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Bolus Fluorouracil and Leucovorin With Oxaliplatin as First-Line Treatment in Metastatic Colorectal Cancer

From the Department of Oncology, Infermi Hospital, Rimini; Department of Oncology, Santa Maria delle Croci Hospital, Ravenna; Department of Oncology, Cervesi Hospital, Cattolica; Department of Oncology, Bufalini Hospital, Cesena; Department of Oncology, Pierantoni Hospital, Forlì; and Department of Oncology Hospital, Lugo, Italy.

Address reprint requests to Alberto Ravaioli, MD, Department of Oncology, Infermi Hospital, Via Settembrini, 2, 47900 Rimini, Italy; email: aravaiol{at}auslrn.net

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer.

PATIENTS AND METHODS: Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m² on the first day of each course and 5-FU and LV 350 mg/m² and 20 mg/m², respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses.

RESULTS: Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m². Reversible neurologic toxicity occurred in 44.4% of patients.

CONCLUSION: Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m² dosage offered improved dose-intensity compared with the initial dosage.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
OXALIPLATIN (ELOXATIN; Sanofi-Synthelabo, Paris, France), a compound of the diaminocyclohexane platinum family, underwent preclinical study in the late 1980s by Mathé et al,¹ who found that many cisplatin-resistant tumors responded to oxaliplatin. Phase I studies with oxaliplatin² demonstrated a favorable pharmacokinetic, activity, and safety profile against colorectal cancer, both as a single agent and in combination with fluorouracil (5-FU) and leucovorin (LV, also known as folinic acid). Since then, much clinical experience has been accumulated with oxaliplatin,^3-12 and the drug has been registered for use in first-line treatment of advanced colorectal cancer (ACRC) in combination with 5-FU and is being further developed in the adjuvant setting.

As a single agent, the recommended oxaliplatin dose is 130 mg/m² as a 2-hour intravenous infusion every 3 weeks. Clinical experience indicated that oxaliplatin demonstrated specific antitumor activity as a single agent, both in refractory^13-20 and untreated^3-7 patients with advanced disease. Many investigators have tried to optimize its use in the treatment of ACRC by adding 5-FU and LV in different ways. The activity of the oxaliplatin–5-FU combination regimen has been confirmed in 5-FU–refractory patients.¹² The most recently published phase III trials investigating the combination of oxaliplatin and 5-FU plus LV as first-line treatment of metastatic colorectal cancer, reported interesting data, with a two-fold increase in response rate and a 3-month extension in time to progression in favor of the oxaliplatin arm.^5-7 Until now, experience with the combination of oxaliplatin plus 5-FU and LV as used in the Machover²¹ scheme (monthly 5-day courses of bolus 5-FU/LV) has not been published extensively.^10,11

In our phase II trial, we tried to optimize the oxaliplatin/5-FU/LV combination as a bolus administration schedule. Our objective was to define the activity and toxicity of our schedule in patients with untreated ACRC, building on our experience in second-line chemotherapy.²²

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients with metastatic colorectal carcinoma were eligible for inclusion in this multicenter, open, nonrandomized study. The study was approved by the local biomedical ethic committees of the seven oncology institutions participating in the trial (Rimini, Cattolica, Cesena, Faenza, Forlì, Lugo, and Ravenna, Italy). Written informed consent was obtained for each participant. The study was conducted according to globally accepted standards of good clinical practice and in agreement with the latest revision of the Declaration of Helsinki (Somerset West amendment) and local regulations.

Eligibility Criteria
Patients enrolled onto the trial had to be aged 18 years with histologically proven adenocarcinoma of the colon or rectum, a minimum life expectancy of 6 months, serum creatinine less than 1.25 times the institution’s upper limit of normal, total bilirubin less than two times the upper limit of the normal range at the institution, or AST less than two times the upper limit of normal, absolute neurophil count more than 1.5 x 10⁹/L, or platelet count more than 100 x 10⁹/L.

