Search

One hundred and ten consecutive patients suffering from a colorectal cancer received chronotherapy infused over two days every two weeks. Each course comported 5 FU 3g/m(2), folinic acid (600 mg/m(2) - l. form or 1200 mg/m(2)--racemic form) and oxaliplatin (85/mg/m(2)--adjuvant indication or 100mg/m(2)--palliative indication). According to chronobiological concepts, 5 FU and folinic acid were infused from 10 pm to 10 am with a peak at 4 am while oxaliplatin was delivered from 10 am to 10 pm with a peak at 4 pm. The overall tolerance was excellent with a maximum of 17% patients experiencing a grade 3 toxicity. The toxicity was higher in women, in older patients (>=70) or in case of flat infusion. In adjuvant situation (60 cases), progression free and overall survivals established respectively at 76% (42+months) and 88% (45+months). Fifty-two percent response rate were recorded within the palliative group (50 cases) with an overall 68% disease control. Median progression free survival was seven months but median survival was not attained at 31+ months. Thirty percent patients could benefit from a curative surgery after chemotherapy. Older patients (>=70) experienced worsened survival. In conclusion, we think that our chrono-FOLFOX 2-12 should be proposed as standard treatment for colorectal cancer patients., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Thirty-six metastatic colorectal cancer patients received every 2 weeks, as first- (17) or second-line (19) treatment a combined chronotherapy with CPT-11 (infused at day 1 from 2 to 8 a.m.; peak at 5 a.m.), given with 5FU (700 mg/m(2) per day; days 2-5) and folinic acid (300 mg/m(2) per day; days 2-5) both infused from 10 p.m. to 10 a.m. with a peak at 4 a.m., and carboplatin (40 mg/m(2) per day; days 2-5; infused from 10 a.m. to 10 p.m.; peak at 4 p.m.). The doses of CPT11 could be easily pushed from 120 to 180 mg/m(2) in successive cohorts in the phase I part of the study (11 cases). Twenty-five patients were then treated in the phase II of the trial. The overall toxicity was mild leading to dose-reductions in only 11-13% courses. The tumoral activity was interesting with 81% responses and 94% tumour control. Also prolonged survivals were recorded with 8.8 months of progression free and 15.6 months overall survivals. More prolonged survivals were observed in chemotherapy naive patients. Seven patients (19%) could be reoperated from their residual disease., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Seventy-two patients suffering from a metastatic colorectal cancer received, as first line treatment, a combination chronotherapy with 5-FU and folinic acid (infused from 10 pm to 10 am with a peak at 4 am, respectively at doses of 700 and 300 mg/m2 per day) and carboplatin (infused at the dose of 40 mg/m2 per day from 10 am to 10 pm with a peak at 4 pm). The courses of four days were repeated every two weeks. A major tumoral response was observed in 60% cases (68% in those not previously treated with adjuvant chemotherapy). The median times to progression and overall survival established at 11 and 27 months. The clinical (grades 3-4 in maximum 5% cases) and hematological (grades 3-4 in maximum 10-29% cases) toxicities were quite limited. Our observations suggest the interest to incorporate carboplatin in the combined infusional treatment of colorectal cancer.

Seventeen colorectal cancer patients received as first (12 cases) or second line (5 cases) treatment a combined chronotherapy with CPT 11 (infused at day 1 from 2 to 8 am; peak at 5 am), given with 5 FU (700 mg/m2 per day ; days 2-5) and folinic acid (300 mg/m2 per day, days 2-5) both infused from 10 pm to 10 am with a peak at 4 am, and carboplatin (40 mg/m3/day - days 2-5 ; infused from 10 am to 10 pm - peak at 4 pm). The doses of CPT 11 could be easily increased from 120 up to 180 mg/m2 in successive cohorts of four patients through acceptable toxicity. Thus, five patients have already been treated in the phase II part of the trial. An interesting tumoral outcome has been observed: 88% major responses with no progression; median time to progression: nine months and median survival: 19.7 months.

