Patricia A. Tang

Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy

PURPOSE Our aims were to determine the correlations between progression-free survival (PFS), time to progression (TTP), and response rate (RR) with overall survival (OS) in the first-line treatment of metastatic colorectal cancer (MCRC), and to identify a potential surrogate for OS. METHODS Randomized trials of first-line chemotherapy in MCRC were identified, and statistical analyses were undertaken to evaluate the correlations between the end points. RESULTS Thirty-nine randomized controlled trials were identified containing a total of 87 treatment arms. Among trials, the nonparametric Spearman rank correlation coefficient (r(s)) between differences (Delta) in surrogate end points (DeltaPFS, DeltaTTP, and DeltaRR) and DeltaOS were 0.74 (95% CI, 0.47 to 0.88), 0.52 (95% CI, 0.004 to 0.81), 0.39 (95% CI, 0.08 to 0.63), respectively. The r(s) for DeltaPFS was not significantly different from the r(s) DeltaTTP (P = .28). Linear regression analysis was performed using hazard ratios for PFS and OS. There was a strong relationship between hazard ratios for PFS and OS; the slope of the regression line was 0.54 +/- 0.10, indicating that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% +/- 1% risk reduction for OS. CONCLUSION In first-line chemotherapy trials for MCRC, improvements in PFS are strongly associated with improvements in OS. In this patient population, PFS may be an appropriate surrogate for OS. As a clinical end point, PFS offers increased statistical power at a given time of analysis and a significant lead time advantage compared with OS.

Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer

Purpose: Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR) 1 and VEGFR2 extracellular domains. We assessed the safety and efficacy of aflibercept in patients with metastatic colorectal cancer (MCRC) who had received at least one prior palliative regimen. Experimental Design: Seventy-five patients were enrolled onto this two-stage phase II trial in two cohorts, bevacizumab naïve (n = 24) and prior bevacizumab (n = 51). Aflibercept was administered at 4 mg/kg i.v. in two-week cycles. The primary endpoint was a combination of objective response rate and 16-week progression-free survival (PFS). Results: In the bevacizumab-naïve cohort (n = 24), the best response was stable disease for 16 weeks or more in five of 24 patients. In the prior bevacizumab cohort (n = 50), one patient achieved a partial response and six patients had stable disease for 16 weeks or more. The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was two months [95% confidence interval (CI): 1.7–8.6 months] and 2.4 months (95% CI: 1.9–3.7 months), respectively. Median overall survival (OS) was 10.4 months (95% CI: 7.6–15.5) and 8.5 months (95% CI: 6.2–10.6), respectively. The most common grade 3 or higher treatment-related adverse events were hypertension, proteinuria, fatigue, and headache. Ten patients discontinued study treatment due to toxicity. Mean free to VEGF-bound aflibercept ratio was 1.82, suggesting that free aflibercept was present in sufficient amount to bind endogenous VEGF. Conclusion: Aflibercept showed limited single-agent activity in patients with pretreated MCRC with moderate toxicity. Further study of aflibercept with chemotherapy is ongoing. Clin Cancer Res; 18(21); 6023–31. ©2012 AACR.

