Saltar para: Posts [1], Pesquisa e Arquivos [2]


Quarta-feira, 19.08.15

Oncolytic virotherapy lends benefits to melanoma patients

Oncolytic virotherapy lends benefits to melanoma patients

Published on August 19, 2015 at 6:12 AM

Recent study published online by Melanoma Research journal indicates that melanoma patients would significantly benefit from prolonging the survival with oncolytic viroherapy treatment (

The study  revealed that the early stage  melanoma patients treated with oncolytic medicine Rigvir were 4 to 6 times more likely to survive than those who following the current guidelines for the treatment of melanoma were only observed.

Oncolytic virotherapy

Melanoma is one of the fastest-growing cancers and has the highest mortality rate of skin cancers. More than half of melanoma patients experience progression of disease within next 3 years after diagnosis. Unfortunately, current clinical practice guidelines for early stage melanoma patients provide few, if any, recommendations for treatment after surgery.

Rigvir is a live nonpathogenic enterovirus, adapted and selected for melanoma that has not been genetically modified. Rigvir has oncotropic and oncolytic properties. Rigvir finds and infects tumour cells, a process called oncotropism. Then, Rigvir replicates in tumour cells and destroys them. This process is called oncolysis.

Both of these processes, oncotropism and oncolysis, are selective for tumour cells and normal healthy cells are minimally, if at all, affected. Moreover, Rigvir demonstrated an outstanding safety profile because there was no record of any untoward side effect from Rigvir treatment or its discontinuation.

Melanoma treatment using oncolytic virus is a cancer treatment option that has been observed for over a century and is presently being studied intensively. The effect of viruses on cancers, including melanoma, has been tested in clinical trials, however the effectivness of an approved and marketed virus has not yet  been shown in a clinical setting.

Rigvir is the first oncolytic virus in the world with anticancer and immunomodulating effects, which is registered for cancer virotherapy and introduced in medical practice. Rigvir was approved in 2004 in Latvia for melanoma therapy and since 2011 is fully reimbursed by government for skin melanoma patients here. Since 2015 Rigvir is included in the national guidelines for the skin cancer and melanoma treatment.


International Virotherapy Center

Autoria e outros dados (tags, etc)

por cyto às 12:10

Quarta-feira, 19.08.15

Unituxin (dinutuximab) granted EC Marketing Authorisation for treatment of childhood neuroblastoma

Unituxin (dinutuximab) granted EC Marketing Authorisation for treatment of childhood neuroblastoma

Published on August 17, 2015 at 7:21 AM ·

United Therapeutics Corporation (NASDAQ: UTHR) announced today that the European Commission (EC) has granted Marketing Authorisation for Unituxin™ (dinutuximab) for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation (ASCT). Unituxin is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence in the European Union of approximately 1500 patients, of whom 50% are diagnosed as having high-risk disease.

The European approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) sponsored by the US National Cancer Institute under a Cooperative Research and Development Agreement with United Therapeutics and conducted by the Children's Oncology Group (COG).

Trial design and results

The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid (RA) arm or the RA alone arm. Patients in each arm received six cycles of treatment. The Unituxin/RA arm consisted of Unituxin in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), Unituxin in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age (median age 3.8 years).

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death. The primary intent-to-treat analysis found an improvement in EFS associated with dinutuximab immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66% among subjects receiving dinutuximab immunotherapy plus isotretinoin as compared with 48% in subjects receiving isotretinoin alone (log-rank test p = 0.033) although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses. In addition, OS was evaluated with 3 years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among ITT subjects randomly allocated to receive dinutuximab immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80% compared with 67% among subjects receiving dinutuximab immunotherapy plus isotretinoin and isotretinoin alone, respectively (log-rank test p = 0.0165). Long-term overall survival was evaluated with five years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received dinutuximab immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74% for dinutuximab immunotherapy compared to 57% for isotretinoin alone (log-rank test p = 0.030).

Frequently occurring adverse reactions

The most frequently occurring (more than 30% of patients) adverse reactions reported during the neuroblastoma studies were hypotension (67%), pain (66%), hypersensitivity (56%), pyrexia (53%), urticaria (49%), capillary leak syndrome (45%), anaemia (45%), hypokalaemia (41%), platelet count decreased (40%), hyponatraemia (37%), alanine aminotransferase increased (35%), decreased lymphocyte count (34%) and decreased neutrophil count (31%). Additional adverse reactions characteristic of an allergic response were also reported – including anaphylactic reaction (18%) and bronchospasm (4%).

Posology and method of administration

Unituxin is to be administered by intravenous infusion over five courses at a daily dose of 17.5 mg/m2. It is administered on days 4-7 during courses 1, 3 and 5 (each course lasting approximately 24 days) and on days 8-11 during courses 2 and 4 (each course lasting approximately 28 days).

The treatment regimen consists of Unituxin, GM-CSF, IL-2, and isotretinoin, administered over six consecutive courses.


United Therapeutics Corporation

Autoria e outros dados (tags, etc)

por cyto às 12:08

Quarta-feira, 19.08.15

Low-fat diets better than low-carb diets for weight loss, NIH study finds

Low-fat diets better than low-carb diets for weight loss, NIH study finds

Published on August 14, 2015 at 7:30 AM ·

In a recent study, restricting dietary fat led to body fat loss at a rate 68 percent higher than cutting the same number of carbohydrate calories when adults with obesity ate strictly controlled diets. Carb restriction lowered production of the fat-regulating hormone insulin and increased fat burning as expected, whereas fat restriction had no observed changes in insulin production or fat burning. The research was conducted at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. Results were published August 13 in Cell Metabolism.

