Search

Importance: Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited., Ojectives: To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma., Design, Setting, and Participants: The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy., Intervention: Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023., Main Outcome and Measures: The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators., Results: Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%)., Conclusions and Relevance: Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03959293.

Background: Platinum + fluoropyrimidine is a standard front-line therapy for unresectable gastroesophageal adenocarcinoma (GA). Subsequent therapy recommendations are ramucirumab + paclitaxel (RAM/PAC), taxane, irinotecan, or trifluridine-tipiracil. RAM/PAC is the preferred second-line choice; however, patients can have a contraindication due to cumulative neuropathy. Our study assessed varied sequencing of second-line and third-line therapies comparing RAM/PAC followed by fluoropyrimidine + irinotecan (FOLFIRI/CAPEIRI) versus the opposite sequence., Methods: We retrospectively analyzed metastatic GA patients who received at least 3 lines of therapy. Two cohorts were studied. Group A: RAM/PAC second-line with FOLFIRI/CAPEIRI third-line or group B: FOLFIRI/CAPEIRI second-line followed by RAM/PAC. Primary outcome was overall survival (OS)., Results: Ninety-four patients were available for analysis (51 pts group A: 43 pts group B). No difference was observed in median OS from the start of second-line therapy (group A = 10.5 months vs. group B = 11.1 months, p = 0.97) or median OS from metastatic disease diagnosis (group A = 19.8 months vs. group B = 19.4 months, p = 0.73)., Conclusions: Our study, examining a practical issue of how to sequence second- and third-line therapies, documents that one sequence versus the other does not compromise patient outcomes and overall, our patients had an outstanding OS of beyond 19 months when they receive third-line therapy., (© 2021 S. Karger AG, Basel.)

Aims: to describe, using data from a cancer registry in a well-defined French population, the therapeutic strategies and survival of patients with metastatic colon cancer (mCC)., Methods: all patients with synchronous mCC diagnosed within the 2005-2014 period recorded in the digestive cancers registry of Burgundy were included., Results: 1286 mCC patients were included (57% male), of which 34.5% did not receive any antitumor treatment. Both, advanced age (≥75 years) and the Charlson comorbidity score ≥2 were significantly associated with the absence of antitumor treatment. Among the patients treated with chemotherapy, 59 and 33% received at least two and three lines, respectively. Most patients treated with chemotherapy (68%) did not receive first-line targeted therapy. Of patients aged ≥75 years, 57% received no chemotherapy and 56% of treated patients had first-line treatment only., Conclusion: this population-based study shows that more than one-third of patients with mCC receive no chemotherapy and that only 59% of treated patients receive treatment beyond the first line. This study also highlights the fact that more than half of patients ≥75 years do not get any antitumor treatment. In patients <75 years, the proportion of patients receiving chemotherapy and/or undergoing curative intent surgery tended to increase over time., Competing Interests: Declaration of Competing Interest L. Mas declare no competing interests. J.B. Bachet has received personal fees from Amgen, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, Roche, Sanofi, Servier, Shire, and nonfinancial support from Amgen, Merck Serono, and Roche. V. Jooste declare no competing interests. C. Lepage has received personal fees from Advanced Accelerator Application, Merck Serono, and nonfinancial support from Amgen, Pierre Fabre, Merck Serono and Ipsen. A.M. Bouvier declare no competing interests., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in patients with HER2-positive breast cancer (N = 337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd area under the concentration-time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and duration of response or progression-free survival; however, follow-up was limited. All evaluated safety end points demonstrated a significant (P < 0.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs. 62.9%) and toxicity (e.g., grade ≥ 3 all-cause treatment-emergent AEs: 61% vs. 54%) with T-DXd 6.4 vs. 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic breast cancer., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Importance: To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM)., Objective: To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment., Design, Setting, and Participants: An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment., Interventions: Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles., Main Outcomes and Measures: Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm)., Results: In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively., Conclusions and Relevance: In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial., Trial Registration: ClinicalTrials.gov Identifier: NCT02758951.

Advanced esophago-gastric (OG) adenocarcinomas have a high mortality rate and new therapeutic options are urgently required. Despite recent advances in understanding the molecular characteristics of OG cancers, tumor heterogeneity poses a challenge in developing new therapeutics capable of improving patient outcomes. Consequently, chemotherapy remains the mainstay of systemic treatment, with the HER2 being the only predictive biomarker routinely targeted in clinical practice. Recent data indicate that immunotherapy will be incorporated into first-line chemotherapy, but further research is required to refine patient selection. This review will summarize the clinical strategies being evaluated to utilize our knowledge of predictive biomarkers with reference to novel therapeutics, and discuss the barriers to implementing precision oncology in OG adenocarcinoma.

Gastric or gastro-oesophageal junction (GEJ) adenocarcinomas present poor overall survival (OS). First-line chemotherapy regimen for patients with HER2-negative tumours is based on a doublet or triplet of fluoropyrimidine plus platinum salt ± taxane. Second-line chemotherapy (Docetaxel or Irinotecan) improves OS which nonetheless remains poor (around 5 months). The first results of immune checkpoint inhibitors (anti-PD-1) combined with chemotherapy in metastatic gastric and GEJ cancers were discordant in recent phase III trials. Data on dual-blockade (anti-PD-L1 or anti-PD-1 plus anti-CTLA-4) plus chemotherapy are lacking. DURIGAST is a randomised, multicenter, non-comparative, phase II study, evaluating safety and efficacy of FOLFIRI plus Durvalumab (anti-PD-L1) versus FOLFIRI plus Durvalumab and Tremelimumab (anti-CTLA-4) as second-line treatment of advanced gastric and GEJ adenocarcinoma. The primary objective is the rate of patients alive and without progression at 4 months. The main inclusion criteria are: patients with advanced gastric or GEJ adenocarcinoma, pre-treated with fluoropyrimidine + platinum salt ± taxane. Due to a lack of data on FOLFIRI, Durvalumab and Tremelimumab combination, a 2-step safety run-in phase has been performed before the randomised phase II. The safety run-in phase did not show any safety issue and the randomised phase II starts in September 2020., Competing Interests: Conflict of interest None declared., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Chemotherapy is effective in metastatic pancreatic adenocarcinoma (mPA), but new approaches are still needed to improve patients' survival and quality of life. We have previously published good efficacy and tolerability results on a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI (5FU+irinotecan) regimen. In the present study, we evaluated the same sequence but replaced gemcitabine by the new gemcitabine + nab-paclitaxel standard first-line combination., Patients and Methods: We randomised chemotherapy-naive patients with proven mPA, bilirubin levels ≤1.5 upper limit of normal values and performance status 0-2 to alternately receive gemcitabine + nab-paclitaxel for 2 months then FOLFIRI.3 for 2 months in arm A, or gemcitabine + nab-paclitaxel alone until progression in arm B. The primary objective was to increase the 6-month progression-free survival (PFS) rate from 40% (H 0 ) to 60% (H 1 ); using the binomial exact method, 124 patients were required. Analyses were carried out in preplanned modified intention-to-treat (mITT) and per-protocol (PP) populations., Results: Between November 2015 and November 2016, 127 patients were enrolled. Main grade III-IV toxicities (% in arm A/B) were: diarrhoea (12.5/1.7), neutropenia (46.9/31, including febrile neutropenia: 1.6/0), skin toxicity (6.3/13.8), and peripheral neuropathy (6.3/8.6). No toxic deaths occurred. The objective response rate was 40.3% (95% confidence interval [CI]: 28.1-53.6) in arm A and 26.7% (95% CI: 16.1-39.7) in arm B. The primary end-point (6-month PFS rate) was 45.2% [one-sided 95% CI: 34.3-56.4] in arm A and 23.3% in arm B [one-sided 95% CI: 14.3-32.3] in the mITT population. In the PP population, median PFS and OS were 7.6 months and 6 months and 14.5 months and 12.2 months in arm A and B, respectively., Conclusions: The FIRGEMAX strategy with gemcitabine + nab-paclitaxel alternating with FOLFIRI.3 every 2 months, appears feasible and effective, with manageable toxicities, in patients able to reach >2mo of treatment., Trial Registration Information: EudraCT: 2014-004449-28: NCT: 0282701., Competing Interests: Conflict of interest statement T.J. reported receiving honoraria from Merck, Roche, Amgen, Lilly, Sanofi, Samsung, MSD, Servier, Celgene, Pierre Fabre; has been a member of the consulting or advisory role for Roche, Merck KGaA, Amgen, Lilly, MSD, Servier, Pierre Fabre, Sanofi, Samsung; speakers' Bureau for Servier, Amgen, Roche, Sanofi, Merck, Lilly, Pierre Fabre. R.Y. reported receiving honoraria from Roche, Sanofi, Merck, Amgen, Bayer and Servier. B.J-.B reported receiving honoraria from Amgen, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, Roche, Sanofi, Servier. All the remaining authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m 2 ), irinotecan (IRI: 200 mg/m 2 ), and BEV (7.5 mg/m 2 )] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy., Methods: QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be "0.8 < HR < 1.25" under the assumption of the true HR of 1.0, and 100 patients will be evaluated during the 3-year study period. Secondary endpoints include overall survival, overall response rate, safety, and patient reported outcome (PRO) (FACT/GOG-Ntx4)., Discussion: Considering the lower incidence of hematologic toxicities with modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising treatment option if sufficient efficacy and lower hematologic toxicities are indicated in this study. Additionally, a lower incidence of peripheral sensory neuropathy (PSN) reported following CAPEOX treatment compared to that after FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can mitigate OX-induced PSN., Trial Registration: Clinicaltrials.gov NCT04097444 . Registered September 20, 2019, https://clinicaltrials.gov/ct2/show/study/NCT04097444 / Japan Registry of Clinical Trials jRCTs041190072. Registered October 9, 2019.

