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Reintroduction of Oxaliplatin Is Associated With Improved Survival in Advanced Colorectal Cancer

Aimery de Gramont, Marc Buyse, Jose Cortinas Abrahantes, Tomasz Burzykowski, Emmanuel Quinaux, Andres Cervantes, Arie Figer, Gérard Lledo, Michel Flesch, Laurent Mineur, Elisabeth Carola, Pierre-Luc Etienne, Fernando Rivera, Isabel Chirivella, Nathalie Perez-Staub, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Christophe Tournigand

From the Hôpital Saint Antoine; Hôpital Tenon; Sanofi-aventis, Paris; Clinique Saint Jean, Lyon; Hôpital Devron, Dijon; Clinique Sainte Catherine, Avignon; Hôpital de Senlis, Senlis; and Clinique Radiologique Armoricaine, Saint Brieuc, France; International Drug Development Institute, Louvain-la-Neuve; Hasselt University, Hasselt, Belgium; Hospital Clínico Universitario, Valencia; Hospital Universitario Marques de Valdecilla, Santander, Spain; and Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel

Address reprint requests to Aimery de Gramont, MD, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France; e-mail: aimery.de-gramont{at}sat.aphp.fr

	ABSTRACT

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Purpose In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the control arm or in a stop-and-go fashion in the experimental arm. The randomly assigned treatment groups did not differ significantly in terms of response rate, progression-free survival, and overall survival (OS). However, the impact of oxaliplatin reintroduction on OS was potentially masked by the fact that a large number of patients did not receive the planned oxaliplatin reintroduction or received oxaliplatin after second-line therapy in both treatment groups.

Patients and Methods A Cox model was fitted with all significant baseline factors plus time-dependent variables reflecting tumor progression, reintroduction of oxaliplatin, and use of second-line irinotecan. A shared frailty model was fitted with all significant baseline factors plus the number of lines of chemotherapy received by the patient and the percentage of patients with oxaliplatin reintroduction in the center. An adjusted hazard ratio (HR) was calculated for three reintroduction classes (1% to 20%, 21% to 40%, and > 40%), using centers with no reintroduction (0%) as the reference group.

Results Oxaliplatin reintroduction had an independent and significant impact on OS (HR = 0.56, P = .009). The percentage of patients with oxaliplatin reintroductions also had a significant impact on OS. Centers in which more than 40% of the patients were reintroduced had an adjusted HR for OS of 0.59 compared with centers in which no patient was reintroduced.

Conclusion Oxaliplatin reintroduction is associated with improved survival in patients with advanced colorectal cancer.

	INTRODUCTION

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Chemotherapy for advanced colorectal cancer has made much progress over the last 15 years, with infusional fluoropyrimidines modulated by folinic acid forming the basis of many current regimens involving oxaliplatin and irinotecan^1-4 as well as more recently approved biologic therapies.^5,6

The leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) 4 regimen has become established as a standard first-line therapy for advanced disease after the European C95 and the US N9741 studies, which demonstrated superiority over LV/FU and LV/FU bolus plus irinotecan, respectively.^3,5 The two limiting toxicities of FOLFOX4 in these studies were neutropenia and the specific reversible sensory neuropathy of oxaliplatin. The occurrence of sensory neuropathy is significant because it may cause patients who are continuing to respond to treatment to discontinue. One potential approach to avoiding the problem of oxaliplatin neurotoxicity is to administer the FOLFOX regimen for a defined period of time, stopping therapy before severe neurotoxicity develops, and then later reintroduce the regimen.⁷

The OPTIMOX1 trial, which was reported elsewhere,⁸ investigated the use of oxaliplatin discontinuation and reintroduction using a stop-and-go strategy that consisted of the oxaliplatin dose-dense FOLFOX7 regimen administered for six cycles of 2 weeks each, followed by 12 cycles of maintenance without oxaliplatin and subsequent reintroduction of FOLFOX7 for another six cycles. This regimen was compared with the FOLFOX4 regimen administered until progression or occurrence of unacceptable toxicity. The intent-to-treat analysis showed no significant difference between the randomly assigned arms in terms of response rate, progression-free survival, or overall survival (OS).⁸ However, oxaliplatin reintroduction was not performed according to protocol in all patients in the experimental arm, and a large number of patients received oxaliplatin and/or irinotecan in both arms after being taken off the study. Therefore, the trial may have lacked power to detect an impact of the reintroduction of oxaliplatin on OS. The purpose of the present retrospective analysis is to investigate this question further using statistical methods that control to the extent for the bias inherent in nonrandomized comparisons.

