Thomas H. Cartwright

Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial

BACKGROUND Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma. METHODS Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 1; leucovorin 200 mg/m(2) plus fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m(2) on day 1 every 2 weeks plus oral capecitabine 1000 mg/m(2) twice daily on days 1-15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4-8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918. FINDINGS Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab-FOLFOX4, and 952 to receive bevacizumab-XELOX. After a median follow-up of 48 months (range 0-66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab-FOLFOX4 group, and 253 (27%) in the bevacizumab-XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98-1·39; p=0·07), and for bevacizumab-XELOX versus FOLFOX4 was 1·07 (0·90-1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·27 (1·03-1·57; p=0·02), and for bevacizumab-XELOX versus FOLFOX4 was 1·15 (0·93-1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3-5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab-XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab-FOLFOX4: 297 [26%]; bevacizumab-XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab-FOLFOX4, and five receiving bevacizumab-XELOX. INTERPRETATION Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer. FUNDING Genentech, Roche, and Chugai.

Phase III Trial of Capecitabine Plus Oxaliplatin As Adjuvant Therapy for Stage III Colon Cancer: A Planned Safety Analysis in 1,864 Patients

PURPOSE To report the results of a planned safety analysis from a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus fluorouracil/leucovorin (FU/LV) as adjuvant therapy for stage III colon cancer. PATIENTS AND METHODS Patients with stage III colon carcinoma were randomly assigned to receive either XELOX (intravenous oxaliplatin plus oral capecitabine; 3-week cycle for eight cycles) or standard intravenous bolus FU/LV administered as the Mayo Clinic (Mayo; Rochester, MN) or Roswell Park (RP; Buffalo, NY) regimen for a similar length of time. A total of 1,886 patients were randomly assigned. RESULTS The safety population comprised 1,864 patients, of whom 938 received XELOX and 926 received FU/LV. Most treatment-related adverse events (AEs) occurred at similar rates in both treatment arms. However, patients receiving XELOX experienced less all-grade diarrhea, alopecia, and more neurosensory toxicity, vomiting, and hand-foot syndrome than those patients receiving FU/LV. Compared with Mayo, XELOX showed fewer grade 3/4 hematologic AE and more grade 3/4 gastrointestinal AE. Compared with RP, XELOX showed less grade 3/4 gastrointestinal AE and more grade 3/4 hematologic AE. As expected grade 3/4 neurosensory toxicity and grade 3 hand-foot syndrome were higher with XELOX. Treatment-related mortality within 28 days from the last study dose was 0.6% in the XELOX group and 0.6% in the FU/LV group. CONCLUSION XELOX has a manageable tolerability profile in the adjuvant setting. Efficacy data will be available within the next 24 months.

Phase II Study of Oral Capecitabine in Patients With Advanced or Metastatic Pancreatic Cancer

PURPOSE To determine the safety and efficacy of capecitabine (Xeloda; Roche Laboratories, Nutley, NJ) in patients with metastatic or unresectable, locally advanced pancreatic cancer. PATIENTS AND METHODS Forty-two patients were treated with oral capecitabine 1,250 mg/m(2) administered twice daily (2,500 mg/m(2)/d) as intermittent therapy in 3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment. Tumor lesions were assessed by computed tomography scan or physical examination at 6-week intervals (after every two cycles). Adverse events were monitored continuously during treatment and for 28 days after the last dose of study drug. RESULTS Ten (24%) of 42 patients experienced a clinical benefit response (95% confidence interval [CI], 12.1% to 39.5%) as evidenced by improvement in pain intensity, analgesic consumption, and/or Karnofsky performance status. Three (7.3%) of the 41 patients with measurable disease had an objective response (partial). The median time to objective response was 85 days (range, 47 to 91 days) and duration of response was 208, 260, and 566 days for the three responding patients. One patient with nonmeasurable but assessable disease had improved residual disease with a positive clinical benefit response, for a total of four responses among the 42 assessable patients, for an overall response rate of 9.5% (90% CI, 3.3% to 20.5%). Capecitabine was generally well tolerated. CONCLUSION Treatment with capecitabine resulted in clinically significant beneficial effects on tumor-related symptoms and yielded objective response activity in patients with metastatic or locally advanced pancreatic cancer. These results together with its generally tolerable safety profile and the added advantage of oral administration provide the basis for further evaluating capecitabine as a single agent or in combination with other treatment modalities in this patient population.

