Willett, Christopher G.

Purpose: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. Methods: Eligibility—within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm—6 cycles of gemcitabine. Gemcitabine+erlotinib arm—gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. Results: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, ( P =0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P =0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). Conclusions: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.

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.

Abstract Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

368 Background: 5-Fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer is associated with high rates of acute morbidity. We have previously shown that dose-painted IMRT (DP-IMRT) significantly reduces grade 3+ GI and dermatologic acute toxicity, as compared to the RTOG 9811 5FU/MMC arm, which used non-conformal radiation techniques. We now report on the two-year outcomes of this DP-IMRT approach. Methods: T2-4N0-3M0 anal canal cancers received 5FU (1,000 mg/m2/day 96 hour infusion) and MMC (10 mg/m2 bolus) days 1 and 29 of DP-IMRT prescribed as follows - T2N0: 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs), 28 fractions; T3-4N0-3: 45 Gy elective nodal, 50.4 Gy ≤ 3 cm and 54 Gy > 3 cm metastatic nodal and 54 Gy anal tumor PTVs, 30 fractions. The following two-year outcomes were assessed: local-regional (LRF) and colostomy failures (CF) using the cumulative incidence method, and disease-free (DFS), overall (OS) and colostomy-free survivals (CFS) using the Kaplan-Meier method. Results: Of 63 accrued patients, 52 were analyzable. Median age was 58 years; 81% female; 54% stage II; 25% IIIA; 21% IIIB. Median follow-up was 23.2 months (0.2-33). Two-year LRF, CF, DFS and 95% confidence intervals are 20% (9%, 31%), 8% (0.4%, 15%) and 77% (62%, 86%), respectively. The causes of death for the 7 patients that died are: anal cancer in 5, morbidity in one and second primary outside the radiation field in one. Two-year comparison data from the RTOG 9811 5FU/MMC arm are shown in the table below. Conclusions: DP-IMRT with 5FU/MMC for the treatment of anal canal cancer yields similar two-year outcomes as the RTOG 9811 conventional radiation, 5FU/MMC arm. Because of the associated acute toxicity sparing, DP-IMRT will be used as the platform, and may allow for radiation dose escalation, in future RTOG anal canal trials. Supported by RTOG U10 CA21661, CCOP U10 CA3742 and ATC U24 CA 81647 NCI grants. [Table: see text] No significant financial relationships to disclose.

367 Background: On initial publication of GI Intergroup RTOG 98-11, concurrent chemoradiation with 5FU+mitomycin (MMC) decreased colostomy failure (CF) vs induction plus concurrent 5FU+cisplatin (CDDP), but did not significantly impact disease free or overall survival (DFS, OS). The intent of the current analysis is to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free [CFS]), CF and relapse (local-regional [LRF], distant [DM]) in this patient group. Methods: Stratification factors included gender, clinical node status, and primary size. DFS/OS were estimated univariately by Kaplan-Meier method and treatment arms compared by log-rank test. Time to relapse/CF were estimated by cumulative incidence method and treatment arms compared by Gray's test. Multivariate analyses were done with Cox proportional hazard models to test for treatment differences, adjusting for stratification factors. Results: Of 682 patients accrued, 649 were analyzable for outcomes. As seen in the table, 5-yr DFS and OS were statistically better for RT+5FU/MMC vs RT+5FU/CDDP (67.7 v 57.6%, p=.0.0045; 78.2 v 70.5%, p=0.021) with trends toward statistical significance for CFS, LRF, and CF (71.8 v 64.9%, p=0.053; 20 v 26.5%, 11.9 v 17.3%, p=0.092 and 0.075). Similar results were seen in multivariate analysis. Conclusions: Concurrent chemoradiation with 5FU-MMC has a statistically significant impact on DFS and OS vs induction + concurrent 5FU-CDDP and borderline significance for CFS, CF and LRF. Therefore, RT+5FU/MMC remains the preferred standard of care. Potential strategies to improve outcomes include treatment intensification and individualized molecular-based treatment. Supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). [Table: see text] No significant financial relationships to disclose.

