A phase II study of guadecitabine combined with irinotecan vs regorafenib or TAS-102 in irinotecan-refractory metastatic colorectal cancer patients.

DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle. Between January 15, 2016 and October 24, 2018, 104 pts were randomized at four international sites, with 96 pts undergoing treatment, 62 in Arm A and 34 in Arm B. Median overall survival was 7.15 months for Arm A and 7.66 months for Arm B (HR 0.93, 95% CI: 0.58-1.47, P = .75). The Kaplan-Meier rates of progression free survival at 4 months were 32% in Arm A and 26% in Arm B. Common ≥Grade 3 treatment related adverse events in Arm A were neutropenia (42%), anemia (18%), diarrhea (11%), compared to Arm B pts with neutropenia (12%), anemia (12%). Guadecitabine and irinotecan had similar OS compared to standard of care TAS-102 or regorafenib, with evidence of target modulation. Clinical trial information: NCT01896856.

Role of PD-1 Inhibitors in the Treatment of Esophagogastric Adenocarcinoma: Patient Selection and Reported Outcomes.

Esophagogastric cancers are aggressive malignancies, with poor prognosis despite current standard-of-care therapies. PD-1 inhibitors are a newer class of antitumor agents with the potential to improve outcomes among appropriately selected patients. This review provides an overview of the key trials that have guided the use of PD-1 and PD-L1 inhibitors in the refractory and first-line settings. We highlight recent studies investigating the role of genomic classification in predicting therapeutic activity of PD-1 inhibitors. In addition, there is a discussion of the use of different scoring systems and criteria to determine PD-L1 positivity, the impact on the therapeutic use of immune checkpoint inhibition with anti-PD-1 agents, and the controversies in current methods of PD-L1 testing and their implications in patient selection for anti-PD-1 therapy.

Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study.

BACKGROUND: Outcomes in advanced anal squamous cell carcinoma are poor, with few treatment options and controlled clinical trials. We evaluated the efficacy and safety of pembrolizumab in patients with advanced anal squamous cell carcinoma (cohort A) from the phase 2 KEYNOTE-158 study. METHODS: Eligible patients enrolled in the ongoing non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study, which was done across 38 centres worldwide, were aged 18 years or older; had histologically or cytologically confirmed advanced or metastatic anal squamous cell carcinoma; had previous failure of or intolerance to standard therapy or no standard therapy options; and had a PD-L1-evaluable tissue sample. Patients received pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or until disease progression, unacceptable toxicity, investigator's decision to withdraw the patient from the study, or withdrawal of patient consent. The primary endpoint was objective response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy and safety analyses included all patients who received at least one dose of pembrolizumab. The trial is registered with ClinicalTrials.gov, NCT02628067. FINDINGS: Between March 3, 2016, and July 23, 2018, 163 patients were screened, of whom 112 were enrolled and treated in the anal cancer cohort. 91 (81%) patients were female, 104 (93%) had M1 disease, and 75 (67%) had PD-L1-positive tumours. The median time from first dose to data cutoff (June 27, 2019) was 34·7 months (IQR 32·5-36·4). 12 (11%, 95% CI 6-18) patients had an objective response, including 11 (15%, 8-25) of 75 patients with PD-L1-positive tumours and one (3%; 0-17) of 30 patients with PD-L1-negative tumours. 68 (61%) patients had treatment-related adverse events (20 [18%] patients had grade 3-4 adverse events), the most common of which were fatigue (17 patients), diarrhoea (13), hypothyroidism (13), and nausea (13). Serious treatment-related adverse events occurred in 12 (11%) patients. 25 (22%) patients had immune-mediated adverse events, and one (1%) had an infusion reaction. There were no treatment-related deaths. INTERPRETATION: Pembrolizumab monotherapy is a possible treatment option with a favourable benefit-risk ratio for patients with previously treated advanced anal squamous cell carcinoma who have no alternative satisfactory treatment options. FUNDING: Merck Sharp & Dohme.

Comprehensive Genomic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs).