Background: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer., Methods: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety., Results: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group., Conclusions: Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: A combination of nab-paclitaxel plus gemcitabine (N+G) has recently become a standard first-line treatment in patients with metastatic pancreatic adenocarcinoma (MPA), but there are currently no published data concerning second-line treatment after N+G. The aim of this study was to evaluate the survival outcomes and tolerability of three usual fluoropyrimidine-based regimens FOLFOX, FOLFIRI and FOLFIRINOX after N+G failure in MPA patients., Methods: Patients receiving N+G as first-line regimen were prospectively identified in 11 French centers between January 2014 and January 2017. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were enrolled in the study. The primary endpoint was overall survival following the second-line regimen. Secondary endpoints were objective response, progression-free survival and safety., Results: Out of 137 patients treated with N+G as first-line regimen, 61 (44.5%) received second-line chemotherapy, including FOLFOX (39.4%), FOLFIRI (34.4%) or FOLFIRINOX (26.2%). Baseline characteristics were not different between the 3 groups. In particular, median age was 71.7 years, sex ratio was 1/1, and performance status (PS) was 0 in 11.5% of case. Main grade 3 toxicities were neutropenia (4.9%) and nausea (3.3%), without major differences between the groups. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2.95 (95% CI: 2.3-5.4) and 5.97 months (95% CI: 4.0-8.0), respectively, with no difference between the 3 groups. Median OS from the start of first-line chemotherapy was 12.7 months (10.4-15.1) and was significantly better in patients receiving FOLFIRI after N+G failure, 18.4 months (95% CI: 11.7-24.1, P<0.05), as compared with FOLFOX or FOLFIRINOX (10.4 and 12.3 months, respectively)., Conclusion: This study suggests that second-line fluoropyrimidine-based regimens after N+G failure are feasible, have a manageable toxicity profile in selected patients with MPA, and are associated with promising clinical outcomes, in particular when combined with irinotecan. Randomized phase 3 trials are needed to confirm this trend., (Copyright © 2019. Published by Elsevier Masson SAS.)

We here explore the soluble Human Leukocyte Antigen-G (sHLA-G) expression level as clinical biomarker in metastatic colorectal cancer (mCRC). To this aim the sHLA-G protein was measured in plasma samples of 40 patients with mCRC treated with the FOLFIRI (irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and leucovorin (LV)) regimen. The results suggest a link between HLA-G levels and irinotecan (CPT-11) pharmacokinetic, leading to hypothesize a molecular interaction between sHLA-G and CPT-11. This interaction was confirmed experimentally by fluorescence spectroscopy. HLA-G is known to exist in a number of polymorphs that affect both the protein expression levels and its peptide-binding cleft. The interaction between HLA-G polymorphs and CPT-11 was explored by means of computational modelling, confirming the hypothesis that CPT-11 could actually target the peptide binding cleft of the most common HLA-G polymorphs.

Rationale: Cutaneous metastases from colorectal cancer are extremely rare and generally appear several years after diagnosis or resection of the primary colorectal tumor. Although cutaneous metastasis is unusual, it often indicates a poor prognosis., Patient Concerns: We treated a 62-year-old woman with multiple cutaneous metastatic nodules on the chest, back, and armpit 7 months after resection of ascending colon cancer., Diagnoses: The patient was diagnosed with cutaneous metastasis of ascending colon cancer with BRAF V600E mutation., Interventions: After 6 cycles of fluorouracil, leucovorin, oxaliplatin, cetuximab, and emurafenib, most of the metastatic lesions had begun to shrink, and no new metastases were observed. Serum tests showed that the levels of several tumor markers were decreased., Outcomes: The patient responded well to treatment and survived for 6.5 months after presentation with skin metastasis., Lessons: Cutaneous metastasis of colorectal cancer with BRAF V600E mutation is a rare but important phenomenon that should not be ignored. Cutaneous metastasis of colorectal cancer frequently indicates advanced disease and poor prognosis. The SWOG 1406 program is one of the treatment options, but this needs further exploration.

