A Snapshot of Change in Prostate Cancer: Innovations in Screening, Detection, Management

2015 Genitourinary Cancers

Symposium DAILY NEWS


A Snapshot of Change in Prostate Cancer: Innovations in Screening, Detection, Management

Jan 30, 2014

More than 2 million men have been diagnosed with prostate cancer in the past decade. Despite a considerable rise in the age-adjusted incidence of prostate cancer in the United States over the previous two decades, the incidence of prostate cancer has remained stable in this decade, with 180 cases per 100,000 men diagnosed since 2001.1,2 However, the incidence has substantially increased among men younger than age 50, and a majority of tumors are now classified as well- or moderately differentiated (Gleason score ≤ 6) using the National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program data.3 However, the age-adjusted mortality rate in the United States has dramatically decreased by more than 40%. These epidemiologic changes over the past 10 years have been due, in part, to advances in prostate cancer detection and treatment, and these innovations have inspired greater emphasis on individualization of disease management based on risk stratification. 

The past decade witnessed the publication of landmark clinical trials on the early detection and prevention of prostate cancer, comparative analyses of treatment for localized disease, and management of high-risk disease. In addition, the development and dissemination of novel prediction tools have been complemented by studies on patient-reported outcomes to improve individualization of disease management. The focus of local therapy has shifted from men with low-grade, organ-confined cancers, now managed conservatively with active surveillance, to aggressive, potentially lethal cancers, which require intensive, sometimes multimodality therapy.



Several large, randomized placebo-controlled trials have reported results of pharmacologic chemoprevention. Lifestyle modifications, including the use of vitamin supplements, have also been studied. 

The Prostate Cancer Prevention Trial (PCPT) was designed to evaluate the effectiveness of finasteride in reducing the detection of prostate cancer in men with low risk of disease.4 The results of this trial were unexpected: prostate cancer was detected by biopsy in a remarkable 24.4% of the study participants, and finasteride decreased the overall relative risk of prostate cancer by 25%. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE trial) examined the effects of dutasteride in a higher-risk cohort, with a similar relative risk reduction of 25% and an absolute reduction of 5.1%. In both trials, however, all risk reduction occurred in men with Gleason score of 5 or 6.5 The U.S. Food and Drug Administration Oncologic Drug Advisory Committee refused to issue an indication for the prevention of prostate cancer with either of these 5-alpha reductase inhibitors. This decision was based largely on the premise that low-grade prostate cancers pose little threat to health and should not be treated; therefore, preventing them is of no value. In addition, the Advisory Committee raised concerns that the risk of high-grade cancers (Gleason scores of 8 to 10) may be slightly increased in patients receiving these drugs. Notably, the drugs remain approved for the relief of symptomatic benign prostatic hyperplasia.

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) randomized 35,533 men at low risk for prostate cancer in a double-blind design to regimens of either vitamin or to combinations of these supplements.6 No significant differences were found in rates of prostate cancer across the intervention groups. Based on these results, neither agent is recommended for the prevention of prostate cancer.


Early Detection

Several large, prospective randomized trials addressed the hypothesis that screening using prostate-specific antigen (PSA) values can reduce mortality for prostate cancer. The results remain controversial, and in 2012 the U.S. Preventive Services Task Force recommended against PSA screening on the grounds that there is no net benefit and that the potential harms outweigh the benefits.7 The Task Force’s conclusions have been criticized, however, as premature in a rapidly evolving area of intensive research.8 The U.S.-based Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial found no reduction in prostate cancer-specific mortality associated with screening after a median follow-up of 10 years, but the study was flawed by pretesting with PSA in 40% of the study participants and contamination (by PSA testing) in 70% of the individuals in the “unscreened” control cohort.9 However, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a statistically significant relative reduction of 21% in prostate cancer mortality at 11 years.10 In the longest and largest independent trial, prostate cancer mortality was reduced by 46% at 14 years;11 in a modeling study of the ERSPC trial cancer deaths were reduced by 21%, and five cancers needed to be detected over the lifetime of the screened subjects to prevent one death from prostate cancer.12 In these studies, more than 250,000 men were randomly assigned to screening and followed for prostate cancer death.

