Reduced-dose radiation in human papillomavirus-associated oropharyngeal carcinoma can improve outcome: a systematic review and meta-analysis

Introduction

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors worldwide, with about 750,000 new cases and 360,000 cancer-related deaths in 2020 (1). About 60% of HNSCC cases are locally advanced at the time of diagnosis, and the current standard of treatment is radical concurrent chemoradiation or surgery followed by radiation therapy (2). HNSCC includes cancers of the oral cavity, larynx, hypopharynx, and oropharynx (3), while oropharyngeal carcinoma (OPC) involves carcinomas of the tonsils, base of the tongue, soft palate, and uvula. Although the incidence of head and neck cancer has steadily declined over the past few decades as smoking rates have decreased, the incidence of OPC is generally ascending, mainly due to the increase in human papillomavirus (HPV) infection (4). According to previous studies, HPV-related OPC reached 71% and 51.8% in the United States and the United Kingdom, respectively (5-8). Of these, 85–96% of cases are caused by HPV-16 infection. The latest version of the American Joint Committee on Cancer (AJCC) staging system classifies OPC into HPV-positive (HPV+) and HPV-negative (HPV–) based on their different molecular profiles, tumor characteristics, and outcomes (9). A series of preclinical and clinical studies (10,11) have shown that HPV-associated OPC has increased sensitivity to chemoradiotherapy and is associated with a more favorable prognosis (12).

Despite its effectiveness, the standard 7-week course of chemoradiotherapy for HPV-related OPC results in considerable treatment-related adverse effects (13), Radiotherapy can cause acute and late complications. Acute complications consist of dermatitis, mucositis, dysphagia, odynophagia, alopecia and so on. Besides, skin changes, xerostomia, dental caries, trismus, lymphedema, and swallowing dysfunction are common in late complications. Reports showed the interaction between the dose of radiotherapy and adverse reactions. Such as, the dose of middle and superior constrictors exceeded 55 Gy lead to long-term swallowing dysfunction, and radiotherapy combined with high-dose cisplatin can cause severe late toxicity (14). Acute and late complications give rise to discontinuation of treatment and decreased the quality of life. After radiation and high-dose cisplatin, patients with HPV-related OPC have significantly longer survival periods than those without (10), but the quality of life of these patients is significantly impaired for decades. De-escalation treatment for HPV-related OPC aims to minimize the post-treatment side effects while simultaneously prolonging survival. Research on de-escalation strategies involves the following: (I) reducing the radiotherapy dose while increasing induction chemotherapy; (II) reducing the radiotherapy dose by increasing transoral robotic surgery; (III) reducing radiotherapy dose and cisplatin; and (IV) replacing cisplatin with cetuximab (15-19).

Several clinical trials (16,18,19) have shown that the radiation dose to gross disease can be safely reduced in HPV-positive OPC patients, typically by 10–16 Gy. However, some scholars hold that reduced-dose in HPV-positive patients would only quickly reduce the tumor volume in a short period of time, but it may cause risks to patients in the long term (20). Few studies conducted systematic reviews and meta-analyses to determine whether lowering the radiation dose affects survival and adverse effects in HPV-related OPC patients. Therefore, in our study, we compared the radiation effect of reduced-dose and standard-dose treatments on prognosis in HPV-related OPC and conducted a systematic review of the adverse effects following dose reduction. We present the following article in accordance with the MOOSE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5935/rc).

Methods

Search strategy

A systematic search was conducted for relevant studies published before September 15, 2021, in the PubMed, Embase, Cochrane, ProQuest, Scopus, ScienceDirect, and the Web of Science electronic databases. The subject terms “oropharynx cancer/ carcinoma” or “OPC” were combined with the following specific terms: “human papillomavirus viruses”, “human papillomavirus”, “HPV”, “P16”, and “radiotherapy”.

