Neoadjuvant chemotherapy in locally advanced (T3-T4) external auditory canal carcinoma: A retrospective observational study

External auditory canal cancers are rare head-and-neck malignancies.[1,2] Multiple histologies are seen at this site, with squamous cell carcinoma being the most common.[3] There is currently no universally accepted staging system for this disease with different institutes following different staging systems, of which “modified Pittsburgh” is the commonest in use. Patients with external auditory canal cancers often present late and nearly 80% are diagnosed with advanced stage disease; these patients have a 5-year survival of 0%.[4] Radical surgery remains the cornerstone of management in locally advanced stage IV external auditory canal cancers.[5] Patients with T3 or T4 external auditory canal cancers require partial or total temporal bone resection by an expert surgeon because of the complex anatomy involving critical organs and the rarity of the tumor. The results of chemoradiation in T3-T4 resectable tumors are unsatisfactory.[6] However, sometimes in very locally advanced external auditory canal cancers, surgery is not possible due to the risk of R1 (positive margins) or R2 (gross residual disease) resections, despite the availability of expert surgeons. The management of these lesions is complicated and there is limited literature available for guidance. At our institute, we treat patients with locally advanced and unresectable external auditory canal cancers with neoadjuvant chemotherapy (NACT). We aimed to study the outcomes of this novel treatment approach for locally advanced unresectable external auditory canal cancers, or in cases in which surgery would have been excessively morbid. This was a retrospective, single-center study conducted in the Department of Medical Oncology at the Tata Memorial Center in Mumbai, India, and was approved by the Institutional Ethics Committee. Given the retrospective nature of the study, the ethics committee waived the requirement for written informed consent. The study was conducted in accordance with the guidelines laid down by the International Conference on Harmonization-Good Clinical Practice (ICH-GCP). The patients were identified from our prospectively maintained head-and-neck NACT database. The keywords used were “adult,” “EAC,” and “T3-4 inoperable cancer.” The staging system used was the University of Pittsburgh Tumor nodes metastasis (TNM) Staging System.[7] All confirmed cases of locally advanced and inoperable external auditory canal cancers with an indication for NACT from the years 2010 to 2020 were included. All patients were discussed in a multidisciplinary tumor board. They were planned for two cycles of NACT followed by radiological and clinical response re-assessment categorized as per response evaluation in solid tumors (RECIST) in the multidisciplinary tumor board. Depending upon the response, the patient underwent either surgery followed by adjuvant therapy, chemoradiation, or palliative therapy. Data were extracted from the patient files as well as their electronic medical records. Data recorded included age, sex, comorbidities, disease stage, performance status, and management. This included the indications for NACT, treatment regimen, response, number of cycles of chemotherapy administered as well as all treatments given post-NACT and dates of progression, death and the last follow-up. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The study included 16 patients. The baseline characteristics are shown in Table 1. The indications for NACT included surgically unresectable disease in 4 (25%), extensive disease in 8 (50%), and long delay in surgery in 4 (25%) patients. NACT was administered to 14 patients (87.5%); 2 (12.5%) refused NACT. The NACT regimen was weekly paclitaxel with carboplatin in 6 (42.6%), docetaxel with cisplatin in 4 (28.6%), docetaxel with cisplatin and 5-fluorouracil (TPF) in 3 (21.4%), and docetaxel with carboplatin in 1 (7.1%); the median number of cycles was 2 (Interquartile range, 2-2). In 9 of the 14 patients who received NACT, radiologic response could not be confirmed as per RECIST criteria. Of these 9 patients, 4 (44.4%) had a partial response, 4 (44.4%) had stable disease, and 1 (11.1%) had progressive disease. The scans could be retrieved in the remaining 5 cases. After NACT, 6 (42.9%) patients underwent surgery, 5 (35.7%) received radical concurrent chemoradiation, and 3 (21.4%) received palliative care. Resection was R0 in 4 (66.7%), and R1 in 2 (33.3%) of the 6 who underwent surgery.Table 1: Baseline characteristics of patients with indications for neoadjuvant chemotherapy in external auditory canal carcinoma. The staging used was the University of Pittsburgh Tumor-Node-Metastasis (TNM) staging systemThe median follow-up was 5.2 years (95% CI, 4.83-10.06). Eleven patients had an event for PFS analysis. The median PFS was 1.67 years (95% CI, 0.36-6.18) [Figure 1A]. Similarly, 11 patients had an event for OS analysis. The median OS was 1.99 years (95% CI, 0.46-6.18) [Figure 1B].Figure 1: Panels (A): Overall survival (OS), and Panel (B) Progression-free survival (PFS) in patients with advanced unresectable external auditory canal carcinoma who received neoadjuvant chemotherapyTo the best of our knowledge, this is the largest series evaluating the role of NACT in locally advanced external auditory canal carcinoma. This study provides important insights into the outcomes of NACT. We found that (NACT) resulted in a 44.4% response rate and that surgery could be done in 42.8% of the patients who initially presented with extensive unresectable disease. This was a real-world, pragmatic study and the decision to give NACT was based on the patient’s fitness, affordability, and logistic considerations. The three-drug TPF regimen was used in only 21% of the patients; this is similar to what has been published in other Indian studies dealing with technically unresectable head-and-neck cancers.[8] Utilization of the TPF regimen is limited in India, mainly due to the excessive toxicity resulting from the high rate (25-30%) of dihydropyrimidine dehydrogenase (DPYD) mutations seen in patients with head-and-neck carcinomas in India.[9] The logistic challenge of the TPF regimen is another limiting factor in India. The response rate may potentially have been higher if the three-drug TPF regimen had been used more extensively, as TPF leads to a higher response rate, PFS and OS in head-and-neck cancers, when compared to the two-drug regimen of cisplatin and 5-FU, as shown in TAX323 and TAX324.[10–12] Our study was limited by the fact that it was a single-center retrospective study. At our center, we have a dedicated skull-based surgical unit; thus, the results of our study may not be applicable to centers that lack this expertise. Furthermore, heterogeneous chemotherapy regimens were used. Few patients received the three-drug TPF regimen, which is considered the best NACT regimen in terms of response rate. Hence, our real-world results may not reflect the optimal outcomes in this case series of rare tumors. Patients who receive NACT for locally advanced unresectable external auditory canal cancers have a response rate of 44.4%; 42.8% manage to undergo surgical resection. Thus, NACT can be considered a potential therapeutic option in T3-T4 stage locally advanced external auditory canal carcinoma for which surgical resection is considered problematic. Financial support and sponsorship Nil. Conflicts of interest Vanita Noronha and Kumar Prabhash are members of the editorial board of Cancer Research, Statistics and Treatment. As such, they may have had access to information and/or participated in decisions that could be perceived as influencing the publication of this manuscript. However, they had recused themselves from the peer review, editorial, and decision-making process for this manuscript, to ensure that the content is objective and unbiased.