A randomized clinical trial evaluating the efficacy and safety of the addition of oral metronomic chemotherapy after completion of standard chemoradiation versus observation in patients with locally advanced esophageal and gastroesophageal junction squamous cell carcinoma.
Authors: Noronha Vanita , Patil Vijay Maruti , Joshi Amit , Menon Nandini Sharrel , Goud Supriya , More Sucheta , Nakti Dipti , Yadav Akanksha , Shah Srushti , Mahajan Abhishek , Janu Amit , Kumar Rajiv , Kannan Sadhana , Agarwal Jai Prakash , Tibdewal Anil , Mummudi Naveen , Banavali Shripad Dinanath , Prabhash Kumar 
Published: January 2021

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Background: In RTOG 85-01, patients with locally advanced esophageal and gastroesophageal junction (GEJ) cancer treated with concurrent chemoradiotherapy (CRT) had a median overall survival (OS) of 14 months and 5-year OS of 27%. Improving outcomes in these patients is an unmet need. We investigated the addition of oral metronomic chemotherapy (OMC) following definitive CRT. Methods: A randomized integrated phase II/III clinical trial (CTRI/2015/09/006204) in patients with squamous cell carcinoma of the esophagus or the GEJ who had completed definitive radical CRT within the past 12 weeks, had an ECOG PS 0-2 and no clinical or radiologic evidence of progressive disease. Patients were stratified based on whether or not they had received induction chemotherapy followed by CRT, and then randomized 1:1 to receive OMC (celecoxib 200 mg twice daily and methotrexate 15 mg/m2 weekly) for 12 months or observation. The primary efficacy endpoint for the phase II portion was progression free survival (PFS). The secondary endpoints were OS and toxicity. With a power of 70% and an alpha of 10%, we hypothesized a hazard ratio of 1.5, with a median follow-up of 6 months. The planned sample size for the phase II portion was 151 patients. The p-value for stopping the trial after the phase II part of the study was set at 0.2 for the PFS. Results: Between Jan 2016 and Dec 2019, we enrolled 151 patients, 75 to the OMC arm and 76 to observation. The median age was 57 years, 59% were male. The tumor originated in the upper thoracic esophagus in 79% patients, with median tumor length 6 cm. Induction chemotherapy was received by 14% of the patients. Concurrent CRT consisted of median 63 Gy in median 35 fractions; 91% patients received concurrent weekly paclitaxel and carboplatin with radiation. OMC was started at a median of 11 weeks (IQR, 9 to 12) from the start of CRT. Grade 3 or higher toxicities (regardless of relatedness to study intervention) were noted in 27 patients (17.9%), 18 in the OMC arm and 9 in the observation arm; P=0.071. The median time to disease progression or death was 23 months (95% CI, 7.9-38.1) in the OMC arm and not reached in the observation arm; HR, 1.33, 95% CI, 0.83-2.14; P=0.23. The 1-year PFS was 67% in both the arms; the 2-year PFS were 48% and 61% in the OMC and observation arms respectively. The median OS was 36 months (95% CI, 17.9-54) in the OMC arm and not reached in the observation arm; HR, 1.75; 95% CI, 1.02-2.99; P, 0.037. The 1-year OS was 74.7% in the OMC arm and 88% in the observation arm; the 2-year OS was 53.9% in the OMC arm and 75% in the observation arm. Conclusion: Adjuvant oral metronomic chemotherapy after radical CRT does not improve outcomes in patients with locally advanced esophageal or GEJ squamous cell carcinoma. Clinical trial information: CTRI/2015/09/006204.