Clinical value of circulating endothelial cell levels in metastatic colorectal cancer patients treated with first-line chemotherapy and bevacizumab.

BACKGROUND: We investigated whether circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: In a substudy of the randomized phase II FNCLCC ACCORD 13/0503 trial, CECs (CD45- CD31+ CD146+ 7-amino-actinomycin- cells) were enumerated in 99 patients by four-color flow cytometry at baseline and after one cycle of treatment. We correlated CEC levels with objective response rate (ORR), 6-month progression-free survival (PFS) rate (primary end point of the trial), PFS, and overall survival (OS). Multivariate analyses of potential prognostic factors, including CEC counts and Köhne score, were carried out. RESULTS: By multivariate analysis, high baseline CEC levels were the only independent prognostic factor for 6-month PFS rate (P < 0.01) and were independently associated with worse PFS (P = 0.02). High CEC levels after one cycle were the only independent prognostic factor for ORR (P = 0.03). High CEC levels at both time points independently predicted worse ORR (P = 0.025), 6-month PFS rate (P = 0.007), and PFS (P = 0.02). Köhne score was the only variable associated with OS. CONCLUSION: CEC levels at baseline and after one treatment cycle may independently predict ORR and PFS in mCRC patients starting first-line bevacizumab and chemotherapy.

A randomized phase II trial evaluating safety and efficacy of an experimental chemotherapy regimen (irinotecan + oxaliplatin, IRINOX) and two standard arms (LV5 FU2 + irinotecan or LV5 FU2 + oxaliplatin) in first-line metastatic colorectal cancer: a study of the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer.

BACKGROUND: To assess activity and safety of an experimental combination of irinotecan and oxaliplatin (IRINOX) as first-line treatment in advanced colorectal cancer. PATIENTS AND METHODS: In this randomized phase II trial, 80 patients were treated: arm A (IRINOX) in 40 patients received at day 1 oxaliplatin 85 mg/m(2) and irinotecan 180 mg/m(2) biweekly, standard arm B received a biweekly simplified folinic acid (FA) and fluorouracil (FU), FA 200 mg/m(2) in a 2-h infusion and bolus injection of 5FU 400 mg/m(2) on day 1, then a two 400 mg/m(2) continuous infusion of FU on days 1 and 2 with either oxaliplatin 85 mg/m(2) (20 patients) or irinotecan 180 mg/m(2) (20 patients). RESULTS: Twenty-one partial responses (52.5%, median duration 7.2 months) were observed with the IRINOX arm and two complete and 20 partial responses (55%, median duration 6.4 months) with arm B. Median progression-free and overall survival times were 8.4 and 19 months, respectively, in the IRINOX arm and 8.1 and 20.4 months in arm B. Main grade 3/4 toxic effects were, respectively, neutropenia 42.5% and 32.5%; febrile neutropenia 10% and 5%; diarrhea 32.5% and 7.5%; vomiting 10.0% and 5%; neurosensory toxicity 17.5% and 7.5%. CONCLUSION: The IRINOX arm has a manageable toxicity and is active.

'A phase II study of oral uracil/ftorafur (UFT) plus leucovorin combined with oxaliplatin (TEGAFOX) as first-line treatment in patients with metastatic colorectal cancer'.