	PATIENTS AND METHODS

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Patient Selection
The eligibility criteria for inclusion in the study were as follows: adenocarcinoma of the colon or rectum; unresectable metastases; at least one bidimensionally measurable lesion of 1 cm or a nonmeasurable assessable lesion; adequate bone marrow, liver (alkaline phosphatase < 5x the upper limit of the normal laboratory value [ULN]), and renal function (creatinine 3x ULN); WHO performance status of 0 to 2; age 18 to 80 years; and no previous chemotherapy for metastatic disease. Previous adjuvant chemotherapy was required to have been completed at least 6 months before inclusion. Patients with CNS metastases, second malignancies, bowel obstruction, peripheral neuropathy more than grade 1, symptomatic angina pectoris, or disease confined to previous radiation fields were excluded. Written informed consent was required, and the ethical committee approved the study at all participating centers. The population included an exploratory cohort of elderly patients (age > 75 years) and/or poor prognosis patients (alkaline phosphatase > 3x ULN).

Chemotherapy
In the control arm of the OPTIMOX1 trial, patients received FOLFOX4, which consisted of a 2-hour infusion of l-LV (100 mg/m²) or dl-LV (200 mg/m²) followed by an FU bolus (400 mg/m²) and a 22-hour infusion of FU (600 mg/m²) for 2 consecutive days every 2 weeks, with oxaliplatin (85 mg/m²) as a 2-hour infusion on day 1. In the investigational arm, patients received FOLFOX7 for six cycles, which consisted of a 2-hour infusion of l-LV (200 mg/m²) or dl-LV (400 mg/m²) followed by a 46-hour infusion of FU (2,400 mg/m²) every 2 weeks, with oxaliplatin (130 mg/m²) as a 2-hour infusion on day 1; patients then received 12 cycles of the LV5FU2 regimen consisting of a 2-hour infusion of l-LV (200 mg/m²) or dl-LV (400 mg/m²) followed by an FU bolus (400 mg/m²) and a 46-hour infusion of FU (3,000 mg/m²) every 2 weeks, and finally, patients received six additional cycles of FOLFOX7, the per-protocol oxaliplatin reintroduction. In case of progression during LV5FU2 alone and sensory neuropathy less than grade 2, reintroduction of oxaliplatin was scheduled in the investigational arm and allowed in the control arm.

Late Reintroduction of Oxaliplatin and Second-Line Therapies
Both treatments were continued until progression, unacceptable toxicity, or patient choice. Surgery of metastases was allowed in patients with tumor response. After surgery, the patient was scheduled to receive at least 12 cycles (6 months) of their randomly allocated treatment. In case of relapse after complete surgical resection, chemotherapy was resumed in both arms. Second and subsequent lines of therapy at the discretion of the investigators were prospectively recorded in both arms. Dates of administration, of progression, and of tumor evaluation were monitored for oxaliplatin- and irinotecan-based regimens.

Statistical Analyses
Oxaliplatin reintroduction as a time-dependent variable. A Cox regression model was fitted to identify baseline factors having a significant impact (P < .05) on OS.⁹ Baseline patient and tumor-related factors were first included in the model and then removed using a backward selection procedure. The resulting model was then fitted with three additional time-dependent variables reflecting tumor progression, use of oxaliplatin treatment (regardless of schedule, and whether according to a protocol-mandated reintroduction or not), and use of second-line irinotecan (regardless of schedule). Each time-dependent variable was constructed as a step function initially set at 0 and increased by 1 unit each time the corresponding event was observed. Treatments other than oxaliplatin or irinotecan administered on tumor progression consisted most often of fluoropyrimidines (FU, capecitabine, and uracil and tegafur alone or with mitomycin) and were ignored in the analyses. Figure 1 illustrates the three time-dependent variables for a patient who started FOLFOX7 in January 2001, was reintroduced to oxaliplatin according to protocol in August 2001, and received an irinotecan-based regimen on first tumor progression in September 2002 and an oxaliplatin-based regimen on second tumor progression in April 2003. In all Cox regression analyses, the assumption of proportional hazards was tested using Schoenfeld residuals, which are independent of time if the assumption holds.^10,11

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Time-dependent variables describing tumor progression and use of oxaliplatin and irinotecan for an individual patient.

