The 2008 annual American Society of Clinical Oncology Genitourinary (ASCO GU) meeting, held in San Francisco, continued the tradition of delivering progressive and thought-provoking data and discussions, with the focus being refinement of optimal care for patients with genitourinary cancers. Results from the meeting focused on prostate cancer, renal cell carcinoma, bladder cancer, and testicular cancer. Specifically, some of the highlights of the 2008 ASCO GU conference included:
- Conservative management as an acceptable treatment approach for elderly patients with early prostate cancer
- Radiation therapy as an effective treatment modality for prostate cancer recurrences
- Treatment for metastases of renal cell carcinoma
Results presented at the 2008 ASCO GU added momentum to the already robust movement toward individualized treatment approaches for nearly all types of cancers. Emerging results continue to aid in guiding therapeutic decisions; however, more questions continue to develop as it becomes increasingly evident that we are still in the infancy of “tailoring” therapy.
Optimal treatment of elderly patients with early prostate cancer continues to be a source of debate, as many of these patients will die from causes other than prostate cancer. Thus, the balance between providing optimal survival while preventing over-treatment, which can severely diminish quality of life, remains a key challenge in this patient population. Identification of clinical and patient variables that can help guide treatment decisions, a focus of current research, is often accomplished through extensive reviews and retrospective analyses.
Lu-Yao G, et al. from the University of Medicine and Dentistry of New Jersey in New Brunswick conducted a population-based cohort study evaluating the trajectory of prostate cancer among men who received initial conservative management for early-stage disease in the PSA era. Most studies to date that evaluate the efficacy of initial conservative management in early-stage prostate cancer include data obtained from the pre-PSA era, generally considered to be before 1985, the year in which routine PSA screening became common.
The study included 9,018 men, 64% of whom had T1 disease, 36% of whom had T2 disease, and more than 5,000 of whom were over age 75. Patients were diagnosed with prostate cancer between 1992 and 2002 and had not received initial local therapy or androgen deprivation therapy within six months of their diagnosis. Data from the study were obtained from Medicare claims data linked with the Surveillance, Epidemiology, and End Results (SEER) database.
- 2,675 men received some form of therapy at a median of 10.6 years from diagnosis.
- 10-year prostate cancer mortality rates for men aged 70-74 were approximately 2%, less than 5% and 20% for low-, moderate- and high-grade prostate cancers, respectively.
- Among men aged 66 and older, more than 80% remained alive without complications or had died of causes other than prostate cancer at over 10 years following diagnosis.
These data indicate that conservative management may be an appropriate therapeutic decision for elderly men with low-grade, early prostate cancer. However, caution was expressed that conservative management places some elderly patients with early-stage prostate cancer at risk, particularly those with higher-grade cancers. Importantly, co-morbidities and patient wishes play crucial roles in deciding upon the most appropriate therapy for these patients.
Although routine PSA screening may improve survival in prostate cancer, a diagnosis of prostate cancer is also linked to significantly increased fatal cardiovascular events within the year of diagnosis. In fact, this risk was significantly increased within the first seven days of diagnosis.
Researchers from the Karolinska Institute in Stockholm, Sweden, conducted a study in which outcomes for incident prostate cancer of nearly 150,000 person-years was analyzed. Data were obtained from recordings in the Swedish Cancer Register, which includes nearly complete coverage of the Swedish population. Five matched controls per case of prostate cancer were randomly selected from the Swedish national census in 1990.
- Fatal cardiovascular events occurred at a 50% greater rate among patients diagnosed with prostate cancer than controls (even after controlling for year of diagnosis [1961 to 2004] and age).
- Nonfatal events occurred at a 30% greater rate among those with prostate cancer than controls.
- Interestingly, men without traditional risk factors assumed the greatest risk for a fatal cardiovascular event.
- The first seven days following diagnosis carried the greatest risk for events; during this time period, fatal events increased by eightfold among those with prostate cancer compared with controls.
