FROM THE 2006 ASCO/ASTRO/SUO/PCF PROSTATE CANCER SYMPOSIUM

Merel Nissenberg, President of the National Alliance of State Prostate Cancer Coalitions (NASPCC), attended the 2006 Prostate Cancer Symposium in San Francisco this past Friday through Sunday. Here is her Report:

The meeting started off with exciting news regarding the reporting of a newly identified virus that may be causative of some prostate cancers. The research is in its infancy but Dr. Eric Klein of the Cleveland Clinic and researchers at UCSF discussed the newsworthy possibilities.

Highlights of Day One: Obesity and Prostate Cancer: UCSF reported that obese men are more likely to have positive surgical margins but that their risk of biochemical recurrence, second treatment and prostate-related death appeared to be no different than the non-obese group. They also stated that although diet and supplements may reduce the risk of prostate cancer, it is unknown whether they have an effect in men already diagnosed. Duke researchers believe that obesity seems to be associated with more aggressive prostate cancer but stated that recent studies show that obese men may actually have a lower risk of being diagnosed with the disease. (There may be other barriers to diagnosis.) There was also news of several trials involving micronutrients i.e. PRPI Trial and the Selenium and Vitamin E Cancer Prevention Trial.

Finasteride: There was early closure of the PCPT trial, due partly to an unexpected high rate of high-grade disease in that arm (Gleason 8-10). Dr. Peter Scardino
recommended that the drug not be used solely to prevent prostate cancer.

PSA and Screening: Dr. Talcott from Mass General argued that 80% of diagnosed men have unnecessary treatment with unwanted side effects and that the treatment does not improve overall survival. On the other hand, Dr. Bill Catalona, giving the SUO Lectureship, argued that benefit outweighs the harm. He stated that the majority of PSA-detected cancers are clinically significant and that PSA correlates with the risk of cancer as well as with Gleason grade and PSA Volume, which in turn correlate with progression-free survival. His studies show that less than 10% of tumors would have been classified as “insignificant” but that 20-30% of those had positive margins and beyond. He cited the Scandinavian study (4), reporting benefits in men undergoing radical prostatectomy (RP), rather than watchful waiting (WW). He urged wise clinical judgment.

Dr. Mitchell Benson, Chair of Urology at Columbia, maintained that PSA is an important component in diagnosing T1c Gleason 8-10 prostate cancer and that it provides an opportunity for timely treatment and cure. He suggested we treat prostate cancer aggressively, using multimodal adjuvant therapy where appropriate, including new drugs from trials involving men with hormone refractory disease.

Markers for Diagnosis of Prostate Cancer: There are new PSA Isoforms and other new avenues for diagnosis, such as by testing urine. There is now the PCA3 test - molecular testing of urine - and GSTP1 (urine), among others, which test serum, plasma, blood, urine or a combination.

Dr. Judd Moul of Duke University presented an Abstract showing that PSA Velocity (PSA-V) is age-sensitive and that the rate of change does in fact vary by age. Clifton Leaf of Fortune Magazine gave the PCF Special Lectureship and postulated that we need a large Google-like sharing of information in the field of prostate cancer so that we can make the appropriate advances and win the war on cancer. His ideas would transform the manner in which cancer research is compiled, stored and, more importantly, shared.

Day Two:
Best Treatment for Low and Intermediate Risk Prostate Cancer Here are the viewpoints:
a. Surgery: Benefits include the fact that we can remove the prostate with
precision and spare the neurovascular bundle and the sphincter, but of course this would be surgeon-dependent. Dr. Hartwig Huland of the University of Hamburg said that this is the treatment of choice for presumed pT2 tumors.
b. Brachytherapy: According to Louis Potters of the New York Prostate Institute,
it should be used only in organ-confined disease. The quality of the implant is paramount to determining the outcome. Age and treatment factors are significant in causing morbidity, but we derive greater benefit now from being able to determine the biologic effective dose (BED).
c. EBRT (External Beam): Dr. Deborah Kuban of M. D. Anderson described the recent technological advances being utilized. These include Intensity Modulated Radiation Therapy (IMRT), use of a Dose-Volume Histogram individualized to each patient, and the use of ultrasound or CT on the day of procedure to account for the “dancing prostate”. There is also hyperfractionated dosing. She presented data on an 89% 8-year disease free survival for low risk patients (78% for intermediate risk patients) at Memorial Sloan-Kettering using this modality.
d. Active Surveillance: (Formerly “watchful waiting”!) Dr. Laurence Klotz of the University of Toronto told attendees that 50% of newly diagnosed prostate cancer is “favorable risk”, that is, a Gleason 6 or less, with PSA less than 10 and the tumor T1c to T2a. Yet we must be cognizant of the risk that some patients, without therapy, will go on to become incurable while being “watched”. There is a challenge to stratify patients according to their risk of progression with active surveillance, using estimates of PSA doubling time (PSA-DT). If the PSA-DT is 3 years or less, the patients should be offered radical intervention, while the rest are monitored with serial PSA’s, and with repeat biopsies (at 1.5, 5 and 10 years). The START Trial is currently investigating this approach: Active Surveillance in 1 arm and the patient’s choice of standard therapy in the other (NCI).

