Oxaliplatin reintroduction in patients previously treated with leucovorin, fluorouracil and oxaliplatin for metastatic colorectal cancer

F. Maindrault-Goebel1, C. Tournigand1, T. André2, E. Carola3, M. Mabro1, P. Artru1, C. Louvet1 and A. de Gramont1,* On behalf of the French Oncology Research Group (GERCOR)

1 Service de Médecine Interne-Oncologie, Hôpital Saint-Antoine, Paris; 2 Service d'Oncologie Médicale, Hôpital Tenon, Paris; 3 Hôpital de Senlis, Service de Médecine 2, Senlis, France

* Correspondence to: Professor A. de Gramont, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. Tel: +33-1-49-28-23-36; Fax: +33-1-49-28-23-44; Email: aimery.de-gramont{at}sat.ap-hop-paris.fr


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: FOLFOX, a bimonthly combination of leucovorin, 5-fluorouracil and oxaliplatin, is active in metastatic colorectal cancer, but sometimes causes cumulative sensory neurotoxicity. This retrospective study investigated FOLFOX reintroduction after a break in treatment or following disease progression on another regimen.

Patients and methods: FOLFOX was reintroduced in 29 patients. During their previous FOLFOX therapy, 24 had achieved a response, four were stable and one had progression. Median progression-free survival (PFS) was 33 weeks. Grade 3 neuropathy developed in nine and grade 2 neuropathy in eight patients.

Results: Following FOLFOX reintroduction, six patients (21%) showed a response, 15 (52%) were stable and eight (28%) had progression. Median PFS was 18 weeks. Grade 3 neuropathy developed in four patients and grade 2 neuropathy in 11. Two patients with previous grade 3 neuropathy had no recurrence of neuropathy after eight and 18 cycles, respectively. Among 13 patients who received no treatment between periods of FOLFOX therapy, four (31%) had a response and eight (62%) had stable disease.

Conclusion: Reintroduction of oxaliplatin was feasible and achieved a response or stabilization in 73% of patients. These results support the concept of intensified, repeated short courses of FOLFOX, a strategy currently being evaluated prospectively in the OPTIMOX study.

Key words: 5-fluorouracil, leucovorin, metastatic colorectal cancer, neurotoxicity, oxaliplatin


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Oxaliplatin in combination with leucovorin and 5-fluorouracil (5-FU) represents an effective treatment in advanced colorectal cancer, significantly improving response rates, extending progression-free and overall survival, and enabling surgical resection to be performed in a subset of patients with previously non-resectable metastases [1Go–4Go]. Treatment must sometimes be stopped, however, due to a cumulative, sensory neurotoxicity that spares the motor neurons and affects the dorsal root ganglia [5Go]. In one randomized study, grade 3 neurotoxicity was observed in 18% of patients, and the estimated incidence of severe neuropathy, with a dose of 85 mg/m2 per cycle, was 10% after nine cycles, 25% after 12 cycles and 50% after 14 cycles [1Go]. Unlike cisplatin neurotoxicity, oxaliplatin sensory neurotoxicity is reversible, even where it persists for several months, but requires discontinuation of treatment [1Go, 6Go]. Since oxaliplatin-related neurotoxicity is reversible, this raises the question of whether oxaliplatin reintroduction is beneficial in patients who are withdrawn from treatment prior to developing resistance to oxaliplatin. Here, we report our experience of reintroducing oxaliplatin in patients with advanced colorectal cancer.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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This was a retrospective study of all patients at our center with measurable lesions who had been previously treated with a FOLFOX regimen (bimonthly leucovorin, 5-FU and oxaliplatin) and who received a second course of therapy with a FOLFOX regimen for metastatic colorectal cancer between May 1997 and February 2000.

Patient selection
Patients were required to have histologically proven adenocarcinoma of the colon or rectum, and to have undergone documented progression prior to FOLFOX reintroduction. Patients were required to be between 18 and 80 years of age; to have residual neuropathy no greater than National Cancer Institute Common Toxicity Criteria (NCI CTC) grade 2 in severity; a life expectancy of at least 3 months; and a World Health Organization (WHO) performance status of 0–2. Patients with central nervous system metastases and exclusive bone metastases were excluded. The presence of metastases outside the irradiation field was required in patients who had received prior radiation therapy. Alternative chemotherapeutic regimens not involving oxaliplatin were allowed between the two periods of FOLFOX therapy.

