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The least toxic time (LTT) of irinotecan varied by up to 8 hours according to sex and genetic background in mice. The translational relevance was investigated within a randomized trial dataset, where no LTT stood out significantly in the whole population. 130 male and 63 female eligible patients with metastatic colorectal cancer were randomized to receive chronomodulated Irinotecan with peak delivery rate at 1 of 6 clock hours staggered by 4 hours on day 1, then fixed‐time chronomodulated Fluorouracil‐Leucovorin‐Oxaliplatin for 4 days, q3 weeks. The sex‐specific circadian characteristics of grade (G) 3‐4 toxicities were mapped with cosinor and time*sex interactions confirmed with Fisher's exact test. Baseline characteristics of male or female patients were similar in the six treatment groups. Main grade 3‐4 toxicities over six courses were diarrhea (males vs females, 39.2%; vs 46.0%), neutropenia (15.6% vs 15.0%), fatigue (11.5% vs 15.9%), and anorexia (10.0% vs 7.8%). They were reduced following irinotecan peak delivery in the morning for males, but in the afternoon for females, with statistically significant rhythms (P <.05 from cosinor) and sex*timing interactions (Fisher's exact test, diarrhea, P =.023; neutropenia, P =.015; fatigue, P =.062; anorexia, P =.032). Irinotecan timing was most critical for females, with grades 3‐4 ranging from 55.2% of the patients (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. The study results support irinotecan administration in the morning for males and in the afternoon for females, in order to minimize adverse events without impairing efficacy. [ABSTRACT FROM AUTHOR]

BACKGROUND Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS The proportions of patients in the 4 subgroups were comparable in both treatment arms ( P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup ( P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP ( P < .0001) and OS ( P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy. Cancer 2013;119:2564-2573. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Circadian clocks control cellular proliferation and drug metabolism over the 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (chronoFLO4) offered no survival benefit as compared with the non-time-stipulated FOLFOX2, in an international randomized trial involving patients with previously untreated metastatic colorectal cancer (EORTC 05963). The authors hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Patients with available data (N == 556) were categorized into three subgroups according to the worst grade (G) of neutropenia experienced during treatment. Distinct multivariate models with time-dependent covariates were constructed for each treatment schedule. Neutropenia incidence (all grades) was 33%% on chronoFLO4 and 61%% on FOLFOX2 ( p < .0001), and G3-4 were 7%% and 25%%, respectively ( p < .0001). Neutropenia was significantly more frequent in women than men on either schedule (FOLFOX2, p == .003; chronoFLO4, p == .04). Median survival was 20.7 mo in patients with G3-4 neutropenia versus 12.5 mo in neutropenia-free patients on FOLFOX2 ( p < .0001). Corresponding figures were 13.7 and 19.4 mo, respectively, on chronoFLO4 ( p == .36). Multivariate analysis confirmed occurrence of severe neutropenia independently predicted for better overall survival on FOLFOX2 (HR == 0.56; p == .015), and worse survival on chronoFLO4 (HR == 1.77, p == .06), with a significant interaction test ( p < .0001). Prediction of better survival in neutropenic patients on FOLFOX2 supports the administration of conventional chemotherapy near maximum tolerated dose. The opposite trend shown here for chronoFLO4 supports the novel concept of jointly optimized hematologic tolerability and efficacy through personalized circadian-timed therapy. (Author correspondence: ) [ABSTRACT FROM AUTHOR]

Background: The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting. Methods: Nine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period. Results: The most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists. Conclusions: Despite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable. [ABSTRACT FROM AUTHOR]

Background Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m 2 ) and triplet hepatic artery infusion (HAI) within European trial OPTILIV. Methods Irinotecan (180 mg/m 2 ), 5-fluorouracil (2800 mg/m 2 ) and oxaliplatin (85 mg/m 2 ) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models. Results Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33–76 years, with a median of 12 liver metastases (LMs) (2–50), involving five segments (1–8). Ten patients had a late response, and 31 patients had no response. Grade 3–4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation—odds ratio (OR): 6.0 (1.2–29.8; p = 0.029)—and LM diameter ≤57 mm—OR: 5.3 (1.1–25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection—OR: 11.8 (1.4–100.2; p = 0.024) and overall survival—hazard ratio: 0.39 (0.17–0.88; p = 0.023) in multivariate analyses. Conclusions Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers : EUDRACT 2007-004632-24 NCT00852228 . [ABSTRACT FROM AUTHOR]