Search

What's known on the subject? and What does the study add? Targeted agents have greatly changed the therapeutic landscape in RCC. A substantial number of trials have been published in recent years. The current review summarises and analyses the available data to date. OBJECTIVE • To estimate the effects of drugs with molecular targets on patients with advanced renal cell cancer (RCC). PATIENTS AND METHODS • MEDLINE, EMBASE, and the Cochrane Collaboration Library were systematically searched on-line through to June 2011 to identify eligible randomised trials. We also searched abstract reports from major oncology and urology meetings. • We included randomised trials that tested a targeted agent and reported at least one outcome by allocation on an intent-to-treat basis. Completeness of ascertainment and risk of bias were assessed. • Our primary outcome was progression-free survival (PFS). RESULTS • In all, 28 studies met our inclusion criteria and 10 were placebo-controlled. Two studies were too small to assess, and five early studies used nonspecific anti-angiogenic agents with poor activity. In all, 15 studies, in 5587 patients, tested anti-vascular epithelial growth factor (VEGF) agents: bevacizumab (BEV), sorafenib, sunitinib, pazopanib, tivozanib, or axitinib. Three studies, in 1147 patients, tested the mammalian target of rapamycin (mTOR) inhibitors, temsirolimus or everolimus. Two studies included epidermal growth factor receptor (EGFR) inhibitors, and one tested the combination of temsirolimus plus BEV. • In treatment-naive patients with mostly good–moderate prognostic risk, in separate trials oral sunitinib (one trial) and intravenous BEV plus subcutaneousinterferon-α (two trials) improved PFS compared with the previous standard of care interferon-α within randomised phase III trials. Sorafenib did not improve PFS over interferon-α in the first-line setting and the addition of cytokines did not improve sorafenib efficacy. In poor-risk patients, the mTOR inhibitor temsirolimus improved PFS and overall survival (OS). The studies of other VEGF inhibitors have used placebo controls no longer appropriate in this setting, although pazopanib is an approved option. • Several trials examined agents in the second-line setting. After cytokine therapy, sorafenib (one study) and pazopanib (one study) prolonged PFS over placebo. A preliminary report of the investigational VEGF receptorinhibitor axitinib gave superior PFS to sorafenib after either prior cytokine or prior sunitinib treatment. After cancer progression ≤6 months of sunitinib and/or sorafenib therapy, everolimusprolonged PFS. • OS was marginally improved in several studies. A more substantial effect on OS may have been diluted by crossover from control therapy to the investigational arm and/or by other anti-angiogenic agents after trial closure. Patient-reported outcomes were considered unreliable in trials without ‘blinding’. • A clear cell RCC (ccRCC) component was required for most trials, and information for non-ccRCCs is consequently limited CONCLUSIONS • Agents targeting VEGF and mTOR pathways improve PFS in both first-line and second-line settings. These treatments rarely yield complete responses and thus are not curative. • No placebo-controlled trial has reported a health-related quality of life benefit.

PURPOSE To evaluate the efficacy of an abbreviated treatment plan consisting of two cycles of chemotherapy plus thoracic irradiation in a population of limited-stage small-cell lung cancer (LSCLC) patients who were elderly, infirm, or noncompliant with standard-duration therapy. PATIENTS AND METHODS Fifty-five LSCLC patients (median age, 73) were treated with one cycle of cyclophosphamide, doxorubicin, and vincristine (CAV) followed 3 weeks later by one cycle of etoposide and cisplatin (EP). Both regimens were administered at conventional full dose. Thoracic irradiation (20 to 30 Gy) was delivered concurrently with EP. RESULTS Complete response occurred in 28 patients (51%) and partial response in 21 (38%). The median survival time was 54 weeks; the 2-year survival rate was 28% and the actual 5-year survival rate was 18%. Three patients died of toxicity. CONCLUSION Elderly, infirm, or noncompliant LSCLC patients who are unable to receive standard-duration chemotherapy may have useful palliation and potential for long-term survival with abbreviated chemotherapy (two cycles) and thoracic irradiation.

