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Quinta-feira, 13.08.15

A Decade of Dramatic Change in the Treatment of Prostate Cancer

A Decade of Dramatic Change in the Treatment of Prostate Cancer

Major treatment strategies have been approved over the past decade, dramatically increasing survival rates and changing the treatment paradigm for prostate cancer. Greater improvements are expected within the next decade through precision medicine.

In 2005, there were only a handful of approved medications. However, today there are many more and they work by several different mechanisms, allowing them to extend life in novel ways.

In 2005, the relative 10-year survival rate for prostate cancer was 92% and the relative 15-year survival rate was 61%, according to the American Cancer Society.1

Today, the numbers are significantly higher: the relative 5-year survival rate for all stages of prostate cancer is almost 100%, the relative 10-year survival rate is 99%, and the 15-year relative survival rate is 94%.2

“The greatest advances in the management of prostate cancer in the last decade have come directly from our understanding of the biology of what causes prostate cancer cells to become resistant to treatments we had a decade ago,” said Anthony D'Amico, MD, PhD, of Brigham and Women's Hospital and Dana-Farber Cancer Institute, in Boston, MA.

He said the Prostate Cancer Foundation (PCF), which was formerly the Association for the Cure of Cancer of the Prostate (CaP CURE), helped usher in a new era in terms of research. It included leading scientific and clinical experts and it helped expedite new treatments.

In 2004, the U.S. Food and Drug Administration (FDA) approved docetaxel after the publication of two random controlled trials, one of which was led by a PCF clinical investigator.3

Over the past decade, the FDA has approved the pure luteinizing hormone–releasing hormone antagonist degarelix (Firmagon), the first immunotherapy for prostate cancer, sipuleucel-T (Provenge), and a taxane-based chemotherapy, cabazitaxel (Jevtana).

The FDA also approved denosumab (Prolia/Xgeva) as a treatment to increase bone mass in patients at high risk for fracture receiving androgen-deprivation therapy (ADT).

Enzalutamide (Xtandi) has been approved to treat men with metastatic castration-resistant prostate cancer that has spread or recurred, even with medical or surgical therapy to minimize testosterone. Enzalutamide was approved for patients who have previously been treated with docetaxel.

In May 2013, the FDA approved radium Ra 223 dichloride (Xofigo) to treat symptomatic late-stage metastatic castration-resistant prostate cancer that had spread to bones, but not to other organs.

“Provenge and radium 223 dichloride have helped a lot for patients in the late stages of the disease,” Dr. D'Amico told Cancer Therapy Advisor. “In the future, we hope to do more than just extend life more than several months in late stage disease.”

It is now estimated that one in seven men will be diagnosed with prostate cancer during his lifetime and approximately 220,800 new cases of prostate cancer will be diagnosed in 2015 alone.4 The American Cancer Society predicts in 2015 there will be approximately 27,540 deaths from prostate cancer.

 

RELATED: Post-diagnostic Dietary Changes Among Men with Prostate Cancer Beneficial

Yair Lotan, MD, who is a professor of urology and chief of urologic oncology at University of Texas Southwestern Medical Center, in Dallas, TX, said no one agent has been a home run, even though there have been significant advances in the past decade.

“The advancements of the past decade have been mostly small incremental changes. Each of the new therapies provides modest survival benefits, 3 to 4 months,” Dr. Lotan told Cancer Therapy Advisor. “There is still a desperate need for effective therapy for patients with castrate resistant prostate cancer and it is unclear whether this will be provided by novel targeted therapies.”

Tomasz Beer, MD, who is chair for prostate cancer research and the deputy director of the Oregon Health & Science University (OHSU) Knight Cancer Institute, in Portland, OR, said clinicians should be cautious when analyzing the 5- and 10-year survival numbers.

He said while treatment improvements are partly responsible for better outcomes, a part of this trend reflects early diagnosis and stage migration.

“Having said that, there have been major advances; the most notable of which is the development of two new drugs that target androgen receptor signaling, abiraterone and enzalutamide. But in total six agents that extend survival have been approved, approximately five in the last 5 years. That is real progress,” Dr. Beer told Cancer Therapy Advisor.

“Further, and importantly, we have learned that earlier use of chemotherapy in metastatic but hormone responsive disease substantially magnified the benefits of chemotherapy. Taken together, the early application of chemotherapy coupled with compelling new androgen receptor signaling inhibitors have transformed the management of advanced disease.”

Measuring circulating tumor cells (CTC) following first-line therapy is changing how patients are managed. This past year, researchers reported that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in CTC from men with advanced prostate cancer may be associated with resistance to enzalutamide and abiraterone.5

“The biggest changes in the landscape of advanced prostate cancer include discovery of CTC, genetic testing on them (AR-V7), improvement in overall survival from various drugs like abiraterone, enzalutamide, radium-223, sipuleucel-T, and cabazitaxel. The most striking data are from the ECOG-3805 trial, which changed the standard of care for de novo metastatic prostate cancer by adding six cycles of docetaxel to ADT. This significantly changed the overall survival,” said Saby George, MD, an assistant professor of oncology at Roswell Park Cancer Institute, in Buffalo, NY.

Novel agents that work by different mechanism and are matched to genetic signatures may soon significantly change the management of metastatic prostate cancer. Gerald Andriole, MD, chief of urologic surgery at Washington University School of Medicine in Saint Louis, MO, said experimental therapeutic vaccines and check-point inhibitors are showing promise and may soon be part of the armamentarium.

Recently, researchers discovered that cytotoxic T lymphocyte antigen 4 (CTLA-4) is a receptor on the surface of T cells that blocks the immune response by inhibiting T cell activation. Now, studies are looking at whether an antibody (anti–CTLA-4) can block the “immune checkpoint” protein.

"More complete obliteration of the androgenic pathways has played a major role for men with advanced prostate cancer. Going forward, efforts to better understand the role of immunotherapy with vaccines, checkpoint inhibitors, and other approaches, hold great promise, and may be applied to men with earlier stages of prostate cancer," Dr. Andriole told Cancer Therapy Advisor.

 

RELATED: No Link Between Shift Work, Prostate Cancer Incidence, Study Shows

Dr. George said there is a strong possibility that prostate cancer could become a manageable chronic disease. However, he said it is important that clinicians not give their patients false hope. Dr. George said many patients may mistakenly have too high of expectations based on recent reports about precision medicine and what it can and cannot do.

“Precision medicine is a loose term. The clinical development of second-line hormonal manipulation like enzalutamide and abiraterone are examples of how to optimize the targeting of the androgen receptor signaling axis. There needs to be a lot more development to make this disease a chronic disease. Cure is an elusive term in advanced prostate cancer as of today,” Dr. George told Cancer Therapy Advisor.

References

  1. American Cancer Society. Cancer facts & figures 2005. http://www.cancer.org/acs/groups/content/@nho/documents/document/caff2005f4pwsecu redpdf.pdf. Published 2005. Accessed July 30, 2015.
  2. American Cancer Society. Survival rates for prostate cancer. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates. Revised March 12, 2015. Accessed July 30, 2015.
  3. D'Amico AV. US Food and Drug Administration approval of drugs for the treatment of prostate cancer: a new era has begun. J Clin Oncol. 2014;32(4):362-364.
  4. American Cancer Society. What are the key facts about prostate cancer?. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Revised March 12, 2015. Accessed July 30, 2015.
  5. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028-1038.

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