Basic and clinical studies on small bowel adenocarcinoma (SBA) are limited due to the rare nature of this cancer. We established a patient-derived xenograft (PDX) model from the tumor tissue of an advanced SBA patient with liver and peritoneal metastasis, and a cell line from the PDX. In the PDX model, compared to the control group, 5-fluorouracil (5-FU) treatment resulted in statistically significant tumor growth inhibition (TGI), while oxaliplatin (OHP) and irinotecan had no significant inhibitory effects. In combination with 5-FU, OHP showed the highest rate of TGI. The IC 50 for OHP was significantly lower than those for paclitaxel, gemcitabine, and trifluorothymidine in the PDX-derived cell line when compared to in HT29, a colon cancer cell line. Genetic analysis of the patient tumor, PDX tumor, and the cell line demonstrated consistency in the microsatellite status and mutations in TP53, APC, HRAS, CSF1R, FGFR3, FLT3, PDGFRA, and RET genes. However, the PDX tumor alone had additional mutations, indicating that the PDX-derived cell line may support the unstable genetic status of the PDX. Our findings confirmed the effectiveness of the combination of OHP and 5-FU, which is a common treatment for advanced SBA and advanced colorectal cancer, in a preclinical model. This preclinical model of SBA can help in further understanding the biology of SBA., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Arl4c is overexpressed in several cancer tissues and is involved in cancer development. Nevertheless, the exact mechanism that regulates Arl4c expression in lung cancer has not been fully elucidated. The aim of this study was to investigate the regulatory mechanism of Arl4c and to explore potential chemotherapeutic drugs targeting Arl4c., Methods: Immunohistochemistry was used to examine Arl4c expression levels in human lung adenocarcinoma cancer specimens. Protein expression was detected by western blot. Overexpression of Arl4c-Flag protein was used to detect the ubiquitination of Arl4c. A short interfering RNA against Arl4c was used for gene silencing., Results: Arl4c was overexpressed in lung cancer tissues, and knockdown of Arl4c expression by siRNA decreased lung cancer A549 and 95-D cell proliferation. In addition, Arl4c expression was downregulated via inhibition of the AKT pathway in A549 and 95-D cells, whereas exposure to benzo (a) pyrene (a carcinogen in smoke) increased Arl4c expression in 16HBE cells via AKT activation. Finally, we found that chemotherapy drug hydroxycamptothecin (HCPT) could decrease Arl4c expression levels by inhibiting the activation of the AKT pathway in A549 and 95-D cells. Moreover, accumulation of ubiquitinated Arl4c protein was increased by HCPT and LY294002 (an AKT inhibitor) treatment whereas the proteasome inhibitor MG-132 attenuated the inhibitory effect of HCPT and LY294002 on Arl4c expression., Conclusion: Here, we highlighted the AKT pathway as an important regulatory pathway for Arl4c expression in lung cancer cells and identified HCPT as a promising drug for lung adenocarcinoma treatment that functioned by targeting Arl4c expression., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti- Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For in vitro experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test in vivo antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan in vitro, with IC 50 values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). In conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2.

Background: Using data from the 4-year follow-up results of an open, randomised, phase II study, this patient-based cost-effectiveness analysis compares mFOLFIRI (irinotecan, 5-fluorouracil and leucovorin, the IRI arm) with mFOLFOX7 (oxaliplatin, 5-fluorouracil and leucovorin, the OXA arm) as first-line treatments in patients with locally advanced gastric adenocarcinoma (GC)., Methods: A Markov model was created based on previous results reported at the 2016 Gastrointestinal Cancers Symposium to evaluate mFOLFIRI and mFOLFOX7 for advanced GC quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were examined as the primary outcomes., Results: For the evaluable 128 patients, treatment efficacy was 0.59 QALYs for the IRI arm and 0.70 QALYs for the OXA arm, with a total cost of $13,861.34 for the IRI arm and $14,127.30 for the OXA arm. Hence, the ICER was $2,417.82 per QALY the OXA arm, which was below the threshold of 3 × per capita GDP of China. For subgroup analysis of those receiving mFOLFIRI followed by mFOLFOX7 (the IRI arm) and the reverse (the OXA arm), the OXA arm gained 0.44 more QALYs than the IRI arm with a total cost of $28,890.09 for the IRI arm and $31,147.30 for the OXA arm. However, the cost per QALY was also lower for the OXA arm than for the IRI arm, and the cost per QALY gained was $5,129.55 (below the Chinese WTP)., Conclusion: mFOLFOX7 is a very high cost-effective alternative as the first-line treatment for those patients with advanced GC compared with mFOLFIRI., (© 2019 John Wiley & Sons Ltd.)

Objectives: Limited evidence exists for chemotherapy selection in advanced pancreatic cancer (APC) after first-line FOLFIRINOX. Second-line gemcitabine/nab-paclitaxel (GEMNAB) is publicly funded in the Canadian provinces of Alberta (AB) and Manitoba (MB), but not in British Columbia (BC). We compared population-based outcomes by region to examine the utility of second-line GEMNAB versus gemcitabine (GEM) alone., Methods: We identified patients treated with first-line FOLFIRINOX between 2013 and 2015 across BC, AB, and MB. Baseline characteristics and treatment regimens were compared between AB/MB and BC. Survival outcomes were assessed by the Kaplan-Meier method and compared with log-rank test., Results: A total of 368 patients were treated with first-line FOLFIRINOX (143 AB/MB, 225 BC): median age 61 (interquartile range: 55 to 68) years, 42% comprising female individuals, and 67% with metastatic disease. Receipt of second-line therapy was 48% in AB/MB versus 44% in BC (P=0.35), and time from diagnosis to second-line therapy was 7.7 (AB/MB) versus 9.4 months (BC; P=0.1). Distribution of second-line GEM use: 73% GEMNAB, 23% GEM (AB/MB) versus 27% GEMNAB, 66% GEM (BC; P<0.001). Median overall survival (OS) from diagnosis was similar: 12.4 (AB/MB) versus 11.5 months (BC; P=0.91). On Cox regression analysis, region was not significant. Secondary survival analysis by second-line regimen demonstrated a median OS of 18.0 months with GEMNAB versus 14.3 months with GEM (P<0.01)., Conclusions: In this population-based comparison of APC patients treated with first-line FOLFIRINOX, survival outcomes were comparable regardless of funded access to second-line GEMNAB. OS by regimen favored second-line GEMNAB, but patient selection may be largely responsible for this difference.

Background/aim: Patients affected with Stage IV colorectal cancer and unresectable metastases represent a heterogeneous group. Resection of the primary tumor or stent positioning followed by chemotherapy and/or targeted therapies still represent a difficult choice for surgeons., Patients and Methods: From February 2013 to September 2019, 46 patients were enrolled into a prospective randomized open label parallel trial presenting with Stage IVA and IVB rectal cancer, unresectable metastases and symptoms of subacute large bowel obstruction. Our population was divided into two groups: Group 1 included 20 patients who underwent placement of a self-expandable metal stent and Group 2 included 26 patients in whom primary tumor resection was performed., Results: One-year actuarial survival rate of Group 1 was significantly lower compared to Group 2. Overall 17 patients had survival longer than 1-year (3 in Group 1 and 14 in Group 2). Cox regression analysis showed that endoscopic stent positioning and the suspension of the chemotherapy because of deterioration of liver function tests were the two most important factors negatively influencing survival., Conclusion: Patients affected with stage IVA and IVB rectal cancer and symptoms of bowel obstruction had a significant longer survival rate when submitted to surgical rectal resection followed by chemotherapy., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Cancer antigen (CA)-125 influences progression, metastasis, and outcomes in pancreatic cancer. This phase I/II trial (NCT01959672) evaluated the safety, efficacy, and immunologic correlates of chemoimmunotherapy (CIT) with oregovomab (anti-CA-125), followed by stereotactic body radiotherapy (SBRT) with the radiosensitizer nelfinavir., Materials and Methods: Following imaging, pathologic confirmation, and staging laparoscopy, subjects received three 3-week cycles of CIT (gemcitabine/leucovorin/fluorouracil/oregovomab). Thereafter, nelfinavir was delivered (1250 mg bid) for 5 weeks, with SBRT (40 Gy/5 fractions) occurring during the third week of nelfinavir. Following another cycle of CIT, pancreaticoduodenectomy was performed if resectable. Three more cycles of CIT were then delivered (total 7 cycles). In subjects with high (≥10 U/mL) CA-125, oregovomab (2 mg) was administered for 7 total doses (3 pre-SBRT, 1 between SBRT and resection, and 3 postoperatively). The enzyme-linked immunospot assay evaluated the development of CA-125-specific CD8 T-lymphocytes., Results: The trial was prematurely closed because gemcitabine/leucovorin/fluorouracil was replaced by FOLFIRINOX and gemcitabine/nab-paclitaxel as the standard of care. Median follow-up was 13 months. Of 11 enrolled patients, 10 had high CA-125; 1 patient suffered an unexpected cardiac-related death, so 9 subjects received oregovomab. Ten received SBRT and 4 underwent resection. Overall, 6/11 patients experienced any grade ≥3 event. The median survival and time to progression were 13 and 8.6 months, respectively. Five patients had samples available for immunospot testing, of whom 2 (40%) developed CA-125-specific CD8 T-lymphocytes., Conclusion: A combined pancreatic cancer multimodality approach using CIT and radiosensitized radiotherapy is feasible and safe; delivery of immunotherapy can lead to T-cell immunity. Re-evaluation with modern systemic paradigms is recommended.