PURPOSE The Canadian multicenter trial for advanced non-small-cell lung cancer (NSCLC) reported survival benefit for chemotherapy when best supportive care was compared with vindesine-cisplatin (VP) and the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). We examined received drug delivery to document dose-intensity (DI) and total dose of drugs given to various groups in this patient population. PATIENTS AND METHODS Plots of cumulatively received chemotherapy against time were used to evaluate drug delivery by regimen, major prognostic factors, and response status. RESULTS Individual CAP patients show a narrow range of received DI, with the median similar to protocol. Drug delivery analysis exposed a wide range of received DI for both drugs in the more intensive VP regimen, and the median received DI was below protocol. The median received DI for cisplatin was still higher for VP than CAP, but only during the first 8 weeks of protocol treatment (20 v 10 mg/m2/wk); thereafter, the ongoing received cisplatin DI was the same (10 mg/m2/wk). The median received DI for cisplatin in each regimen was not influenced by stage, performance status, prior weight loss, sex, or response status. VP-treated patients received a higher total dose of cisplatin than CAP patients (median, 255 mg/m2 v 112.5 mg/m2; P < .0001). Median cisplatin total dose was similar for patients with a chemotherapy response or stable disease and threefold greater than for patients with progressive disease for both regimens. Although patients with chemotherapy response and stable disease had similar survival outcomes for both CAP and VP, the VP regimen had a higher proportion of patients without progressive disease (P = .004), which resulted in an overall survival advantage (P = .01). CONCLUSION The major prognostic factors for advanced NSCLC do not exert their influence on outcome by affecting deliverable chemotherapy DI. Regimen and treatment response determined total dose. Because stable disease patients usually outnumber responding patients in advanced NSCLC trials, controlled studies should be performed that allow assessment of the impact of total received dose on outcome according to response status.

To estimate the effects of drugs with molecular targets on patients with advanced renal cell cancer (RCC).MEDLINE, EMBASE, and the Cochrane Collaboration Library were systematically searched on-line through to June 2011 to identify eligible randomised trials. We also searched abstract reports from major oncology and urology meetings. We included randomised trials that tested a targeted agent and reported at least one outcome by allocation on an intent-to-treat basis. Completeness of ascertainment and risk of bias were assessed. Our primary outcome was progression-free survival (PFS).In all, 28 studies met our inclusion criteria and 10 were placebo-controlled. Two studies were too small to assess, and five early studies used nonspecific anti-angiogenic agents with poor activity. In all, 15 studies, in 5587 patients, tested anti-vascular epithelial growth factor (VEGF) agents: bevacizumab (BEV), sorafenib, sunitinib, pazopanib, tivozanib, or axitinib. Three studies, in 1147 patients, tested the mammalian target of rapamycin (mTOR) inhibitors, temsirolimus or everolimus. Two studies included epidermal growth factor receptor (EGFR) inhibitors, and one tested the combination of temsirolimus plus BEV. In treatment-naive patients with mostly good-moderate prognostic risk, in separate trials oral sunitinib (one trial) and intravenous BEV plus subcutaneousinterferon-α (two trials) improved PFS compared with the previous standard of care interferon-α within randomised phase III trials. Sorafenib did not improve PFS over interferon-α in the first-line setting and the addition of cytokines did not improve sorafenib efficacy. In poor-risk patients, the mTOR inhibitor temsirolimus improved PFS and overall survival (OS). The studies of other VEGF inhibitors have used placebo controls no longer appropriate in this setting, although pazopanib is an approved option. Several trials examined agents in the second-line setting. After cytokine therapy, sorafenib (one study) and pazopanib (one study) prolonged PFS over placebo. A preliminary report of the investigational VEGF receptorinhibitor axitinib gave superior PFS to sorafenib after either prior cytokine or prior sunitinib treatment. After cancer progression ≤6 months of sunitinib and/or sorafenib therapy, everolimusprolonged PFS. OS was marginally improved in several studies. A more substantial effect on OS may have been diluted by crossover from control therapy to the investigational arm and/or by other anti-angiogenic agents after trial closure. Patient-reported outcomes were considered unreliable in trials without 'blinding'. A clear cell RCC (ccRCC) component was required for most trials, and information for non-ccRCCs is consequently limitedAgents targeting VEGF and mTOR pathways improve PFS in both first-line and second-line settings. These treatments rarely yield complete responses and thus are not curative. No placebo-controlled trial has reported a health-related quality of life benefit.