A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer

BACKGROUND Erlotinib induced skin toxicity has been associated with clinical benefit in several tumour types. This phase II study evaluated the efficacy of erlotinib, dose escalated to rash, in patients with advanced pancreatic cancer previously treated with gemcitabine. METHODS Erlotinib was given at an initial dose of 150 mg/day, and the dose was escalated by 50mg every 2 weeks (to a maximum of 300 mg/day) until >grade 1 rash or other dose limiting toxicities occurred. Erlotinib pharmacokinetics were performed, and baseline tumour tissue was collected for mutational analysis and epidermal growth factor receptor (EGFR) expression. The primary end-point was the disease control rate (objective response and stable disease >8 weeks). RESULTS Fifty-one patients were accrued, and 49 received treatment. Dose-escalation to 200-300 mg of erlotinib was possible in 9/49 (18%) patients. The most common ⩾ grade 3 adverse events included fatigue (6%), rash (4%) and diarrhoea (4%). Thirty-seven patients were evaluable for response, and the best response was stable disease in 12 patients (32% (95% confidence interval (CI) 17-47%)). Disease control was observed in nine patients (24% (95% CI: 10-38%)). Median survival was 3.8 months, and 6 month overall survival rate was 32% (95% CI 19-47%). Mutational analysis and EGFR expression were performed on 29 patients, with 93% having KRAS mutations, none having EGFR mutations, and 86% expressing EGFR. Neither KRAS mutational status nor EGFR expression was associated with survival. CONCLUSIONS Erlotinib dose escalated to rash was well tolerated but not associated with significant efficacy in non-selected patients with advanced pancreatic cancer.

Predictors of Pathologic Complete Response After Neoadjuvant Treatment for Rectal Cancer: A Multicenter Study

BACKGROUND Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) for rectal cancer is associated with better long-term outcomes, and is used as an early indicator of response to novel agents. To assess the rate and predictors of pCR, we performed a retrospective multicenter study involving 5 Canadian cancer centers. PATIENTS AND METHODS Cancer registries identified consecutive patients with locally advanced rectal adenocarcinoma from the Tom Baker Cancer Centre, Cross Cancer Institute, British Columbia Cancer Agency, Ottawa Hospital Cancer Centre, and the Dr H. Bliss Murphy Cancer Centre who received fluoropyrimidine-based CRT and had curative intent surgery from 2005 to 2012. Patient, tumor, and therapy characteristics were correlated with response. RESULTS Of the 891 patients included, 885 patients had pCR data available. Of the included patients, 161 (18.2%) had a pCR to CRT, and 724 (81.8%) did not. Patients with a pCR had a lower pretreatment carcinoembryonic antigen (CEA) level, and higher hemoglobin level in univariate analysis. In multivariable analysis, statin use at baseline (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.02-2.92; P = .04), lower pretreatment CEA level (OR, 1.03; 95% CI, 1.01-1.06; P = .03), and distance closer to anal verge (OR, 1.07; 95% CI, 1.01-1.15; P = .04) were significant predictors of pCR. The 3-year disease-free survival was 86% in those with a pCR versus 62.5% in those without a pCR (P < .0001) and pCR was associated with improved overall survival (hazard ratio, 0.29; 95% CI, 0.17-0.51; P < .0001). CONCLUSION Lower pretreatment CEA level, proximity to anal verge, and statin use are predictors of pCR in our large retrospective cohort. Clinical trials to investigate statins combined with neoadjuvant CRT might be warranted.

Impact of body composition on clinical outcomes in metastatic renal cell cancer.