Background: Sarcopenia, the presence of skeletal muscle mass depletion, can be objectively quantified, whereas subjective global assessment (SGA) is a widely utilized subjective instrument to assess nutritional status. Both the presence of sarcopenia and SGA-assessed malnutrition, in isolation, have been shown to be associated with worse overall survival in a wide range of cancers. However, there is no research evaluating the independent prognostic significance of both the presence of sarcopenia and malnutrition as part of the same analysis. We investigated the impact of sarcopenia on overall survival in colorectal cancer specifically controlling for malnutrition., Methods: We examined a consecutive case series of 112 patients with colorectal cancer first seen at our institution between August 2012 and October 2017. Using computed tomography (CT) imaging, the cross-sectional area of muscles at the L3 vertebral level was measured and then divided by height squared to calculate skeletal muscle index (SMI). Sarcopenia was defined as SMI ≤38.5 cm2/m2 for women and ≤52.4 cm2/m2 for men. SGA assessments were completed within 2 weeks of CT imaging. The association of sarcopenia and malnutrition with overall survival was assessed using univariate and multivariate Cox regression analysis., Results: Median age at presentation was 53.3 years. Sixty-six (58.9%) patients had metastatic disease at diagnosis. Using SMI, 46 (41.1%) patients were sarcopenic, while 66 (58.9%) were non-sarcopenic. Using SGA, 69 (61.6%) patients were assessed as well-nourished, while 43 (38.4%) were malnourished. Of 69 patients classified as well-nourished by SGA, 22 (31.9%) were sarcopenic. Similarly, of 43 patients categorized as malnourished by SGA, 19 (44.2%) were non-sarcopenic. On multivariate analysis, after adjusting for age, gender, tumor stage, BMI, treatment history and SGA, patients with sarcopenia had 3 times greater risk of mortality compared to those without sarcopenia (p = 0.001). The median survival of patients with both sarcopenia and malnutrition (n = 24) was 14.6 months (95% CI: 10.5 to 18.6) compared to the median survival of 25.9 months (95% CI: 7.8 to 44.0) in patients who were either sarcopenic or malnourished but not both (n = 41; p = 0.001). The median survival of patients who were non-sarcopenic and well nourished (n = 48; p = 0.001) was 38.6 months (95% CI: 25.6 to 51.6)., Conclusions: The exploratory study suggests that presence of sarcopenia supersedes the presence of malnutrition as a predictor of survival in colorectal cancer. Co-existence of sarcopenia and malnutrition is associated with worse survival in colorectal cancer compared to just one of those conditions being present. Prospective studies with large sample sizes are needed to confirm these findings., Competing Interests: The authors have declared that no competing interests exist.

Panitumumab is a recombinant human IgG 2 monoclonal antibody which is used for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or following FOLFIRI (fluoropyrimidine, oxaliplatin and irinotecan) containing chemotherapy regimen. We report a case of an 83-year-old Hispanic man, non-smoker, with KRAS/NRAS wild-type mCRC of the liver who was treated with 9 cycles of FOLFOX4 (fluorouracil, leucovorin and oxaliplatin) and cetuximab. Follow-up abdominal imaging showed progression of CRC, requiring initiation of panitumumab in addition to FOLFIRI. After 2 cycles of this combination chemotherapy, he presented with acute hypoxaemic respiratory failure. Pulmonary imaging showed new onset of interstitial lung disease (ILD). He was treated with systemic corticosteroids with marked improvement of ILD. We aim to highlight the risk of severe life-threatening ILD associated with panitumumab. Early recognition of this serious adverse event helps avoid unnecessary administration of systemic antibiotics and prevent mortality., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: MMR-D pancreatic cancer have been reported to respond to checkpoint inhibitor therapy. Here, we report the first case of acquired resistance to immunotherapy in MMR-D pancreatic cancer., Case Presentation: A 45-year-old woman with unresectable MMR-D pancreatic cancer was initially treated with FOLFIRINOX, FOLFIRI, and stereotactic body radiation with stable disease burden. After 3 months, imaging showed progression of disease with an increase in CA19-9. She was subsequently enrolled in a clinical trial of an anti-PD-L1 antibody in combination with an IDO1 inhibitor. She demonstrated a partial response to therapy by RECIST 1.1 criteria with declining tumor markers. Twenty-two months after beginning immunotherapy, imaging revealed an increasing left ovarian cystic mass. There were no other sites of progressive disease. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and pelvic lymphadenopathy. Pathology was consistent with a metastasis from the pancreas involving the endometrium and left ovary. Thereafter, the patient continued with PD-1 blockade therapy off protocol with no further progressive disease. Immune profiling showed high levels of CD8+ T cells and PD-1 positive immune cells infiltrating the tumor, with a moderate level of PD-L1 expression in both the immune cells and the tumor cells. Next generation sequencing found only the KRAS G12D and RNF43 G659Vfs*41 mutations were retained from the pre-treatment tumor in the treatment-resistant tumor., Conclusions: This is the first report describing acquired resistance to immunotherapy in MMR-D pancreatic cancer with accompanying genomic and immune profiling. This case of oligoprogression in the setting of immunotherapy demonstrates the feasibility of localized treatment followed by continuation of immunotherapy to sustain ongoing response.

This is the case report of a patient with right-sided, RAS and BRAF wild-type metastatic colorectal cancer, with borderline/potentially resectable liver-limited disease. Following neoadjuvant treatment with FOLFOX plus bevacizumab and radical resection, an early intra-hepatic disease relapse was observed and deemed as potentially resectable. Therefore, treatment with FOLFIRI plus aflibercept was started: a major partial response and radical re-resection were achieved. Following unresectable disease relapse, second-line treatment with FOLFIRI aflibercept was resumed and achieved again a partial response that is still ongoing after more than 9 months. This case report highlights how treatment goals (potentially curative resection vs palliation), molecular status and primary tumor location influence treatment strategies in order to maximize patients' outcomes.

The inhibition of the antiangiogenic pathway in association with chemotherapy significantly improved disease control and overall survival both in the upfront and in second line treatment of metastatic colorectal cancer patients. The VELOUR study had showed a significant improvement in overall survival with the addition of aflibercept, an antiangiogenic chimeric protein, to FOLFIRI (5-flourouracil, leucovorin, irinotecan) in patients who progressed after an oxaliplatin based chemotherapy (with or without bevacizumab) in first line treatment or within 6 months from the completion of adjuvant chemotherapy. Subgroup analyses from VELOUR trial show that the benefit of aflibercept is independent from previous exposure to bevacizumab in first line. We reported the case of a patient affected by metastatic colorectal adenocarcinoma RAS/ BRAF wild-type, with an initial liver-limited presentation. In this case we used a second line treatment with FOLFIRI aflibercept after a first-line oxaliplatin-based chemotherapy plus an anti-EGFR antibody.

