Concomitant Chemo Regimens Most Effective for Locally Advanced Nasopharyngeal Carcinoma

Kwan-Hwa Chi, MD

The addition of chemotherapy, either adjuvant or induction, to concomitant chemoradiotherapy (CRT) achieved a significantly high survival benefit for patients with locally advanced nasopharyngeal carcinoma (NPC), according to the results of a recent meta-analysis published in the Journal of Clinical Oncology.

The analysis showed that, overall, regimens containing concomitant chemotherapy generally ranked better than schedules without concomitant chemotherapy. Moreover, for the treatments that did include CRT, the addition of adjuvant chemotherapy (AC) specifically ranked better than CRT alone. However, those differences in head-to-head comparison were only found to be significant for progression-free survival (PFS) and locoregional control.

Induction chemotherapy (IC), on the other hand, when added to CRT, ranked better than CRT alone for PFS, locoregional control, and distant control.

Despite the fact that the individual patient data Meta-Analysis of Chemotherapy (MAC) in NPC (MAC-NPC) has demonstrated that the addition of concomitant chemotherapy to radiotherapy improves outcomes for patients—including overall survival (OS), PFS, locoregional control, and distant control—controversy remains regarding potential additional benefits of IC or AC to CRT. Current treatment guidelines reflect these lingering controversies, allowing multiple treatment options.

“I have a long debate with ‘pure medical oncologists’ that IC is not a right idea to go even in patients with high metastatic potential,” Kwan-Hwa Chi, MD, one of the authors on the study, said in an interview with OncLive. “Most physicians regard CRT as nothing but killing cells, but we should look at the things on immunologic points.”

Chi also said he thinks of CRT as a method of immunotherapy, such that it can induce immunogenic death.

“For example most NPC patients regain immunity against EBV-associated immunity. RT alone usually failed to achieve this goal. The IC initially shrank tumor size but rarely evoked immunity, and might create drug-resistant clones left for CRT, which is difficult to induce successful immunity.”

According to Chi, the “low intensity” AC followed by CRT is a good strategy for these patients, as it maintains the immunity created by CRT.

The MAC-NPC is a meta-analysis of individual patient data that includes most randomized trials conducted up to December 31, 2010, and evaluates the benefit of adding chemotherapy to local treatment in patients with nonmetastatic NPC. The primary endpoint was OS, and secondary endpoints included PFS, locoregional, and distant control. Only severe acute toxicities were assessed in this study, including acute neutropenia, mucositis, weight loss, and hearing loss.

The network consists of a total of 20 trials and 5144 patients. Seven different treatment options were evaluated overall: radiotherapy (RT) alone (which was used as a reference category), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), CRT, IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). Only IC-CRT was not directly compared with RT.

The median follow-up was 7.4 years (6.2 -11.9). Patients in the analysis were mostly male (3826 patients; 74%), under the age of 50 (3177 patients; 62%), and had good performance status (0 in 2743 patients [65%] and 1 in 1404 patients [33%]). Patients most frequently presented with locally advanced tumors (stage III in 2,519 patients [49%]; stage IVA-B in 2,133 patients [42%]; and nonkeratinizing histology [WHO grade I in 196 patients; 4%]).

CRT-AC (P score of 96%), CRT (P score of 70%), and IC-CRT (P score of 63%) all had the highest effect on OS. The corresponding absolute benefit at 5 years was, respectively, 12%, 8%, and 6% compared with RT alone.

There was no significant heterogeneity (I² = 5.5%; P = .30) or inconsistency (P = .53). Compared with RT alone, the HRs (95% CIs) for OS for CRT-AC, CRT, and IC-CRT, were, respectively, 0.65 (0.56-0.75), 0.77 (0.64-0.92), and 0.81 (0.63-1.04). The HRs (95% CIs) of CRT-AC compared with CRT or IC-CRT demonstrated no significant differences, with respective values of 0.85 (0.68-1.05) and 0.81 (0.61-1.07).

The PFS results were generally consistent with OS findings in this study. No heterogeneity (I² = 0%; P = .25) or inconsistency (P = .96) was detected. The 3 best treatments for OS were the same for the PFS endpoint, with CRT-AC ranking as the most effective (P score of 94%), followed by IC-CRT (P score of 79%) and CRT (P score of 52%). The HRs (95% CIs) of CRT-AC compared with CRT or IC-CRT were, respectively, 0.81 (0.66-0.98) and 0.92 (0.71-1.18).

In terms of locoregional control, the 3 best treatments were IC-RT-AC (P score of 90%), CRT-AC (P score of 82%), and RT-AC (P score of 58%), and there was no heterogeneity (I² = 0%; P = .50) or inconsistency (P = .75).

According to 2 sensitivity analyses for OS in the study, CRT-AC remained the most effective treatment, followed closely by IC-CRT and CRT.

The toxicity analyses showed CRT-AC and RT-AC to be the most toxic regimens for mucositis/hearing loss and neutropenia/weight loss, respectively. This underscores the potential toxicity of AC when administered either alone or in combination with CRT.

Despite those toxicities, Chi supports the use of CRT-AC overall in the treatment of this patient population.

“Accordingly, we need CRT plus AC,” he said. “The risk of IC is high because patients suffered more unnecessary toxicities. However, the AC intensity should not go high to avoid the extra-inflammation from CRT to be boosted, which may further decrease the immunity benefit created from AC.”

Ribassin-Majed L, Marguet S, Lee A, et al. What is the best treatment of locally advanced nasopharyngeal carcinoma? An individual patient data network meta-analysis [published online December 5, 2016] J Clin Oncol. doi:10.1200/JCO.2016.70.4775