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INTRODUCTION
Malignant neoplasms of the nasal cavity and paranasal sinuses are an aggressive form of tumour that tends to be diagnosed at a locoregionally advanced stage [1]. Among its various histological subtypes, squamous cell carcinomas (SCC) are the most common form of sinonasal cancer, with approximately 50%–60% of sinonasal malignancies being SCC [2].
Currently, surgery is the mainstay definitive treatment option for patients with sinonasal squamous cell carcinomas (SNSCC), with open surgery rather than endoscopic surgery being the more commonly used approach [3]. For locally unresectable tumours, chemoradiotherapy may be used as an alternative to surgical intervention with a curative intent. However, induction chemotherapy has not traditionally been used as a standard-of-care for patients with SNSCC. Sinonasal malignancies are also rarer than other types of tumours. Hence, a limited number of studies are available on the use of induction chemotherapy for sinonasal malignancies, and they tend to be smaller case series [4]. To date, no meta-analysis evaluating induction chemotherapy for SNSCC has yet been published. However, a growing body of evidence demonstrates that induction chemotherapy improves overall survival and other related parameters for patients with both early- and late-stage SNSCC. By pooling individual studies together, this review aims to illuminate the role of induction chemotherapy on survival outcomes and inform patient care practices for patients undergoing cancer care for SNSCC.
METHODOLOGY
Search strategy and data extraction
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [5]. The finalised review protocol was prospectively registered and published in the international review database PROSPERO (CRD 42024498043) [6]. Ethical approval was not required for this study. We consulted a medical librarian from Imperial College London before commencing a systematic literature search in the following bibliographic databases: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science. An example search strategy is published below (Table 1). In order to identify any additional relevant studies, we hand-searched the reference lists of included studies and references cited in reviews on similar topics. We also screened through grey literature, including conference abstracts, theses and journal preprints. No language or start date restrictions were imposed on our search, which covered published material up to and including August 1, 2024.
The two reviewers (RSG and CGHK) independently assessed all search results by title and abstract, and then by full text for potential eligible studies. Any disagreements were resolved through joint discussion. The results of the search were managed on Covidence. The primary outcome of interest was overall survival and the secondary outcome was disease-free survival. Studies had to meet all inclusion and exclusion criteria to be included in the review. The inclusion and exclusion criteria are detailed below and structured using the PICO(S) framework.
1) Population: Studies with a patient population of 10 or more patients with SNSCC.
2) Intervention: Patients in the study underwent induction or neoadjuvant chemotherapy prior to definitive local therapy. Patients in studies who underwent previous sinonasal cancer treatment were excluded from the review.
3) Comparison/control: Patients in the study who were not exposed to induction chemotherapy but who underwent definitive treatment for SNSCC, including definitive surgery, chemotherapy, radiotherapy or chemoradiotherapy. The patients may or may not have undergone adjuvant therapy. Included studies must have a control group.
4) Outcomes: Overall survival (OS) or disease-free survival (DFS). Studies needed to have published data for at least one category of survival outcome in order to be included.
5) Study design: Retrospective studies, prospective studies or clinical trials. Case reports, literature reviews, and systematic reviews were excluded from this review.
Patients in the treatment group received induction chemotherapy prior to definitive local therapy, while patients in the control group did not receive induction chemotherapy. Examples of definitive local therapy include radiotherapy, chemoradiotherapy or surgery. Patients who received adjuvant or post-operative therapy, including adjuvant chemotherapy, radiotherapy and chemoradiotherapy, were eligible for inclusion in this study. Data was extracted independently by both reviewers from all full-text articles screened for eligibility via a customised data extraction form Supplementary Material (in the online-only Data Supplement). Study authors were contacted for further information when required. Two measures of inter-coder reliability, PABAK and Cohen’s Kappa, were used to evaluate the levels of inter-coder agreement.
Data analysis
Critical appraisal was conducted independently by the two reviewers, and inconsistencies were resolved through joint discussion. The Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool was used in accordance with Cochrane Collaboration guidelines [7]. Any study with a serious risk of bias was excluded from the analysis.
