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Superiority of Oxaliplatin and Fluorouracil-Leucovorin Compared With Either Therapy Alone in Patients With Progressive Colorectal Cancer After Irinotecan and Fluorouracil-Leucovorin: Interim Results of a Phase III Trial

Mace L. Rothenberg, Amit M. Oza, Robert H. Bigelow, Jordan D. Berlin, John L. Marshall, Ramesh K. Ramanathan, Lowell L. Hart, Sunil Gupta, Carlos A. Garay, Brent G. Burger, Nathalie Le Bail, Daniel G. Haller

From the Vanderbilt-Ingram Cancer Center, Nashville, TN; Princess Margaret Hospital, Toronto, Ontario, Canada; Sanofi-Synthelabo Research, Malvern; University of Pittsburgh Cancer Institute, Pittsburgh; University of Pennsylvania Cancer Center, Philadelphia, PA; Lombardi Cancer Center, Washington, DC; and Florida Cancer Specialists, Fort Myers, FL.

Address reprint requests to Mace L. Rothenberg, MD, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307; email: mace.rothenberg{at}vanderbilt.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: In North America, no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan, bolus fluorouracil (FU), and leucovorin (IFL).

Patients and Methods: Patients with metastatic colorectal cancer who progressed after IFL therapy were randomly assigned to bolus and infusional FU and leucovorin (LV5FU2), single-agent oxaliplatin, or the combination (FOLFOX4). This planned interim analysis evaluated objective response rate (RR), time to tumor progression (TTP), and alleviation of tumor-related symptoms (TRS) in an initial cohort of patients.

Results: Between November 2000 and September 2001, 463 patients from 120 sites in North America were randomly assigned to treatment. FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy. Objective RRs determined by an independent radiology panel were 9.9% for FOLFOX4 versus 0% for LV5FU2 (Fisher’s exact test, P < .0001). Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (two-sided, stratified log-rank test, P < .0001). Relief of TRS occurred in 33% of patients treated with FOLFOX4 versus 12% of patients treated with LVFU2 (² test, P < .001). Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy. Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate.

Conclusion: For patients with metastatic colorectal cancer, second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR, TTP, and relief of TRS.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
IN 2002, colorectal cancer was diagnosed in 165,900 people in the United States and Canada and resulted in 63,200 deaths.^1,2 Although not curative, systemic chemotherapy improves survival and delays the onset of tumor-related symptoms (TRS).³ Since 2000, the combination of irinotecan, bolus fluorouracil, and leucovorin (IFL) has been the most widely used front-line chemotherapy in North America for medically fit patients with metastatic colorectal cancer.⁴ This three-drug combination is superior to fluorouracil (FU) and leucovorin in terms of objective response rate (RR), time to tumor progression (TTP), and overall survival whether the FU component of the regimen is administered as a bolus (IFL or Saltz regimen) or as a bolus and infusion (Douillard regimen).^4–6 In the United States, it is estimated that approximately 70% of patients with newly diagnosed metastatic colorectal cancer receive IFL as first-line chemotherapy. Although irinotecan was originally approved for use as second-line treatment in patients with recurrent colorectal cancer, its integration into first-line therapy left a therapeutic void for colorectal cancer patients with progressive disease after front-line treatment with IFL.

When this study was initiated, there were no data regarding the efficacy of other chemotherapeutic agents after treatment with IFL. However, a number of phase II trials had been performed in patients with progressive colorectal cancer after treatment with bolus FU and leucovorin; these trials indicated activity for three different therapeutic approaches that could be extrapolated to this setting. One option was to change the schedule of FU administration from bolus to infusion. Preclinical studies showed that short exposure to FU preferentially inhibits RNA synthesis, whereas protracted exposure to FU has a predominant effect on inhibition of thymidylate synthase and DNA synthesis.⁷ Although these results were inconsistent and largely specific to individual cell lines, they provided the theoretical basis for several clinical trials in which patients with colorectal cancer whose disease progressed after administration of bolus FU were subsequently treated with infusional FU. Objective RRs of 7% to 16%, median TTPs of 3 to 4 months, and median survival times of 7.5 to 9 months were reported for this strategy.^8–11 Although the oral FU prodrug, capecitabine, did not produce any objective responses in a phase II trial performed in this setting, one third of patients experienced disease stabilization for 4 months, indicating incomplete clinical cross-resistance for this related approach.¹²

