Hugo Ford

Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial

BACKGROUND Second-line chemotherapy for patients with oesophagogastric adenocarcinoma refractory to platinum and fluoropyrimidines has not shown benefits in health-related quality of life (HRQoL). We assessed whether the addition of docetaxel to active symptom control alone can improve survival and HRQoL for patients. METHODS For this open-labelled, multicentre trial, we recruited patients aged 18 years or older from 30 UK centres. Patients were eligible if they had an advanced, histologically confirmed adenocarcinoma of the oesophagus, oesophagogastric junction, or stomach that had progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. Patients could have an Eastern Cooperative Oncology Group performance status of 0-2. We randomly assigned patients using a central, computerised minimisation procedure to receive docetaxel plus active symptom control, or active symptom control alone (1:1; stratified by disease status, disease site, duration of response to previous chemotherapy, and performance status). Docetaxel was given at a dose of 75 mg/m(2) by intravenous infusion every 3 weeks for up to six cycles. The primary endpoint was overall survival, analysed by intention to treat. This is the report of the planned final analysis. This study is an International Standardised Randomised Controlled Trial, number ISRCTN13366390. FINDINGS Between April 21, 2008, and April 26, 2012, we recruited 168 patients, allocating 84 to each treatment group. After a median follow-up of 12 months [IQR 10-21]) and 161 (96%) deaths (80 in the docetaxel group, 81 in the active symptom control group), median overall survival in the docetaxel group was 5.2 months (95% CI 4.1-5.9) versus 3.6 months (3.3-4.4) in the active symptom control group (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.01). Docetaxel was associated with higher incidence of grade 3-4 neutropenia (12 [15%] patients vs no patients), infection (15 [19%] patients vs two [3%] patients), and febrile neutropenia (six [7%] patients vs no patients). Patients receiving docetaxel reported less pain (p=0.0008) and less nausea and vomiting (p=0.02) and constipation (p=0.02). Global HRQoL was similar between the groups (p=0.53). Disease specific HRQoL measures also showed benefits for docetaxel in reducing dysphagia (p=0.02) and abdominal pain (p=0.01). INTERPRETATION Our findings suggest that docetaxel can be recommended as an appropriate second-line treatment for patients with oesophagogastric adenocarcinoma that is refractory to treatment with platinum and fluoropyrimidine. FUNDING Cancer Research UK.

Gefitinib Versus Vinorelbine in Chemotherapy-Naïve Elderly Patients With Advanced Non–Small-Cell Lung Cancer (INVITE): A Randomized, Phase II Study

PURPOSE This phase II, open-label, parallel-group study compared gefitinib with vinorelbine in chemotherapy-naïve elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS Chemotherapy-naïve patients (age >or= 70 years) were randomly assigned to gefitinib (250 mg/d orally) or vinorelbine (30 mg/m(2) infusion on days 1 and 8 of a 21-day cycle). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and tolerability. Exploratory end points included epidermal growth factor receptor (EGFR) gene copy number by fluorescent in situ hybridization (FISH). RESULTS Patients were randomly assigned to gefitinib (n = 97) or to vinorelbine (n = 99). Hazard ratios (HR; gefitinib v vinorelbine) were 1.19 (95% CI, 0.85 to 1.65) for PFS and 0.98 (95% CI, 0.66 to 1.47) for OS. ORR and disease control rates were 3.1% (95% CI, 0.6 to 8.8) and 43.3% (for gefitinib) and 5.1% (95% CI, 1.7 to 11.4) and 53.5% (for vinorelbine), respectively. Overall QOL improvement and PSI rates were 24.3% and 36.6% (for gefitinib) and 10.9% and 31.0% (for vinorelbine), respectively. In the 54 patients who were EGFR FISH-positive, HRs were 3.13 (95% CI, 1.45 to 6.76) for PFS and 2.88 (95% CI, 1.21 to 6.83) for OS. There were fewer treatment-related grade 3 to 5 adverse events with gefitinib (12.8%) than with vinorelbine (41.7%). CONCLUSION There was no statistical difference between gefitinib and vinorelbine in efficacy in chemotherapy-naïve, unselected elderly patients with advanced NSCLC, but there was better tolerability with gefitinib. Individuals who were EGFR FISH-positive benefited more from vinorelbine than from gefitinib; this unexpected finding requires further study.

