Investigating the feasibility of tumour molecular profiling in gastrointestinal malignancies in routine clinical practice.

Background: Targeted capture sequencing can potentially facilitate precision medicine, but the feasibility of this approach in gastrointestinal (GI) malignancies is unknown. Patients and methods: The FOrMAT (Feasibility of a Molecular Characterisation Approach to Treatment) study was a feasibility study enrolling patients with advanced GI malignancies from February 2014 to November 2015. Targeted capture sequencing (mainly using archival formalin-fixed paraffin-embedded diagnostic/resection samples) was carried out to detect mutations, copy number variations and translocations in up to 46 genes which had prognostic/predictive significance or were targets in current/upcoming clinical trials. Results: Of the 222 patients recruited, 215 patients (96.8%) had available tissue samples, 125 patients (56.3%) had ≥16 genes successfully sequenced and 136 patients (61.2%) had ≥1 genes successfully sequenced. Sample characteristics influenced the proportion of successfully sequenced samples, e.g. tumour type (colorectal 70.9%, biliary 52.6%, oesophagogastric 50.7%, pancreas 27.3%, P = 0.002), tumour cellularity (high versus low: 78.3% versus 13.3%, P ≤ 0.001), tumour content (high versus low: 78.6% versus 27.3%, P = 0.001) and type of sample (resection versus biopsy: 82.4% versus 47.6%, P ≤ 0.001). Currently, actionable alterations were detected in 90 (40.5%) of the 222 patients recruited (66% of the 136 patients sequenced) and 2 patients subsequently received a targeted therapy. The most frequently detected currently actionable alterations were mutations in KRAS, BRAF, TP53 and PIK3CA. For the 205 patients with archival samples, the median time to obtain sequencing results was 18.9 weeks, including a median of 4.9 weeks for sample retrieval and 5.1 weeks for sequencing. Conclusions: Targeted sequencing detected actionable alterations in formalin-fixed paraffin-embedded samples, but tissue characteristics are of critical importance in determining sequencing success. Routine molecular profiling of GI tumours outside of clinical trials is not an effective use of healthcare resources unless more targeted drugs become available. ClinicalTrials.gov identifier: NCT02112357.

Patupilone in patients with pretreated metastatic/locally recurrent colorectal cancer: results of the Phase II CINATRA trial.

BACKGROUND: Phase I trials of the microtubule stabilising agent patupilone showed encouraging tumour control and response rates in patients with metastatic colorectal cancer. METHODS: Patients with metastatic or locally recurrent colorectal cancer who had progressed following treatment with oxaliplatin, irinotecan and fluoropyrimidines were treated with patupilone (8 mg/m(2) IV every 3 weeks) in combination with dexamethasone or prednisolone. RESULTS: The trial was closed early after 29 patients had been enrolled due to concerns about toxicity. 20 patients (71.4 %) experienced at least one grade 3-5 toxicity, most commonly diarrhoea (14 patients), dehydration (7 patients) and lethargy (6 patients). The 12 week progression-free survival rate was 16.7 % (95 % CI 6.1 %-36.5 %) in the 24 patients with a 12 week scan available or who had died prior to the 12 week scan. No complete or partial responses were seen by 12 weeks. The median progression-free survival was 2.6 months (95 % CI 2.3-2.9) and median overall survival was 6.1 months (95 % CI 3.7-8.4). CONCLUSION: Patupilone given at a dose of 8 mg/m(2) IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre-treated colorectal cancer.

Simple nutritional intervention in patients with advanced cancers of the gastrointestinal tract, non-small cell lung cancers or mesothelioma and weight loss receiving chemotherapy: a randomised controlled trial.