"Compared to the reduced-fat diet, the reduced-carb diet was particularly effective at lowering insulin secretion and increasing fat burning, resulting in significant body fat loss," said Kevin Hall, Ph.D., NIDDK senior investigator and lead study author. "But interestingly, study participants lost even more body fat during the fat-restricted diet, as it resulted in a greater imbalance between the fat eaten and fat burned. These findings counter the theory that body fat loss necessarily requires decreasing insulin, thereby increasing the release of stored fat from fat tissue and increasing the amount of fat burned by the body."

The researchers studied 19 non-diabetic men and women with obesity in the Metabolic Clinical Research Unit at the NIH Clinical Center in Bethesda, Maryland. Participants stayed in the unit 24 hours per day for two extended visits, eating the same food and doing the same activities. For the first five days of each visit they ate a baseline balanced diet. Then for six days, they were fed diets containing 30 percent fewer calories, achieved by cutting either only total carbs or total fat from the baseline diet, while eating the same amount of protein. They switched diets during the second visit.

The researchers had previously simulated the study with a math model of human metabolism, whose body fat predictions matched the data later collected in the study. When simulating what might happen over longer periods, the model predicted relatively small differences in body fat loss with widely varying ratios of carbs to fat. Those results suggest the body may eventually minimize differences in body fat loss when diets have the same number of calories. More research is needed to assess the physiological effects of fat and carb reduction in the long term.

"This NIH study provides invaluable evidence on how different types of calories affect metabolism and body composition," said NIDDK Director Griffin P. Rodgers, M.D. "The more we learn about the complicated topic of weight loss, the better we can find ways to help people manage their health."

More than two-thirds of American adults are overweight or obese. Maintaining a healthy weight can help prevent complications related to overweight and obesity such as heart disease, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death.

"Our data tell us that when it comes to body fat loss, not all diet calories are exactly equal," Hall said. "But the real world is more complicated than a research lab, and if you have obesity and want to lose weight, it may be more important to consider which type of diet you'll be most likely to stick to over time."


NIH/National Institute of Diabetes and Digestive and Kidney Diseases


Autoria e outros dados (tags, etc)

por cyto às 11:47

Quarta-feira, 19.08.15

ImmunoCellular signs agreement with FDA for phase 3 registrational trial of cancer immunotherapy ICT-107


ImmunoCellular signs agreement with FDA for phase 3 registrational trial of cancer immunotherapy ICT-107

Published on August 13, 2015 at 8:32 AM ·

ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) announced today that it has reached agreement with the US Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) for the phase 3 registrational trial of its cancer immunotherapy ICT-107 to treat patients with newly diagnosed glioblastoma.

The phase 3 trial is designed as a randomized, double-blind, placebo-controlled study of about 400 HLA-A2 positive subjects, which will be conducted at about 120 sites in the US, Canada and the EU. The primary endpoint in the trial is overall survival, which the FDA and EU regulators have stated is the appropriate endpoint for registrational clinical studies in glioblastoma. Secondary endpoints include progression-free survival and safety, as well as overall survival in the two pre-specified MGMT subgroups. Patient enrollment is anticipated to begin in the late third quarter or early fourth quarter of 2015.

A Special Protocol Assessment is a written agreement between the sponsor company and the FDA on the design, clinical endpoints, size and statistical design of a clinical trial intended to form the primary basis of an efficacy claim in the marketing application, such as a biologic licensing application (BLA) or a new drug application (NDA). Final marketing approval depends upon the safety and efficacy results demonstrated in the phase 3 clinical program.

Andrew Gengos, ImmunoCellular's Chief Executive Officer Commented: "We are pleased to have achieved this important milestone, and think that successful completion of the SPA process adds meaningful validation to the ICT-107 phase 3 program and design, especially the use of the gold standard primary endpoint of overall survival. With this SPA in place, we think that ICT-107 is uniquely positioned in the field of immuno-oncology approaches being tested in glioblastoma. We are making significant progress toward establishing our clinical site network and obtaining the necessary institutional review board approvals. We are confident that we are on track to begin patient enrollment in the late third quarter or early fourth quarter of this year."


ImmunoCellular Therapeutics, Ltd.

Autoria e outros dados (tags, etc)

por cyto às 11:37

Quinta-feira, 23.07.15

Dartmouth researchers perform first total syntheses of compounds involved in rapid cell death in leukemia


Dartmouth researchers perform first total syntheses of compounds involved in rapid cell death in leukemia

Published on July 22, 2015 at 5:18 AM 

Dartmouth researchers and their colleagues have carried out the first total syntheses of certain compounds involved in excessive cell death in leukemia.

The findings appear in the journal Angewandte Chemie International Edition. A PDF is available on request.

"We anticipate that these compounds will serve as useful tools for dissecting an important but as yet undefined step in the regulation of apoptosis," says senior author Jimmy Wu, an associate professor of chemistry at Dartmouth. "Studies to clarify the biological mechanism by which they operate are ongoing."

The researchers completed the total syntheses of several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily. These are structurally complex molecules that are capable of including apoptosis, or programmed cell death, in certain human leukemia cell lines faster than any other small molecule. The researchers also were able to synthesize some related structures that they predict might exist in nature but have not yet been found.

There have been only two reports that attempt to explain the biological mechanism of action of these molecules. But these are incomplete and more research is required to fully reveal how these compounds work. The Dartmouth-led team's synthetic efforts now provide a means to a steady supply of the active compounds for further study. Preliminary biological tests conducted by co-author Alan Eastman, a professor of pharmacology and toxicology at Dartmouth's Geisel School of Medicine, indicate that all the compounds, both naturally occurring and ones predicted to be exist in nature, are capable of inducing extremely rapid apoptosis in leukemia cells. The researchers are in the process of studying their biological mechanism of action.

