Flu-like symptoms Severe allergic reaction Lowered blood counts Changes in blood chemistry Organ damage (usually to heart, lungs, kidneys, liver or brain)

Treatment vaccines

Flu-like symptoms Severe allergic reaction BCG Flu-like symptoms Severe allergic reaction Urinary side effects: Pain or burning sensation during urination Increased urgency or frequency of urination Blood in the urine

Oncolytic viruses

Flu-like symptoms Tumor lysis syndrome: severe, sometimes life-threatening alterations in blood chemistry following the release of materials formerly contained within cancer cells into the bloodstream

Gene therapy

.Flu-like symptoms

.Secondary cancer: techniques that insert DNA into a host cell chromosome can cause cancer to develop if the insertion inhibits expression of a tumor suppressor gene or activates an oncogene; researchers are working to minimize this possibility

.Mistaken introduction of a gene into healthy cells, including reproductive cells

.Overexpression of the introduced gene may harm healthy tissues

.Virus vector transmission to other individuals or into the environment

 

  1. How can people obtain information about clinical trials of biological therapies for cancer?

Both FDA-approved and experimental biological therapies for specific types of cancer are being studied in clinical trials. The names of the biological therapy types listed below are links to descriptions of ongoing clinical trials that are testing those types of biological therapies in cancer patients. These trial descriptions can also be accessed by searching NCI’s list of cancer clinical trials on the NCI website. NCI’s list of cancer clinical trials includes all NCI-funded clinical trials as well as studies conducted by investigators at hospitals and medical centers throughout the United States and around the world.

Monoclonal antibodies

Cytokine therapy

Vaccine therapy

Adoptive T-cell therapy

Oncolytic virus therapy

Gene therapy

DNA oligonucleotide therapy

RNA oligonucleotide therapy

 

 

 

Selected References
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  26. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. New England Journal of Medicine 2011;365(8):725-733.[PubMed Abstract]
  27. Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know. Nature Reviews Clinical Oncology 2011;8(10):577-585.[PubMed Abstract]
  28. Grupp SA, Kalos M, Barrett D, et al. Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia. New England Journal of Medicine 2013;368(16):1509-1518.[PubMed Abstract]
  29. Brentjens RJ, Davila ML, Riviere I, et al. CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia. Science Translational Medicine 2013;5(177):177ra138.[PubMed Abstract]

 

 

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por cyto às 01:59

Sexta-feira, 30.01.15

Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation

Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation

Key Points

  • Bone marrow transplantation and peripheral blood stem cell transplantation are procedures that restore stem cells that were destroyed by high doses of chemotherapy and/or radiation therapy.
  • After being treated with high-dose anticancer drugs and/or radiation, the patient receives the harvested stem cells, which travel to the bone marrow and begin to produce new blood cells.
  • A “mini-transplant” uses lower, less toxic doses of chemotherapy and/or radiation to prepare the patient for transplant.
  • A “tandem transplant” involves two sequential courses of high-dose chemotherapy and stem cell transplant.
  • The National Marrow Donor Program® operates Be The Match®, which provides patient support and maintains an international registry of volunteer stem cell donors.
  1. What are bone marrow and hematopoietic stem cells?

Bone marrow is the soft, sponge-like material found inside bones. It contains immature cells known as hematopoietic or blood-forming stem cells. (Hematopoietic stem cells are different from embryonic stem cells. Embryonic stem cells can develop into every type of cell in the body.) Hematopoietic stem cells divide to form more blood-forming stem cells, or they mature into one of three types of blood cells: white blood cells, which fight infection; red blood cells, which carry oxygen; and platelets, which help the blood to clot. Most hematopoietic stem cells are found in the bone marrow, but some cells, called peripheral blood stem cells (PBSCs), are found in the bloodstream. Blood in the umbilical cord also contains hematopoietic stem cells. Cells from any of these sources can be used in transplants.

  1. What are bone marrow transplantation and peripheral blood stem cell transplantation?

Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:

    • In autologous transplants, patients receive their own stem cells.
    • In syngeneic transplants, patients receive stem cells from their identical twin.
    • In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.
  1. Why are BMT and PBSCT used in cancer treatment?

One reason BMT and PBSCT are used in cancer treatment is to make it possible for patients to receive very high doses of chemotherapy and/or radiation therapy. To understand more about why BMT and PBSCT are used, it is helpful to understand how chemotherapy and radiation therapy work.

Chemotherapy and radiation therapy generally affect cells that divide rapidly. They are used to treat cancer because cancer cells divide more often than most healthy cells. However, because bone marrow cells also divide frequently, high-dose treatments can severely damage or destroy the patient’s bone marrow. Without healthy bone marrow, the patient is no longer able to make the blood cells needed to carry oxygen, fight infection, and prevent bleeding. BMT and PBSCT replace stem cells destroyed by treatment. The healthy, transplanted stem cells can restore the bone marrow’s ability to produce the blood cells the patient needs.

In some types of leukemia, the graft-versus-tumor (GVT) effect that occurs after allogeneic BMT and PBSCT is crucial to the effectiveness of the treatment. GVT occurs when white blood cells from the donor (the graft) identify the cancer cells that remain in the patient’s body after the chemotherapy and/or radiation therapy (the tumor) as foreign and attack them. (A potential complication of allogeneic transplants called graft-versus-host disease is discussed in Questions 5 and 14.)

  1. What types of cancer are treated with BMT and PBSCT?

BMT and PBSCT are most commonly used in the treatment of leukemia and lymphoma. They are most effective when the leukemia or lymphoma is in remission (the signs and symptoms of cancer have disappeared). BMT and PBSCT are also used to treat other cancers such as neuroblastoma (cancer that arises in immature nerve cells and affects mostly infants and children) and multiple myeloma. Researchers are evaluating BMT and PBSCT in clinical trials (research studies) for the treatment of various types of cancer.

  1. How are the donor’s stem cells matched to the patient’s stem cells in allogeneic or syngeneic transplantation?

To minimize potential side effects, doctors most often use transplanted stem cells that match the patient’s own stem cells as closely as possible. People have different sets of proteins, called human leukocyte-associated (HLA) antigens, on the surface of their cells. The set of proteins, called the HLA type, is identified by a special blood test.

In most cases, the success of allogeneic transplantation depends in part on how well the HLA antigens of the donor’s stem cells match those of the recipient’s stem cells. The higher the number of matching HLA antigens, the greater the chance that the patient’s body will accept the donor’s stem cells. In general, patients are less likely to develop a complication known as graft-versus-host disease (GVHD) if the stem cells of the donor and patient are closely matched. GVHD is further described in Question 14.

Close relatives, especially brothers and sisters, are more likely than unrelated people to be HLA-matched. However, only 25 to 35 percent of patients have an HLA-matched sibling. The chances of obtaining HLA-matched stem cells from an unrelated donor are slightly better, approximately 50 percent. Among unrelated donors, HLA-matching is greatly improved when the donor and recipient have the same ethnic and racial background. Although the number of donors is increasing overall, individuals from certain ethnic and racial groups still have a lower chance of finding a matching donor. Large volunteer donor registries can assist in finding an appropriate unrelated donor (see Question 19).

Because identical twins have the same genes, they have the same set of HLA antigens. As a result, the patient’s body will accept a transplant from an identical twin. However, identical twins represent a small number of all births, so syngeneic transplantation is rare.

  1. How is bone marrow obtained for transplantation?

The stem cells used in BMT come from the liquid center of the bone, called the marrow. In general, the procedure for obtaining bone marrow, which is called “harvesting,” is similar for all three types of BMTs (autologous, syngeneic, and allogeneic). The donor is given either general anesthesia, which puts the person to sleep during the procedure, or regional anesthesia, which causes loss of feeling below the waist. Needles are inserted through the skin over the pelvic (hip) bone or, in rare cases, the sternum (breastbone), and into the bone marrow to draw the marrow out of the bone. Harvesting the marrow takes about an hour.

The harvested bone marrow is then processed to remove blood and bone fragments. Harvested bone marrow can be combined with a preservative and frozen to keep the stem cells alive until they are needed. This technique is known as cryopreservation. Stem cells can be cryopreserved for many years.

  1. How are PBSCs obtained for transplantation?

The stem cells used in PBSCT come from the bloodstream. A process called apheresis or leukapheresis is used to obtain PBSCs for transplantation. For 4 or 5 days before apheresis, the donor may be given a medication to increase the number of stem cells released into the bloodstream. In apheresis, blood is removed through a large vein in the arm or a central venous catheter (a flexible tube that is placed in a large vein in the neck, chest, or groin area). The blood goes through a machine that removes the stem cells. The blood is then returned to the donor and the collected cells are stored. Apheresis typically takes 4 to 6 hours. The stem cells are then frozen until they are given to the recipient.

  1. How are umbilical cord stem cells obtained for transplantation?

Stem cells also may be retrieved from umbilical cord blood. For this to occur, the mother must contact a cord blood bank before the baby’s birth. The cord blood bank may request that she complete a questionnaire and give a small blood sample.

