Novel Application of Iterative Hyperthermic Intraperitoneal Chemotherapy for Unresectable Peritoneal Metastases from High-Grade Appendiceal Ex-Goblet Adenocarcinoma.

BACKGROUND: Peritoneal metastases (PMs) from appendiceal ex-goblet adenocarcinoma (AEGA) are associated with a poor prognosis. While cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to prolong survival, the majority of patients are ineligible for complete cytoreduction. We describe a novel approach to the management of such patients with iterative HIPEC (IHIPEC). METHODS: Patients with signet ring/poorly differentiated AEGA with high Peritoneal Cancer Index (PCI) and extensive bowel involvement underwent IHIPEC with mitomycin C at 6-week intervals for a total of three cycles. Survival outcomes for these patients were compared with patients with high-grade appendiceal tumors matched for tumor burden who were treated with other conventional approaches, i.e. systemic chemotherapy only (SCO) or complete CRS + HIPEC. RESULTS: Between 2016 and 2019, seven AEGA patients with high PCI (median 32.5 [range 21-36]) underwent 18 IHIPEC cycles (median cycles per patient 3 [2-3]) in combination with systemic chemotherapy (median 2 lines [1-3], 12 cycles [10-28]). IHIPEC was delivered laparoscopically in 14/18 cases. Postoperatively, the median length of stay was 1 day (1-8 days), no procedure-related complications were reported, and five (28%) 90-day readmissions for bowel obstruction were documented. Median overall survival after IHIPEC was better compared with a matched group of patients (n = 16) receiving SCO (24.6 vs. 7.9 months; p = 0.005), and similar to those (n = 7) who underwent CRS + HIPEC (24.6 vs. 16.5 months; p = 0.62). CONCLUSIONS: IHIPEC in combination with systemic chemotherapy is tolerable, safe, and may be associated with encouraging survival outcomes compared with SCO in selected patients with high-grade, high-burden AEGA PM.

Obstruction predicts worse long-term outcomes in stage III colon cancer: A secondary analysis of the N0147 trial.

BACKGROUND: Patients with colon cancer often present with obstruction. Large series have reported obstruction among the high-risk features, yet prospective data on its specific prognostic influence are lacking. We hypothesized that obstruction is an independent risk factor for poor prognosis in patients with stage III colon cancer. METHODS: N0147 was a trial conducted between 2004 and 2009 that randomly assigned patients with stage III colon cancer to adjuvant regimens of folinic acid (leucovorin calcium), fluorouracil, and oxaliplatin or fluorouracil, leucovorin, and irinotecan, with or without cetuximab. Patient-level data from the control chemotherapy-only arms were obtained. Patient, tumor, and treatment characteristics were abstracted. Disease-free survival and overall survival were estimated by the Kaplan-Meier method. Proportions were compared by χ2 and Fisher exact tests. Univariable and multivariable survival analyses were performed using Cox proportional hazards models. RESULTS: Of 1,543 patients with stage III colon cancer, 250 (16.2%) presented with obstruction. Patients with obstruction were equally likely to complete 12 cycles of adjuvant chemotherapy (75.9% vs 77.1%, P = .6). With median follow-up time of 30.9 months among survivors, five-year overall survival and disease-free survival were worse among patients with obstruction (overall survival 67.7% vs 78.0%, P < .001; disease-free survival 53.9% vs 67.0%, P < .0001). On multivariable analysis, obstruction remained significantly associated with worse survival after adjusting for T stage, N stage, performance status, age, sex, histologic grade, and body mass index (overall survival hazard ratio 1.57, 95% confidence interval 1.12-2.20, P = .001; disease-free survival 1.52, 95% confidence interval 1.18-1.95, P < .001). CONCLUSION: In this prospectively followed cohort of patients with stage III colon cancer treated with adjuvant chemotherapy, obstruction was associated with recurrence and worse survival. Moreover, this effect was independent of T and N stage and histologic grade. These results suggest that obstruction should be incorporated into novel risk-stratification models.

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial.

BACKGROUND: Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response. OBJECTIVE: The purpose of this study was to analyze disease-free and overall survival. DESIGN: This was a nonrandomized phase II trial. SETTINGS: The study was conducted at multiple institutions. PATIENTS: Four sequential study groups with stage II or III rectal cancer were included. INTERVENTION: All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6. MAIN OUTCOME MEASURES: The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study. RESULTS: Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03). LIMITATIONS: The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients. CONCLUSIONS: Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.

Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.

BACKGROUND: Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response. METHODS: We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II-III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m(2) per day by continuous infusion throughout radiotherapy, and 45·0 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 5·4 Gy). Patients in group 1 had total mesorectal excision 6-8 weeks after chemoradiation. Patients in groups 2-4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m(2) or 400 mg/m(2), according to the discretion of the treating investigator, oxaliplatin 85 mg/m(2) in a 2-h infusion, bolus fluorouracil 400 mg/m(2) on day 1, and a 46-h infusion of fluorouracil 2400 mg/m(2). The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816. FINDINGS: Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10-30) of 60 patients in group 1, 17 (25%, 16-37) of 67 in group 2, 20 (30%, 19-42) of 67 in group 3, and 25 (38%, 27-51) of 65 in group 4 achieved a pathological complete response (p=0·0036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 3·49, 95% CI 1·39-8·75; p=0·011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients). INTERPRETATION: Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to increase the proportion of patients eligible for less invasive treatment strategies; this strategy is being tested in phase 3 clinical trials. FUNDING: National Institutes of Health National Cancer Institute.

Combined-modality therapy for rectal cancer: analysis of potential differences in disease presentation, treatment adherence, and treatment outcome according to race.

OBJECTIVES: Population-based studies suggest African Americans (AAs) with rectal cancer have a worse overall outcome compared with non-AAs. This relationship was explored in a cohort of rectal cancer patients treated with preoperative chemoradiation therapy (CRT) and surgery at 2 academic cancer centers. METHODS: A total of 146 patients (26 AA, 120 non-AA) underwent treatment with curative intent. The median age was 57 years. Median dose was 50.4 Gy, given with 5-fluorouracil-based concurrent chemotherapy. Differences in disease presentation, adherence to recommended therapy, and treatment outcome (freedom from failure) by race were analyzed. Median follow-up was 34 months from completion of CRT. RESULTS: AAs had longer time from diagnosis to start of therapy (median, 45 vs. 35 d; P<0.01) and from CRT completion to surgery (median, 42 vs. 46 d; P=0.03). AA patients presented with more favorable disease (20% stage I, 33% stage III) compared with non-AA patients (0% stage I, 48% stage III, P<0.01). AA patients were less likely to receive adjuvant chemotherapy (58% vs. 89%, P=0.01). Log-rank analysis showed AAs were not more likely to recur after therapy (freedom from failure at 3 y, 100% for AA patients vs. 81% for non-AA patients, P=0.09). The difference in time from preoperative therapy to surgery and a lower rate of adjuvant therapy in AA patients did not seem to result in inferior disease outcome for this cohort. CONCLUSIONS: Further study is necessary to explore the reasons underlying the delays in therapy and lower rates of adjuvant chemotherapy for AA patients.