Comparative efficacy of six therapies for Hypopharyngeal and laryngeal neoplasms: a network meta-analysis

Hypopharyngeal neoplasm, as a term used for malignancies of a subsite of the upper aerodigestive tract, is difficult to catch in its earliest stages. Meanwhile it is reported to have the highest mortality rates among kinds of head and neck cancers [1]. Laryngeal neoplasms are mostly squamous cell carcinomas, which reflect they originate from the skin of the larynx. Its 5 years survival rates in the United States are 60% [2]. So far multiple treatments for hypopharyngeal or laryngeal neoplasms have been developed and compared, which include surgery, radiation therapy (RT), chemoradiation therapy (CRT), or kinds of combination of treatments aforementioned [3]. One of the main targets of treating patients with locoregional advanced laryngeal cancer is to maintain larynx function. Yet surgery, though providing satisfying local control, might impair life quality of patients. Thus the application of surgery alone in treating laryngeal neoplasms and hypopharyngeal neoplasms has been reduced while chemotherapy (CT) and RT have been more widely used in clinical practice these days [2]. However, RT and CT being applied separately or combined have triggered worries regarding a decrease in overall survival rate (OSR) since they are reckoned to have caused acute toxicity and disrupted laryngeal function [4].

Many meta-analyses related to head and neck cancer, hypopharyngeal neoplasm, and laryngeal neoplasms have been conducted to evaluate the efficacy of CT, RT, and CRT. Whereas, there were several deficiencies in prior studies such as small sample sizes [5] or a lack of sufficient prospective studies [5]. Besides, the nature of conventional meta-analysis prevents it from performing more comprehensive analysis of multiple treatments. It is known that network meta-analysis (NMA) could combine both direct and indirect evidence, thus considered to be of high clinical value. Based on the facts mentioned above, NMA might be the most adequate way to compare different regimens of hypopharyngeal neoplasms and laryngeal neoplasms.

Notably, most of existing NMAs comparing treatments for head and neck cancers failed to pay attention to certain specific types of cancers, which are hypopharyngeal and laryngeal neoplasms in our case. Hence it is necessary to conduct a systematic review in order to get more comprehensive results regarding regimens for hypopharyngeal and laryngeal neoplasms.

Our NMA focused on comparative efficacies of six therapies of hypopharyngeal neoplasms and laryngeal neoplasms. Results of NMA indicated that surgery alone were significantly better than RT and CCRT according to 1-OS outcome. RT + S were significantly superior to RT, ICRT, and CCRT in terms of 3-OS. Meanwhile RT + S and surgery alone had significant advantage over RT in 5-OS. CCRT proved to be better than RT in 3-DFS. With regards to relative ranking analysis, RT + S performed desirably in both OS and DFS while CCRT and ICRT were advantageous in DFS.

RT is utilized as the primary treatment for early laryngeal cancer in northern Europe and North America for its being an acknowledged treatment for selected laryngeal carcinomas that educes beneficial oncologic results [32]. For instance, RT could provide a possibility of curing un-resectable tumor. When compared with surgery, RT might provide less morbidity regarding subclinical disease and advantageous organ preservation [33].

Yet RT performed poorly in both OS and DFS according to our results, which is contrary to the results of a prior NMA claiming that RT was associated with higher rates of OS and DFS than CT, CRT, and laryngectomy [32]. However, our results that CCRT and ICRT took advantageous over RT turned out to be consistent with paper conducted by Zackrisson et al., which concluded that CRT was better than RT [34]. Besides, TLM has been used in laryngeal malignant lesions since 1972. As pointed out in prior NMAs, there are controversies in clinical literature regarding oncologic outcomes of TLM and RT for T1 glottis carcinoma, and plenty of comparisons between TLM and RT have been made. RT was inferior to TLM for T1 glottic carcinoma in OS according to Mo et al. [35], Zhong et al. [36], and Huang et al. [5]. Whereas Abdurehim et al. thought this question remained unanswered in systematic review since no significant difference was shown between RT and TLM [37], which is also consistent with our results. More random-controlled and prospective trials should be conducted, based on which a more clinically reliable conclusion would be reached in future NMAs.

Furthermore, CCRT and ICRT demonstrated no significant difference on survival control in our analysis. Similar results were shown in Ma et al. paper which claimed that ICRT had no significant benefit compared to CCRT regarding OS or locoreginal control [38]. Yet Ma also claimed that ICRT generated desirable outcomes in larynx preservation [39]. More outcomes should be explored with regard to the effectiveness of ICRT and CCRT. The subgroup analysis of 17 studies reported patients with larynx stage III-IV and hypopharynx stage II-IV also showed similar results in term of 3-OS, 5-OS, 3-DFS, 5-DFS except that the results were all not statistically significant. More clinical researches will be required in the future.

There still exist several limitations in our NMA despite that we have conducted our work as meticulous as possible. First of all, there might be several deficiencies caused by the quality and non-unified standards of the included trials. For instance, patients’ or surgeon’s preference in these trials might lead to selection bias inevitably. Besides, a great proportion of the included trials were non-randomized or retrospective trials, which could increase heterogeneity of our NMA. Notably, toxicity of treatments analyzed in our NMA has not been investigated thoroughly because of a lack of data and comparable outcomes. It should not be ignored that a lack of full consideration on dose of RT and type of TLM might undermine the clinical value of our results to some extent. Secondly, we failed to take more combination therapies into consideration. Several trials and conventional meta-analyses have discovered an increase in efficacy of combination therapies such as chemotherapy combined with CCRT on survival control for some types of head and neck cancers [40‐42]. Yet a comprehensive analysis regarding various combination treatments is hard to conduct on account of insufficient data in our included studies. Thirdly, sample sizes for some specific comparisons were not big enough. For instance, there were only 23 subjects treated by TLM in 3-DFS and 5-DFS. More prospective trials should be performed to reach more reliable conclusions and further studies focusing on combination therapies should be carried out. Fourthly, due to limited studies and insufficient data on early-stage patients, our analysis could not make a subgroup analysis of these patients. Therefore, future studies are needed to assess the impact of various treatments in the management of early-stage glottic larynx patients in order to provide more credible medical guideline.

RT combined with surgery turned out to be optimal therapy of all the outcomes while the efficacy of RT was relatively poorer in the treatment of patients with larynx stage III-IV and hypopharynx stage II-IV. Also, the good performance of CCRT and ICRT in terms of DFS made them as secondary recommended therapies. There is no significant difference between surgery and TLM. The comparison of more related therapies will be better understood once results of more high-quality clinical trials conducted.