Chris CoppinBC Cancer Agency and University of British Columbia, Vancouver, CanadaAbstract: Renal cell cancer has been refractory to drug therapy in the large majority of patients. Targeted agents including sunitinib have been intensively evaluated in renal cell cancer over the past 5 years. Sunitinib is an oral small molecule inhibitor of several targets including multiple tyrosine kinase receptors of the angiogenesis pathway. This review surveys the rationale, development, validation, and clinical use of sunitinib that received conditional approval for use in North America and Europe in 2006. In patients with the clear-cell subtype of renal cell cancer and metastatic disease with good or moderate prognostic factors for survival, sunitinib 50 mg for 4 weeks of a 6-week cycle provides superior surrogate and patient-reported outcomes when compared with interferon-alfa, the previous commonly used first-line drug. Overall survival has not yet shown improvement over interferon and is problematic because of patient crossover from the control arm to sunitinib at disease progression. Toxicity is significant but manageable with experienced monitoring. Sunitinib therapy is an important step forward for this condition. High cost and limited efficacy support the ongoing search for further improved therapy.Keywords: renal cell cancer, targeted therapy, sunitinib

Until recently, cytokine therapy has been the only validated option for patients with advanced renal cancer. IFN-alpha is one of very few treatments that have demonstrated improved median survival compared with the appropriate control. In patients with synchronous metastases at diagnosis, debulking nephrectomy prior to interferon, further improves overall survival. High-dose IL-2 appears to be able to cure a small percentage of highly selected patients. There is potential to further improve patient selection for these options. The demonstrated value of cytokines should not be overlooked in the rush to use new drugs. In the adjuvant setting, vaccine therapy has provided the only systemic approach that has any promise. New insights into the complexities of the immune system at the molecular level, as well as the ingenuity and enthusiasm of immunotherapists, will undoubtedly lead to continuing attempts to identify and overcome obstacles to achieve the grail of human tumor rejection in clinical practice. Targets within the immune regulatory system and the use of vaccines as targeting agents may bring together the fields of immunotherapy and targeted therapy in the near future.

Background Advanced renal cell carcinoma has been resistant to drug therapy of different types and new types of drug therapy are needed. Targeted agents inhibit known molecular pathways and have been tested in renal cancer for just over a decade. Objectives 1) To provide a systematic and regularly updated review of randomized studies testing targeted agents in advanced renal cell cancer. 2) To identify the type and degree of clinical benefit of targeted agents over the prevailing standard of care. Search methods Period of search: January 2000 to June 2010. 1) Electronic search of CENTRAL, MEDLINE and EMBASE databases. 2) Hand search of international cancer meeting abstracts. Selection criteria Randomized, controlled studies, including a targeted agent in patients with advanced renal cell cancer reporting any pre-specified cancer outcome by allocation. Data collection and analysis The majority of the standardized search and data extraction was conducted independently by two investigators with subsequent resolution of differences. Handsearching, quality of life and toxicity data extraction, most of the initial analysis, and risk of bias assessment, was carried out by one investigator and verified by additional authors as required. Twenty-five fully eligible studies tested thirteen different targeted agents in a total of 7484 patients with mostly Stage IV disease; 61% had not received prior systemic treatment. The majority of patients were good performance status (ECOG (Eastern Cooperative Oncology Group) 0 to 1). Most comparisons were each examined in only a single study. Risk of bias was considered low for studies that were placebo-controlled, had a primary outcome of overall survival, or that evaluated progression by independent radiologic reviewers unaware of the intervention allocation. Main results Most progress has been made in patients with advanced renal cancer of the clear cell subtype, a condition with a clearly defined molecular pathology promoting angiogenesis. In systemically untreated patients, two approaches to angiogenesis inhibition have demonstrated benefit. Compared with interferon-alfa monotherapy, oral sunitinib improved multiple outcomes including overall survival (18% risk reduction for death; median survival improved from 21.8 to 26.4 months, P = 0.049) without correction for crossover) in patients with mostly good or moderate prognosis. In the same setting, two studies have shown that the addition of biweekly intravenous bevacizumab to interferon-alfa also improved the chance of major remission and prolonged progression-free survival. These two bevacizumab plus interferon studies each observed improved overall survival approaching statistical significance (each study observed a 14% risk reduction for death). Additional anti-angiogenesis agents, such as pazopanib and tivozanib, are in earlier stages of evaluation. After progression of clear cell disease on prior cytokine therapy, oral sorafenib results in a better quality of life than placebo. In patients with clear cell disease with progression on or within 6 months of first-line targeted therapy with sunitinib or sorafenib, the targeted oral mTOR (mammalian target of rapamycin) inhibitor everolimus resulted in prolonged disease-free survival without detriment to quality of life. Remissions were very infrequent and no improvement in overall survival was observed in this study where the majority of placebo-assigned patients received everolimus at disease progression. In untreated patients with unselected renal cancer histology and poor prognostic features, weekly intravenous temsirolimus, an mTOR inhibitor, improved outcomes compared with interferon-alfa (median overall survival improved from 7.3 to 10.9 months, P = 0.008). Of particular interest, an exploratory analysis observed a marked reduction in hazard for death in the non-clear cell subgroup. Combinations of targeted agents are being evaluated, but toxicity is problematic. Authors' conclusions Several agents with specified molecular targets have demonstrated clinically useful benefits over interferon-alfa, and also after either prior cytokine or initial anti-angiogenesis therapy. More research is required to fully establish the role of targeted agents in this condition.