In the case of overlapping populations between studies, we selected the study with lowest risk of bias, or, should multiple studies have the same risk, the study with the largest population. Pooled statistics, including forest plots and sensitivity analyses, were synthesised using Review Manager (RevMan) Web Version 7.4.0 (The Cochrane Collaboration). In order to synthesise time-to-event data, the Inverse Variance statistical method (95% confidence interval [CI]) with hazard ratio (HR) as the effect measure was selected. Where the HR and standard error were not published in the included papers, Tierney et al. [8] and Parmar et al’s algorithm [9] was used to derive the HR and standard error from the logrank, Mantel Haenszel or Cox-regression p-value and the numbers of events on each arm. If the paper did not present a p-value with at least two significant figures, data was derived from Kaplan-Meier curves using R Version 4.3.2 (R Foundation for Statistical Computing).
The authors recognise that individual measures of heterogeneity may carry a degree of uncertainty and should not be used in isolation to diagnose statistical heterogeneity. Accordingly, χ2, p-values, Tau2 and I2 were used in combination to assess heterogeneity. The following thresholds were used to guide the interpretation of the I2 value: 0%–40%: low heterogeneity, 40%–75%: moderate heterogeneity, 75%–100%: considerable heterogeneity. In evaluating the point estimate, should induction chemotherapy result in a risk reduction of at least 10 percentage points, the intervention was likely clinically meaningful for the outcome. A risk reduction of fewer than 10 percentage points would not necessarily indicate a minimally significant difference but would simply warrant further investigation by the authors [10].
RESULTS
Study selection
A total of 2,118 citations were identified from the four databases and the grey literature combined. After 332 duplicates were removed, 1,786 unique citations were screened by title, subheading and abstract. Of these, 1,754 studies were excluded. At this stage, inter-coder reliability (PABAK=0.92, Cohen’s kappa=0.88) was high. Next, 32 full-text articles were assessed for eligibility and 4 studies were included in the final analysis. At this stage, inter-coder reliability remained high (PABAK=0.85, Cohen’s kappa=0.77). The process is reflected in detail in the PRISMA flow diagram above (Fig. 1).
Patient characteristics
Patient characteristics identified from the data extraction process are displayed below (Table 2) [11-14]. A total of 267 patients across 4 studies were included in this analysis. The majority of patients were male (n=194, 72.7%), above 55 years old (mean age 61.7) and had late-stage (T3-4) cancer (90.7%). The most common primary site was the maxillary sinus.
Overall survival
The forest plot for overall survival (Fig. 2) reveals a positive and statistically significant result that favours the incorporation of induction chemotherapy into treatment regimens for patients with SNSCC. Results suggest a remarkable risk reduction of 44% for patients under induction chemotherapy regimens over the control regimens (HR=0.56, 95% CI=[0.36, 0.86], p<0.009). A total of 267 patients were included in this analysis.
Due to the smaller number of studies, a fixed-effects model was used for a robust estimate of the average intervention effect. The low I2 value (I2=26%), coupled with the low χ2 value (χ2=4.07) relative to its degree of freedom (df=3) suggested likely insignificant heterogeneity levels.
When individual studies were omitted from the pooled analysis one at a time for sensitivity analysis, endpoints did not change significantly. The results remained in favour of induction chemotherapy (HR<1.0) and of statistical significance (p<0.10).
Disease-free survival
The above forest plot (Fig. 3) suggests that the use of induction chemotherapy provides a noteworthy 18% risk reduction for patients undergoing definitive treatment for SNSCC (HR=0.82, 95% CI=[0.62, 1.08], p=0.16). A total of 182 patients were included in this analysis.
For this forest plot, due to the smaller number of studies, a fixed-effects model was used for a robust estimate of the average intervention effect. The low I2 value (I2=38%) and low χ2 value (χ2=3.21) relative to its degree of freedom (df=2) signalled that heterogeneity was low and likely insignificant.