Oxaliplatin is a platinum analog that differs from cisplatin or carboplatin by having a diaminocyclohexane moiety that is retained after drug aquation. This bulky side chain is believed to contribute to its distinct spectrum of activity in preclinical models and clinical trials.^13,14 Nowhere is this difference more striking than in the activity observed for oxaliplatin in colorectal cancer, a cancer in which cisplatin and carboplatin are inactive.¹⁴ Preclinical studies demonstrated that oxaliplatin had significant activity against six of the eight colorectal cancer cell lines contained in the National Cancer Institute’s Human Tumor Cell Line screen and could inhibit tumor-colony formation in one third of explanted human colorectal cancers.^13,14 Three phase II studies using single-agent oxaliplatin as second-line therapy in patients with FU-leucovorin–pretreated metastatic colorectal cancer reported objective RRs of 10% to 11% and median survival of 8.2 to 9.2 months.^15,16 An even larger number of studies were performed using the combination of oxaliplatin, FU, and leucovorin in patients with progressive disease after treatment with FU and leucovorin (the third therapeutic option in this situation). The overall RRs in these trials were 13% to 55%, with progression-free survival ranging from 3 to 10 months and median survival ranging from 7 to 17 months.^17–22 To control for the potential effect of changing the schedule of FU administration on the observed antitumor activity, several trials added oxaliplatin to the same regimen of FU and leucovorin on which the patient had progressed. In these trials, RRs of 11% to 21%, progression-free survivals of 4 to 5 months, and median survivals of 10 to 11 months were obtained.^23,24

Given the similarity of data from all three therapeutic approaches, this trial was designed as a three-arm trial comprising bolus and infusional FU and leucovorin, single-agent oxaliplatin, and the combination of oxaliplatin, FU, and leucovorin (FOLFOX4) to address the following questions: How effective is changing the FU administration schedule from bolus to bolus and infusion in patients who develop progressive disease during or shortly after front-line IFL chemotherapy? How effective is single-agent oxaliplatin in this setting? Does the addition of oxaliplatin to bolus and infusional FU confer any therapeutic advantage over bolus and infusional FU alone? This report summarizes the results of a planned analysis in which objective RR was the primary end point. This analysis was undertaken after the first 450 patients enrolled onto the study had been observed for at least 3 months, representing sufficient time for all patients to undergo 6-week and 12-week tumor re-evaluation.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Eligibility Criteria
Patients were required to have histologically or cytologically confirmed adenocarcinoma arising in the colon or rectum and radiographic evidence of metastatic, progressive disease during or within 6 months of completing therapy with IFL as reported by Saltz et al.⁴ The IFL regimen comprises irinotecan 125 mg/m², bolus FU 500 mg/m², and leucovorin 20 mg/m² administered weekly for 4 consecutive weeks, followed by a 2-week rest. IFL treatment could have been administered as first-line chemotherapy for metastatic colorectal cancer or as adjuvant therapy for patients with locally advanced disease. Slight variations in the standard regimen of IFL were allowed to reflect common clinical practice, including administration of therapy on a 2-week on and 1-week off or 3-week on and 1-week off schedule, or dosing of the irinotecan at 100 mg/m² and FU at 400 mg/m².

Other inclusion criteria consisted of age 18 years old; Karnofsky performance score (KPS) of 50; measurable disease by Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria; completion of IFL chemotherapy at least 3 weeks before random assignment of treatment and resolution of any treatment-related toxicities; serum creatinine 1.5 times the institution upper limit of normal (IULN); total bilirubin 1.5 times IULN; AST and ALT 2 times IULN (or 5 times IULN if liver metastases are present); alkaline phosphatase 2 times IULN (or 5 times IULN if liver metastases are present); absolute neutrophil count 1.5 x 10⁹/L; and platelet count 100 x 10⁹/L. Prior radiation therapy was allowed provided that it had been completed at least 3 weeks before random assignment to treatment. A previously radiated lesion could be used for tumor measurement only if it had demonstrated clear evidence of progression. Patients had to be capable of completing a daily analgesic consumption diary and a questionnaire that summarized the nature and severity of specific TRS, such as pain and limitations on normal daily activities. All patients had to sign a consent form approved by the institutional review board or institutional ethics committee in adherence with provisions set forth in the Helsinki Agreement.

The following were considered exclusion criteria: concomitant treatment with other anticancer therapy; prior chemotherapy for metastatic colorectal cancer with anything other than IFL; prior therapy with oxaliplatin; current, active cancer originating from a site other than colon or rectum; myocardial infarction within 6 months before study entry; interstitial lung disease or pulmonary fibrosis; peripheral neuropathy that interfered with function; uncontrolled intercurrent illness; known dihydropyrimidine dehydrogenase deficiency; and current pregnancy or lactation.