We evaluated the outcome of patients with embryonal carcinoma predominant (ECP) clinical stage (CS) I nonseminomatous testicular germ cell tumors (NSGCT) treated with primary surveillance or primary retroperitoneal lymph node dissection (RPLND).This study was a retrospective evaluation of the pathology, use of chemotherapy, surgery and outcomes in all patients with CS I NSGCT who were diagnosed within the province of British Columbia between 1990 and 2000.A total of 205 patients were identified, of whom 107 (52%) had ECP disease. Of these patients 72 (67%) underwent primary surveillance, 32 (33%) underwent primary RPLND and 3 refused treatment. Median followup was 4 years (range 1 to 10). In the primary surveillance group 24 patients (33%) had relapse and all were treated initially with chemotherapy with 6 also requiring RPLND. The remaining 48 patients (67%) in the surveillance group were cured of disease with orchiectomy alone. In the primary RPLND group 18 patients (56%) had pathological stage I disease and 14 (44%) had pathological stage II disease. In the primary RPLND group 15 patients (46%) required chemotherapy with 11 (34%) receiving adjuvant chemotherapy and 4 receiving chemotherapy for post-RPLND relapse. No deaths from ECP testicular cancer occurred in either group. The 4-year chemotherapy-free survival rate was 65% in the surveillance group vs 50% in the RPLND group (p = 0.2).For appropriately selected patients with CS I ECP NSGCT, primary surveillance results in fewer therapeutic interventions compared to RPLND without compromising the probability of cure.

Reason for withdrawal from publication This review is being updated and replaced following the publication of a new protocol (Unverzagt S, Moldenhauer I, Coppin C, Greco F, Seliger B. Immunotherapy for metastatic renal cell carcinoma [Protocol]. Cochrane Database of Systematic Reviews 2015, Issue 4. Art. No.: CD011673. DOI: 10.1002/14651858.CD011673). It will remain withdrawn when the new review is published.

Many patients with metastatic transitional-cell carcinoma (TCC) are not appropriate candidates for standard cisplatin-based combination, because of inadequate renal function, poor performance status (PS), and other comorbid medical conditions. We have evaluated the efficacy and toxicity of a combination of carboplatin and vinblastine (CV) as a palliative regimen in these patients. The medical records of patients with metastatic TCC, who had been treated with CV at the British Columbia Cancer Agency from 1995 until 1999, were retrospectively reviewed. Treatment consisted of carboplatin (area under the curve = 5) on day 1, and vinblastine (4 mg/m(2)) on days 1 and 8, repeated every 4 weeks. A total of 42 patients were included in this study, of whom 39 had measurable disease. Median age was 73 years. Fifty-two percent of patients had a PS (Eastern Cooperative Oncology Group) of 2 or 3. Node-only disease was present in 26% of patients, bone metastasis in 26%, and liver metastasis in 24%. A total of 119 cycles were administered. Grade IV granulocytopenia occurred in 26% of patients, grade III anemia in 12%, and there were 3 episodes of febrile neutropenia occurring in two patients. The major nonhematologic toxicity was grade III fatigue in 17% of patients. There were no grade IV nonhematologic toxicity or treatment-related deaths. The overall response rate was 33% (13 of 39). Five patients (13%) achieved a complete response and 8 patients (20%) a partial response. The median duration of response was 32 weeks and median overall survival for all patients was 26 weeks. The combination of carboplatin and vinblastine given in this schedule is a feasible, well-tolerated, and active alternative for patients with metastatic TCC unfit for standard chemotherapy.