PurposeOn initial publication of GI Intergroup Radiation Therapy Oncology Group (RTOG) 98-11 [A Phase III Randomized Study of 5-Fluorouracil (5-FU), Mitomycin, and Radiotherapy Versus 5-Fluorouracil, Cisplatin and Radiotherapy in Carcinoma of the Anal Canal], concurrent chemoradiation (CCR) with fluorouracil (FU) plus mitomycin (MMC) decreased colostomy failure (CF) when compared with induction plus concurrent FU plus cisplatin (CDDP), but did not significantly impact disease-free survival (DFS) or overall survival (OS) for anal canal carcinoma. The intent of the updated analysis was to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free survival [CFS]), CF, and relapse (locoregional failure [LRF], distant metastasis) in this patient group.Patients and MethodsStratification factors included sex, clinical node status, and primary size. DFS and OS were estimated univariately by the Kaplan-Meier method, and treatment arms were compared by log-rank test. Time to relapse and CF were estimated by the cumulative incidence method and treatment arms were compared by using Gray's test. Multivariate analyses used Cox proportional hazard models to test for treatment differences after adjusting for stratification factors.ResultsOf 682 patients accrued, 649 were analyzable for outcomes. DFS and OS were statistically better for RT + FU/MMC versus RT + FU/CDDP (5-year DFS, 67.8% v 57.8%; P = .006; 5-year OS, 78.3% v 70.7%; P = .026). There was a trend toward statistical significance for CFS (P = .05), LRF (P = .087), and CF (P = .074). Multivariate analysis was statistically significant for treatment and clinical node status for both DFS and OS, for tumor diameter for DFS, and for sex for OS.ConclusionCCR with FU/MMC has a statistically significant, clinically meaningful impact on DFS and OS versus induction plus concurrent FU/CDDP, and it has borderline significance for CFS, CF, and LRF. Therefore, RT + FU/MMC remains the preferred standard of care.

PurposeTo determine whether increased duration of radiation therapy (RT) and overall treatment (RX) time has a detrimental effect in anal cancer.Patients and MethodsData from Radiation Therapy Oncology Group (RTOG) 87-04 and RTOG 98-11 trials were combined to form three treatment groups: RT/fluorouracil (FU)/mitomycin (n = 472), RT/FU/cisplatin (n = 320), and RT/FU (n = 145). Cox proportional hazards models were used with the following variables: RT duration, RT intensity, RX duration, treatment group, age, sex, Karnofsky performance score (KPS), T stage, N stage, and RT dose.ResultsIn the univariate analysis, there was a significant association between RX duration and colostomy failure (CF; hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.14; P = .02), local failure (HR = 1.52; 95% CI, 1.14 to 2.03; P = .005), locoregional failure (HR = 1.51; 95% CI, 1.15 to 1.98; P = .003), and time to failure (HR = 1.40; 95% CI, 1.10 to 1.79; P = .007). The significance of RX duration was maintained after adjusting for treatment group. In multivariate modeling there was a trend toward an association between RX duration and CF (HR = 1.57; 95% CI, 0.98 to 2.50; P = .06) and a statistically significant association with local failure (HR = 1.96; 95% CI, 1.34 to 2.87; P = .0006). Age, sex, KPS, T stage, N stage, and RT dose, but not RT duration, RT intensity, or RX duration, were found to be statistically significant predictors of OS and colostomy-free survival.ConclusionTotal treatment time, but not duration of radiation therapy, seems to have a detrimental effect on local failure and colostomy rate in anal cancer. Induction chemotherapy may contribute to local failure by increasing total treatment time.