Treatment
FU and leucovorin were obtained from commercial sources at the discretion of the individual treatment centers. Oxaliplatin (Eloxatin, Sanofi-Synthelabo Research, Malvern, PA) was supplied as a freeze-dried powder in 50- and 100-mg vials. Oxaliplatin was reconstituted by adding 10 mL (for the 50-mg vials) or 20 mL (for the 100-mg vials) of water for injection or D₅W and then by diluting it in an infusion solution of 250 to 500 mL of D₅W. Patients were randomly assigned to one of three treatment regimens (Fig 1). The first regimen consisted of leucovorin 200 mg/m² intravenously (IV) for 120 minutes, followed by FU 400 mg/m² IV bolus for 2 to 4 minutes, followed by FU 600 mg/m² infusion for 22 hours (LV5FU2). This therapy was administered on day 1 and repeated on day 2 of a 14-day treatment cycle. The single-agent oxaliplatin arm consisted of oxaliplatin 85 mg/m² IV for 120 minutes, administered on day 1 of a 14-day treatment cycle. The third arm combined both regimens: oxaliplatin 85 mg/m² and leucovorin 200 mg/m² IV administered simultaneously for 120 minutes (using separate bags and a Y-connector) followed by FU 400 mg/m² IV bolus followed by FU 600 mg/m² infusion for 22 hours on day 1 and the same therapy, without the oxaliplatin, administered on day 2 of a 14-day treatment cycle (FOLFOX4). All therapy was administered on an outpatient basis. Pretreatment with a 5-hydroxytryptamine-3 antagonist and dexamethasone was strongly recommended for patients receiving oxaliplatin-containing regimens.

View larger version (27K): [in this window] [in a new window]   Fig 1. Drug administration schema. (A) Bolus and infusional fluorouracil (FU) and leucovorin; (B) single-agent oxaliplatin; (C) combination of regimens A and B (FOLFOX4).

Assessment Criteria
The primary efficacy variable in this prospectively planned interim analysis was objective RR using RECIST response criteria. To qualify as an objective response, all responses had to be confirmed on a subsequent scan performed at least 4 weeks after the initial scan demonstrating a 30% reduction in the sum of the longest diameters of all measured lesions. All scans were evaluated in a central facility (RadPharm, Princeton, NJ) where they were reviewed by board-certified radiologists who were blinded to study treatment and disease assessment by the treating physician. Secondary efficacy end points for this report include TTP and improvement in TRS in the subpopulation of patients who were symptomatic at the time of entry onto this study. TTP, as determined by the treating physician, was measured as the number of months from the date of random assignment to treatment to the date of radiographic demonstration of disease progression, the date of death, or deterioration in clinical status caused by TRS (clinical progression). TTP, as determined by the independent radiologic review panel, was measured as the number of months from the date of random assignment to treatment to the date of radiographic disease progression. In the TTP assessment by the independent radiologic review panel, patients who discontinued treatment without radiographic evidence of tumor progression were considered censored as of the date of last tumor evaluation showing stable disease or better.

Another secondary objective of this analysis was to estimate the proportion of patients who demonstrated improvement in TRS that were present at baseline. Patients were classified as symptomatic at baseline if they had a KPS 80, visual pain analog score of 20 mm on a 100-mm scale, consumption of analgesics equivalent to at least 10 mg/d of intravenous morphine, or weight loss of more than 10% from usual body weight. Criteria used to determine improvement in TRS were similar to the clinical benefit response criteria used in trials evaluating gemcitabine in patients with advanced pancreatic cancer.²⁵ However, some modifications were made. TRS assessment in this trial used KPS as determined by both the physician and the patient (whichever was lower) as compared with the clinical benefit response assessment used in the gemcitabine trials, which involved KPS assessment by two healthcare professionals and selection of the lower of the two determinations. In addition, a significant improvement in weight required weight gain of 5% over baseline for this study and 7.5% over baseline for the gemcitabine studies. Dose-intensity (in milligrams per square meter per week) was calculated as total cumulative dose divided by the duration of dosing ([{start date of last cycle} - {start date of first cycle} + 14]/7). Relative dose-intensity (RDI) was calculated as the dose-intensity divided by the planned dose-intensity, multiplied by 100. Planned dose-intensities, expressed as milligrams per square meter per week, were 1,000 for FU and 42.5 for oxaliplatin.