Objective: To assess the clinicopathological feature and prognosis of gastric cancer associated with pregnancy in Chinese population. Methods: We collected the clinical features, pathological findings, treatment modalities, the health status of infants and the information of prognosis for ten patients developed gastric cancer associated with pregnancy between 2001 and 2016 in our hospital and the counterpart 12 patients reported in China National Knowledge Internet (CNKI), Wanfang database and China Science and Technology Journal Database. Results: The most common symptoms were nausea and vomiting ( n =14). Melena ( n =8), abdominal distension ( n =7) and abdominal pain ( n =6) were also frequent. When considering the complications, gastrointestinal bleeding ( n =9), intestinal obstruction ( n =3) and gastric perforation ( n =2) were common. The vast majority of pathology showed poorly differentiated tumors, poorly differentiated adenocarcinoma ( n =14) and signet ring cell carcinoma ( n =7). Only one patient was diagnosed at stage Ⅰ. And 17 patients developed metastatic disease of stage Ⅳ. Peritoneum ( n =7) and ovary ( n =5) were the most common metastasis sites. Three patients received abortion immediately after diagnosis in the first trimester of pregnancy. For the five patients in the second trimester of pregnancy, pregnancy termination was given to three patients. Caesarean section followed by gastrectomy was performed on three patients who were after the third trimester of gestation. Curative resection and palliative operation were carried out on six and five patients respectively. Combined chemotherapy based on oxaliplatin and fluorouracil was the common treatment for the peri-operative patients. For the metastatic gastric caner, platinum in combination with fluorouracil was recommended in the first line condition, irinotecan or raltitrexed were used in the second line treatment. One-year survival rate was 23.1%, and two-years survival was 15.4%. Three patients after R0 resection were alive without relapse over 18 months. Conclusions: The poor prognosis of gastric cancer associated with pregnancy may due to the late stage and the poor pathological type. There still lacks data of the appropriate treatment in these patients. It was demonstrated most patients have no chance of tumor resection due to the late stage. For the metastatic patients, platinum in combination with fluorouracil was recommended in the first line treatment. Irinotecan or raltitrexed were considered the choice for the second line treatment.

Combinational cancer therapy has been considered as a promising strategy to achieve synergetic therapeutic effects and suppression of multidrug resistance. Herein, we adopted a combination of methotrexate (MTX), an antimetabolite acting on cytoplasm, and 10-hydroxycamptothecin (HCPT), an alkaloid acting on nuclei, to treat cancer. Given the different solubilities, membrane permeabilities, and anticancer mechanisms of both drugs, we developed a dual-targeting delivery system based on 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-hyaluronic acid (a principal ligand of CD44 receptors)-MTX (a selective ligand of folate receptors) nanoparticles, which was exploited to carry HCPT-MTX conjugate for synergistically boosting dual-drug co-delivery. The HCPT-MTX conjugate was synthesized by a blood-stable yet intracellularly hydrolysable ester bond. The core-shell-corona DSPE-HA-MTX nanoparticles encapsulating HCPT-MTX (HCPT-MTX@DHM) exhibited high drug entrapment efficiency (∼91.8%) and pH/esterase-controlled release behavior. Cellular uptake studies confirmed significant increase in the efficiency of selective internalization of HCPT-MTX@DHM via CD44/folate receptors compared with those of DSPE-HA nanoparticles encapsulating HCPT-MTX (HCPT-MTX@DH), both drugs, or each individual drug. Furthermore, in vivo near-infrared fluorescence and photoacoustic dual-modal imaging indicated that DiR-doped HCPT-MTX@DHM nanoparticles efficiently accumulated at the tumor sites through passive-plus-active targeting. Finally, the synergistic active targeting and synchronous dual-drug release at a synergistic drug-to-drug ratio resulted in highly synergetic tumor cell-killing and tumor growth inhibition in MCF-7 tumor-bearing mice. Therefore, HCPT-MTX@DHM nanoparticles can be an efficient and smart platform for tumor-targeting therapy.

Background: FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet., Patients and Methods: This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety., Results: A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004)., Conclusions: FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with advanced gastric cancer (AGC) are often treated with irinotecan monotherapy as salvage-line therapy. However, the survival benefit of this therapy remains to be elucidated., Methods: Medical records of AGC patients who were treated with irinotecan monotherapy as salvage-line treatment in six institutions from 2007 to 2014 were reviewed., Results: A total of 146 patients had prior fluoropyrimidine and taxane therapies, and 75.3% had prior platinum therapy. The median age was 66 (range 27-81) years, and 102 males (69.9%) were included. Performance status (PS) was 0/1/2/3 in 53/70/19/4 patients. Eighty-nine patients (61.0%) had two or more metastatic sites. Irinotecan monotherapy as 3rd-/4th-line therapy was performed in 135/11 (92.5%/7.5%). The median number of administrations was 4 (range 1-62). Forty-six patients (31.5%) required initial dose reduction at the physician's discretion. The overall response rate was 6.8%, and the disease control rate was 43.1%. The median PFS was 3.19 months [95% confidence interval (CI) 2.30-4.08 months], and the median OS was 6.61 months (95% CI 5.94-7.28 months). Grade 3/4 adverse events were hematological toxicity (46 patients, 31.5%) and non-hematological toxicity (50 patients, 34.2%). Hospitalization due to adverse events was required in 31 patients (21.2%). Patients with relative dose intensity (RDI) less than 80% showed similar survival to those with RDI 80% or higher., Conclusions: Irinotecan monotherapy was relatively safely performed as salvage-line treatment for AGC in Japanese clinical practice. Careful patient selection and intensive modification of the dose of irinotecan might possibly be associated with favorable survival.