Systemic therapy for metastatic renal cell cancer (mRCC) currently revolves around inhibition of angiogenesis through the vascular endothelial growth factor (VEGF) pathway or the mammalian target of rapamycin (mTOR) pathway. Unfortunately, there are no validated predictive factors that can accurately determine whether a patient will benefit from treatment with molecularly targeted agents. However, many groups have identified prognostic factors that provide insight into a patients overall disease outcome independent of treatment [1]. These prognostic factors have been incorporated into multivariate models that stratify patients into poor, intermediate, and favorable risk groups. Commonly used models include the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria [2, 3], derived in the immunotherapy era, and the Heng criteria [4], derived from patients treated with novel anti-VEGF therapies (Table 1). Table 1. Comparison of multivariate prognostic factor models in metastatic renal cell carcinoma Obesity is an established risk factor for developing RCC [5–8], and several studies suggested, perhaps counterintuitively, that a high body mass index (BMI) confers a survival advantage to patients undergoing nephrectomy [9, 10]. In the particular setting of mRCC and targeted therapy, the prognostic impact of obesity and body mass is not clear. Potential mechanisms by which obesity could influence clinical outcomes include alterations in pharmocokinetics and drug concentrations as well as the presence of associated comorbidities such as diabetes and cardiovascular disease [11]. Obesity induces a “state of inflammation,” which results in elevations in tumor necrosis factor, interleukin (IL)-1β, IL-6, IL-1 receptor antagonist, and C-reactive protein [12]. Adipocytes produce multiple angiogenic factors such as VEGF and leptin [13]. Obesity can also activate the phosphoinositide 3-kinase–Akt–mTOR pathway via reactive oxygen species [14] and hyperinsulinemia/insulin like growth factor [15]. Several groups (Table 2) have evaluated the association between obesity or high BMI and survival in mRCC patients. Choueiri et al. [16] found that a high BMI was independently associated with a longer overall survival (OS) time (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.49–0.91; p = .01) after adjusting for the Heng criteria in 475 mRCC patients treated with antiangiogenic therapy. Furthermore, patients with a normal BMI or low body surface area (BSA) had a shorter time to progression (TTP) and OS time than the obese group. However, BMI and BSA are relatively crude measurements of body composition. Table 2. Retrospective studies evaluating the impact of body composition on outcome in metastatic renal cell carcinoma patients treated with antiangiogenic therapies In the article that accompanies this commentary, Steffens et al. [17] evaluate the prognostic potential of four measures of body composition in 116 mRCC patients: BMI (kg/m2), BSA (m2), visceral fat area (VFA, in mm2), and superficial fat area (SFA, in mm2). Obesity was defined as a BMI ≥30 kg/m2 based on current World Health Organization standards or a BSA above the European average for men (1.98 m2) and women (1.74 m2) [18, 19]. Baseline VFA and SFA were calculated based on baseline computed tomography (CT) scans using the methods of Yoshizumi et al. [20]. Given the paucity of normative data on VFA and SFA, the threshold for obesity was arbitrarily defined as a value above the median observed in the patient cohort. Obesity was present in 19.8% of patients based on BMI and in 62.9% of patients based on BSA. On multivariate Cox regression analysis, including histological subtype and MSKCC status, there was no significant association between the progression-free survival and OS and elevated BMI and BSA, the traditional definitions of obesity. However, elevated VFA and SFA were both independently associated with a longer progression-free survival and OS time (VFA: HR, 2.97; 95% CI, 1.36–6.47; p = .006; SFA: HR, 3.41; 95% CI, 1.61–7.25; p = .001). This is in stark contrast to the results of Ladoire et al. [21], who evaluated the prognostic impact of BMI, SFA, and VFA in French patients with mRCC. The same definition of obesity was used as in the German cohort (BMI >30 kg/m2, SFA above the median, VFA above the median using the methods of Yoshizumi et al. [20]). The French cohort had mean baseline SFA and VFA similar to those of the German group, but more patients had a poor performance status (20 of 113 with a Karnofsky performance status score <80). On multivariate analysis, including the MSKCC group, high VFA was associated with a significantly shorter TTP and OS time (HR, 6.26; 95% CI, 2.29–17.08; p < .001) in patients treated with antiangiogenic drugs (n = 59), but not in patients treated with cytokines. BMI and SFA were not prognostic. Ladoire et al. [21] suggested that high VFA was a predictive factor because it was associated with worse outcomes for patients treated with antiangiogenic therapy but not cytokines. Another potentially important aspect of body composition is sarcopenia, or skeletal muscle wasting. In a single-institution study of patients with advanced lung and gastrointestinal malignancies, the concurrent presence of sarcopenia and obesity was associated with a worse OS outcome (HR, 4.2; 95% CI, 2.4–7.2; p .0001) than in nonsarcopenic obese patients [22]. The impact of sarcopenia on long-term outcomes in mRCC patients is unknown. Limited data are available from a subset of mRCC patients who participated in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), a randomized trial of sorafenib compared with placebo after failure of standard therapy [23]. Sarcopenia was present in 72% of patients with a BMI 25 kg/m2 [24]. Treatment with sorafenib led to a significant loss of skeletal muscle at 12 months (8.0% decrease; p 25 kg/m2 [26]. Despite the small sample size, these data suggest that sarcopenia exacerbates sorafenib-induced toxicities. Sorafenib, in turn, exacerbates skeletal muscle loss, creating a vicious circle in this setting, leading to worse clinical outcomes. It is also worth mentioning that the better prognosis in obese patients observed by Choueiri et al. [16] and Steffens et al. [17] may be related to better tolerability of targeted agents that are dosed independently of body weight. However, intuitively, a major concern with obese patients is underdosing. The routine use of CT to assess therapeutic response provides an unparalleled opportunity to precisely quantify body composition. Superior outcomes were associated with elevated BMI and BSA in the study of Choueiri et al. [16] and with elevated SFA or VFA in the study of Steffens et al. [17]; conversely, poorer outcomes were linked with elevated VFA in the study of Ladoire et al. [21]. This may be a result of an imbalance in prognostic factors that were not controlled for and/or an unknown interaction or effect modifier more prevalent in one study than in another. Both Ladoire et al. [21] and Steffens et al. [17] performed their respective multivariate analyses controlling for the MSKCC criteria, which were validated in clinical trial patients in the immunotherapy era [2, 3]. Given the widely disparate results, the prognostic value of body composition (BMI, BSA, SFA, VFA, and sarcopenia) should be evaluated in a larger patient population to validate threshold values for SFA, VFA, and sarcopenia. Such studies will help determine whether body composition provides further refinement of the current prognostic models and pave the way for better prognostication. Editors Note: See the accompanying article, “Does obesity influence the prognosis of metastatic renal cell carcinoma in patients treated with vascular endothelial growth factor-targeted therapy?” by S. Steffens, V. Grunwald, K.I. Ringe, et al., on pages 1565–1571 of this issue.