Determination of Sample Size and Statistical Analysis
Randomization was performed centrally and was stratified by KPS (50 to 60 and 70 to 100), number of organs involved by metastatic disease (one v two), and lactate dehydrogenase ( 1.5 times IULN and > 1.5 times IULN). This protocol-specified analysis was performed after 150 patients had been enrolled onto each of the three study arms and had had at least 3 months of follow-up. This sample size provided more than 80% power to detect an anticipated 12% difference in objective RR (8% v 20%) in the control arm (LVFU2) versus the test arm (FOLFOX4) using a two-sided Fisher’s exact test at the .05 level of significance. A secondary analysis was performed to determine whether there was a significant difference in RRs between the single-agent oxaliplatin arm versus the control LVFU2 arm. This trial ultimately accrued a total of 821 patients and, when mature, will have sufficient power to detect a 3-month difference in median survival between the FOLFOX4 investigational treatment arm and the LVFU2 control arm at the .05 level of significance (two-sided, log-rank test).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Baseline Characteristics
Between November 2000 and September 2001, a total of 463 patients were randomly assigned to treatment in this North American clinical trial. Four patients were not eligible for this study and are not included in the intent-to-treat efficacy analysis: two patients did not have colorectal cancer, one patient did not receive prior therapy with IFL, and one patient did not provide informed consent. Eighteen patients never received treatment during the study. Of these, 16 patients were eligible for study and are included in the intent-to-treat efficacy analysis, and two patients were not eligible and were not included in either the efficacy or safety analysis. Therefore, the intent-to-treat efficacy analysis consists of 459 patients and the safety analysis consists of 445 patients. All three arms were well balanced for known prognostic factors (Table 3). More than 90% of patients had KPS of 70 to 100 in each of the treatment arms. Approximately 70% of patients had at least two organs involved with metastases and 40% of patients had baseline lactate dehydrogenase more than 1.5 times the IULN. Ninety-eight percent of patients had received prior IFL therapy for metastatic disease and the remaining patients had received IFL as adjuvant therapy. The median duration of first-line IFL treatment was 6.2 months. This is consistent with the median 7.0-month TTP reported in other phase III trials.^4,6 Approximately two thirds of patients were symptomatic at entry onto this study by at least one of the four parameters of TRS (ie, KPS 80; pain severity of 20 mm on a 100-mm scale; analgesic consumption 10 mg intravenous morphine equivalents per day; or 10% weight loss from the patient’s usual weight). The most common TRS at baseline was impaired KPS.

View larger version (17K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves of time to tumor progression (TTP) as determined by independent radiologic reviewers. (——) Bolus and infusional fluorouracil (FU) and leucovorin plus oxaliplatin (OXAL) (median TTP, 4.6 months); (•- - - -•) bolus and infusional fluorouracil and leucovorin (median TTP, 2.7 months); (*- - - -*) single-agent oxaliplatin (median TTP, 1.6 months).

Safety
The most frequent adverse events encountered by patients treated in this clinical trial were gastrointestinal (primarily nausea, vomiting, diarrhea, and stomatitis), hematologic (primarily neutropenia), and neurosensory (primarily peripheral neuropathy in those patients who received oxaliplatin alone or in combination with FU and leucovorin). The most common adverse events are summarized in Table 7.

Neutropenia was the most common grade 3 to 4 hematologic toxicity and occurred more commonly in patients treated with FOLFOX4 than in those who received either LV5FU2 or oxaliplatin. Of the patients treated with FOLFOX4, 27% experienced grade 3 and 17% experienced grade 4 neutropenia, accounting for 9% and 3% of all FOLFOX4 treatment cycles, respectively. Ten patients developed febrile neutropenia, nine (6%) of whom were treated with FOLFOX4 and one (1%) of whom was treated with LV5FU2. Grade 3 to 4 thrombocytopenia was more common in the FOLFOX4 arm, where it was experienced by 5% of patients, than in the LV5FU2 arm, where it did not occur in any patients. However, there were no episodes of severe bleeding in any of the patients who experienced this toxicity. There was no difference among treatment arms in the rates of grade 3 to 4 anemia.

Peripheral neuropathy was the most common toxicity observed in patients who received oxaliplatin either alone or in combination with FU and leucovorin. The peripheral neuropathy appeared in two forms. In the first form, an acute, transient, cold-exacerbated dysesthesia or paresthesia occurred shortly after administration of oxaliplatin; affected the hands, feet, perioral area, and throat; and typically lasted for several days after drug administration. In the second form, a delayed-onset, cumulative, dose-related peripheral neuropathy was characterized by paresthesias affecting the hands and feet that did not remit between cycles of treatment. Both toxicities were significantly more common in patients treated with oxaliplatin than in patients treated in the LV5FU2 control arm. However, the rates of grade 3 cumulative dose-related neuropathy (ie, sensory neuropathy interfering with activities of daily living, such as buttoning a shirt or picking up a coin) were low. Grade 3 cumulative neuropathy was experienced by 2% of the patients treated with oxaliplatin alone and 3% of the patients treated with FOLFOX4. These low rates of grade 3 neuropathy reflect the gradual onset and progression of grade 1 to 2 neuropathy that can result from continued treatment with oxaliplatin. The low rates also reflect the effect of early dose reduction or cessation in preventing the development of higher grades of oxaliplatin-induced peripheral neuropathy. Notably, the frequency and severity of cumulative, dose-related neuropathy may be underestimated because of the interim nature of this analysis and the maximum 14-month follow-up for patients included in this report.

