Prostate Cancer

The American Society of Clinical Oncology's newest practice guidelines for the treatment of prostate cancer, published this spring, were based on seven randomized trials, a systematic review of the literature, and one meta-analysis, yet questions regarding optimal treatment still leave oncologists in a quandary, noted experts interviewed for this article. “We have resolved some issues,” said Philip Kantoff, MD, Professor of Medicine at Harvard Medical School and the Scientific Program Committee Track Leader in Genitourinary Cancer for this year's ASCO Annual Meeting. “For instance, we know that intermittent androgen-deprivation therapy is a reasonable strategy—as good as, or even better than continuous therapy, and certainly preferable to surgical castration—but we don't know whether adding chemotherapy provides additional clinical benefit.” He said that whereas some treatments are well accepted, others are controversial and challenging. He listed the following as being in the “iffy” zone: ▪ The length of time that patients should be kept on androgen-deprivation therapy, especially in locally advanced disease. ▪ Intermittent vs continuous androgen-deprivation therapy, as well as immediate vs delayed treatment and how to account for various confounding factors. ▪ The presence of serious and common side effects of androgen-deprivation therapy. ▪ The development of other treatment modalities that could enhance the clinical benefits of androgen-deprivation therapy (ADT). Figure: Philip Kantoff, MD: “We know that intermittent androgen-deprivation therapy is a reasonable strategy—as good as, or even better than continuous therapy, and certainly preferable to surgical castration—but we don't know whether adding chemotherapy provides additional clinical benefit.”Age Makes a Difference “In hormone therapy, it's not how much you give, but how long the effect lasts—and it's much longer in older men,” said Anthony V. D'Amico, MD, Professor and Chief of Genitourinary Radiation Oncology at Dana-Farber Cancer Institute. Men over age 70 are much more sensitive to hormone treatment than younger ones are, and “if you give an older man six months of ADT, you'll probably get two years of benefit. Recent data have shown that there is a longer time to return to baseline testosterone level with advancing age, as well as a significantly lower risk of prostate cancer-specific and all-cause mortality.” He described a study of 214 men who received radiation therapy and six months of androgen-deprivation therapy. There was a significant association between return to baseline testosterone level and the risk of mortality. Moreover, the study validated the association between advancing age and time to baseline testosterone after discontinuing ADT. Thus, said Dr. D'Amico, “Older men will generally require shorter courses of ADT than younger men to achieve the same survival benefit.” He added that this is particularly important in view of the growing evidence of ADT's metabolic and cardiovascular toxicity. Immediate vs Delayed Treatment Dr. D'Amico said that patients with localized disease have a small but statistically significant increase in overall survival if hormone therapy is begun immediately after diagnosis—that is, external-beam radiation and three years of androgen-deprivation therapy—compared with the use of radiotherapy alone. In high-grade disease (Gleason 7 and a prostate-specific antigen level of 10 ng/mL or higher), a six-month course of ADT along with radiation confers a better survival benefit than radiation alone. However, ADT is known to cause serious cardiovascular events, he noted. “Before we begin hormone therapy, we do a cardiac evaluation, and we pay special attention to men known to have preexisting problems. If we find something, we clear it up before we start the cancer treatment.” The short delay makes sense. “You can die of heart disease in an instant, whereas prostate cancer takes years to kill you, so you take care of the faster disease first.” Lars Holmberg, MD, of the Department of Surgical Sciences at University Hospital in Uppsala, Sweden, said that deciding who should receive immediate treatment and who can wait is notoriously difficult because so many factors are associated with disease progression—for example, age at diagnosis, comorbidity, and Gleason score. Thus, observational studies of treatment effects run a high risk of selection bias. And because the confounding factors are often measured incorrectly, especially in retrospective studies, analysis is difficult. Nevertheless, he conducted the Scandinavian Prostate Cancer Group Study 4 (SPCG-4) from 1989 to 1999, with additional follow-up through 2003. A total of 695 men with T1b, T1c, and T2 disease were divided into two groups: One underwent immediate prostatectomy, and the other was assigned to watchful waiting. Other inclusion criteria were age younger than 75, life expectancy longer than 10 years, and a PSA of 50 ng/mL or less.Figure: Anthony V. D'Amico, MD: “In hormone therapy, it's not how much you give, but how long the effect lasts—and it's much longer in older men….Older men will generally require shorter courses