Renowned Prostate Cancer Experts Translate Research into Practice at the IPCC

OBTN, April 2010, Volume 4, Issue 4

Three presentations at the recent Third Annual Interdisciplinary Prostate Cancer Congress in New York are reviewed. Urologist Leonard Gomella, MD, addresses truths and myths about prostate cancer prevention;Daniel P. Petrylak, MD, discusses the timely topic of immunotherapy; and E. David Crawford, MD, talks about screening controversies.

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The Third Annual Interdisciplinary Prostate Cancer Congress (IPCC) took place March 27 in New York, New York. ArcMesa Educators organized the event, which was open to urologists, radiologists, and medical oncologists. Seating was limited, and Judy Lum, MPA, president of ArcMesa, said they had to add extra rows to accommodate the number of people who signed up to hear the nationally known experts speaking at the event.

Prostate cancer is the most common cancer in men of all races in the United States, with an annual incidence of ~153 cases per 100,000 men. This exceeds the 119 cases of breast cancer diagnosed per 100,000 women each year. The yearly number of deaths from breast and prostate cancer per capita are nearly the same, at 23.6 prostate cancer deaths per 100,000 men and 23.4 breast cancer deaths per 100,000 women. Even so, there are far more national meetings dedicated exclusively to breast cancer than to prostate cancer, creating a need for regional meetings like the IPCC to keep community oncologists and others who treat men with prostate cancer abreast of the latest developments.

Co-chair Leonard G. Gomella, MD, Bernard W. Godwin Professor of Prostate Cancer, chairman of the Department of Urology, and associate director of clinical affairs at the Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, opened the meeting. “When you look at different people with prostate cancer, it is really almost different diseases—how it is detected and how it is treated,” said Gomella.

FIRST THINGS FIRST: RISK REDUCTION

The first session, presented by Gomella, focused on prostate cancer prevention, a logical place to begin since preventing the disease would be greatly preferred to treating it. “In reference to prostate cancer chemoprevention…it’s not really clear if we’re preventing prostate cancer from developing per se or reducing the risk of being diagnosed with clinically important prostate cancer,” Gomella said.

Prostate cancer is an ideal malignancy to seek to prevent because it takes years to grow, said Gomella, and it begins with a precursor lesion, such as a prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP). “Now, some people debate whether a PIN or an ASAP are histologically early markers of the development of prostate cancer,” Gomella said, “but in general, it’s accepted.” This gives clinicians ample time to intercede, either in the premalignant state or in early disease.

Gomella described a famous study done at Wayne County University in Detroit, Michigan, in the early 1990s. Any male aged 10 to <50 years whose death was due to traumatic causes and required an autopsy had his prostate removed and examined for signs of cancer. Out of 152 prostate glands, 36 (24%) had PIN. The incidence of PIN for men in their 20s was 9%, but all cases were low-grade and none in this subgroup had prostate cancer. The rate of PIN jumped to 20% for men in their 30s, who had a 27% rate of prostate cancer; rates were even greater in the 40- to 49-year-old demographic, reaching 44% for PIN and 34% for cancer. Gomella said, “Clearly, this is a wake-up call to say, ‘Gee, if we’re going to prevent prostate cancer, maybe we need to start thinking about it a little earlier than waiting until a man is 50 to 60 years old,’” a man who Gomella described as only becoming concerned about prostate health after hearing one of the many radio advertisements targeting his demographic.

Prevention Strategies

“Hormonal prevention today is really the big dog,” explained Gomella. “Other strategies being looked at include dietary factors—fat, soy, lycopenes; COX-2 inhibitors; vitamins D and E; and micronutrients like selenium,” he said. Gomella noted there are data from large clinical trials that support or refute some of the recent thinking on prostate cancer prevention and seem to indicate that dietary measures have limited utility.

In recent decades, several major trials have investigated various avenues for preventing prostate cancer, Gomella said, singling out SELECT (Selenium and Vitamin E Cancer Prevention Trial), PCPT (Prostate Cancer Prevention Trial), and REDUCE (Reduction by Dutasteride of Prostate Cancer Events). “The field should be very proud of [these chemoprevention trials] and they deserve more attention,” he added.

SELECT tested claims that selenium and vitamin E could reduce the risk of prostate cancer. Approximately 32,000 men aged >55 years with a low risk of prostate cancer were randomized to take placebo only, vitamin E or selenium, or vitamin E plus selenium. Not only did the supplements fail to reduce cancer, men taking only vitamin E had a higher rate of cancer (Table 1). Investigators also observed a statistically insignificant increase in diabetes among men taking only selenium. The study closed about 6 years ago because of these adverse findings but the men continue to be followed. “Our patients are still taking a lot of vitamins under the misperception that vitamins help,” Gomella cautioned.