366 patients fully resected from a Dukes B2 or C colorectal cancer were randomised to receive 6 courses of systemic chemotherapy comprising either 5-fluorouracil (5 FU) alone (arm A: 450 mg/m2/day-5/21 days) or combined folinic acid (FOL) and 5 FU (arm B: respectively 200 mg/m2 racemic form or 100 mg/m2-l-form and 370 mg/m2/day-5/21 days). 173 patients had also been initially randomised to receive one course of intraportal chemotherapy just after surgery or no portal treatment. Oral levamisole (150 mg/day; 3 days every other week) was given to all patients for one year. A significantly higher incidence of leuco-granulocytopenia was observed in the arm A (5 FU alone) inducing more frequent dose delays and adaptations as well as levamisole's withdrawal. Then dose-intensities and dose-intensity products were lower in this arm but the dose intensity expressed in mg/m2/week remained higher (631 +/- 107 vs 557 +/- 99; p < 0.001). The median follow-up in the study was 4.5 years. Relapse free (RFS) and overall survivals (OAS) were prolonged in the 5 FU alone group peculiarly in those patients who had not been randomised for portal treatment. Curves diverged progressively with longer follows-up (at 8 years; RFS in arm A: 67-71% vs 59-53% in arm B; OAS in arm A: 72-74% vs 56-46% in arm B). Patients suffering from a colon or a Dukes C cancer benefited the most from the treatment with 5 FU alone. The results are discussed in the light of other recent adjuvant trials. Well dosed 5 FU over a short period of time without folinic acid may be a valuable and inexpensive adjuvant treatment for colorectal cancer. Levamisole may no longer be recommended in this setting.

The aim of this study was to develop a phase II study gauging the contribution of a daily low-dose of carboplatin combined with 5-fluorouracil (5-FU) and folinic acid (FOL) in a chronotherapy schedule for advanced colorectal cancer patients. 60 patients with metastatic colorectal cancer were included in a phase II trial in which 50% of patients had received prior chemotherapy of up to three regimens. Treatment consisted of a combination of 5-FU (700 mg/m(2)/day) and FOL (300 mg/m(2)/day) infused from 10.00 pm to 10. 00 am peaking at 4.00 am with carboplatin infused from 10.00 am to 10.00 pm at 40 mg/m(2)/day with a peak at 4.00 pm. 4-day courses were repeated every 2 weeks in an ambulatory setting with a programmable pump. Patients experienced excellent tolerance (grades III-IV%): diarrhoea, 8.1; nausea/vomiting, 4.8; mucositis, 3.2; skin or neurological 1.7; granulocytes 29.0; platelets and haemoglobin (Hb) 9.7. Major tumour responses were observed in 47% of cases, 4 complete response (CR), 24 partial response (PR); 3 CR and 6 PR (69%) were recorded in 13 previously untreated patients; 11 (18%) underwent subsequent surgical resection of residual metastases. Median survival was 14.6 months with 22% patients surviving over 2 years (35% survival for responders versus 0 for non-responders). In conclusion, this chronotherapy determined administration of 5-FU/FOL and carboplatin yielded an excellent therapeutic index for the combination and warrants further evaluation in the first-line treatment of metastatic colorectal cancer.

High-dose chemotherapy combining regional hepatic artery infusion (HAI) of fluorodeoxyuridine (HAI FUDR) and systemic venous infusion of 5-fluorouracil (i.v. 5-FU) was delivered against liver metastases from colorectal cancer. The hypothesis that chronomodulation of delivery rate along the 24 h time scale would improve the tolerable doses of both drugs was tested. Combined HAI FUDR (80 mg/m2/day) and i.v. 5-FU (1200 mg/m2/day) were administered for five consecutive days every 3 weeks, either as a constant rate infusion (schedule A, 27 patients) or as chronotherapy (schedule B, 29 patients). This latter regimen consisted of a sinusoidal modulation of the delivery rate over the 24 h scale with a maximum at 16:00 for FUDR and 4:00 for 5-FU. Intrapatient dose escalation up to the individual maximum tolerated doses (MTD) was planned for both drugs in the absence of any previous grade 3 or 4 toxicity. All patients had metastatic colorectal cancer, with adjuvant or palliative chemotherapy given to six patients (22%) on schedule A and 12 patients on schedule B (41%). Severe stomatitis occurred in 71% of the patients and was dose limiting. No hepatic toxicity was encountered. Dose reductions of 5-FU and/or FUDR were required for 17 of 27 patients on schedule A (63%) as compared to 11 of 29 patients on schedule B (38%), following reaching the individual MTD (p<0.05). Over the first six cycles, patients on schedule B received higher doses (mg/m2/cycle; FUDR: 522 +/- 85 versus 499 +/- 50, p=0.004 and 5-FU: 5393 +/- 962 versus 5136 +/- 963, p=0.009) and higher dose intensities (mg/m2/week; FUDR: 164 +/- 46 versus 151 +/- 52, p=0.018 and 5-FU: 1652 +/- 478 versus 1553 +/- 535, p<0.041) of both drugs than patients on schedule A. As a result the number of courses with doses of 5-FU above 1200 mg/m2/day and/or FUDR above 110 mg/m2/day was larger in group B than in group A (5-FU, A: 67 of 268, 25% versus B: 133 of 321, 41% and FUDR, A: 86 of 268, 32% versus B: 155 of 321, 48%; p<0.001). Objective responses were observed in 13 patients on schedule A (48%) and 11 patients on schedule B (38%). The results support the need for further exploration of chronotherapy of colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy.