Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Phase II study of capecitabine single-agent therapy in patients with metastatic renal cell carcinoma.

Fluoropyrimidines are known to have modest activity in the treatment of metastatic renal cell carcinoma (RCC). Capecitabine is an orally administered prodrug that is converted to fluorouracil and is of potential use in the treatment of this disease. We conducted a Phase II clinical trial of capecitabine administered as a single agent to patients with metastatic RCC. The treatment consisted of 1250 mg/m(2) capecitabine orally, twice daily (2500 mg/m(2) per day) days 1-14, repeated every 21 days. There were 15 patients, including 13 men and 2 women, who underwent a total of 67 cycles (median 3.5; range 1-15). Nine patients had undergone prior systemic therapy consisting of interferon-alpha in 3, interleukin-2 in 1, interferon-alpha plus interleukin-2 in 4, and investigational therapy with bryostatin-1 in 1. There were 14 patients assessable for response (one withdrew), and no responses were seen. Median time to progression was 9 weeks (range 1-45). There were 3 patients (21%) who had stable disease for 18, 39, and 45 weeks. Hematologic toxicity was mild. Three patients had grade 3 or 4 gastrointestinal toxicity, and 3 required dose reductions. There were 2 early deaths, including 1 patient with pulmonary edema and 1 with hypotension. The study was terminated because there were no responses in the first 14 assessable patients, indicating that the response rate was likely to be less than 20%. We conclude that single-agent capecitabine has minimal activity for the treatment of metastatic RCC.

Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: a modular phase I trial in androgen-independent prostate cancer.

PURPOSE: To study the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (AIPC), alone and in combination with docetaxel, we designed a modular phase I trial. Our goals were to (1) evaluate the toxicity and maximum-tolerated dose of docetaxel with imatinib, and (2) evaluate the decline of prostate-specific antigen (PSA) induced by imatinib alone, and imatinib and docetaxel. PATIENTS AND METHODS: Twenty-eight men with AIPC and bone metastases were enrolled to receive imatinib 600 mg daily lead-in for 30 days, then imatinib 600 mg daily and one of six possible doses of docetaxel weekly for 4 weeks every 6 weeks. RESULTS: During the imatinib lead-in module, one dose-limiting toxicity (DLT) event was observed, while two (7%) of 28 had PSA decline (both < 50%). With imatinib and docetaxel, cycle 1 DLT was found in three of 12 patients at docetaxel 30 mg/m(2), in three of four patients at docetaxel 45 mg/m(2), and in five of six patients at docetaxel 35 mg/m(2). DLTs (n = 40 total events) were principally fatigue (35%) and nausea (20%). Eight (38%) of 21 had PSA decline greater than 50%, and six (29%) of 21 had PSA decline less than 50%. Serial PSA declines beyond 18 months were observed. PDGFR-expressing tumor declined on serial bone marrow biopsies with combination therapy alone. CONCLUSION: With imatinib 600 mg daily, the maximum-tolerated dose of docetaxel was determined to be 30 mg/m(2) weekly for 4 weeks every 6 weeks. Long-term responses were observed. The role of imatinib in modulating outcomes to docetaxel in AIPC is being tested in a randomized phase II trial.

Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer.

PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa). PATIENTS AND METHODS: Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)). RESULTS: A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.

Employing the treatment-free interval of intermittent androgen ablation to screen candidate prostate cancer therapies.

BACKGROUND: Because neither continuous nor intermittent hormonal therapy is curative, we designed a clinical model to screen new drugs for additive or synergistic effects with hormonal therapy and used IM862, a naturally occurring dipeptide with antiangiogenic and immunomodulatory properties, to test it. METHODS: Patients with prostate cancer who had rising PSA levels after radical prostatectomy and/or radiation therapy were given combined androgen ablation for 3 months. After 2 months' treatment, patients were randomly assigned in a double-blind fashion to receive intranasal IM862 or placebo daily. Treatment continued for 6 months or until disease progression, which was defined by a rising serum PSA level, the appearance of new skeletal or extraskeletal metastatic disease, or new symptoms requiring intervention. RESULTS: Seventy-one patients were evaluable for response. Median time to PSA progression was not reached in either group. At 6 months, disease had progressed in 14 (41%) of the 34 patients receiving treatment and 18 (49%) of the 37 receiving placebo (P = 0.39). No significant toxicities emerged. CONCLUSIONS: The model was demonstrated to be an efficient platform for new drug screening; however, IM862, though well tolerated, failed to demonstrate superiority over placebo in prolonging time to PSA progression.