No previous chemotherapy for metastatic disease was allowed; patients treated with adjuvant chemotherapy were considered eligible if relapse of disease occurred at least 1 year later the ending of adjuvant treatment. Metastatic disease had to be bidimensionally measurable; pretreatment evaluation of targets was performed with thoracoabdominal and pelvic computed tomographic (CT) scan and liver echography. All of these tests were performed within the month preceding study entry. Clinical examination and blood determinations were repeated before each chemotherapy course. CT scans were performed for disease evaluation purposes after every two courses of chemotherapy.

Chemotherapy Regimen
Patients received oxaliplatin 130 mg/m² on the first day of each course of chemotherapy and 5-FU/LV at a dosage of 350 mg/m² and 20 mg/m², respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses of therapy or until disease progression or unacceptable toxicity occurred. The dosage of 5-FU was adjusted to 300 mg/m² as a daily bolus for 5 days every 21 days after the treatment of the first nine patients because of the occurrence of grade 3 to 4 toxicity, especially diarrhea and neutropenia.

Assessment of Toxicity
Toxicity was assessed before each chemotherapy course according to the criteria of the World Health Organization (WHO).

Dose-Intensity
The dose-intensity of 5-FU and oxaliplatin (mean, mg/m²/wk) was calculated over the entire treatment period.

Assessment of Response and Survival
Responses were assessed after every two treatment courses according to WHO criteria. Responses were confirmed by two different CT scans or measurements at least 2 months apart. Partial responses were categorized on the basis of a bidimensional measurement. Time to disease progression (progression-free survival [PFS]) and survival were determined from the date of inclusion in the trial.

Statistical Methods
A target population size of 45 patients was calculated according to Simon,²³ assuming that the objective response rate would be 40%. This sample size gave a 5% probability of a type I error and a power of 90% to detect a 20% increase in objective response rate over that (20%) already achieved with a 5-FU and LV regimen.

Data were monitored on site by an outside oncologist every month. The main outcome criterion was maximum tumor response, as reviewed centrally by a panel consisting of the coordinator and independent radiologists. All data were analyzed on an intent-to-treat (ITT) basis by SPSS software (SPSS, Chicago, IL). Median and quartile (25% and 75%) values were calculated to describe the data. Kaplan-Meier curves were drawn for PFS and survival. The Cox proportional hazard model was applied to survival data. The significance of each of the following factors was tested in the analysis: sex, age, adjuvant chemotherapy versus no adjuvant chemotherapy, performance status, synchronous versus metachronous metastasis, liver metastasis versus no liver metastasis, time between diagnosis of colorectal cancer and metastasis, and negative carcino-embryonic antigen (CEA) blood levels versus positive CEA blood levels at diagnosis. P .05 was taken to indicate statistical significance.

	RESULTS

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Patient Characteristics
From December 1998 to December 1999, 45 consecutive eligible patients were included in the study. Demographic and baseline disease characteristics of the ITT population are listed in Table 1. Patients were predominantly male (64.5%), with a median age of 62 years. Thirty-six patients (80%) had a WHO performance status of 0, 8 (17.7%) had a WHO performance status of 1, and only one patient (2.3%) had a WHO performance status of 2. These data might select a "good performance" population, as our Cox regression analysis seems to suggest. Only 20% had received adjuvant chemotherapy. In two-thirds of patients, the colon was the primary tumor site. The liver was the predominant metastatic site (68.8%); most patients (62%) had only one metastatic site. A total of 165 treatment courses were provided. Each patient received a mean of four courses (range, one to six courses). Four patients were not assessable for treatment efficacy; these patients were retained for the ITT analysis. At the cutoff date (April 1, 2001), the median potential follow-up period for the entire cohort was 11 months.

View larger version (11K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimate of cumulative probability of PFS.

View larger version (10K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimate of cumulative probability of survival.

In view of the high incidence of grade 3 to 4 neutropenia and diarrhea observed in the first nine patients, in the remaining 36 patients the dose of 5-FU was reduced to 300 mg/m² as a daily bolus for 5 days every 21 days for six courses of therapy. For the entire patient population, mean dose intensities for 5-FU, LV, and oxaliplatin were 436, 31, and 38 mg/m²/wk, respectively; these were equivalent to 92%, 95%, and 86%, respectively, of the scheduled doses for the entire treatment period.