Purpose The US Gastrointestinal Intergroup Radiation Therapy Oncology Group 98-11 anal carcinoma trial showed that cisplatin-based concurrent chemoradiotherapy resulted in a significantly higher rate of colostomy compared with mitomycin-based therapy. Established prognostic variables for patients with anal carcinoma include tumor diameter, clinical nodal status, and sex, but pretreatment variables that would predict the likelihood of colostomy are unknown. Methods A secondary analysis was performed by combining patients in the two treatment arms to evaluate whether new predictive and prognostic variables would emerge. Univariate and multivariate analyses were carried out to correlate overall survival (OS), disease-free survival, and time to colostomy (TTC) with pretreatment and treatment variables. Results Of 682 patients enrolled, 644 patients were assessable and analyzed. In the multivariate analysis, tumor-related prognosticators for poorer OS included node-positive cancer (P ≤ .0001), large (> 5 cm) tumor diameter (P = .01), and male sex (P = .016). In the treatment-related categories, cisplatin-based therapy was statistically significantly associated with a higher rate of colostomy (P = .03) than was mitomycin-based therapy. In the pretreatment variables category, only large tumor diameter independently predicted for TTC (P = .008). Similarly, the cumulative 5-year colostomy rate was statistically significantly higher for large tumor diameter than for small tumor diameter (Gray's test; P = .0074). Clinical nodal status and sex were not predictive of TTC. Conclusion The combined analysis of the two arms of RTOG 98-11, representing the largest prospective database, reveals that tumor diameter (irrespective of the nodal status) is the only independent pretreatment variable that predicts TTC and 5-year colostomy rate in patients with anal carcinoma.

Abstract The 2007 Santa Monica Conference on Assessing and Treating Early-Stage Colon and Rectal Cancer, a multidisciplinary meeting of leaders in surgery, medical and radiation oncology, and pathology, was convened on January 12 to 13, 2007. The purpose of the meeting was to assess current data and issues in the field and to develop recommendations for advancing patient care and clinical research. Topics included pathologic assessment and staging, transanal versus laparoscopic versus open resection, adjuvant therapy, genetic testing and counseling, cooperative group strategies, and the use of biological therapies and novel agents. A review of the key issues discussed, as well as conclusions and recommendations considered significant to the field, is summarized below and presented at greater length in the individual manuscripts and accompanying discussion that comprise the full conference proceedings. Although the management of early-stage colon and rectal cancers remains a challenge for all of us, the development and use of new technologies and methods of assessment and treatment over the past several decades is yielding encouraging results. A variety of opportunities to further improve outcomes were addressed in this forum, including recommendations that specific protocols be adopted regarding surgical and pathologic dissection and reporting, particularly for stage II disease; the corollary need to increase active multidisciplinary collaboration; and the development of comprehensive consensus guidelines and recommendations to standardize care in early-stage colorectal cancer.

Purpose We update Radiation Therapy Oncology Group trial 8911 (USA Intergroup 113), a comparison of chemotherapy plus surgery versus surgery alone for patients with localized esophageal cancer. The relationship between resection type and between tumor response and outcome were also analyzed. Patients and Methods The chemotherapy group received preoperative cisplatin plus fluorouracil. Outcome based on the type of resection (R0, R1, R2, or no resection) was evaluated. The main end point was overall survival. Disease-free survival, relapse pattern, the influence of postoperative treatment, and the relationship between response to preoperative chemotherapy and outcome were also evaluated. Results Two hundred sixteen patients received preoperative chemotherapy, 227 underwent immediate surgery. Fifty-nine percent of surgery only and 63% of chemotherapy plus surgery patients underwent R0 resections (P = .5137). Patients undergoing less than an R0 resection had an ominous prognosis; 32% of patients with R0 resections were alive and free of disease at 5 years, only 5% of patients undergoing an R1 resection survived for longer than 5 years. The median survival rates for patients with R1, R2, or no resections were not significantly different. While, as initially reported, there was no difference in overall survival for patients receiving perioperative chemotherapy compared with the surgery only group, patients with objective tumor regression after preoperative chemotherapy had improved survival. Conclusion For patients with localized esophageal cancer, whether or not preoperative chemotherapy is administered, only an R0 resection results in substantial long-term survival. Even microscopically positive margins are an ominous prognostic factor. After a R1 resection, postoperative chemoradiotherapy therapy offers the possibility of long-term disease-free survival to a small percentage of patients.