The Value of Routine Serum Carcino-Embryonic Antigen Measurement and Computed Tomography in the Surveillance of Patients After Adjuvant Chemotherapy for Colorectal Cancer

PURPOSE This analysis aims to evaluate routine carcino-embryonic antigen (CEA) and computed tomography (CT) of thorax, abdomen, and pelvis as part of protocol-specified follow-up policy for colorectal cancer (CRC). PATIENTS AND METHODS Patients with resected stage II and III CRC were randomly assigned to bolus fluorouracil/leucovorin or protracted venous infusion fluorouracil. Following completion of chemotherapy, patients were seen in clinic at regular intervals for 5 years. CEA was measured at each clinic visit, and CT of thorax, abdomen, and pelvis was performed at 12 and 24 months after commencement of chemotherapy. RESULTS Between 1993 and 1999, 530 patients were recruited. The median follow-up was 5.6 years. Disease relapses were observed in 154 patients. Relapses were detected by symptoms (n = 65), CEA (n = 45), CT (n = 49), and others (n = 9). Fourteen patients, whose relapses were detected by CT, had a concomitant elevation of CEA and were included in both groups. The CT-detected group had a better survival compared with the symptomatic group from the time of relapse (P =.0046). Thirty-three patients (21%) proceeded to potentially curative surgery for relapse and enjoyed a better survival than those who did not (P <.00001). For patients who underwent hepatic or pulmonary metastatic resection, 13 (26.5%) were in the CT group, eight (17.8%) in the CEA group, and only two (3.1%) in the symptomatic group (CT v symptomatic, P <.001; CEA v symptomatic, P =.015). CONCLUSION Surveillance CT and CEA are valuable components of postoperative follow-up in stage II and III colorectal cancer.

Chemotherapy vs supportive care alone for relapsed gastric, gastroesophageal junction, and oesophageal adenocarcinoma: a meta-analysis of patient-level data.

Background:Second-line chemotherapy treatment of patients with relapsed gastric and oesophageal cancers in comparison with supportive care (SC) alone has been supported by recent phase 3 clinical trials, but a meta-analysis of patient-level data is lacking.Methods:We searched Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Web of Science for phase 3 clinical trials that compared second-line chemotherapy with SC alone for gastric and oesophageal cancers. A meta-analysis of the comprehensive patient-level data from the three identified trials was performed.Results:A total of 410 patients with gastric (n=301), gastroesophageal junction (n=76), or oesophageal (n=33) adenocarcinoma were identified. In all, 154 patients received single-agent docetaxel and 84 patients received single-agent irinotecan, each with SC. SC alone was given to 172 patients. Chemotherapy significantly reduced the risk of death (hazard ratio (HR)=0.63, 95% confidence interval (CI)=0.51–0.77, P<0.0001). This effect was observed for treatment with docetaxel (HR=0.71, 95% CI=0.56–0.89, P=0.003) and irinotecan (HR=0.49, 95% CI=0.36–0.67, P<0.001). Overall survival (OS) benefit was greatest for patients who progressed 3–6 months following first-line chemotherapy (HR=0.39, 95% CI=0.26–0.59, P<0.0001). Performance status (PS) 0–1 compared with PS 2 (HR=0.66, 95% CI=0.46–0.94, P=0.02), locally advanced disease compared with metastatic disease (HR=0.41, 95% CI=0.25–0.67, P=0.0004) and older age (HR=0.94 per 5 years, 95% CI=0.90–0.99, P=0.01) were significant predictors of improved OS. Progression of disease during first-line treatment (HR=1.24, 95% CI=0.96–1.59) or within the first 3 months of completion of first-line treatment (HR=1.42, 95% CI=1.09–1.83) were predictors of an increased risk of death compared with progression between 3 and 6 months (P=0.03). Health-related quality of life outcomes were reported in only one of the three trials, precluding meta-analysis of these parameters.Conclusions:This meta-analysis of patient-level data confirms that second-line chemotherapy treatment results in significantly better OS compared with SC alone in patients with platinum and fluoropyrimidine refractory gastric and oesphageal adenocarcinoma. Health-related quality of life outcomes should be included in future trials in this setting.

Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma

Background:Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo.Methods:Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/− Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity.Results:The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules.Conclusions:Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.

