In this study, we compared the clinical characteristics and survival outcomes for patients with LA-NPC who received definitive CCRT with either 3-weekly cisplatin or 3-weekly carboplatin. As expected, more patients in carboplatin group had comorbidity of vascular risk factors and lower baseline CCr; both factors are considered high risk for cisplatin ineligibility (15). In cisplatin-ineligible patients with locally advanced non-NPC head and neck squamous cell carcinoma, cetuximab is recommended for concurrent use with RT (16, 17). However, recommendation for the agent being used in cisplatin-ineligible patients with LA-NPC is limited. In standard guideline, carboplatin has been for decades recommended for concurrent use with RT (18), according to data from phase II studies (10-12). In addition, anti-EGFR monoclonal antibodies such as cetuximab and nimotuzumab were evaluated as radiosensitisers in patients with LA-NPC, albeit with limited data (19-23).
The INT 0099 study was the first landmark trial that demonstrated the survival benefits of CCRT with high-dose cisplatin followed by three cycles of adjuvant chemotherapy over RT alone in patients with LA-NPC; hence, this protocol has become standard practice (3). In our study, we observed comparable survival outcomes between patients who received cisplatin and those who received carboplatin. The 5-year DFS and 5-year OS of patients treated with cisplatin in our study (61.0% and 64.0%, respectively) were similar to those reported by the INT 0099 study, which indicated a 5-year PFS of 58.0% and 5-year OS of 67.0%. Interestingly, although more patients in our study were able to complete three cycles of adjuvant CT (78.7%) in comparison to those in the INT 0099 study (55.0%), the higher survival outcomes that we anticipated were not observed. A potential explanation might be due to the fact that the survival benefits of adjuvant CT after CCRT remain controversial (24, 25). In particular, the results of a phase III trial showed no significant improvements of survival when adjuvant CT was added to CCRT versus CCRT alone (25, 26). In terms of the carboplatin group, we found a slightly lower 3-year DFS (66.0%) and 3-year OS (75.0%) than those of the previous study (10), which reported a 3-year PFS of 72.7% and 3-year OS of 89.7%. This might be explained by the fact that there was a lower proportion of patients in our study (88.2%) that were able to complete three planned cycles of carboplatin during CCRT as compared to the previous study (98.0%). Hence, this finding might emphasise the importance of cumulative dose of CT.
In this study, we ultimately evaluated the effect of chemotherapy regimens on survival using propensity score adjusted probability of receiving cisplatin or carboplatin together with known post-treatment prognostic factors for multivariable Cox Regression model. We found that after adjustment for propensity score and those prognostic factors, DFS and OS remain comparable between the two groups.
One main issue for high-dose cisplatin is toxicity, leading to the low compliance rate. In our study, patients treated with carboplatin had a better compliance rate for CT than those treated with cisplatin. More patients in the carboplatin group than in the cisplatin group were able to complete planned cycles of CT. This result appeared similar to that of the INT 0099 study, which showed that only 63.0% and 55.0% of patients received three planned cycles of cisplatin during CCRT and adjuvant CT, respectively, and that the main reason for discontinuation of treatment was patient intolerance to toxicities (3). Additionally, we found significantly more patients in the cisplatin group who required a dose reduction for CT due to toxicities. In contrast, a study using 3-weekly carboplatin demonstrated that 98.0% of patients could complete planned cycles of CT (10). Taken together, this affirms a better tolerability of carboplatin over cisplatin in this setting.
IMRT is an advanced mode of RT that is expected to improve survival and reduce local toxicities; however, the superior survival benefits of IMRT over 2D-RT technique remains uncertain (27-32). Although the mean actual dose of RT was not different, the RT technique used was significantly dissimilar between the two arms of our study. IMRT was the most-used technique in the cisplatin group (62.3%), whereas the 2D-RT technique was practised the most in the carboplatin group (97.4%). Though significantly fewer patients in cisplatin group were able to tolerate CT, we found no survival differences between the two arms. It is still hard to conclude whether these findings were affected by the enhanced benefit of IMRT. If the IMRT technique truly improves survival in patients with LA-NPC, the tolerability and survival outcome of patients receiving carboplatin concurrently with IMRT remains unknown because in our study, no patient in this arm received IMRT.
Our study is limited by its retrospective nature and relatively small number of patients in the carboplatin group. The selection bias of treating physicians is unavoidable in a retrospective study. In addition, owing to incomplete control of confounders such as ECOG PS and histology, which may have influenced the outcomes, our results should be interpreted with caution. However, given a larger sample size and longer duration of follow-ups, our study results were consistent with those of previous phase II studies that support the use of carboplatin CCRT in patients with LA-NPC .