Pathways, Outcomes, and Costs in Colon Cancer: Retrospective Evaluations in Two Distinct Databases

PURPOSE The goal of this study was to use two separate databases to evaluate the clinical outcomes and the economic impact of adherence to Level I Pathways, an evidence-based oncology treatment program in the treatment of colon cancer. PATIENTS AND METHODS The first study used clinical records from an electronic health record (EHR) database to evaluate survival according to pathway status in patients with colon cancer. Disease-free survival in patients receiving adjuvant treatment and overall survival in patients receiving first-line therapy for metastatic disease was calculated. The second study used claims data from a national administrative claims database to examine direct medical costs and use, including the cost of chemotherapy and of chemotherapy-related hospitalizations according to pathway status. RESULTS Overall costs from the national claims database-including total cost per case and chemotherapy costs-were lower for patients treated according to Level I Pathways (on-Pathway) compared with patients not treated according to Level I Pathways. Use of pathways was also associated with a shorter duration of therapy and lower rate of chemotherapy-related hospital admissions. Survival for patients on-Pathway in the EHR database was comparable with those in the published literature. CONCLUSION Results from two distinct databases suggest that treatment of patients with colon cancer on-Pathway costs less; use of these pathways demonstrates clinical outcomes consistent with published evidence.

Cancer of the Pancreas: Are We Making Progress? A Review of Studies in the US Oncology Research Network

BACKGROUND Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. In 2008, approximately 37,680 people will be diagnosed with pancreatic cancer and 34,290 will die of this disease. METHODS The authors reviewed the literature on treatment of pancreatic cancer with an emphasis on studies conducted in the US Oncology Research (USOR) Network. RESULTS Although much research has been conducted to develop improved systemic therapies of pancreatic cancer, gemcitabine as a single agent remains the current standard of care. Combinations with other chemotherapeutic drugs or biological agents have resulted in limited improvement. CONCLUSIONS Despite aggressive efforts to improve treatment for patients with pancreatic cancer, limited progress has been made. It is hoped that new studies being planned and conducted will improve outcomes for patients with this disease.

Evaluating the quality of psychosocial care in outpatient medical oncology settings using performance indicators.

Objective: An American Psychosocial Oncology Society workgroup has developed indicators of the quality of psychosocial care that can be measured through review of medical records. The present report describes the first large‐scale use of these indicators to evaluate psychosocial care in outpatient medical oncology settings.

Treatment Decisions After Diagnosis of Metastatic Colorectal Cancer

Treatment of metastatic colorectal cancer (mCRC) involves the use of active cytotoxic drugs (irinotecan, oxaliplatin, 5-fluorouracil [5-FU], and capecitabine) and biological agents (bevacizumab, cetuximab, and panitumumab) either in combination or as single agents. Until recently, the only biological agent with proven first-line efficacy was bevacizumab, but options have expanded from the data generated with anti-endothelial growth factor (EGFR) monoclonal antibodies. Anti-EGFR agents can be added to first-line FOLFIRI (5-fluorouracil, leucovorin [folinic acid], irinotecan) or FOLFOX (5-fluorouracil, leucovorin [folinic acid], oxaliplatin) in patients whose tumors express wild-type KRAS. These agents may improve outcomes when added to chemotherapy, particularly progression-free survival (PFS), and in the case of cetuximab, overall survival (OS) and response rates. The selection of first-line therapy should be based on the individual treatment goals after considering the efficacy and tolerability of each regimen. For patients with metastases confined to the liver, surgical resection offers a potentially curative approach. For initially unresectable lesions, treatment regimens offering high response rates may produce sufficient tumor shrinkage to permit complete resection. Regimens with high response rates are also preferable for patients requiring symptom relief or for those with large tumor burdens. The choice between intensive vs. nonintensive management also depends on other factors, including the patients functional status, comorbidities, and desires. A sequential single-agent strategy or an intermittent approach (combination therapy followed by maintenance) may minimize toxicity and be appropriate for patients who are not surgical candidates, irrespective of treatment response. Guidelines, such as those of the National Comprehensive Cancer Network (NCCN), recommend that KRAS mutational status should be determined at mCRC diagnosis to identify candidates for anti-EGFR therapy whether they are used in first or subsequent lines of treatment.