Trends in the application of dynamic allocation methods in multi-arm cancer clinical trials

Background Dynamic allocation (DA) methods which attempt to balance baseline prognostic factors between treatment arms, can be used in multi-arm clinical trials to sequentially allocate patients to treatment. Although some experts express concern regarding the validity of inference from trials using DA, others believe DA methods produce more credible results. Purpose A review of published multi-arm cancer clinical trials was conducted to explore the frequency of DA use in oncology. Methods Multi-arm phase III clinical trials of at least 100 patients per arm, published in 13 major oncology journals from 1995—2005 were manually reviewed. Information about reported use of DA methods, or randomization via random permuted blocks (PB), was extracted along with trial characteristics. Results Of 476 published clinical trials, 112 (23.5%) reported using some form of DA method, while 103 (21.6%) reported using PB methods. Most trials (403 or 84.7%) reported stratifying on at least one baseline factor. The mean number of stratification factors was 2.70 per trial, and 78.6% of DA trials reported 3 or more stratification factors compared with 30.2% of non-DA trials (p < 0.001). The frequency of DA use increased over time, with 20.2%, 21.3%, 25.8%, 28.8% and 38.9% of trials reported use in 1995—2001, 2002, 2003, 2004, and 2005, respectively. Use of DA methods was more frequently reported in trials involving an academic co-operative group (28.4% vs. 13.8%), however, no difference was observed between industry-funded and other-funded trials (24.0% vs. 23.2%) or geographical region (19.7% of North American trials, 26.2% of European trials and 21.7% of multinational/other trials). Limitations As a retrospective analysis, the true frequency of DA use is likely underreported. Few trials gave complete details of the allocation method used, thus it is possible some manuscripts reported incorrect allocation methods. Journals were selected which were assumed to publish most large, multi-arm clinical trials in cancer from 1995—2005, however, some trials were likely reported in journals other than what was reviewed. Conclusions DA methods are frequently used in multi-arm cancer clinical trials. The use of DA appears to becoming more common over time and are used more frequently when an academic cooperative group is involved. No relationship between industry funded trials or geographic region and allocation method was observed. Clinical Trials 2010; 7: 227—234. http://ctj.sagepub.com