Grade 3 laryngopharyngodysesthesia, an acute loss of the sensation of breathing after oxaliplatin infusion, was a rare event and occurred in 4% of patients who received single-agent oxaliplatin, in 2% of patients who received FOLFOX4, and in none of the patients who received LV5FU2. Hypersensitivity reactions were reported in 11% of patients treated with FOLFOX4, compared with 3% of patients treated with single-agent oxaliplatin and 1% of patients treated with LV5FU2. However, all but one of these episodes were grade 1 or 2 in intensity. Premedication with dexamethasone and H₁- and H₂-blockers in subsequent cycles enabled all of these patients to continue on with full-dose treatment. The one patient who experienced a grade 3 hypersensitivity reaction was being treated with FOLFOX4 and was the only patient to discontinue treatment because of this toxicity. Grade 3 to 4 thromboembolic events were slightly more frequent in patients treated with FOLFOX4 than in patients treated with LV5FU2. The majority of these events were peripheral deep-vein thromboses.

Overall, 53 of 445 patients (12%) required dose modification during treatment: five patients (4%) in the LV5FU2 arm, six patients (4%) in the oxaliplatin arm, and 39 patients (26%) in the FOLFOX4 arm. The most frequent reasons for dose modification were neutropenia (1%, 0%, and 9% of patients in the three arms, respectively) and diarrhea (0%, 0%, and 7% of patients in the three arms, respectively). The most common reason for treatment discontinuation was progressive disease. Rates for discontinuation because of events regardless of relationship to the study drug were similar across all three treatment arms: 6% for patients treated with LV5FU2, 5% for patients treated with single-agent oxaliplatin, and 8% for patients treated with FOLFOX4. Deaths occurring within 60 days after initiation of treatment are summarized in Table 7. Treatment-induced or treatment-exacerbated deaths were low in all three arms, ranging from 1% to 2%. Deaths occurring within 30 days of last treatment ranged from 24% for patients treated with FOLFOX4 to 32% for patients treated with LV5FU2 to 34% for patients treated with single-agent oxaliplatin. The majority of these deaths were the result of disease progression.

There was no difference in the rate or severity of toxicities when analyzed by age (< or 65 years), sex, or prior history of pelvic irradiation. The incidence of grade 3 to 4 adverse events was higher in patients with baseline KPS less than 80 (69%) than in patients with KPS 80 (50%).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
In North America, front-line treatment of patients with metastatic colorectal cancer has shifted during the last few years from a two-drug regimen of FU and leucovorin to a three-drug combination of irinotecan, FU, and leucovorin. This change occurred after the emergence of data from two large, randomized trials demonstrating higher RRs, longer TTP, and improved survival in patients treated with irinotecan, FU, and leucovorin compared with patients treated with FU and leucovorin alone.^4,5 In the United States, this regimen most commonly involves the use of bolus FU in a regimen known as IFL or Saltz regimen, whereas in Europe, the FU is administered as a bolus and infusion or infusion alone in a variety of regimens. By mid-2002, it was estimated that approximately 70% of all patients with metastatic colorectal cancer in the United States were receiving first-line IFL chemotherapy. Although this treatment clearly improved the outcome for many patients with metastatic colorectal cancer, it left a therapeutic void for patients whose disease progressed during or shortly after IFL therapy. This trial was designed to evaluate the efficacy of three chemotherapeutic alternatives in this situation. The LV5FU2 regimen takes advantage of potential non–cross-resistance between bolus and infusional FU, uses a higher dose of leucovorin than that used in IFL, and served as the control arm for this study. The single-agent oxaliplatin arm was based on promising preclinical and clinical data indicating that this agent was active against colorectal cancer when administered alone to chemotherapy-naive patients or patients previously treated with FU and leucovorin. The FOLFOX4 regimen, combining oxaliplatin with LV5FU2, represented the most extensively studied oxaliplatin-containing regimen with consistently high levels of antitumor activity against colorectal cancer in phase II and III clinical trials. The three-arm design of this trial allowed us to isolate the effect of each component—oxaliplatin and LV5FU2—on the combined regimen of FOLFOX4. As determined by an independent radiologic review panel, patients treated with FOLFOX4 had a significantly higher objective RR (9.9%) and longer TTP (4.6 months) than those patients treated with LV5FU2 (0% RR, P < .0001; 2.7 months TTP, P < .0001). Our results indicate that the addition of oxaliplatin to FU-leucovorin is essential to the antitumor activity achieved with FOLFOX4 as second-line therapy in patients with progressive colorectal cancer after IFL chemotherapy.

In a similar setting, Tournigand et al²⁶ observed an investigator-assessed 15% objective RR and 4.3-month median TTP in patients with advanced colorectal cancer treated with a regimen similar to FOLFOX4 (except for omission of bolus FU on day 2) following progression on a regimen composed of irinotecan with infusional FU and leucovorin. These results are consistent with our own, in which we observed an investigator-assessed 13.8% RR and 4.0-month median TTP. This indicates similar activity for the combination of oxaliplatin, FU, and leucovorin in the second-line setting regardless of whether patients received irinotecan with bolus or infusional FU as first-line treatment.