of ADT than younger men to achieve the same survival benefit, and this is particularly important in view of the growing evidence of ADT's metabolic and cardiovascular toxicity.”Thirty men in the prostatectomy group died of prostate cancer, as did 50 in the watchful waiting group—a cumulative incidence of death at 10 years of 9.6% vs 14.9%. Dr. Holmberg also performed subgroup analyses (Gleason greater of less than 7; PSA of more or less than 10 ng/mL; tumor T1b-c or T2; and age younger or older than 65) to determine if any of these factors modified the effect of treatment. The only one that made a difference was age: Younger men in the watchful waiting group had a poorer prognosis, whereas older men had a prognosis similar to those in the radical prostatectomy group. Dr. Holmberg concluded, “The relative risk reductions indicate that there is a substantial potential to alter the natural history of the disease with early treatment, and the findings should inspire oncologists to continue developing new modalities.” Caveat However, he added a caveat about generalizing from these results: The study was conducted before PSA screening was in widespread use, which means that undetected micrometastases at the time of diagnosis and the element of overdiagnosis could not be taken into consideration. He also said there are obvious flaws in the subgroup analyses, especially the lack of power, so the absolute benefits of radical prostatectomy will differ in different subsets of men. Identifying Patients Who Can Wait Laurence Klotz, MD, Chief of the Division of Urology at Sunnybrook Health Sciences Center in Toronto, observed that there are 2.74 million men age 50 to 70 in the United States with a PSA of more than 2.5 ng/mL. If this was the only indication for biopsy, then some 775,000 cases of prostate cancer would be diagnosed this year alone—543,000 more than there actually are and 25 times more than will die of the disease. Since this is not a smart thing to do—nor is it practical—how does one identify the men who are at such low risk that they can have watchful waiting rather than be treated immediately? Dr. Klotz said that favorable risk can be predicted to some extent by a Gleason score of 6 or lower, a PSA level of 10 ng/mL or lower, and T1c-T2a disease. Gleason score is especially predictive, he said. Of a large group of patients in Connecticut, 23% of those with untreated Gleason 6 died of prostate cancer within 20 years, whereas 65% of those with untreated Gleason 7 did. But when the slides were looked at again after the Gleason grade interpretation shift, those scored as 6 two decades ago would now be classified as Gleason 7. Today, prostate cancer mortality of untreated Gleason 6 is probably as low as 10% at 20 years, Dr. Klotz said. Then, how to identify men for watchful waiting? The gold standard is a radical prostatectomy specimen containing less than 5 ml of Gleason 6 or lower, he said. However, this is not entirely foolproof. Other parameters include less than 3 mm of cancer in total and less than one-third of cores involved, but none of these have ever been validated in a clinical trial.Figure: Laurence Klotz, MD, said that current data suggest that prostate cancer patients do not need immediate treatment if they have a Gleason score of 6 or less, a PSA level of 10 ng/mL or lower, and T1c-T2a disease.In addition, because a short doubling time (less than three years) correlates with aggressive disease, median PSA doubling time (PSADT) in seven years may constitute acceptable risk, he said. However, using that as a trigger for treatment is also not entirely accurate because it may indicate aggressive disease that is no longer localized. Of a group of 299 patients (80% with Gleason 6 and 80% with PSA of 10 ng/mL or lower), after 72 months of follow-up, 101 came off active surveillance and 198 remained. After seven years, the overall survival rate was 85% and disease-specific survival rate was 99% for all patients. Only three of the original 299 patients have died of prostate cancer so far, all of whom were in the intervention group. As a result of these and other observations, Dr. Klotz concluded that patients do not need immediate treatment if they have a Gleason score of 6 or less, a PSA level of 10 ng/mL or lower, and T1c-T2a disease. If patients are younger than age 60, the Epstein criteria of one-third or fewer positive cores and no more than 50% involvement of any one core should be applied. For men over age 75 (or who have a life expectancy of less than 10 years), PSA can be more than 10 ng/mL and Gleason score can be 7. Patients should have radical intervention during surveillance if the PSADT is less than three years, or grade progression is Gleason 7 or higher, Dr. Klotz said. Intermittent vs Continuous Treatment ASCO's guidelines say that current data are insufficient to recommend intermittent androgen blockade. Still, Dr. Kantoff said he is in favor of that, citing a randomized trial that compared it with continuous treatment, with a primary outcome of time to androgen independence of the tumor or escalating PSA despite androgen-deprivation therapy. Median follow-up was 29 months, and