Scandinavian Prostate Cancer Trial 4: Between 1989 and 1999 695 men were randomized to either a radical prostatectomy (RP) or watchful waiting (WW). 30 men in the RP group died, compared to 50 in the WW arm. Extracting out other causes of death, 23 more men died with WW. Importantly, in men younger than 65, the cumulative incidence of death was 2x that observed in the RP group. They concluded that RP allows for a statistically significant reduction in disease-specific mortality, overall mortality, risk of metastases and local progression.

PROTECT Study: Dr. Freddie Hamdy of the University of Sheffield charmed the audience with his picture on the left of the screen of a prostate and the question whether
RP improves the quality of life for the patient…and then showing a large yacht on the
right side of the screen with bikini-clad women aboard and the question: “…or the quality of life of the surgeon?”!!!! (He then admitted it wasn’t his boat and they weren’t his nieces…) He reported on the Phase II (the main treatment) trial taking place in the UK at 9 clinical centers. The report was interesting because the UK has never prioritized screening for prostate cancer. The primary endpoint of the 3-arm study will be survival to 10 years. The patients will be randomized to monitoring, surgery or radiation therapy.

Unfavorable Risk Prostate Cancer: Dr. James Montie of the University of Michigan told the attendees that you must have successful local therapy first – either by RP or RT. A combination of both (with RT either adjuvant or salvage) seems to provide the best control. Outstanding control can be achieved by RP + RT =/- Androgen Deprivation Therapy (ADT). He cited an article in the Journal of Oncology 20: 3199, 2002. Dr. Mack Roach of UCSF recommends RT in very high doses for these unfavorable-risk patients. He stressed the need for prospective, randomized trials, and stated that currently it seems that local, regional and systemic disease can best be treated with neoadjuvant hormonal therapy, followed by IMRT to the pelvic nodes and brachytherapy followed by long-term androgen deprivation.

Oral Abstract Presentations on Locally Advanced and Recurrent Disease: Chaired by Dr. Maha Hussain of the University of Michigan, this informative session covered various papers, such as one detailing how blacks with prostate cancer still have a large survival difference (11% less) from white prostate cancer patients even in the face of more organ-confined disease for African-American males. Access to screening, diagnosis and therapy must be increased for this group. Another Abstract presented data that showed that in men undergoing RP, the outcome was less a result of biology and stage of prostate cancer and more the end-product of the skill of the surgeon in doing the RP.

Following PSA Failure: Dr. Anthony D’Amico of the Dana Farber Cancer Institute in Boston discussed the calculations of PSA Doubling Time (PSA-DT). It is comprised of PSA greater than 1.0 ng/ml and 2 consecutive rises of at least 0.2 ng/ml; no androgen suppression until the PSA reaches 10. If the patient at PSA failure was younger than 75 and the PSA-DT was less than 6 months there was a significant decrease in overall survival. (The PSA-DT value for this in younger men would likely be higher.) Additionally, PSA failure deaths predominantly occurred in men with a PSA-DT of less than 6 months, regardless of age. PSA failure did not appear to shorten survival unless the PSA-DT was less than 6 months.