The p>0.10 (p=0.16), and correspondingly, the 95% CI was relatively wide, and included the null value of a difference of 0%. Taken together with the notable HR of 0.82, which indicates a 12% risk reduction for the induction chemotherapy group compared to the control group, these results suggest a possible but statistically insignificant trend towards improvement in disease-free survival, and hence the need for additional research into the topic.
Risk of bias
Quality assessment was undertaken via the ROBINS-I tool. 3 studies included in the final meta-analysis had a low risk of bias and 1 study had an unclear risk of bias (Fig. 4).
DISCUSSION
This study demonstrates that induction chemotherapy may improve survival outcomes for patients with SNSCC. Previously, studies have suggested that induction chemotherapy may be a viable therapeutic add-on for patients with sinonasal malignancies. For example, pooled K-M curves from Khoury et al’s [15] paper revealed a 51% overall survival rate over 5 years in a cohort with fairly advanced locoregional disease. The most common adverse effects noted in this study were grade 3/4 neutropenia noted for 11 patients, followed by grade 3/4 febrile neutropenia noted for 10 out of 159 patients. Other studies have also shown an improvement in orbital preservation with induction chemotherapy in the treatment of advanced sinonasal malignancies [16,17]. Our findings add to the current understanding by providing a precise pooled estimate of the favourable effects, demonstrating that induction chemotherapy is not just a feasible option but is also clinically meaningful when compared to definitive local therapy as a standalone treatment. Our control group included patients who underwent adjuvant chemotherapy or chemoradiotherapy in addition to definitive local treatment, demonstrating that induction chemotherapy has a potential benefit to patient survival over a wide range of other multimodality treatment regimens. One study in this meta-analysis [14] included a small number of patients (n=7) in the treatment arm who received induction radiotherapy, without chemotherapy, prior to surgery. These patients could not be statistically omitted due to a lack of sufficiently stratified data available in the paper, and remain in the analysis.
This meta-analysis has many strengths. Firstly, the last 5 years has seen an uptick of studies published on the impact of induction chemotherapy on SNSCC, enabling this systematic review to incorporate an appreciable body of recent evidence from 2020 till present. In addition, patient demographics in this study fairly accurately represent the wider SNSCC patient population. In an epidemiological study on 4,994 patients with SNSCC in the United States, the female-to-male ratio was 1:2.3, and close to 80% of patients were 55 years old or older. This study’s 1:2.6 female-to-male ratio and 61.7 years’ mean age reflects the older male-dominant demographic of the general SNSCC patient population [18]. In addition, SNSCC is an aggressive cancer that tends to be diagnosed at a late stage. Accordingly, 90.7% of the patients in this review had locally-advanced T3 or T4 tumours. These results make this review particularly pertinent to the treatment of locoregionally-advanced SNSCC.
This meta-analysis is, to our knowledge, the first published meta-analysis on the impact of induction chemotherapy on SNSCC. Hence, this study importantly highlights a lack of existing meta-analyses on this topic, and will, hopefully, encourage further research on this topic.
This systematic review consists of retrospective studies of high methodological quality. Out of the 4 studies included in this meta-analysis, 3 had a low risk of bias when evaluated for quality assessment and 1 had an unknown risk of bias. However, no clinical trials have yet been published on this topic and the authors welcome such studies to increase the growing body of evidence. For example, preliminary results of an MD Anderson Cancer Center phase II, open-label trial on patients with SNSCC have been promising. Results suggest that induction chemotherapy, when added to traditional management regimens, achieved a median survival of four years in a cohort with very advanced SNSCC, with a majority achieving organ preservation [19].
Overall, findings from this meta-analysis suggest that definitive local therapy preceded by induction chemotherapy for SNSCC is associated with clinically meaningful improvements in survival outcomes when compared with definitive treatment alone. In particular, induction chemotherapy likely results in a significant improvement in overall survival and a potential improvement in disease-free survival. Hence, clinicians could consider incorporating induction chemotherapy as a routine treatment option for locally advanced-stage SNSCC. The authors also recommend incorporating induction chemotherapy as standard-of-care into best-practice guidelines, in order to improve the quality and efficacy of the management of patients with SNSCC.
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