Cord blood banks may be public or commercial. Public cord blood banks accept donations of cord blood and may provide the donated stem cells to another matched individual in their network. In contrast, commercial cord blood banks will store the cord blood for the family, in case it is needed later for the child or another family member.

After the baby is born and the umbilical cord has been cut, blood is retrieved from the umbilical cord and placenta. This process poses minimal health risk to the mother or the child. If the mother agrees, the umbilical cord blood is processed and frozen for storage by the cord blood bank. Only a small amount of blood can be retrieved from the umbilical cord and placenta, so the collected stem cells are typically used for children or small adults.

  1. Are any risks associated with donating bone marrow?

Because only a small amount of bone marrow is removed, donating usually does not pose any significant problems for the donor. The most serious risk associated with donating bone marrow involves the use of anesthesia during the procedure.

The area where the bone marrow was taken out may feel stiff or sore for a few days, and the donor may feel tired. Within a few weeks, the donor’s body replaces the donated marrow; however, the time required for a donor to recover varies. Some people are back to their usual routine within 2 or 3 days, while others may take up to 3 to 4 weeks to fully recover their strength.

  1. Are any risks associated with donating PBSCs?

Apheresis usually causes minimal discomfort. During apheresis, the person may feel lightheadedness, chills, numbness around the lips, and cramping in the hands. Unlike bone marrow donation, PBSC donation does not require anesthesia. The medication that is given to stimulate the mobilization (release) of stem cells from the marrow into the bloodstream may cause bone and muscle aches, headaches, fatigue, nausea, vomiting, and/or difficulty sleeping. These side effects generally stop within 2 to 3 days of the last dose of the medication.

 

  1. How does the patient receive the stem cells during the transplant?

After being treated with high-dose anticancer drugs and/or radiation, the patient receives the stem cells through an intravenous (IV) line just like a blood transfusion. This part of the transplant takes 1 to 5 hours.

  1. Are any special measures taken when the cancer patient is also the donor (autologous transplant)?

The stem cells used for autologous transplantation must be relatively free of cancer cells. The harvested cells can sometimes be treated before transplantation in a process known as “purging” to get rid of cancer cells. This process can remove some cancer cells from the harvested cells and minimize the chance that cancer will come back. Because purging may damage some healthy stem cells, more cells are obtained from the patient before the transplant so that enough healthy stem cells will remain after purging.

  1. What happens after the stem cells have been transplanted to the patient?

After entering the bloodstream, the stem cells travel to the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets in a process known as “engraftment.” Engraftment usually occurs within about 2 to 4 weeks after transplantation. Doctors monitor it by checking blood counts on a frequent basis. Complete recovery of immune function takes much longer, however—up to several months for autologous transplant recipients and 1 to 2 years for patients receiving allogeneic or syngeneic transplants. Doctors evaluate the results of various blood tests to confirm that new blood cells are being produced and that the cancer has not returned. Bone marrow aspiration (the removal of a small sample of bone marrow through a needle for examination under a microscope) can also help doctors determine how well the new marrow is working.

  1. What are the possible side effects of BMT and PBSCT?

The major risk of both treatments is an increased susceptibility to infection and bleeding as a result of the high-dose cancer treatment. Doctors may give the patient antibiotics to prevent or treat infection. They may also give the patient transfusions of platelets to prevent bleeding and red blood cells to treat anemia. Patients who undergo BMT and PBSCT may experience short-term side effects such as nausea, vomiting, fatigue, loss of appetite, mouth sores, hair loss, and skin reactions.

Potential long-term risks include complications of the pretransplant chemotherapy and radiation therapy, such as infertility (the inability to produce children); cataracts (clouding of the lens of the eye, which causes loss of vision); secondary (new) cancers; and damage to the liver, kidneys, lungs, and/or heart.

With allogeneic transplants, GVHD sometimes develops when white blood cells from the donor (the graft) identify cells in the patient’s body (the host) as foreign and attack them. The most commonly damaged organs are the skin, liver, and intestines. This complication can develop within a few weeks of the transplant (acute GVHD) or much later (chronic GVHD). To prevent this complication, the patient may receive medications that suppress the immune system. Additionally, the donated stem cells can be treated to remove the white blood cells that cause GVHD in a process called “T-cell depletion.” If GVHD develops, it can be very serious and is treated with steroids or other immunosuppressive agents. GVHD can be difficult to treat, but some studies suggest that patients with leukemia who develop GVHD are less likely to have the cancer come back. Clinical trials are being conducted to find ways to prevent and treat GVHD.

The likelihood and severity of complications are specific to the patient’s treatment and should be discussed with the patient’s doctor.

  1. What is a “mini-transplant”?

A “mini-transplant” (also called a non-myeloablative or reduced-intensity transplant) is a type of allogeneic transplant. This approach is being studied in clinical trials for the treatment of several types of cancer, including leukemia, lymphoma, multiple myeloma, and other cancers of the blood.

A mini-transplant uses lower, less toxic doses of chemotherapy and/or radiation to prepare the patient for an allogeneic transplant. The use of lower doses of anticancer drugs and radiation eliminates some, but not all, of the patient’s bone marrow. It also reduces the number of cancer cells and suppresses the patient’s immune system to prevent rejection of the transplant.

Unlike traditional BMT or PBSCT, cells from both the donor and the patient may exist in the patient’s body for some time after a mini-transplant. Once the cells from the donor begin to engraft, they may cause the GVT effect and work to destroy the cancer cells that were not eliminated by the anticancer drugs and/or radiation. To boost the GVT effect, the patient may be given an injection of the donor’s white blood cells. This procedure is called a “donor lymphocyte infusion.”

  1. What is a “tandem transplant”?

A “tandem transplant” is a type of autologous transplant. This method is being studied in clinical trials for the treatment of several types of cancer, including multiple myeloma and germ cell cancer. During a tandem transplant, a patient receives two sequential courses of high-dose chemotherapy with stem cell transplant. Typically, the two courses are given several weeks to several months apart. Researchers hope that this method can prevent the cancer from recurring (coming back) at a later time.

  1. How do patients cover the cost of BMT or PBSCT?

Advances in treatment methods, including the use of PBSCT, have reduced the amount of time many patients must spend in the hospital by speeding recovery. This shorter recovery time has brought about a reduction in cost. However, because BMT and PBSCT are complicated technical procedures, they are very expensive. Many health insurance companies cover some of the costs of transplantation for certain types of cancer. Insurers may also cover a portion of the costs if special care is required when the patient returns home.

There are options for relieving the financial burden associated with BMT and PBSCT. A hospital social worker is a valuable resource in planning for these financial needs. Federal government programs and local service organizations may also be able to help.

NCI’s Cancer Information Service (CIS) can provide patients and their families with additional information about sources of financial assistance at 1–800–422–6237 (1–800–4–CANCER). NCI is part of the National Institutes of Health.

  1. What are the costs of donating bone marrow, PBSCs, or umbilical cord blood?

All medical costs for the donation procedure are covered by Be The Match® (see Question 19), or by the patient’s medical insurance, as are travel expenses and other non-medical costs. The only costs to the donor might be time taken off from work.

A woman can donate her baby’s umbilical cord blood to public cord blood banks at no charge. However, commercial blood banks do charge varying fees to store umbilical cord blood for the private use of the patient or his or her family.

  1. Where can people get more information about potential donors and transplant centers?

The National Marrow Donor Program® (NMDP), a nonprofit organization, manages the world’s largest registry of more than 11 million potential donors and cord blood units. The NMDP operates Be The Match®, which helps connect patients with matching donors.

A list of U.S. transplant centers that perform allogeneic transplants can be found at BeTheMatch.org/access. The list includes descriptions of the centers, their transplant experience, and survival statistics, as well as financial and contact information.

 

Organization:

National Marrow Donor Program

Address:

Suite 100 3001 Broadway Street, NE. Minneapolis, MN 55413–1753

Telephone:

612–627–5800 1–800–627–7692 (1–800–MARROW–2) (Be The Match Registry) 1–888–999–6743 (Be The Match Patient Services)

E-mail:

patientinfo@nmdp.org

Autoria e outros dados (tags, etc)

por cyto às 01:57

Sexta-feira, 30.01.15

Targeted Cancer Therapies

Targeted Cancer Therapies

Key Points

  • Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.
  • Because scientists call these specific molecules “molecular targets,” therapies that interfere with them are sometimes called “molecularly targeted drugs,” “molecularly targeted therapies,” or other similar names.
  • Targeted cancer therapies that have been approved for use in specific cancers include drugs that interfere with cell growth signaling or tumor blood vessel development, promote the specific death of cancer cells, stimulate the immune system to destroy specific cancer cells, and deliver toxic drugs to cancer cells.
  1. What are targeted cancer therapies?

Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. Because scientists often call these molecules “molecular targets,” targeted cancer therapies are sometimes called “molecularly targeted drugs,” “molecularly  targeted therapies,” or other similar names. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy and radiotherapy, and less harmful to normal cells.