Treat or not treat after PSA failure: Dr. See of the Medical College of Wisconsin advised that these patients should be treated but that the physician should educate the patient regarding the advantages and disadvantages of salvage therapy i.e. individualize recommendations, especially considering there is no proven survival benefit for salvage therapy but there is patient demand. Let the patient decide. On the other hand, Dr. Ian Tannock of Princess Margaret Hospital in Toronto recommended NOT treating. He believes that immediate treatment after PSA failure is not justified. We need to balance benefit and harm, he urged; he reported that there is no data to support the routine use of additional local therapy, nor that treatment of a PSA relapse will improve survival or
prevent/delay symptoms.

Survivors’ Perspective: Dr. John Wei of the University of Michigan discussed the increased emphasis on health-related quality of life (HRQOL) outcome measures in recommending treatment for prostate cancer patients. He told the attendees that, in general, post RP complications peak and remain stable after 2 years, while post-radiation HRQOL may continue to evolve. Dr. Tia Higano of the University of Washington offered “A Survivor’s Guide” to hormone therapy, broken down into symptoms of what you feel,
what you see, and what you don’t see, relative to the “Big 3”: Loss of Libido, Erectile Dysfunction and Hot Flashes. She urged physicians to prevent further morbidity for these patients by employing interventions for various complications.

Dr. Raghaven of the Cleveland Clinic discussed the two important trials regarding chemotherapy: Tax 327 and SWOG 9916. Both demonstrated levels of toxicity with chemotherapy. He stated that there may in fact be an UNDERestimation of the late toxic effects of chemotherapy.

Day Three:
Optimizing Systemic Therapy for Prostate Cancer: Dr. Robert Dreicer also of the Cleveland Clinic discussed hormonal therapy as monotherapy. There has been a large increase in the use of ADT, especially early use of such therapy. He stated that cure is not a goal but rather possible improvement in survival and a drive to lessen/delay the morbidity associated with the disease. Dr. Dreicer stressed that hormonal therapy is NOT benign and we need to consider alternative strategies to continuous testicular suppression. He suggested increased monitoring of serum testosterone levels.
Dr. Cora Sternberg of San Camillo and Florlanini Hospitals in Rome described when and how to treat with chemotherapy for hormone-refractory disease. She stated that both TAX 327 and SWOG 9916 demonstrated that a docetaxel regimen can reduce the risk of death by 20-24%. She also mentioned the SPARC trial underway which will compare satraplatin plus prednisone to prednisone alone. However, there are no trials regarding the timing of chemotherapy. She recommended chemo if the patient is asymptomatic with extensive metastases or symptomatic with mets. Intermittent chemo may also address toxicity concerns. Finally, Dr. Hussain discussed several new agents in clinical trials, addressing such targets as DNA, VEGF, histones, EGFR and HER-2, and the endothelin receptor. This last target is being studied in a clinical trial involving Atrasentan.

Novel Targets and Approaches: Dr. Eric Small of UCSF presented a talk on the rationale for Immunotherapy in prostate cancer. He discussed G-VAX, Provenge and CTLA-4 Blockade-based Immunotherapy, all of which have exciting possibilities. He stated that the overall survival benefit seen with Provenge seemed to be significant. There were other papers covering other targets arising out of epigenetics and modification of proteins. EGFR and HER-2 were discussed as potential therapeutic targets.

ASCO Special Lectureship – by Dr. Donald Coffey: In his own inimitable way, Dr. Coffey’s presentation was provocative and asked WHY some treatments work – citing

Lance Armstrong as an example. The talk included self-organization, chaos and how hyperthermia increases the effect of chemotherapy and radiation. He said that cancer cells are sensitive to heat and are killed by heat before normal cells. If you direct the hyperthermia directly to the tumor, you can enhance immunology, RT and chemotherapy.

Measuring Outcomes: Finally, there were presentations on PSA as a surrogate marker, using the Prentice Criteria – which must meet four statistical tests. There was also advice
on how to get a drug through the FDA – citing the fact that docetaxel plus prednisone was approved for patients with hormone-refractory metastatic prostate cancer based upon the fact that there was an improvement in survival compared to mitoxantrone plus prednisone.

All in all, the 2006 Prostate Cancer Symposium was an exciting and informative meeting, with many exciting possibilities on the frontier. We look forward to the 2007 meeting!

More more information from the ASCO Meeting.

Merel Nissenberg, President, NASPCC