Axitinib and/or bevacizumab with modified FOLFOX‐6 as first‐line therapy for metastatic colorectal cancer: A randomized phase 2 study

In this multicenter, open‐label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first‐line treatment of metastatic colorectal cancer (mCRC).

Survival outcomes of bevacizumab beyond progression in metastatic colorectal cancer patients treated in US community oncology.

BACKGROUND Bevacizumab prolongs OS when added to first- or second-line chemotherapy for mCRC. This retrospective analysis evaluated the association between the continued use of BBP and survival outcomes in mCRC patients treated in a community oncology setting. PATIENTS AND METHODS Data were derived from the US Oncology iKnowMed electronic medical record system. Patients with mCRC who received first-line bevacizumab-containing therapy between July 1, 2006 and June 30, 2009, were dichotomized into 2 second-line treatment cohorts: those receiving BBP and No-BBP. Clinical outcomes, including OS and postprogression OS (ppOS; time from start of second-line therapy to any-cause death), were calculated using Kaplan-Meier methods. A Cox proportional hazards model was used to assess the effects of patient and treatment characteristics on survival outcomes, adjusting for covariates. RESULTS Overall, 573 patients met the inclusion criteria for analysis-BBP (n = 267) and No-BBP (n = 306). Median OS and ppOS were longer in the BBP cohort (27.9 and 14.6 months, respectively) compared with the No-BBP cohort (21.4 and 10.1 months). According to multivariate analyses, BBP was associated with longer OS (HR, 0.76; 95% CI, 0.61-0.95) and ppOS (HR, 0.74; 95% CI, 0.60-0.93) after adjusting for potential confounders. CONCLUSIONS In the community oncology setting, BBP treatment was correlated with prolonged OS and ppOS in patients with mCRC. These results provide insight into real-world patterns of care and resultant bevacizumab use in this patient population.

Degree of Variability in Performance on Breast Cancer Quality Indicators: Findings From the Florida Initiative for Quality Cancer Care

PURPOSE The Florida Initiative for Quality Cancer Care (FIQCC) comprises 11 Florida practice sites that participate in comprehensive reviews of quality of care specific to patients with cancer. Here, we examined site adherence to performance indicators to assess quality of care for patients with breast cancer (BC). METHODS Quality indicators were scripted on the basis of accepted guidelines from the Quality Oncology Practice Initiative, National Comprehensive Cancer Network, American College of Surgeons, and site-specific expert panel consensus. Comprehensive chart reviews, including both medical and surgical oncology quality measures, were conducted for patients with BC first seen in 2006 by a medical oncologist at one of the sites. Statistical comparisons were made by the Pearson χ(2) exact test, using Monte Carlo estimation. RESULTS Charts of 622 patients were reviewed. Of the 34 indicators, seven for medical oncology and four for surgical oncology fell below the 85% level of adherence. A statistically significant difference (P < .001) in variation of performance across the sites was found for the following medical and surgical oncology indicators: documentation of menopausal status, family history, informed consent, planned chemotherapy regimen and flow sheet, American Joint Committee on Cancer staging, HER2/neu status, reporting of margin orientation and inking of the margins, histological grade, having a sentinel lymph node biopsy for invasive BC, and obtaining a mammogram within 14 months of definitive surgery. CONCLUSION The FIQCC has identified how multiple aspects of BC care can be improved. Findings are being used at the participating institutions to guide quality improvement efforts.