Selection criteria

The inclusion criteria were as follows: (I) Articles involving patients diagnosed with oral cancer; (II) studies with more than 20 patients; (III) research involving patients confirmed as HPV+ or P16+ by immunohistochemistry or other evidence; and (IV) studies involving a therapeutic plan that applies dose reduction; (V) Studies of all language. (The enrolled articles were all in English after screening.); (VI) case reports, comments, editorials, and reviews were excluded.

Articles were independently screened and then selected by two reviewers. In cases of studies overlapping, only the study with the most comprehensive data was selected when the patient populations were from the same institution, based on the consensus between the two reviewers. If differences in opinion between the two reviewers needed to be resolved, a third reviewer was consulted.

Data extraction

Relevant characteristics were extracted from each study, including the first author’s name, publication year, country, study design, sample size, study participant age, study participant sex (the percentage of males), stage, smoking status (the percentage of fewer than 20 packs per year), and follow-up period (Table 1). Two reviewers independently extracted the information from the included studies. We then extracted the radiation and chemotherapy schemes for reduced dose (RD) and standard dose (SD), respectively (Tables 2,3). According to the clinical outcomes, the 2- and 3-year overall survival (OS) and progression-free survival (PFS) rates were also obtained. Several studies reported Kaplan-Meier survival curves rather than survival outcomes directly, but the survival outcomes could also be extracted from these survival curves. During this analysis, we did not attempt to obtain missing data by contacting the studies’ authors. Also, given the lack of reports on adverse reactions (AEs) in the standard dose group, only the AEs of the reduced-dose group were counted, as shown in Table 4.

Statistical analysis

Both random and fixed effects models were used to pool analysis of the OS and PFS for SD and RD. Given that few articles contained both the standard and reduced-dose treatments, a meta-analysis of the standard and reduced-dose treatment subsets was conducted separately. The I² statistic was used to measure the degree of heterogeneity caused by variability in the true effect size. Statistical analysis was performed using the SPSS (version 15.0) and R language (version 1.6.3, http://www.Rproject.org). Meta-analysis was conducted by using the R package meta (34). Forest plots were created by the metaprop function of meta package, and funnel plots were constructed by the funnel function to estimate the publication bias. Egger’s test was performed to estimate the indexes of funnel asymmetry. If the funnel plot was not significantly asymmetrical, trim- and fill- analyses were performed.

Results

Literature search and study characteristics

The search process is displayed in Figure 1. A total of 4,634 articles published before September 15th, 2021 were identified through the initial database search. We then excluded 869 overlapping studies, and a further 3,720 articles were excluded based on their improper titles and abstracts. The full texts of the remaining 45 studies were assessed, and studies with insufficient data or inappropriate populations, treatments, and sizes were excluded. Finally, 13 studies were included in the meta-analysis, among which nine were SD studies and 13 were RD studies (Table 1). The selected articles were single-arm observational articles, controlled trials, or randomized studies.

Figure 1 Flowchart of study selection. Of the 13 studies included in this meta-analysis, 9 studies included both RD and SD, and 4 studies just included in RD. SD, standard dose; RD, reduced dose.

The sample sizes of the SD studies ranged from eight to 2,049 (Table 2) and those of the RD studies ranged from 12 to 157 (Table 3). The ages of patients treated with SD were similar to those who received RD (60.9±5.9 vs. 58.6±2.4 years). There were no significant gender differences observed between the SD and RD groups (percentage of males, 85.8% vs. 84.8%). Also, the mean follow-up times of the RD and SD studies were compared. Regarding the SD treatment regimen, the total dose ranged from 66 to 70 Gy, while that of the RD regimen was <66 Gy.

OS comparison between SD and RD in HPV-related OPC patients

We conducted a meta-analysis of the SD and RD treatment groups. The results showed that the 2-year overall survival (2y-OS) and 3-year overall survival (3y-OS) were better in the RD group compared to the SD group (P<0.05, Figure 2). Four SD trials showed that the 2y-OS was 88.36% (86.23–90.49%), and eight SD trials indicated that the 3y-OS was 87.46% (86.91–88.01%). Meanwhile, seven RD trials showed that the 2-year OS was 95.66% (94.74–96.59%), and 11 RD trials showed that the 3-year OS was 91.51% (90.61–92.41%). There was no significant difference in PFS between RD and SD; the 2y-PFS and 3y-PFS rates were 89.29% vs. 90.7% and 87.07% vs. 89.71%, respectively (P≥0.05, Figure 3).

