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Randomized Multicenter Phase II Trial of Oxaliplatin Plus Irinotecan Versus Raltitrexed as First-Line Treatment in Advanced Colorectal Cancer

From the Department of Internal Medicine I, Division of Oncology, Vienna University Medical School; Departments of Internal Medicine, General Hospitals of St Pölten and Kirchdorf/Krems; and Departments of Surgery, General Hospitals of Neunkirchen and Wr Neustadt, Vienna, Austria.

Address reprint requests to Werner Scheithauer, MD, Department of Internal Medicine I, Division of Oncology, Vienna University Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria; email: werner.scheithauer{at}akh-wien.ac.at

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting.

PATIENTS AND METHODS: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m² plus irinotecan 175 mg/m² or raltitrexed 3 mg/m² given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected.

RESULTS: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P = .0025) and longer progression-free survival (median, 7.1 v 5.0 months; P = .0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P = .3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m², tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%).

CONCLUSION: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
COLORECTAL CANCER is one of the most common malignancies in the Western world.¹ Despite continuing improvements in surgical resection techniques and the documented effectiveness of adjuvant therapies in patients with regional lymph node involvement, up to 50% of all affected patients will ultimately develop locally recurrent or disseminated disease recurrence. In the palliative treatment setting, after four decades of rather limited, almost exclusively fluoropyrimidine-based treatment options, only recently has the therapeutic armamentarium been improved by the availability of a number of new promising anticancer agents, directed against different cellular targets.² Notable among these new drugs are the third-generation 1,2-diaminocyclohexane-platinum derivative oxaliplatin and the topoisomerase I inhibitor irinotecan, a semisynthetic derivative of the natural alkaloid camptothecin. Both drugs are non–cross-resistant with fluorouracil (FU)/leucovorin (LV) and have documented antitumor activity in the first- and second-line treatment of patients with advanced colorectal cancer.^3,4 When combined with FU/LV, they seem to exert a synergistic effect, which results in major improvements in overall response rate and progression-free survival.^5-8 For FU/LV/irinotecan, a significant prolongation in overall survival has also been demonstrated in two large randomized trials.^7,8

In vitro studies of the combination of oxaliplatin and SN-38, the active metabolite of irinotecan, have demonstrated cytotoxic synergism in the established human colon cancer cell lines HT29 and HCT-8.^9,10 This effect was shown to be related to the stabilization of DNA platinum adducts, when cells were exposed to the topoisomerase inhibitor after the platinum compound. These experimental data, the lack of pharmacokinetic interactions,¹¹ the nonoverlapping toxicity profiles, and the well-documented activity of both drugs when used as single agents have stimulated a number of phase I/II trials in patients for whom FU/LV-based chemotherapy has failed.^12-15 Confirmed objective response rates in the range of 23% to 54%, and progression-free survival times ranging from 5.0 to 7.5 months have been reported in these trials, with febrile neutropenia and diarrhea constituting the dose-limiting toxicities.

In view of these encouraging clinical data and the continuing need for active regimens with an alternative mechanism of action than FU/LV, eg, in patients with high intratumoral thymidylate synthase expression,¹⁶ evaluation of the therapeutic potential of this combination in the front-line setting seems to be of considerable interest. We thus decided to initiate a randomized phase II study of oxaliplatin plus irinotecan in previously untreated patients with advanced colorectal cancer using the recommended drug doses for the biweekly regimen described by Wasserman et al.¹² For the control arm, we chose the specific thymidylate synthase inhibitor raltitrexed, which—apart from its comparable antitumor activity with bolus FU/LV¹⁷—seems to have certain advantages, including a markedly lower rate of mucositis and leukopenia and a more convenient administration schedule, ie, a 15-minute infusion once every 3 weeks.^17,18