Gomella said hormonal manipulation appears to be the way we are headed with prostate cancer prevention and highlighted data from PCPT, which enrolled nearly 18,000 men considered at low risk for prostate cancer, and REDUCE, which had 8121 patients evaluable for efficacy. These placebo-controlled studies affirmed that 5-alpha reductase inhibitors (5-ARIs) such as dutasteride (Avodart) and finasteride (Proscar) decrease the relative risk of prostate cancer. After 7 years of treatment, PCPT associated finasteride with an 18.4% relative risk of prostate cancer compared with 24.4% for placebo. REDUCE looked at men believed to be at high risk of prostate cancer. Biopsies in the first 2 years found higher rates of prostate cancer in men on placebo, but biopsies in the next 2 years showed higher rates of prostate cancer for men on dutasteride.

Unlike PCPT, the REDUCE trial did not find a significant increase in high-grade tumors for men on dutasteride. Gomella believes the higher rate of cancers seen in the second years of the REDUCE trial with finasteride is because 5-AR inhibition resulted in slower tumor growth, while cancers in the placebo group grew unabated and were detectable earlier. These men were weeded out, which meant cancers in the placebo group at the second go-around were new cancers, whereas cancers in the dutasteride group at the second round of biopsies probably included some that were simply too small to be detected the first time around. A similar effect may account for the greater number of highgrade cancers seen in men taking finasteride in the PCPT study: low-grade tumors remained too small to detect, but finasteride could not hold the growth of the aggressive high-grade tumors in check.

Contrary to the idea that using finasteride and dutasteride might invalidate the clinical utility of PSA, Gomella said they actually enhance its usefulness. “Both studies showed the performance of the PSA [prostate-specific antigen] and PSA rise were actually improved in the 5-ARI arm…[In REDUCE], men who experienced any increase in PSA levels were likely to have prostate cancer on biopsy,” Gomella said and suggested this should be investigated further.

While both 5-ARIs have been approved as treatments for benign prostatic hyperplasia (BPH) and finasteride is also approved to treat male-patterned baldness, neither is approved to prevent prostate cancer. In 2009, the American Society of Clinical Oncology and the American Urology Association released new guidelines on prostate cancer chemoprevention using 5-ARIs. The guidelines recommend using a 5-ARI in asymptomatic men who have a PSA ≤3.0 ng/mL and receive regular prostate screenings.

There is no consensus on whether men at greater risk of prostate cancer should be treated with 5-ARIs. Gomella said because the risk of the disease in men with certain elevations in PSA clearly exceeds the risk of stroke or invasive breast cancer— both conditions where medication is prescribed to mediate risk—the studies suggest it is “reasonable to move forward with more clinically firm recommendations.” Data from REDUCE were published last month in the New England Journal of Medicine and confirm that dutasteride was associated with an absolute risk reduction in prostate cancer of 5.1% compared with placebo. It also reduced the rate of precursor lesions and improved symptoms of BPH.

In addition to considering finasteride or dutasteride with informed consent for men at high risk of prostate cancer, Gomella advised clinicians to encourage patients to participate in clinical trials, get screened, follow low-fat diets, and exercise. He advised against recommending vitamin E and selenium but said vitamin D and soy supplements probably will not hurt. He finished by paraphrasing a Chinese quote he said was from 2600 BC: “Superior doctors prevent the disease, mediocre doctors treat the disease before it is evident, and inferior doctors treat the disease when it is evident.”

IMMUNOTHERAPY

Daniel P. Petrylak, MD, director of the Prostate Cancer Program and professor of medicine, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York, also co-chaired the IPCC. With the pending FDA approval of Provenge (sipuleucel T), an immunotherapy vaccine for prostate cancer that uses dendritic cells (DCs), his presentation on immune therapy approaches to prostate cancer was highly relevant to the audience. Petrylak discussed available data on the effectiveness of some of the vaccines in development and other options under investigation for immune modulation in prostate cancer. He also talked about the questions that remain unanswered, such as when it is the optimal time to administer an immunotherapy vaccine.

Among vaccines, Petrylak said there are tumorantigen vaccines to immunize a patient against the antigens that activate tumor-specific T-cell responses and vaccines using autologous DCs. Petrylak said DCs can be stimulated by agents such as granulocyte macrophage colony-stimulating factor (GM-CSF) and lenalidomide (Revlimid), a drug Approved for multiple melanoma. “Cytokines can be combined with DC stimulation; anti-CTLA-4 blockade, which essentially blocks T suppressor cells, can engender an immune effect; and there are small molecule agents that can cause immunemodulating activity,” he said.