Figure 2 Meta-analysis (forest plot) of the OS reported in RD and SD studies. OS, overall survival; RD, reduced dose; SD, standard dose.

Figure 3 Meta-analysis (forest plot) of the PFS reported in RD and SD studies. PFS, progression-free survival; RD, reduced dose; SD, standard dose.

Analysis of the adverse reactions in RD patients

We performed a systematic review and analysis of the articles on RD treatment (Table 4). Among the four studies analyzed, Misiukiewicz et al. showed that the incidence rates of oral mucositis, neutropenia, and urinary retention were all 8.3%. According to Marur et al., rash was the most common adverse reaction (54.9%) followed by neutrophil count reduction (23.5%), dehydration, lymphocyte count reduction, and leukocyte count reduction (all 11.8%). The top three adverse reactions reported by Chera et al. were dry mouth (38.6%), oral mucositis (34.1%), and nausea (18.2%). Compared with the other three studies, Chen et al. reported the most AEs, with 43 people suffering from dry mouth, 40 people suffering from decreased white blood cell (WBC) count, and 38 people suffering from oral mucositis. In summary, the most common complication of RD was mucositis oral, affecting 36.4% of patients, followed by decreased WBC count (30.5%) and dry mouth (29.1%).

Sensitivity analysis and evaluation of publication bias

Following sensitivity analysis using the elimination method, no significant change was observed in the results, which indicated their robustness. Egger’s test was performed on the indexes with more than three included studies, and the results showed no obvious publication bias.

Discussion

It is known that patients with HPV-associated OPC have an excellent prognosis. Studies have shown that these patients are more sensitive to radiation therapy (35), and can achieve the same therapeutic effect by reducing the radiation dose. Although this topic is at the forefront of oncologic research, there is currently a lack of summative assessment. Therefore, we compared the effects of reduced and standard doses in HPV-related OPC on survival and the incidence of AEs. Our results suggested that patients with HPV-related OPC could be treated with a lower dose compared to standard treatment, and there are fewer AEs after radiotherapy. This study may lead to a change in the treatment options for patients with oropharyngeal cancer.

In this study, we selected patients who were HPV-related and divided them into two groups: SD and RD treatment groups, and observed their survival conditions. As mentioned above, we observed that patients who received a RD had superior 2y-OS and 3y-OS rates than those who received SD treatment (95.66 vs. 91.51; 88.36 vs. 87.46, respectively). Moreover, the 2- and 3-year PFS rates were not significantly different between the two groups. Numerous factors influence the prognosis of OPC, such as disease stage, gender, smoking state, HPV subtype, etc. (10,23,24,36). In our research, the disease stage, gender, and smoking state were not disparate between the two groups, so we excluded their influence. HPV infection can be classified into P16+/HPV+, p16+/HPV−, or p16−/HPV+. Some studies have reported that the OS of p16+/HPV− and p16−/HPV+ are poor (37). However, the included studies in this meta-analysis failed to distinguish between these three specific categories, and thus, we could determine whether our results were affected by HPV status in the two groups. It is hoped that the currently ongoing clinical trials (38) consider the subtype of HPV states to ascertain whether different HPV states affect the prognosis of treatment to varying degrees and clarify which HPV has a superior effect.