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients with histologically confirmed, nonresectable, metastatic or locally recurrent colorectal adenocarcinoma and bidimensionally measurable disease (defined as presence of at least one index lesion capable of two-dimensional measurement by computed tomography [CT] scan outside any irradiated zone and > 2 cm in diameter) were considered candidates for this study. Eligibility criteria also included age between 19 and 75 years, a World Health Organization (WHO) performance status of 2 or less, adequate bone marrow reserve (leukocyte count 4,000/µL, platelet count 100,000/µL), adequate renal function (serum creatinine concentration < 132 µmol/L), and adequate hepatic function (serum bilirubin level < 34 µmol/L and serum transaminase level < two times the upper limit of normal). Patients may have received adjuvant fluoropyrimidine-based chemotherapy and/or radiation therapy, which must have been completed at least 6 months before study entry. Similarly, palliative radiation therapy was allowed, provided that less than 20% of the bone marrow was involved, a target lesion was present outside the radiation port, and toxicities had been fully resolved. Patients with serious or uncontrolled concurrent medical illness or a history of other malignancies, with the exception of excised cervical or basal skin/squamous cell carcinoma, were not eligible for treatment. Also ineligible were those who had CNS metastases. All patients gave informed consent according to institutional guidelines before study registration.

Randomization Procedures. Before randomization, patient eligibility was confirmed by a protocol-specific checklist. After signing informed consent documents, patients were stratified according to WHO performance status (score 0 to 1 v 2), number of metastatic sites (single v multiple sites), and prior adjuvant (radio)chemotherapy. Patients were then randomly assigned to one treatment regimen by the central office located at the University of Vienna. Balance across strata was attained using the method of Pocock and Simon.¹⁹

Treatment Protocol. Chemotherapy consisted of 4-weekly courses either of oxaliplatin 85 mg/m², diluted in 250 mL of 5% glucose, followed by irinotecan 175 mg/m² (both administered as a 2-hour intravenous infusion on days 1 and 15; arm A) or of raltitrexed 3 mg/m² given as a 15-minute intravenous infusion on day 1 every 3 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months (six courses in arm A and eight courses in arm B) unless there was prior evidence of progressive disease (PD). According to a cross-over study design, in patients with PD as well as in those relapsing after withholding of chemotherapy, second-line treatment with the opposite arm was effected. Concomitant medications routinely given before cytotoxic drug administration included 8 mg of ondansetron plus 8 mg of dexamethasone in arm A and 8 mg of ondansetron in arm B. In the combination arm, if severe cholinergic symptoms were observed during or after irinotecan infusion, subcutaneous injection of 0.25 mg of atropine was recommended and prophylactically administered during subsequent courses. Specific guidelines for treatment of delayed diarrhea were provided which recommended 2 mg of loperamide every 2 hours until more than 12 hours had passed after the last loose stool.

Toxicity and Dosage Modification Guidelines
Adverse reactions were evaluated according to the National Cancer Institute’s common toxicity criteria.²⁰ In the event of grade 4 hematologic or any other severe ( grade 3) organ toxicity in individual patients, in both treatment arms, chemotherapeutic drug doses were reduced by 25% for subsequent courses. In arm A, oxaliplatin was discontinued if paraesthesia associated with pain or functional impairment persisted between treatment courses, or if a patient had experienced any other severe neurotoxicity. Treatment could be delayed for up to 2 weeks if symptomatic toxicity persisted and/or the absolute neutrophil count was lower than 1,000/µL and/or the platelet count was lower than 75,000/µL. Subcutaneous administration of granulocyte colony-stimulating factor 5 µg/kg/d on 5 consecutive days was recommended in the former group of patients. Any patient who required more than 2 weeks for recovery of adverse reactions was taken off the study.

Pretreatment and Follow-Up Evaluation
Within 2 weeks before initiating chemotherapy, all patients were assessed by physical examination, routine hematology and biochemistry analyses, ECG, chest x-ray, and CT scans to define the extent of disease. Complete blood cell counts with platelet and differential counts were obtained weekly during chemotherapy, and serum chemistries were repeated at least once every course. Subjective symptoms, body weight, physical examination, performance status, and all adverse reactions were recorded before each treatment course. Measurable lesions were reassessed every 8 weeks by CT scan, x-ray, or any other technique that allowed retrospective and independent evaluation.