Chemotherapy
During the study period, patients received at least one of the following FOLFOX regimens [7Go]: FOLFOX2, comprising oxaliplatin 100 mg/m2 as a 2-h infusion on day 1, leucovorin 500 mg/m2 as a 2-h infusion on days 1 and 2, followed by 5-FU 1500–2000 mg/m2 as a 22-h infusion—this regimen was repeated every 2 weeks; FOLFOX3, comprising the same bimonthly regimen except that the 2-h infusion of oxaliplatin was given at a lower dose of 85 mg/m2; FOLFOX4, comprising oxaliplatin 85 mg/m2, given as a 2-h infusion on day 1, leucovorin 200 mg/m2 as a 2-h infusion on days 1 and 2, followed by a 5-FU bolus of 400 mg/m2/day and a 22-h infusion 5-FU 600 mg/m2/day—this regimen was repeated every 2 weeks, the oxaliplatin infusion on day 1 was given concurrently with leucovorin; FOLFOX6, comprising a higher dose of oxaliplatin added to a new, simplified bimonthly leucovorin–5-FU regimen: oxaliplatin 100 mg/m2 and leucovorin 400 mg/m2 were administered as 2-h infusions on day 1, followed by a 5-FU bolus of 400 mg/m2 and a 46-h infusion of 5-FU 2400–3000 mg/m2 over days 1 and 2; and, finally, FOLFOX7, consisting of oxaliplatin 130 mg/m2 as a 2-h infusion given concurrently with the 2-h infusion of leucovorin 400 mg/m2, followed by a 5-FU bolus of 400 mg/m2 on day 1 and a 46-h infusion of 5-FU 2400 mg/m2.

When NCI CTC neurosensory toxicity of grade ≥2 persisted between cycles, with pain or functional impairment, oxaliplatin was discontinued. Following discontinuation of the first period of FOLFOX therapy and prior to its reintroduction, patients were initially treated either with 5-FU–leucovorin alone, or had a complete break in chemotherapeutic treatment. In both cases, a second line of FOLFOX therapy was initiated at progression. Irinotecan-based treatment was given if residual neuropathy did not permit reintroduction of oxaliplatin, in which case oxaliplatin was reintroduced after progression occurred on irinotecan.

Dose-intensity analysis
The dose-intensity analysis included all patients who received at least four consecutive cycles of chemotherapy. Oxaliplatin dose intensity over a 2-week period was calculated on a per-patient basis from the start date of cycle 1 to the start date of cycle 5, in patients who received more than four cycles, or to the start-date of cycle 4 plus the estimated fourth interval (equal to one-third of the interval between cycles 1 and 4) in patients who received only four cycles.

Evaluation criteria
Physical examination and complete blood counts were performed at the start of each cycle. Assays for carcinoembryonic antigen (CEA) and alkaline phosphatase, and computed tomography (CT) scans were repeated every four cycles, or earlier in the case of clinical deterioration. Only patients with bi-dimensionally measurable lesions (largest diameter ≥2 cm) on CT scan could be evaluated for tumor response. Complete response (CR) was defined as the complete disappearance of all assessable disease for at least 4 weeks. Partial response (PR) was categorized as a decrease of at least 50% in the sum of the products of the diameters of measurable lesions, for at least 4 weeks. Stable disease (SD) was defined as a decrease of <50% or an increase of <25% in tumor size. Progressive disease (PD) was identified by an increase in tumor size of at least 25% or by the appearance of one or more new neoplastic lesions. For rectal cancers, assessable metastases had to be outside the pelvis. External review of CT scans was not undertaken. Decreased CEA concentrations were considered a biological effect in patients whose CEA levels had been elevated at baseline.

Statistical analysis
Survival from the commencement of FOLFOX chemotherapy reintroduction was calculated using the Kaplan–Meier method [8Go]. The duration of response and progression-free survival (PFS) were calculated from the date on which therapy began to the date on which disease progression was observed.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Initial period of FOLFOX treatment
In total, 29 patients were included in the study (Table 1). During the initial period of FOLFOX therapy, 24 of the 29 patients (83%) achieved a PR; four (14%) had SD; and one (3%), who received low dose-intensity FOLFOX4, had PD. Patients received a median of eight cycles of FOLFOX treatment and a median oxaliplatin cumulative dose of 752 mg/m2. The median oxaliplatin dose intensity was 44 mg/m2/week. A total of nine patients (31%) developed grade 3 sensory neurotoxicity with functional impairment. Median PFS was 33 weeks.