"Insufficient apoptosis is strongly linked to cancer and autoimmune disorders," Wu says. "There are also numerous diseases associated with excessive cell death, such as AIDS, Alzheimer's, Huntington's, Parkingson's and ALS. A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics and other diseases attributed to abnormal apoptosis."


Dartmouth College

Autoria e outros dados (tags, etc)

por cyto às 22:57

Quinta-feira, 23.07.15

Researchers find easy way to produce carbon nanoparticles that can carry drugs to targeted tissues


Researchers find easy way to produce carbon nanoparticles that can carry drugs to targeted tissues

Published on June 19, 2015 at 3:57 AM ·

Researchers have found an easy way to produce carbon nanoparticles that are small enough to evade the body's immune system, reflect light in the near-infrared range for easy detection, and carry payloads of pharmaceutical drugs to targeted tissues.

Unlike other methods of making carbon nanoparticles - which require expensive equipment and purification processes that can take days - the new approach generates the particles in a few hours and uses only a handful of ingredients, including store-bought molasses.

The researchers, led by University of Illinois bioengineering professors Dipanjan Pan and Rohit Bhargava, report their findings in the journal Small.

"If you have a microwave and honey or molasses, you can pretty much make these particles at home," Pan said. "You just mix them together and cook it for a few minutes, and you get something that looks like char, but that is nanoparticles with high luminescence. This is one of the simplest systems that we can think of. It is safe and highly scalable for eventual clinical use."

These "next-generation" carbon spheres have several attractive properties, the researchers found. They naturally scatter light in a manner that makes them easy to differentiate from human tissues, eliminating the need for added dyes or fluorescing molecules to help detect them in the body.

The nanoparticles are coated with polymers that fine-tune their optical properties and their rate of degradation in the body. The polymers can be loaded with drugs that are gradually released.

The nanoparticles also can be made quite small, less than eight nanometers in diameter (a human hair is 80,000 to 100,000 nanometers thick).

"Our immune system fails to recognize anything under 10 nanometers," Pan said. "So, these tiny particles are kind of camouflaged, I would say; they are hiding from the human immune system."

The team tested the therapeutic potential of the nanoparticles by loading them with an anti-melanoma drug and mixing them in a topical solution that was applied to pig skin.

Bhargava's laboratory used vibrational spectroscopic techniques to identify the molecular structure of the nanoparticles and their cargo.

"Raman and infrared spectroscopy are the two tools that one uses to see molecular structure," Bhargava said. "We think we coated this particle with a specific polymer and with specific drug-loading - but did we really? We use spectroscopy to confirm the formulation as well as visualize the delivery of the particles and drug molecules."

The team found that the nanoparticles did not release the drug payload at room temperature, but at body temperature began to release the anti-cancer drug. The researchers also determined which topical applications penetrated the skin to a desired depth.

In further experiments, the researchers found they could alter the infusion of the particles into melanoma cells by adjusting the polymer coatings. Imaging confirmed that the infused cells began to swell, a sign of impending cell death.

"This is a versatile platform to carry a multitude of drugs - for melanoma, for other kinds of cancers and for other diseases," Bhargava said. "You can coat it with different polymers to give it a different optical response. You can load it with two drugs, or three, or four, so you can do multidrug therapy with the same particles."

"By using defined surface chemistry, we can change the properties of these particles," Pan said. "We can make them glow at a certain wavelength and also we can tune them to release the drugs in the presence of the cellular environment. That is, I think, the beauty of the work."


University of Illinois at Urbana-Champaign

Autoria e outros dados (tags, etc)

por cyto às 22:55

Quinta-feira, 23.07.15

Magnetic nanoparticles may hold key to bringing immunotherapy into successful clinical use


Magnetic nanoparticles may hold key to bringing immunotherapy into successful clinical use

Published on July 16, 2015 at 1:54 AM

In recent years, researchers have hotly pursued immunotherapy, a promising form of treatment that relies on harnessing and training the body's own immune system to better fight cancer and infection. Now, results of a study led by Johns Hopkins investigators suggests that a device composed of a magnetic column paired with custom-made magnetic nanoparticles may hold a key to bringing immunotherapy into widespread and successful clinical use. A summary of the research, conducted in mouse and human cells, appears online July 14 in the journal ACS Nano.

The Johns Hopkins team focused on training and rapidly multiplying immune system white blood cells known as T cells because of their potential as an effective weapon against cancer, according to Jonathan Schneck, M.D., Ph.D., a professor of pathology, medicine and oncology at the Johns Hopkins University School of Medicine's Institute for Cell Engineering. "The challenge has been to train these cells efficiently enough, and get them to divide fast enough, that we could use them as the basis of a therapy for cancer patients. We've taken a big step toward solving that problem," he says.

In a bid to simplify and streamline immune cellular therapies, Schneck, Karlo Perica, a recent M.D./Ph.D. graduate who worked in Schneck's lab, and others worked with artificial white blood cells. These so-called artificial antigen-presenting cells (aAPCs) were pioneered by Schneck's lab and have shown promise in activating laboratory animals' immune systems to attack cancer cells.

To do that, Perica explains, the aAPCs must interact with naive T cells already present in the body, awaiting instructions about which specific invader to target and battle. The aAPCs bind to specialized receptors on the T cells' surfaces and "present" them with distinctive proteins called antigens. This process activates the T cells to ward off a virus, bacteria or tumor, as well as to make more T cells.