Study End Points and Assessment of Response
The primary end point of this study was objective response rate, which was evaluated according to WHO criteria.²¹ A complete response (CR) was defined as the disappearance of all perceptible disease on two consecutive evaluations 4 weeks apart. A partial response (PR) was defined as a greater than 50% reduction in sum of the products of the longest perpendicular diameters of all measurable disease with no new lesions appearing and none progressing for at least 4 consecutive weeks. Patients were declared to have PD if new lesions appeared or tumor size increased by 25% over pretreatment measurements. Stable disease (SD) was defined as an inability to meet CR, PR, or progression criteria. All tumor measurements were reviewed and confirmed by an independent panel of oncologists and radiologists blinded to treatment to confirm responses and the date of progression.

Secondary efficacy end points included progression-free survival (calculated from the randomization date to the date when PD was first observed or, if the patient died without evidence of progression, to the date of death) and overall survival.

Sample Size and Statistical Considerations
To define the sample size, the Simon’s minimax two-stage design for phase II clinical trials was utilized,²² setting the alpha and beta errors as 0.05 and 0.10, respectively, and defining the minimum activity of interest (p0) for the experimental treatment as a response rate of 20%. To test the alternative (p1) hypothesis of a 40% activity, at least 14 responses had to be reported among the final sample of 45 patients.

This sample size was also sufficient to make an interim comparison of activity between the experimental and control treatments, according to the two-stage design for phase III randomized trials.²³ In fact, with a 20% difference in response rate (20% v 40%) between the control and experimental regimen, a difference of at least 4% in response rate should have been observed (with a 90% power) among the first 40 treated patients per arm. If this were not the case, the study could be terminated early. Otherwise, accrual should have continued until it reached a total of 98 patients per arm, and a second comparison would have been made on the final sample size.

Differences in distribution of patients between the two arms of the trial were evaluated with the ² test.²⁴ The exact binomial confidence interval was applied to estimate the response rates. Progression-free and overall survival were examined with the Kaplan-Meier product-limit method, and treatment arms were compared using the log-rank test.²⁵

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients Characteristics
Between May 1999 and June 2000, a total of 92 patients were entered onto the study and received the allocated treatment subsequent to randomization. Forty-six patients were randomized to arm A (oxaliplatin/irinotecan), and 46 were randomized to the control arm, arm B (raltitrexed). As shown in Table 1, the two groups were well matched for pretreatment characteristics, with the exception that more patients in the raltitrexed arm were female and had intra-abdominal/pelvic extension than patients in the experimental arm. However, no significant imbalances in major prognostic variables occurred in the randomization. The patients’ median age was 66 years, and the majority (74%) had a WHO performance status of 0 or 1. Most patients had moderately differentiated tumors (66.3%) and two or more metastatic sites (60.9%) involving the liver (70.6%). The primary tumor site was the colon in 51 patients and the rectum in 41 patients, and approximately one third (34.8%) had received adjuvant FU/LV with or without radiotherapy.

At the cutoff date (9-month minimum follow-up duration), all data were mature except for those relating to the definitive effect of second-line treatment after cross-over.

Treatment Tolerance
In the oxaliplatin/irinotecan arm, toxicity was recorded in 46 patients, who received a median of six courses (range, one to six; 213 courses were analyzed). In the raltitrexed control arm, toxicity was recorded in 45 patients, who received a median of six courses (range, one to eight; 233 courses were analyzed). In arm A, 10 out of the first 20 patients who were entered at the initial dose level (oxaliplatin 85 mg/m² and irinotecan 175 mg/m²) experienced severe adverse events (SAEs) necessitating a 25% dose adjustment of chemotherapeutic drugs according to the study protocol. In eight of these 10 patients, SAEs occurred during the first two treatment courses. Seven patients experienced grade 3 or 4 diarrhea alone (n = 1) or combined with grade 3 emesis (n = 3), grade 3 infection (n = 2), or grade 4 neutropenia (n = 1). Three additional patients experienced grade 4 neutropenia, grade 3 emesis, or peripheral sensory neuropathy. In accordance with the poor tolerance of the experimental treatment in this initial cohort of patients, a dose adjustment of irinotecan to 150 mg/m² (on days 1 + 15) was effected. Twenty-six patients were subsequently treated at this dose level. SAEs were noted in six (23%) of these patients—grade 3 diarrhea in two, grade 4 neutropenia in three, and grade 3 peripheral neuropathy. A summary of treatment-associated toxicities according to irinotecan dose level is shown in Table 2. After adjustment of the irinotecan dose to 150 mg/m², the most commonly encountered events (all grades) included neutropenia (81%), anemia (77%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%).

