Bruzzi, Paolo

4010 Background: Survival outcomes in patients with stage III colon cancer varies widely according to T-N sub-stages. The ability to estimate the benefit of each therapeutic option (surgery alone, fluoropyrimidines alone, oxaliplatin-based doublet for either 3 or 6 months) in each T-N subgroup within stage III, may provide more accurate information helping doctors and patients in the complex shared decision-making process surrounding adjuvant therapy. Methods: Theoutcomedata of 12,834 patients with stage III colon cancer enrolled in the IDEA trial served as our database. Patients were categorized in 16 sub-stages, based on the T-N categories. We created a meta-regression model to predict the expected 3-year DFS within each T-N sub-stage and hence the 5-year DFS rates were projected. We then evaluated the efficacy of each therapeutic option in every sub-stage, working backward by subtraction, using an average of the HRs reported in the pertinent trials publication as conversion factor. Results: Large differences in 3-year DFS rate were observed among the subgroups, ranging from 95% (T1N1a) to 29% (T4N2b) in the overall population. The contribution to outcome of each therapeutic option in this setting varied widely across sub-stages. According to our model, patients with T1N1a cancers have a projected 5-year DFS of 85% with surgery alone. Adjuvant fluoropyrimidine alone results in 4.2% absolute DFS gain; an additional 1.7% and 0.6% gain is seen with oxaliplatin for 3 and 6 months, respectively. Patients with T4N2b cancers show a 4.7% 5-year DFS with surgery alone, and a 7.1%, 5.0%, 2.1% increase with the aforementioned adjuvant options, respectively. Conclusions: The resulting overlay bar graph gives patients and doctors the projected relative benefit of each treatment option and may substantially help the shared decision-making process.

Abstract Purpose: To establish the concept of minimum clinically meaningful outcome (mCMO) of treatment in advanced solid tumors, to establish its threshold and evaluate how many superiority trials of new antineoplastic agents pass this threshold. Experimental Design: We chose overall survival as the primary indicator of patient benefit. Four conceptually different types of treatment effect can be identified in OS curves: HR, gains in median OS, proportional, and absolute increases at long-term OS. We postulated threshold levels for these four parameters defining the mCMO and set the bar at three different levels of required benefit: high, medium, and low. The postulated values were then studied by comparing our thresholds with the actual results of the pivotal superiority phase III trials on new drugs reporting on mature OS data. Results: Forty-three trials on 35,419 patients in 12 cancer types on 23 novel agents met these criteria. Only two trials reached the postulated “high” thresholds for HR and median OS. The number of “positive trials” increased to eight and 15 when the bar was lowered to the “medium” and “low” levels, respectively. The same analysis was done for proportional and absolute increases in long-term OS. No trial satisfied the criteria for long-term benefit, whereas only two and nine trials satisfied both parameters for the “medium and low” required benefit levels, respectively. Conclusions: All four OS-related parameters contribute to define the mCMO. If the bar for the mCMO is raised too much, positive trials are exceptional. Clin Cancer Res; 21(5); 1036–43. ©2014 AACR. See related commentary by Schilsky, p. 947