PURPOSE: GEP-NENs are rare malignancies with increasing incidence. Their molecular characteristics are still undefined. We explored the underlying biology of GEP-NENs and the differences between gastrointestinal (GI) and pancreatic (PNEN), high-grade (HG), and low-grade (LG) tumors. EXPERIMENTAL DESIGN: GEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), IHC, and in situ hybridization. Tumor mutational burden (TMB) was calculated on the basis of somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. RESULTS: In total, 724 GEP-NENs were examined: GI (N = 469), PNEN (N = 255), HG (N = 135), and LG (N = 335). Forty-nine percent were female, and median age was 59. Among LG tumors, the most frequently mutated genes were ATRX (13%), ARID1A (10%), and MEN1 (10%). HG tumors showed TP53 (51%), KRAS (30%), APC (27%), and ARID1A (23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared with HG [MSI-H 0% vs. 4% (P = 0.04), PD-L1 overexpression 1% vs. 6% (P = 0.03), TMB-high 1% vs. 7% (P = 0.05)]. Compared with LG, HG NENs showed a higher mutation rate in BRAF (5.4% vs. 0%, P < 0.0001), KRAS (29.4% vs. 2.6%, P < 0.0001), and PI3KCA (7% vs. 0.3%, P < 0.0001). When compared with GI, PNEN carried higher frequency of MEN1 (25.9% vs. 0.0%, P < 0.0001), FOXO3 (8.6% vs. 0.8%, P = 0.005), ATRX (20.6% vs. 2.0%, P = 0.007), and TSC2 (6.3% vs. 0.0%, P = 0.007), but lower frequency of mutations in APC (1.0% vs. 13.8%, P < 0.0001). CONCLUSIONS: Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.

Phase II Trial of Neoadjuvant Bevacizumab with Modified FOLFOX7 in Patients with Stage II and III Rectal Cancer.

LESSONS LEARNED: Neoadjuvant bevacizumab with modified FOLFOX7 without radiation failed to meet the goal of pathological complete response rate; however, the low number of recurrence and disease-free survival in this population, with predominantly stage III, is encouraging and worth further exploration. The racial distribution of the patient population, as well as a wait time of more than 4 weeks after last chemotherapy, may have contributed to the findings. BACKGROUND: Combination chemotherapy in lieu of radiation in rectal adenocarcinoma is under exploration in multiple trials. We evaluated the efficacy of neoadjuvant FOLFOX + bevacizumab in patients (pts) with clinical stage II and III disease. METHODS: Pts received six cycles of bevacizumab (5 mg/kg) and modified FOLFOX7 (oxaliplatin 85 mg/m2 , leucovorin 20 mg/m2 , and fluorouracil [5-FU] 2,400 mg/m2 ). Surgical resection was performed 6-8 weeks after completion of treatment and upon confirmation of nonmetastatic disease. We employed a Simon two-stage design and required three pathological complete responses (pCR) in the first 18 pts, with a prespecified pCR rate of 25% before moving to the next stage. RESULTS: Seventeen pts enrolled; 65% at stage III. Median age was 57 (35-79), 65% were male, 47% were Hispanic, 35% were white, and 18% were Asian. All pts but one completed six cycles of therapy. One pCR was observed (6%), and 11 of 17 (65%) pts had pathological downstaging. One patient experienced systemic recurrence and remains on treatment. Probability of disease-free survival (DFS) at 5 years is 0.94 (SE, 0.06). CONCLUSION: The study failed to meet the required three pCRs in the first 18 pts. The DFS in this population is encouraging and supports the hypothesis that select pts with rectal cancer may be spared from radiation.

Randomized, Phase II Study Prospectively Evaluating Treatment of Metastatic Esophageal, Gastric, or Gastroesophageal Cancer by Gene Expression of ERCC1: SWOG S1201.