Dose Intensities
In the experimental arm, at the initial 175-mg/m² irinotecan dose level, the mean given dose-intensity of oxaliplatin was 84.8% of the projected dose and 86.9% for irinotecan. The mean dose of oxaliplatin was 36 mg/m²/wk (range, 29.1 to 42.5 mg/m²/wk), and the mean dose of irinotecan was 76 mg/m²/wk (range, 59.9 to 87.5 mg/m²/wk). At the 150-mg/m² irinotecan dose level, the relative dose-intensity was 92.6% for oxaliplatin and 94.9% for irinotecan; mean given doses were 39.4 mg/m²/wk (range, 32.7 to 42.5 mg/m²/wk) and 71.2 mg/m²/wk (range, 58 to 75 mg/m²/wk), respectively. In the control arm, the relative dose-intensity of raltitrexed was 98.7%, and the mean given dose was 0.98 mg/m²/wk (range, 0.72 to 1.0 mg/m²/wk).

Response to Treatment
According to the independent review committee, out of the 86 patients assessable for radiologic response, there were three CRs and 26 PRs (overall response rate, 33.7%). As indicated in Table 3, 20 (43.5%; 95% CI, 29% to 58.9%) of 46 patients randomized to oxaliplatin/irinotecan responded (three CRs and 17 PRs), compared with nine (19.6%; 95% CI, 9.4% to 34%) of 46 patients randomized to raltitrexed (all PRs). The difference in response rates was statistically significant (P = .0025), although the median duration was comparable between the two treatment arms (7.2 v 6.0 months; P = .0637). In the experimental combination arm A, the objective response rate for patients treated at the irinotecan starting dose of 175 mg/m² was 50% (10 of 20 patients), and the rate among those who were treated at the reduced dose level of 150 mg/m² was 38.5% (10 of 26 patients) (P = .629). Thirty-one patients were rated as having SD, 15 in arm A (32.6%) and 16 (34.8%) in arm B. Thus, the rate of disease control (CR + PR + SD) was 76.1% versus 54.3%, whereas PD was documented in nine and 17 patients in arms A and B, respectively.

Overall, 27 patients initially treated with raltitrexed were crossed over to oxaliplatin/irinotecan after the development of PD, and five patients received other second-line chemotherapy. Twenty-five patients who were first treated in the combination arm were crossed over to raltitrexed. There was a 33.3% (eight of 24) radiologic response rate with oxaliplatin/irinotecan (three patients are not yet assessable), compared with 14.2% (three of 21 assessable patients) for second-line raltitrexed on disease progression. At the time of this report, a third-line regimen (with capecitabine or a farnesyl transferase inhibitor) was effected in 15 patients, including nine of the patients in arm A and six patients on arm B.

Progression-Free and Overall Survival
As shown in Fig 1, with a median follow-up duration of 15 months (range, 9 to 22 months), progression-free survival was significantly increased for patients treated with oxaliplatin/irinotecan: median progression-free survival was 7.1 months, with a 1-year progression-free survival of 23.8%, compared with 5.0 months and a 1-year progression-free survival of 4.8% for raltitrexed (P = .0033). However, there was no benefit in overall survival. The median overall survival times were 16.0 and 16.5 months for oxaliplatin/irinotecan and raltitrexed, with 1-year survival rates of 60.8% and 58.9% (P = .3943), respectively. At the time of analysis, 45 patients had died, 21 treated with oxaliplatin/irinotecan and 24 treated with raltitrexed (Fig 2).

