Diabetes mellitus and the incidence and time to onset of oxaliplatin-induced peripheral sensory neuropathy in patients with colorectal cancer: A pooled analysisof three randomized studies

Ramanathan RK,1 André T,2 Rothenberg ML,3 de Gramont A,4 Tournigand C,4 Goldberg RM,5 Gupta S6

1Scottsdale Clinical Research Institute and TGen, Scottsdale, AZ, USA; 2Hôpital Tenon, Paris, France; 3Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 4Hôpital Saint-Antoine, Paris, France; 5University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 6sanofi-aventis, Malvern, PA, USA

Introduction

• Neurotoxicity is the chief dose-limiting toxicity of oxaliplatin, with grade 3/4 peripheral sensory neuropathy (PSN) seen in 10–15% of patients after a cumulative dose of 780–850 mg/m2.1

• In a pivotal Phase III trial in advanced colorectal cancer (CRC), grade 3 PSN was reported in 18% of patients receiving first-line FOLFOX4 (oxaliplatin plus 5-fluorouracil [5-FU] and leucovorin [LV])2

• Factors predisposing patients to oxaliplatin-associated PSN have not been determined, although patients with the glutathione S-transferase P1 I105V polymorphism appear to have early onset of oxaliplatin-induced PSN3

• It is also unknown whether therapy with oxaliplatin or other platinum agents

• increases the risk of PSN in patients with diabetes mellitus (DM)

• The present retrospective analysis of three major published randomized studies of oxaliplatin regimens in patients with CRC4–7 was conducted to determine whether the presence of DM influences the incidence and/or course of PSN after therapy with oxaliplatin

1. J Clin Oncol 2004;22:23–30; 2. Semin Oncol 2002;29:21–33; 3. J Clin Oncol 2005;23(16S):3509;4. N Engl J Med 2004;350:2343–51; 5. J Clin Oncol 2003;21:2059–69; 6. Internal sanofi-aventis Clinical Study Report; 2004; 7. J Clin Oncol 2000;18:2938–47

Objective

• To determine the influence of DM on the incidence and time to onset of oxaliplatin-induced PSN

Methods (I)

• Pooled analysis of data from three published, multicenter, randomized and controlled trials in which FOLFOX4 was included as a treatment arm:• EFC3313 (MOSAIC): An international Phase III study of 5-FU

(bolus and continuous infusion) and LV (LV5–FU2) with or without oxaliplatin in the adjuvant treatment of CRC1

• EFC4584: A North American three-arm study of LV5–FU2 alone or with oxaliplatin, or oxaliplatin alone in the second-line treatment of metastatic CRC2,3

• EFC2962: A European Phase II/III study of LV5–FU2 with or without oxaliplatin in the first-line treatment of metastatic CRC4

1. N Engl J Med 2004;350:2343–51; 2. J Clin Oncol 2003;21:2059–69; 3. Internal sanofi-aventis Clinical Study Report; 2004; 4. J Clin Oncol 2000;18:2938–47

Methods (II)

• Patients with DM were eligible for all studies, but were required either to have PSN grade ≤1 (National Cancer Institute Common Toxicity Criteria) or no PSN at study entry

• Data held in the sanofi-aventis clinical trials database were analyzed retrospectively for details of patients with pre-existing DM

Methods (III)

• PSN data were evaluated in the overall study population and in FOLFOX4-treated patient subgroups with or without DM at baseline• Incidence rates were presented for the overall population and

for DM patients

• Time-to-onset data were presented for DM and non-DM patients as Kaplan–Meier curves showing the cumulative probability of PSN by increasing cumulative dose of oxaliplatin

• Kaplan–Meier curves were inspected for trends indicating clinically relevant differences in the incidence and severity of PSN

Results: Patients and studies (I)

Results: Patients and studies (II)

• In total, 1585 patients were treated with FOLFOX4 (EFC3313, n=1108; EFC4584, n=268; EFC2962, n=209)

• A total of 135 patients (8.5%) were identified as having DM at study entry (EFC3313, n=85; EFC4584, n=34; EFC2962, n=16); however, diabetes status information was not collected consistently in EFC2962

• Overall characteristics of patients with DM and their cumulative exposures to oxaliplatin did not differ from the overall study populations to any clinically relevant extent (data not shown)

Results:Probabilities and time courses of PSN (I)

• Overall incidence of PSN by grade was similar in patients with DM and in the overall study populations when the results from the three studies were pooled (Figure 1)

Results:Probabilities and time courses of PSN (II)

• In the two studies for which DM status information was collected consistently at baseline (ECF3313 and EFC4584), the probability of PSN by cumulative dose of oxaliplatin was similar for patients with and without DM (Figures 2–5)

• In EFC3313, PSN grade ≥1 was reported in 93% and 92% of patients with and without DM, respectively; the probability of onset of PSN approached 1.0 for both patients with and without DM at a cumulative oxaliplatin dose above approximately 800 mg/m2

(Figure 2)

Results:Probabilities and time courses of PSN (III)

Results:Probabilities and time courses of PSN (IV)

• Probabilities of moderate to severe PSN (grade ≥3) were much lower, but were still very similar between patients with DM (13%) and those without (12%) (Figure 3)

Results:Probabilities and time courses of PSN (V)

• The overall probability of PSN of any grade was lower in EFC4584 than in EFC3313, possibly because of the relatively low cumulative dose of oxaliplatin administered in this trial (median cumulative dose 510 mg/m2; 6 cycles). At this level, approximately half of all patients with or without DM experienced PSN of any severity (59% and 53% of patients with or without DM, respectively) (Figure 4)

Results:Probabilities and time courses of PSN (VI)

• The probability of moderate to severe PSN (grade ≥3) by cumulative dose of oxaliplatin in EFC4584 was very low, with a total incidence of 6%, regardless of DM status (Figure 5)

Conclusions (I)

• In this retrospective analysis of Phase III data, no relationship was observed between DM status at baseline and the probability of developing PSN among patients receiving oxaliplatin therapy for CRC

• The data indicate that patients with DM and with PSN of grade ≤1 or with no PSN can be treated with FOLFOX regimens with no greater risk of cumulative neurotoxicity than patients without DM

Conclusions (II)

• Genetic polymorphisms that may predict for developing PSN need to be validated in prospective studies

• Because of the inherent limitations of this retrospective analysis, careful monitoring for PSN and appropriate dose reductions are necessary in all patients treated with oxaliplatin-based regimens

Acknowledgement: We would like to thank Brent Burger (sanofi-aventis, Malvern, PA, USA)