Many targeted cancer therapies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of specific types of cancer (see details in Questions 4 and 5). Others are being studied in clinical trials (research studies with people), and many more are in preclinical testing (research studies with animals).

Targeted cancer therapies are being studied for use alone, in combination with other targeted therapies, and in combination with other cancer treatments, such as chemotherapy.

  1. How do targeted cancer therapies work?

Targeted cancer therapies interfere with cancer cell division (proliferation) and spread in different ways. Many of these therapies focus on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, cell responses to specific external stimuli, and even cell death. By blocking signals that tell cancer cells to grow and divide uncontrollably, targeted cancer therapies can help stop cancer progression and may induce cancer cell death through a process known as apoptosis. Other targeted therapies can cause cancer cell death directly, by specifically inducing apoptosis, or indirectly, by stimulating the immune system to recognize and destroy cancer cells and/or by delivering toxic substances directly to the cancer cells.

The development of targeted therapies, therefore, requires the identification of good targets—that is, targets that are known to play a key role in cancer cell growth and survival. (It is for this reason that targeted therapies are often referred to as the product of “rational drug design.”)

For example, most cases of chronic myeloid leukemia (CML) are caused by the formation of a gene called BCR-ABL. This gene is formed when pieces of chromosome 9 and chromosome 22 break off and trade places. One of the changed chromosomes resulting from this switch contains part of the ABL gene from chromosome 9 fused to part of the BCR gene from chromosome 22. The protein normally produced by the ABL gene (Abl) is a signaling molecule that plays an important role in controlling cell proliferation and usually must interact with other signaling molecules to be active. However, Abl signaling is always active in the protein (Bcr-Abl) produced by the BCR-ABL fusion gene. This activity promotes the continuous proliferation of CML cells. Therefore, Bcr-Abl represents a good molecule to target.

 

  1. How are targeted therapies developed?

Once a target has been identified, a therapy must be developed. Most targeted therapies are either small-molecule drugs or monoclonal antibodies. Small-molecule drugs are typically able to diffuse into cells and can act on targets that are found inside the cell. Most monoclonal antibodies cannot penetrate the cell’s plasma membrane and are directed against targets that are outside cells or on the cell surface.

Candidates for small-molecule drugs are usually identified in studies known as drug screens—laboratory tests that look at the effects of thousands of test compounds on a specific target, such as Bcr-Abl. The best candidates are then chemically modified to produce numerous closely related versions, and these are tested to identify the most effective and specific drugs.

Monoclonal antibodies, by contrast, are prepared first by immunizing animals (typically mice) with purified target molecules. The immunized animals will make many different types of antibodies against the target. Next, spleen cells, each of which makes only one type of antibody, are collected from the immunized animals and fused with myeloma cells. Cloning of these fused cells generates cultures of cells that produce large amounts of a single type of antibody, known as a monoclonal antibody. These antibodies are then tested to find the ones that react best with the target.

Before they can be used in humans, monoclonal antibodies are “humanized” by replacing as much of the animal portion of the antibody as possible with human portions. This is done through genetic engineering. Humanizing is necessary to prevent the human immune system from recognizing the monoclonal antibody as “foreign” and destroying it before it has a chance to interact with and inactivate its target molecule.

  1. What was the first target for targeted cancer therapy?

The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone estrogen, which many breast cancers require for growth. When estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation. Research has shown that interfering with estrogen’s ability to stimulate the growth of breast cancer cells that have these receptors (ER-positive breast cancer cells) is an effective treatment approach.

Several drugs that interfere with estrogen binding to the ER have been approved by the FDA for the treatment of ER-positive breast cancer. Drugs called selective estrogen receptor modulators (SERMs), including tamoxifen and toremifene (Fareston®), bind to the ER and prevent estrogen binding. Another drug, fulvestrant (Faslodex®), binds to the ER and promotes its destruction, thereby reducing ER levels inside cells.

Aromatase inhibitors (AIs) are another class of targeted drugs that interfere with estrogen’s ability to promote the growth of ER-positive breast cancers. The enzyme aromatase is necessary to produce estrogen in the body. Blocking the activity of aromatase lowers estrogen levels and inhibits the growth of cancers that need estrogen to grow. AIs are used mostly in women who have reached menopause because the ovaries of premenopausal women can produce enough aromatase to override the inhibition. Three AIs have been approved by the FDA for the treatment of ER-positive breast cancer: Anastrozole (Arimidex®), exemestane (Aromasin®), and letrozole (Femara®).

  1. What are some other targeted therapies?

Targeted cancer therapies have been developed that interfere with a variety of other cellular processes. FDA-approved drugs that target these processes are listed below.

Some targeted therapies block specific enzymes and growth factor receptors involved in cancer cell proliferation. These drugs are sometimes called signal transduction inhibitors. 

Imatinib mesylate (Gleevec®) is approved to treat gastrointestinal stromal tumor (a rare cancer of the gastrointestinal tract), certain kinds of leukemia, dermatofibrosarcoma protuberans, myelodysplastic/myeloproliferative disorders, and systemic mastocytosis. The drug targets several members of a class of proteins called tyrosine kinase enzymes that participate in signal transduction. These enzymes are overactive in some cancers, leading to uncontrolled growth. It is a small-molecule drug, which means that it can pass through cell membranes and reach targets inside the cell.

Dasatinib (Sprycel®) is approved to treat some patients with CML or acute lymphoblastic leukemia. The drug is a small-molecule inhibitor of several tyrosine kinase enzymes.

Nilotinib (Tasigna®) is approved to treat some patients with CML. The drug is another small-molecule tyrosine kinase inhibitor.

Bosutinib (Bosulif®) is also approved to treat some patients with CML. The drug is a small-molecule tyrosine kinase inhibitor.

Trastuzumab (Herceptin®) is approved to treat certain types of breast cancer as well as some types of gastric or gastroesophageal junction adenocarcinoma. The therapy is a monoclonal antibody that binds to the human epidermal growth factor receptor 2 (HER-2). HER-2, a receptor with tyrosine kinase activity, is expressed at high levels in some breast cancers and also some other types of cancer. The mechanism by which trastuzumab acts is not completely understood, but one likely possibility is that it prevents HER-2 from sending growth-promoting signals. Trastuzumab may have other effects as well, such as inducing the immune system to attack cells that express high levels of HER-2.

Pertuzumab (Perjeta™) is approved to be used in combination with trastuzumab and docetaxel to treat metastatic breast cancer that expresses HER-2 and has not been treated with chemotherapy or a HER-2-directed therapy. Pertuzumab is a monoclonal antibody that binds to HER-2 at a region distinct from trastuzumab. This region allows HER-2 to interact with other receptors, such as the epidermal growth factor receptor (EGFR), to send growth-promoting signals. The drug likely prevents HER-2 from sending growth signals and induces the immune system to attack HER-2-expressing cells.

Lapatinib (Tykerb®) is approved for the treatment of certain types of advanced or metastatic breast cancer. This small-molecule drug inhibits several tyrosine kinases, including the tyrosine kinase activity of HER-2. Lapatinib treatment prevents HER-2 signals from activating cell growth.

Gefitinib (Iressa®) is approved to treat patients with advanced non-small cell lung cancer. This small-molecule drug is restricted to use in patients who, in the opinion of their treating physician, are currently benefiting, or have previously benefited, from gefitinib treatment. Gefitinib inhibits the tyrosine kinase activity of EGFR, which is overproduced by many types of cancer cells.

Erlotinib (Tarceva®) is approved to treat metastatic non-small cell lung cancer and pancreatic cancer that cannot be removed by surgery or has metastasized. This small-molecule drug inhibits the tyrosine kinase activity of EGFR.

Cetuximab (Erbitux®) is a monoclonal antibody that is approved to treat some patients with squamous cell carcinoma of the head and neck or colorectal cancer. The drug binds to the external portion of EGFR, thereby preventing the receptor from being activated by growth signals, which may inhibit signal transduction and lead to antiproliferative effects.

Panitumumab (Vectibix®) is approved to treat some patients with metastatic colon cancer. This monoclonal antibody attaches to EGFR and prevents it from sending growth signals.

Temsirolimus (Torisel®) is approved to treat patients with advanced renal cell carcinoma. This small-molecule drug is a specific inhibitor of a serine/threonine kinase called mTOR that is activated in tumor cells and stimulates their growth and proliferation.

Everolimus (Afinitor®) is approved to treat patients with advanced kidney cancer whose disease has progressed after treatment with other therapies, patients with subependymal giant cell astrocytoma who also have tuberous sclerosis and are unable to have surgery, some patients with advanced breast cancer, or patients with pancreatic neuroendocrine tumors that cannot be removed by surgery, are locally advanced, or have metastasized. This small-molecule drug binds to a protein called immunophilin FK binding protein-12, forming a complex that in turn binds to and inhibits the mTOR kinase.