During this same era, large case-controlled studies found that PSA levels at mid-life (ages 45 to 60) strongly predicted prostate cancer metastases and death over the next 25 years, suggesting that PSA testing should not be abandoned but should be used more appropriately to risk-adjust screening strategies.13 New panels of biomarkers for detecting prostate cancer, especially high-grade, potentially lethal cancers, offer marked increases in specificity while retaining sensitivity and could substantially reduce unnecessary biopsies and over-detection of low-risk cancers.14,15


Active Surveillance

With widespread PSA screening for prostate cancer, concerns have arisen about overdetection and overtreatment. In intensely screened populations, 40% to 50% of cancers in the United States have low-risk characteristics and seem to pose little immediate threat to life or health. Large cohorts of men with low-risk cancer have been followed in active surveillance programs with little risk of prostate cancer mortality (at least within 10 years), and those cancers that do appear to progress generally respond to delayed treatment with surgery or radiation.16,17 The feasibility of active surveillance for men with low-risk prostate cancer was initially confirmed in a prospective observational study conducted at the University of Toronto.18 Since that study, multi-institutional reports have been published that describe the safety of active surveillance16 and the substantial improvement in quality of life for men on watchful-waiting protocols, compared with those undergoing radical prostatectomy.16,19 New efforts are needed to standardize the evaluation and follow-up of men on active surveillance, and to define the criteria for eligibility and appropriate triggers for intervention. Molecular profiles  and biomarkers in serum (e.g., phi, 4K score) and in urine (e.g., PCA3) are being developed to enhance initial and delayed triage to active surveillance versus active therapy.14,15,20,21

The harms of early diagnosis of prostate cancer are primarily associated with radical treatment, either surgery or radiotherapy. Although these treatments are effective in eradicating most tumors, patients risk post-treatment morbidity and a significant reduction in quality of life through development of side effects such as incontinence, erectile dysfunction, rectal injury, and bowel urgency.22 In the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial, men with nonscreen-detected prostate cancer were randomly assigned to watchful waiting or to radical prostatectomy. Surgery significantly reduced prostate cancer-specific mortality (HR 0.62, 95% CI, 0.44 to 0.87; p=0.01), overall mortality (HR 0.75, 95% CI, 0.61 to 0.92; p=0.007), the risk of metastasis (HR 0.59, 95% CI, 0.45 to 0.79; p<0.001), and of local progression (HR 0.34, 95% CI, 0.26 to 0.45; p<0.001) after a median follow-up of 12.8 years.23 In contrast, the Prostate Cancer Intervention Versus Observation Trial (PIVOT) studied U.S. men randomly assigned to radical prostatectomy versus observation. After 12 years there was an absolute risk reduction in prostate cancer mortality of 3%, which was not statistically significant.24 These discordant results may be explained by the prevalence of screening in men enrolled in PIVOT, in which 50% of the tumors (compared with 12% in SPCG-4) were classified as T1c. When statistical methods were used to adjust for overdiagnosis and lead time due to screening detection, the absolute mortality difference in PIVOT was comparable to that of the SPCG-4 trial.25 These studies confirm that many patients with intermediate- and high-risk cancers benefit from immediate treatment, while active surveillance is more appropriate for most men with low-risk prostate cancer.


Radical Prostatectomy

Open radical prostatectomy has been the standard surgical approach in men with localized prostate cancer during most of the past century. Over the past decade, however, the use of robotic-assisted laparoscopic prostatectomy has increased considerably. In 2009, 61% of radical prostatectomy procedures were performed using robotic technology, according to case logs submitted for board recertification.26,27 In the absence of any randomized trials, evidence on outcomes of these procedures is documented in population-based observational studies and single-institution case series.27,28 The rapid growth of robotic-assisted laparoscopic prostatectomy, fueled by direct-to-consumer advertising, has raised concerns about the quality of data that patients with prostate cancer are likely to find on the Internet, as well as about the regulation and credentialing of surgical training conducted prior to adopting novel advanced technologies.29

Whatever the effect of these advances in surgical technology, it is now clear that the skill level of the surgeon, independent of surgical approach, has a major effect on prostate cancer treatment outcomes. The positive association of surgical volume with improved outcomes has been mapped in learning curves charting surgeon experience with cancer-specific and patient-reported functional outcomes.30 Subsequently, innovative web-based tools have been developed to gather patient-reported information and provide individualized real-time feedback to surgeons on the outcomes of their procedures.31,32 Novel prediction tools and nomograms have been further developed and disseminated to assist in shared decision-making by physicians and patients about treatment options for localized prostate cancer.33