Irofulven, a novel inhibitor of DNA synthesis, in metastatic renal cell cancer.

Irofulven (6-Hydroxymethylacylfulvene, MGI-114) is the first of a new class of anticancer compounds the acylfulvenes which are derived from the natural product, illudin S. Irofulven is a potent anticancer agent with activity against a broad range of human tumors in vitro and in vivo. Irofulven covalently binds to DNA, inhibits DNA synthesis and induces apoptosis. Clinical activity has been observed in phase I studies. Because disease stabilizations were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of irofulven in this patient population. Twenty patients were accrued. Irofulven (11 milligrams per meter squared per day) was administered as a 5 minute intravenous infusion for 5 consecutive days, and response was evaluated every 8 weeks. There were no objective responses. The most common toxicities were nausea, emesis, and thrombocytopenia. Irofulven, at the dose and schedule administered in this trial, showed no effect in metastatic renal cell cancer.

Continuing education: The emergence of thalidomide in treating advanced renal cell carcinoma.

PURPOSE/OBJECTIVES: To review standard and investigational treatments in advanced renal cell carcinoma, with a focus on thalidomide. DATA SOURCES: Published articles, conference proceedings, treatment guidelines, and textbooks. DATA SYNTHESIS: The prognosis for advanced renal cell carcinoma when treated with standard regimens is poor; therefore, new treatments are needed. CONCLUSIONS: Treatment with thalidomide, alone and in combination with other therapies, may improve survival for patients with advanced renal cell carcinoma. IMPLICATIONS FOR NURSING: Proactive management of adverse effects associated with thalidomide, alone and in combination, may increase patient tolerance and compliance.

A pilot study of thalidomide in patients with progressive metastatic renal cell carcinoma.

BACKGROUND: The highly vascular nature of renal cell carcinoma (RCC) suggests that angiogenesis inhibition may be therapeutic for patients with this disease. Thalidomide inhibits basic fibroblast growth factor and vascular endothelial growth factor (VEGF)-induced angiogenesis. METHODS: In a pilot study, we evaluated the safety and efficacy of escalating doses of thalidomide in patients with progressive metastatic RCC (mRCC), measurable disease, and good organ function. Patients received oral thalidomide starting at 200 mg per day and increasing by 100-200 mg per day weekly until a target dose of 1200 mg per day was reached. Study endpoints were objective tumor response and toxicity. RESULTS: Of the 20 patients enrolled, 19 were evaluable for response. Eighteen achieved the target dose. The most common, but reversible, toxicities were constipation, somnolence, and fatigue. Peripheral neuropathy was seen after prolonged therapy, necessitating dose reduction. Two patients achieved a partial response and nine had stable disease for a median of 14 months (range, 3-17 months). Median time to progression was 4.7 months (range, 0.7-31.3 months). Fifteen patients died (median survival, 18.1 months; 95% lower confidence bound 10.7). Survival was significantly longer in patients with higher hemoglobin level and longer time from first metastasis to start of thalidomide, but significantly shorter in patients with multiple organ involvement and previous treatments. CONCLUSIONS: Thalidomide at this dose is associated with manageable acute toxicities but long-term dose-limiting neuropathy. Objective responses are rare in patients with mRCC and are characterized by delay in achieving maximum tumor reduction. Prolonged stable disease is seen in some patients, but the benefit of thalidomide, as well as other angiogenesis inhibitors, in that setting needs to be studied in controlled, randomized trials.