Vandetanib (Caprelsa®) is approved to treat patients with metastatic medullary thyroid cancer who are ineligible for surgery. This small-molecule drug binds to and blocks the growth-promoting activity of several tyrosine kinase enzymes, including EGFR, several receptors for vascular endothelial growth factor receptor (VEGF), and RET.

Vemurafenib (Zelboraf®) is approved to treat certain patients with inoperable or metastatic melanoma. This small-molecule drug blocks the activity of a permanently activated mutant form of the serine/threonine kinase BRAF (known as BRAF V600E).

Crizotinib (Xalkori®) is approved to treat certain patients with locally advanced or metastatic non-small cell lung cancer. This small-molecule drug inhibits the tyrosine kinase activity of a fusion protein called EML4-ALK, resulting in decreased tumor cell growth, migration, and invasiveness.

Other targeted therapies modify the function of proteins that regulate gene expression and other cellular functions.

Vorinostat (Zolinza®) is approved to treat cutaneous T-cell lymphoma (CTCL) that has persisted, progressed, or recurred during or after treatment with other medicines. This small-molecule drug inhibits the activity of a group of enzymes called histone deacetylases (HDACs), which remove small chemical groups called acetyl groups from many different proteins, including proteins that regulate gene expression. By altering the acetylation of these proteins, HDAC inhibitors can induce tumor cell differentiation, cell cycle arrest, and apoptosis.

Romidepsin (Istodax®) is approved to treat CTCL in patients who have received at least one prior systemic therapy. This small-molecule drug inhibits members of one class of HDACs and induces tumor cell apoptosis.

Bexarotene (Targretin®) is approved to treat some patients with CTCL. This drug belongs to a class of compounds called retinoids, which are chemically related to vitamin A. Bexarotene binds selectively to, and thereby activates, retinoid X receptors. Once activated, these nuclear proteins act in concert with retinoic acid receptors to regulate the expression of genes that control cell growth, differentiation, survival, and death.

Alitretinoin (Panretin®) is approved to treat cutaneous lesions in patients with AIDS-related Kaposi sarcoma. This retinoid binds to both retinoic acid receptors and retinoid X receptors.

Tretinoin (Vesanoid®) is approved for the induction of remission in certain patients with acute promyelocytic leukemia. This retinoid binds to and thereby activates retinoic acid receptors.

 

Some targeted therapies induce cancer cells to undergo apoptosis (cell death).

Bortezomib (Velcade®) is approved to treat some patients with multiple myeloma and some patients with mantle cell lymphoma. Bortezomib causes cancer cells to die by interfering with the action of a large cellular structure called the proteasome, which controls the degradation of many proteins that regulate cell proliferation. Drugs that block this process are called proteasome inhibitors. Proteasome inhibitors affect normal cells, too, but to a lesser extent.

Carfilzomib (Kyprolis™) is approved to treat some patients with multiple myeloma whose disease has progressed after treatment with bortezomib. Carfilzomib is another proteasome inhibitor.

Pralatrexate (Folotyn®) is approved for the treatment of some patients with peripheral T-cell lymphoma. Pralatrexate is an antifolate, which is a type of molecule that interferes with DNA synthesis. Other antifolates, such as methotrexate, are not considered targeted therapies because they interfere with DNA synthesis in all dividing cells. However, pralatrexate appears to selectively accumulate in cells that express RFC-1, a protein that may be overexpressed by some cancer cells.

Other targeted therapies block the growth of blood vessels to tumors (angiogenesis). To grow beyond a certain size, tumors must obtain a blood supply to get the oxygen and nutrients needed for continued growth. Treatments that interfere with angiogenesis may block tumor growth.

Bevacizumab (Avastin®) is a monoclonal antibody that is approved for the treatment of glioblastoma. The therapy is also approved to treat some patients with non-small cell lung cancer, metastatic colorectal cancer, and metastatic kidney cancer. Bevacizumab binds to VEGF and prevents it from interacting with receptors on endothelial cells, blocking a step that is necessary for the initiation of new blood vessel growth.

Ziv-aflibercept (Zaltrap®) is a recombinant fusion protein that is approved for the treatment of some patients with metastatic colorectal cancer. Ziv-aflibercept consists of portions of two different VEGF receptors fused to a portion of an immune protein. By binding to VEGF, ziv-aflibercept prevents it from interacting with receptors on endothelial cells, thereby blocking the growth and development of new blood vessels.

Sorafenib (Nexavar®) is a small-molecule inhibitor of tyrosine kinases that is approved for the treatment of advanced renal cell carcinoma and some cases of hepatocellular carcinoma. One of the kinases that sorafenib inhibits is involved in the signaling pathway that is initiated when VEGF binds to its receptors. As a result, new blood vessel development is halted. Sorafenib also blocks an enzyme that is involved in cell growth and division.

Sunitinib (Sutent®) is another small-molecule tyrosine kinase inhibitor that is approved for the treatment of patients with metastatic renal cell carcinoma, gastrointestinal stromal tumor that is not responding to imatinib, or pancreatic neuroendocrine tumors that cannot be removed by surgery, are locally advanced, or have metastasized. Sunitinib blocks kinases involved in VEGF signaling, thereby inhibiting angiogenesis and cell proliferation.

Pazopanib (Votrient®) is approved to treat patients with advanced renal cell carcinoma and advanced soft tissue sarcoma. Pazopanib is a small-molecule inhibitor of several tyrosine kinases, including VEGF receptors, c-KIT, and platelet-derived growth factor receptor (PDGFR).

Regorafenib (Stivarga®) is approved for the treatment of some patients with metastatic colorectal cancer. Regorafenib is a small-molecule inhibitor of several tyrosine kinases that are involved in angiogenesis and tumor cell growth, including VEGF receptors, the angiopoietin-1 receptor (TIE2), PDGFR, RET, c-KIT, and RAF.

Cabozantinib (Cometriq™) is approved for the treatment of some patients with metastatic medullary thyroid cancer. Cabozantinib is a small-molecule inhibitor of several tyrosine kinases, including VEGF receptors, RET, MET, TRKB, and TIE2.

Some targeted therapies act by helping the immune system to destroy cancer cells.

Rituximab (Rituxan®) is a monoclonal antibody that is approved to treat certain types of B-cell non-Hodgkin lymphoma and, when combined with other drugs, to treat chronic lymphocytic leukemia (CLL). The therapy recognizes a molecule called CD20 that is found on B cells. When rituximab binds to these cells, it triggers an immune response that results in their destruction. Rituximab may also induce apoptosis.

Alemtuzumab (Campath®) is approved to treat patients with B-cell CLL. The therapy is a monoclonal antibody directed against CD52, a protein found on the surface of normal and malignant B and T cells and many other cells of the immune system. Binding of alemtuzumab to CD52 triggers an immune response that destroys the cells.

Ofatumumab (Arzerra®) is approved for the treatment of some patients with CLL that does not respond to treatment with fludarabine and alemtuzumab. This monoclonal antibody is directed against the B-cell CD20 cell surface antigen.

Ipilimumab (Yervoy™) is approved to treat patients with unresectable or metastatic melanoma. This monoclonal antibody is directed against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which is expressed on the surface of activated T cells as part of a “checkpoint” to prevent a runaway immune response. By inhibiting CTLA-4, ipilimumab stimulates the immune system to attack melanoma cells.

Another class of targeted therapies includes monoclonal antibodies that deliver toxic molecules to cancer cells specifically.

Tositumomab and 131I-tositumomab (Bexxar®) is approved to treat certain types of B-cell non-Hodgkin lymphoma. The therapy is a mixture of monoclonal antibodies that recognize the CD20 molecule. Some of the antibodies in the mixture are linked to a radioactive substance called iodine-131. The 131I-tositumomab component delivers radioactive energy to CD20-expressing B cells specifically, reducing collateral damage to normal cells. In addition, the binding of tositumomab to the CD20-expressing B cells triggers the immune system to destroy these cells.

Ibritumomab tiuxetan (Zevalin®) is approved to treat some patients with B-cell non-Hodgkin lymphoma. The therapy is a monoclonal antibody directed against CD20 that is linked to a molecule that can bind radioisotopes such as indium-111 or yttrium-90. The radiolabeled forms of Zevalin deliver a high dose of radioactivity to cells that express CD20.

Denileukin diftitox (Ontak®) is approved to treat some patients with CTCL. Denileukin diftitox consists of interleukin-2 (IL-2) protein sequences fused to diphtheria toxin. The drug binds to cell surface IL-2 receptors, which are found on certain immune cells and some cancer cells, directing the cytotoxic action of the diphtheria toxin to these cells.

Brentuximab vedotin (Adcetris®) is approved for the treatment of systemic anaplastic large cell lymphoma and Hodgkin lymphoma that has not responded to prior chemotherapy or autologous stem cell transplantation. This agent consists of a monoclonal antibody directed against a molecule called CD30, which is found on some lymphoma cells, linked to a drug called monomethyl auristatin E (MMAE). The antibody part of the agent binds to and is internalized by CD30-expressing tumor cells. Once inside the cell, the MMAE is released, where it induces cell cycle arrest and apoptosis.