This phase II trial was performed to evaluate the efficacy and tolerability of a new combination of Uracil/Ftorafur (UFT)/leucovorin (LV) and oxaliplatin in patients (pts) with metastatic colorectal cancer (MCRC) who had not received prior chemotherapy for metastatic disease. Between February 2002 and October 2002, 64 patients received UFT 300 mg m(-2) day(-1) and LV 90 mg day(-1) from day 1 to day 14 combined with oxaliplatin 130 mg m(-2) on day 1, every 3 weeks. All patients were evaluable for safety analysis and 58 of 64 patients were eligible for efficacy. Responses were reviewed by an independent review committee. Of the 58 per-protocol defined assessable patients, 1 complete response and 20 partial responses were observed yielding a response rate of 34% (95% CI: 22-47). The median response duration was 8.74 months (range 1.6-14). The median time to progression and the median survival were 5.88 months (95% CI: 4.34-8.21) and 18.2 months (95% CI: 10-20.7), respectively. Diarrhoea and peripheral neuropathy were the most frequent and predictable toxicities. These events were reversible, noncumulative and manageable. Grade 3 diarrhoea occurred in only 11% of the patients. No grade 4 gastrointestinal toxicity was reported in the study. The incidence of grade 3/4 (National Cancer Institute Common Toxicity Criteria 2: NCI-CTC 2) peripheral neuropathy was 15%. Haematological toxicity was of mild to moderate intensity with 10% of the patients with Grade 3/4 neutropenia without any episode of complication. The TEGAFOX regimen, a new combination using UFT/LV and oxaliplatin every 3 weeks is feasible on an outpatient basis. The combination is safe and active and may offer a promising alternative to the intravenous route. Nevertheless this efficacy results should be confirmed by randomized phase III trials.

Drug-induced cardiotoxicity studied by longitudinal B-type natriuretic peptide assays and radionuclide ventriculography.

BACKGROUND: To study the longitudinal variations of plasma B-type natriuretic peptide (BNP) with reference to left ventricular ejection fraction (LVEF) during and after chemotherapy with cardiotoxic drugs. PATIENTS AND METHODS: We prospectively measured plasma BNP using an immunoradiometric assay in 12 anthracycline-treated breast cancer patients monitored for a mean time of 880+/-293 days (pilot group). Prior to each cycle and throughout the following year, LVEF and cardiac output were measured by radionuclide ventriculography. Anthracycline pharmacokinetics was studied during the first cycle. Relationships between serial observations were analysed with the general linear mixed effects model. Identical methods were subsequently applied to a test group of 67 anthracycline or trastuzumab-treated patients. RESULTS: Five out of 70 (6.33%) patients developed anthracycline-induced heart failure. BNP concentrations were found to be positively correlated to anthracycline cumulative dose and negatively to LVEF values. Variables entering the mixed models were cumulative anthracycline dose, time and cardiac output. CONCLUSION: An infra-clinical cardiotoxicity of anthracyclines as defined by BNP elevation is frequent but reversible. Patients who developed heart failure showed a continuous BNP increase and concentrations over 100 ng/ml.

A phase I clinical and pharmacokinetic study of capecitabine (Xeloda) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours.

Capecitabine is a highly active oral fluoropyrimidine that is an attractive alternative to 5-fluorouracil in colorectal cancer treatment. The current study, undertaken in 27 patients with gastrointestinal tumours, aimed to assess the toxicity and potential for significant pharmacokinetic interactions of a combination regimen incorporating capecitabine with 3-weekly irinotecan (XELIRI). Irinotecan (200 and 250 mg m(-2)) was administered as a 90-min infusion on day 1 in combination with escalating capecitabine doses (700-1250 mg m(-2) twice daily) administered on days 2-15 of a 3-week treatment cycle. Pharmacokinetics were characterised on days 1 and 2 of the first two cycles. A total of 103 treatment cycles were administered. The principal dose-limiting toxicities were diarrhoea and neutropenia. Capecitabine 1150 mg m(-2) twice daily with irinotecan 250 mg m(-2) was identified as the maximum-tolerated dose and capecitabine 1000 mg m(-2) with irinotecan 250 mg m(-2) was identified as the recommended dose for further study. Analyses confirmed that there were no significant pharmacokinetic interactions between the two agents. The combination was clinically active, with complete and partial responses achieved in heavily pretreated patients. This study indicates that XELIRI is a potentially feasible and clinically active regimen in patients with advanced gastrointestinal cancer.

Multicenter non-randomized phase II study of raltitrexed (Tomudex) and oxaliplatin in non-pretreated metastatic colorectal cancer patients.

BACKGROUND: This multicenter, phase II, open-label study evaluated the antitumor efficacy and safety of oxaliplatin and raltitrexed (Tomudex) in non-pretreated advanced colorectal cancer patients. PATIENTS AND METHODS: Seventy-one patients received oxaliplatin 130 mg/m(2) and raltitrexed 3 mg/m(2) intravenously on an outpatient basis every 3 weeks. All patients had histologically proven metastatic colorectal adenocarcinoma, performance status

A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma.

