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In lymph-node-positive colorectal cancer, surgical resection alone might not be curative, and additional systemic chemotherapy might be indicated. Reported 5-year survival rates after surgical resection alone are 99% for stage I and 68% 83% for stage II, whereas in patients with stage III, lymph-node-positive disease a 5-year survival of 45% 65% was seen (Brierley et al., 2016). To determine who might benefit from additional systemic adjuvant therapy, an adequate assessment of the risk of relapse is essential. Next to the disease stage, this risk of relapse can be determined by clinicopathological features of the tumor, molecular markers, and DNA mismatch repair (dMMR)/microsatellite instability (MSI) status. The presence of circulating tumor cells and circulating tumor DNA (ctDNA) postresection can be a potential prognostic biomarker and is currently the subject of ongoing trials (Tie et al., 2019). Different chemotherapy regimens, mainly 5-fluorouracil(FU)-based with or without additional oxaliplatin, and treatment durations have been proposed for adjuvant treatment of stage II and stage III disease. In this chapter, we will discuss risk assessment of stage II disease, selection and duration of a chemotherapy regimen in stage II and III, nonchemotherapy-based interventions, and use of adjuvant treatment in specific populations. Finally, we will review neoadjuvant approaches and future perspectives for adjuvant therapy in colorectal cancer.

Item does not contain fulltext BACKGROUND: Both perioperative chemotherapy and postoperative chemoradiotherapy improve survival in patients with resectable gastric cancer from Europe and North America. To our knowledge, these treatment strategies have not been investigated in a head to head comparison. We aimed to compare perioperative chemotherapy with preoperative chemotherapy and postoperative chemoradiotherapy in patients with resectable gastric adenocarcinoma. METHODS: In this investigator-initiated, open-label, randomised phase 3 trial, we enrolled patients aged 18 years or older who had stage IB- IVA resectable gastric or gastro-oesophageal adenocarcinoma (as defined by the American Joint Committee on Cancer, sixth edition), with a WHO performance status of 0 or 1, and adequate cardiac, bone marrow, liver, and kidney function. Patients were enrolled from 56 hospitals in the Netherlands, Sweden, and Denmark, and were randomly assigned (1:1) with a computerised minimisation programme with a random element to either perioperative chemotherapy (chemotherapy group) or preoperative chemotherapy with postoperative chemoradiotherapy (chemoradiotherapy group). Randomisation was done before patients were given any preoperative chemotherapy treatment and was stratified by histological subtype, tumour localisation, and hospital. Patients and investigators were not masked to treatment allocation. Surgery consisted of a radical resection of the primary tumour and at least a D1+ lymph node dissection. Postoperative treatment started within 4-12 weeks after surgery. Chemotherapy consisted of three preoperative 21-day cycles and three postoperative cycles of intravenous epirubicin (50 mg/m(2) on day 1), cisplatin (60 mg/m(2) on day 1) or oxaliplatin (130 mg/m(2) on day 1), and capecitabine (1000 mg/m(2) orally as tablets twice daily for 14 days in combination with epirubicin and cisplatin, or 625 mg/m(2) orally as tablets twice daily for 21 days in combination with epirubicin and oxaliplatin), received once every three weeks. Chemoradiotherapy consisted of 45 Gy in 25 fractions of 1.8 Gy, for 5 weeks, five daily fractions per week, combined with capecitabine (575 mg/m(2) orally twice daily on radiotherapy days) and cisplatin (20 mg/m(2) intravenously on day 1 of each 5 weeks of radiation treatment). The primary endpoint was overall survival, analysed by intention-to-treat. The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02. FINDINGS: Between Jan 11, 2007, and April 17, 2015, 788 patients were enrolled and randomly assigned to chemotherapy (n=393) or chemoradiotherapy (n=395). After preoperative chemotherapy, 372 (95%) of 393 patients in the chemotherapy group and 369 (93%) of 395 patients in the chemoradiotherapy group proceeded to surgery, with a potentially curative resection done in 310 (79%) of 393 patients in the chemotherapy group and 326 (83%) of 395 in the chemoradiotherapy group. Postoperatively, 233 (59%) of 393 patients started chemotherapy and 245 (62%) of 395 started chemoradiotherapy. At a median follow-up of 61.4 months (IQR 43.3-82.8), median overall survival was 43 months (95% CI 31-57) in the chemotherapy group and 37 months (30-48) in the chemoradiotherapy group (hazard ratio from stratified analysis 1.01 (95% CI 0.84-1.22; p=0.90). After preoperative chemotherapy, in the total safety population of 781 patients (assessed together), there were 368 (47%) grade 3 adverse events; 130 (17%) grade 4 adverse events, and 13 (2%) deaths. Causes of death during preoperative treatment were diarrhoea (n=2), dihydropyrimidine deficiency (n=1), sudden death (n=1), cardiovascular events (n=8), and functional bowel obstruction (n=1). During postoperative treatment, grade 3 and 4 adverse events occurred in 113 (48%) and 22 (9%) of 233 patients in the chemotherapy group, respectively, and in 101 (41%) and ten (4%) of 245 patients in the chemoradiotherapy group, respectively. Non-febrile neutropenia occurred more frequently during postoperative chemotherapy (79 [34%] of 233) than during postoperative chemoradiotherapy (11 [4%] of 245). No deaths were observed during postoperative treatment. INTERPRETATION: Postoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery. In view of the poor postoperative patient compliance in both treatment groups, future studies should focus on optimising preoperative treatment strategies. FUNDING: Dutch Cancer Society, Dutch Colorectal Cancer Group, and Hoffmann-La Roche.

Background Survival of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP-group) compared with trastuzumab-naive patients (TN-group) in order to investigate the possibility of trastuzumab resistance. Patients and methods Patients treated with first-line HER2-targeted-containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP-group. OS and TNT were estimated using Kaplan-Meier curves and multivariable Cox proportional hazards models. Results Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP-group and 387 were in the TN-group. Median OS and TNT were significantly worse in the TP-group compared with the TN-group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15-2.96], p = .01 and 7 vs. 13 months, adjusted HR 1.65 [1.06-2.58], p = .03) after adjustment for age, year of diagnosis, disease-free interval, hormone receptor status, metastatic site, and cytotoxic regimens. Conclusion First-line trastuzumab-containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab-naive patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2-targeted treatment lines need further investigation. Implications for practice Evidence on the efficacy of palliative trastuzumab-based therapy after failure of trastuzumab in the adjuvant setting is limited because of a minority of patients treated with adjuvant trastuzumab in clinical trials. In this study, less clinical benefit of palliative trastuzumab-based therapy was observed in patients relapsing after adjuvant trastuzumab compared with no adjuvant trastuzumab treatment. Subgroup analyses and multivariable analyses revealed that this was independent of possible confounding factors, including adjuvant taxane-treatment. This might suggest a clinically meaningful impaired efficacy of trastuzumab after previous, in this case adjuvant, trastuzumab therapy. These results could have implications for treatment decision-making after short progression-free intervals on trastuzumab-containing regimens in the palliative setting.