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Abstract and Introduction
Abstract
Background: The perception that older cancer patients may be at higher risk than younger patients of toxic effects from cancer therapy but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials and the known toxic effects of cytotoxic chemotherapy. It is not known how older patients respond to targeted therapy.
Methods: This retrospective subgroup analysis of data from the phase 3, randomized Treatment Approach in Renal Cancer Global Evaluation Trial examined the safety and efficacy of sorafenib in older (age ≥70 years, n = 115) and younger patients (age <70 years, n = 787) who received treatment for advanced renal cell carcinoma. Patient demographics and progression-free survival were recorded. Best tumor response, clinical benefit rate (defined as complete response plus partial response plus stable disease), time to self-reported health status deterioration, and toxic effects were assessed by descriptive statistics. Health-related quality of life was assessed with a Cox proportional hazards model. Kaplan-Meier analyses were used to summarize time-to-event data.
Results: Median progression-free survival was similar in sorafenib-treated younger patients (23.9 weeks; hazard ratio [HR] for progression compared with placebo = 0.55, 95% confidence interval [CI] = 0.47 to 0.66) and older patients (26.3 weeks; HR = 0.43, 95% CI = 0.26 to 0.69). Clinical benefit rates among younger and older sorafenib-treated patients were also similar (83.5% and 84.3%, respectively) and were superior to those of younger and older placebo-treated patients (53.8% and 62.2%, respectively). Adverse events were predictable and manageable regardless of age. Sorafenib treatment delayed the time to self-reported health status deterioration among both older patients (121 days with sorafenib vs 85 days with placebo; HR = 0.66, 95% CI = 0.43 to 1.03) and younger patients (90 days with sorafenib vs 52 days with placebo; HR = 0.69, 95% CI = 0.59 to 0.81) and improved quality of life over that time.
Conclusions: Among patients with advanced renal cell carcinoma receiving sorafenib treatment, outcomes of older (≥70 years) and younger (<70>
Introduction
Renal cell cancer, the 14th most common cancer worldwide,[1] accounts for approximately 2% of all new cancer cases[2] and approximately 102 000 deaths worldwide.[3] Rates have increased in Europe and the United States over the past 30 years, in part because of improved imaging technologies but also because of other factors.[2] For example, cigarette smoking and obesity may each account for more than 20% of the cases of renal cell cancer. Increases in the incidence of renal cell carcinoma and in the average age of patients with advanced renal cell carcinoma are predicted because of the aging population.[4] Although a higher risk of cancer is associated with advanced age, older patients are frequently underrepresented in oncology trials.[5] Thus, there is a lack of detailed data on how this important subgroup of patients tolerates and responds to emerging cancer therapies.
The perception that older patients are at higher risk for toxicity and less likely to benefit from treatment has itself contributed to a lower accrual rate of older patients in these trials.[6] Physician surveys have found that comorbid conditions and toxic effects of treatment are the most frequently cited barriers to recruitment of older patients.[7,8] A growing body of data, however, indicates that older patients with adequate organ function and a reasonable life expectancy should receive the same treatment as younger patients. A retrospective analysis[9] of 401 patients from 19 studies that evaluated 13 different molecularly targeted cancer therapies found similar frequencies of drug-related adverse events among patients who were younger than 65 years and those who were 65 years or older, regardless of whether the therapies were administered as monotherapy or in combination with chemotherapy. Similarly, older patients with non-small-cell lung cancer who were 70 years or older tolerated cisplatin-based regimens as well as younger patients, with response rates and time to progression similar to those of younger patients.[10]
Although more data are needed, current evidence indicates that age has a minimal influence on the nature and treatment of advanced renal cell carcinoma. Older (>70 years) and younger (≤70 years) patients diagnosed with renal cell carcinoma present with similar clinical and laboratory features, incidences of nephrectomy, and probabilities of survival.[11] A moderately greater mortality rate has been observed in some older patient populations with advanced renal cell carcinoma, perhaps because older patients in these studies were at a more advanced stage at diagnosis.[12] In another analysis,[13] older patients (≥60 years; n = 174) with advanced renal cell carcinoma who received subcutaneous cytokine-based therapy (either interleukin-2 or interferon-2α therapy) had similar objective response rates (27% vs 31%), median overall survival (22 vs 19 months), and median progression-free survival (6 vs 5 months), as younger patients (<60 n =" 251).
Sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals, Montville, NJ) is a novel multikinase inhibitor with antiangiogenic and proapoptotic activity. Sorafenib inhibits such tyrosine kinases as vascular endothelial growth factor receptor-1, -2, and -3; platelet-derived growth factor receptor-?; c-Kit; and Flt-3.[14] Sorafenib, an oral agent, was approved as a treatment for renal cell carcinoma in the United States in December 2005 on the basis of results of the pivotal phase 3 Treatment Approach in Renal Cancer Global Evaluation Trial (TARGET), the largest randomized placebo-controlled trial in renal cell carcinoma to date. The final independently assessed analysis,[15] as of January 2005, found a statistically significant doubling of progression-free survival from 2.8 to 5.5 months (P < .001) for sorafenib-treated patients and a clinically meaningful trend toward improved overall survival (median = 14.7 months in the placebo group compared with median not reached in sorafenib group; hazard ratio [HR] of death from any cause = 0.72, P = .018). Because of the statistically significantly improved progression-free survival, trend toward improved overall survival, and manageable toxicity profile, the trial was stopped early and patients who had been randomly assigned to receive placebo were allowed to cross over to treatment with sorafenib. The final progression-free survival data supported global approval of sorafenib, the first systemic agent approved for renal cell carcinoma in over a decade. In this retrospective analysis of data collected before placebo patients were allowed to cross over to sorafenib therapy, we evaluated the association of age with results of treatment with sorafenib in patients with advanced renal cell carcinoma by comparing outcomes between younger (<70>
Materials and Methods
Eligibility
The study population in TARGET consisted of patients who were at least 18 years of age with histologically confirmed metastatic renal cell carcinoma. Patients with disease progression after they received at least one systemic treatment for metastatic renal cell carcinoma (within the previous 8 months) were enrolled in the study. Other eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 or 1; a Memorial Sloan-Kettering Cancer Center prognostic score indicating low or intermediate risk; and adequate bone marrow, liver, pancreatic, and renal function. Patients with brain metastases were excluded from the study. All patients provided written informed consent before study entry in accordance with the institutional review board of each participating institution.