Advanced imaging modalities could provide standard, reliable methods for accurately identifying tumor size, location, and extent. In addition to facilitating individualized risk stratification, new imaging techniques could be helpful in directing therapy, assessing treatment effect, and monitoring for disease recurrence or progression. Over the past decade, multiparametric MRI has emerged as the most accurate imaging technique for detecting clinically important prostate cancers.34


Molecular and Genetic Studies

A landmark discovery in the past decade was the identification of a chromosomal rearrangement in an androgen-regulated gene. The fusion between transmembrane protease serine 2 (TMPRSS2) and ERG, an erythroblast transformation-specific (ETS) transcription factor family member, is identified in approximately 50% of primary and metastatic prostate cancer tumors and most often correlated with poor prognosis.35,36 Although the effects of identifying the fusion of these factors on clinical management decisions can be debated, the high prevalence of these fusions provides an important pathway for investigation of new diagnostic and prognostic indications, as well as for potential targets for tailored therapies. A comprehensive, integrated genomic profile of prostate cancer found alterations in key molecular pathways in a surprisingly large number of primary, as well as metastatic tumors, which suggests that the degree of copy number alterations may affect the prognosis of primary tumors treated with surgery.37

Next-generation sequencing technologies have enabled rapid and comprehensive interrogation of genomic data implicated in human diseases. Targeted sequencing of exons located on chromosome 17q21-22, a region previously linked with prostate cancer, has resulted in the identification of a recurrent mutation in HOXB13 among families with a history of prostate cancer.38HOXB13 is the first gene associated with a substantial risk of hereditary prostate cancer and, despite the low prevalence of this mutation in the population, further research on HOXB13 may lead to the identification of pathways found to be abnormal in a greater number of occurrences of sporadic disease.


Going Forward

Progress in the detection, treatment, and understanding of localized prostate cancer has been rapid over the past decade. Major randomized trials were published that examined the role of screening, chemoprevention, and surgical treatment. Tools for assessing patient-reported outcomes and prognosis have been refined. Landmark clinical trials have been complemented by breakthroughs in translational research, improving our understanding of the molecular and genetic factors in prostate cancer. In the near future, we anticipate the use of molecular and genetic tests in the clinic, improvements in the quality of care through reliable metrics of performance and feedback to physicians, and the continuing evolution of surgical technology and advanced imaging. 


About the Authors: Dr. Ehdaie is a surgeon at the Sidney Kimmel Center for Prostate and Urologic Cancers. Dr. Scardino is chair of the Department of Surgery and the David H. Koch Chair at Memorial Sloan-Kettering Cancer Center. Dr. Scardino will be presenting his Decade in Review lecture on prostate cancer, “The Urology Perspective,” Thursday, 3:15 PM-4:00 PM.


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4.     Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215-224. Epub 2003 Jun 24.

5.     Andriole GL, Bostwick DG, Brawley OW,  et al. Effect of dutasteride on the risk of prostate cancer. New EnglJ Med. 2010;362(13):1192-1202.

6.     Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1):39-51. Epub 2008 Dec 9.

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8.     Carlsson S, Vickers AJ, Roobol M, et al. Prostate cancer screening: facts, statistics, and interpretation in response to the US Preventive Services Task Force Review. J Clin Oncol. 2012;30(21):2581-2584. Epub 2012 Jun 18.

9.     Andriole GL, Crawford ED, Grubb RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310-1319. Epub 2009 Mar 18.

10.  Schroder FH, Hugosson J, Roobol MJ,  et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-1328. Epub 2009 Mar 18.

11.  Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11(8):725-732. Epub 2010 Jul 2.

12.  Heijnsdijk EA, Wever EM, Auvinen A, et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med. 2012;367(7):595-605.

13.  Lughezzani G, Briganti A, Karakiewicz PI, et al. Predictive and prognostic models in radical prostatectomy candidates: a critical analysis of the literature. Eur Oncol. 2010;58(5):687-700. Epub 2010 Aug 6.

14.  Stephan C, Vincendeau S, Houlgatte A, et al. Multicenter evaluation of [-2]proprostate-specific antigen and the prostate health index for detecting prostate cancer. Clin Chem. 2013;59(1):306-314. Epub 2012 Dec 4.