A randomised, open-label phase II trial of afatinib versus cetuximab in patients with metastatic colorectal cancer

PURPOSE This randomised phase II trial aimed to compare efficacy of the irreversible ErbB family blocker, afatinib, with cetuximab in patients with KRAS wild-type metastatic colorectal adenocarcinoma (mCRC) with progression following oxaliplatin- and irinotecan-based regimens. Efficacy in patients with KRAS mutations was also evaluated. PATIENTS AND METHODS Patients with KRAS wild-type tumours were randomised 2:1 to afatinib (40 mg/day, increasing to 50 mg/day if minimal toxicity) or cetuximab weekly (400 mg/m2 loading dose, then 250 mg/m2/week) according to number of previous chemotherapy lines. All patients with KRAS-mutated tumours received afatinib. Primary end-points were objective response (OR) for the wild-type group and disease control for the KRAS-mutated group. Secondary end-points were progression-free survival (PFS) and overall survival (OS). RESULTS Patients with KRAS wild-type tumours (n=50) received afatinib (n=36) or cetuximab (n=14). Unconfirmed and confirmed ORs were 3% and 0% for afatinib versus 20% and 13% for cetuximab (odds ratio: 0.122 [P=0.0735] and <0.001, respectively). Median PFS was 46.0 and 144.5 days for afatinib and cetuximab, respectively. Median OS was 355 days with afatinib but not reached for cetuximab. In the KRAS-mutated group (n=41), five (12%) patients achieved confirmed disease control (stable disease; P=0.6394 [comparison versus 10%]); no ORs were reported. Median PFS and OS were 41.0 and 173days, respectively. Most frequent treatment-related adverse events were diarrhoea and rash across groups. CONCLUSIONS The efficacy of afatinib was inferior to cetuximab in patients with KRAS wild-type mCRC. In patients with KRAS-mutated tumours, disease control was modest with afatinib. Afatinib had a manageable safety profile.

Improved long-term survival after resection of colorectal liver metastases following staging with FDG positron emission tomography.

Actual long‐term survival of patients with colorectal liver metastases staged by PET CT has not been reported. Objectives were to investigate whether PET CT staging results in actual improved long‐term survival, to examine outcome in patients with ‘equivocal’ PET CT scans, and those excluded from hepatectomy by PET CT.

Docetaxel and its potential in the treatment of refractory esophagogastric adenocarcinoma

Adenocarcinomas of the esophagus and stomach are a major cause of cancer-related morbidity and mortality worldwide. For patients with advanced disease, first-line chemotherapy with platinum–fluoropyrimidine combinations prolongs survival, but inevitably the disease progresses with a median progression-free survival of approximately 6 months. At the time of progression, approximately 40–50% of patients remain fit and eligible for second-line treatment. Docetaxel has been extensively studied in this chemorefractory setting, mostly in small single arm studies, either as a single agent or in combination with platinum agents, fluoropyrimidines or anthracyclines. However, two randomized controlled trials published since 2012 have convincingly shown that treatment with docetaxel modestly prolongs survival compared with best supportive care alone. Moreover, treatment with docetaxel is associated with relief from cancer-related constitutional and gastrointestinal symptoms with manageable, predominantly haematological, toxicity. Therefore, it represents a valuable treatment option for patients with relapsed esophagogastric cancer. Nevertheless, in view of the short survival time for the majority of these patients, further research is necessary to identify, on the one hand, combinations with targeted agents that will further improve outcomes and, on the other, biomarkers that will allow selection of those patients most likely to benefit.

Gefitinib for oesophageal cancer: a cog in need of a wheel?