In a previous study in mice, Schneck's team found that naive T-cells activated more effectively when multiple aAPCs bound to different receptors on the cells, and then were exposed to a magnetic field. The magnets brought the aAPCs and their receptors closer together, priming the T cells both to battle the target cancer and divide to form more activated cells.

But naive T cells are as rare in the blood as a "needle in a haystack," Perica says. Because the ultimate goal is to harvest a patient's T cells from a blood sample, then train them and expand their numbers before putting them back into the patient, Schneck's research team looked to magnets as a potential way to separate the naive T cells from others in the blood.

The team mixed blood plasma from mice and, separately, humans with magnetic aAPCs bearing antigens from tumors. They then ran the plasma through a magnetic column. The tumor-fighting T cells bound to aAPCs and stuck to the sides of the column, while other cells washed straight through and were discarded. The magnetic field of the column activated the T cells, which were then washed off into a nourishing broth, or culture, to grow and divide. After one week, their numbers had expanded by an estimated 5,000 to 10,000 times. Because numbers of these cells could be expanded quickly enough to be therapeutically useful, the approach could open the door to individualized immunotherapy treatments that rely on a patient's own cells, says Perica.

Schneck says that the use of naive T cells could make the new technique useful for more patients than another immunotherapy now being tested, which relies on other white blood cells called tumor-infiltrating lymphocytes. Those cells are already "trained" to fight cancer, and researchers have shown some success isolating some of the cells from tumors, inducing them to divide, and then transferring them back into patients. But, Schneck says, not all patients are eligible for this therapy, because not all have tumor-infiltrating lymphocytes. By contrast, all people have naive T cells, so patients with cancer could potentially benefit from the new approach whether or not they have tumor-infiltrating lymphocytes.

"The aAPCs and magnetic column together provide the foundation for simplifying and streamlining the process of generating tumor-specific T cells for use in immunotherapy," says Juan Carlos Varela, M.D., Ph.D., a former member of Schneck's laboratory who is now an assistant professor at the Medical University of South Carolina.

The researchers found that the technique also worked with a mixture of aAPCs bearing multiple antigens, which they say could help combat the problem of tumors mutating to evade the body's defenses. "We get multiple shots on the goal," Schneck says.

While the team initially tested the new method only on cancer antigens, Schneck says it could also potentially work for therapies against chronic infectious diseases, such as HIV. He says that if further testing goes well, clinical trials of the technique could begin within a year and a half.


Johns Hopkins Medicine

Autoria e outros dados (tags, etc)

por cyto às 22:49

Quinta-feira, 23.07.15

New UW-Madison study links two unrelated cancer treatments


New UW-Madison study links two unrelated cancer treatments

Published on July 14, 2015 at 5:10 AM 

A new study at the University of Wisconsin-Madison has linked two seemingly unrelated cancer treatments that are both now being tested in clinical trials.

One treatment is a vaccine that targets a structure on the outside of cancer cells, while the other is an altered enzyme that breaks apart RNA and causes the cell to commit suicide. The study was published July 13 in the new journal of the American Chemical Society: ACS Central Science.

The new understanding could help both approaches, says UW-Madison professor of biochemistry Ronald Raines, who has long studied ribonucleases -- enzymes that break apart RNA, a messenger with multiple roles inside the cell. In 1998, he discovered how to alter one ribonuclease to avoid its deactivation in the body. Soon thereafter, he found that the engineered ribonuclease was more toxic to cancer cells than to others.

Raines patented the advance through the Wisconsin Alumni Research Foundation and with UW-Madison chemist Laura Kiessling cofounded Quintessence Biosciences in Madison. They remain shareholders in the firm, which has licensed the patent from WARF and begun early-phase human trials with the ribonuclease at the UW Carbone Cancer Center and MD Anderson Cancer Center in Houston.

The current study began as an effort to figure out why the ribonuclease was selective for cancer cells. To identify which structure on the cell surface helped it enter the cell, Raines screened 264 structures using a specially designed chip. The winner was a carbohydrate called Globo H.

"We were surprised -- delighted -- to see that because we already knew that Globo H is an antigen that is abundant in many tumors," Raines says. Antigens are complex molecules with structures that are recognizable to proteins called antibodies. "Globo H is under development as the basis for a vaccine that will teach the immune system to recognize and kill cancer cells," he says.

Working with Samuel Danishefsky, who solved the difficult problem of synthesizing Globo H at the Memorial Sloan-Kettering Cancer Center in New York, Raines found that reducing the Globo H display on the surface made breast cancer cells less vulnerable to ribonucleases like those that Quintessence is testing. "This was exciting, as we now have a much clearer idea of how our drug candidate is working."

Biochemistry Professor John Markley aided the research with studies of the structure of the molecules in question.

The picture that emerges from the work is of ribonucleases patrolling our bodies, looking for telltales of cancer cells, Raines says. "We are working to demonstrate this surveillance more clearly in mice, but don't have direct evidence yet."

As other scientists test whether using a vaccine will start an immune attack on Globo H, Raines says, "we are probing a different type of immunity. This innate immunity does not involve the immune system. It's a way for our bodies to fight cancer without using white blood cells or antibodies, just an enzyme and a carbohydrate."