- The rate of fatal cardiovascular events has dropped since 1961; however, the rate of nonfatal events has remained steady.
Following the presentation of these data, the inevitable risk/benefit discussion surrounding screening of the general population arose. Although there was mention that general PSA screening may be an excessive practice, the ultimate emphasis of the discussion focused on the idea that physicians need to discuss PSA testing with their patients prior to ordering the test. This way patients are able to ask questions and understand potential consequences of test results as well as options available to them. These discussions may ultimately help to ease emotional stress associated with a diagnosis of prostate cancer, the suspected culprit of the increased cardiovascular events.
In line with the findings that conservative management may be the most appropriate therapeutic option for some elderly patients with low-grade, early-stage prostate cancer, and that cardiovascular events are significant following the diagnosis of prostate cancer, Dr. Katz and colleagues from Saints Medical Center in Lowell, Massachusetts, explained that the majority of deaths within four years of diagnosis of prostate cancer were not related to the cancer itself. The researchers conducted a retrospective, observational study that included the analysis of 7,042 men in the observational CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) study who were treated with either a radical prostatectomy or radiation therapy. Patients had biopsy-proven prostate cancer diagnosed between 1990 and 2003. The median time to death from any cause was four years after treatment. Analysis of the data also included the effects of statin or NSAID use on overall mortality among these men.
- Risk of death from any cause was reduced by 41–65% among men who reported taking statins following therapy.
- As well, the use of NSAIDs following therapy also reduced risk of death from any cause by 53–61%.
- The benefit from statins or NSAIDs was not realized if patients reported taking the medication only within the first year following therapy.
- Men taking statins and/or NSAIDs tend to have more comorbid conditions than other patients, such as hypertension, diabetes, lung disease, prior stroke, and obesity.
- Mortality from prostate cancer at four years was too uncommon to statistically analyze.
Data from this study provide supportive results that statins and NSAIDs may either play a role in the pathogenesis of prostate cancer and/or provide cardioprotective properties that all result in improved survival for patients with this disease. However, caution was expressed by the researchers that this study did not include variables-such as dose of statin, cardiovascular risk, or other important factors-that could potentially affect outcomes.
For men with node-positive prostate cancer, optimal timing of androgen deprivation therapy in the course of the disease remains unresolved. The standard therapeutic approach for these patients is early endocrine challenge; however, a significant number of practitioners remain proponents of delaying endocrine therapy until relapse. Again, the balance between providing optimal survival while maintaining quality of life for as long as possible among this group of patients remains the primary objective, while no clear-cut answers have been consistently produced by trials evaluating this issue. The trial that was the basis of adapting early endocrine therapy as standard-of-care in node-positive prostate cancer was published in the New England Journal of Medicine in 1999. This study, however, was heavily underpowered, but at the time provided data to fill a gap where answers were needed.
Researchers from Rotterdam conducted a clinical trial in an attempt to provide some clarification on this matter; specifically, the timing of androgen suppression therapy among men with node-positive prostate cancer. This trial was closed in 1998 due to slow accrual, with 234 patients who were randomized to either immediate endocrine therapy with goserelin monthly plus cyproterone acetate or the same treatment regimen upon disease progression. Patients had T2 to T3 non-metastatic prostate cancer with one to three positive nodes; follow-up was approximately 13 years.
- Overall survival and disease-specific survival were not significantly different between the two groups of patients.
- In nearly all patients in the delayed group, hormone therapy was initiated within four years of diagnosis.
Unfortunately, this trial was also underpowered, Nevertheless, it appears that these results have prompted new discussions into the optimal timing of androgen deprivation therapy for patients with node-positive prostate cancer. As well, these findings support the favored approached of some healthcare providers who recommend delay of ADT until disease progression in this group of patients. Future comparative trials are necessary to truly answer this question; such trials will need to include subgroup analyses in order to remain up-to-date with the idea of individualizing therapeutic approaches.