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Table 1. Patient characteristics

 
Intervening treatment
Between the two periods of FOLFOX therapy, 16 patients received other chemotherapy regimens, of whom four received 5-FU–leucovorin alone and 12 received irinotecan-based regimens. The remaining 13 patients did not receive intervening chemotherapy; seven of these patients took part in the FOLFOX7 second-line study, which, per protocol, specified a break in chemotherapy after eight cycles [9Go]. The median interval between the two periods of FOLFOX therapy was 12 weeks (range 3–99) among patients who did not receive chemotherapy and 48 weeks (range 22–106) when intervening chemotherapy was administered. The median interval between periods of FOLFOX therapy for the entire cohort was 30 weeks.

Oxaliplatin reintroduction
A median of six cycles of FOLFOX were given following reintroduction (range 3–35 cycles). In total, 208 cycles were evaluable in the 29 patients. The median oxaliplatin dose intensity was 43 mg/m2/week and the median cumulative dose was 492 mg/m2.

Toxicity
The incidences of main toxic effects per patient are listed in Table 2. Grade 3 sensory neuropathy occurred in four patients (14%). Among the nine patients who had grade 3 sensory neuropathy after the first period of FOLFOX, only three developed a grade 3 recurrence, after three, three and six cycles, respectively. Two more of these nine patients received either the same number of cycles or more cycles at FOLFOX reintroduction than at the first FOLFOX therapy, without developing neurotoxicity. The remaining four patients developed grade 1 or 2 neurotoxicity. Laryngospasm was observed in one patient. Grade 3/4 neutropenia occurred in 21% of the patients, but was not febrile and was never a reason for discontinuing therapy. Asymptomatic grade 3 thrombocytopenia developed in three patients (10%), and grade 4 thrombocytopenia, requiring platelet transfusion, in one patient (3%). Grade 3 vomiting occurred in three patients (10%). Mucositis or diarrhea never reached grade 3 in severity.


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Table 2. Percentage toxicities per patient (maximum NCI CTC grade) evaluated for 199 cycles given to 29 patients

 
Objective tumor responses
Tumor responses are summarized in Table 3. In total, six patients achieved an objective response, corresponding to a rate of 20.7% [95% confidence interval (CI) 5.7% to 35.7%] (Table 3). Among patients who received no intervening chemotherapy, the objective response rate was 31%, whereas for patients who received intervening chemotherapy the objective response rate was 12%. The six individual responses lasted 18, 20+, 27, 34, 36 and 99 weeks. Five of the responses were observed among patients who had responded to the first period of FOLFOX treatment, whereas one response occurred in a patient who had had progression at the first use of FOLFOX. In this particular patient, dose intensity during the first period of FOLFOX treatment was only 28 mg/m2/week, whereas following reintroduction, the dose intensity was increased to 42 mg/m2/week. SD was achieved in 15 patients (52%), including seven patients (44%) who received no intervening chemotherapy and eight (62%) who received intervening chemotherapy.


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Table 3. Tumor response rates following oxaliplatin reintroduction

 
Survival
Survival curves following oxaliplatin reintroduction are shown in Figure 1. From the commencement of oxaliplatin reintroduction, median PFS for the 29 patients included in the study was 18 weeks (range 15–23) and median overall survival was 42 weeks (range 36–52). The 13 patients who received no intervening chemotherapy between initial FOLFOX treatment and its reintroduction had a median PFS of 27 weeks and a median overall survival of 58 weeks. The 16 patients who received intervening chemotherapy had a median PFS of 11 weeks and a median overall survival of 36 weeks.



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Figure 1. Kaplan–Meier survival curves for progression-free (dashed line) and overall (solid line) survival following reintroduction of oxaliplatin.