University of Wisconsin-Madison

Autoria e outros dados (tags, etc)

por cyto às 22:46

Terça-feira, 21.07.15

Postoperative Radiation Therapy for Endometrial Cancer


Postoperative Radiation Therapy for Endometrial Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline

  1. Larissa A. Meyer,
  2. Kari Bohlke,
  3. Matthew A. Powell,
  4. Amanda N. Fader,
  5. Gregg E. Franklin,
  6. Larissa J. Lee,
  7. Daniela Matei,
  8. Lourie Coallier and
  9. Alexi A. Wright

+Author Affiliations

  1. Larissa A. Meyer, University of Texas MD Anderson Cancer Center, Houston, TX; Kari Bohlke, American Society of Clinical Oncology, Alexandria, VA; Matthew A. Powell, Washington University School of Medicine, St Louis, MO; Amanda N. Fader, Kelly Gynecologic Oncology Service, Johns Hopkins Hospital, Baltimore, MD; Gregg E. Franklin, New Mexico Cancer Center, Albuquerque, NM; Larissa J. Lee, Brigham and Women's Hospital, Dana-Farber Cancer Institute; Alexi A. Wright, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA; Daniela Matei, Indiana University School of Medicine, Indianapolis, IN; and Lourie Coallier, patient representative, Stanford, CA.
  1. Corresponding author: American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; e-mail:


Purpose To provide guidance on the role of adjuvant radiation therapy in the treatment of endometrial cancer.

Methods “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 in Practical Radiation Oncology, was reviewed for developmental rigor by methodologists. The American Society for Radiation Oncology (ASTRO) guideline content and recommendations were further reviewed by the American Society of Clinical Oncology (ASCO) Endorsement Panel.

Results The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline are clear, thorough, and based on the most relevant scientific evidence. ASCO endorsed the ASTRO guideline with several qualifying statements.

Recommendations Surveillance without adjuvant radiation therapy is a reasonable option for women without residual disease in the hysterectomy specimen and for women with grade 1 or 2 cancer and < 50% myometrial invasion, especially when no other high-risk features are present. For women with grade 1 or 2 cancer and ≥ 50% myometrial invasion or grade 3 cancer and < 50% myometrial invasion, vaginal brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence and is preferred. Patients with grade 3 cancer and ≥ 50% myometrial invasion or cervical stroma invasion may benefit from pelvic radiation to prevent pelvic recurrence. For women with high-risk early-stage disease and advanced disease, the ASCO Endorsement Panel added qualifying statements to the ASTRO recommendations to provide stronger statements in favor of chemotherapy (with or without radiation therapy).


Endometrial cancer is the most common gynecologic cancer among women in the United States, with roughly 54,000 new cases expected in 2015.1 Worldwide, endometrial cancer is the second most common gynecologic cancer (after cervical cancer) and the sixth most common cancer overall among women.2

Surgery is the primary treatment for endometrial cancer, and many women with early-stage endometrial cancer and a low risk of cancer recurrence require no additional treatment.3,4 Adjuvant treatment for women with an intermediate or high risk of recurrence continues to evolve, and options include radiation therapy, chemotherapy, or a combination of these modalities. To provide guidance on the use of postoperative radiation therapy for endometrial cancer, the American Society for Radiation Oncology (ASTRO) published evidence-based recommendations inPractical Radiation Oncology in 2014.5

The purpose of this American Society of Clinical Oncology (ASCO) guideline is to critically appraise and endorse the ASTRO guideline on postoperative radiation therapy for endometrial cancer. This endorsement reinforces the recommendations provided in the ASTRO guideline and acknowledges the effort put forth by ASTRO to produce an evidence-based guideline informing practitioners who care for women with endometrial cancer. The ASTRO recommendations are listed in the Bottom Line Box, with qualifying statements from the ASCO Endorsement Panel. The full ASTRO guideline is available at, with supplemental material available at


The American Society of Clinical Oncology (ASCO) endorses “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline,” With Qualifying Statements

Guideline Questions

After surgery for endometrioid endometrial cancer, which women require no additional therapy? Which women should receive vaginal cuff brachytherapy, external-beam radiation therapy, or multimodality treatment?

Target Population
  • Women who have had surgery for endometrial cancer

Target Audience
  • Medical oncologists, gynecologic oncologists, radiation oncologists, and surgical oncologists


An ASCO Endorsement Panel was convened to consider endorsing “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline.” The American Society for Radiation Oncology (ASTRO) guideline was based on a systematic review of the medical literature. The ASCO Endorsement Panel considered the methodology employed in the ASTRO guideline and carefully reviewed the ASTRO guideline content to determine appropriateness for ASCO endorsement.


ASTRO recommendations are listed here, with qualifying statements added by the ASCO panel listed in bold italics.*

Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy?

  • Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients without residual disease in the hysterectomy specimen, despite positive biopsy (despite a positive prehysterectomy biopsy of any grade).

  • Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients with grade 1 or 2 cancers with either no invasion or < 50% myometrial invasion.

  • Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 3 tumor without myometrial invasion.

  • Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 1 or 2 tumors with < 50% myometrial invasion and higher-risk features, such as age > 60 and/or LVSI [lymphovascular space invasion].

Which patients with endometrioid endometrial cancer should receive vaginal cuff irradiation?

  • Vaginal cuff brachytherapy is as effective as pelvic radiation at preventing vaginal recurrence for patients with: (1) grade 1 or 2 tumors with 50% myometrial invasion or (2) grade 3 tumors with < 50% myometrial invasion.

  • Vaginal cuff brachytherapy is preferred to pelvic radiation in patients with the above risk factors, particularly in patients who have had comprehensive nodal assessment.

Which women should receive postoperative external beam radiation?

  • Patients with grade 3 cancer with ≥ 50% myometrial invasion or cervical stroma invasion (of any grade; personal communication, A. Klopp, February 2015) may benefit from pelvic radiation to reduce the risk of pelvic recurrence.