Low ATM protein expression in malignant tumor as well as cancer-associated stroma are independent prognostic factors in a retrospective study of early-stage hormone-negative breast cancer

IntroductionThe serine/threonine protein kinase ataxia telangiectasia mutated (ATM) is critical in maintaining genomic integrity. Upon DNA double-strand breaks, ATM phosphorylates key downstream proteins including p53 and BRCA1/2, thereby orchestrating complex signaling pathways involved in cell cycle arrest, DNA repair, senescence and apoptosis. Although sporadic mutation of ATM occurs rarely in breast cancer, the status of its protein expression and its clinical significance in breast cancer remain not well established. Our study was designed to investigate the influence of ATM protein in both tumor and cancer-associated stroma on clinical outcome in hormone-positive (HPBC) and hormone-negative (HNBC) early-stage breast cancer (EBC).MethodsTissue microarrays (TMAs), containing formalin-fixed, paraffin-embedded resected tumors from two cohorts of patients (HPBC cohort: n = 130; HNBC cohort: n = 168) diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, were analyzed for ATM protein expression using fluorescence immunohistochemistry (IHC) and automated quantitative analysis (AQUA). ATM expression levels were measured within the tumor as a whole (tATM) as indicated by pan-cytokeratin expression, tumor nuclear compartment (nATM) as indicated by both DAPI and pan-cytokeratin-positive results, and cancer-associated stroma (csATM) as indicated by vimentin-positive and pan-cytokeratin-negative results. ATM expression levels within these compartments were correlated with clinical outcome.ResultsWhile tATM and nATM were significantly lower in tumors compared to normal breast epithelial tissues, csATM was significantly higher than the corresponding normal tissue compartment. In addition, the median expression level of both tATM and nATM were two- to threefold lower (P <0.001) in HNBC than in HPBC. In both HNBC and HPBC cohorts, patients with low tATM, nATM and csATM tumors had significantly poorer survival outcomes than those with a high tATM, nATM and csATM, but this effect was more pronounced in HNBC. A multivariate analysis demonstrates that these biomarkers predict survival independent of tumor size and lymph node status, but only in the HNBC cohort (P <0.001).ConclusionsLow ATM protein expression in both malignant tumor and stromal compartments likely contributes to the aggressive nature of breast cancer and is an independent prognostic factor associated with worse survival in HNBC patients.

Aflibercept in the treatment of patients with metastatic colorectal cancer: latest findings and interpretations.

Inhibition of angiogenesis is an established adjunct in the treatment of metastatic colorectal cancer. Bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) A, improves clinical outcomes when added to standard chemotherapy for metastatic colorectal cancer. Unfortunately, the development of resistance is inevitable, and novel therapeutic strategies are needed. Aflibercept is an intravenously administered fusion protein of the human vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 extracellular domains. This antiangiogenic agent binds to VEGF A, VEGF B, and placental growth factor 1 (PlGF1) and PlGF2 with high affinity and inhibits downstream signaling. Common side effects of single agent aflibercept are similar to other antiangiogenic drugs and include hypertension, proteinuria, fatigue, and headache. Recent clinical data regarding the efficacy of aflibercept with standard chemotherapy for metastatic colorectal cancer, associated adverse events, and future areas of research are reviewed.

Comparison of oncology drug approval between Health Canada and the US Food and Drug Administration

The drug approval timeline is a lengthy process that often varies between countries. The objective of this study was to delineate the Canadian drug approval timeline for oncology drugs and to compare the time to drug approval between Health Canada (HC) and the US Food and Drug Administration (FDA).

Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer

BACKGROUND Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database. PATIENTS AND METHODS Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors. RESULTS Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04). CONCLUSIONS Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.