the estimated three-year androgen-independent disease rate was significantly lower in the intermittent group. More studies are obviously needed, and to that end, two large Intergroup trials are under way. One is still accruing patients, and the other will not produce results until 2013. How Long is Long Enough? A randomized study of localized prostate cancer was conducted in Canada to determine the optimum duration of hormone therapy. All the men had radiation therapy and were randomly assigned to receive either three or eight months of neoadjuvant androgen-deprivation therapy. After 3.7 years of follow-up, there was no significant difference in survival, and the five-year estimates also were about equal. Dr. D'Amico explained why the longer duration failed to show a benefit: “A course of ADT as short as three months is enough to provide its benefit when combined with radiation therapy.” What remains to be seen, he said, is whether radiation dose escalation above 70 Gy will improve outcome. The European Organization for Research and Treatment of Cancer Trial 22961 of 970 patients compared two groups of men with locally advanced prostate cancer. One group received two and a half years of ADT, and the other had radiation therapy plus eight months of ADT. The purpose was to determine whether men who have received radiation plus ADT need hormone treatment for more than six months in order to prolong survival. The results showed that progression-free survival was shorter for patients who received radiation and eight months of ADT. The bottom line for locally advanced prostate cancer, Dr. D'Amico said, is that use of external-beam radiation and three years of ADT has a survival benefit over the use of radiation alone. By the same token, men with localized disease will have a survival benefit after six months of ADT and radiation compared with radiation alone. When the cancer advances locally, treatment remains controversial for several reasons, he added: ▪ Ambiguities in staging. ▪ Inadequate knowledge of the natural history of the disease. ▪ Too few randomized trials that compare treatment efficacy. ▪ Uncertainty over chemotherapy for hormone-refractory patients. Androgen Receptors & Heat Shock Protein Androgen receptors play a crucial role in prostate cancer tumor development and progression. The disease depends on androgen, and most patients respond well to ADT—at least for a while. But many become refractory to hormone therapy while the androgen receptor continues to be expressed, noted Len Neckers, PhD, Senior Investigator in the Urologic Oncology Branch of the NCI's Center for Cancer Research. He suggested three mechanisms to explain how the receptor remains functional even though androgen levels are low: ▪ Although the androgen receptor gene is generally not amplified in primary prostate cancer, it is in about 30% of refractory disease. ▪ Androgen receptor mutations arise in hormone-refractory tumors, allowing the receptor to bind to and be activated by adrenal androgens and alternative steroids, including those used in hormone therapy. ▪ Activation of receptors can occur via phosphorylation mediated by various transmembrane tyrosine kinases, including epidermal growth factor receptor 2 (i.e., HER-2/neu), implicated in hormone-independent progression of the disease. Unfortunately, little progress has been made in translating basic science about androgen receptors into clinical therapy. There is ongoing debate about their role in proliferation vs differentiation in prostate cancer, and some experimental results have shown that androgen receptor levels can be modulated during intermittent ablation, Dr. Neckers said. But there's one piece of potentially good news: heat shock protein 90 (HSP90), a molecular chaperone for stability and function of a number of conditionally activated and/or expressed signaling proteins that promote cancer cell growth. When HSP90 inhibitors interact with a singular target, they cause inactivation, destabilization, and eventual degradation of several HSP90 “client” proteins. In addition, they have shown promising anti-tumor activity in preclinical models. “HSP90 inhibitors are unique in that, although they are directed toward a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival,” he said. Phase I and II studies are now being conducted with the HSP90 inhibitors 17-allyaminogeldanamycin (17-AAG), and 17-NN dimethyl ethylene diamine-geldanamycin (17-DMAG). Both can short-circuit the HSP90 chaperone machine, much as one would stop the rotation of a bicycle wheel by putting a stick between the spokes, Dr. Neckers explained. HER2 is an extremely sensitive HSP90 client protein. Within 90 minutes of exposure to 17-AAG, HER2 cells lose half of their overexpressing protein, which falls to undetectable levels in several hours, he said. “Thus, 17-AAG, by modulating HSP90 activity, promotes not only inactivation and destabilization of the androgen receptor itself, but also destruction of key components of the dual-kinase cascades that promote activation of the androgen receptor in advanced hormone-refractory prostate cancer.”

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