Toxicity
Of the 165 courses of therapy, 98% were evaluated for toxicity (Table 4). Acute dose-limiting toxicities were grade 3 or 4 diarrhea, which occurred in 26.7% and 2.2% of all patients, respectively. Dose reduction of 5-FU (from 350 to 300 mg/m²/d for 5 days every 21 days) or the administration of supportive care allowed the incidence of grade 3 and 4 diarrhea per cycle to be limited to 19.4% and 2.7% of patients receiving the reduced dose, respectively. Dose adaptation or modification of antiemetic prophylactic therapy allowed adequate control of grade 3 nausea and vomiting (6.7% and 8.9% of the patients, respectively).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
There are few reports describing the results of oxaliplatin in combination with 5-day courses of 5-FU/LV bolus therapy, and such reports are only preliminary observations.^10,11 These preliminary results demonstrated response rates in assessable patients of approximately 34%. Our schedule of treatment with the same bolus administration (Machover’s modified scheme²¹) has reached sufficient maturity to observe comparable results. Thus, in our study, the percentage of overall responses reached 40% (95% CI, 33.0% to 47.0%), with a median PFS of 5.9 months (95% CI, 3.9 to 7.8 months) and a median survival of 14 months (95% CI, 6.2 to 21.6 months) at a median follow-up period of 11 months. No clinical factor, apart from performance status and CEA value, influenced survival in the Cox regression analysis.

Historically, 5-FU has been the mainstay of chemotherapy in ACRC, and different 5-FU regimens have been developed to improve the efficacy/safety ratio while taking into account differences in medical practice between different countries. This has led to a variety of therapy approaches, including bolus and continuous-infusion regimens or hybrid regimens.²⁴

Oxaliplatin has been demonstrated to be effective when used in combination with different 5-FU regimens for both first- and second-line treatment of ACRC.²⁵ However, in first-line therapy, most phase III data have been obtained using combinations with infusional 5-FU regimens.^6,7,26 These trials have consistently demonstrated a doubling in response rate, a significant increase in PFS, and overall survival durations of between 16 and 20 months. In the study of Giacchetti et al,⁶ 200 patients were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV with or without oxaliplatin. In patients receiving 5-FU/LV and oxaliplatin, 53% had an objective response; the median PFS time was 8.7 months; and the median survival time was 19.4 months. In the de Gramont et al⁷ phase III study, more than 400 patients were randomized to receive a 2-hour infusion of LV followed by a 5-FU bolus and 22-hour infusion for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin as a 2-hour infusion on day 1. Patients allocated to oxaliplatin plus 5-FU/LV had significantly longer PFS (median, 9.0 v 6.2 months, P = .0003) and a better response rate (50.7% v 22.3%. P = .0001) compared with the control arm. Overall survival reached 16.2 months in the oxaliplatin-containing arm. Results of another phase III trial were reported at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology and demonstrated in 252 ACRC patients that a weekly regimen of a 2-hour infusion of oxaliplatin 50 mg/m² plus a 24-hour infusion of 5-FU 2,000 mg/m²/LV 500 mg/m² had superior efficacy to the standard Mayo regimen.²⁶

The topoisomerase I inhibitor irinotecan has also demonstrated significant activity in combination with 5-FU. In a phase III trial²⁷ comprising 387 patients previously untreated with chemotherapy for ACRC, the combination of irinotecan with a 5-FU/calcium folinate infusional regimen demonstrated a higher response rate and a survival advantage compared with the 5-FU/calcium folinate infusional regimen alone. Significantly increased PFS and overall survival have also been reported in 231 patients with metastatic colorectal cancer treated with weekly irinotecan plus bolus 5-FU/LV compared with 226 patients treated with a 5-FU/LV bolus regimen alone.²⁸ However, the combination of irinotecan with this same 5-FU/LV bolus regimen was found to be too toxic when used later in two separate cooperative group clinical trials sponsored by the National Cancer Institute.²⁹ Indeed, although bolus 5-FU may be more convenient to administer, it seems difficult to combine with new agents such as irinotecan and oxaliplatin, particularly as a result of safety concerns as highlighted by the early termination of the two combined Mayo arms of the North Central Cancer Treatment Group N9741 phase III trial in ACRC.³⁰