Cancer vaccines and gene therapy are often considered to be targeted therapies because they interfere with the growth of specific cancer cells. Information about these treatments can be found in the following NCI fact sheets, which are available online or by calling NCI’s Cancer Information Service at 1–800–4–CANCER:

Biological Therapies for Cancer includes information about monoclonal antibodies and cancer vaccines.

Cancer Vaccines contains information on vaccines intended to treat cancer, as well as those intended to prevent it.

Gene Therapy for Cancer discusses research with genetic material in developing cancer therapies, including risks, benefits, and ethical issues.

  1. What impact will targeted therapies have on cancer treatment?

Targeted cancer therapies give doctors a better way to tailor cancer treatment, especially when a target is present in some but not all tumors of a particular type, as is the case for HER-2. Eventually, treatments may be individualized based on the unique set of molecular targets produced by the patient’s tumor. Targeted cancer therapies also hold the promise of being more selective for cancer cells than normal cells, thus harming fewer normal cells, reducing side effects, and improving quality of life.

Nevertheless, targeted therapies have some limitations. Chief among these is the potential for cells to develop resistance to them. In some patients who have developed resistance to imatinib, for example, a mutation in the BCR-ABL gene has arisen that changes the shape of the protein so that it no longer binds this drug as well. In most cases, another targeted therapy that could overcome this resistance is not available. It is for this reason that targeted therapies may work best in combination, either with other targeted therapies or with more traditional therapies.

  1. Where can I find information about clinical trials of targeted therapies?

The list below provides links to active clinical trials of FDA-approved targeted therapies. Because trials begin and end regularly, it is possible that, at any given time, a particular drug will not have any trials available. If you are viewing this fact sheet online, the drug names are links to search results for trials in NCI’s clinical trials database. For information about how to search the database, see “Help Using the NCI Clinical Trials Search Form.” The database includes all NCI-funded clinical trials and many other studies conducted by investigators at hospitals and medical centers in the United States and other countries around the world.

Targeted Cancer Therapies Being Studied in Clinical Trials: Alemtuzumab (Campath®) Alitretinoin (Panretin®) Anastrozole (Arimidex®) Bevacizumab (Avastin®) Bexarotene (Targretin®) Bortezomib (Velcade®) Bosutinib (Bosulif®) Brentuximab vedotin (Adcetris®) Cabozantinib (Cometriq™) Carfilzomib (Kyprolis™) Cetuximab (Erbitux®) Crizotinib (Xalkori®) Dasatinib (Sprycel®) Denileukin diftitox (Ontak®) Erlotinib hydrochloride (Tarceva®) Everolimus (Afinitor®) Exemestane (Aromasin®) Fulvestrant (Faslodex®) Gefitinib (Iressa®) Ibritumomab tiuxetan (Zevalin®) Imatinib mesylate (Gleevec®) Ipilimumab (Yervoy™) Lapatinib ditosylate (Tykerb®) Letrozole (Femara®) Nilotinib (Tasigna®) Ofatumumab (Arzerra®) Panitumumab (Vectibix®) Pazopanib hydrochloride (Votrient®) Pertuzumab (Perjeta™) Pralatrexate (Folotyn®) Regorafenib (Stivarga®) Rituximab (Rituxan®) Romidepsin (Istodax®) Sorafenib tosylate (Nexavar®) Sunitinib malate (Sutent®) Tamoxifen Temsirolimus (Torisel®) Toremifene (Fareston®) Tositumomab and 131I-tositumomab (Bexxar®) Trastuzumab (Herceptin®) Tretinoin (Vesanoid®) Vandetanib (Caprelsa®) Vemurafenib (Zelboraf®) Vorinostat (Zolinza®) Ziv-aflibercept (Zaltrap®)

  1. What are some resources for more information?

NCI’s Molecular Targets Laboratory (MTL), part of NCI’s Center for Cancer Research (CCR), is working to identify and evaluate molecular targets that may be candidates for drug development. The initial goal of the MTL is to facilitate the discovery of compounds that may serve as bioprobes for functional genomics, proteomics, and molecular target validation research, as well as leads or candidates for drug development.

NCI’s Chemical Biology Consortium (CBC) facilitates the discovery and development of new agents to treat cancer. The CBC is part of the NCI Experimental Therapeutics Program, which is a collaborative effort of CCR and NCI’s Division of Cancer Treatment and Diagnosis.

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por cyto às 01:56

Sexta-feira, 30.01.15

Angiogenesis Inhibitors

Angiogenesis Inhibitors

Key Points

  • Angiogenesis is the formation of new blood vessels. Tumors need blood vessels to grow and spread.
  • Angiogenesis inhibitors are designed to prevent the formation of new blood vessels, thereby stopping or slowing the growth or spread of tumors.
  • The U.S. Food and Drug Administration has approved several angiogenesis inhibitors for the treatment of cancer.
  • Angiogenesis inhibitors may have side effects that are different from those of other cancer treatments. In addition, they may only stop or slow the growth of a cancer, not completely eradicate it.
  1. What is angiogenesis?

Angiogenesis is the formation of new blood vessels. This process involves the migration, growth, and differentiation of endothelial cells, which line the inside wall of blood vessels.

The process of angiogenesis is controlled by chemical signals in the body. These signals can stimulate both the repair of damaged blood vessels and the formation of new blood vessels. Other chemical signals, called angiogenesis inhibitors, interfere with blood vessel formation. Normally, the stimulating and inhibiting effects of these chemical signals are balanced so that blood vessels form only when and where they are needed.

  1. Why is angiogenesis important in cancer?

Angiogenesis plays a critical role in the growth and spread of cancer. A blood supply is necessary for tumors to grow beyond a few millimeters in size. Tumors can cause this blood supply to form by giving off chemical signals that stimulate angiogenesis. Tumors can also stimulate nearby normal cells to produce angiogenesis signaling molecules. The resulting new blood vessels “feed” growing tumors with oxygen and nutrients, allowing the cancer cells to invade nearby tissue, to move throughout the body, and to form new colonies of cancer cells, called metastases.

Because tumors cannot grow beyond a certain size or spread without a blood supply, scientists are trying to find ways to block tumor angiogenesis. They are studying natural and synthetic angiogenesis inhibitors, also called antiangiogenic agents, with the idea that these molecules will prevent or slow the growth of cancer.

 

 

  1. How do angiogenesis inhibitors work?

Angiogenesis requires the binding of signaling molecules, such as vascular endothelial growth factor (VEGF), to receptors on the surface of normal endothelial cells. When VEGF and other endothelial growth factors bind to their receptors on endothelial cells, signals within these cells are initiated that promote the growth and survival of new blood vessels.

Angiogenesis inhibitors interfere with various steps in this process. For example, bevacizumab (Avastin®) is a monoclonal antibody that specifically recognizes and binds to VEGF (1). When VEGF is attached to bevacizumab, it is unable to activate the VEGF receptor. Other angiogenesis inhibitors, including sorafenib and sunitinib, bind to receptors on the surface of endothelial cells or to other proteins in the downstream signaling pathways, blocking their activities (2).

  1. Are any angiogenesis inhibitors currently being used to treat cancer in humans?

Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab to be used alone for glioblastoma that has not improved with other treatments and to be used in combination with other drugs to treat metastatic colorectal cancer, some non-small cell lung cancers, and metastatic renal cell cancer. Bevacizumab was the first angiogenesis inhibitor that was shown to slow tumor growth and, more important, to extend the lives of patients with some cancers.

The FDA has approved other drugs that have antiangiogenic activity, including sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), and everolimus (Afinitor®). Sorafenib is approved for hepatocellular carcinoma and kidney cancer, sunitinib and everolimus for both kidney cancer and neuroendocrine tumors, and pazopanib for kidney cancer. Researchers are exploring the use of angiogenesis inhibitors to treat other types of cancer (see Question 7). In addition, angiogenesis inhibitors are being used to treat some diseases that involve the development of abnormal blood vessel growth in noncancer conditions, such as macular degeneration.

  1. How are angiogenesis inhibitors different from conventional anticancer drugs?

Angiogenesis inhibitors are unique cancer-fighting agents because they tend to inhibit the growth of blood vessels rather than tumor cells. In some cancers, angiogenesis inhibitors are most effective when combined with additional therapies, especially chemotherapy. It has been hypothesized that these drugs help normalize the blood vessels that supply the tumor, facilitating the delivery of other anticancer agents, but this possibility is still being investigated. Angiogenesis inhibitor therapy does not necessarily kill tumors but instead may prevent tumors from growing. Therefore, this type of therapy may need to be administered over a long period.

