GEM and Nab-P is a standard first line therapy for mPDAC based on the MPACT Trial. D is a human monoclonal antibody (mAb) that inhibits binding PD-L1 to its receptor. T is a mAb directed against CTLA-4. PA.7 is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases treatment efficacy. This randomized phase II study (NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs GEM and Nab-P (arm B) in patients (pts) with mPDAC (n=191). Pts with untreated mPDAC and good performance status (ECOG PS 0-1) were eligible. A safety run in was conducted for 11 pts receiving GEM, Nab-P, D and T. The study then randomized 180 pts in a 2:1 ratio to receive GEM (1000mg/m2 D1, 8, 15); Nab-P (125mg/m2 D1, 8, 15); D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles vs. GEM and Nab-P alone. The primary endpoint is overall survival (OS); secondary endpoints include progression free survival (PFS), safety, overall response rate (ORR) and quality of life. 180 pts were randomized (119 to arm A and 61 to arm B) between April 2017 and July 2018. Baseline characteristics were well balanced. With a median (med) follow-up of 28.5 months (mo) there was no significant difference in OS (med 9.8 mo in arm A vs. 8.8 mo in arm B, Hazard Ratio (HR)=0.94, 90% confidence interval (CI) 0.71-1.25, p=0.72). There was no significant difference in PFS (med 5.5 mo vs 5.4 mo respectively, HR=0.98, 90% CI 0.75-1.29, p=0.91). ORR was not significantly different, 30.3% vs. 23.0% respectively (Odds Ratio=1.49, 90% CI 0.81-2.72, p=0.28). Disease control rate (DCR) was 70.6% vs 57.4% respectively (difference=13.2%, 90% CI 0.7-25.7%, p=0.096). The only significant difference in grade 3 or greater adverse events was lymphopenia (38% vs 20% respectively, p=0.02). The addition of dual immune checkpoint inhibitors to Gem and Nab-P did not result in a significant improvement in OS, PFS, or ORR. There is a trend to improved DCR. Correlative analyses to assess biomarkers that may predict immune sensitivity in this setting are underway.

Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths in Canada and mainly affects individuals older than 60 years of age. Because of its retroperitoneal location, pancreatic cancer follows a relatively silent clinical course and is more often diagnosed at an advanced stage. When faced with a diagnosis of unresectable pancreatic adenocarcinoma, patients may be offered palliative chemotherapy. Unfortunately, a paucity of data exists regarding the use of chemotherapeutic agents in the elderly population with pancreatic cancer. The objective of this study is to obtain adequate profiling of the elderly patients with pancreatic cancer to better assess factors influencing outcomes and decision-making. This is a retrospective observational study of all patients aged older than 75 years old with a diagnosis of unresectable or metastatic pancreatic cancer at the CHUS between June 2005 and June 2015. Data was retrieved using the local patient database program Ariane. During the study period, 225 patients were included according to the entry criteria. Median age at diagnosis was 82 years old with a slight female gender predominance (52% vs 48%). Location of the primary tumor was in the head of the pancreas in 46% of cases, and evenly distributed between the pancreatic body and tail. Diagnosis was made by the general practitioners or gastroenterologists in 73.4% of cases. High blood pressure, diabetes mellitus and coronary atherosclerosis were the most frequently encountered comorbidities. Other biochemistry parameters at diagnosis suggested a more fragile population; median albumin level of 32 g/L, median creatinine value of 155 µmol/L and minor anemia (median = 11.7 g/dL). Among all patients, only 10 opted for palliative chemotherapy. ECOG status was unfortunately far from uniformly documented, although among the 10 patients treated, all had either ECOG 0 or 1 scores. Nine received Gemcitabine as first line whereas one patient was treated with Folfirinox. Seven completed the treatment with the standard regimen dosage for each cycle. Patients received a median of 5 cycles and end of treatment was dictated by severe asthenia complicating treatment. Only 2 patients, non-responders, received second-line agents (5FU/LV) that were subsequently stopped, again for non-response. Results of this unicentric observational retrospective study suggest an overall diminished clinical performance status in elderly patients diagnosed with unresectable or metastatic pancreatic cancer when compared to their younger counterparts. Due to our small sample size, it remains difficult to draw conclusions on ideal patient selection criterion and palliative treatment for advanced pancreatic cancer in the elderly. The present study does, however, underline the dire need for further studies on the matter. None