We also sought to determine whether similar results could be obtained with oxaliplatin alone, thereby avoiding the inconvenience and additional toxicities associated with infusional FU and leucovorin. We observed no significant advantage of single-agent oxaliplatin compared with FU and leucovorin in any parameter of activity. In fact, the TTP for patients treated with single-agent oxaliplatin might have been slightly shorter than the TTP for patients treated with LV5FU2 (1.6 v 2.7 months; P = .03), although this isolated finding on a secondary end point should be interpreted with caution. Clearly, our results indicate that oxaliplatin, bolus and infusional FU, and leucovorin are all necessary components in the delivery of optimal salvage therapy for patients with progressive colorectal cancer after IFL chemotherapy. Although this beneficial interaction has been described in a number of preclinical models, the molecular basis for this interaction is only beginning to be understood.^27,28 In preclinical models, oxaliplatin appears to both reduce the catabolism of FU to dihydrofluorouracil and reduce cellular thymidylate synthase activity, each of which could increase the cytotoxic effect of FU.²⁹ What effect, if any, FU has on oxaliplatin cytotoxicity is currently unknown. Given these data and the lack of clinical activity observed with single-agent oxaliplatin in our study, it is tempting to speculate that the role of oxaliplatin may be more that of a biochemical modulator than a true cytotoxic agent, but we believe that this explanation is unlikely because of the consistent single-agent activity demonstrated for oxaliplatin in preclinical models and the activity demonstrated in a number of other clinical trials.

Although it is clear that both oxaliplatin and FU are required to obtain the beneficial effects of this therapy, oxaliplatin has also been evaluated in combination with FU using several alternative administration methods. These include short-term (24- or 46-hour) or long-term (continuous) infusions of FU (with or without the bolus FU component), daily or weekly bolus FU without the infusional component, or substitution for FU with the oral FU prodrug, capecitabine.^21,30–33 Although many of these schedules have reported substantial activity, it is unknown how they would fare in a randomized setting. In addition, one of these alternative schedules, involving daily bolus FU, has proven to be prohibitively toxic in a large-scale clinical trial.³¹ Therefore, extrapolation of the results of this study to include other schedules of FU drug administration may be premature. Chronomodulated oxaliplatin, FU, and leucovorin has demonstrated substantial antitumor activity in phase II and III clinical trials and is being compared to FOLFOX4 in an ongoing phase III trial in Europe.³⁴

Palliation is an important goal of chemotherapy for patients with unresectable metastatic colorectal cancer.³⁵ Assessment of tumor symptom burden by both the patient and the healthcare team can provide a direct and clinically meaningful parameter by which to measure the effect of chemotherapy. Our assessment of TRS involved a regularly scheduled evaluation of performance status, pain, analgesic consumption, and weight. One surprising finding of our study was that two thirds of patients with progressive, metastatic colorectal cancer suffered from TRS at baseline. This result was higher than anticipated and may reflect the subtle nature of decreased performance status, which was the most common TRS present at baseline in this study. Patients who received FOLFOX4 experienced a higher rate of relief from TRS than those treated with LV5FU2 (33% v 12%, respectively; P < .001). The superiority of FOLFOX4 compared with LV5FU2 for alleviation of TRS is consistent with advantages observed in other measures of clinical activity, including higher objective RR and longer TTP, and allows us to gain a more comprehensive appreciation of the overall effect of this therapy on the patient.

The toxicity and tolerability profiles of the regimens evaluated in this study were similar in scope, frequency, and intensity to those reported by others.^36,37 Grade 3 to 4 nausea, vomiting, and diarrhea were observed in 3% to 4% of patients treated with LV5FU2 or single-agent oxaliplatin and in 9% to 11% of those treated with FOLFOX4. Pretreatment with a serotonin antagonist and dexamethasone, and appropriate use of antidiarrheal agents, helped to control these side effects. Myelosuppression, primarily in the form of neutropenia, was more pronounced in patients treated with FOLFOX4, with 44% of patients experiencing at least one episode of grade 3 to 4 neutropenia. Grade 4 neutropenia occurred in 17% of patients and in 3% of treatment cycles of FOLFOX4. However, only nine patients (6%) treated with FOLFOX4 developed neutropenic fever. Neuropathy of any grade, either in the form of acute, cold-sensitive paresthesia or cumulative peripheral neuropathy, was observed with equal frequency (50% to 60%) in patients treated with single-agent oxaliplatin and those treated with FOLFOX4. Neurotoxicity interfering with function (grade 3) was observed in 5% of patients. On the basis of prior published experience, it is anticipated that the majority of patients will have partial or total resolution of the cumulative peripheral neuropathy after discontinuation of oxaliplatin therapy, but it is not possible to estimate that percentage in this interim analysis.³⁶ Measures to delay the onset or reduce the intensity of this toxicity are being evaluated.

