Citations

Purpose The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. Methods Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. Results DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. Conclusion DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.

Emerging technologies have greatly expanded our ability to detect, characterize, and treat colorectal cancer. The Coalition of Cancer Cooperative Groups convened a multidisciplinary panel, the Scientific Leadership Council in GI cancer, to discuss and advise on the priorities and opportunities to advance current and future approaches into the clinical arena to impact most rapidly the morbidity and mortality from this disease. The Council's recommendations for research priorities are the result of engagement of community and academic oncologists, patient advocacy groups, and other stakeholders including the pharmaceutical industry and governmental agencies. We detail some key prospects for investigation in the areas of colon cancer detection, prevention, and surgical and medical management. Many are in early or definitive clinical trials, and a focus on rapid accrual is urged. The implementation of biology-directed laboratory investigations, both in association with ongoing clinical trials and as a separate developmental strategy for targeted therapies, is supported as the route to individualized therapy.

AbstractThe aim was to determine whether changes in enteric bacteriology, absorption, morphology, and emptying occur after ileal pouch–anal anastomosis for ulcerative colitis, and to relate any changes to the clinical result. Twenty patients were studied 26 ± 2 months (mean ± s.e.m.) after operation. Eight patients had a good result, six a poor result, and six a history of recurrent pouch ileitis. Anaerobic and aerobic overgrowth occurred in the jejunum of patients with a poor result, but not in those with a good result or with pouch ileitis. In contrast, ileal pouch bacterial overgrowth occurred in all patients regardless of the clinical result. Patients with jejunal overgrowth had increased 24 h stool volume and stool nitrogen, but other patients did not. The larger the stool volume, the greater the anaerobic overgrowth. Pouch biopsies showed chronic inflammation in all patients, while 45 per cent had colonic metaplasia. Neither the inflammation nor the metaplasia correlated with the clinical result, nor did the clinical result correlate with the efficiency of pouch emptying. In conclusion, jejunal bacterial overgrowth after ileal pouch–anal anastomosis was associated with an increased stool output, azotorrhoea, and a poor clinical result. A distinguishing bacterial, absorptive, morphological, or emptying abnormality was not found in patients with a history of recurrent pouch ileitis.

Purpose Adverse events (AEs) are monitored in clinical trials for patient safety, to satisfy reporting requirements, and develop safety profiles. Recently, much attention has been placed on the reporting of serious AEs (SAEs) that are either life threatening or lethal in clinical trials. However, SAEs comprise a small subset of all AE data collected for trials; the majority of AE data collected are routine AEs (RAEs) regarding non–life-threatening events. We assessed the utility of the RAE data collected, relative to the volume. Patients and Methods We surveyed the RAE data from 26 North Central Cancer Treatment Group coordinated trials. Results A total of 8,318 (11%) of 75,598 of RAEs required queries. Of these, 86% were protocol-required RAEs, 83% of RAEs required per protocol were within normal limits (eg, platelets) or not present, and 61% of extra AEs were mild. One fifth of RAEs were considered unlikely to be related or unrelated to treatment. Overall, 3% of events were severe, life threatening, or caused death. Only 1% of RAE data reported required expedited reporting (eg, via Adverse Event Expedited Reporting System). Results indicate that 72% of RAEs would be eliminated if only the maximum severity per patient and type were required. These results were validated in a large phase III trial. Conclusion The majority of RAEs identified, transcribed, and entered are not clinically important. Our data suggest that reducing the number of AEs monitored will affect substantially neither overall patient safety nor compromise evaluation of regimens undergoing testing. We present several considerations for such a reduction in data collection, as well as a policy that we have used to address the deluge of RAE data.

Purpose A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

AbstractSurgical resection continues to be the primary curative modality for patients with adenocarcinoma of the rectum. However, local tumor recurrence in the pelvis and/or distant metastasis may occur in spite of complete excision of grossly visible malignant disease. Surgical and pathologic staging can identify a subset of surgically treated rectal cancer patients at high risk for tumor relapse and death. Irradiation and chemotherapy have been used as adjuvant therapy in conjunction with surgery as single modalities and in combination for patients with high risk rectal cancer. Evidence from controlled clinical trials indicates a significant decrease in local tumor recurrence, and a significant improvement in disease‐free and overall survival with the use of combined postoperative irradiation and chemotherapy in this setting. A current national clinical trial in the United States of America is studying whether irradiation can be combined with new chemotherapy regimens which have shown significant therapeutic benefit as surgical adjuvant therapy for patients with high risk colon cancer (5FU + levamisole) and for patients with metastatic colorectal cancer (5FU + leucovorin) to further improve the efficacy of surgical adjuvant therapy for adenocarcinoma of the rectum.