PURPOSE: Platinum-based therapy is the standard of care in patients who have HER2-negative, advanced esophagogastric cancer (AEGC). Retrospective data suggest that intratumoral ERCC1 levels may determine platinum sensitivity. A randomized, phase II study was performed in patients with AEGC to explore whether the efficacy of a platinum-based therapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) versus a non-platinum-containing regimen of irinotecan and docetaxel (IT) differed according to ERCC1 levels. PATIENTS AND METHODS: Overall, 202 untreated patients with HER2-negative AEGC and a Zubrod performance status of 0-1 were evaluated prospectively for mRNA expression of ERCC1 level and then randomly assigned to FOLFOX or IT, stratified by the intratumoral statuses of ERCC1 low (< 1.7) or high (≥ 1.7). Objectives were to assess progression-free survival (PFS) and overall survival (OS) in all patients treated with FOLFOX compared with IT, stratified by low and high ERCC1 levels, and to assess for interactive effects between ERCC1 expression and treatment arm. RESULTS: Eighty-six percent of patients had ERCC1 values < 1.7. Thus, evaluation of the ERCC1-high subgroup was limited. Grade ≥ 3 anemia, dehydration, diarrhea, and fatigue were greater in patients with IT. Occurrences of grade ≥ 3 neuropathy and decreased neutrophils were greater in patients with FOLFOX. In all patients, FOLFOX had a statistically superior median PFS compared with IT (5.7 v 2.9 months; hazard ratio, 0.68; P = .02). In patients with ERCC1 levels < 1.7 receiving FOLFOX, PFS and response rate were statistically superior to IT, with no significant difference in OS. CONCLUSION: The evaluation of ERCC1 in patients with upper GI tumors was thwarted by an overwhelming predominance of low ERCC1 mRNA expression. Nonetheless, distribution of treatment effects on PFS did not vary with expression. For all patients and for those with low ERCC1 expression, FOLFOX was superior in efficacy to IT.

Acute esophageal necrosis: a case series and its management.

'Black Esophagus' or acute esophageal syndrome (AEN) is extremely rare entity characterized by patchy or diffuse circumferential necrosis of esophagus. To date, there is minimal number of cases described with this phenomenon. The main objective of this case series is to discuss the diagnosis of extremely rare condition seen in two patients within 1 year and its effective management by adopting conservative measures in a tertiary hospital. The objective of our case series is to discuss the diagnosis of an extremely rare condition seen in two patients within a short span of 6 months and its effective management by adopting conservative measures in a tertiary care hospital. An overall conservative approach, serial endoscopic monitoring and effective follow-up resulted in zero mortality with successful outcomes.

A case report of acalculous cholecystitis due to Salmonella paratyphi B.

Acute acalculous cholecystitis (AAC) is a rare condition occurring in only 5%-10 % of patients with acute cholecystitis. Systemic illness caused, for example, by E coli, Klebsiella pneumoniae, Vibrio cholera, and Salmonella species can result acute inflammation of gallbladder wall. It is a surgical emergency and if left untreated can lead to high mortality due to gangrene or perforation of gallbladder. We managed a 60-year-old female with clinical presentation of acute cholecystitis caused by Salmonella-induced gastroenteritis. Prompt use of radiological modalities such as computer tomography (CT scan) and ultrasound played an important role in pathologic diagnosis, overall follow up, and management of the patient.

Acute Myelomonocytic Leukemia Presenting as Perianal Pain.

Extramedullary involvement of the gastrointestinal tract (GIT) is a rare entity as most patients present with lymphoreticular organ involvement. Its detection and diagnosis can be extremely challenging, as these patients would present with unusual clinical symptoms. We diagnosed and managed a patient with leukemic infiltration of GIT who presented with perianal pain. Prompt use of MRI played an important role in detecting underlying pathology, and effective tissue sampling confirmed the diagnosis. This resulted in overall successful management of the patient.

Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study.

BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. METHODS: We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. RESULTS: We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. INTERPRETATION: To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. FUNDING: National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Phase 2 study of MK-2206, an allosteric inhibitor of AKT, as second-line therapy for advanced gastric and gastroesophageal junction cancer: A SWOG cooperative group trial (S1005).