  • Patients with grade 1 or 2 tumors with ≥ 50% myometrial invasion may also benefit from pelvic radiation to reduce pelvic recurrence if other risk factors are present, such as age > 60 years and/or LVSI.Vaginal brachytherapy may be a better option for patients with these features, especially if surgical staging was adequate, and nodes were negative.

  • The best available evidence at this time suggests that reasonable options for adjuvant treatment of patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum include external beam radiation therapy, as well as adjuvant chemotherapy. The best evidence for this population supports the use of chemotherapy, but consideration of external beam radiation therapy is reasonable.

  • Chemotherapy without external beam radiation may be considered for some patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence.

  • Radiation therapy without chemotherapy may be considered for some patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence. Patients receiving chemotherapy seem to have improved survival compared with radiation therapy alone.

When should brachytherapy be used in addition to external beam radiation?

  • Prospective data are lacking to validate the use of vaginal brachytherapy after pelvic radiation, and most retrospective studies show no evidence of a benefit, albeit with small patient numbers. Use of vaginal brachytherapy in patients also undergoing pelvic external beam radiation is not generally warranted, unless risk factors for vaginal recurrence are present.

How should radiation therapy and chemotherapy be integrated in the management of stage I to III endometrioid endometrial cancer?

  • The best available evidence suggests that concurrent chemoradiation followed by adjuvant chemotherapy is indicated for patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum. Evidence regarding concurrent chemoradiation is limited at this time, and this recommendation is based on expert opinion; we anticipate level-one evidence from upcoming prospective randomized clinical trials (GOG 0258 and PORTEC-3). Chemotherapy may also be considered in certain patients with high-risk early-stage endometrial cancer, and clinical trials addressing this question are under way.

  • Alternative sequencing strategies with external beam radiation and chemotherapy are also acceptable. Prospective trials have examined sequential radiation therapy and chemotherapy. Evidence supporting sandwich-type therapy is currentlylimited.

Additional Resources

More information, including a Methodology Supplement, is available Patient information is available Full text of “The Role of Postoperative Radiation Therapy for Endometrial Cancer: Executive Summary of an American Society for Radiation Oncology Evidence-Based Guideline” is available, with supplemental material available These publications include information about the strength of each recommendation and the quality of the evidence.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate.

* Recommendations reprinted from Klopp A et al, Practical Radiation Oncology, 4:137-144, 2014, with permission from Elsevier.


ASCO has policies and procedures for endorsing practice guidelines that have been developed by other professional organizations. The goal of guideline endorsement is to increase the number of high-quality, ASCO-vetted guidelines available to the ASCO membership. The ASCO endorsement process involves an assessment by ASCO staff of candidate guidelines for methodologic quality using the Rigour of Development subscale of the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. (Methodology Supplement provides more detail.)


The clinical practice guideline and other guidance published herein are provided by ASCO to assist providers in clinical decision making. The information herein should not be relied on as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified herein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Furthermore, the information is not intended to substitute for the independent professional judgment of the treating provider, because the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like “must,” “must not,” “should,” and “should not” indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an as-is basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.

Guideline and Conflicts of Interest

The ASCO Endorsement Panel (Appendix Table A1, online only) was assembled in accordance with the ASCO Conflicts of Interest Management Procedures for Clinical Practice Guidelines (summarized at Members of the panel completed the ASCO disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include Employment; Leadership; Stock or Other Ownership; Honoraria, Consulting or Advisory Role; Speaker's Bureau; Research Funding; Patents, Royalties, Other Intellectual Property; Expert Testimony; Travel, Accommodations, Expenses; and Other Relationships. In accordance with these procedures, the majority of the members of the panel did not disclose any such relationships.


The ASTRO guideline addressed five key questions: (1) Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy? (2) Which patients with endometrioid endometrial cancer should receive vaginal cuff radiation? (3) Which women with early-stage endometrial cancer should receive postoperative external beam radiation therapy (EBRT), and which women with stage III to IVA endometrial cancer should receive postoperative EBRT? (4) When should brachytherapy be used in addition to EBRT? (5) How should radiation therapy and chemotherapy be integrated in the management of endometrial cancer? The clinical questions and corresponding recommendations are provided in the Bottom Line Box.

The target population for the ASTRO guideline is women with stage I to IV endometrial cancer of any histologic grade.


The ASTRO guideline was developed by an expert panel that included radiation oncologists, gynecologic oncologists, and radiation physicists in both academic and private practice settings. The literature search of MEDLINE PubMed, EMBASE, and the Specialized Register of the Cochrane Gynaecological Cancer Review Group spanned the period from 1980 through 2011. Details of the search strategies and the study inclusion criteria and outcomes of interest are available The search identified 330 studies that were fully extracted to provide supportive evidence for the guideline recommendations.

Guideline statements were developed based on the body of evidence categorized by the American College of Physicians strength-of-evidence rating. The level of consensus among the panelists was evaluated using a modified Delphi approach. An initial draft of the guideline was reviewed by three expert reviewers, and a revised draft was made available for public comment.


The methodology review of the ASTRO guideline was completed independently by two ASCO guideline staff members using the Rigour of Development subscale from the AGREE II instrument. Detailed results of the scoring for this guideline are available in the Methodology Supplement. Overall, the ASTRO guideline scored 68%. Scores were generally high, with the exception of those for procedures for updating. The preliminary ASCO content reviewers of the ASTRO guideline, as well as the ASCO Endorsement Panel, found the recommendations well supported in the original guideline. Each section was clear and well referenced from the systematic review.