Vaccines

Petrylak began by questioning whether the lack of evidence demonstrating progression-free survival (PFS) with vaccines would influence views on using this method to treat endocrine-resistant prostate cancer. “If you don’t see an improvement in PFS but there is an improvement in overall survival (OS), is that something that causes concern?” he asked the audience. Their electronically tabulated responses showed that most clinicians in attendance felt it was important that vaccines improve PFS. Petrylak said he planned to repeat the query at the conclusion of his presentation to see whether any minds were changed.

“[Vaccines are] an active form of immune therapy,” said Petrylak, “and prostate cancer seems to be an ideal candidate for this type of treatment.” He said there were several disease states in which a vaccine could be used, like in cases of PSA progression following androgen resistance. He noted that prostate cancer has a panoply of antigens that could be potential targets for vaccine therapy, such as PSA, prostate acid phosphatase (PAP), prostate membrane-specific antigen, and MUC-1.

Various vaccines have been studied, including vaccinia and fowlpox viruses engineered to express human PSA, which were administered alone or in different sequences. The 21 patients that received 1 dose of vaccinia followed by 3 doses of fowlpox had the highest rate of stable disease, at 85.7%. At 19-month follow-up, 45.3% of patients had not experienced PSA progression, 78.1% had clinical PFS, and 46% had an increase in PSA-reactive T cells, data that Petrylak said “tell us that we are hitting the target with this particular approach.” The vaccines were not particularly cytotoxic, and all adverse events were grade 1-2. The vaccines are still being studied.

GVAX was an allogeneic vaccine evaluated in metastatic prostate cancer. It showed great promise initially, but 2 phase III studies were terminated early after a high number of deaths in the treatment arm were observed in one and after it failed to improve OS in the other. Cell Genesys, which created GVAX, discontinued further study of the vaccine in prostate cancer.

Autologous DC vaccination is another way to stimulate the immune system in men with castrateresistant prostate cancer (CRPC), and Petrylak said sipuleucel T was the most developed and studied of DC vaccines. Sipuleucel T is an antigen stimulated against PAP and trains the immune system to attack prostate cancer cells. “One of the advantages of using PAP is that it is not expressed anywhere other than the prostate, and it is expressed in about 90% of prostate cancer tumors,” Petrylak said.

To create the sipuleucel T vaccine requires obtaining recombinant PAP molecules and DCs from the patient using apheresis. After the resting antigen presenting cell takes up the PAP, the cells are reinfused in the patient. The process takes approximately 4 days and is repeated 3 times. Sipuleucel activates the T cells, which proliferate and attack the cancer cells.

In D9901, the first randomized trial, and the subsequent D9902A and IMPACT trials, sipuleucel T demonstrated significantly improved T-cell mediated immune response and consistent improvement in median OS. This ranged from 3.3 months for D9902A to 4.1 months for IMPACT and 4.5 months for D9901 (Table 2). In addition, Petrylak said better 3-year survival was consistent across the board for patients treated with sipuleucel T, at 32% for both D9902A and IMPACT and 34% for D9901. This compares with OS rates in the placebo groups of 21% for D9902A, 23% for IMPACT, and 11% for D9901. In the first two trials, these results were considered significant, though Petrylak acknowledged the trials’ small size might be a limiting factor.

“The approval of sipuleucel T will require clinicians to rethink how they will sequence therapy,” Petrylak cautioned. He said there is evidence to suggest that sipuleucel T results in prolonged activation in the immune system, and it is important to consider whether this would affect subsequent therapies, such as chemotherapy. Additional trials are needed, he said, to determine the optimal order for treatment.

Petrylak said he believes the 18- to 24-month period of stability that begins rapidly after castration— when patients are asymptomatic and have a lower burden of disease—is the “ideal place in the metastatic setting to go forth with immunotherapy for prostate cancer.” He said he does not think PFS is likely the appropriate endpoint for evaluating immunotherapies and other measures should be considered. Petrylak touched briefly on CTLA-4 blockade as a way of stopping immune suppression. He said there might be effective ways to use it to augment DC vaccination.

As promised, before closing his remarks on this topic, Petrylak again surveyed the audience on whether the poor showing for PFS associated with immunotherapy gave them concern about using it in prostate cancer. The number of people answering “yes” dropped significantly.

SCREENING CONTROVERSIES

E. David Crawford, MD, professor of Surgery (Urology) and Radiation Oncology Head, Urologic Oncology and E. David Crawford Endowed Chair in Urologic Oncology, University of Colorado Health Sciences Center, Denver, addressed controversies in screening, which have escalated in the past month. Like the previous speakers, Crawford is well known for his active involvement in prostate cancer research. He has been an author on many major published studies.