  1. Do angiogenesis inhibitors have side effects?

Initially, it was thought that angiogenesis inhibitors would have mild side effects, but more recent studies have revealed the potential for complications that reflect the importance of angiogenesis in many normal body processes, such as wound healing, heart and kidney function, fetal development, and reproduction. Side effects of treatment with angiogenesis inhibitors can include problems with bleeding, clots in the arteries (with resultant stroke or heart attack), hypertension, and protein in the urine (35). Gastrointestinal perforation and fistulas also appear to be rare side effects of some angiogenesis inhibitors. Animal studies have revealed the potential for birth defects, although there is no clinical evidence for such effects in humans.

It is likely that some of the possible complications of angiogenesis inhibitor therapy remain unknown. As more patients are treated with these agents, doctors will learn more about possible rare side effects.

  1. What is the ongoing research on angiogenesis inhibitors?

In addition to the angiogenesis inhibitors that have already been approved by the FDA, others that target VEGF or other angiogenesis pathways are currently being tested in clinical trials (research studies involving patients). If these angiogenesis inhibitors prove to be both safe and effective in treating human cancer, they may be approved by the FDA and made available for widespread use.

In addition, phase I and II clinical trials are testing the possibility of combining angiogenesis inhibitor therapy with other treatments that target blood vessels, such as tumor-vascular disrupting agents, which damage existing tumor blood vessels (6).

The list below includes cancers that are being studied in active phase III treatment clinical trials using angiogenesis inhibitors. The clinical trials can be found in NCI’s list of clinical trials. For information about how to search the list, see “Help Using the NCI Clinical Trials Search Form.”

Types of Cancer in Active Phase III Treatment Clinical Trials of Angiogenesis Inhibitors:

For more information about NCI’s clinical trials database and other cancer-related information, call NCI’s Cancer Information Service at 1–800–4–CANCER (1–800–422–6237).

Selected References
  1. Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clinical Therapeutics 2006; 28(11):1779–1802. [PubMed Abstract]
  2. Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010; 13(1):1–14. [PubMed Abstract]
  3. Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA: A Cancer Journal for Clinicians 2010; 60(4):222–243. [PubMed Abstract]
  4. Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nature Reviews Clinical Oncology 2009; 6(8):465–477. [PubMed Abstract]
  5. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nature Reviews Cancer 2007; 7(6):475–485. [PubMed Abstract]
  6. Siemann DW. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by Tumor-Vascular Disrupting Agents. Cancer Treatment Reviews 2011; 37(1):63–74. [PubMed Abstract]
Related Resources : Biological Therapies for Cancer, Cancer Clinical Trials, Targeted Cancer Therapies
 
 
 
 
 
 
 

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por cyto às 01:54

Sexta-feira, 30.01.15

Cancer Vaccines

Cancer Vaccines

Key Points

  • Cancer vaccines are designed to boost the body’s natural ability to protect itself, through the immune system, from dangers posed by damaged or abnormal cells such as cancer cells.
  • The U.S. Food and Drug Administration (FDA) has approved two types of vaccines to prevent cancer: vaccines against the hepatitis B virus, which can cause liver cancer, and vaccines against human papillomavirus types 16 and 18, which are responsible for about 70 percent of cervical cancer cases.
  • The FDA has approved one cancer treatment vaccine for certain men with metastatic prostate cancer.
  • Researchers are developing treatment vaccines against many types of cancer and testing them in clinical trials.
  1. What are vaccines?

Vaccines are medicines that boost the immune system's natural ability to protect the body against “foreign invaders,” mainly infectious agents, that may cause disease.

The immune system is a complex network of organs, tissues, and specialized cells that act collectively to defend the body. When an infectious microbe invades the body, the immune system recognizes it as foreign, destroys it, and “remembers” it to prevent another infection should the microbe invade the body again in the future. Vaccines take advantage of this response.

Traditional vaccines usually contain harmless versions of microbes—killed or weakened microbes, or parts of microbes—that do not cause disease but are able to stimulate an immune response against the microbes. When the immune system encounters these substances through vaccination, it responds to them, eliminates them from the body, and develops a memory of them. This vaccine-induced memory enables the immune system to act quickly to protect the body if it becomes infected by the same microbes in the future.

The immune system’s role in defending against disease-causing microbes has long been recognized. Scientists have also discovered that the immune system can protect the body against threats posed by certain damaged, diseased, or abnormal cells, including cancer cells(1).

  1. How do vaccines stimulate the immune system?

White blood cells, or leukocytes, play the main role in immune responses. These cells carry out the many tasks required to protect the body against disease-causing microbes and abnormal cells.

Some types of leukocytes patrol the circulation, seeking foreign invaders and diseased, damaged, or dead cells. These white blood cells provide a general—or nonspecific—level of immune protection.

Other types of leukocytes, known as lymphocytes, provide targeted protection against specific threats, whether from a specific microbe or a diseased or abnormal cell. The most important groups of lymphocytes responsible for carrying out immune responses against such threats are B cells and cytotoxic (cell-killing) T cells.

B cells make antibodies, which are large secreted proteins that bind to, inactivate, and help destroy foreign invaders or abnormal cells. Most preventive vaccines, including those aimed at hepatitis B virus (HBV) and human papillomavirus (HPV), stimulate the production of antibodies that bind to specific, targeted microbes and block their ability to cause infection. Cytotoxic T cells, which are also known as killer T cells, kill infected or abnormal cells by releasing toxic chemicals or by prompting the cells to self-destruct (a process known as apoptosis).

Other types of lymphocytes and leukocytes play supporting roles to ensure that B cells and killer T cells do their jobs effectively. These supporting cells include helper T cells and dendritic cells, which help activate killer T cells and enable them to recognize specific threats.

Cancer treatment vaccines are designed to work by activating B cells and killer T cells and directing them to recognize and act against specific types of cancer. They do this by introducing one or more molecules known as antigens into the body, usually by injection. An antigen is a substance that stimulates a specific immune response. An antigen can be a protein or another type of molecule found on the surface of or inside a cell.

Microbes are recognized by the immune system as a potential threat that should be destroyed because they carry foreign or “non-self” antigens. In contrast, normal cells in the body have antigens that identify them as “self.” Self antigens tell the immune system that normal cells are not a threat and should be ignored (2).

Cancer cells can carry both self antigens and cancer-associated antigens. The cancer-associated antigens mark the cancer cells as abnormal, or foreign, and can cause B cells and killer T cells to mount an attack against them.

Cancer cells may also make much larger amounts of certain self antigens than normal cells. Because of their high abundance, these self antigens may be viewed by the immune system as being foreign and, therefore, may trigger an immune response against the cancer cells (1–6).

 

  1. What are cancer vaccines?

Cancer vaccines are medicines that belong to a class of substances known as biological response modifiers. Biological response modifiers work by stimulating or restoring the immune system’s ability to fight infections and disease. There are two broad types of cancer vaccines:

Preventive (or prophylactic) vaccines, which are intended to prevent cancer from developing in healthy people; and

Treatment (or therapeutic) vaccines, which are intended to treat an existing cancer by strengthening the body’s natural defenses against the cancer (7).

Two types of cancer preventive vaccines are available in the United States (see Question 5), and one cancer treatment vaccine has recently become available (see Question 8).

  1. How do cancer preventive vaccines work?

Cancer preventive vaccines target infectious agents that cause or contribute to the development of cancer (8). They are similar to traditional vaccines, which help prevent infectious diseases, such as measles or polio, by protecting the body against infection. Both cancer preventive vaccines and traditional vaccines are based on antigens that are carried by infectious agents and that are relatively easy for the immune system to recognize as foreign.

  1. What cancer preventive vaccines are approved in the United States?

The U.S. Food and Drug Administration (FDA) has approved two vaccines, Gardasil® and Cervarix®, that protect against infection by the two types of HPV—types 16 and 18—that cause approximately 70 percent of all cases of cervical cancer worldwide. At least 17 other types of HPV are responsible for the remaining 30 percent of cervical cancer cases (9). HPV types 16 and/or 18 also cause some vaginal, vulvar, anal, penile, and oropharyngeal cancers (10).

In addition, Gardasil protects against infection by two additional HPV types, 6 and 11, which are responsible for about 90 percent of all cases of genital warts in males and females but do not cause cervical cancer.

Gardasil, manufactured by Merck & Company, is based on HPV antigens that are proteins. These proteins are used in the laboratory to make four different types of “virus-like particles,” or VLPs, that correspond to HPV types 6, 11, 16, and 18. The four types of VLPs are then combined to make the vaccine. Because Gardasil targets four HPV types, it is called a quadrivalent vaccine (11). In contrast with traditional vaccines, which are often composed of weakened whole microbes, VLPs are not infectious. However, the VLPs in Gardasil are still able to stimulate the production of antibodies against HPV types 6, 11, 16, and 18.

Cervarix, manufactured by GlaxoSmithKline, is a bivalent vaccine. It is composed of VLPs made with proteins from HPV types 16 and 18. In addition, there is some initial evidence that Cervarix provides partial protection against a few additional HPV types that can cause cancer. However, more studies will be needed to understand the magnitude and impact of this effect.

