Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become the standard of care for numerous malignancies. Emerging evidence suggests that the time of day (ToD) of ICI administration could impact the outcomes of patients with cancer. The consistency of ToD effects on ICI efficacy awaits initial evaluation. MATERIALS AND METHODS: This meta-analysis integrates progression-free survival (PFS) and overall survival (OS) data from studies with a defined 'cut-off' ToD. Hazard ratios (HRs) [95% confidence interval (CI)] of an earlier progression or death according to 'early' or 'late' ToD of ICIs were collected from each report and pooled. RESULTS: Thirteen studies involved 1663 patients (Eastern Cooperative Oncology Group performance status 0-1, 83%; males/females, 67%/33%) with non-small-cell lung cancer (47%), renal cell carcinoma (24%), melanoma (20%), urothelial cancer (5%), or esophageal carcinoma (4%). Most patients received anti-programmed cell death protein 1 or anti-programmed death-ligand 1 (98%), and a small proportion also received anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) (18%). ToD cut-offs were 13:00 or 14:00 (i.e. ICI median infusion time), for six studies, and 16:00 or 16:30 (i.e. reported threshold for weaker vaccination responses) for seven studies. Pooled analyses revealed that the early ToD groups had longer OS (HR 0.50, 95% CI 0.42-0.58; P < 0.00001) and PFS (HR 0.51, 95% CI 0.42-0.61; P < 0.00001) compared with the late ToD groups. CONCLUSIONS: Patients with selected metastatic cancers seemed to largely benefit from early ToD ICI infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking. Prospective randomized trials are needed to establish recommendations for optimal circadian timing of ICI-based cancer therapies.

Circadian and chemotherapy-related changes in urinary modified nucleosides excretion in patients with metastatic colorectal cancer.

Urinary levels of modified nucleosides reflect nucleic acids turnover and can serve as non-invasive biomarkers for monitoring tumour circadian dynamics, and treatment responses in patients with metastatic colorectal cancer. In 39 patients, median overnight urinary excretion of LC-HRMS determinations of pseudouridine, was ~ tenfold as large as those of 1-methylguanosine, 1-methyladenosine, or 4-acetylcytidine, and ~ 100-fold as large as those of adenosine and cytidine. An increase in any nucleoside excretion after chemotherapy anticipated plasma carcinoembryonic antigen progression 1-2 months later and was associated with poor survival. Ten fractionated urines were collected over 2-days in 29 patients. The median value of the rhythm-adjusted mean of urinary nucleoside excretion varied from 64.3 for pseudouridine down to 0.61 for cytidine. The rhythm amplitudes relative to the 24-h mean of 6 nucleoside excretions were associated with rest duration, supporting a tight link between nucleosides turnover and the rest-activity rhythm. Moreover, the amplitude of the 1-methylguanosine rhythm was correlated with the rest-activity dichotomy index, a significant predictor of survival outcome in prior studies. In conclusion, urinary excretion dynamics of modified nucleosides appeared useful for the characterization of the circadian control of cellular proliferation and for tracking early responses to treatments in colorectal cancer patients.

Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV.

BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228.

Feasibility of cetuximab given with a simplified schedule every 2 weeks in advanced colorectal cancer: a multicenter, retrospective analysis.

Cetuximab was approved using a weekly schedule, alone or in combination with chemotherapy (CT). However, many CT regimens in metastatic colorectal cancer (CRC) are delivered every 2 weeks (q2wks). Preliminary data suggested that a simplified schedule using cetuximab q2wks, 500 mg/m² would be equivalent to the standard weekly administration. Medical data of all patients with advanced CRC who received cetuximab q2wks were retrospectively collected and checked for consistency by an independent monitor in 4 European centers. Ninety-one patients were treated between 2005 and 2007 when the K-RAS mutational status of tumors was not determined routinely. They received a median of 4 (0-5) previous drugs, including previous weekly cetuximab in 38.5% of patients. Cetuximab q2wks was associated with an irinotecan-based regimen in 85.7% of patients. The median number of cetuximab administrations was 6 (1-23). Skin toxicity was observed in 68.2% of evaluable patients (grade 3 in 15%). Only one grade 1 allergy was reported. In the 84 patients beyond first-line therapy, response rate was 29.3%. The median progression-free survival was 3.0 months (range 2.2-3.8), and median overall survival was 9.0 months (range 6.2-11.8). Cetuximab q2wks appears safe and effective in heavily pretreated patients and convenient in combination with q2wks CT schedules.

Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer.

BACKGROUND: Few data are available from clinical trials for elderly patients receiving cetuximab. PATIENTS AND METHODS: The clinical data of consecutive patients aged > or =70 years given cetuximab for metastatic CRC were retrospectively captured from hospital pharmacy registries in seven centers. RESULTS: Fifty-six patients received cetuximab+/-with irinotecan. Median age was 76 years (70-84), 86% of patients were pretreated with fluoropyrimidines, irinotecan and oxaliplatin and 69.6% had documented resistance to irinotecan. Objective response rate was 21% (95% CI: 11-32%). The median progression-free survival was 4.4 months (95% CI: 3.0-5.7 months) and the median overall survival was 16.0 months (95% CI: 13.5-18.5 months). Skin rash occurred in 75% of the patients (11% grade 3) and diarrhea in 80% (20% grades 3-4). CONCLUSION: Tolerability of cetuximab was acceptable in elderly patients with pretreated metastatic CRC. Efficacy appeared similar to that observed in younger patients.