BACKGROUND: Weight loss in patients with cancer is common and associated with a poorer survival and quality of life. Benefits from nutritional interventions are unclear. The present study assessed the effect of dietary advice and/or oral nutritional supplements on survival, nutritional endpoints and quality of life in patients with weight loss receiving palliative chemotherapy for gastrointestinal and non-small cell lung cancers or mesothelioma. METHODS: Participants were randomly assigned to receive no intervention, dietary advice, a nutritional supplement or dietary advice plus supplement before the start of chemotherapy. Patients were followed for 1 year. Survival, nutritional status and quality of life were assessed. RESULTS: In total, 256 men and 102 women (median age, 66 years; range 24-88 years) with gastrointestinal (n = 277) and lung (n = 81) cancers were recruited. Median (range) follow-up was 6 (0-49) months. One-year survival was 38.6% (95% confidence interval 33.3-43.9). No differences in survival, weight or quality of life between groups were seen. Patients surviving beyond 26 weeks experienced significant weight gain from baseline to 12 weeks, although this was independent of nutritional intervention. CONCLUSIONS: Simple nutritional interventions did not improve clinical or nutritional outcomes or quality of life. Weight gain predicted a longer survival but occurred independently of nutritional intervention.

Defining patient outcomes in stage IV colorectal cancer: a prospective study with baseline stratification according to disease resectability status.

BACKGROUND: Stage IV colorectal cancer encompasses a broad patient population in which both curative and palliative management strategies may be used. In a phase II study primarily designed to assess the efficacy of capecitabine and oxaliplatin, we were able to prospectively examine the outcomes of patients with stage IV colorectal cancer according to the baseline resectability status. METHODS: At enrolment, patients were stratified into three subgroups according to the resectability of liver disease and treatment intent: palliative chemotherapy (subgroup A), conversion therapy (subgroup B) or neoadjuvant therapy (subgroup C). All patients received chemotherapy with capecitabine 2000 mg m(-2) on days 1-14 and oxaliplatin 130 mg m(-2) on day 1 repeated every 3 weeks. Imaging was repeated every four cycles where feasible liver resection was undertaken after four or eight cycles of chemotherapy. RESULTS: Of 128 enrolled patients, 74, 22 and 32 were stratified into subgroups A, B and C, respectively. Attempt at curative liver resection was undertaken in 10 (45%) patients in subgroup B and 19 (59%) in subgroup C. The median overall survival was 14.6, 24.5 and 52.9 months in subgroups A, B and C, respectively. For patients in subgroups B and C who underwent an attempt at curative resection, 3-year progression-free survival was 10% in subgroup B and 37% for subgroup C. CONCLUSIONS: This prospective study shows the wide variation in outcome according to baseline resectability status and highlights the potential clinical value of a modified staging system to distinguish between these patient subgroups.

Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials.

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand- foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs.

Oxaliplatin and capecitabine chemotherapy for advanced colorectal cancer: a single institution's experience.

AIMS: To determine the efficacy of the combination of oxaliplatin and capecitabine in patients with advanced colorectal cancer. MATERIALS AND METHODS: A retrospective review of all patients with advanced colorectal cancer treated with oxaliplatin 130 mg/m2 on day 1 and capecitabine 2 g/m2 daily in two divided doses days 1-14 every 3 weeks, outside of a clinical trial at the Royal Marsden Hospital. Patients could have received any number of lines of previous treatment. RESULTS: Between September 2000 and March 2002, 47 patients were treated with the combination. Fifteen patients had not received previous chemotherapy for advanced disease, 10 had received one line of treatment and 21 had received two or more lines of previous treatment. The overall response rate was 27.6%, with a complete response rate of 2.1%. Overall response rates according to line of treatment were 33% for non pre-treated patients, 36% for second line and 19% for third and more lines. The median overall survival was 13.4 months and the median failure-free survival was 6.5 months. There were no treatment-related deaths and no grade 4 haematological toxicity. CONCLUSIONS: The combination of oxaliplatin and capecitabine is active in advanced colorectal cancer. It can result in down-staging of tumours to enable hepatic resection. In addition, it is a well-tolerated regimen.