Dr. D’Amico and colleagues conducted a trial comparing ADT plus radiation therapy with radiation therapy alone for the treatment of localized prostate cancer. This was a prospective randomized trial conducted between 1995 and 2001 that included 206 men with at least one unfavorable prognostic factor. All-cause mortality (ACM) was analyzed by treatment arm as well as stratified by the Adult Comorbidity Evaluation-27 comorbidity score. Androgen deprivation therapy (ADT) was administered for six months, and median follow up was 7.6 years.
- The risk of ACM was significantly decreased among those treated with ADT and radiation compared with those treated with radiation only (Hazard Ratio [HR] = 1.8; p=0.01).
- Men with minimal or no comorbidities were the only patients to derive benefit from the addition of ADT.
- Men with moderate or severe comorbidities who were treated with radiation only experienced a decreased risk of ACM that approached statistical significance (p=0.09) compared with this group of men treated with ADT and radiation.
The researchers concluded: “A significant interaction between comorbid illness and AST exists highlighting the importance of considering comorbidity when determining how best to manage a given individual.”
Researchers from Johns Hopkins University conducted a retrospective study to continue the evaluation of treatment upon biochemical recurrence following a radical prostatectomy. Dr. Trock and colleagues analyzed data from 635 men who had undergone a radical prostatectomy and experienced a biochemical recurrence. Of these patients 160 received salvage radiation therapy alone, 78 received salvage radiation and hormone therapy, and 397 received neither salvage radiation nor hormone therapy. The median follow-up was six years post-recurrence.
- 18% of patients died from prostate cancer.
- 98% of men with a PSA doubling time of six months or greater survived five years, regardless of treatment with radiation therapy.
- 95% of men with a PSA doubling time of less than six months who received salvage radiation survived five years compared with only 60% of this group of patients who did not received salvage radiation therapy.
- The 10year survival for men with a PSA doubling time less than six months was 82% for those who received salvage radiation therapy compared with only 30% among those who did not receive radiation.
- Results indicating an improvement with radiation therapy did not change after adjustment for Gleason score, time from surgery to recurrence, and year of surgery.
Although this was a retrospective study, the author suggested that if validated, these results could potentially support the use of radiation therapy as salvage therapy versus immediate adjuvant therapy for appropriate patients.
There were also presentations that included men who had advanced prostate cancer and had undergone extensive therapy already. Of concern recently has been the loss of bone mineral density (BMD) and increased fracture risk among men who have been on hormone therapy for any extended length of time. Bisphosphonates such as zoledronic acid and pamidronate have been extensively studied in these patients and have demonstrated an improvement in BMD with studies continuing. As well, agents such as denosumab are also being evaluated for improvements in BMD in the hopes that these patients can continue to benefit from hormone therapy while minimizing bone complications.
Dr. Broderick and colleagues from Loyola University Medical Center in Illinois randomized 93 prostate cancer patients at VA medical centers to zoledronic acid or placebo. Patients had nonmetastatic prostate with no osteoporosis at baseline. Fifty patients had been on hormone therapy for less than one year at baseline, and 43 patients had been on hormone therapy for more than a year upon initiation of the trial. All patients were started on vitamin D, calcium, and weight-bearing exercise.
- Among patients who had been on hormone therapy for less than one year upon initiation of the trial, BMD increased nearly 6% with zoledronic acid while decreasing 3.23% with placebo (P=0.0044).
- Among patients who had been on hormone therapy for more than a year upon initiation of the trial, BMD increased nearly 6.1% with zoledronic acid and nearly 1.6% with placebo (P=0.0005).
- The most dramatic BMD increases were the lumbar spine.
Follow-up of the trial was not long enough to evaluate bone fracture rates; however, the authors speculate that BMD measurements are assumed to be associated with bone fracture rates. These results indicate that bisphosphonate therapy also improves BMD following treatment on hormone therapy for more than one year as well as for those who have been on hormone therapy for less than that time. This provides more evidence that bisphosphonates or other agents increasing BMD may provide an important measure for patients on hormone therapy.
