Concurrent Chemoradiation versus Neoadjuvant Chemotherapy followed by Definitive Therapy for management of Locally Advanced Resectable Hypopharyngeal Squamous Cancers: A Phase III Randomized Controlled Trial.

Aim: The aim of this study will be to examine whether neoadjuvant chemotherapy before definitive therapy (surgery or CCRT) can improve disease free survival in locally advanced (Stage III & IV M0) hypopharyngeal squamous cell cancers compared to standard definitive CCRT.

• Management of Locally advanced hypopharyngeal squamous cell cancers has undergone a paradigm shift over past few decades and organ preservation therapies are being preferred over ablative surgeries without compromise on survival. The results of EORTC trial 24891 comparing a larynx preservation approach to immediate surgery in hypopharynx and lateral epilarynx squamous cell carcinoma showed no compromise of disease control or survival and allowed more than half of the survivors to retain their larynx. The organ preservation arm in this trial was neoadjuvant chemotherapy followed by radiotherapy which was compared with the standard arm of surgery followed by adjuvant therapy. In this trial there was no concurrent chemoradiotherapy arm.
• Data from RTOG 91-11 trial for laryngeal squamous cell cancers treatment has shown superiority of concurrent chemoradiation(CCRT) approach to radiation alone or to neoadjuvant chemotherapy followed by radiotherapy approach. This result of laryngeal cancers management is extrapolated to hypopharyngeal cancers today and we are using CCRT in cancers of hypopharynx for larngeal preservation. This trial did not have a surgery arm.
• The hypopharyngeal cancers are biologically different from laryngeal cancers. They are usually poorly differentiated. They present at a late stage and are usually high in disease volume. Early presentations are unfortunately quite uncommon as most patients do not have symptoms until late, at which point the prognosis is poor. Approximately 60-80 % of the patients reported in large series have stage III or IV disease at presentation, and the 5-year overall survival rate is reported to be around 15% to 45%. In the review by Gourin and Terris, the important factors in the poor prognosis of patients who present with a hypopharyngeal cancer are the high rates of regional and distant metastasis. Nearly 60% to 80% of these patients have clinically positive regional lymph nodes, and in approximately 40% of cases contralateral occult nodal metastases are present. The number of patients who develop distant metastasis, is reported to be between 10% and 30% or even higher, and this is an even more important prognostic factor. Distant metastatic spread has been reported to occur in up to 60% of hypopharyngeal cancer cases, either at presentation or during follow-up. The frequency of distant metastases is also among the highest of all head and neck cancers for this primary site. Therefore, these cancers are much more aggressive as compared to laryngeal cancers. The survival rates for stage III/IV laryngeal cancers is about 55%. Therefore the treatment options for laryngeal cancers should not be extrapolated to hypopharyngeal cancers.
• The salvage surgery rates are poor and it entails more extensive and morbid procedures as compared to laryngeal cancer.as well for these patients and in salvage settings the surgeries are known to be much more morbid for this primary site. The percentage of patients who can be salvaged after CCRT for this site is also very low.

According to NCCN guidelines today, the patients eligible for this trial can be offered any of the following three modalities of treatment today:

1. CCRT
2. NACT followed by CCRT or surgery depending on response to NACT
3. Upfront surgery

• Majority of these patients are treated with concomitant CT+ RT based on data extrapolated from RTOG 91-11 and the MACH-NC data which demonstrated that concurrent chemotherapy with radiation therapy produces best results.
• The problem with the above mentioned approach is that RTOG 91-11 dealt with only laryngeal cancers and not hypopharyngeal cancers.
• In view of the more aggressive behavior of these cancers as compared to laryngeal cancers it is felt that level I evidence is required for deciding on treatment option for this group of patients instead of extrapolating data from RTOG 91-11 since that trial was for laryngeal cancers alone.