BACKGROUND: The AKT inhibitor MK-2206 at a dose of 60 mg every other day was evaluated in gastric/gastroesophageal junction cancers. METHODS: Patients who had progressed after first-line treatment were eligible. Pertinent eligibility criteria included adequate organ function, a fasting serum glucose level ≤ 150 mg/dL, and less than grade 2 malabsorption or chronic diarrhea. MK-2206 was given orally (60 evaluable patients required). The primary endpoint was overall survival, and a median survival of 6.5 months (power, 89%; significance level, 0.07) was considered encouraging for further investigation. RESULTS: Seventy patients were included in the final analyses. The median age was 59.8 years (range, 30.4-86.7 years); 70% were male, 89% were white, and 7% were Asian. There were 2 deaths possibly related to the study drug (cardiac arrest and respiratory failure). Grade 4 adverse events included hyperglycemia, anemia, and lung infection (1 each). Grade 3 adverse events occurred in < 5% of patients except for fatigue (6%). Other adverse events (all grades) included anemia (17%), anorexia (30%), diarrhea (26%), fatigue (50%), hyperglycemia (30%), nausea (40%), vomiting (22%), dry skin (19%), maculopapular rash (30%), and acneiform rash (13%). The response rate was 1%, the median progression-free survival was 1.8 months (95% confidence interval, 1.7-1.8 months), and the median overall survival was 5.1 months (95% confidence interval, 3.7-9.4 months) CONCLUSIONS: MK-2206 as second-line therapy was well tolerated by an unselected group of patients with gastric/gastroesophageal junction cancers, but it did not have sufficient activity (response rate, 1%; overall survival, 5.1 months) to warrant further testing in this population.

Prognostic impact of the c-MET polymorphism on the clinical outcome in locoregional gastric cancer patients.

OBJECTIVE: Dysregulation of the c-MET signaling pathway results from various molecular mechanisms including mutation, amplification, and overexpression. Overexpression and amplification of c-MET have been correlated with poor clinical outcome in gastric cancer, whereas the associations between c-MET polymorphisms and prognosis have not been well defined. We examined the prognostic impact of functional polymorphisms of the MET gene on clinical outcome in gastric cancer. METHODS: Candidate polymorphisms of the MET gene were analyzed by PCR-based direct sequencing for the associations with clinical outcome across three independent cohorts, including 161 Japanese, 101 US, and 63 Austrian patients, with locoregional gastric cancer, treated with surgery. RESULTS: The univariable analysis showed that patients with any G (A/G or G/G genotype) allele of MET rs40239 had significantly longer disease-free survival and overall survival compared with those with the AA genotype in the Japanese cohort [hazard ratio (HR): 0.43, P=0.001, and HR: 0.47, P=0.006, respectively]; this remained significant upon multivariable analysis adjusted for age, sex, stage, and type of adjuvant therapy (HR: 0.48; P=0.009, HR: 0.50; P=0.017, respectively). However, there was no significant association of the polymorphism with clinical outcome in the US and Austrian cohorts. When stratified by sex in the Japanese cohort, male individuals, but not female individuals, with the G allele maintained a clinical outcome benefit in both univariable and multivariable analyses. CONCLUSION: MET rs40239 may serve as a prognostic biomarker in locoregional gastric cancer. These data also suggest that genetic variants of c-MET may show sex-related differences in the impact on clinical outcome.

Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727).

BACKGROUND: Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance METHODS: This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied RESULTS: The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. CONCLUSIONS: Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.

New directions in perioperative management of locally advanced esophagogastric cancer.

Cancers of the esophagus arise as adenocarcinomas and squamous cell carcinomas; these represent distinct diseases, with differing prognosis, yet they are often studied in common trials. With surgery alone, 5 year survival for T2-T3N0 disease is less than 30% to 40%, and declines to less than 25% with nodal involvement. The CROSS randomly assigned patients to surgery alone or to weekly carboplatin/paclitaxel X 5 and 41.4 Gy concurrent radiotherapy, followed by surgery. Seventy-five percent of enrolled patients had adenocarcinoma. Preoperative combined-modality therapy improved R0 resection from 69% to 92% (p < 0.001 and improved median survival from 24 months to 49.4 months (p < 0.003). This regimen reduced both locoregional recurrence (34% to 14%; p < 0.001) and the development of peritoneal carcinomatosis (14% to 4%; p < 0.001). Systemic perioperative therapy may have a greater effect on distant disease, the predominant mode of failure for these patients, and current trials compare preoperative chemoradiation with periooperative systemic therapy. PET scan response during preoperative chemotherapy without radiotherapy correlates with improvements in pathologic response and with improved survival. Nonresponse on early PET scan allows identification of patients for earlier surgery and discontinuation of ineffective preoperative chemotherapy, without survival detriment. There is no predictive benefit for early PET scan during the course of chemotherapy followed by chemoradiotherapy. The use of early PET scan during induction chemotherapy is being evaluated in CALGB/Alliance trial (NCT01333033). Molecular profiling has identified somatic gene mutations and pathways that may be oncogenic in upper gastrointestinal cancers. Potential targets include the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), HER2, mammalian target of rapamycin (mTOR), fibroblast growth factor receptor (FGFR), MEK, and others. Targeted therapies with known survival benefit in esophagogastric cancer are currently limited to trastuzumab for HER2 overexpressing cancers, or ramicirumab.

Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients.

PURPOSE: Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. PATIENTS AND METHODS: This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. RESULTS: Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5-4.9) and median overall survival was 3.7 months (95 % CI, 1.6-7.9). CONCLUSION: Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.

A phase I trial of oxaliplatin in combination with docetaxel in patients with advanced solid tumors.

The primary objective of this trial was to establish the maximum tolerated dose (MTD) of oxaliplatin 130 mg/m² preceded by escalating doses of docetaxel 60 mg/m² (75, 90, 100 mg/m²) administered every 3 weeks. A total of 11 patients were entered; 10 evaluable for response: 4 stable disease (liver, ovary and esophagus) and 1 partial remission (esophagus). At dose level 1, there was 1 dose-limiting toxicity (DLT) (grade 3 allergic reaction). At dose level 2, there were 3 DLTs (3 grade 4 neutropenia, grade 3 gastritis, diarrhea, hypophosphatemia, neuro-mood). The MTD is docetaxel 60 mg/m² with oxaliplatin 130 mg/m².

Postoperative intraperitoneal 5-fluoro-2'-deoxyuridine added to chemoradiation in patients curatively resected (R0) for locally advanced gastric and gastroesophageal junction adenocarcinoma.

PURPOSE: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment. METHODS: Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival. RESULTS: Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached. CONCLUSIONS: IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival.

S0356: a phase II clinical and prospective molecular trial with oxaliplatin, fluorouracil, and external-beam radiation therapy before surgery for patients with esophageal adenocarcinoma.

PURPOSE: Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival. PATIENTS AND METHODS: Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m(2) on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m(2)/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair. RESULTS: Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS. CONCLUSION: Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.

A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: Southwest Oncology Group study S0202.

PURPOSE: Patients with gallbladder cancer or cholangiocarcinoma were treated with the combination of gemcitabine 1,000 mg/m(2) IV over 100 min on days 1 and 8 and capecitabine 650 mg/m(2) BID PO on days 1-14, administered every 21 days. METHODS: The primary objective of this study was to assess the response rate (confirmed complete and partial responses) of gemcitabine and capecitabine used in advanced/metastatic biliary neoplasms. Secondary objectives included overall survival and toxicities. RESULTS: The study accrued 57 patients from September 2003 to April 2005. Three patients were ineligible, and two others received no treatment. Characteristics of analyzable patients: 35 (67%) cholangiocarcinoma, 17 (33%) gallbladder cancer; PS 0 (18 pts), 1 (26 pts), 2 (8 pts); 26 (50%) men; median age 58.8 years (29.5-85.6). Among 51 patients evaluated for toxicity, 6 experienced grade 4 toxicities. Among 52 patients, there were 7 confirmed partial responses for a confirmed response probability of 13% (95% CI: 6-26%). Six patients had an unconfirmed partial response for an overall response probability of 25% (95% CI: 14-39%). Twelve patients (23%) demonstrated stable disease. The 6-month overall survival was 55% (95% CI: 41-69%), and median survival was 7 months (95% CI: 5-8 months). CONCLUSIONS: The combination of gemcitabine and capecitabine is a well-tolerated regimen with activity in patients with advanced gallbladder cancer and cholangiocarcinoma.