Recent progress in kidney cancer has been attributed to targeted agents such as sunitinib and sorafenib. Enthusiasm generated from these agents for the treatment of kidney cancer has spurred initiation of clinical trials evaluating other targeted agents for this disease, including bevacizumab.
Dr. Rini and colleagues from the Cleveland Clinic recently conducted a clinical trial further evaluating bevacizumab in metastatic kidney cancer. This randomized controlled trial compared bevacizumab plus alpha-interferon to alpha-interferon alone as initial therapy in more than 730 patients with untreated metastatic kidney cancer. Eighty-five percent of patients had received a prior nephrectomy; interferon was given at 9 MU three times per week and bevacizumab was given as a 10 mg/kg injection on days one and 15. An interim analysis was conducted, and results were presented at the meeting.
- Median progression-free survival was 8.5 months for those treated with combination therapy compared with 5.2 months for those treated with interferon alone (P<0.0001).
- Patients with no risk factors achieved the greatest improvements with the addition of bevacizumab: those with no risk factors experienced more than a five-month increase in progression-free survival; those with one to two risk factors experienced an approximate three-month increase; and those with three or more risk factors did not achieve even one month of benefit in terms of median progression-free survival.
- Objective response rates were also improved among patients receiving bevacizumab.
- Bevacizumab was associated with grades 3 and 4 fatigue, anorexia, hypertension, and proteinuria.
- Overall survival data are awaited pending longer follow-up.
The researchers indicated that the addition of bevacizumab to standard interferon for metastatic kidney cancer improves progression-free survival similar to that achieved with sunitinib. However, it was also mentioned that although bevacizumab undoubtedly appears to improve progression-free survival, it does not appear to improve outcomes compared with other available agents; it is associated with side effects; it is given as an injection versus orally as sunitinib and sorafenib; and it is prohibitively costly if other options exist. For now, bevacizumab provides intrigue as yet another targeted agent in the armamentarium for kidney cancer; however, it’s potential role for treatment of this disease is not yet clear.
There is, however, concern regarding the actual risk of heart failure with sunitinib, which may be higher in the real world than expected. Dr. Telli and colleagues from Stanford conducted a review of patients treated with sunitinib to further explore potential cardiotoxicity associated with the drug.
Previous studies that led to the FDA approval of sunitinib reported cardiotoxicity ranging from greater than 8% to more than 20%. For the most part, these cardiotoxicities were reversible and did not result in sustained, negative clinical effects. However, these trials typically did not include patients with pre-existing heart conditions. Conversely, in a “real world” setting, a significant portion of patients may indeed have comorbid cardiac conditions, a situation that needs to be addressed if sunitinib exacerbates their condition.
Researchers at Stanford noticed a higher-than-usual rate of cardiac complications among their patients on sunitinib, prompting analysis of data including 48 patients with kidney cancer or gastrointestinal stromal tumors (GIST) treated with sunitinib at Stanford between 2004 and 2007.
- 15% of patients developed symptomatic and clinically significant heart failure.
- Patients with coronary artery disease, low body mass index, or pre-existing heart failure were at a higher risk for developing subsequent heart failure on sunitinib.
- The majority of patients who developed heart failure on sunitinib did so within the first three weeks of treatment.
The researchers suggested that cardiac monitoring should be routine among patients treated with sunitinib. Because this was a retrospective analysis including a small number of patients, the true incidence of heart failure associated with sunitinib may be greater or less than 15%.
Among patients with small renal tumors, kidney-sparing surgery has been introduced as an effective treatment measure that is superior to radical nephrectomy in younger patients with renal cell carcinoma. However, it appears that partial nephrectomies for the treatment of small renal tumors are significantly underutilized for reasons not entirely understood. Researchers affiliated with New York University recently conducted a large population-based study using data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry linked with Medicare claims from 1995 to 2002 in an attempt to determine which factors are associated with more or less aggressive surgery.
