Optimal management of metastatic renal cell carcinoma: an algorithm for treatment.

The treatment of metastatic renal cell carcinoma (mRCC) has been changed by the introduction of targeted agents. Consideration of individual patient factors, such as previous treatment and prognostic risk, e.g. according to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria), can assist in ensuring that patients receive appropriate targeted therapies. Available clinical evidence shows sunitinib to be the reference standard of care for the first-line treatment of mRCC in patients at favourable or intermediate prognostic risk according to MSKCC criteria. Combined treatment with bevacizumab plus interferon-alpha can also be considered for the first-line treatment of mRCC in this setting. For the first-line treatment of poor-risk patients, temsirolimus has shown benefit in a phase III study, while sunitinib can also be considered. For second-line treatment in cytokine-refractory patients, sorafenib is recommended based on phase III trial results; sunitinib has also shown activity after failure of cytokine therapy or targeted agents. As well as antitumour activity, the tolerability of targeted agents should be evaluated in the context of individual patients, considering factors such as comorbidities and age. As our understanding of the activity of targeted agents for mRCC increases, we should ensure that these agents are used appropriately to provide patients with optimal treatment benefits.

Docetaxel Versus Surveillance After Radical Prostatectomy for High-risk Prostate Cancer: Results from the Prospective Randomised, Open-label Phase 3 Scandinavian Prostate Cancer Group 12 Trial.

BACKGROUND: Adjuvant chemotherapy is standard treatment for other solid tumours, but to date has not proven effective in prostate cancer. OBJECTIVE: o evaluate whether six cycles of docetaxel alone improve biochemical disease-free survival after radical prostatectomy for high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomised multinational phase 3 trial. Enrolment of 459 patients after prostatectomy. INCLUSION CRITERIA: high-risk pT2 margin positive or pT3a Gleason score ≥4+3, pT3b, or lymph node positive disease Gleason score ≥3+4. Patients assigned (1:1) to either six cycles of adjuvant docetaxel 75mg/m2 every 3 wk without daily prednisone (Arm A) or surveillance (Arm B) until endpoint was reached. Primary endpoint was prostate-specific antigen progression ≥0.5 ng/ml. INTERVENTION: Docetaxel treatment after prostatectomy. RESULTS AND LIMITATIONS: Median time to progression, death, or last follow-up was 56.8 mo. Primary endpoint was reached in 190/459 patients-the risk of progression at 5 yr being 41% (45% in Arm A and 38% in Arm B). There was evidence of nonproportional hazards in Kaplan-Meier analysis, so we used the difference in restricted mean survival time as the primary estimate of effect. Restricted mean survival time to endpoint was 43 mo in Arm A versus 46 mo in Arm B (p=0.06), a nonsignificant difference of 3.2 mo (95% confidence interval: 6.7 to -1.5 mo). A total of 116 serious adverse events were recorded in Arm A and 41 in Arm B with no treatment-related deaths. Not all patients received docetaxel by protocol. The endpoint is biochemical progression and some patients received radiation treatment before the endpoint. CONCLUSIONS: Docetaxel without hormonal therapy did not significantly improve biochemical disease-free survival after radical prostatectomy. PATIENT SUMMARY: In this randomised trial, we tested whether chemotherapy after surgery for high-risk prostate cancer decreases the risk of a rising prostate-specific antigen. We found no benefit from docetaxel given after radical prostatectomy.

Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma.

PURPOSE: Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen. PATIENTS AND METHODS: Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures. RESULTS: One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM. CONCLUSION: Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

A systematic overview of radiation therapy effects in urinary bladder cancer.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for urinary bladder cancer is based on data from 3 meta-analyses and 33 randomized trials. The studies include 4333 patients. The results were compared with those of a similar overview from 1996 including 15,042 patients. The conclusions reached can be summarized as these points: There is moderate evidence for an overall survival benefit with preoperative radiotherapy followed by cystectomy compared to curative radiotherapy based on early studies (1964-1986). Since that time surgical as well as radiation techniques have developed considerably. Therefore, the conclusion may not be relevant to modern treatment of invasive urinary bladder carcinoma. There is only one small study reporting on curative radiotherapy where increased dose per fraction is compared with conventionally fractionated radiotherapy to the same total dose. Thus, no conclusions can be drawn concerning optimal fraction dose. A meta-analysis based on two studies on hyperfractionated radiotherapy gives moderate evidence of a survival benefit at 5 and 10 years and an increased local control rate compared with conventional fractionation. The documentation of local control and overall survival rate after split-course radiation treatment compared to continuous therapy is conflicting. No firm conclusions can be drawn. Four small and early studies have compared radiation treatment using neutrons with photon treatment. The reports favour therapy with photons with respect to overall treatment results. There is moderate evidence for this conclusion. There is fairly strong evidence in early studies that radiation treatment in combination with hyperbaric oxygen does not confer a treatment benefit compared to radiation in normal atmosphere. There is no indication of a treatment benefit with the addition of either hyperthermia or misonidazole. A large number of phase II studies, suggesting an increased possibility for bladder preservation with concomitant chemoradiotherapy compared to radiotherapy alone, have been reviewed in a previous SBU report on chemotherapy. Only one small randomized study has been reported where concomitant chemoradiotherapy with cisplatin is compared to radiation alone. No conclusion on the therapeutic benefit of combined treatment can be drawn. Large randomized studies are needed. There is some evidence that preoperative radiotherapy followed by cystectomy does not confer any significant survival benefit compared to cystectomy alone. There is moderate evidence that palliative radiotherapy of invasive bladder carcinoma can rapidly induce tumour-related symptom relief. There is moderate evidence that palliative hypofractionated radiotherapy, 3 fractions during one week, gives the same relief of symptoms as 10 fractions during 2 weeks.