First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial.

BACKGROUND: We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. METHODS: Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. RESULTS: Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. CONCLUSIONS: The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).

Chemotherapy reduces long-term quality of life in recurrence-free colon cancer survivors (LaTE study)-a nationwide inverse probability of treatment-weighted registry-based cohort study and survey.

AIM: Stage III colon cancer is routinely treated with adjuvant chemotherapy, which causes significant short-term morbidity. Its effect on long-term quality of life (QoL) is poorly investigated. The aim of this study was to investigate long-term QoL after curative treatment for colon cancer and explore the impact of chemotherapy on general and disease-specific QoL. METHOD: All patients aged under 75 years operated on for colon cancer between 30 September 2007 and 1 October 2019 were identified by the Cancer Registry of Norway. Exclusion criteria were distant metastasis, recurrence, dementia and rectal/rectosigmoid cancer operation. The primary outcome measure was Gastrointestinal Quality of Life Index (GIQLI). Secondary outcome measures included the Short Form Health Survey (SF-36). To achieve balanced groups when assessing differences in outcome measures the analyses were weighted by inverse probability weights based on a multiple logistic regression model with prechosen confounders. RESULTS: A total of 8627 patients were invited and 3109 responded (36% response rate). After exclusions 3025 patients were included, of whom 1148 (38%) had received adjuvant chemotherapy and 1877 (62%) had surgery alone, with mean follow-up of 75.5 versus 74.5 months, respectively. The GIQLI differed significantly between the groups [mean 111.0 (SD 18.4) vs. 115.6 (SD 17.8), respectively; mean difference: -4.6 (95% CI -5.9; -3.2); p < 0.001]. Those with the highest neurotoxicity exhibited the lowest GIQLI. The adjuvant chemotherapy group scored significantly lower in six of eight SF-36 domains compared with the surgery alone group. The main differences were found in social, physical and emotional function. CONCLUSION: Long-term QoL was significantly lower in patients who received adjuvant chemotherapy than in patients who did not. Neurotoxicity was closely related to reduced QoL in these patients. The low response rate limits the generalizability of the results.

Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer.

BACKGROUND: Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility. METHODS: Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint. RESULTS: Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3-19.7) and 3.9 months (95% CI, 2.3-5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9-14.7) for control arm patients (N = 31). CONCLUSIONS: Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).

Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade.

The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

Providing information about late effects after childhood cancer: lymphoma survivors' preferences for what, how and when.

OBJECTIVE: Childhood cancer survivors need information about risks of late effects to manage their health. We studied how and when adult, long-term survivors prefer to receive information about late effects. METHODS: Five focus-groups with adult survivors of childhood lymphomas who had completed routine follow-up care and participated in a preceding follow-up study (n = 34, 19 females, mean age = 39). We used thematic analysis to identify themes regarding providing late effects information. RESULTS: The survivors wanted information about late effects (symptoms, prevention and treatment), lifestyle and social security rights. Information should be tailored, carefully timed, given "face-to-face" and in written format. Many expressed ambivalence regarding receiving information as adolescents, but it was seen as essential "to know" once a late effect occurred. A "re-information" consultation about late effects around age 25 was suggested as beneficial. CONCLUSION: Although ambivalent, all survivors wanted information about late effects. They preferred individualized information, disclosed "step-by-step" and in a "re-information consultation" when reaching young adulthood. PRACTICE IMPLICATIONS: Providing information about late effects should be an on-going process across the cancer care trajectory. (Re-)Informing survivors when older would enhance their understanding of their health risks and could aid better health self-management beyond completion of follow-up care.