Gardasil is approved for use in females to prevent cervical cancer and some vulvar and vaginal cancers caused by HPV types 16 and 18, and for use in males and females to prevent anal cancer and precancerous anal lesions caused by these HPV types. Gardasil is also approved for use in males and females to prevent genital warts caused by HPV types 6 and 11. The vaccine is approved for these uses in females and males ages 9 to 26. Cervarix is approved for use in females ages 9 to 25 to prevent cervical cancer caused by HPV types 16 and 18.

The FDA has also approved a cancer preventive vaccine that protects against HBV infection. Chronic HBV infection can lead to liver cancer. The original HBV vaccine was approved in 1981, making it the first cancer preventive vaccine to be successfully developed and marketed. Today, most children in the United States are vaccinated against HBV shortly after birth (12).

  1. Have other microbes been associated with cancer?

Many scientists believe that microbes cause or contribute to between 15 percent and 25 percent of all cancers diagnosed worldwide each year, with the percentage being lower in developed than developing countries (4, 8, 13).

The International Agency for Research on Cancer (IARC) has classified several microbes as carcinogenic (causing or contributing to the development of cancer in people), including HPV and HBV (14). These infectious agents—bacteria, viruses, and parasites—and the cancer types with which they are most strongly associated are listed in the table below.

Infectious Agents

Type of Organism

Associated Cancers

hepatitis B virus (HBV)

virus

hepatocellular carcinoma (a type of liver cancer)

hepatitis C virus (HCV)

virus

hepatocellular carcinoma (a type of liver cancer)

human papillomavirus (HPV) types 16 and 18, as well as other HPV types

virus

cervical cancer; vaginal cancer; vulvar cancer; oropharyngeal cancer (cancers of the base of the tongue, tonsils, or upper throat); anal cancer; penile cancer; squamous cell carcinoma of the skin

Epstein-Barr virus

virus

Burkitt lymphoma; non-Hodgkin lymphoma; Hodgkin lymphoma; nasopharyngeal carcinoma (cancer of the upper part of the throat behind the nose)

Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8)

virus

Kaposi sarcoma

human T-cell lymphotropic virus type 1 (HTLV1)

virus

adult T-cell leukemia/lymphoma

Helicobacter pylori

bacterium

stomach cancer; mucosa-associated lymphoid tissue (MALT) lymphoma

schistosomes (Schistosoma hematobium)

parasite

bladder cancer

liver flukes (Opisthorchis viverrini)

parasite

cholangiocarcinoma (a type of liver cancer)

 

  1. How are cancer treatment vaccines designed to work?

Cancer treatment vaccines are designed to treat cancers that have already developed. They are intended to delay or stop cancer cell growth; to cause tumor shrinkage; to prevent cancer from coming back; or to eliminate cancer cells that have not been killed by other forms of treatment.

Developing effective cancer treatment vaccines requires a detailed understanding of how immune system cells and cancer cells interact. The immune system often does not “see” cancer cells as dangerous or foreign, as it generally does with microbes. Therefore, the immune system does not mount a strong attack against the cancer cells.

Several factors may make it difficult for the immune system to target growing cancers for destruction. Most important, cancer cells carry normal self antigens in addition to specific cancer-associated antigens. Furthermore, cancer cells sometimes undergo genetic changes that may lead to the loss of cancer-associated antigens. Finally, cancer cells can produce chemical messages that suppress anticancer immune responses by killer T cells. As a result, even when the immune system recognizes a growing cancer as a threat, the cancer may still escape a strong attack by the immune system (15).

Producing effective treatment vaccines has proven much more difficult and challenging than developing cancer preventive vaccines (16). To be effective, cancer treatment vaccines must achieve two goals. First, like traditional vaccines and cancer preventive vaccines, cancer treatment vaccines must stimulate specific immune responses against the correct target. Second, the immune responses must be powerful enough to overcome the barriers that cancer cells use to protect themselves from attack by B cells and killer T cells. Recent advances in understanding how cancer cells escape recognition and attack by the immune system are now giving researchers the knowledge required to design cancer treatment vaccines that can accomplish both goals (17, 18).

  1. Has the FDA approved any cancer treatment vaccines?

In April 2010, the FDA approved the first cancer treatment vaccine. This vaccine, sipuleucel-T (Provenge®, manufactured by Dendreon), is approved for use in some men with metastatic prostate cancer. It is designed to stimulate an immune response to prostatic acid phosphatase (PAP), an antigen that is found on most prostate cancer cells. In a clinical trial, sipuleucel-T increased the survival of men with a certain type of metastatic prostate cancer by about 4 months (19).

Unlike some other cancer treatment vaccines under development, sipuleucel-T is customized to each patient. The vaccine is created by isolating immune system cells called antigen-presenting cells (APCs) from a patient’s blood through a procedure called leukapheresis. The APCs are sent to Dendreon, where they are cultured with a protein called PAP-GM-CSF. This protein consists of PAP linked to another protein called granulocyte-macrophage colony-stimulating factor (GM-CSF). The latter protein stimulates the immune system and enhances antigen presentation.

APC cells cultured with PAP-GM-CSF constitute the active component of sipuleucel-T. Each patient’s cells are returned to the patient’s treating physician and infused into the patient. Patients receive three treatments, usually 2 weeks apart, with each round of treatment requiring the same manufacturing process. Although the precise mechanism of action of sipuleucel-T is not known, it appears that the APCs that have taken up PAP-GM-CSF stimulate T cells of the immune system to kill tumor cells that express PAP.

  1. What types of vaccines are being studied in clinical trials?

Vaccines to prevent HPV infection and to treat several types of cancer are being studied in clinical trials.

The list below shows the types of cancer that are being targeted in active cancer prevention or treatment clinical trials using vaccines. If you are accessing this fact sheet online, the cancer names are links to search results from NCI’s clinical trials database.

Active Clinical Trials of Cancer Treatment Vaccines by Type of Cancer:

Active Clinical Trials of Cancer Preventive Vaccines by Type of Cancer:

  1. How are cancer vaccines made?

All cancer preventive vaccines approved by the FDA to date have been made using antigens from microbes that cause or contribute to the development of cancer. These include antigens from HBV and specific types of HPV (see Question 5). These antigens are proteins that help make up the outer surface of the viruses. Because only part of these microbes is used, the resulting vaccines are not infectious and, therefore, cannot cause disease.

Researchers are also creating synthetic versions of antigens in the laboratory for use in cancer preventive vaccines. In doing this, they often modify the chemical structure of the antigens to stimulate immune responses that are stronger than those caused by the original antigens.

Similarly, cancer treatment vaccines are made using antigens from cancer cells or modified versions of them. Antigens that have been used thus far include proteins, carbohydrates (sugars), glycoproteins or glycopeptides (carbohydrate-protein combinations), and gangliosides (carbohydrate-lipid combinations).

Cancer treatment vaccines are also being developed using weakened or killed cancer cells that carry a specific cancer-associated antigen or immune cells that are modified to express such an antigen. These cells can come from a patient himself or herself (called an autologous vaccine, such as sipuleucel-T) or from another patient (called an allogeneic vaccine).

Other types of cancer treatment vaccines are made using molecules of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) that contain the genetic instructions for cancer-associated antigens. The DNA or RNA can be injected alone into a patient as a “naked nucleic acid” vaccine, or researchers can insert the DNA or RNA into a harmless virus. After the naked nucleic acid or virus is injected into the body, the DNA or RNA is taken up by cells, which begin to manufacture the tumor-associated antigens. Researchers hope that the cells will make enough of the tumor-associated antigens to stimulate a strong immune response.

Scientists have identified a large number of cancer-associated antigens, several of which are now being used to make experimental cancer treatment vaccines. Some of these antigens are found on or in many or most types of cancer cells. Others are unique to specific cancer types (1, 5, 6, 18–22).

  1. Can researchers add ingredients to cancer vaccines to make them work better?

Antigens and the substances discussed in Question 10 are often not strong enough inducers of the immune response to make effective cancer treatment vaccines. Researchers often add extra ingredients, known as adjuvants, to treatment vaccines. These substances serve to boost immune responses that have been set in motion by exposure to antigens or other means. Patients undergoing experimental treatment with a cancer vaccine sometimes receive adjuvants separately from the vaccine itself (23).

Adjuvants used for cancer vaccines come from many different sources. Some microbes, such as the bacterium Bacillus Calmette-Guérin (BCG) originally used as a vaccine against tuberculosis, can serve as adjuvants (24). Substances produced by bacteria, such as Detox B, are also frequently used. Biological products derived from nonmicrobial organisms can be used as adjuvants, too. One example is keyhole limpet hemocyanin (KLH), which is a large protein produced by a sea animal. Attaching antigens to KLH has been shown to increase their ability to stimulate immune responses. Even some nonbiological substances, such as an emulsified oil known as montanide ISA–51, can be used as adjuvants.

