Saltz, Leonard B.

6 Background: Rates and survival outcomes for second-line therapy for mCRC for OA vs. YA are poorly understood. Methods: Pts with available subsequent treatment data after progression from 10 1st line trials were included. Associations between key clinical/disease characteristics, time to initial progression (TTiP) and rate of receipt of second-line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA who were enrolled on second-line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: OA comprised 16.4% of first-line trials. OA and ECOG PS >0 were less likely to receive second-line therapy than YA. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariate analysis (p=0.0117). OA enrolled in second-line trials experience similar mTTP and mOS as YA (5.1 vs. 5.2mos; 11.6 vs 12.4mos, respectively). Conclusions: OA are less likely to receive 2nd line therapy for mCRC. We did not observe a statistical difference in survival outcomes for OA vs. YA following second-line therapy. Further study is needed to examine unmeasured factors, including comorbidity and functional status given observed inferior outcomes among adults with ECOG PS >0, and consideration given to inclusion of geriatric assessment to select OA likely to benefit from 2nd line therapy for mCRC. [Table: see text]

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.

3539 Background: Previous studies suggest a possible gender-specific response to Bev in mCRC, showing a benefit in males, while the effect in females is less significant. Therefore, we evaluated response to Bev according to gender. Methods: Data from 3369 mCRC patients enrolled on 4 first-line randomized trials testing Bev (2000-2007) were pooled. Association between gender and progression-free survival (PFS)/overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction (inter.) effect between gender and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut-point of 60 years (commonly used in breast cancer trials) to evaluate the possible role of menopausal-related effects. Results: OS was not statistically different between males and females (median OS [mOS], 18.8 vs. 17.6 months [mo], adjusted hazard ratio [HRadj], 0.93, 95% confidence interval [CI], 0.84-1.03, p, 0.15) in the overall population. Bev was associated with an improved mOS in males and females, with a 2.3 and 0.6 mo benefit, respectively, as well as an improved PFS. There was no statistically significant interaction effect between gender and treatment (see table). Further stratified by age (< vs. ≥ 60 years), Bev resulted in improved PFS and OS in both genders, at all ages, except for the effect in young females which did not reach statistical significance (see table). Conclusions: Our results confirmed the mOS benefit from addition of Bev to first-line chemotherapy in mCRC in both genders, although the benefit in females was < 1 month. For females under the age of 60, there are uncertainties for mOS benefit from addition of Bev and further evaluation is needed. [Table: see text]

3502 Background: DFS with 3 years median follow-up (3yDFS) was validated as a surrogate for OS with 5 years median follow-up (5yOS) in adjuvant chemotherapy CC trials prior. Recent data showed improved survival after recurrence and OS, over time, in pts who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS, as well as the optimal follow-up of OS to aid its utility in future adjuvant trials is needed. Methods: Individual patient data from 8 randomized adjuvant studies conducted from 1998-2009 were included; 3 trials tested anti-VEGF or anti-EGFR agents. Trial-level surrogacy examining the correlation of treatment effect estimates (i.e. hazard ratios) of 3yDFS and 5y to 8yOS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models. For the R2, a value closer to 1 indicates a stronger correlation. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% Confidence Interval (CI) > 0.60. The rank correlation coefficient (ρ) quantified the individual-level surrogacy. Results: Total of 18,886 pts were analyzed, with median age 60, 54% male, 83% stage III, 59% > 12 nodes examined. Median follow-up for survival ranged from 5 to 10 years across trials. Trial level correlation between 3yDFS and OS remained strong (R2WLS ≥0.74; R2Copula ≥ 0.89) and increased as the median follow-up of OS extended longer (see table). Analyses limited to stage III pts and/or trials tested biologics showed consistent results. Conclusions: 3yDFS remains a validated surrogate endpoint for 5yOS in adjuvant trials in CC pts per prespecified criteria. The correlation was strengthened with more than 6 years of follow-up for OS. [Table: see text]

Background More than half of the 40,000 incident rectal cancer patients in the United States each year are diagnosed at clinical stage II and III (locally advanced stage). For this group, high rates of cure can be achieved with the combination of pelvic radiation and sensitizing 5-fluorouracil (chemoradiation), surgery and chemotherapy, but treatment is long, arduous and toxicities are substantial. The PROSPECT trial (N1048, NCT01515787) was designed to determine whether neoadjuvant chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX) could be used as an alternative to neoadjuvant chemoradiation without compromising treatment outcomes and to spare these patients excess toxicity. The statistical design balanced the twin co-primary goals of achieving low local and distant recurrence rates. Study design features contended with the need for stringent safeguards given limited phase II data, the need for straightforward criteria to facilitate both accrual and protocol fidelity and the importance of patients’ perspectives on symptom burden and treatment toxicity. Methods PROSPECT is an ongoing multi-site two-group seamless phase II/III randomized trial comparing standard neoadjuvant chemoradiation versus neoadjuvant chemotherapy with selective use of chemoradiation for patients with locally advanced rectal cancer. Challenges addressed in the design and conduct of PROSPECT have included the following: (1) setting safety thresholds given limited single-center phase II data, (2) establishing workable eligibility criteria, (3) balancing competing time to local and distant recurrence as co-primary endpoints and (4) obtaining reliable and complete data for patients’ symptom burden. The design and implementation challenges, choices, modifications and their implications for the design of future national cooperative group clinical trials are presented. Results PROSPECT incorporated stringent thresholds for both complete surgical resection (R0) and the time to local recurrence as early stopping rules. When predetermined stopping criteria were not met after evaluation of the first 366 participants in the randomized phase II, the study transitioned seamlessly to phase III with cumulative accrual of over 1000 participants. Eligibility criteria stipulating rectal tumor location based on distance from the anal verge were unworkable, and the protocol was amended to a more pragmatic approach that assigned surgeons with primary responsibility for determining eligibility. Central radiology review was feasible and in some cases prompted discontinuation of protocol treatment. Participation in toxicity reporting using the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events was uniformly high and was well accepted by participants from over 200 sites in the United States, Canada and Switzerland. Conclusion The strategies used to overcome these obstacles may inform the design of other studies that involve multi-modality treatment interventions, particularly trials where implementation of consistent criteria for eligibility and outcomes across hundreds of practice settings is necessary.