Study Design
This was a retrospective analysis of outcomes in patients younger than 70 years or 70 years or older who were a part of the pivotal phase 3 double-blind international randomized parallel-group multicenter TARGET, which compared sorafenib treatment with placebo treatment in patients with advanced renal cell carcinoma who had received one previous regimen of systemic therapy. The details of the TARGET trial design are reported elsewhere.[15] Briefly, from November 24, 2003, when the first patient was assessed for eligibility, until March 31, 2005, when enrollment closed, 903 patients were enrolled and randomly assigned to receive either sorafenib or placebo treatment. There were 451 patients in the sorafenib group and 452 in the placebo group. Baseline disease characteristics (see Table 1 ) were collected at the time of study entry in the clinic and recorded on the study case report forms in conjunction with treatment group randomization. Patients were stratified by country and Memorial Sloan-Kettering Cancer Center prognostic score and then were randomly assigned to treatment with 400 mg of sorafenib twice daily or with placebo (in 6-week cycles for the first 24 weeks and 8-week cycles thereafter) in a continuous dosing fashion until progressive disease or unacceptable toxicity was encountered.
Because 115 patients in this study were aged 70 years or older, this population provided a rare opportunity to assess the benefits and side effects of treatment in the elderly. Consultations with clinicians in the field of geriatrics indicated that 70 years was the age beyond which individuals tend to be classified as elderly.
A single planned, independently assessed analysis of progression-free survival in January 2005[15] found that sorafenib was associated with a statistically significant increase in progression-free survival (HR for disease progression = 0.44, 95% confidence interval [CI] = 0.35 to 0.55, P < .001, with the median progression-free survival of the sorafenib group being double that of the placebo group—ie, 24 vs 12 weeks, respectively). Consequently, crossover from placebo to sorafenib was permitted beginning in May 2005. The data in this report are from an updated descriptive analysis of progression-free survival as of May 2005, after the trial was fully accrued but before crossover was allowed.
Outcome Variables
The outcome variables for this retrospective analysis included progression-free survival, best tumor response, clinical benefit rate, and quality of life. A complete response was defined as disappearance of all target lesions. A partial response was defined as a 30% decrease in the sum of the longest diameter of target lesions. Stable disease was defined as small changes in lesions that did not meet criteria for complete response, partial response, or progressive disease. Progression-free survival was defined as the time from randomization to disease progression (as detected radiologically or clinically, whichever was earlier) or death (if death occurred before progression). Tumor assessments by computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis were performed before treatment, on day 1 of cycle 2, and at every cycle thereafter until the end of treatment. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors.[16] Clinical benefit rate was defined as the proportion of patients with a complete response, a partial response, or stable disease.
Patient-reported quality of life outcomes were assessed by use of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) and the Physical Well-Being (PWB) domain of the Functional Assessment of Cancer Therapy-General version (FACT-G).[17,18] FKSI measures patient-reported kidney cancer-related symptoms and concerns. The PWB domain of FACT-G measures the physical functioning aspect of quality of life. In general, higher scores mean a better quality of life, with a change in an individual's score of 4 points considered a meaningful difference. The questionnaires were administered on day 1 of each cycle and at the end of treatment visit.
Safety analysis measured treatment-related adverse events; it distinguished between drug-related vs non-drug-related events. Adverse events were graded by use of the Common Terminology Criteria for Adverse Events from the National Cancer Institute. Quality of life data were obtained during the first five cycles of treatment.
Statistical Methods
The subgroup analyses were conducted among the intent-to-treat older and younger subgroups and included data obtained through May 2005. Statistical analyses were performed in an exploratory fashion and their results are mainly descriptive in nature. Toxic effects were evaluated by use of the Common Terminology Criteria for Adverse Events version 3.0, and all events referred to were treatment related. Descriptive statistics were used to describe patient characteristics, best tumor response, clinical benefit rate, and safety for patients who were younger than 70 years or 70 years or older by treatment group. Kaplan-Meier estimates and curves were used to summarize time-to-event data, such as the analysis of progression-free survival. Treatment-related differences in response were evaluated by the Cochran-Mantel-Haenszel test. Progression-free survival was compared by the log-rank test (stratified by prognostic group and country).
The median time to health status deterioration was calculated for FKSI and the PWB domain of FACT-G by use of the Cox proportional hazards model. Schoenfeld residual plots were used to evaluate the proportional hazard assumption. For FKSI and PWB, the median time to health status deterioration was defined as a 4-point drop in total score from FKSI-15 or PWB or as clinical progression, or death if the FKSI-15 or PWB score was missing. A 4-point drop in total score was chosen to be consistent with published data on what constitutes a clinically significant deterioration. Details of the number of assessments completed at each time point and the mean scores for FKSI-15 and PWB have been described elsewhere.[17] In addition, the condition of patients was rated as improved, no change, or worsened, according to how their scores compared with baseline for each cycle, on the basis of a 4-point change for total score of FKSI-15 and PWB scores. All reported P values are two-sided.
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