Natural or synthetic cytokines can also be used as adjuvants. Cytokines are substances that are naturally produced by white blood cells to regulate and fine-tune immune responses. Some cytokines increase the activity of B cells and killer T cells, whereas other cytokines suppress the activities of these cells. Cytokines frequently used in cancer treatment vaccines or given together with them include interleukin 2 (IL2, also known as aldesleukin), interferon alpha (INF–a), and GM–CSF, also known as sargramostim (see Question 8).

 

 

  1. Do cancer vaccines have side effects?

Vaccines intended to prevent or treat cancer appear to have safety profiles comparable to those of traditional vaccines (6). However, the side effects of cancer vaccines can vary among vaccine formulations and from one person to another.

The most commonly reported side effect of cancer vaccines is inflammation at the site of injection, including redness, pain, swelling, warming of the skin, itchiness, and occasionally a rash.

People sometimes experience flu-like symptoms after receiving a cancer vaccine, including fever, chills, weakness, dizziness, nausea or vomiting, muscle ache, fatigue, headache, and occasional breathing difficulties. Blood pressure may also be affected.

Other, more serious health problems have been reported in smaller numbers of people after receiving a cancer vaccine. These problems may or may not have been caused by the vaccine. The reported problems have included asthma, appendicitis, pelvic inflammatory disease, and certain autoimmune diseases, including arthritis and systemic lupus erythematosus.

Vaccines, like any other medication affecting the immune system, can cause adverse effects that may prove life threatening. For example, severe hypersensitivity (allergic) reactions to specific vaccine ingredients have occurred following vaccination. However, such severe reactions are quite rare.

  1. Can cancer treatment vaccines be combined with other types of cancer therapy?

Yes. In many of the clinical trials of cancer treatment vaccines that are now under way, vaccines are being given with other forms of cancer therapy. Therapies that have been combined with cancer treatment vaccines include surgery, chemotherapy, radiation therapy, and some forms of targeted therapy, including therapies that are intended to boost immune system responses against cancer.

Several studies have suggested that cancer treatment vaccines may be most effective when given in combination with other forms of cancer therapy (21, 25). In addition, in some clinical trials, cancer treatment vaccines have appeared to increase the effectiveness of other cancer therapies (21, 25).

Additional evidence suggests that surgical removal of large tumors may enhance the effectiveness of cancer treatment vaccines (25). In patients with extensive disease, the immune system may be overwhelmed by the cancer. Surgical removal of the tumor may make it easier for the body to develop an effective immune response.

Researchers are also designing clinical trials to answer questions such as whether a specific cancer treatment vaccine works best when it is administered before chemotherapy, after chemotherapy, or at the same time as chemotherapy. Answers to such questions may not only provide information about how best to use a specific cancer treatment vaccine but also reveal additional basic principles to guide the future development of combination therapies involving vaccines.

  1. What additional research is under way?

Although researchers have identified many cancer-associated antigens, these molecules vary widely in their capacity to stimulate a strong anticancer immune response. Two major areas of research aimed at developing better cancer treatment vaccines involve the identification of novel cancer-associated antigens that may prove more effective in stimulating immune responses than the already known antigens and the development of methods to enhance the ability of cancer-associated antigens to stimulate the immune system. Research is also under way to determine how to combine multiple antigens within a single cancer treatment vaccine to produce optimal anticancer immune responses (26).

Perhaps the most promising avenue of cancer vaccine research is aimed at better understanding the basic biology underlying how immune system cells and cancer cells interact. New technologies are being created as part of this effort. For example, a new type of imaging technology allows researchers to observe killer T cells and cancer cells interacting inside the body (27).

Researchers are also trying to identify the mechanisms by which cancer cells evade or suppress anticancer immune responses. A better understanding of how cancer cells manipulate the immune system could lead to the development of new drugs that block those processes and thereby improve the effectiveness of cancer treatment vaccines (28). For example, some cancer cells produce chemical signals that attract white blood cells known as regulatory T cells, or Tregs, to a tumor site. Tregs often release cytokines that suppress the activity of nearby killer T cells (21, 29). The combination of a cancer treatment vaccine with a drug that would block the negative effects of one or more of these suppressive cytokines on killer T cells might improve the vaccine’s effectiveness in generating potent killer T cell antitumor responses.

Selected References
  1. Pardoll DM. Cancer immunology. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, editors. Abeloff's Clinical Oncology. 4th ed. Philadelphia: Churchill Livingstone, 2008.
  2. Murphy KM, Travers P, Walport M, editors. Janeway's Immunobiology. 7th ed. New York: Garland Science, 2007.
  3. Waldmann TA. Effective cancer therapy through immunomodulation. Annual Review of Medicine 2006;  57:65–81. [PubMed Abstract]
  4. Emens LA. Cancer vaccines: on the threshold of success. Expert Opinion on Emerging Drugs 2008; 13(2):295–308. [PubMed Abstract]
  5. Sioud M. An overview of the immune system and technical advances in tumor antigen discovery and validation. Methods in Molecular Biology 2007; 360:277–318. [PubMed Abstract]
  6. Pazdur MP, Jones JL. Vaccines: an innovative approach to treating cancer. Journal of Infusion Nursing 2007; 30(3):173–178. [PubMed Abstract]
  7. Lollini PL, Cavallo F, Nanni P, Forni G. Vaccines for tumour prevention. Nature Reviews Cancer 2006; 6(3):204–216. [PubMed Abstract]
  8. Frazer IH, Lowy DR, Schiller JT. Prevention of cancer through immunization: prospects and challenges for the 21st century. European Journal of Immunology 2007; 37(Suppl 1):S148–S155. [PubMed Abstract]
  9. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clinical Science 2006; 110(5):525–541. [PubMed Abstract]
  10. Parkin DM. The global health burden of infection-associated cancers in the year 2002. International Journal of Cancer 2006; 118(12):3030–3044. [PubMed Abstract]
  11. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. Journal of Clinical Investigation 2006; 116(5):1167–1173. [PubMed Abstract]
  12. U.S. Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part 1: immunization of infants, children, and adolescents. Morbidity and Mortality Weekly Report 2005; 54(No. RR–16):1–31. [PubMed Abstract]
  13. Mueller NE. Cancers caused by infections: unequal burdens. Cancer Epidemiology, Biomarkers & Prevention 2003; 12(3):237s. [PubMed Abstract]
  1. International Agency for Research on Cancer (2011). Agents Classified by the IARC Monographs , Volumes 1–100. Retrieved November 15, 2011.
  1. Rivoltini L, Canese P, Huber V, et al. Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: how can we tilt the balance towards immune-mediated cancer control? Expert Opinion on Biological Therapy 2005; 5(4):463–476. [PubMed Abstract]
  2. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nature Medicine 2004; 10(9):909–915. [PubMed Abstract]
  3. Renkvist N, Castelli C, Robbins PF, Parmiani G. A listing of human tumor antigens recognized by T cells. Cancer Immunology and Immunotherapy 2001; 50(1):3–15. [PubMed Abstract]
  4. Parmiani G, Russo V, Marrari A, et al. Universal and stemness-related tumor antigens: potential use in cancer immunotherapy. Clinical Cancer Research 2007; 13(19):5675–5679. [PubMed Abstract]
  5. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New England Journal of Medicine 2010; 363(5):411–422. [PubMed Abstract]
  6. Parmiani G, De Filippo A, Novellino L, Castelli C. Unique human tumor antigens: immunobiology and use in clinical trials. The Journal of Immunology 2007; 178(4):1975–1979. [PubMed Abstract]
  7. Finn OJ. Cancer immunology. The New England Journal of Medicine 2008; 358(25):2704–2715. [PubMed Abstract]
  8. Curigliano G, Spitaleri G, Dettori M, et al. Vaccine immunotherapy in breast cancer treatment: promising, but still early. Expert Review of Anticancer Therapy 2007; 7(9):1225–1241. [PubMed Abstract]
  9. Chiarella P, Massi E, De Robertis M, Signori E, Fazio VM. Adjuvants in vaccines and for immunisation: current trends. Expert Opinion on Biological Therapy 2007; 7(10):1551–1562. [PubMed Abstract]
  10. Herr HW, Morales A. History of Bacillus Calmette-Guérin and bladder cancer: an immunotherapy success story. The Journal of Urology 2008; 179(1):53–56. [PubMed Abstract]
  11. Emens LA. Chemotherapy and tumor immunity: an unexpected collaboration. Frontiers in Bioscience 2008; 13:249–257. [PubMed Abstract]
  12. Schlom J, Arlen PM, Gulley JL. Cancer vaccines: moving beyond current paradigms. Clinical Cancer Research 2007; 13(13):3776–3782. [PubMed Abstract]
  13. Ng LG, Mrass P, Kinjyo I, Reiner SL, Weninger W. Two-photon imaging of effector T-cell behavior: lessons from a tumor model. Immunological Reviews 2008; 221:147–162. [PubMed Abstract]
  14. Garnett CT, Greiner JW, Tsang KY, et al. TRICOM vector based cancer vaccines. Current Pharmaceutical Design 2006; 12(3):351–361. [PubMed Abstract]
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