Classes of oxaliplatin reintroduction. Centers were grouped according to percentage of patients who had a reintroduction of oxaliplatin, and a reintroduction class variable was defined as 1 = 1% to 20%, 2 = 21% to 40%, or 3 40%. The adjusted hazard ratio (HR) was calculated for each reintroduction class, using centers with no reintroduction (0%) as the reference group in a Cox regression model with all significant baseline factors. A measurement error linear regression model was fitted between the reintroduction class and the adjusted HR, with allowance for the estimation errors in both. The simulation extrapolation (SIMEX) method was used to ensure convergence of the model.^13,14 The SIMEX method reduces the bias induced by measurement error by establishing a relationship between measurement error–induced bias and the variance of the error. OS curves were estimated by reintroduction class both as Kaplan-Meier estimated curves and as Cox model predicted curves.¹⁵

	RESULTS

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Patient Characteristics
From January 2000 to June 2002, 621 eligible patients were randomly assigned at 56 institutions in five countries.⁸ The median follow-up time at the time of this analysis was 33 months. The six largest centers included 50% of the patients. In these centers, oxaliplatin reintroduction at any time was performed in 4% to 50% of the patients in the control arm and in 29% to 62% of the patients in the experimental arm.

Oxaliplatin Reintroduction and Second-Line and Subsequent Therapy
In the control arm, 78% of the patients received second-line chemotherapy, 46% received third-line therapy, and 18% received fourth-line therapy. In the experimental arm, 40% of the patients had per-protocol reintroduction, 73% received second-line chemotherapy (independently from the scheduled oxaliplatin reintroduction), 39% received third-line therapy, and 20% received fourth-line therapy. During the course of second-line and subsequent therapies, 27% of patients in the control arm had oxaliplatin reintroduction, 70% received irinotecan-based chemotherapy, and 32% received other chemotherapy regimens. In the experimental arm, 55% had oxaliplatin reintroduction per protocol or later, 61% received irinotecan-based chemotherapy, and 33% received other chemotherapy regimens.

Oxaliplatin Reintroduction As a Time-Dependent Variable
The following baseline factors were tested for their impact on OS: performance status, sex, age, metachronous or synchronous cancer, number of metastatic sites, tumor localization, adjuvant chemotherapy, lactate dehydrogenase (LDH), alkaline phosphatase, carcinoembryonic antigen, and treatment arm. Five factors were identified as statistically significant (Table 1), of which four remained significant in the Cox regression analysis.

Percentage of Oxaliplatin Reintroductions Per Center
The percentage of patients with oxaliplatin reintroductions, estimated in each center, varied from 0% to 100%, with a mean of 34% and a median of 20%. The shared frailty model fitted with the same baseline factors as mentioned earlier plus the number of lines of chemotherapy received by the patient and the estimated percentage of patients with oxaliplatin reintroductions is demonstrated in Table 2. The percentage of oxaliplatin reintroduction had a highly significant impact on OS (HR = 0.51; P = .009) in a model that contained the same baseline factors as mentioned earlier, plus the number of chemotherapy lines to reflect the better prognosis of patients who could be reintroduced more than once.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Random effects linear regression model between hazard ratio for overall survival and class of oxaliplatin reintroduction. SIMEX, simulation extrapolation.

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Overall survival curves by percentage of patients with oxaliplatin reintroduction: (——) Kaplan-Meier estimated curves; (– – – –) Cox model predicted curves.

	DISCUSSION

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Naïve analyses of oxaliplatin reintroduction would be subject to obvious biases; a comparison of patients with and without oxaliplatin reintroduction would be confounded by the patient prognosis and by length-biased sampling.¹⁶ A Cox regression model including all known baseline prognostic factors removed confounding to the extent possible, whereas use of time-dependent variables to model tumor progression, oxaliplatin reintroduction, and use of second-line irinotecan removed length-biased sampling to the extent possible. This model (Table 1) indicated that oxaliplatin reintroduction has a highly significant impact on the hazard of death (P < .0001) after adjustment for baseline prognostic factors and for the fact that patients were at a much elevated risk of death when their tumor progressed (P < .0001). The results of the time-dependent covariate analyses are not driven by the stop-and-go arm. In fact, they are almost identical if the analysis is limited to the arm in which patients are treated until progression or toxicity, which indeed makes the case for a true benefit of reintroduction (or treatment with irinotecan) more convincing.