This is the most recent information as of the publication date. For updates, the most recent information, and to submit new evidence, please and the ASCO Guidelines Wiki (


ASCO guidelines staff conducted an updated literature search. MEDLINE was searched for entries dating from September 1, 2011, to September 10, 2014 (inclusive). The search was restricted to articles published in English and to systematic reviews, meta-analyses, and randomized controlled trials.

The updated search yielded 68 records. A review of these results by the ASCO Endorsement Panel revealed no new evidence that would warrant substantive modification of the ASTRO recommendations. To help inform the discussion and qualifying statements, eight publications from the ASTRO systematic review,613 four publications from the updated literature search,1417 and two additional publications identified by the ASCO Endorsement Panel and reviewers18,19 are discussed.


The ASCO Endorsement Panel reviewed the ASTRO guideline and concurs that the recommendations are clear, thorough, based on the most relevant scientific evidence in this content area, and present options that will be acceptable to patients. Overall, the ASCO Endorsement Panel agrees with the recommendations as stated in the guideline, with several qualifications discussed in the next section.


The ASCO Endorsement Panel emphasized a few points regarding postoperative therapy for endometrial cancer:

Lack of a survival benefit with EBRT in early-stage disease.

In a 2012 Cochrane review of adjuvant radiotherapy for stage I endometrial cancer, EBRT reduced the risk of locoregional recurrence (hazard ratio [HR], 0.36; 95% CI, 0.25 to 0.52) but did not have a statistically significant effect on overall survival (HR, 0.99; 95% CI, 0.82 to 1.20) or endometrial cancer–specific survival (HR, 0.96; 95% CI, 0.72 to 1.28).16 The lack of a survival benefit was observed among women in each risk group (low, intermediate, or high). Although the possibility of a benefit among high-risk women could not be excluded, EBRT increased morbidity and reduced quality of life.

Choosing vaginal brachytherapy over EBRT in high-intermediate-risk disease for locoregional control.

The preference of the ASCO Endorsement Panel for vaginal brachytherapy over EBRT for patients with endometrioid histology, grade 1 or 2 tumors, and ≥ 50% myometrial invasion was based primarily on results from the GOG-99 (Gynecologic Oncology Group), PORTEC-1 (Post Operative Radiation Therapy in Endometrial Carcinoma), and PORTEC-2 trials. In GOG-99, EBRT reduced the risk of locoregional recurrence, particularly among women with high-intermediate-risk disease.8 In women randomly assigned to no additional therapy, a majority of the locoregional recurrences occurred in the vagina. EBRT also reduced the risk of locoregional recurrence in the PORTEC-1 trial, but it increased the risk of treatment-related toxicities, including bowel and bladder complications.6,18 The PORTEC-2 trial built on these findings by comparing EBRT with vaginal brachytherapy among women with high-intermediate-risk disease. The two approaches resulted in similar rates of disease-free and overall survival, but vaginal brachytherapy was associated with lower rates of acute GI toxicity.11 The risk of second malignancy after adjuvant radiation therapy was not significantly increased in the PORTEC patient population,14,19although higher rates of secondary cancers have been reported in younger women with longer follow-up.17

Chemotherapy in women with high-risk early-stage or advanced disease.

The ASCO Endorsement Panel emphasized the potential benefits of chemotherapy for women with high-risk early-stage or advanced disease. The GOG-122 trial compared whole-abdominal radiation therapy with doxorubicin and cisplatin chemotherapy in women with stage III or IV endometrial cancer and ≤ 2 cm of postoperative residual disease. Stage-adjusted results suggested that chemotherapy was associated with higher progression-free and overall survival, but also higher rates of acute toxicity.12 In the JGOG 2033 (Japanese Gynecologic Oncology Group) trial, women with stage IC to IIIC endometrial cancer were randomly assigned to pelvic radiotherapy or cyclophosphamide, doxorubicin, and cisplatin chemotherapy. The overall results demonstrated no statistically significant difference between study arms in progression-free or overall survival, suggesting that either treatment approach is reasonable.13 However, in a higher-risk subgroup, defined as either patients age > 70 years with stage IC or grade 3 endometrioid cancer or patients with stage II to IIIA (positive cytology) disease with > 50% myometrial invasion, there was an improvement in overall survival associated with chemotherapy (89.7% v 73.6%; P = .006). In another trial of women with high-risk endometrial cancer by Maggi et al,10no statistically significant differences in outcome among women treated with external radiotherapy or cisplatin, doxorubicin, and cyclophosphamide chemotherapy were reported. However, in a pooled analysis of GOG-122 and the Maggi et al trial, chemotherapy resulted in better overall and progression-free survival than radiotherapy among women with stage III or IV disease (overall survival: HR, 0.75; 95% CI, 0.57 to 0.99; progression-free survival: HR, 0.74; 95% CI, 0.59 to 0.92).15

The effect of adding chemotherapy to radiotherapy was evaluated in a pooled analysis of two randomized trials. Among women with stage I to III endometrial cancer and high-risk features, sequential adjuvant chemotherapy and radiotherapy resulted in better progression-free survival than radiotherapy alone (HR, 0.63; 95% CI, 0.44 to 0.89).7 However, the addition of chemotherapy did not improve progression-free or overall survival in another trial of sequential therapy versus radiotherapy.9

Women with early-stage high-risk disease, including those with deep myometrial invasion and grade 3 tumors, were excluded from the PORTEC trials and under-represented in GOG-99 and the other studies discussed. Given the high rate of distant metastasis in this setting, the role of chemotherapy is being evaluated for patients with early-stage high-risk disease in the GOG-0249 and PORTEC-3 trials. Combinations of chemotherapy and radiation therapy are also being evaluated for patients with advanced-stage disease in the GOG-0258 trial, as well as in the PORTEC-3 study.