Introduction: Ampullary adenocarcinoma is a rare entity with limited data on prognostic factors. The aim of this study is to identify prognostic factors and assess the benefit of adjuvant therapy in patients with ampullary adenocarcinoma who underwent pancreatoduodenectomy., Methods: A cohort of 121 consecutive patients underwent pancreatoduodenectomy for ampullary adenocarcinoma from 2006 to 2016 at Mayo Clinic in Rochester, MN. All patients were confirmed by independent pathologic review to have ampullary carcinoma. Patient survival and its correlation with patient and tumor variables were evaluated by univariate and multivariate analysis., Results: Fifty three patients (45%) received adjuvant therapy (34 patients had chemotherapy alone, while 19 patients received both chemotherapy and radiation therapy). Fifty seven percent of the patients were diagnosed with advanced stage disease (Stage IIB or higher). Nearly all patients (98.3%) had negative surgical margins. Median overall survival (OS) was 91.8 months (95% CI:52.6 months-not reached). In multivariate analysis, excellent performance status (ECOG: 0), adjuvant therapy, and advanced stage remained statistically significant. Adjuvant therapy was independently associated with improved disease free survival (Hazard ratio [HR]:0.52, P = 0.04) and overall survival (HR:0.45, P = 0.03) in patients with advanced disease., Conclusions: Adjuvant therapy was associated with improved survival in patients with resected ampullary cancer, especially with advanced stage disease. A multi-institutional randomized trial is needed to further assess the role of adjuvant therapy in ampullary adenocarcinoma., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Studies of a modified XELIRI (mXELIRI; capecitabine plus irinotecan) regimen suggest promising efficacy and tolerability profiles in the first-line and second-line settings. Therefore, we aimed to compare the efficacy and safety of the mXELIRI regimen with that of standard FOLFIRI (leucovorin, fluorouracil, and irinotecan), with or without bevacizumab in both regimens, as a second-line therapy for metastatic colorectal cancer., Methods: We did a multicentre, open-label, randomised, non-inferiority, phase 3 trial. We enrolled patients from 98 hospitals in Japan, China, and South Korea who were aged 20 years or older with histologically confirmed and unresectable colorectal adenocarcinoma, and who had withdrawn from first-line chemotherapy for metastatic colorectal cancer. We randomly assigned patients (1:1) to receive either mXELIRI with or without bevacizumab (irinotecan 200 mg/m 2 intravenously on day 1 plus oral capecitabine 800 mg/m 2 twice daily on days 1-14, repeated every 21 days, with or without bevacizumab 7·5 mg/kg intravenously on day 1) or FOLFIRI with or without bevacizumab (irinotecan 180 mg/m 2 intravenously on day 1, leucovorin 200 mg/m 2 intravenously on day 1, fluorouracil 400 mg/m 2 intravenously on day 1, and a 46-h continuous intravenous infusion of fluorouracil [2400 mg/m 2 ], repeated every 14 days, with or without the addition of bevacizumab 5 mg/kg intravenously on day 1) via a centralised electronic system. We used the minimisation method to stratify randomisation by country, Eastern Cooperative Oncology Group performance status, number of metastatic sites, previous oxaliplatin treatment, and concomitant bevacizumab treatment. Patients and clinicians were not masked to the allocated treatment. The primary endpoint was overall survival analysed on an intention-to-treat basis with a non-inferiority upper margin of 1·30 for the hazard ratio (HR). This study is registered with ClinicalTrials.gov, number NCT01996306, and is ongoing but no longer recruiting participants., Findings: Between Dec 2, 2013, and Aug 13, 2015, 650 patients were enrolled and randomly assigned to receive mXELIRI with or without bevacizumab (n=326) or FOLFIRI with or without bevacizumab (n=324). After a median follow-up of 15·8 months (IQR 8·7-24·9), a total of 490 patients had died (242 in the mXELIRI with or without bevacizumab group and 248 in the FOLFIRI with or without bevacizumab group) and the median overall survival was 16·8 months (95% CI 15·3-19·1) in the mXELIRI group and 15·4 months (13·0-17·7) in the FOLFIRI group (HR 0·85, 95% CI 0·71-1·02; p non-inferiority <0·0001). In the per-protocol safety population, the most common grade 3-4 adverse event was neutropenia (affecting 52 [17%] of 310 patients in the mXELIRI group and 133 [43%] of 310 in the FOLFIRI group). Incidences of grade 3-4 diarrhoea were higher in the mXELIRI group (22 [7%]) than in the FOLFIRI group (ten [3%]). Serious adverse events were reported in 46 (15%) of 310 patients in the mXELIRI group and 63 (20%) of 310 in the FOLFIRI group. Two treatment-related deaths (one pneumonitis and one lung infection) were observed in the mXELIRI group and there was one treatment-related death (lung infection) in the FOLFIRI group., Interpretation: mXELIRI with or without bevacizumab is well tolerated and non-inferior to FOLFIRI with or without bevacizumab in terms of overall survival. mXELIRI could be an alternative to FOLFIRI as a standard second-line backbone treatment for metastatic colorectal cancer, at least for Asian patient populations., Funding: Chugai Pharmaceutical and F Hoffmann-La Roche., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: The combination of a triple-drug chemotherapy regimen with an anti-epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastatic colorectal cancer (mCRC) showed promising activity along with safety concerns in single-arm phase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and the optimal regimen to be adopted are not established., Objectives: To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI (mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab in RAS and BRAF wild-type mCRC., Design, Setting, and Participants: In a prospective, noncomparative, open-label, multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable, previously untreated RAS and BRAF wild-type (before amendment, KRAS wild-type) mCRC were recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015 (followed up through May 31, 2017). In total, 323 patients were screened and 143 were randomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRI plus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until disease progression. Primary analyses were conducted in a modified intention-to-treat population., Interventions: mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression., Main Outcomes and Measures: The primary end point was the 10-month progression-free rate (PFR); secondary end points included progression-free and overall survival, response rate, rate of metastases resection, and adverse events., Results: Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age, 59.5 [53-67] years; 34 [29.3%] women) had RAS and BRAF wild-type mCRC. At a median (IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI, 39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia (occurring in 36 patients [31%]), diarrhea (in 21 patients [18%]), skin toxic effects (in 18 patients [16%]), asthenia (in 11 patients [9%]), stomatitis (in 7 patients [6%]), and febrile neutropenia (in 3 patients [3%])., Conclusions and Relevance: Although neither of the 2 arms met the primary end point, the findings indicate that a 4-month induction regimen of mFOLFOXIRI plus cetuximab is feasible and provides relevant activity results, leading to a high surgical resection rate., Trial Registration: clinicaltrials.gov Identifier: NCT02295930.

Background: Köhne prognostic score is used to classify patients with metastatic colorectal cancer (mCRC) as high, intermediate, or low risk. Using data from 2 phase III trials, we analyzed survival in patients categorized according to Köhne prognostic category and virus-induced rapidly accelerated fibrosarcoma murine sarcoma viral oncogene homolog B (BRAF) mutation., Patients and Methods: PRIME (Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) (first-line) and 20050181 (second-line) were studies of chemotherapy with or without panitumumab. Progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively in rat sarcoma viral oncogene homolog (RAS) wild type (WT) and RAS WT+BRAF WT mCRC in each Köhne category, and in BRAF mutant (MT) mCRC., Results: In PRIME (n = 495) and 20050181 (n = 420), 53 (11%) and 44 (10%) patients, respectively, had BRAF MT mCRC. Of the RAS WT+BRAF WT/unknown populations, 85/267/90 and 82/211/83 were categorized as high/medium/low risk, respectively. PFS and OS hazard ratios (HRs), adjusted for Köhne group, for patients with RAS WT + BRAF WT/unknown mCRC favored panitumumab with chemotherapy versus chemotherapy alone in both studies. In PRIME, the PFS HR was 0.74 (95% confidence interval [CI], 0.61-0.90) and OS HR was 0.78 (95% CI, 0.64-0.95). In 20050181, PFS and OS HRs were 0.80 (95% CI, 0.65-0.99) and 0.78 (95% CI, 0.62-0.99), respectively. Median PFS and OS were lower in patients with BRAF MT mCRC than in any of the 3 risk categories for patients with RAS WT+BRAF WT/unknown mCRC., Conclusion: During first- and second-line treatment, Köhne prognostic score allows accurate risk classification in RAS WT mCRC. BRAF MT mCRC should be classified as high risk regardless of other parameters. Panitumumab with chemotherapy might provide survival benefits versus chemotherapy alone in RAS WT and RAS WT+BRAF WT/unknown mCRC, overall and across risk categories., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), compared with FOLFIRI alone, in patients with metastatic colorectal cancer previously treated with oxaliplatin-based therapy. This subset analysis of the VELOUR study investigates aflibercept plus FOLFIRI versus placebo plus FOLFIRI according to age., Methods: Efficacy and safety were analyzed by treatment arm and age (≥ or <65years)., Results: Overall, 443 patients were ≥65years old (205 in aflibercept arm; 238 in placebo arm) and 783 were <65years old (407 in aflibercept arm; 376 in placebo arm). Median OS was 12.6 versus 11.3months (hazard ratio [HR]: 0.85; 95.34% CI 0.68-1.07) in patients ≥65years old and 14.5 versus 12.5months (HR: 0.80; 95.34% CI 0.67-0.95) in those patients <65years old, for patients receiving FOLFIRI plus aflibercept or placebo, respectively. There was no interaction between treatment and age. Treatment-emergent adverse events (AEs) were comparable for patients <65years and ≥65years old. The incidence of grade 3/4 AEs was higher for patients ≥65years old than for those <65years old in both the aflibercept (89.3% versus 80.5%) and placebo (67.4% versus 59.4%) arms. Interaction tests for grade 3/4 antiangiogenic agent-related AEs suggested no heterogeneity between the older and younger patient populations (p>0.1)., Conclusion: A limited but consistent benefit on both OS and PFS was associated with the addition of aflibercept to FOLFIRI compared with placebo in patients <65 and ≥65years old, with a marked but manageable increase in the toxicity profile in older patients., Trial Registration: clinicaltrials.govNCT00561470., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Chemotherapy is essential to most patients with gastric cancer and the anticancer drug, irinotecan (CPT-11), and its metabolite, SN-38, an inhibitor of DNA topoisomerase I, are first-line chemotherapies for gastric cancer. Quercetin, a flavonoid that is widely found in various vegetables and fruits, has the ability to potentiate the efficacy of anticancer drugs. The purpose of this study was to investigate the therapeutic effect of quercetin combined with irinotecan/SN-38 in the AGS human gastric cancer cell line in vitro and in vivo. The in vitro study evaluated the efficacy of high-dose SN-38 and quercetin combined with low-dose SN-38 on cell viability, apoptosis, and β-catenin expression. Results showed that cell viability and the percentage of apoptosis in combined treatments with quercetin and SN-38 were comparable to treatment with high-dose SN-38 alone. AGS cells treated with a high dose of SN-38 exhibited up-regulation of β-catenin protein expression, whereas quercetin-treated cells (either quercetin alone or combined with low-dose SN-38) exhibited lower protein levels of β-catenin. In the AGS xenograft mouse model, gene expression of cyclooxygenase-2 and epithelial-mesenchymal transition-related markers, such as Twist1 and ITGβ6, were lower in combined treatments with quercetin and low-dose irinotecan than high-dose irinotecan alone. Furthermore, the concentration of angiogenesis-associated factors (vascular endothelial growth factor (VEGF)-A and VEGF-receptor 2) and percentage of Tie2-expressing monocytes was significantly down-regulated in combined treatments with quercetin and irinotecan. These results suggest that quercetin may enhance the efficacy of irinotecan/SN-38 in the human AGS cell line., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: FOLFIRINOX is a first-line treatment option for patients with metastatic pancreatic cancer (MPC) and is associated with improved survival yet significantly more toxicities than standard gemcitabine. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX based upon the pivotal ACCORD study criteria., Methods: Patients with confirmed MPC at the time of referral to the BC Cancer Agency between 2004 and 2007 were identified from the Gastrointestinal Cancers Outcomes Unit Database (GICOU). Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics., Results: A total of 100 consecutive patients with complete chart records and MPC were identified. Fifty-two (52%) were male and the median age was 68 years (range, 42 to 98 y). The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor Eastern Cooperative Oncology Group score of ≥2 (64%), age of 76 years or greater (22%), elevated bilirubin (22%), and inadequate renal function (6%)., Conclusions: Despite the proven survival benefit of FOLFIRINOX, only approximately one quarter of patients in the real-world setting with MPC would have been considered eligible for such therapy based upon the ACCORD eligibility criteria. Careful patient selection and more tolerable therapies are required.

Background: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and is postulated to be more effective and less toxic than conventionally fractionated intensity modulated radiation therapy (IMRT)., Material and Methods: We retrospectively reviewed unresectable stage I-III pancreatic adenocarcinoma treated from 2008 to 2016 at our institution with SBRT (five fractions, 30-33 Gy) or IMRT (25-28 fractions, 45-56 Gy with concurrent chemotherapy). Groups were compared with respect to overall survival (OS), local and distant failure, and toxicity. Log-rank test and Cox proportional hazards regression model, and competing risks methods were used for univariate and multivariate analysis., Results: SBRT patients (n = 44) were older than IMRT (n = 226) patients; otherwise there was no significant difference in baseline characteristics. There was no significant difference in OS or local or distant failure. There was no significant difference in rates of subsequent resection (IMRT =17%, SBRT =7%, p = .11). IMRT was associated with more acute grade 2+ gastrointestinal toxicity, grade 2+ fatigue, and grade 3+ hematologic toxicity (p = .008, p < .0001, p = .001, respectively)., Conclusions: In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.

In patients with malignancy who receive aflibercept based chemotherapy, gastrointestinal perforation is among the reported adverse events with a prevalence of 1.9%. This complication may lead to mortality up to 10.8%. We here report a case of small bowel perforation that occurred fifteen days after the first cycle of aflibercept in a 58-year old female who had metachronous colorectal liver metastases. Emergency laparotomy was performed and revealed a small bowel perforation without any anastomotic dehiscence. Surgery was followed by uneventful outcome. The use of aflibercept in patients with malignancy may be associated with very early gastrointestinal perforation and this should be known by oncologist and surgeons.

Background: The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain., Methods: In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen., Results: Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73-88%) (four patients with clinical complete response declined surgery). Twenty-four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05-1.03, P=0.055)., Conclusions: This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss.

Case report presents the successful treatment of unresectable liver metastasis in a patient with colon cancer. A 44-year-old male underwent right hemicolectomy followed by capecitabine for a moderately differentiated adenocarcinoma of the colon. 2 years later, a liver metastatic lesion was detected and had increased in size despite chemotherapy with capecitabine plus oxaliplatin (XELOX). Curative liver resection was conducted after conversion of unresectable tumor to resectable by transarterial chemoembolization followed by chemotherapy - irinotecan with fluorouracil and folinic acid (FOLFIRI). No recurrence was observed during 22-month follow-up after hepatectomy.

Necrotizing Infundibular Crystalline Folliculitis (NICF) is rare entity of unknown pathogenesis presenting as follicular crystalline papules arising in seborrheic areas. We report 2 cases of NICF in patients under targeted therapy for metastatic adenocarcinoma. In one case, the lesions reappeared cyclically every 3 weeks after each injection and in the other case, lesions persisted until disruption of the continuous oral therapy. Punch-biopsies demonstrated folliculitis with a plugging crystalline material associated with either bacteria or yeast. These are the first descriptions of drug-induced NICF.