Death within 60 days of initiation of treatment was observed in approximately 10% of patients treated with LV5FU2 or single-agent oxaliplatin and in 5% of patients treated with FOLFOX4. Most of those deaths were caused by progression of colorectal cancer. Sixty-day mortality that was considered to be treatment-induced or treatment-exacerbated occurred in 1% to 2% of patients, emphasizing the safety of all three regimens.³⁸

In conclusion, this randomized, three-arm trial demonstrated that FOLFOX4 produces a higher objective RR, longer TTP, and higher rate of relief from TRS than LV5FU2 in patients with progressive colorectal cancer after treatment with IFL. The combination of oxaliplatin, FU, and leucovorin is required to achieve this effect because it is not observed when oxaliplatin is administered as a single agent. FOLFOX4 represents the first effective treatment option for patients with progressive, metastatic colorectal cancer after treatment with IFL. In recognition of this, the United States Food and Drug Administration granted accelerated approval to oxaliplatin (administered with FU and leucovorin) for this indication in August 2002. Final results from this study are anticipated in 2003 and will include data on median survival and time to worsening of tumor symptoms.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following investigators and institutions participated in this study: Harish G. Ahuja, University of Wisconsin Cancer Center, Wausau; Michael Schuetz, Advanced Healthcare, Mequon; James P. Thomas, University of Wisconsin Hospital and Clinics, Madison, WI; Lowell B. Anthony, Louisiana State University Cancer Center, New Orleans; Jayne S. Gurtler, Metairie; David Rinaldi, Louisiana Oncology Associates, Lafayette; Gerald Miletello, Baton Rouge General Regional Cancer Center, Baton Rouge, LA; Stephen P. Anthony, Cancer Care Northwest, Colbert; Gary E. Goodman, Swedish Medical Center and Andrew Jacobs, Virginia Mason Medical Center, Seattle; David A. Smith, Northwest Cancer Specialists, Vancouver, WA; Edward Arrowsmith, Memorial Hospital Cancer Center and Larry Schlabach, University Oncology/Hematology Associates, Chattanooga; Natalie Dickson, Tennessee Oncology, Nashville; Tracy Dobbs, Baptist Regional Cancer Center, Knoxville; Lee Schwartzberg, The West Clinic, Donald Strickland, The Memphis Cancer Center, Memphis, TN; Robert Asbury, Interlakes Oncology/Hematology, Rochester; Hoo Chun, New York Medical College, Valhalla; Lawrence Garbo, Capital District Hematology/Oncology, Albany; Howard Hochster, New York University Cancer Center, New York; A. Kaubisch, Montefiore Medical Center, Bronx; Edward Samuel, North Shore Hematology/Oncology Associates, East Setauket, NY; Jean-Pierre Ayoub, Hôpital Notre Dame, Montreal, Quebec; Georg A. Bjarnason, Toronto-Sunnybrook Regional Cancer Center and Ronald Burkes, Mount Sinai Hospital, Toronto; Mark Vincent, London Regional Cancer Center, London; R. Wierzbicki, Peterborough Regional Health Centre, Peterborough, Ontario; Anthony Fields, Alberta Cancer Board, Edmonton, Alberta; Michael Goodyear, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; Carlos R. Becerra, Simmons Cancer Center, Mark C. Capistrano, Center for Oncology Research and Treatment, John V. Cox, The Texas Cancer Center Southwest, R. Steven Paulson, Texas Oncology, and Michael Savin, Texas Cancer Center at Medical City, Dallas; John J. Costanzi, Lone Star Oncology Consultants, Austin; Billie Marek, South Texas Regional Cancer Center, McAllen; Jairo Olivares, Texas Oncology, Garland; Donald Richards, Tyler Cancer Center, Tyler; TX; Robert J. Belt, Oncology and Hematology Clinics of Kansas City, Kansas City; Shaker R. Dakhil, Cancer Center of Kansas, Witchita, KS; John R. Eckardt, Saint Johns Mercy Medical Center and Alan P. Lyss, Missouri Baptist Cancer Center, St Louis; Ali Khojasteh, Columbia Comprehensive Cancer Care Clinic, Columbia; Timothy Pluard, Missouri Cancer Center, Saint Charles, MO; Al B. Benson III, Northwestern University Cancer Center, Chicago; Ramesh Kola, Dreyer Medical Clinic, Aurora; Brian Samuels, Lutheran General Hospital, Park