Research Article: Oxaliplatin-Based Chemotherapy Is More Beneficial in KRAS Mutant than in KRAS Wild-Type Metastatic Colorectal Cancer Patients

Date Published: February 4, 2014

Publisher: Public Library of Science

Author(s): Yu-Lin Lin, Yi-Hsin Liang, Jia-Huei Tsai, Jau-Yu Liau, Jin-Tung Liang, Been-Ren Lin, Ji-Shiang Hung, Liang-In Lin, Li-Hui Tseng, Yih-Leong Chang, Kun-Huei Yeh, Ann-Lii Cheng, Zhuang Zuo.

http://doi.org/10.1371/journal.pone.0086789

Abstract

To identify better regimens in currently available chemotherapy would be beneficial to KRAS mutant metastatic colorectal cancer (mCRC) patients because they have fewer treatment options than KRAS wild-type mCRC patients. Clinicopathologic features and overall survival (OS) of KRAS mutant and wild-type mCRC patients who had used oxaliplatin-based, irinotecan-based, bevacizumab-based, as well as cetuximab-based regimens were compared to those who had never-used oxaliplatin-based, irinotecan-based, bevacizumab-based, as well as cetuximab-based regimens respectively. Between 2007 and 2012, a total of 394 mCRC patients, in whom 169 KRAS mutant and 225 KRAS wild-type, were enrolled. In KRAS mutant patients who had used oxaliplatin-based regimens (N = 131), the OS was significantly longer than that in KRAS mutant patients who had never-used oxaliplatin-based regimens (N = 38). The OS was 28.8 months [95% confidence interval (CI): 23.2–34.4] in KRAS mutant patients who had used oxaliplatin-based regimens versus 17.8 months [95% CI: 6.5–29.1] in KRAS mutant patients who had never-used oxaliplatin-based regimens (P = 0.026). Notably, OS in KRAS wild-type mCRC patients who had used oxaliplatin-based regimens (N = 185) was not significantly longer than that in KRAS wild-type mCRC patients who had never-used oxaliplatin-based regimens (N = 40) (P = 0.25). Furthermore, the OS in KRAS mutant patients who had used either irinotecan-based, bevacizumab-based or cetuximab-based regimens was not significantly different than that in KRAS mutant patients who had never-used either irinotecan-based, bevacizumab-based or cetuximab-based regimens respectively. In multivariate analyses, patients who had used oxaliplatin-based regimens remains an independent prognostic factor for longer OS in KRAS mutant mCRC patients. In conclusion, oxaliplatin-based regimens are more beneficial in KRAS mutant than in KRAS wild-type mCRC patients.

Partial Text

To identify potentially better regimens in currently available systemic chemotherapy, if existed, would be crucial to KRAS mutant metastatic colorectal cancer (mCRC) patients because they do not benefit from epidermal growth factor receptor (EGFR) monoclonal antibody and have fewer treatment options than KRAS wild-type mCRC patients. Mutation of the KRAS gene in mCRC has been identified as a negative predictor to EGFR monoclonal antibody [1]. Prospective randomized clinical trials have further demonstrated this finding [2]–[4]. In patients who received first-line chemotherapy plus EGFR monoclonal antibodies, progression-free survival (PFS) in KRAS mutant mCRC patients was shorter than that in KRAS wild-type patients. The PFS was 7.6 months in KRAS mutant group and 9.9 months in KRAS wild-type group in the CRYSTAL study [2]; 5.5 months in KRAS mutant group and 7.7 months in KRAS wild-type group in the OPUS study [3]; and 7.3 months in KRAS mutant group and 9.6 months in KRAS wild-type group in the PRIME [4] study. Based on the results of these randomized clinical studies, KRAS mutant mCRC patients have no longer been suggested to use EGFR monoclonal antibody [5]. Therefore, to identify potentially better regimens from currently available systemic treatments or to explore newer agents for the treatment of KRAS mutant mCRC patients is thus warranted.

According to the current and our previously published studies, oxaliplatin-based regimens are more beneficial in KRAS mutant mCRC patients, because, theoretically, the earlier the effective regimens can be used, the greater probability cancers can be controlled. KRAS mutant mCRC patients, currently, were facing hurdles of treatment with fewer treatment options than KRAS wild-type mCRC patients. It is reasonable and superior to use an optimal agent first while it is currently available and has been approved on markets rather than to continuously explore new agents for which the efficacy of new agents remains uncertain. Our previously published findings and currently reported results demonstrated that oxaliplatin-based regimens in currently available treatments might result in longer first-line PFS in KRAS mutant than that in KRAS wild-type mCRC patients [7]. In addition, the median OS in KRAS mutant mCRC patients who had used oxaliplatin-based regimens was significantly longer than that in KRAS mutant mCRC patients who had never-used oxaliplatin-based regimens. To avoid the possible arguments that our current finding was resulted from selection bias and the dogma that more drugs always result in longer OS, we also validated this issue to KRAS wild-type mCRC patients who had used and never-used oxaliplatin-based regimens as a control group. Notably, median OS in KRAS wild-type mCRC patients who had used oxaliplatin-based regimens was not significantly longer than that in KRAS wild-type patients who had never-used oxaliplatin-based regimens. Besides, we also validated the frequency of oxaliplatin-based regimens used in either adjuvant, metastatic or both setting (Table 3) and measured median time to recurrence from locally advanced (stage II or III) to metastatic setting (Table 6) between KRAS mutant and wild-type patients to ensure all of these parameters between these two groups calculated in our current study were relatively balanced. Furthermore, median OS in KRAS mutant patients who had used either irinotecan-based, bevacizumab-base or cetuximab-based regimens was not consistently and significantly longer than that in KRAS mutant patients who had never-used either irinotecan-based, bevacizumab-base or cetuximab-based regimens. These findings further strengthened and highlighted the potential crucial role of oxaliplatin in KRAS mutant mCRC.

 

Source:

http://doi.org/10.1371/journal.pone.0086789