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This retrospective study on a limited number of patients found that the reintroduction of oxaliplatin, following its suspension prior to tumor progression, can be both feasible and safe, regardless of whether the intervening period is treatment-free or involves intervention with alternative chemotherapeutic agents. Reintroduction of oxaliplatin achieved a response or stabilization in 73% of patients studied; overall response or stabilization was achieved in >90% of patients who had received treatment between periods of FOLFOX therapy, with a median survival of 42 weeks. Even among the patients who had received intervening chemotherapy, 50% had SD or response, and median survival was 36 weeks. This high level of response following reintroduction is consistent with the fact that the majority of patients had a good response during their first period of oxaliplatin treatment. The results do not suggest that reintroduction is indicated in oxaliplatin-refractory patients, except if a very low dose intensity was administered during the first period of treatment.

It is notable that among the patients included in this study, oxaliplatin-based therapy was discontinued after a relatively short period, with a median of eight cycles. In part, this reflects the high oxaliplatin dose intensities used during first-line treatment, when only six patients received 85 mg/m2, 14 received 100 mg/m2 and nine received 130 mg/m2. The overall median dose of 752 mg/m2 was, however, typical of the total exposure patients receive during first-line therapy. In addition, seven patients within the study were on the FOLFOX7 protocol, which specifies discontinuation after eight cycles [9Go].

FOLFOX treatment was well tolerated, not only following its reintroduction, but furthermore appeared to be better tolerated than during the first period of administration, with a lower incidence of cumulative grade 3 neurotoxicity, even in patients who had experienced such neurotoxicity during their first period of oxaliplatin treatment. This is probably partly a reflection of the modifications to the FOLFOX regimen, and partly due to better dose adaptation in patients who had already received a similar regimen. We have no explanation for the good neurological tolerance in patients previously exposed to oxaliplatin; it may reflect either the difficulty of assessing sensory neurotoxicity, or changes in the patient's motivation.

Sensory neurotoxicity is a potentially limiting factor in many patients who might otherwise achieve good results with oxaliplatin therapy, but it may be overcome in several ways. Prevention or cure is one option, for which glutathione, carbamazepine and gabapentin have already been investigated [10Go–12Go]. Another option is to alternate oxaliplatin and irinotecan-based chemotherapy [13Go, 14Go]. A further option, supported by the results described in this report, is to administer a limited number of cycles of oxaliplatin at an optimal dose intensity, but to suspend treatment after delivering a total dose below that of the oxaliplatin cumulative toxic dose and before the development of resistance, thus enabling later reintroduction of the drug. Such a strategy is likely to be most successful when used as a first-line approach, rather than being held in reserve until chemotherapy based on another agent (such as irinotecan) fails.

In conclusion, the results of this study suggest that reintroduction of oxaliplatin following a break for neurotoxicity or to delay the development of resistance is safe and proves clinically beneficial in many cases. The concept of intensified and repeated short courses of FOLFOX is currently being evaluated prospectively in the OPTIMOX study. This study is comparing treatment with FOLFOX4 until progression (i.e. without breaks in oxaliplatin therapy) with treatment consisting of FOLFOX7 for six cycles, followed by maintenance with leucovorin–5-FU alone and FOLFOX7 reintroduction for a further six cycles.

Received for publication August 27, 2003. Revision received March 18, 2004. Accepted for publication March 22, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947.[Abstract/Free Full Text]

2. Goldberg RM, Morton RF, Sargent DJ et al. N9741: oxaliplatin or CPT-11 plus 5-fluorouracil/leucovorin or oxaliplatin plus CPT-11 in advanced colorectal cancer. Initial toxicity and response data from a GI Intergroup study. Proc Am Soc Clin Oncol 2002; 21: 128a.

3. André T, Bensmaine M, Louvet C et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999; 17: 3560–3568.[Abstract/Free Full Text]

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11. Eckel F, Schmelz R, Adelsbeerger H et al. Prevention of oxaliplatin-induced neuropathy by carbamazepine. A pilot study. Dtsch Med Wochenschr 2002; 127: 78–82.[CrossRef][ISI][Medline]

12. Mariani G, Garone O, Granetto C et al. Oxaliplatin induced neuropathy: could gabapentin be the answer? Proc Am Soc Clin Oncol 2000; 19: 609a (Abstr 2397).

13. Becouarn Y, Gamelin E, Coudert B et al. Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. J Clin Oncol 2001; 19: 4195–4201.[Abstract/Free Full Text]

14. Hebbar M, Tournigand C, Lledo G et al. Phase II evaluation of an alternated FOLFOX/FOLFIRI regimen in patients with resistant metastatic colorectal cancer. Eur J Cancer 2001; 37 (Suppl 6): S308 (Abstr 1138).