Ridge; Shelby Rifkin, Hematology/Oncology Consultants, Arlington Heights; James Wade, Cancer Care Specialists, Decatur; Israel Wiznitzer, Hematology/Oncology Associates of Illinois, Highland Park, IL; Stephen A. Bernard, University of North Carolina Cancer Center, Chapel Hill; Richard A. Brodkin, Piedmont Hematology/Oncology, Winston-Salem, NC; Bill Bhaskar, Medical Oncology Care Associates, Orange; Sant P. Chawla, Los Angeles; Peter Eisenberg, California Cancer Care, Greenbrae; Louis Fehrenbacher, Kaiser Permanente Medical Group, Vallejo; Robert Lemon, Cancer and Blood Institute of the Desert, Rancho Mirage; Jonathan Polikoff, Kaiser Hospital San Diego, San Diego; Joseph Szumowski, Valley Medical Oncology Consultants, Pleasanton; Sharon Yee, Arcadia, CA; Debra S. Brandt, Northwestern Connecticut Oncology/Hematology Associates, Torrington, CT; Thomas H. Cartwright, Ocala Oncology, Ocala; Paul M. Dodd, Halifax Medical Center, Daytona Beach; Lowell Hart, Florida Cancer Specialists, Fort Myers; Leonard Kalman, Oncology Hematology Group of South Florida, Miami; Alan J. Koletsky, Comprehensive Cancer Center Specialists, Boca Raton; Richard Levine, Space Coast Medical Associates, Titusville; Rogerio Lilenbaum, Mount Sinai Comprehensive Cancer Center, Miami Beach; Robert Marsh, University of Florida Health Science Center, Gainesville; Thomas Marsland, Orange Park Cancer Center, Orange Park; Andrew Pippas, Watson Clinic, Lakeland; Sumit Sawhney, Oncology & Hematology Associates of West Broward, Tamarac; Ron Schiff, Tampa; Joel Stone, North Florida Hematology & Oncology Association, Jacksonville; Michael Wertheim, Hematology/Oncology Associates, Port Saint Lucie; Lee Zehngebot, Hematology/Oncology Consultants, Orlando, FL; Naveed Mahfooz Chowhan, Cancer Care Center, New Albany; David M. Loesch, Oncology and Hematology Associates, Indianapolis, IN; Allen L. Cohn, Rocky Mountain Cancer Center, Denver, CO; Thomas Ervin, Maine Center for Cancer Medicine, Scarborough, ME; Charles Fuchs, Dana Farber Cancer Institute, Boston, MA; Chirantan Ghosh, Iowa Oncology Associates, Cedar Rapids, IA; Alexandre Hageboutros, Cooper Cancer Institute, Camden, NJ; F. Hendler, James Graham Brown Cancer Center, Louisville, KY; Jeremy Hon, Comprehensive Cancer Institute, Huntsville; Michael Meshad, Oncology Center at Providence Park, Mobile, AL; Leslie Laufman, Hematology Oncology Consultants, Columbia; Robert N. Raju, Dayton Oncology/Hematology Consultants, Dayton, OH; David Mintzer, Pennsylvania Oncology/Hematology Associates, Edith Mitchell, Thomas Jefferson University, Philadelphia; P. Pickens, Abington Hematology Oncology Associates, Inc, Abington, PA; Manuel Modiano, Arizona Oncology Associates, Tucson, AZ; Michael Monticelli, Williamette Valley Cancer Center, Springfield, OR; W. Muir, Hematology-Oncology Associates, Fredricksburg; Joseph Schulz, Virginia Oncology Associates, Newport News, VA; Mark Olsen, Cancer Care Associates, Tulsa, OK; Mark O’Rourke, Cancer Center of the Carolinas, Greenville, SC; Philip Philip, Karmanos Cancer Institute, Detroit; Trevor Singh, Michigan State University, Flint; Philip Stella, St. Joseph Mercy Hospital, Ann Arbor, MI; Charles R. Tweedy, Jr, Ivinson Cancer Center, Ft Collins, WY; Fatih Uckun, Hughes Institute, Roseville, MN; and Richard Wheeler, III, University of Utah Huntsman Cancer Institute, Salt Lake City, UT.

	ACKNOWLEDGMENTS

 
We thank Robert Ford, MD, Donald Rosen, MD, and colleagues at RadPharm, who performed the independent radiologic review; and Monica Freese at Sanofi-Synthelabo Research for superb study management. We also thank the patients who participated in this study.

	NOTES

 
Supported by Sanofi-Synthelabo. Additional support was also received from the National Cancer Institute (5K24CA82301; M.L.R.) and the Ingram Charitable Trust (M.L.R.).

Presented in part at the Twenty-Seventh Congress of the European Society for Medical Oncology, Nice, France, October 18–22, 2002.

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Submitted November 25, 2002; accepted February 28, 2003.

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