The importance of clinical trials.

Given the questions that remain about the optimal postoperative treatment of endometrial cancer, particularly for women with high-risk disease, participation in clinical trials must be encouraged.

Consideration of fertility and quality of life.

When considering the postoperative treatment options available to women with endometrial cancer, discussions with patients must include the impact of treatment options on both short- and longer-term quality of life. Furthermore, management of premenopausal women with endometrial cancer should include a discussion of the effect of treatment on fertility and options available for preservation of ovarian function. ASCO recommendations regarding fertility preservation in patients with cancer are available at


ASCO endorses “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 inPractical Radiation Oncology, with qualifying statements.


Disclosures provided by the authors are available with this article at


Manuscript writing: All authors

Final approval of manuscript: All authors


Postoperative Radiation Therapy for Endometrial Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to

Larissa A. Meyer

Travel, Accommodations, Expenses: AstraZeneca

Kari Bohlke

No relationship to disclose

Matthew A. Powell

Honoraria: Roche/Genetech

Consulting or Advisory Role: Roche/Genentech, Arno Therapeutics, Eisai

Speakers' Bureau: Genentech/Roche

Amanda N. Fader

Speakers' Bureau: Ethicon Endosurgery

Travel, Accommodations, Expenses: Intuitive Surgical

Gregg E. Franklin

Employment: New Mexico Cancer Center

Stock or Other Ownership: New Mexico Cancer Center, RainTree

Consulting or Advisory Role: Varian Medical Systems

Speakers' Bureau: Bayer Healthcare

Larissa J. Lee

Travel, Accommodations, Expenses: Intuitive Surgical (I)

Daniela Matei

Honoraria: AstraZenecca

Consulting or Advisory Role: AstraZeneca

Travel, Accommodations, Expenses: AstraZeneca

Lourie Coallier

No relationship to disclose

Alexi A. Wright

No relationship to disclose


We thank Gunter von Minckwitz, Jeffrey M. Clarke, and the Clinical Practice Guidelines Committee for their thoughtful reviews and insightful comments on this guideline endorsement.


Table A1.

Endorsement Panel Members



  • Clinical Practice Guideline Committee approval: January 30, 2015.

  • Editor's note: This American Society of Clinical Oncology (ASCO) clinical practice guideline endorsement provides recommendations based on the review and analyses of the relevant literature in “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 in Practical Radiation Oncology. Additional information, which may include a Methodology Supplement, Data Supplements, slide sets, patient versions, frequently asked questions, and other clinical tools and resources, is available at

  • Authors' disclosures of potential conflicts of interest are found in the article online at Author contributions are found at the end of this article.


Autoria e outros dados (tags, etc)

por cyto às 18:51

Terça-feira, 21.07.15

Scientists elucidate which mechanisms block natural killer cells and how this could be lifted


Scientists elucidate which mechanisms block natural killer cells and how this could be lifted

Published on July 8, 2015 at 12:00 PM 

Natural killer cells of the immune system can fend off malignant lymphoma cells and thus are considered a promising therapeutic approach. However, in the direct vicinity of the tumor they lose their effect. Scientists of Helmholtz Zentrum München have now elucidated which mechanisms block the natural killer cells and how this blockade could be lifted. The results were recently published in the European Journal of Immunology.

Natural killer cells (NK cells) are part of the immune system and provide an innate immunity against exogenous and altered endogenous structures. This also appears to apply to tumor cells, against which the body could develop immunity as it does against pathogens, e.g. against viruses. Tumors of the lymph nodes, called lymphomas, are malignant neoplasms that originate from the B cells or T cells of the lymphatic system. B cell lymphomas are very difficult to treat - which is why innovative approaches to therapy are needed. Earlier studies have shown that NK cells have the potential to attack B lymphoma cells and are therefore considered a possible approach to new treatment strategies. In the living organism, however, tumor control by NK cells has been found to be clearly limited.

NK cells become functionally impaired in the tumor microenvironment

In their experiments, the team led by Prof. Dr. Ralph Mocikat of the Institute of Molecular Immunology (IMI) at Helmholtz Zentrum München, found that the NK cells in the immediate vicinity of the tumor showed reduced function. If the cells were placed in a normal environment, their function could be restored within a few hours. This suggests that the factors responsible for the inactivation of the NK cells derive from the tumor itself.

An inflammatory cytokine inactivates NK cells - altered surface molecules block immune activation

The scientists engaged in the research project identified two important tumor-specific factors that are associated with impaired NK cell function. First, a specific inflammatory cytokine (IL-10) is indirectly involved in the inactivation of NK cells. Second, the tumor cells develop protective mechanisms against the NK cells. Thus, the research group showed that specific surface molecules of the tumor cells (NKG2D ligands) which NK cells could bind are down-regulated. Consequently, the NK cells lack an important activation mechanism and are no longer able to carry out cytotoxic activity. Despite the inhibitory strategies of the tumor cells, at an early stage the NK cells produce the cytokine interferon-gamma (IFN-γ), the scientists reported. IFN-γ is essential to activate further immune responses that support the fight against the tumor.

Immunotherapy possible using NK cells - with optimization potential

"Our results show that the transfer of NK cells is a possible strategic option to treat B cell lymphoma. According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity," said study leader Mocikat.


Helmholtz Zentrum München - German Research Center for Environmental Health

Autoria e outros dados (tags, etc)

por cyto às 18:20

Mais sobre mim

foto do autor

Subscrever por e-mail

A subscrição é anónima e gera, no máximo, um e-mail por dia.


Pesquisar no Blog  


Fevereiro 2016