Colorectal cancer (CRC) is a very common cancer for both sexes and this disease will affect over 150,000 patients in the year 2009. Oxaliplatin is FDA-approved as both adjuvant and metastatic treatment for CRC. Its side effect profile includes the dose-limiting toxicity of peripheral sensory neuropathy (PSN). Clinicians have struggled with how best to manage oxaliplatin-induced peripheral neuropathy (OIPN) with effective strategies currently limited.
Diabetes mellitus (DM) affects approximately 18 million people in the United States and can also produce peripheral neuropathy in 10%-20% of those patients.1 The presence of neuropathy associated with DM may be considered an additional risk factor for OIPN. Studies have shown that neuropathy may be present in up to half of all patients with DM. However, no data are available to demonstrate if patients with DM-associated neuropathy have an increased risk of developing PSN while on chemotherapy or if these agents increase the incidence or severity of this side effect. Although a baseline assessment prior to therapy is recommended to identify additional factors which could increase a patient’s risk for OIPN, there are no studies which examine the role of DM in selection of patients for chemotherapy with agents that can cause PSN.2,3
In the absence of data, Ramanathan and colleagues,2 examined whether PSN would be initiated or worsened by agents with this side effect profile in patients with DM who had no symptoms of PSN at the start of therapy.
Study facts
- A pooled analysis was conducted using data from three multicenter, randomized controlled trials in which FOLFOX4 was included as a treatment arm
- The studies were chosen because data for DM were available for analysis (obtained from patient-reported history at baseline and further study information)
- The 3 studies
- MOSAIC, an international phase III study with 5-FU/LV with or without oxaliplatin (Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer)
- EFC4584, a North American three arm phase III study of bolus/infusional 5FU/LV alone, oxaliplatin alone, or the combination of 5FU/LV and oxaliplatin in treatment of metastatic CRC (mCRC)
- EFC2962, a European phase II/III study of 5FU with or without oxaliplatin in the first-line treatment of mCRC
Patients with DM were not excluded from the analysis provided they had no PSN or PSN grade < 1
The studies used different scales at screening for assessing neuropathy at study entry and during treatment (NCI-CTC v.1.0 and the oxaliplatin-specific neurotoxicity scale)
Data were analyzed retrospectively for the association of pre-existing PSN and the occurrence of this side effect during treatment with FOLFOX. The incidence of PSN was evaluated in patient subgroups with or without DM at baseline in these patients and Kaplan-Meier curves were constructed to demonstrate the probability of PSN in relation to increased dose of oxaliplatin as cycles progressed.
Results
- A total of 1587 patients were treated with FOLFOX4 in the three studies; 135 (8.5%) [MOSAIC, 7.7%; EFC4584 12.7%; and EFC2962 7.2%] were identified as having DM at baseline
- The demographics were not significantly different for patients with DM versus those without DM, although the DM patients trended toward an older population
- Almost all patients had no subjective symptoms, even with the allowed baseline PSN of grade <1
- The incidence of PSN by grade was similar in patients with DM and in those without DM for each study individually and when pooled together
Conclusion
The retrospective analysis demonstrates that the pre-existing DM is not associated with an increased risk of developing PSN in patients receiving oxaliplatin for CRC. The study showed that diabetic patients without pre-existing subjective symptoms of PSN can be treated with FOLFOX and not be at a higher risk for cumulative PSN compared to nondiabetic patients. However, the authors caution that the findings of this study should be interpreted with caution due to the modest sample size and the retrospective nature of the analysis. It is possible that patients who have had DM for longer periods of time may be more at risk for PSN when receiving chemotherapy or that patients treated with insulin versus non-insulin may experience different results. More data are needed to definitively determine the role of DM and PSN when administering oxaliplatin and the mechanism of action of OIPN. Prospective data are needed to further examine the role of DM and the potential for PSN with chemotherapy administration.
References
- Smith T, Nicholson RA. Review of duloxetine in the management of diabetic peripheral neuropathic pain. Vasc Health Risk Manag. 2007;3:833-44. Free full text may be viewed at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2350145/?tool=pubmed.
- Ramanathan RK, Rothenberg ML, de Gramont A, et al. Incidence and evolution of oxaliplatin-induced peripheral sensory neuropathy in diabetic patients with colorectal cancer: a pooled analysis of three phase III studies. Ann Oncol, published ahead of print November 3, 2009. Abstract may be viewed at: http://www.ncbi.nlm.nih.gov/pubmed/19887466?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1.
- Viale PH, Sommers R. Nursing care of patients receiving chemotherapy for metastatic colorectal cancer: Implications of the treatment continuum concept. Sem Onc Nurs. 2007;23 [suppl 1], 22-35. Abstract may be viewed at http://www.seminarsoncologynursing.com/article/S0749-2081(06)00113-6/abstract