In order to evaluate risk factors for germ cell cancers, we conducted a case-control study of 510 men with testicular cancer aged 15 to 79 years and 996 randomly selected age-matched controls in the provinces of British Columbia and Alberta, Canada. Subjects completed a mailed questionnaire providing data on education level, ethnic origin, medical history, smoking, occupation, and recreational and sports activity. The response rate among cases was 80.3 percent and among controls was 68.1 percent. After controlling for age and ethnic origin, undescended testis was associated positively with risk of testicular cancer (odds ratio [OR] = 3.5; 95 percent confidence interval [CI] = 2.2-5.7) as was inguinal hernia requiring surgery (OR = 2.0, CI = 1.3-2.9), and hydrocoele (OR = 2.6, CI = 1.4-5.1). Risk of testicular cancer increased with height, with subjects taller than 180 cm having a significantly increased risk compared with those 174 cm or less (OR = 1.5, CI = 1.1-2.1). A moderate to high level of recreational activity level was associated inversely with testicular cancer risk (OR = 0.6, CI = 0.5-0.8).

Publisher Summary This chapter focuses on high-dose chemotherapy with antilogous marrow rescue for germ cell salvage consolidation. The overall outcome for patients with metastatic germ cell testis cancers is remarkably good with cisplatin-based combination chemotherapy. Two categories of patients are appropriate to consider for experimental approaches: (1) those with extremely adverse prognostic factors at presentation and (2) those whose cancer has recurred despite standard cisplatin-based chemotherapy. Patients who recur despite initial intensive treatment are usually beyond cure with chemotherapy but may be salvaged surgically if the problem is growing teratoma or localized drug resistant disease. A total of 22 Vancouver patients with germ cell cancers are assessable for toxicity associated with high-dose chemotherapy regimens. Peripheral neuropathy was mostly attributable to cisplatin in the induction phase and was incapacitating in one patient who made a full recovery. High-dose chemotherapy with carboplatin, etoposide, and cyclophosphamide with antilogous bone marrow rescue appears to have the potential to improve the results of difficult germ cell cancers.

Cyproterone acetate is a steroidal antiandrogen with weak progestational activity that results in the partial suppression of pituitary gonadotropin. We demonstrate that the associated decrease in serum testosterone is more complete and prolonged if cyproterone acetate (200 mg. daily) is combined with a low dose of diethylstilbestrol (0.1 mg. daily). The effectiveness of the combination in the treatment of prostatic carcinoma was investigated in 51 patients with stage D2 malignancy. From an initial concentration of 360 +/- 23 ng. per dl. (mean +/- standard error), serum testosterone decreased to 56 +/- 5 ng. per dl. after 1 week and reached a plateau of approximately 30 ng. per dl. after 2 months. This was accompanied by a decrease in serum prostatic acid phosphatase from a mean starting concentration of 43 +/- 11 ng. per ml. to a low of 3 +/- 1 ng. per ml. at 12 months; the proportion of normal values increased from 10 to 80 per cent. A complete response was observed in 7 patients (13 per cent), partial response in 35 (69 per cent) and stable disease in 8 (16 per cent), yielding an over-all objective response rate of 98 per cent (1980 National Prostatic Cancer Project criteria). The actuarial median time to progression was 17 months and the median survival time was 23.5 months. In 26 patients who subsequently had signs of progressive carcinoma the relapse rate in bone (85 per cent) far exceeded that in nonskeletal sites (23 per cent). The incidence of cardiovascular toxicity was 12 per cent. These results indicate that cyproterone acetate and low dose diethylstilbestrol may be co-administered to achieve a synergistic and potent androgen withdrawal effect in the treatment of advanced prostatic carcinoma.