Andrew Weaver

Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial

BACKGROUND Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. METHODS For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. FINDINGS Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00-5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5-78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7-80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89-1·25, p=0·54). The most common grade 3-4 adverse events were hand-foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27%] of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 [11%] vs 104 [11%]), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 [33%] vs 75 [8%]), proteinuria (197 [21%] vs 49 [5%]), and wound healing problems (30 [3%] vs 17 [2%]). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. INTERPRETATION The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used. FUNDING Roche.

Chemotherapy side-effect management using mobile phones

Colorectal cancer is a major health problem in developed countries, accounting for a significant proportion of deaths in the population. Advances in chemotherapy treatment have led to therapy being delivered in the home-setting, which presents challenges in ensuring that treatment-related side-effects are detected and reported to clinical staff in an appropriate time-frame. A telemedicine system has been developed using a mobile-phone platform to allow patients to complete symptom diaries which trigger alerts paged to their nurse in the event of severe side-effects. Six patients used this system for two cycles of oral chemotherapy. Two cases of moderate symptoms deteriorating to more severe conditions were observed, and individual self-care and treatment advice were presented to these patients.

Mobile health for drug dose optimisation

Mobile health monitoring in the management of long term conditions has potential benefits for patient care, especially when coupled with active adjustment of medication dosage. We report studies of patient-led self-titration of oral glucose lowering medication (OGLM) and insulin in type 2 diabetes, and dose adjustments (including dose increases) in oral chemotherapy for metastatic colorectal or breast cancer. Monitoring compliance was high in each case, and the feasibility of patients self-titrating OGLM or insulin following an agreed treatment plan was demonstrated. Chemotherapy dose increases supported by detailed toxicity profiles collected by phone have also been demonstrated.

3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.

Summary Background 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment. Methods The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing. Findings 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1–78·2) for the 3 month group and 77·1% (75·6–78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909–1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group). Interpretation In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care. Funding Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK.

‘I know I'm not invincible’: An interpretative phenomenological analysis of thyroid cancer in young people

Objective Thyroid cancer is one of the most common cancers affecting young people and carries an excellent prognosis. Little is known about the psychosocial issues that face young people diagnosed with a treatable cancer. This study explored how young people experienced diagnosis, treatment, and how they made sense of an experience which challenged their views on what it means to have cancer. Method Semi‐structured interviews were conducted with eight young people diagnosed with either papillary or follicular thyroid cancer, and analysed with interpretative phenomenological analysis (IPA). Results Two inter‐related aspects of their experience are discussed: (1) the range of feelings and emotions experienced including feeling disregarded, vulnerability, shock and isolation; (2) how they made sense of and ascribed meaning to their experience in the light of the unique nature of their cancer. A thread running throughout the findings highlights that this was a disruptive biographical experience. Conclusions Young people experienced a loss of youthful immunity which contrasted with a sense of growth and shift in life perspective. Having a highly treatable cancer was helpful in aiding them to reframe their situation positively but at the same time left them feeling dismissed over a lack of recognition that they had cancer. The young peoples’ experiences point to a need for increased understanding of this rare cancer, more effective communication from health care professionals and a greater understanding of the experiential impact of this disease on young people. Suggestions to improve the service provision to this patient group are provided. Statement of contribution What is already known on this subject? Differentiated thyroid cancer has an excellent prognosis. Quality of life of thyroid cancer has marginally been explored in the literature. Little is known on the support needs of young people diagnosed with thyroid cancer. What does this study add? Increased understanding of how young people make sense and cope with thyroid cancer despite the lack of support resources. Addressing illness perceptions through improved information support may aid coping and adjustment. Insight into the needs of young people diagnosed with thyroid cancer and recommendations on service improvements.