790 www.thelancet.com/oncology Vol 15 July 2014 Oesophageal cancer remains a deadly cancer, with a 5-year survival of 13%. Worldwide, squamous-cell carcinoma predominates. However, in western populations squamous tumours are now rarer than adenocarcinoma, because of increasing obesity and refl ux disease. After failure of platinum and fl uoropyrimidine, second-line chemotherapy provides a survival advantage in oesophagogastric adeno carcinoma, but evidence for second-line therapy in squamous cancer is sparse. In The Lancet Oncology, Susan Dutton and colleagues present the results of the COG study, the largest second-line trial in oesophageal cancer. It is a major addition to the literature as the fi rst such study to include a large number of patients with squamouscell carcinoma. The trial included 341 patients with adenocarcinoma (including 97 patients with tumours of the oesophagogastric junction) and 106 patients with squamous-cell cancer. Patients were randomly assigned to receive either placebo or gefi tinib, an EGFR tyrosine kinase inhibitor. The investigators should be particularly commended for the collection of patient-reported outcomes, which contribute greatly to the results. Gefi tinib did not show improvement in overall survival compared with placebo (3·73 months, 95% CI 3·23–4·50, for gefi tinib vs 3·67 months, 2·97–4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74–1·09, p=0·29), but progression-free survival was marginally improved (1·57 months, 95% CI 1·23–1·90, vs 1·17 months, 95% CI 1·07–1·37; HR 0·80, 95% CI 0·66–0·96, p=0·020) and odynophagia was improved with gefi tinib (adjusted mean diff erence –8·61, 95% CI –14·49 to –2·73; p=0·004). Although objective responses were rare, a few patients had durable benefi t from treatment: eight patients (4%) remained progression free after 12 months on gefi tinib. Despite these data, the study is unlikely to lead to further development of gefi tinib for this indication, because the level of activity does not pass conventional criteria for registration. However the results do point to the possible existence of a subset of patients who might benefi t disproportionately from the use of secondline gefi tinib if they could be identifi ed, and if the translational analysis of the samples collected in the COG study (TRANSCOG) were to identify a sensitive subgroup, gefi tinib would be a much more plausible therapy. Increasingly biomarker identifi cation is an integral part of the development of new anticancer drugs. In early trials of EGFR inhibitors for non-small-cell lung cancer, responses were low, but subsequent work identifi ed specifi c mutations in EGFR, conferring increased sensitivity, which became a clinically useful biomarker. The response rate to EGFR tyrosine kinase inhibitors is as high as 70% in patients with an inframe exon 19 deletion or exon 21 Leu858Arg point mutation, with associated improvements in survival. Similarly, many patients with colorectal cancer were treated with EGFR monoclonal antibodies in clinical trials before retrospective analyses showed that the 60% of patients whose tumours carry mutations in KRAS, NRAS, BRAF, or PIK3CA exon 20 derive little benefi t from such treatment. While preclinical modelling remains imperfect, we can still treat unselected patients in clinical trials such as the COG study and hope subsequently to identify potentially sensitive or resistant subsets, but both for researchers and for patients identifi cation of such cohorts before they are tested in the clinic is infi nitely preferable and more cost-eff ective. Were the investigators right to include both squamous-cell cancer and adenocarcinoma? They argue that little was known of the diff erences between these entities when the trial was conceived, and the results from COG suggest that the benefi t of gefi tinib was not signifi cantly diff erent between the phenotypes. There are biological similarities—for instance, the high incidence of TP53 mutations and amplifi cation or gain in function of EGFR. However comparative analysis has confi rmed that they also have some very diff erent characteristics. In the COG study, baseline stratifi cation by disease type might therefore have been desirable. In future, though, patients are likely to be selected for targeted therapy by the presence or absence of specifi c molecular characteristics rather than by morphological phenotype or even site of origin. Where does this leave patients? For patients with adenocarcinoma progressing after initial treatment the evidence still favours second-line chemotherapy with a taxane or irinotecan, and the addition of ramucirumab, an antibody to VEGF receptor 2, might add further benefi t. However for squamous carcinoma the evidence is much less clear. Fit patients might be off ered Gefi tinib for oesophageal cancer: a cog in need of a wheel?

The role of multi-disciplinary teams in decision-making for patients with recurrent malignant disease.

Background: It is mandatory in many countries for decisions for all new patients with cancer to be made within multi-disciplinary teams (MDTs). Whether patients with disease recurrence should also routinely be discussed by the MDT is unknown. Aim: This study investigated the role of an upper gastro intestinal (UGI) MDT in decision-making for patients with disease recurrence. Design: A retrospective review of prospectively kept MDT records (2010 to 2011) was performed identifying patients discussed with recurrence of oesophagogastric cancer. Information was recorded about: i) why an MDT referral was made, ii) who made the referral and iii) the final MDT recommendation. Implementation of the MDT recommendation was also examined. Participants: All patients discussed with recurrence of cancer at a central UGI cancer MDT were included. Results: During the study 54 MDT meetings included discussions regarding 304 new patients and 29 with disease recurrence. Referrals to the MDT for patients with recurrence came from outpatient clinics (n=19, 65.5%) or following emergency admission (n=10). Most referrals were made by the surgical team (n=25, 86.2%). MDT recommendations were best supportive care (n=11, 37.9%), palliative chemotherapy (n=9, 31.0%), stent (n=5, 17.2%), palliative radiotherapy (n=3, 10.3%) and further surgery (n=1, 3.4%), with 25 (86.2%) of these implemented. Conclusion: UGI MDTs focus on new referrals and only a small proportion of patients with recurrent disease are re-discussed. Many patients go on to receive further treatments. Whether such patients are optimally managed within the standard MDT is uncertain, however, and warrants further consideration.