Background: Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used as first-line therapy for patients with small bowel adenocarcinoma. The addition of irinotecan improves survival in other gastrointestinal tumors but at the cost of hematologic toxicity. The authors performed a phase 2 cooperative group study (North Central Cancer Treatment Group N0543, Alliance) using genotype-dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX), with dosing assigned based on UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genotype to test: 1) whether the addition of irinotecan would improve outcomes; and 2) whether UGT1A1 genotype-based dosing could optimize tolerability., Methods: Previously untreated patients with advanced small bowel adenocarcinoma received irinotecan (day 1), oxaliplatin (day 1), and capecitabine (days 2-15) in a 21-day cycle and were dosed with gCAPIRINOX according to UGT1A1*28 genotypes (6/6, 6/7, and 7/7)., Results: A total of 33 patients (17 with the 6/6 genotype, 10 with the 6/7 genotype, and 6 with the 7/7 genotype) were enrolled from October 2007 to November 2013; 73% were male, with a mean age of 64 years (range, 41-77 years). Location of the primary tumor included the duodenum (58%), jejunum (30%), and ileum (9%). The regimen yielded a confirmed response rate of 37.5% (95% confidence interval, 21%-56%), with a median progression-free survival of 8.9 months and a median overall survival of 13.4 months. Neither hematologic toxicity (grade ≥3 in 52.9%, 30.0%, and 33.3%, respectively, of the 6/6, 6/7, and 7/7 genotype groups) nor tumor response rate (41.2%, 33%, and 33%, respectively) were found to differ significantly by UGT1A1 genotype., Conclusions: UGT1A1 genotype-directed dosing (gCAPIRINOX) appears to be feasible with favorable rates of hematologic toxicity compared with prior 3-drug studies in unselected patients. Larger studies would be needed to determine the regimen's comparability to oxaliplatin and capecitabine (CapeOx) alone or if response/toxicity differs among patients with different UGT1A1 genotypes. Cancer 2017;123:3494-501. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: For borderline resectable colorectal cancer liver metastases (CLM), systemic treatment can help to achieve R0 resection and reduce the risk of relapse. We assessed the role of perioperative triplet chemotherapy in combination with cetuximab in patients with RAS wild type high recurrence risk and/or borderline resectable CLM., Patients and Methods: This was a monocenter, open-label phase II study. Borderline resectability was defined technically as tumor involvement of >1 hepatic vein, or >4 hepatic segments, need for 2-stage hepatectomy or radiofrequency ablation, and/or biologically (high risk): ≥4 metastatic nodules, or synchronous metastases. Patients were treated with 4 pre- and postoperative cycles of biweekly COI-E (cetuximab 500 mg/m 2 and irinotecan 180 mg/m 2 on day 1, oxaliplatin 85 mg/m 2 on day 2, and capecitabine 1000 mg/m 2 twice per day on days 2-6). The primary end point was overall response rate., Results: Forty patients were enrolled. Nine patients with KRAS mutation were excluded after amendment in 2010. In an extended RAS test we did not find additional RAS mutations. The final population was comprised of 31 patients with RAS wild type CLM (technically borderline resectable 39%; synchronous 84%; ≥4 metastatic nodules 29%). The overall response, R0 resection, and pathological response rates were 87%, 84%, and 33%, respectively. At a median follow-up of 4 years, median progression-free survival and overall survival were 17.8 and 62.5 months, respectively. Treatment toxicity was relevant but did not jeopardize the surgical plan., Conclusion: The COI-E regimen was associated with high response and R0 resection rates in patients with RAS wild type CLM with borderline resectability and/or high-risk features., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Given Saskatchewan's size and low population density outside of city centres, many rural and remote residents have issues accessing regional oncology services. We performed a study to determine whether travel distance to cancer treatment centres affects first-line treatment accessibility and survival in patients with metastatic colorectal adenocarcinoma., Methods: Retrospective chart review of patients with stage IV metastatic colorectal adenocarcinoma collected by the Saskatchewan Cancer Agency registry between June 1, 2009, and June 30, 2013. Patients were categorized as living within 100 km of or more than 100 km from the nearest cancer treatment centre offering bevacizumab plus first-line chemotherapy. Main outcome measures were differences in first-line treatment accessibility and overall survival estimates (calculated via the Kaplan-Meier method) between cohorts., Results: Of the 252 included patients, 91 (36.1%) resided more than 100 km from a cancer treatment centre. Accessibility of standard single-agent and combination chemotherapy in the first-line setting, when not prescribed in conjunction with bevacizumab, was comparable between cohorts. Patients living within 100 km of a treatment centre and those living more than 100 km from a treatment centre had comparable access to bevacizumab in conjunction with first-line chemotherapy (57 [62.6%] v. 116 [72.0%] patients; p = 0.1) and similar median overall survival (18.1 v. 25.0 mo; p = 0.2)., Conclusion: Neither access to bevacizumab treatment nor survival times for metastatic colorectal adenocarcinoma were significantly different between the cohorts. This suggests that health care providers in Saskatchewan may be doing well in arranging timely access to advanced oncology centres. Future studies with a larger sample, different tumour types or changes to the definition of remoteness are indicated.

Purpose: Few population studies have examined patterns of systemic therapy administration in metastatic pancreatic cancer (MPC) or the predictors associated with specific treatment choices., Patients and Methods: We assessed 4,011 consecutive MPC patients who received chemotherapy between January 2005 and December 2015 at academic, private, and community-based oncology practices subscribing to a U.S.-wide chemotherapy order entry system capturing disease, patient, provider, and treatment data. Multivariate analyses of these prospectively recorded characteristics identified significant predictors of specific therapeutic choices., Results: Overall, 100 different regimens were used in first-line treatment of MPC. First-line gemcitabine monotherapy usage fell steadily from 72% in 2006 to 16% in 2015. This steep decline mirrored increases in first-line usage of both 5 fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine + nab-paclitaxel. Younger male patients were more likely to receive FOLFIRINOX as first-line treatment, whereas patients treated at community practices and by oncologists with lower MPC patient volume were more likely to receive gemcitabine plus nab-paclitaxel (all p  ≤ .05). Among all patients receiving first-line chemotherapy for MPC, 49% went on to receive second-line therapy and 19% received third-line therapy; administration of second- and third-line therapies increased steadily over the time course of follow-up. Younger patients and those treated by oncologists with higher MPC patient volume were more likely to receive second- and third-line therapies., Conclusion: This population-based study provides insight into treatment patterns of MPC in the U.S. Usage patterns varied greatly according to patient and provider characteristics., Implications for Practice: This study examined real world metastatic pancreatic cancer treatment patterns in the United States with the goals of understanding changes in chemotherapy treatment frequencies over time and determining the individual predictors that underlie the chemotherapy choices oncologists make for their patients. Our data set is unique in that it captured not only patient-level data, but also oncologist-level data. It also captured data from private and community practices as well as academic centers. To our knowledge, this is the only data set that can give this degree of insight into oncologist decision making practices., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Gastric cancer including gastroesophageal junction adenocarcinomas are most challenging and deadly cancers of the gastrointestinal tract. Gastric cancer has a fatality-to-case ratio of 0.66, translating that nearly two thirds of newly diagnosed patients will have disseminated disease and in need of systemic therapy. Advanced gastric adenocarcinoma (AGC) is a heterogenous disease with differences in geographical distribution, histopathology, and molecular subtypes. Fluoropyrimidines (5-FU, S-1, and capecitabine), platinum compounds (cisplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), and the topoisomerase inhibitory irinotecan are active drugs against AGC. The combination of fluoropyrimidines with a platinum compound is the optimal first-line treatment. Trastuzumab (given in combination with chemotherapy for HER2 positive tumors) and ramucirumab are the only targeted agents approved by the food and drug administration for the treatment in AGC for first and second line respectively. Efforts are being directed to harness the immune system with checkpoint inhibitors and to combining these drugs with chemotherapy in clinical trials. Genomic technology advancements might provide us with the tools to create personalized treatment for AGC in the near future with the goal to improve outcomes. In this article we aimed to review current therapeutic regimens for AGC with an update of ongoing clinical trials.

Background: Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined., Methods: In Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 and infusional 5-fluorouracil 2400 mg/m 2 over 2 days for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33-40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy will undergo pancreatectomy and will subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , bolus 5-fluorouracil 400 mg/m 2 , and infusional 5-fluorouracil 2400 mg/m 2 over 2 days for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The primary analysis will compare the 18-month overall survival rate of each arm to a historical control rate of 50%. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site., Discussion: This study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials., Trial Registration: ClinicalTrials.gov : NCT02839343 , registered July 14, 2016.