Background: We have proposed that best, worst and typical scenarios for survival, based on simple multiples of an individual's expected survival time (EST) estimated by their oncologist, are a useful way of formulating and explaining prognosis in advanced cancer. We aimed to determine the accuracy and prognostic significance of such estimates in a multicentre, randomized trial. Methods: 66 oncologists estimated the EST at baseline for each of 152 participants in the INTEGRATE trial. We expected oncologists' estimates of EST to be well calibrated (∼50% of patients living longer or shorter than their EST) and imprecise (<33% living within 0.67 to 1.33 times their EST), but to provide accurate scenarios for survival time (∼10% dying within a quarter of their EST, ∼10% living longer than 3 times their EST and ∼50% living for half to double their EST). We also hypothesized that oncologists' estimates of EST would be independently predictive of overall survival in a multivariable Cox model including conventional prognostic factors and health related quality of life. Results: Oncologists' estimates of EST were well calibrated (45% shorter than observed), imprecise (29% lived within 0.67 to 1.33 times observed), and moderately discriminative (Harrell C-statistic 0.62, P = 0.001). Scenarios derived from oncologists' estimates were remarkably accurate: 9% of patients died within a quarter of their EST, 12% lived longer than three times their EST and 57% lived within half to double their EST. Oncologists estimates of EST (in months) were independently significant predictors of overall survival (HR = 0.89, 95% CI 0.83 to 0.95, P = 0.001) in a Cox model including ECOG performance status, primary site, number of metastatic sites, neutrophil to lymphocyte ratio≥ 3, treatment group, age, and the EORTC QLQC30 physical function score. Conclusions: Oncologists' estimates of survival time were well calibrated, moderately discriminative, and independently significant predictors of overall survival. Best, worst and typical scenarios for survival based on simple multiples of the EST were remarkably accurate and would provide a useful method for estimating and explaining prognosis in this setting. Legal entity responsible for the study: NHMRC Clinical Trials Centre Funding: None Disclosure: N. Pavlakis: Consultant and/or advisory role, honoraria: Specialised Therapeutics, Pfizer, Novartis, Amgen, Bayer, BI, Roche, Sanofi Aventis, Merch-Serono, AstraZeneca. K. Sjoquist: Travel to ASCO funded by Merck-Serono in 2013. S. Snow: Consultant and/or advisory role: Celgene. Honoraria: Celgene, Merck, BMS, Roche, Novartis, BI, Amgen, Eli Lilly, Astra Zenenca. Research funding: Merck, BMS. A. Bonaventura, D.T. Ransom: Travel expenses: Ipsen. M. Khasraw: Consultant and/or advisory role: AbbVie, BMS, Eli Lilly. Research funding: AbbVie and STA. N. Singhal: Honoraria: Novartis, Pfizer. Travel expenses: Astra Zeneca. R. Burkes: Consultant and/or advisory role: Astra Zeneca, Merck Serono, Eli Lilly, Roche, Amgen. Honoraria: AstraZeneca, Merck Serono, Eli Lilly, Roche, Amgen. F. Lemay: Consultant and/or advisory role: Esperas Pharma Inc. Honoraria: Esperas Pharma Inc. All other authors have declared no conflicts of interest.

Oxaliplatin plays a major role in the treatment of colorectal cancer (crc), but is associated with the development of neuropathies. The main objective of the present prospective study was to estimate the proportion of participants with grade 1, 2, 3, or 4 peripheral sensory neuropathies according to the U.S. National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4) among crc patients treated with oxaliplatin (adjuvant or metastatic, folfox or xelox regimens) at the Centre hospitalier universitaire de Sherbrooke. Among the 57 patients so treated between May 2012 and April 2013, about 60% reported grade 2 neuropathy, at maximum, during treatment. About 25% of patients had to stop treatment because of neuropathies. In a subset of patients contacted approximately 22 months after treatment cessation, neuropathies persisted in 70%. Oxaliplatin-induced neuropathy affects a significant number of crc patients and can influence the course of treatment and outcomes.