15.  Carlsson S, Maschino A, Schroder F, et al. Predictive value of four kallikrein markers for pathologically insignificant compared with aggressive prostate cancer in radical prostatectomy specimens: results from the European Randomized Study of Screening for Prostate Cancer section Rotterdam. Eur Oncol. 2013;64(5):693-699. Epub 2013 May 2.

16.  Eggener SE, Mueller A, Berglund RK, et al. A multi-institutional evaluation of active surveillance for low risk prostate cancer. J Urol. 2013;189(1 Suppl):S19-S25.

17.  Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011;29(16):2185-2190. Epub 2011 Apr 4.

18.  Klotz L, Zhang L, Lam A, et al. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol. 2010;28(1):126-131. Epub 2009 Nov 16.

19.  Johansson E, Steineck G, Holmberg L, et al. Long-term quality-of-life outcomes after radical prostatectomy or watchful waiting: the Scandinavian Prostate Cancer Group-4 randomised trial. Lancet Oncol. 2011;12(9):891-899. Epub 2011 Aug 5.

20.  Cuzick J, Berney DM, Fisher G, et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer. 2012;106(6):1095-1099. Epub 2013 May 21.

21.  Knezevic D, Goddard AD, Natraj N, et al. Analytical validation of the Oncotype DX prostate cancer assay - a clinical RT-PCR assay optimized for prostate needle biopsies. BMC Genomics. 2013;14:690.

22.  Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358(12):1250-1261.

23.  Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011;364(18):1708-1717.

24.  Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203-213.

25.  Xia J, Gulati R, Au M, et al. Effects of screening on radical prostatectomy efficacy: the prostate cancer intervention versus observation trial. J Natl Cancer Inst. 2013;105(8):546-550. Epub 2013 Feb 14.

26.  Lowrance WT, Eastham JA, Savage C, et al. Contemporary open and robotic radical prostatectomy practice patterns among urologists in the United States. J Urol. 2012;187(6):2087-2092. Epub 2012 Apr 11.

27.  Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA. 2009;302(14):1557-1564.

28.  Lowrance WT, Elkin EB, Jacks LM, et al. Comparative effectiveness of prostate cancer surgical treatments: a population based analysis of postoperative outcomes. J Urol. 2010;183(4):1366-1372. Epub 2010 Feb 25.

29.  Mirkin JN, Lowrance WT, Feifer AH, et al. Direct-to-consumer Internet promotion of robotic prostatectomy exhibits varying quality of information. Health Aff (Millwood). 2012;31(4):760-769.

30.  Vickers AJ, Bianco FJ, Serio AM, et al. The surgical learning curve for prostate cancer control after radical prostatectomy. J Natl Cancer Inst. 2007;99(15):1171-1177.

31.  Vickers AJ, Savage CJ, Shouery M, et al. Validation study of a web-based assessment of functional recovery after radical prostatectomy. Health Qual Life Outcomes. 2010;8:82.

32.  Vickers AJ, Sjoberg D, Basch E, et al. How do you know if you are any good? A surgeon performance feedback system for the outcomes of radical prostatectomy. Eur Urol. 2012;61(2):284-289. Epub 2011 Nov 4.

33.  Kattan MW, Eastham JA, Stapleton AM, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst. 1998;90(10):766-771.

34.  Vargas HA, Akin O, Franiel T, et al. Diffusion-weighted endorectal MR imaging at 3 T for prostate cancer: tumor detection and assessment of aggressiveness. Radiology. 2011;259(3):775-784. Epub 2011 Mar 24.

35.  Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310(5748):644-648.

36.  Perner S, Demichelis F, Beroukhim R, et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 2006;66(17):8337-8341.

37.  Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11-22. Epub 2010 Jun 24.

38.  Ewing CM, Ray AM, Lange EM, et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med. 2012;366(2):141-149.



The Promise of Immunotherapy

Finding new ways to use the body’s own defense system to treat disease

By Eleanor Mayfield

For decades researchers have sought to better understand the immune system—the elaborate network of cells and organs that protects the body from infection—and find ways of using the body’s innate disease-fighting capability to treat serious illnesses such as cancer and autoimmune and inflammatory bowel diseases.

