[Show abstract][Hide abstract] ABSTRACT: Purpose:
To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC).
The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature.
When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib.
Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients.
[Show abstract][Hide abstract] ABSTRACT: In germ cell cancers, the unique reversibility of malignancy and the balance between somatic differentiation and de-differentiation may be critical to late relapse that is dominated by non-germ cell elements. Targeting regulators of differentiation may provide a solution, which may be elucidated via serial liquid biopsies (assessing circulating tumor cells).
Clinical Cancer Research 05/2014; 20(14). DOI:10.1158/1078-0432.CCR-14-0691 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Postchemotherapy surgery for advanced testicular cancer has evolved over the last couple of decades. Patients with nonseminomatous germ cell tumors and residual retroperitoneal mass ≥1 cm should undergo postchemotherapy retroperitoneal lymph node dissection (RPLND). For seminoma, RPLND is considered in those patients with masses ≥3 cm that are also positron emission tomography positive. Masses that occur outside of the retroperitoneum should be completely resected with the possible exception of bilateral lung masses when resection of the first mass shows necrosis. The role of surgery in patients with extragonadal germ cell tumors is most vital in those with primary mediastinal nonseminomatous germ cell tumors. Importantly, patient selection, surgical planning, and consideration of referral to centers with this expertise are important to optimize success.
The Oncologist 04/2014; 19(5). DOI:10.1634/theoncologist.2013-0379 · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neoadjuvant cisplatin-based combination chemotherapy provides a 5% increase in cure rate, an increase in median survival of
about 3 years, and statistically significant and clinically relevant increments in overall survival for patients with invasive
bladder cancer. Despite compelling level 1 data, it has become quite clear that facts that are similar to those that changed
the paradigm of treatment of breast cancer in the 1970s have not had a similar influence on patterns of practice in bladder
cancer care. Instead of using this proven approach, cystectomy alone or surgery followed by adjuvant chemotherapy is often
used as a functional alternative for patients with deeply invasive and/or node-metastatic disease discovered at radical cystectomy.
However, there is no well-powered level 1 evidence to support routine adjuvant chemotherapy for invasive bladder cancer, and
some randomized trials have shown inferior outcomes. There is a clear need for a well-designed, randomized trial that tests
the utility of adjuvant chemotherapy for invasive bladder cancer, but until that has been completed, neoadjuvant chemotherapy
followed by definitive local treatment should be the standard of care for invasive bladder cancer.
Annals of Oncology 02/2014; 25(10). DOI:10.1093/annonc/mdu092 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To analyze the association between cancer incidence and oral diabetes therapy (biguanide, sulfonylurea, thiazolidinedione, meglitinide) in men and women with type 2 diabetes mellitus.
A retrospective analysis of the electronic health record-based Cleveland Clinic Diabetes Registry (25,613 patients) was cross-indexed with the histology-based Tumor Registry (48,051 cancer occurrences) over an 8-year period (1998-2006). Multiple imputations were used to account for missing data. Cox regression with propensity scores was used to model time to development of incident cancer in each of the imputed datasets and the results were pooled.
During 51,994 person follow-up years, 892 incident cancer cases were identified; prostate (14.5%) and breast (11.7%) malignancies were most frequent. In women, thiazolidinedione use was associated with a 32% decreased cancer risk compared to sulfonylurea use (HR 0.68 [95% CI 0.48-0.97] in the adjusted analysis). Comparison of insulin secretagogues (sulfonylurea, meglitinide) versus insulin sensitizers (biguanide, thiazolidinedione) demonstrated a 21% decreased cancer risk in insulin sensitizers (HR 0.79 [95% CI 0.64-0.98] in the adjusted analysis). Oral diabetes therapy showed no significant difference in men. Adjustments were made for age, BMI, LDL, HDL, triglycerides, CHD, diabetes oral monotherapy, race, gender, hemoglobin A1c, statin use, income, insulin use, GFR, new diabetes status, prior cancer, prior cerebrovascular accident (stroke or transient ischemic event), systolic/diastolic blood pressure, tobacco use (ever/never), and the propensity score for receiving a biguanide.
Oral insulin sensitizers, particularly thiazolidinedione, are associated with decreased malignancy risk in women with type 2 diabetes mellitus.
[Show abstract][Hide abstract] ABSTRACT: Many challenges to clinical trial accrual exist, resulting in studies with inadequate enrollment and potentially delaying answers to important scientific and clinical questions.
The National Cancer Institute (NCI) and the ASCO (ASCO) cosponsored the Cancer Trial Accrual Symposium: Science and Solutions on April 29-30, 2010 to examine the state of accrual science related to patient/community, physician/provider, and site/organizational influences, and identify new interventions to facilitate clinical trial enrollment. The symposium featured breakout sessions, plenary sessions, and a poster session including 100 abstracts. Among the 358 attendees were clinical investigators, researchers of accrual strategies, research administrators, nurses, research coordinators, patient advocates, and educators. A bibliography of the accrual literature in these three major areas was provided to participants in advance of the meeting. After the symposium, the literature in these areas was revisited to determine if the symposium recommendations remained relevant within the context of the current literature.
Few rigorously conducted studies have tested interventions to address challenges to clinical trials accrual. Attendees developed recommendations for improving accrual and identified priority areas for future accrual research at the patient/community, physician/provider, and site/organizational levels. Current literature continues to support the symposium recommendations.
A combination of approaches addressing both the multifactorial nature of accrual challenges and the characteristics of the target population may be needed to improve accrual to cancer clinical trials. Recommendations for best practices and for future research developed from the symposium are provided.
Journal of Oncology Practice 10/2013; 9(6). DOI:10.1200/JOP.2013.001119
[Show abstract][Hide abstract] ABSTRACT: Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.
Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.
A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy groufp and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events.
Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).
New England Journal of Medicine 04/2013; 368(14):1314-25. DOI:10.1056/NEJMoa1212299 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Enzastaurin is an oral serine/threonine kinase inhibitor that inhibits the beta isoform of protein kinase C and which may have therapeutic activity in prostate cancer. We explored the efficacy of docetaxel/prednisone with or without enzastaurin in patients with castration-resistant metastatic prostate cancer.
A nonrandomized safety cohort consisting of 14 patients was followed by a double-blind randomized Phase II trial. Patients received standard doses of docetaxel (75 mg/m(2)) with prednisone 10 mg daily with or without 500 mg/day of enzastaurin.
There was no difference in the objective response rate between the enzastaurin and placebo arms (placebo: 7 [15.2 %]; enzastaurin: 6 [15.0 %]; P = 1.00). The median PFS was 229 days for patients in the enzastaurin arm versus 213 days for the placebo arm (P = 0.524). The 1-year overall survival rates were almost identical, with 76.7 % and 75.1 % in the enzastaurin and placebo arms, respectively. Therapy was well tolerated although the combination of enzastaurin and docetaxel was more myelosuppressive than with docetaxel alone.
The clinical activity of docetaxel/prednisone plus enzastaurin cannot be distinguished from docetaxel/prednisone alone, given the limitations of a randomized Phase II design. Although the toxicity profile was favorable for the enzastaurin-containing regimen, there is no compelling rationale to move this combination forward for the treatment of castration-resistant metastatic prostate cancer.
Investigational New Drugs 02/2013; 31(4). DOI:10.1007/s10637-013-9940-0 · 2.92 Impact Factor