View larger version (14K): [in this window] [in a new window]   Fig 1. Progression-free survival.

View larger version (12K): [in this window] [in a new window]   Fig 2. Overall survival.

Palliative Effects of Treatment
Among patients with a baseline performance status of 1 or 2, an improvement by at least one level during or after completion of treatment was noted in 62% of those who were randomized to oxaliplatin/irinotecan and 29% of those who were randomized to raltitrexed (P = .021). Weight gain 5% of premorbid body weight was recorded in 19.6% of patients in arm A versus 32.6% of patients in arm B (P = .235). Disease-related subjective symptoms regressed or disappeared in seven (58.3%) of 12 assessable patients in arm A and five (35.7%) of 14 in arm B (P = .727). In both arms, palliative benefits were closely related to the effect of treatment, ie, improvements in performance score, body weight, and/or tumor-related symptoms were exclusively observed in patients who achieved either an objective response or SD.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The main aim of this randomized phase II study was to assess the activity and tolerance of a new cytotoxic regimen for the front-line treatment of patients with advanced colorectal cancer. The rational for choosing a combination of oxaliplatin plus irinotecan included both drugs’ well-established single-agent activity in this disease,^3,4 in vitro evidence of cytotoxic synergism,^9,10 lack of pharmacokinetic interactions and of overlapping clinical toxicity profiles,¹¹ and recently documented, encouraging results in patients after unsuccessful FU/LV-based chemotherapy.^12-15 We decided to use a biweekly regimen with the recommended drug doses as described by Wasserman et al¹²; for comparative purposes, we selected a control arm with the specific thymidylate synthase inhibitor raltitrexed, which has demonstrated antitumor activity comparable to bolus FU/LV.¹⁷

The experimental combination arm was found to be highly effective, suggesting a duplication of objective response rates compared with the raltitrexed control arm. The confirmed overall response rate in the intent-to-treat analysis was 43.5% (95% CI, 29% to 58.9%) versus 19.6% (95% CI, 9.4% to 34%) (P = .0025). Similarly, a significantly longer progression-free survival (7.1 versus 5.0 months; P = .0033), a higher rate of disease control (CR + PR + SD) of 76.1% versus 54.3%, and certain advantages in terms of palliative effects of treatment were noted in patients receiving first-line treatment with oxaliplatin plus irinotecan. The superiority of the experimental arm seemed to be maintained after a dose attenuation of the irinotecan starting dose from 175 mg/m² to 150 mg/m², which was considered mandatory because half of our first 20 patients (undergoing chemotherapy in a palliative treatment setting) experienced SAEs, generally during the first two courses of treatment. At the reduced dose level, which resulted in an objective response rate of 38.5% (10 of 26 patients) and a progression-free survival of 6.4 months, the tolerance of treatment was acceptable; the overall rate of severe adverse reactions, in fact, seemed almost similar to that in the (fairly well tolerated) raltitrexed control arm, with nonfebrile neutropenia, alopecia, nausea/emesis, peripheral sensory neuropathy, and diarrhea constituting the most commonly observed side effects. The particularly low rate of grade 3 oxaliplatin-associated neurotoxicity seems noteworthy and is likely to be related to the study protocol’s limited treatment duration, resulting in a lower cumulative dose of the platinum analog. A superior tolerance of cytotoxic chemotherapy when it is given for a limited duration rather than continuously until progression has been documented in other solid tumors as well as in patients with advanced colorectal cancer.^26,27 In the latter randomized trial (MRC Cr06b), comparing 12 weeks of continuous-infusion FU or raltitrexed plus retreatment on progression with therapy until progression, a significant decrease in overall toxicity, SAEs, and a better quality of life were noted in favor of the limited treatment duration arm.²⁷ The observed lack of a difference in progression-free and overall survival in this trial, challenging current orthodoxy on treatment duration, makes it also unlikely that the limited treatment duration strategy in the present study has introduced a bias toward shorter progression-free and overall survival.