BACKGROUND: Chemotherapy is moderately efficient as a treatment for pancreatic adenocarcinoma, but patient survival and quality of life has improved with this modality in some trials. In a previous phase II trial, 5-fluorouracil (5-FU) plus cisplatin (FUP) yielded a 26.5% response rate and a 29% survival rate at 1 year. The present study aimed to compare FUP with 5-FU alone, which was the control arm in former Mayo Clinic trials. PATIENTS AND METHODS: Patients with untreated cytologically or histologically proven metastatic or locally advanced adenocarcinoma of the pancreas were deemed measurable or evaluable. Chemotherapy regimens consisted of a control FU arm (5-FU 500 mg/m(2)/day for 5 days) and the investigational FUP arm (continuous 5-FU 1000 mg/m(2)/day for 5 days plus cisplatin 100 mg/m(2) on day 1 or day 2). In both arms, chemotherapy was repeated at day 29. RESULTS: Two-hundred and seven patients from 18 centres were randomised: 103 in the FU arm and 104 in FUP arm. Treatment arms were balanced with respect to performance status grade 0-1 (83% versus 86%, respectively) and the presence of metastases (92% versus 89%, respectively). The median number of cycles administered was two in both arms (range 0-14). Five patients did not receive any chemotherapy and 45 received only one cycle. Toxicity (WHO grade 3-4) was lower with FU than with FUP (20% versus 48%, P <0.001), as was neutropenia (6% versus 23%), vomiting (4% versus 17%) and toxicity-related deaths (one versus four early in the trial). The response rate was low in both arms, but superior in the FUP arm: 12% versus 0% (intention-to-treat analysis, P <0.01). The survival rates at 6 months were 28% and 38% for the FU and FUP arms, respectively, and 1-year survival rates were 9% and 17% (log-rank test, P = 0.10). One-year progression-free survival was 0% with FU versus 10% with FUP (log-rank test, P = 0.0001). CONCLUSIONS: In advanced pancreatic carcinomas with a poor prognosis, FUP was superior to FU in terms of response and progression-free survival, but not in terms of overall survival. The low response rate is partly related to the number of patients who received only one cycle of chemotherapy. A more effective, better tolerated version of this FUP combination is needed.

High-dose radiation therapy and neoadjuvant plus concomitant chemotherapy with 5-fluorouracil and cisplatin in patients with locally advanced squamous-cell anal canal cancer: final results of a phase II study.

PURPOSE: To analyse toxicity and response to a new scheme of neoadjuvant chemotherapy (CT) and concomitant radiochemotherapy (RT-CT) for locally advanced anal canal squamous-cell carcinoma (ACC). PATIENTS AND METHODS: Eighty patients with an ACC > 40 mm and/or with lymph node involvement were included (1 T1, 52 T2, 14 T3, 13 T4, 18 N0, 30 N1, 32 N2-N3). Two cycles of 5-fluorouracil (5-FU) and CDDP were delivered as neoadjuvant CT and two during RT-CT. Pelvic (+/- inguinal) RT delivered 45 Gy in 25 fractions of 1.8 Gy. Involved fields were boosted after a one to two month gap (15-20 Gy). The median follow-up was 29 months. RESULTS: One patient died of a pulmonary embolism on day 4. All patients received the entire treatment, with reduced 5-FU doses in 27% of the cases because of acute toxicity. Sixty-four grade 3 and five grade 4 toxicities were observed. No toxic death occurred. Complete response (CR) and partial response (PR) rates were, respectively, 10% and 51% after neoadjuvant CT, 67% and 28% after RT-CT and 93% and 5% after treatment completion (including 4 abdomino-perineal resections). The three-year actuarial overall, tumour-specific, colostomy-free, relapse-free, disease-free and event-free survivals were 86%, 88%, 73%, 70%, 67% and 63%, respectively. CONCLUSIONS: Tolerance was good. After neoadjuvant CT, most of the patients were objective responders. After treatment completion, all but five achieved CR. The long-term results confirm the durability of local control and low toxicity on the sphincter. An ongoing phase III intergroup trial analyses the impact of neoadjuvant CT, and the benefit of a high-dose boost irradiation, on local control and colostomy-free survival.