In our retrospective analysis, the main AE of RD treatment was oral mucositis, occurring in 36.4% of patients. Comparing the four studies that mentioned AEs, Fietkau et al. (25), Yom et al. (23), and Echevarria et al. (28) reported fewer AEs, which may be related to the use of the chemotherapy drug, carboplatin. A trial comparing cetuximab and cisplatin chemoradiotherapy (CRT) as presented by a European group at European Society for Medical Oncology (ESMO) 2018 (30), which confirmed that platinum can enhance radiosensitivity and reduce AEs. Although the reported incidence of adverse reactions seemed high in Chen et al. (21), they were mainly concentrated in Grades 1–2, which are relatively mild and do not significantly impact the quality of life of patients. Compared with the other three studies, Chen et al. employed combination treatment using paclitaxel and carboplatin instead of platinum monotherapy; thus, we speculate that the higher rates of adverse reactions in their study may be related to the multiple chemotherapy regimen combinations.

Unfortunately, detailed adverse events in the SD group were not collected in our study, so it was impossible to compare the two groups. Nevertheless, further analysis revealed that all of the relevant research results concerning radiotherapy dose reduction indicated fewer adverse reactions. Standard chemoradiotherapy regimens are associated with substantial toxic effects, including in organs involved in salivation, swallowing, and mucosal integrity, with dose-related side effects. Probability models utilized for complications in normal tissue show that with each 1 Gy increase in the mean dose to the parotid gland, the likelihood of xerostomia increases by about 5% at 1-year post-treatment (39). Likewise, the incidence of late dysphagia and gastrostomy tube dependence rises with increasing pharyngeal constrictor, larynges, and cricopharyngeal inlet doses. Thus, reducing the radiation dose in selected patients with favorable biology (HPV-related) has the potential to improve treatment tolerability while at the same time preserving long-term function.

The systematic review conducted in this study showed that lower doses could reduce post-treatment AEs, either the incidence of decreased quality of life (40) or late adverse reactions (25). Some studies (28,41-43) have shown that, after dose reduction, the symptoms of dry mouth, hypogeusia, and dysphagia continue to improve, and gastrostomy tube (PEG) placement rates and late toxicity were also lower (43-45). It has also been reported (46) that the target volume of OPC could combine dose reduction with unilateral irradiation for improving mild to moderate acute swallowing dysfunction. Taken together, these results indicate that reducing the radiation dose is conducive to improving the quality of life of patients and enhancing the functioning of affected organs.

This article had several limitations that should be noted. Firstly, the sample size of the included trials is small, and there is a lack of randomized phase III clinical trial results. Furthermore, due to the inclusion of clinical trials with potential selection bias, the compared treatment strategies and follow-up periods are largely different among various studies, which may have impacted the results. Lastly, the vast majority of included studies failed to provide long-term follow-up. HPV-related tumor recurrences continue after 3 years of therapy (10) and the cumulative incidence of late AEs consistently increases over a longer period (14), implying that toxicity reporting is likely understated, and the outcomes are likely overestimated to some extent. Nevertheless, these shortcomings do not detract from the promising short-term results of treatment de-escalation a concept that seeks to improve the therapeutic ratio for this expanding population.

Conclusions

This systematic review and pooled analysis revealed that compared to standard radiation doses, radiation dose reduction in patients with HPV-related OPC provided superior therapeutic outcomes and optimized quality of life, but had similar PFS rates. Prospective randomized trials or studies with large sample sizes are needed to validate these findings.

Acknowledgments

We thank all the members of the Radiation Oncology Translational Research Group (ROTRG) who participated in this study.

Funding: The current study was supported by grants from the National Natural Science Foundation of China (No. 81802740 to JD Sui; No. 81972857 to Y Wang), the Chongqing Science and Health Joint Medical Research Project (No. 2022ZDXM028 to JD Sui), and the Natural Science Foundation of Chongqing City (No. cstc2021jscx-msxm0029 to Y Wang).

Footnote

Reporting Checklist: The authors have completed the MOOSE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5935/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5935/coif). JDS reports that the current study was supported by grants from the National Natural Science Foundation of China (No. 81802740), and the Chongqing Science and Health Joint Medical Research Project (No. 2022ZDXM028). YW reports that the current study was supported by grants from the National Natural Science Foundation of China (No. 81972857), and the Natural Science Foundation of Chongqing City (No. cstc2021jscx-msxm0029). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: A. Kaseem)