These efforts are now starting to pay off as novel immunotherapies— treatments that stimulate, boost, or, by contrast, restrain the immune system—reach the market, offering promising new approaches for treating these conditions. Immunotherapies are also known as biologics or biologic response modifiers.

The Immune System and Immunotherapy: A Primer

When Bob Lahita, MD, PhD, talks to his patients about the immune system, he compares it to a metropolitan police department. Within the immune system, he says, the “criminals” are viruses, bacteria, and other foreign substances that can cause disease. Antibodies are the uniformed cops on the beat, patrolling the body and looking for these invaders. T-cells, a type of white blood cell, are the detectives whose job is to arrest the invaders. Other cells and proteins give orders, provide backup, and serve as dispatchers, sending cops or detectives to where they are needed most.

Sometimes, however, the immune system makes a mistake and attacks healthy cells as if they were foreign invaders. This is autoimmunity, explains Dr. Lahita, an autoimmune disease specialist and chair of medicine at Newark Beth Israel Medical Center in New Jersey. As he puts it, “Autoimmunity is when the police department can’t tell the criminals from the innocent bystanders.”

Lupus, multiple sclerosis, and rheumatoid arthritis (RA) are all examples of autoimmune diseases. Crohn’s disease and ulcerative colitis (collectively called inflammatory bowel disease or IBD), while technically not autoimmune diseases, result from a hyperactive immune system that attacks the gastrointestinal system. In both autoimmune diseases and IBD, the immune system’s attack leads to inflammation of the affected body system—for example, the joints in RA and the intestines in IBD—causing pain, swelling, and other symptoms. Immunotherapies for autoimmune diseases and IBD aim to suppress the excessive, inappropriate immune response that is causing the inflammation.

With cancer, by contrast, the problem isn’t a hyperactive immune system but an ineffective one. The immune system recognizes cancer cells as foreign and up to a point can get rid of them or keep them in check. But “cancer is a wily foe,” says Len Lichtenfeld, MD, deputy chief medical officer for the American Cancer Society in Atlanta, Georgia. Cancer cells are very good at finding ways to hide from, suppress, or wear out the immune system. Immunotherapies for cancer stimulate or boost the immune system so that it can more effectively attack tumors.

Blocking Inflammation

Tumor necrosis factor (TNF) is an important player in the immune system, performing multiple jobs, such as helping immune cells communicate and helping wounds heal. A healthy immune system makes just enough TNF for its needs. But when the immune system starts attacking healthy cells, levels of TNF can get too high, causing the inflammation that underlies autoimmune diseases and IBD.

The first drugs to treat Crohn’s disease (Remicade [infliximab]) and RA (Enbrel [etanercept]) by blocking TNF were approved in 1998. Since then several other drugs targeting TNF have come on the market. They are given by injection, either into a vein (intravenous) or under the skin (subcutaneous).

All TNF-blocking drugs suppress the immune system, so one side effect they have in common is an increased risk of infections. Some people using TNF-blocking drugs have developed a rare, fast-growing type of lymphoma (a cancer of white blood cells). One recent study in people with IBD, however, found no increased cancer risk for those treated with TNF blockers compared with those who were not.1

Newer immunotherapies for RA use other strategies to block inflammation. For example, Orencia (abatacept), available since 2005, stops inflammatory cells from communicating with one another. Actemra (tocilizumab), available since 2011, blocks interleukin-6, another substance in the immune system that helps cells communicate and is also implicated in causing inflammation.

A new immunotherapy for IBD, Entyvio (vedolizumab), received US Food and Drug Administration (FDA) approval in May 2014. Instead of blocking TNF, Entyvio reduces inflammation by preventing inflammatory cells circulating in patients’ blood from traveling to the intestines.

“Entyvio is an exciting new treatment option for IBD because the drug has a selective impact on the gut without altering systemic immune function and increasing risk for infections,” says Jean-Frédéric Colombel, MD, co-director of the Leona M. and Harry B. Helmsley Charitable Trust Inflammatory Bowel Disease Center and professor of medicine at the Icahn School of Medicine at Mount Sinai Hospital in New York.

Stelara? (ustekinumab), an immunotherapy drug that blocks the activity of some types of interleukin (another substance that helps immune cells communicate), is being tested as a treatment for Crohn’s disease in late-stage clinical trials.