Overcoming resistance to chronomodulated 5-fluorouracil and folinic acid by the addition of chronomodulated oxaliplatin in advanced colorectal cancer patients.

The addition of oxaliplatin (L-OHP) to a 5-fluorouracil (5-FU)/ leucovorin (FA) regimen was retrospectively evaluated in 35 consecutive advanced colorectal cancer patients after progression of disease. L-OHP, 25 mg/m2/day, was infused from 10.00-22.00 with a peak flow at 16.00 while 5-FU, 700 mg/m2/day and FA, 150 mg/m2/day of the I-form or 300 mg/m2/day of the racemic form, from 22.00 to 10.00 with a nocturnal peak at 4.00, for 5 days every 3 weeks in 24 patients and for 4 days every 2 weeks in the other 11. Diarrhea and sensitive neuropathy were the most relevant types of toxicity (17% of patients). An objective response was achieved in 8/35 patients (23%) [95% CL 9-37], stabilization in 15 patients (43%) which included five minor responses, and progression in 12. There was no relevant difference in quality of life assessed with the EORTC QLQ C30+3 questionnaire before and after treatment. Median duration of response and median progression-free survival were 6 months; median overall survival was 11 months. This retrospective study showed that it is possible to reverse resistance to chronomodulated 5-FU by adding chronomodulated L-OHP to the previous regimen; comparison with different schedules of this combination should be performed in order to identify the best tolerated and active regimen as second-line treatment of advanced colorectal cancer.

Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU-LV occurred in

Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery.

CONTEXT: Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy. OBJECTIVE: We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible. PATIENTS AND METHODS: From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size (> 5 cm), multinodular (> 4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team. RESULTS: In 151 patients, the size of liver metastases decreased by > 50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19-28 months), with 28% surviving at five years (20%-35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25-71), with a five-year survival rate of 50% (38-61). CONCLUSION: This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.

[Treatment of breast cancer after 70 years of age. Report of 1143 cases]. / Le traitement du cancer du sein après 70 ans. A propos de 1143 cas.

STUDY AIM: Breast cancer is the most frequent type of cancer in women, increasing in frequency with the elderly. In Europe, a third of new breast cancers occur in women over 70 years of age. The aim of this retrospective study was to analyse the tumoural lesions and therapeutic results in a female population over 70, treated in the same medical centre over a 15-year period. PATIENTS AND METHODS: From 1978 to 1992, 1,143 female patients aged 70 or over were treated for a unilateral breast cancer without metastases and followed-up during a mean 6-year period. The initial treatment was surgical in 1,012 patients: radical mastectomy in 95% of the cases with axillary node dissection in 97.6%. Adjuvant radiotherapy was performed in 289 patients and adjuvant treatment with Tamoxifen in 411 patients. The results were compared with those obtained in 2,947 patients aged 50 to 69, treated during the same period in the same medical centre. RESULTS: The 5-year survival rate in women 70 and over was 80% vs 85.5% in women aged 50 to 69 (P < 0.000001). The same rate of loco-regional recurrences and metastases occurred in both populations. In the patients who initially underwent surgery, after multivariate analysis according to the Cox model, the prognosis factors (similar to those observed in the group of younger women) were: the number of involved nodes (P = 0.000001), the clinical size of the tumour (P = 0.00001), the histological grade (P = 0.01), and the estrogen receptors (P = 0.02). CONCLUSIONS: In this series, the treatment was focused on surgery complemented with adjuvant radiotherapy according to node invasion and adjuvant hormonotherapy according mostly to hormonal receptors. However, the complete treatment could not be applied to all cases: only 50% of patients with node involvement were irradiated. The 5-year survival rate lower than that of younger patients may be attributed to incomplete adjuvant treatment. Specific controlled trials taking into account quality of life had to be undertaken in elderly patients in order to adjust the treatment in relation with the patients' age and physiological condition.