Introduction: Metastatic colorectal cancer (mCRC) commonly affects elderly patients, who remain an understudied subset of patients. We analyzed the survival impact of the first and subsequent lines of chemotherapy in non-trial, ≥70 year-old patients with mCRC. Methods: Single Centre, retrospective analysis of mCRC patients, aged ≥70 years who were candidates to receive chemotherapy, between 2004 to 2012. Overall survival (OS) and progression-free survival (PFS) were estimated with Kaplan-Meier method. Multivariate analysis (MVA) was used to adjust for age, sex, ECOG, Charlson comorbidity index, dependency to activity of daily living, exposure to ≥1 doublet, capecitabine, or best supportive care (BSC). Results: 109 patients were identified; 29 elected for BSC and 80 received chemotherapy. Patients aged 70-74 (n = 34) and ≥75 years (n = 46) had similar OS: 19.7 [95%CI: 12.6-26.7] and 17.5 months [95%CI: 11.7-23.4], respectively (p = 0.822), despite less intensive chemotherapy in the older group. In MVA, age did not affect OS (HR 0.99 [95%CI: 0.92-1.05]), while ECOG ≥2 decreased likelihood of survival (HR 3.12 [95%CI: 1.87-5.76]) and exposure to ≥1 doublet was associated with improved survival (HR 0.33 [95%CI: 0.17-0.66]). First-line doublet trended toward improved OS compared with capecitabine (HR 0.66 [95%CI: 0.41-1.07]), while PFS was superior (HR 0.46 [95%CI: 0.26-0.84]). Exposure to the 3 cytotoxic chemotherapies was not associated with improved OS compared to one doublet (HR 0.77 [95%CI: 0.41-1.43]). Both arterial and venous thrombosis rate were 8% in patients who received bevacizumab. Conclusion: Non-trial ≥70-year patients benefit from first-line doublet chemotherapy. However, older patients of ≥75 years fared equally well despite less intensive overall treatment course, suggesting that not all elderly patients benefit from exposure to the three backbone chemotherapies. Prospective trial exploring the role of chemotherapy intensity would help optimized treatment in elderly patients.

BACKGROUND:Metastatic colorectal cancer (mcrc) commonly affects elderly people, an understudied subset of patients. We analyzed the survival impact of the first and subsequent lines of chemotherapy in eligible non-trial patients 70 years of age and older with mcrc treated between 2004 and 2012.METHODS:This single-centre retrospective analysis estimated overall survival (os) and progression-free survival (pfs) using the Kaplan-Meier method. Multivariate analysis was used to adjust for age, sex, Eastern Cooperative Oncology Group performance status, score on the Charlson comorbidity index, dependency in activities of daily living, and exposure to 1 or more chemotherapy doublets, capecitabine alone, or best supportive care (bsc).RESULTS:Of 109 patients identified, 29 elected bsc, and 80 received chemotherapy. In multivariate analysis, age was not associated with os [hazard ratio (hr): 0.99; 95% confidence interval (ci): 0.92 to 1.05], but a performance status of 2 or higher was associated with a decreased likelihood of survival (hr: 3.12; 95% ci: 1.87 to 5.76), and exposure to 1 or more doublets was associated with improved survival (hr: 0.33; 95% ci: 0.17 to 0.66). In univariate analysis, a trend toward improved os was observed for first-line doublet chemotherapy compared with capecitabine (hr: 0.66; 95% ci: 0.41 to 1.07), and pfs was superior (hr: 0.46; 95% ci: 0.26 to 0.84). Compared with exposure to 1 doublet, exposure to the 3 potential cytotoxic chemotherapies was not associated with improved os (hr: 0.77; 95% ci: 0.41 to 1.43). The incidence of neutropenia with first-line folfiri was 40%; the incidences of bevacizumab-related arterial and venous thrombosis were both 8%.CONCLUSIONS:Exposure to 1 or more doublet chemotherapies for mcrc was associated with better outcomes in non-trial patients 70 years of age and older. Elderly patients treated with palliative chemotherapy and bevacizumab should be monitored carefully for arterial and venous thrombotic events.