Blocking inflammation may also be an effective strategy in cancer treatment. For example, in patients with advanced pancreatic cancer who had elevated levels of a biomarker for inflammation, those treated with the experimental anti-inflammatory drug Jakafi (ruxolitinib) in addition to the chemotherapy drug Xeloda? (capecitabine) lived longer than those treated with capecitabine plus a placebo.2

Taking the Brakes Off The Immune System

Using the immune system to treat cancer is not a new idea. Immunotherapies such as interferon and interleukin-2 have been used in cancer treatment for years, although with limited success. A major breakthrough occurred when scientists discovered how to disable a “brake” on the immune system, foiling a key strategy used by cancer cells to avoid detection. The first new drug to emerge from this discovery, Yervoy (ipilimumab), received FDA approval in 2011 to treat advanced melanoma, the most serious form of skin cancer.

New drugs that disable a different immune system brake have shown promise in early studies. In patients with advanced melanoma treated with one of these drugs, Keytruda (pembrolizumab), 69 percent were still alive after one year.3 Keytruda received FDA approval in September 2014.

In a study of another drug, nivolumab, median survival (the point at which half of all patients in the study remained alive) was nearly 17 months. By contrast, among similar patients treated with Yervoy in other studies, median survival ranged from six to 11 months.4 Nivolumab is awaiting FDA approval.

“We’re seeing that these new drugs also benefit patients with kidney cancer, pancreatic cancer, lung cancer, and others that many people had not thought would respond to immunotherapy,” says Dr. Lichtenfeld.

Studies also show that tumors may respond differently to immunotherapy than to other types of cancer treatment. For example, tumors may first seem to get larger and what look like new tumors may appear. With chemotherapy these would be signs that treatment is not working. But with immunotherapy “we may see more of a delayed response,” says Lynn Schuchter, MD, chief of hematology-oncology at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia.

Tumors may look larger not because they’re growing, Dr. Schuchter explains, but because they’re being “surrounded” by millions of activated immune cells. Recognizing that the standard way of assessing a cancer treatment’s effectiveness is ill suited to immunotherapy drugs, doctors have developed unique “immune-related response criteria” for measuring how well these drugs work.5

Cancer Vaccines

Vaccines are another approach to cancer immunotherapy. Unlike conventional vaccines that are used to prevent disease, cancer vaccines are often used in treatment. In 2010 Provenge (sipuleucel-T), a treatment for advanced prostate cancer, became the first (and so far only) cancer vaccine to win FDA approval. Treatment with Provenge is customized for each patient by first extracting white blood cells, exposing them to the vaccine in a lab, and reinjecting them into the patient to stimulate an immune response. Numerous other cancer vaccines are being tested in clinical trials.

Promise in the Pipeline

As new insights into the mechanisms of the immune system are translated into innovative therapies that take advantage of the body’s inherent ability to protect itself, patients with cancer, autoimmune or gastrointestinal diseases, and other serious illnesses have reason to hope that immunotherapy lives up to its promise.


Patient Story: Advanced Melanoma

Right Around Christmas 2011, Thèrése Bocklage noticed a lump on her right leg. It wasn’t sore or bruised, but when it was still there a month later, she asked a colleague in the pathology lab where she works to take a look at it.

The news was devastating: melanoma, the most serious form of skin cancer, had already spread to her lungs and to lymph nodes in her abdomen and was inoperable. It was a rare recurrence of a very early-stage melanoma that had been surgically removed 20 years before.

As a pathologist, Thèrése understood all too well that her outlook was dire. She immediately began researching clinical trials of experimental treatments for advanced melanoma. Because she has a sister living in Los Angeles, she decided to look into trials at the UCLA Jonsson Comprehensive Cancer Center.

One trial stood out—that of a novel immunotherapy drug known at the time as MK-3475 (now called Keytruda [pembrolizumab]). It targets a protein on T-cells (the “detectives” of the immune system) that acts as a brake on the body’s immune response. Inactivating that brake enables the immune system to unleash millions of T-cells to attack the melanoma.

By February 2012, Thèrése had enrolled in the MK-3475 trial. She stayed with her sister for three months. After that she flew to Los Angeles from her home in Albuquerque, New Mexico, every other week to receive a 30-minute infusion of the drug. She found that chronic fatigue was the drug’s primary side effect.

The plan for the trial was that patients should be treated for up to two years. In July, five months after she began treat?ment, a CT (computed tomography) scan found no trace of tumors in Thèrése’s body. On a biopsy, “you could see swarms of activated T-cells,” she says. She continued receiving treatment until December 2013.

Now 54, Thèrése says she feels “really healthy.” Chronic fatigue gone, she works “60 to 80 hours a week” as a professor of pathology and the director of a tumor specimen bank at the University of New Mexico Health Sciences Center. In her free time, she enjoys hiking in the Sandia Mountains near Albuquerque.

“I feel I’ve been given extra time. It feels miraculous,” she says, although she knows that many years of research went into developing the drug. She is also acutely aware that “what worked for me doesn’t work for everyone.”

For others facing a similar diagnosis, Thèrése has this advice: “Don’t give up hope. Ask about other treatment options, including clinical trials. If at all possible, get a consultation at a major cancer center.”


Patient Story: Rheumatoid Arthritis

Autoimmune Diseases run in Abby Bernstein’s family: Both her parents had rheumatoid arthritis, and her mother also had lupus. A niece was diagnosed with autoimmune hepatitis (in which the immune system attacks the liver) at age eight.

By the time Abby learned at age 39 that she too had RA, she had already been diagnosed with three other autoimmune diseases. As a child she had psoriasis (now recognized as an autoimmune disease, although at the time it was not). In her early thirties, she learned that she had Raynaud’s disease (numbness in the fingers and toes in response to cold or stress). At 35, after six years of on-again, off-again symptoms and baffled doctors, she was diagnosed with autoimmune hepatitis.

“Because of my autoimmune hepatitis, my treatment options for RA were limited,” she recalls. “Most of the available drugs were broken down in the liver and so might trigger a bout of hepatitis.”

Her doctor finally suggested she try the immunotherapy drug Enbrel, approved in 1998 as one of the first drugs to target tumor necrosis factor, a chemical produced by the immune system that causes inflammation in the body.

Enbrel must be injected under the skin. Abby says she resisted at first, hating the idea of injecting herself. Once she decided to try it, though, she felt better in a week. “I got my life back,” she says.

Abby started having headaches, a drug side effect, but by reducing the frequency of injections, she found she could keep the headaches at bay and still get adequate symptom relief. Once an avid tennis player, she soon felt well enough to play the occasional game again.

Abby is now 56 and has been taking Enbrel for 13 years. She credits the drug with enabling her to remain employed (she works for a labor organization in Washington, DC) and lead a normal life. Because the drug suppresses her immune system, she stops taking it if she has a cold or other infection and before having a medical procedure like a colonoscopy. She is careful to avoid infections, washing her hands frequently and steering clear of anyone who is coughing or sneezing.

“Even my liver seems to be happy on Enbrel,” she says. “From the day I started taking it, I haven’t had a bout of autoimmune hepatitis.”



Autoimmune Diseases/ Rheumatoid Arthritis

  • American Autoimmune Related Diseases Association, aarda.org
  • American College of Rheumatology, rheumatology.org/Practice/Clinical/Patients/ Information_for_Patients
  • Women and Autoimmune Disease: The Mysterious Ways Your Body Betrays Itself, by Robert G. Lahita, MD, PhD (William Morrow Paperbacks, 2005)


  • Biological Therapies for Cancer, cancer.gov/cancertopics/factsheet/Therapy/biological
  • Cancer Immunotherapy, cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-types
  • TheAnswerToCancer.org a resource on cancer immunotherapy for patients and caregivers supported by the Cancer Research Institute, cancerresearch.org)

Inflammatory Bowel Diseases

  • Crohn’s & Colitis Foundation of America, ccfa.org
  • IBDWatch.com (latest IBD news and research)
  • Medications: Biologic Therapy, ccfa.org/assets/pdfs/biologic102011.pdf


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Drug Shows Activity in Men with Advanced Prostate Cancer

Drug Shows Activity in Men with Advanced Prostate Cancer

NEW YORK, Apr 08, 2009 (ASCRIBE NEWS via COMTEX) -- A new multi-center study shows that an experimental drug lowers prostate specific antigen (PSA) levels - a marker for tumor growth - in men with advanced prostate cancer for whom traditional treatment options have failed. The study, led by researchers at Memorial Sloan-Kettering Cancer Center (MSKCC), is published today in Science Express, the online version of the journal Science

FDA Approves Degalerix for Advanced Prostate Cancer

Degarelix prostate cancer drug makes testosterone levels fall dramatically and quickly3. December 2008 22:10

More than 95 per cent of men who took degarelix for prostate cancer saw their testosterone levels fall dramatically as early as three days after they started treatment, according to a paper in the December issue of BJU International. They also experienced much greater falls in their prostate-specific antigen (PSA) levels at 14 and 28 days than men taking leuprolide.

Researchers from Canada, the USA, France, Denmark and the Netherlands studied 610 men as part of the Phase Three trial, randomly assigning them to one of three study groups.

"Androgen deprivation hormone therapy is an effective response to prostate cancer, but the drugs that are most widely used cause an initial rise in testosterone - the hormone we are trying to reduce - when the patient first takes them" explains lead author Dr Laurence Klotz from the Division of Urology at the University of Toronto, Canada.

"We prefer to avoid this biochemical surge as it can stimulate the prostate cancer cells and exacerbate a number of clinical symptoms, such as spinal cord compression and bone pain. It could also result in more rapid growth of microscopic disease that is present in the patient but is too small to be detected.

"Degarelix is a new gonadotrophin-releasing hormone (GnRH) antagonist. It works by binding to, and blocking, the GnRH receptors in the pituitary gland, reducing the amount of LH and FSH hormones that are released. This leads directly to a rapid fall in testosterone."

Group one (207 patients) received an injection of 240mg of degarelix in month one, followed by a maintenance dose of 80mg every month for eleven months and group two (202 patients) received 240mg of degarelix in month one followed by a maintenance dose of 160mg for eleven months.

The third group (201 patients) received a monthly 7.5mg dose of leuprolide, which is a GnRH agonist.

At the start of the trial the study participants had a median testosterone level of 3.93 ng/mL. The aim was to reduce this to 0.5ng/mL or less at all monthly measurements from day 28 to day 364.

Eight out of ten study participants completed the trial (504 patients) between February 2006 and October 2007, with similar drop-out and exclusion rates in all three groups.

The key findings were impressive:

  • Three days after starting their treatment regimes, 96.1 per cent of the patients on 240/80mg degarelix and 95.5 per cent of the patients on 240/160mg degarelix had achieved a testosterone level of 0.5ng/mL or less. In contrast, median testosterone levels in the leuprolide group had increased by 65 per cent by day three, but had reduced by day 28.
  • At the end of the study period, 98.3 per cent of the 240/160mg degarelix group and 97.2 per cent of the 240/80mg degarelix group had achieved a testosterone level of 0.5ng/mL or less. The figure for the leuprolide group was 96.4 per cent.
  • PSA levels fell much faster in the degarelix groups when measured at 14 and 28 days - by 64 per cent and 85 per cent in the degarelix 240/80mg group, 65 per cent and 83 per cent in the 240/160mg degarelix group and 18 per cent and 68 per cent in the leuprolide group.

The hormonal side-effects experienced by the three treatment groups were similar to previously reported effects for androgen deprivation hormone therapy.

Patients receiving degarelix were much more likely to experience injection-site reactions than those receiving leuprolide (40 per cent compared to one per cent).

However degarelix patients suffered fewer urinary tract infections than those in the leuprolide group (three per cent versus nine per cent) together with fewer joint pains and chills (four per cent versus nine per cent).

"More than 2,000 patients have now taken part in clinical trials for degarelix and there have been no signs of immediate or late-onset systemic allergic reactions, in contrast to other reported trials of other GnRH antagonists" points out Dr Klotz.

"The aim of the study was to show that degarelix was not inferior to leuprolide when it came to maintaining low testosterone levels over a one-year treatment period. We have conclusively shown that this is the case.

"However, we have also demonstrated that degarelix - which is an antagonist - offers an advantage, in that it reduces testosterone and PSA levels very quickly. It doesn't cause the initial surge of testosterone seen with agonist drugs like leuprolide - the other drug featured in this study.

"This is relevant as biochemical surges in testosterone can stimulate the prostate cancer cells and cause unpleasant side effects for patients. They may also require further drug therapy to counteract the effects of agonist drugs like leuprolide."