These analyses, based on individual patient data, were confirmed by another Cox regression model including the center-specific percentage of patients with oxaliplatin reintroduction and the number of lines of chemotherapy received. This model (Table 2) indicated that a hypothetical patient treated at a center in which all patients were reintroduced would have approximately half the hazard of death (HR = 0.51; P = .009) compared with an identical patient treated at a center in which no patient was reintroduced. In practice, clearly, it is impossible to expect 100% oxaliplatin reintroduction in all centers, if only because some patients are in poor condition and cannot tolerate further therapy. Therefore, centers were grouped in three reintroduction classes (1% to 20%, 21% to 40%, and > 40%) and compared with the centers without any reintroduction (0%) as the reference group. The HR for OS clearly decreased as the percentage of oxaliplatin reintroduction increased (Table 3). A measurement error linear regression model indicated that the HR for OS in individual centers decreased by approximately 7% for every 10% increase in the rate of oxaliplatin reintroduction (Fig 2). Hence, a center in which 50% of the patients are reintroduced would be expected to have an HR for OS of approximately 0.65 compared with a center in which there is no reintroduction. The survival curves confirmed the impact of class of oxaliplatin reintroduction on OS (Fig 3), whether they were estimated through the Kaplan-Meier method or predicted using a Cox regression model adjusting for performance status, number of metastatic sites, LDH level, alkaline phosphatase level, and number of chemotherapy lines. All of these statistical approaches suggest that the impact of oxaliplatin reintroduction on OS is independent of the other known risk factors, whether measured at baseline or over the course of the trial.

Our results confirm meta-analyses of randomized clinical trials that have suggested that the OS of patients with advanced colorectal cancer has increased with the availability of effective second-line therapy.^17-20 These meta-analyses have their limitations, and so do our analyses, which are retrospective and ad hoc, yet make careful allowance for possible sources of confounding and bias. Despite these methodologic precautions, the analyses presented here cannot claim to yield the same level of evidence as would a prospective randomized trial investigating the impact of second-line therapy. However, such a trial would be difficult to conduct because, today, most patients receive effective second-line therapy.²⁰

Oxaliplatin is a drug with a cumulative sensory neurotoxicity that is reversible with time. This drug is active in combination with fluoropyrimidines in colon cancer therapy and remains active when reintroduced to patients who recovered from neurotoxicity. With the improved survival in advanced colon cancer therapy and the data presented here, the optimal use of oxaliplatin might be the stop-and-go strategy used in platinum-based combinations in ovarian cancer. The next step should be to assess the results of oxaliplatin therapy according to the duration of the platinum-free interval. A full exploration of the effects of oxaliplatin reintroduction has major clinical implications because this drug is now increasingly used in the adjuvant setting and in combination with targeted therapies.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Isabelle Tabah-Fisch, Sanofi-aventis Leadership: N/A Consultant: Aimery de Gramont, Sanofi-aventis Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Aimery de Gramont, Marc Buyse, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Christophe Tournigand

Financial support: Isabelle Tabah-Fisch

Provision of study materials or patients: Aimery de Gramont, Andres Cervantes, Arie Figer, Gérard Lledo, Michel Flesch, Laurent Mineur, Elisabeth Carola, Pierre-Luc Etienne, Fernando Rivera, Isabel Chirivella, Nathalie Perez-Staub, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch

Collection and assembly of data: Aimery de Gramont, Marc Buyse, Jose Cortinas Abrahantes, Tomasz Burzykowski, Emmanuel Quinaux, Gérard Lledo, Michel Flesch, Laurent Mineur, Elisabeth Carola, Pierre-Luc Etienne, Fernando Rivera, Isabel Chirivella, Nathalie Perez-Staub, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Christophe Tournigand

Data analysis and interpretation: Aimery de Gramont, Marc Buyse, Jose Cortinas Abrahantes, Tomasz Burzykowski, Emmanuel Quinaux, Nathalie Perez-Staub, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Christophe Tournigand

Manuscript writing: Aimery de Gramont, Marc Buyse, Jose Cortinas Abrahantes, Tomasz Burzykowski, Emmanuel Quinaux

Final approval of manuscript: Aimery de Gramont, Marc Buyse, Jose Cortinas Abrahantes, Tomasz Burzykowski, Emmanuel Quinaux, Andres Cervantes, Arie Figer, Gérard Lledo, Michel Flesch, Laurent Mineur, Elisabeth Carola, Pierre-Luc Etienne, Fernando Rivera, Isabel Chirivella, Nathalie Perez-Staub, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Christophe Tournigand

	NOTES

 
Supported by the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR), Paris, France.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted December 21, 2006; accepted March 20, 2007.

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