[Mitomycin-vinorelbine combination as second-line chemotherapy in metastatic cancer of the breast]. / Association mitomycine-vinorelbine en deuxième ligne chimiothérapique dans le cancer du sein métastatique.

Fourty-six patients (41 evaluable) were treated in second line chemotherapy of metastatic breast cancer (MBC) by an association of mitomycin (M), vinorelbine (V) (M 8 mg/m2 D1, V 25 mg/m2 D1 and DI 8 every 4 weeks). Median age was 58 years (36-78), median performance status 1 (0-3). Thirty-seven per cent of the tumors were estrogen receptors positive and 17% progesterone receptors positive. Seventeen patients received an adjuvant chemotherapy and 39 a first line chemotherapy with anthracycline (A). The median number of metastatic sites was 2 (1-4) and 27 patients (67%) had visceral metastases. Twelve patients were refractory to anthracyclines and 5 resistant. No toxic death nor hemolytic uremic syndrome were observed. Seven (3.7%) febrile neutropenias happened responsible for 4 hospitalizations. A grade 3 or 4 neutropenia was noted in 34% of the cycles but no other clinic toxicity nor grade 3 or 4 thrombopenia. The rate of objective response (OR) was 37.5% with 2 complete responses (CR) and 13 partial responses (PR). Seven patients had stable disease and 18 progressed. The rate of hepatic OR was 31%. Five (40%) A-refractory patients responded but no resistant patient. Median OR time was 10 weeks (8-12) and median OR duration was 5 months (3-6). Median survival was 11.5 months. MV association is well tolerated and effective in second line chemotherapy for MBC even with hepatic metastasis and in patients refractory to anthracyclines.

Mitomycin-vinorelbine as second line chemotherapy in metastatic breast cancer

Fourty-six patients (41 evaluable) were treated in second line chemotherapy of metastatic breast cancer (MBC) by an association of mitomycin (M), vinorelbine (V) (M 8 mg/m2 D1, V 25 mg/m2 D1 and DI 8 every 4 weeks). Median age was 58 years (36-78), median performance status 1 (0-3). Thirty-seven per cent of the tumors were estrogen receptors positive and 17% progesterone receptors positive.eventeen patients received an adjuvant chemotherapy and 39 a first line chemotherapy with anthracyclin (A). The median number of metastatic sites was 2 (1-4) and 27 patients (67%) had visceral metastases. Twelve patients were refractory to anthracyclins and 5 resistant. No toxic death nor hemolytic uremic syndrom were observed.even (3,7%) febrile neutropenias happened responsible for 4 hospitalizations. A grade 3 or 4 neutropenia was noted in 34% of the cycles but no other clinic toxicity nor grade 3 or 4 thrombopenia. The rate of objective response (OR) was 37,5% with 2 complete responses (CR) and 13 partial responses (PR).even patients had stable disease and 18 progressed. The rate of hepatic OR was 31%. Five (40%) A-refractory patients responded but no resistant patient. Median OR time was 10 weeks (8-12) and median OR duration was 5 months (3-6). Median survival was 11,5 months. MV association is well tolerated and effective in second line chemotherapy for MBC even with hepatic metastasis and in patients refractory to anthracyclins.

Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.

PURPOSE: To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma. PATIENTS AND METHODS: A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive. RESULTS: Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%. CONCLUSION: This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

Preliminary results of a phase II study of high-dose radiation therapy and neoadjuvant plus concomitant 5-fluorouracil with CDDP chemotherapy for patients with anal canal cancer: a French cooperative study.