“I would say that screening today, or early detection, is probably more in the limelight and more controversial than it has ever been in the past,” Crawford said. When prostate cancer became the most commonly diagnosed cancer in American men in 1989 and was identified as the second leading cause of death, Crawford said it left the healthcare system facing the question of what to do about it. “[Do we] throw up our hands and do nothing, try to prevent it, [focus on] early detection (also known as screening), or find a cure for advanced disease so we can cure it when everyone progresses to advanced stage prostate cancer?”

Crawford said there is plentiful data on screening in the SEER database and studies conducted around the world. At least one of these studies, from Tyrol, Austria, is flawed said Crawford. It showed a drop in the mortality rate for men with prostate cancer almost immediately after starting a screening program, with no drop seen in a nearby town that did not have a screening program. This decline in deaths was attributed to earlier intervention afforded by screening. “We looked at all this data…and we concluded it does not make sense to see a change in mortality rates so quickly after adopting screening,” he said and suggested the earlier treatment instead prolonged their lives, increasing the likelihood of death from other causes. “Most patients who are diagnosed with localized prostate cancer today do not die of the disease; they die of something else,” Crawford noted. Other factors, such as overall better medical care and the development of statins might be contributing to longer lives, he theorized.

Crawford said he agreed with assessments of PSA as the “most important tumor marker in oncology,” because it allows clinicians to follow patients, assess response to treatment, and determine recurrence. Although reasonably helpful in testing for disease, Crawford said, “It lacks in specificity and sensitivity— it is not a bad test, but it is not a perfect test.”

Prostate Cancer and Prostatic Disease

He pointed to a study he published recently in that found prostate cancer costs $8 billion per year, accounting for 11.2% of all cancer expenditures. “In the first year after diagnosis, even if you choose watchful waiting, it is expensive. Once that diagnosis is made, the train has left the station, so to speak, in a lot of areas,” Crawford said. He added that his study found the first year of treatment to total a median of $40,873.20. This should be considered, implied Crawford, when deciding how aggressive to be in screening for prostate cancer. “Once you get a biopsy, probably the most dangerous thing is to find cancer, because there is no question that we are overtreating a lot of prostate cancer,” he said.

Crawford highlighted data from the PLCO Cancer Screening Trial, in which he participated. Approximately 155,000 men and women aged 55 to 74 years were screened from 1993 to 2006 for various cancers. A randomized group of 38,000 men received PSA testing annually for 6 years and a digital rectal examination annually for 4 years. Follow-up, which consists of an annual survey and mortality searches, will continue until 2015. The planned analysis at 10-years’ follow-up found that more cancers were detected in the screening arm, as expected, but there was no reduction in prostate cancer deaths in the screening group versus the usual care group (n = 38,000). There were, however, more high-grade cancers detected in the control arm than the screening arm (11% vs 8%, respectively).

What Crawford said was notable is the absolute number of deaths from prostate cancer at 10 years in this very large study. Approximately 3000 cases of prostate cancer were detected, and 92 men in the screened group died from the disease compared with 82 in the control group. “Out of ~3000 cases, not a lot of people had died of prostate cancer at 10 years,” he said. “After subtracting deaths due to prostate, colorectal, and lung cancer, the number one thing people died from was cancer, which caused 23% of deaths in both groups.” This was followed by ischemic heart disease, stroke, other circulatory conditions, respiratory disease, and digestive disease.

Crawford said some might consider the study contaminated because men in the control arm were not prevented from getting screened, and a fairly high percentage of them did so. He said they are conducting surveys to help assess the level of contamination. He said that, regardless, in weighing the benefits of screening against the harm of unnecessary treatment, the data “do not support routine screening at this time.” He suggested the real need is to separate diagnosis from treatment. “A lot of the criticism stems from the fact that men who are diagnosed want to be treated, leading to overtreatment. Maybe we should think of watching them,” said Crawford. He added that it would help if clinicians had better ways to figure out which men are likely to die from prostate cancer and could focus on improving protocols for screening and treating this group.

COMING UP

Oncology Net Guide

Contemporary Oncology

The Congress discussed several other topics, including the latest technologies in radiation oncology, which appears in the May issue of . Crawford reviewed targeted focal therapies for localized prostate cancer, Petrylak talked about the evolving role of systemic chemotherapy in managing CRPC, and Gomella discussed androgen deprivation therapy issues. Robert Dreicer, MD, MS, FACP, chairman of the Department of Solid Tumor Oncology at the Taussig Cancer Institute, Cleveland Clinic; and professor of Medicine at the Cleveland Clinic Lerner College of Medicine in Ohio, spoke on agents being developed and investigated for the management of metastatic CRPC (or HRPC) and on bone targeting in CRPC. Some of these studies will be presented in the June issue of . Videos of the entire conference and a posttest for CME accreditation will be posted online at www.arcmesa.org.