A surprising finding in our study was the lack of a difference in overall survival time between the experimental and control arms, particularly in view of the published results of previous phase II and randomized phase III studies comparing raltitrexed with bolus FU/LV.¹⁷ Median survival times in patients treated with raltitrexed in these studies were in the range of only 9.7 to 11.2 months. Differences in pretreatment characteristics between the study populations may in part have accounted for this divergence. In the present trial, however, the main prognostic factors were very well balanced across the two arms; therefore, a selection bias was unlikely to have occurred. In fact, the most plausible explanation for the equivalent overall survival at the interim comparison of this novel combination regimen with raltitrexed monotherapy seems to be the high rate of cross-over to a very active second-line regimen. Other variables, although less likely to have obscured an impact on survival in the otherwise superior experimental arm, include a too short duration of tumor responses and a too low rate of overall responses and/or CRs.²⁸ In the present study, as opposed to many other FU/LV-based trials which consistently produced overall survival in the 12-month range, as many as 70% of the patients in the control arm received second-line treatment, and the confirmed radiologic response rate among the 24 assessable patients treated with oxaliplatin plus irinotecan was 33.3%. This included two CRs, and there were two responding patients who underwent potential curative liver metastasectomy. Our hypothesis/explanation for the lack of a difference in overall survival times, ie, that effective second-line treatment is able to counterbalance an inferior first-line treatment, is supported by calculations derived from a tumor-specific mathematical model as well as by a number of recently published clinical trials. In the mathematical model, which comprises a database of 3,825 colorectal cancer patients receiving palliative FU treatment, data suggest that a difference in the response rate of 30% may be compensated by an effective second-line regimen.²⁹ As concerns the clinical setting, several studies have demonstrated an impressive survival in metastatic colorectal cancer when two or more lines of treatment are effected.^5,6,30,31 In two randomized studies with a design similar to ours that compared continuous-infusion or chronomodulated FU/LV to the same regimen plus oxaliplatin, there was also no significant difference in overall survival, with a rather high percentage of patients having received effective oxaliplatin and/or irinotecan-based second-line therapy.^5,6 The lack of a difference in survival when using these chemotherapeutic agents in varying order is further supported by a recent study conducted by the Oncology Multidisciplinary Research Group, which demonstrated an almost 2-year median survival for oxaliplatin/FU/LV followed by irinotecan/FU/LV or the same regimens in reverse sequence.³¹

In conclusion, this randomized phase II trial demonstrated that biweekly oxaliplatin plus irinotecan has substantial antitumor activity in patients with previously untreated advanced colorectal cancer. Provided a reduced irinotecan dose of 150 mg/m² is used (rather than 175 mg/m² as recommended in a previous phase I/II study), this regimen was generally well tolerated. Accordingly, this drug combination should be investigated further in the front-line setting in randomized phase III studies, two of which (using different dose schedules) are currently ongoing in the United States (North Central Cancer Treatment Group trial N 9741) and Europe (the FIRE [fluorouracil, folinsäure, irinotecan, and oxaliplatin] protocol, coordinated by A. Schalhorn and V. Heinemann, Klinikum Grosshadern, Germany). The oxaliplatin plus irinotecan combination was also confirmed to be highly effective for second-line treatment, as indicated by the response activity after cross-over and the comparable overall survival time between the experimental and control arms. According to other selected clinical trials, our experience, and present data, it seems that the thymidylate synthase inhibitor raltitrexed, the topoisomerase I inhibitor irinotecan, and the novel platinum analog oxaliplatin, each characterized by a unique mechanism of action and potential synergistic activity with the other drugs, play an equally important role in the management of advanced colorectal cancer, no matter in which order they are given. The imminent question of whether sequential treatment is in fact equivalent to more aggressive front-line treatment should be addressed in future clinical trials that should include two lines of therapy in the study design.⁵ Although it seems likely that the sequential approach is feasible, it remains to be determined which prognostic subgroups are most likely to benefit from a more or less aggressive front-line therapeutic strategy.

	ACKNOWLEDGMENTS

 
Supported in part by the Gesellschaft zur Erforschung der Biologie und Behandlung von Tumorkrankheiten.

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Submitted April 30, 2001; accepted August 10, 2001.

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