In the current study, oxaliplatin is being combined with a bolus 5-FU/LV administration schedule based on the Mayo regimen but in which doses of 5-FU have been adapted to the every 3 weeks oxaliplatin schedule. This combination with oxaliplatin seems to be safe and effective, and it may offer the advantage of increased convenience compared with regimens utilizing continuous 5-FU infusions and lower costs by avoiding the use of high doses of LV. With regard to toxicity in this trial, the main acute side effects associated with oxaliplatin/5-FU/LV therapy have tended to be diarrhea and nausea or vomiting, with a cumulative sensory peripheral neuropathy as the dose-limiting toxicity.^6,7 High rates of severe neutropenia have also been noted in patients receiving fixed-rate infusion schedules.⁷ With bolus administration of 5-FU/LV with oxaliplatin in the current study, grade 3 to 4 diarrhea was observed in 28.9% of patients, grade 3 to 4 neutropenia in 20%, grade 3 to 4 mucositis in 2.2%, and nausea and vomiting in 8.9%. With regard to neurologic toxicity, with the exception of one patient with grade 3 toxicity, we observed only reversible grade 1 (37.7% of patients) and grade 2 (4.4% of patients) toxicity. If we compare the toxicity of the 36 patients treated with 5-FU at the reduced dosage of 300 mg/m²/d for 5 days per cycle with that of the first nine patients treated with 5-FU 350 mg/m²/d for 5 days per cycle, the percentage of side effects is again lower, with the incidence of grade 3 and 4 diarrhea limited to 19.4% and 2.7% of the patients receiving the reduced dose, respectively, and the incidence of grade 3 and 4 neutropenia also reduced to 5.4% and 5.4% of patients, respectively, receiving the reduced dose.

The toxicity profile of the bolus administration of 5-FU/LV with oxaliplatin in the current study compares favorably with that of previous phase III trials that used oxaliplatin/5-FU/LV combination therapy regimens.^5-7 Incidences of grade 3 to 4 diarrhea were reported in 35% of the constant rate treatment arm and 29% of the chronomodulated arm in the study of Lévi et al,⁵ in 43% of the patients in the study of Giacchetti et al,⁶ and in 11.9% of the patients in the study of de Gramont et al.⁷ In these studies, grade 3 to 4 neutropenia was reported by Lévi et al⁵ in 3% of the constant rate arm and 8% of the chronomodulated arm, by Giacchetti et al⁶ in 2% of patients, and by de Gramont et al⁷ in 41.7% of patients. Neurotoxicity was reported by Lévi et al⁵ in 31% of the constant rate arm and 16% of the chronomodulated arm (grade 2 to 3), by Giacchetti et al⁶ in 45% of patients (grade 1 to 2), and by de Gramont et al⁷ in 18.2% of patients (grade 3).

The new regimen evaluated in our study is a safe and effective combination of oxaliplatin and 5-FU/LV and may offer a new alternative in the treatment of ACRC. As yet, we have not had experience with comparing the following regimens: irinotecan and 5-FU/LV (continuous infusion), oxaliplatin and 5-FU/LV (continuous infusion or chronomodulated) and oxaliplatin and 5-FU/LV (bolus infusion). However, the next logical step will be to investigate and compare the efficacy and safety profiles of such regimens as first-line chemotherapy in advanced disease to facilitate their translation to the adjuvant setting. Indeed, in a future phase III trial, along with other collaborative groups, we will be comparing our new scheme with an oxaliplatin and 5-FU/LV continuous-infusion schedule, adding a pharmacoeconomic end point to the efficacy and safety end points.

	ACKNOWLEDGMENTS

 
Supported by Instituto Oncologico Romagnolo grant no. 2001.

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Submitted August 21, 2001; accepted February 27, 2002.

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