Introduction: Neoadjuvant chemoradiotherapy has a proven benefit in non-metastatic locally advanced rectal adenocarcinoma and adjuvant therapy is than often offered to patients. However, the benefits behind these treatments are not as clear for elderly patients (>75 years old) who are frequently frail and more likely to suffer complications. We conducted this study in our population to determine the outcome of patients who have had surgery for non-metastatic rectal adenocarcinoma with a particular focus on the elderly population. Methods: All patients who underwent surgery for non-metastatic rectal adenocarcinoma at the Centre Hospitalier Universitaire de Sherbrooke between 2000 and 2010 were included in this study. Patients who had concomitant neoplasia were excluded. Information about patient's comorbidities, tumour location and histology, staging and treatments (neoadjuvant and adjuvant) were retrospectively analyzed. Overall survival (OS) and disease free survival (DFS) were compared using Kaplan-Meier plots. Multivariate analysis was done with a Cox regression model. Results: A total of 319 patients were included and 86 were 75 years or older (27,0% from 75 to 89 years old). Five-year OS for all patients was 82% whilst five-year DFS for all patients was 75,5%. For people 75 years or older, the five-year OS was 66,8% and the five-year DFS was 69,2%. Comparing patients under and over 75 years old, five-year OS was better in younger patients (p < 0,001). However, the difference was not statistically significant at 3 years, and this worst outcome in elderly patients could be related to their reduced life expectancy. Five-year DFS was not significantly different in the two groups. Neoadjuvant chemoradiotherapy, when compared to no neoadjuvant treatment, was associated with a better OS (p = 0,044) particularly in patients with advanced tumors (T3 or T4 or N+). Older patients receiving neoadjuvant treatment had a similar outcome when compared to the younger ones. Adjuvant chemotherapy after neoadjuvant chemoradiotherapy and surgery was associated with a better DFS (p = 0,032). Once again, older patients receiving this treatment did not seem to present a significantly different outcome than their younger counterparts. Finally, we found that there was a statistically significant difference in the chosen treatments for people younger and older than 75 years old. Older patients tended to have less neoadjuvant chemoradiotherapy (22,1% VS 42,1% in younger people), less invasive surgeries like endoanal excision (8,9% VS 3,1% in younger people) and less adjuvant chemotherapy (26,3% VS 63,3% in younger people). Conclusion: Our study showed that the short-term prognosis (3 years) was similar when comparing patients over and under 75 years old. The difference in five-year OS between these two groups seemed to be more related to their different life expectancies. Elderly patients had a similar outcome when receiving neoadjuvant chemoradiotherapy or adjuvant chemotherapy. However, older patients (>75 y) were more likely to receive less intensive treatment. Figure: P-317

BackgroundHER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients. We conducted a study to compare HER2 expression between diagnostic biopsies (DBs) and surgical specimens (SSs) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression.Patients and methodsPathological specimens from biopsies of 228 patients operated on between 2004 and 2011 were collected. Two cohorts treated (n = 141) or not (n = 87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were carried out using immunohistochemistry (IHC) and colorimetric in situ hybridization (CISH). HER-2 overexpression (HER2+) was defined by a score 3+ in IHC, or 2+ with a positive CISH test, according to the specific HER2 scoring guidelines for GE-ADK.ResultsPaired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2+ rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2+ tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 6% of cases. When DB analyses were added to SS analyses, the relative increase in HER2+ cases was 13.5% (17.1% for patients with NAC and 23.5% for patients with histological response to NAC, versus 7.1% for patients without NAC, P = 0.4, NS). Differences between DB and SS HER2 expression could be explained by intratumoral heterogeneity and by a HER2 expression decrease in SS after NAC in responding patients possibly due to a higher chemosensitivity of HER2-positive clones.ConclusionThe determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, and particularly in previously NAC-responding patients.

Question: A 43-year-old man was evaluated for left tonsil swelling. He had been diagnosed 1 year earlier with a left-sided colon cancer revealed by altered bowel habits. At diagnosis, the preoperative evaluation did not show distant metastasis. The patient underwent left hemicolectomy, which showed a 4-cm, moderately differentiated adenocarcinoma invading the omentum (T4a). Thirty regional lymph nodes were positive for tumor extension (N2b). There was no microsatellite instability, and no KRAS mutations were found. The tumor was classified as stage IIIc disease based on the American Joint Committee on Cancer classification. The patient then received an oxaliplatin-based adjuvant chemotherapy (modified FOLFOX6) for 6 months. Three months after the end of chemotherapy, 2 pulmonary metastases were diagnosed, 1 in each lung. A positron emission tomographycomputed tomography also showed suspicious mediastinal adenopathy. An irinotecan-based treatment (FOLFIRI) with the addition of bevacizumab was then started. Three months later, the size of the lesions diminished and the patient underwent 2 successful lung surgeries to remove the metastases and the adenopathy. In the following months, the patient noticed a painless swelling of his left tonsil. He did not report symptoms of pharyngitis or tonsillitis. Physical examination revealed an ulcerated mass on the upper part of his left tonsil (Figure A, black arrow). There were no palpable ervical lymph nodes. The rest of the physical examination was unremarkable. The carcinoembryonic antigen level was 3.8. The omplete blood count was within normal limits. A biopsy of the left tonsil was performed. What is the diagnosis? Look on page 1625 for the answer and see the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information n submitting your favorite image to Clinical Challenges and Images in GI.