DeMatteo, Ronald P.

6511 Background: In March 1998, the Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AE) to study drug. Collection of attribution adds time and cost to the clinical trial process, and reporting in the literature has varied. At ASCO 2006 results were presented from NCCTG trial 97–24–51 that showed ∼ 50% of events on the placebo arm were reported as attributed to study drug and 25% of the time the same event was not consistently attributed. We sought to validate these results in a second placebo controlled trial. Methods: Patients on the placebo arm of the phase III ACOSOG trial Z9001 (imatinib mesylate vs. placebo after resection of primary gastrointestinal stromal tumors) were evaluated since the reported AEs could not be due to study drug. Attribution was collected per CTCv3.0 as not related, unlikely, possibly, probably, or definitely related, and categorized as “unrelated” (not related or unlikely) and “related” (possible, probable, or definite). Patterns were evaluated using generalized estimating equations adjusting for multiple events per patient. Results: 202 patients and 2871 AEs were included. 52% of AEs were reported as “related”. Known imatinib AEs were more likely to be reported as “related”. The reported rate of AE relatedness varied by AE type. No patterns were observed by gender, age, PS, severity or visit of AE. When the same event was reported on the same patient on multiple visits, the attribution category changed at least once 33% of the time with 19% changing from “related” to “unrelated” or vice versa. Conclusion: 52% of events on the placebo arm of Z9001 were reported as attributed to study drug and 19% of the time the same event was not consistently attributed. These data provide further evidence that attribution is difficult to determine, unreliable, and of questionable value in interpreting randomized clinical trials. No significant financial relationships to disclose. [Table: see text]

e21545 Background: A nocebo is an inert substance that causes adverse events. Although previous studies have examined the favorably positive (placebo) effects of an inert substance, few studies have examined negative (nocebo) effects, particularly in older patients who sometimes experience frequent and severe adverse events from cancer therapy. Methods: This study focused on placebo/nocebo-exposed patients who participated in two double-blind, placebo-controlled, cancer therapeutic studies, namely, North Central Cancer Treatment Group (NCCTG) 97-24-51 and American College of Surgeons Oncology Group (ACOSOG) Z9001, with the goal of reporting comparative, age-based adverse event rates. Results: Among the 446 patients who received placebo/nocebo exclusively, 161 were 65 years of age or older at the time of respective trial entry; 5234 adverse events occurred. Unadjusted adverse event rates did not differ significantly between patients 65 years of age or older and those younger: rate ratio (99% confidence intervals (CI): 1.01 (0.47, 2.02) with similar findings for grade 2 or worse adverse events and for all symptom-driven adverse events (for example, pain, loss of appetite, anxiety). Adjustment for sex, ethnicity, baseline performance score, and trial resulted in no significant age-based rate differences in adverse event rates. Similar findings were observed with an age threshold of 70. Conclusions: A nocebo effect appears to occur irrespective of age. This observation suggests that adverse events should be taken no less seriously in older than in younger cancer patients and that education to manage patients’ expectations from cancer therapy might improve tolerability. [Table: see text]

BACKGROUND A nocebo is an inert substance associated with adverse events. Although previous studies have examined the positive (placebo) effects of such inert substances, few have examined negative (nocebo) adverse event profiles, particularly in older patients who have higher morbidity and can experience frequent and severe adverse events from cancer therapy. METHODS This study focused on placebo/nocebo‐exposed patients who participated in 2 double‐blind, placebo‐controlled, cancer therapeutic studies, namely, North Central Cancer Therapy Group trial NCCTG 97‐24‐51 and American College of Surgeons Oncology Group trial Z9001, with the goal of reporting the comparative, age‐based adverse event rates, as reported during the conduct of these trials. RESULTS Among the 446 patients who received only placebo/nocebo and who were the focus of the current report, 161 were aged ≥65 years at the time of respective trial entry, and 5234 adverse events occurred. Unadjusted adverse event rates did not differ significantly between patients aged ≥65 years and younger patients (rate ratio, 1.01; 99% confidence interval, 0.47‐2.02), and the findings were similar findings for grade 2 or worse adverse events and for all symptom‐driven adverse events (for example, pain, loss of appetite, anxiety). Adjustment for sex, ethnicity, baseline performance score, and individual trial resulted in no significant age‐based differences in adverse event rates. Similar findings were observed with an age threshold of 70 years. CONCLUSIONS Adverse events are equally common in older and younger cancer patients who are exposed to nocebo and thus require the same degree of clinical consideration regardless of age. Cancer 2017;123:4193–4198. © 2017 American Cancer Society .

BACKGROUNDLittle is known about the factors that predict for gastrointestinal stromal tumor (GIST) recurrence in patients treated with adjuvant imatinib.METHODSRisk factors for GIST recurrence were identified, and 2 risk stratification scores were developed using the database of the Scandinavian Sarcoma Group (SSG) XVIII trial, where 358 patients with high‐risk GIST with no overt metastases were randomly assigned to adjuvant imatinib 400 mg/day either for 12 or 36 months after surgery. The findings were validated in the imatinib arm of the American College of Surgeons Oncology Group Z9001 trial, where 359 patients with GIST were randomized to receive imatinib and 354 were to receive placebo for 12 months.RESULTSFive factors (high tumor mitotic count, nongastric location, large size, rupture, and adjuvant imatinib for 12 months) were independently associated with unfavorable recurrence‐free survival (RFS) in a multivariable analysis in the SSGXVIII cohort. A risk score based on these 5 factors had a concordance index with GIST recurrence of 78.9%. When a simpler score consisting of the 2 strongest predictive factors (mitotic count and tumor site) was devised, the groups with the lowest, intermediate high, and the highest risk had 5‐year RFS of 76.7%, 47.5%, and 8.4%, respectively. Both scores were strongly associated with RFS in the validation cohort (P < .001 for each comparison).CONCLUSIONSThe scores generated were effective in stratifying the risk of GIST recurrence in patient populations treated with adjuvant imatinib. Patients with nongastric GIST with a high mitotic count are at a particularly high risk for recurrence. Cancer 2014;120:2325–2333 © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Purpose The ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome. Patients and Methods There were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis. Results RFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model–adjusted P < .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival. Conclusion Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.

Purpose In March 1998, Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AEs) to study drug. We investigate whether attribution adds value to the interpretation of AE data. Patients and Methods Patients in the placebo arm of two phase III trials—North Central Cancer Treatment Group Trial 97-24-51 (carboxyamino-triazole v placebo in advanced non–small-cell lung cancer) and American College of Surgeons Oncology Group Trial Z9001 (imatinib mesylate v placebo after resection of primary gastrointestinal stromal tumors)—were studied. Attribution was categorized as unrelated (not related or unlikely) and related (possible, probable, or definite). Results In total, 398 patients (84 from Trial 97-24-51 and 314 from Trial Z9001) and 7,736 AEs were included; 47% and 50% of the placebo-arm AEs, respectively, were reported as related. When the same AE was reported in the same patient on multiple visits, the attribution category changed at least once 36% and 31% of the time. AE type and sex (Trial Z9001) and AE type and performance status (Trial 97-24-51) were associated with a higher likelihood of AEs being deemed related. Conclusion Nearly 50% of AEs were reported as attributed to study drug on the placebo arm of two randomized clinical trials. These data provide strong evidence that AE attribution is difficult to determine, unreliable, and of questionable value in interpreting AE data in randomized clinical trials.