OBJECTIVE The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. DESIGN, SETTING, AND PARTICIPANTSThis multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty.INTERVENTIONS There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m 2 on day 1, capecitabine 625 mg/m 2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. MAIN OUTCOMES AND MEASURESFirst, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival.RESULTS A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes.CONCLUSIONS AND RELEVANCE This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment.

Metastatic renal cell carcinoma (MRCC) remains a challenging malignancy to treat.Cancer immunotherapies have been extensively explored in melanoma and RCC as they poorly respond to conventional cytotoxic agents but show responses to a variety of immunologic agents. The recent considerable success of T cell-based immunotherapy in melanoma warrants further efforts to apply this treatment to other cancers including MRCC. Although RCC is an immunosensitive cancer, similar attempts in MRCC have shown a very limited success. In this review, we summarize the clinical data on T cell-based immunotherapies for MRCC showing the modest success that has been achieved to date. More importantly, we discuss potential strategies for improving its efficacy for the treatment of MRCC in light of the important achievements for treating metastatic melanoma. In particular, the growing evidence of success by combining expanded tumor-infiltrating lymphocytes with lymphodepletion merits investigation in MRCC. Identifying new RCC-associated antigens, optimized methods, and conditions for detection, isolation, and/or modification and expansion of tumor-specific T cells are all important strategies to be pursued for improving T cell-based immunotherapy of MRCC. (Clin Cancer Res 2009;15(21):6503-10)

Approximately 90% of renal cell tumors overexpress the tumor antigen 5T4. The attenuated strain of vaccinia virus, modified vaccinia Ankara, has been engineered to express 5T4 (TroVax). We conducted an open-label phase 1/2 trial in which TroVax was administered alongside interferon-alpha (IFNalpha) to 11 patients with metastatic renal cell carcinoma. Antigen-specific cellular and humoral responses were monitored throughout the study, and clinical responses were assessed by measuring the changes in tumor burden by computed tomography scan (Response Evaluation Criteria In Solid Tumors). The primary objective was to assess the safety, immunogenicity, and efficacy of TroVax when given alongside IFNalpha. Treatment with TroVax plus IFNalpha was well tolerated with no serious adverse events attributed to TroVax. All 11 patients mounted 5T4-specific antibody responses and 5 (45%) mounted cellular responses. No objective tumor responses were seen, but the overall median time to progression (TTP) of 9 months (range: 2.1 to 26+ mo) was longer than expected for IFNalpha alone. For the 10 clear cell patients the TTP ranged from 3.9 to 26+ months, with a median TTP of 10.4 months. The high frequency of 5T4-specific immune responses and prolonged median TTP for clear cell patients compared with that expected for IFNalpha alone is encouraging and warrants further investigation.