- Among patients with kidney tumors that are smaller than 4 centimeters, 81% underwent a radical nephrectomy while 19% underwent partial nephrectomy.
- Partial nephrectomies occurred more often in patients who were younger, male, married, and treated later during the study period.
- Geographical region, economic status, and race did not affect rates of type of surgery.
Because more than 60% of kidney tumors are diagnosed at less than 4 cm in diameter, and partial nephrectomy is considered the gold standard for eligible patients with these small tumors, it was stated that, “Education of both patients and physicians are required to change the current practice patterns.”
The idea of surgical resection of metastases among patients with advanced stages of cancer has also been gaining noteworthy attention recently; specifically, patients with various types of solid tumors who are eligible for resection can achieve improved survival as well as quality of life with resection. This aggressive approach is in extreme contrast to the idea of best supportive care for palliation for patients with this stage of cancer, and still tends to be utilized in larger, urban centers.
Researchers from Memorial Sloan-Kettering Cancer Center (MSKCC) conducted a retrospective analysis that included 129 patients who had undergone a partial or radical nephrectomy for clinically localized kidney cancer between 1989 and 2005. The patients had developed a recurrence, either local or systemic, and were offered a surgical metastasectomy.
- The median time to recurrence following nephrectomy was 16 months.
- 34% of patients underwent a metastasectomy.
- Patients who underwent a metastasectomy were more than three times less likely to die from kidney cancer (P<0.001).
- Based on an MSKCC score, a validated system to measure risk through prognostic factors, median duration of survival from time of recurrence was 73 months for favorable-risk patients, 28 months for intermediate-risk patients, and six months for poor-risk patients.
- At two years survival for patients who did not undergo a metastasectomy was 0% for poor-risk patients, 48% for intermediate-risk patients, and 72% for favorable-risk patients.
- At two years survival for patients who did undergo a metastasectomy was 50% for poor-risk patients, 68% for intermediate-risk patients, and 89% for favorable-risk patients.
Dr. Kundu stated: “If you have a solitary metastatic lesion, instead of just saying, ‘Look, you have metastatic disease, you’re destined to do poorly,’ this shows that by removing the lesion, you can cure some of those people.”
The 2008 ASCO GU meeting trended away from standard chemotherapy and/or radiation treatment for genitourinary cancers with a movement towards identification of variables to help individualize therapies, as well as treatment with targeted therapies and surgical resection of metastases. It is evident that therapeutic choices are moving into a new realm; however, it is also evident that much work needs to be done moving forward so that these newer approaches may be optimally utilized. Ultimately, patient survival and quality of life will both continue to be improved if the momentum that has been captured in regards to treatment of genitourinary cancers continues along its current path.
Schröder FH, et al. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organization for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up-a Phase III study. ASCO Genitourinary Cancers Symposium, 2008; Abstract 5.
D’Amico, M. Chen, A. Renshaw, M. Loffredo, P. Kantoff. Androgen suppression and radiation versus radiation for prostate cancer: A randomized trial and analysis of the prognostic significance of comorbidity. ASCO Genitourinary Cancers Symposium, 2008; Abstract 13.
Broderick WR, et al. A phase III trial of zoledronic acid (Z) to prevent osteoporosis in men on early and prolonged androgen deprivation therapy (ADT) in a high risk VA population. ASCO Genitourinary Cancers Symposium, 2008; Abstract 177.
Reference: Rini BI, et al. CALGB 90206: a Phase III trial of bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in metastatic renal cell carcinoma. ASCO Genitourinary Cancers Symposium, 2008; Abstract 350.
 Eggener S, Yossepowitch O, Motzer R, Russo P. Objective (risk stratification) and subjective (metastasectomy) factors impact prognosis for recurrent renal cell carcinoma following nephrectomy. ASCO Genitourinary Cancers Symposium, 2008; Abstract 349.