BACKGROUND: Chemotherapy (5-fluorouracil-mitomycin C) concomitant with radiotherapy (RT) increases local control and colostomy-free survival in advanced anal canal carcinomas (ACC). The purpose of this prospective trial was to analyse the toxicity of and response to an induction chemotherapy combining 5-fluorouracil (5-FU) and CDDP administered concomitantly with irradiation. PATIENTS AND METHODS: Thirty patients (24 F/6 M, mean age 60, range 38-74) with an advanced ACC > 40 mm and/or with node involvement were prospectively treated (1 T1, 16 T2, 8 T3, 5 T4, 10 N1, 1 N2, 8 N3) from November 1994 to January 1996. Two induction and two concomitant cycles of 5-FU (800 mg/ m2 D1-4 infusion) and CDDP (80 mg/i.v./m2 at D1) were delivered. RT consisted of 45 Gy (1.8 Gy/fr, 5 fr/w) on pelvis +/- inguinal nodes or 30 Gy (3 Gy/fr, 4 fr/w) by direct perineal field. A boost (15-20 Gy) was delivered six weeks later. TOXICITY: one patient died of a pulmonary embolism on D4. The remaining 29 received the entire treatment, with reduced 5-FU doses in 11 patients because of acute toxicity. The RT boost was delayed for one patient (aplasia). In 109 cycles, 3 grade 4 and 17 grade 3 toxicities were observed; there were no toxic deaths. Tumor response: the complete response (CR) and partial response (PR) rates were, respectively, 11% and 61% after induction chemotherapy, 59% and 31% after concomitant radiochemotherapy and 96% and 0% two months after completion of the treatment. No tumor progression was observed. CONCLUSION: the treatment was well tolerated and there was good compliance. After induction chemotherapy, most of the patients were in PR, with some even in CR. After completion of the treatment all but one were in CR. The tumor response and the long term results of 50 patients will be analysed before initiation of a randomised trial is considered.

Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.

PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.

Circadian rhythm-modulated (CRM) chemotherapy of metastatic breast cancer with mitoxantrone, 5-fluorouracil, and folinic acid: preliminary results of a phase I trial.

A phase I feasibility trial with a 5-day schedule of circadian rhythm-modulated mitoxantrone (MIT), 5-fluorouracil (5-FU, 600 mg/m2/day), and folinic acid (FA, 300 mg/m2/day) was performed in patients with metastatic breast cancer. The MIT dose was escalated from 2 to 2.5 and 2.75 mg/m2/day in consecutive groups of six patients. All three drugs were infused intravenously with a multichannel ambulatory pump. Maximal delivery rate was programmed at 4.00 hours for 5-FU and FA and at 16.00 hours for MIT. Eighteen women with advanced metastatic breast cancer were included in the trial between April 1991 and July 1993. Seventeen of 18 patients had received previous chemotherapy, which contained anthracyling for 16 of them. Tolerability of the first treatment course was assessed 10 and 21 days after course onset. Neutropenia was dose dependent and the most frequent toxicity (grade 3: 4 patients; grade 4: 7 patients), yet only a single hospitalization was required for fever and neutropenia. A single patient exhibited grade 3 mucositis. No grade 3 or 4 diarrhea, nausea, or vomiting was encountered. This chronomodulated infusion of MIT, 5-FU, and FA showed acceptable toxicity in heavily pretreated patients. For the phase II evaluation of the antitumor activity of this circadian schedule, a dose of 2.75 mg/m2/day of MIT is recommended using a monthly regimen. Further dose escalation may be performed in patients without bone metastasis and good performance status.

Circadian rhythm-modulated chemotherapy with high-dose 5-fluorouracil: a pilot study in patients with pancreatic adenocarcinoma.

From November 1986 to April 1989, 16 patients with advanced measurable pancreatic carcinoma were involved in a pilot phase I-II study. 5-Fluorouracil was given every 3 weeks by 5-day continuous chronomodulated venous infusion (CMVI) with peak 5-FU delivery at 4 a.m. Intrapatient dose escalation started at 1200 mg/m2/day up to 1600 mg/m2/day in the absence of grade III (WHO) toxicity. Mucositis and diarrhoea were dose limiting in the 131 cycles given. Three partial responses (21%) and 5 stable diseases were seen in the 14 patients with measurable disease. Dose intensity after three or after six courses (1800 mg/m2/week) was significantly correlated with time to progression (Pearson r = 0.64; P < 0.004). These results, although modest, support a multicentre phase II trial with 5-FU CMVI.