Search

The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin with intravenous cetuximab has safely achieved prolonged survival in colorectal cancer patients with extensive liver metastases and prior treatment. Systemic exposure to the drugs or their main metabolites was determined during the first course of chronomodulated triplet HAI in 11 patients and related to toxicities after one or three courses. Consistent trends were found between the area under the plasma concentration-time curve (AUC) values of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN38; a bioactive metabolite), total oxaliplatin and platinum ultrafiltrate (P-UF), on the one hand, and subsequent leukopenia severity, on the other hand. Moreover, the maximum plasma concentration (C max ) and the AUC of P-UF significantly predicted grades of diarrhoea (p = 0.004 and 0.017, respectively) and anaemia (p = 0.001 and 0.008, respectively) after the first course. Systemic drug exposure helps explain both the adverse events and the low rate of extrahepatic progression-a usual drawback of HAI chemotherapy-thus supporting upfront testing of the regimen. Systems optimization of chronomodulated HAI delivery could further reduce adverse events.

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.

Studies in animals synchronized with an alternation of 12 h of light and 12 h of darkness have showed that hematological and systemic toxicities could be reduced if vinorelbine were administered 19 or 23 hours after light onset (HALO), corresponding to 17:00 and 21:00 h in diurnally active humans. This trial aimed to define the least toxic time of vinorelbine administration in metastatic breast cancer patients. Initially, the study treatment consisted of three courses of vinorelbine of 30 mg/m(2)/d on D1 and D6 and chronomodulated 5-fluorouracil of 850 mg/m(2) from D2 to D5 every 21 days. Ninety metastatic breast cancer patients were randomized to receive vinorelbine at one of the eight possible dosing times. Further to the recommendations of the Independent Data Monitoring Committee, the vinorelbine dose was reduced to 25 mg/m(2)/d midway through the study. The primary objective of the study was detection of the least toxic time based on the incidence of grade 3-4 (G3-4) neutropenia. To show a significant result, the 90% confidence interval width of the least toxic time had to be<6 h. The least toxic time detection based on the incidence of other toxicities was also analyzed. The time of least drug toxic was estimated using a logistic regression model assuming that the logit transformation of the toxicity rate follows a sinusoidal distribution over 24 h. The bootstrap technique was used to obtain the 90% confidence interval. The least toxic time of G3-4 neutropenia was observed at 21:00 h with a non-significant 90% CI. Secondary endpoint analyses indicated the least toxic time could differ when based on other toxicity parameters (e.g., a significant least toxic time of 17:00 h was observed for G3-4 leucopenia), in agreement with animal data. The least toxic time of 10:30 h was estimated for any G3-4 gastrointestinal toxicity. This results of this study do not allow us to recommend an optimal time for vinorelbine administration. It has highlighted, however, the inherent methodological difficulties in the conduct of such a trial in the human setting. It indicates that future optimal time-finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity. The randomized optimal time-finding design may be used to identify the best time of chemotherapy administration.

Background: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes.Methods: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1).Results: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763).Conclusion: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies. [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]

Abstract: The circadian timing system controls drug metabolism and cellular proliferation over the 24 h through molecular clocks in each cell, circadian physiology, and the suprachiasmatic nuclei — a hypothalamic pacemaker clock that coordinates circadian rhythms. As a result, both the toxicity and efficacy of over 30 anticancer agents vary by more than 50% as a function of dosing time in experimental models. The circadian timing system also down-regulates malignant growth in experimental models and possibly in cancer patients. Programmable-in-time infusion pumps and rhythmic physiology monitoring devices have made possible the application of chronotherapeutics to more than 2000 cancer patients without hospitalization. This strategy first revealed the antitumor efficacy of oxaliplatin against colorectal cancer. In this disease, international clinical trials have shown a five-fold improvement in patient tolerability and near doubling of antitumor activity through the chronomodulated, in comparison to constant-rate, delivery of oxaliplatin and 5-fluorouracil–leucovorin. Here, the relevance of the peak time, with reference to circadian rhythms, of the chemotherapeutic delivery of these cancer medications for achieving best tolerability was investigated in 114 patients with metastatic colorectal cancer and in 45 patients with non-small cell lung cancer. The incidence of severe adverse events varied up to five-fold as a function of the choice of when during the 24 h the peak dose of the medications was timed. The optimal chronomodulated schedules corresponded to peak delivery rates at 1 a.m. or 4 a.m. for 5-fluorouracil–leucovorin, at 1 p.m. or 4 p.m. for oxaliplatin, and at 4 p.m. for carboplatin. Sex of patient was an important determinant of drug schedule tolerability. This finding is consistent with recent results from a chronotherapy trial involving 554 patients with metastatic colorectal cancer, where sex also predicted survival outcome from chronotherapy, but not conventional drug delivery. Ongoing translational studies, mathematical modeling, and technology developments are further paving the way for tailoring cancer chronotherapeutics to the main rhythmic characteristics of the individual patient. Targeting therapeutic delivery to the dynamics of the cross-talk between the circadian clock, the cell division cycle, and pharmacology pathways represents a new challenge to concurrently improve the quality of life and survival of cancer patients through personalized cancer chronotherapeutics. [Copyright &y& Elsevier]

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]

Background Epirubicin-based chemotherapy improves the outcome of early breast cancer (BC) patients. However, cardiotoxicity remains an important side effect. Methods We re-consented node-positive BC patients enrolled in a phase III trial between 1988 and 1996 which compared six cycles of oral cyclophosphamide, methotrexate, fluorouracil (CMF) versus two epirubicin–cyclophosphamide regimens differing by the anthracycline cumulative dose [standard-dose epirubicin and cyclophosphamide (SDE) (8 × 60 mg/m 2 ) and higher-dose epirubicin and cyclophosphamide (HDE) (8 × 100 mg/m 2 )]. Eligible patients were those who were alive and free of disease and had no contra-indications to the proposed tests (cardiac evaluation). Cardiotoxicity was defined as asymptomatic systolic dysfunction (left ventricular ejection fraction (LVEF) < 50%, New York Heart Association (NYHA) Class I) or symptomatic heart failure (NYHA Class II–IV). Differences in cardiotoxicity between CMF and SDE/HDE were assessed using chi-square and Fisher Exact tests for binary variables and t -test and Wilcoxon test for continuous variables. Results Among the 777 patients, 20 cases of CHF were reported (CMF = 1, SDE = 5, HDE = 14; p < 0.001). Between September 2010 and June 2013, 82 patients (30%) out of 269 eligible patients accepted to participate in this substudy. Median follow-up was 18 years (range 15–24). Epirubicin-treated patients had significantly higher heart rate, more abnormal echocardiograms and LVEF by magnetic resonance imaging (MRI) compared to CMF-treated ones. A trend towards higher BNP was also observed in the SDE/HDE group ( P = 0.08). No differences were observed in LVEF assessed by echocardiogram or troponin T levels. Conclusions Participation rate in this substudy was lower than expected highlighting the complexity of re-calling patients several years after the initial BC diagnosis. After 18 years, epirubicin-treated patients had a lower LVEF by MRI, more abnormal echocardiograms, higher heart rates compared to patients treated with CMF. However, no major delayed cardiotoxicity was observed. [ABSTRACT FROM AUTHOR]