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Oral metronomic chemotherapy after definitive chemoradiation in esophageal squamous cell carcinoma: a randomized clinical trial

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Abstract

Background

Improving outcomes in locally advanced esophageal/GEJ squamous cell cancer (SCC) is an unmet need. We investigated the addition of oral metronomic chemotherapy (OMC) following definitive chemoradiotherapy (CRT).

Materials and methods

This was a randomized open-label integrated phase II/III study in patients with SCC of esophagus/GEJ following definitive CRT who had no radiologic evidence of progression, and no endoscopically detected disease. Randomization was 1:1 to OMC (celecoxib 200 mg twice daily and methotrexate 15 mg/m2 weekly) for 12 months or observation. The primary endpoint for the phase II portion was progression-free survival (PFS); secondary endpoints were overall survival (OS) and toxicity. P ≤ 0.2 for PFS was required to proceed to phase III.

Results

Between Jan 2016 and Dec 2019, we enrolled 151 patients for the phase II portion, 75 to OMC and 76 to observation. The tumor originated in the upper thoracic esophagus in 79% patients. Concurrent CRT consisted of median 63 Gy in a median of 35 fractions; concurrent chemotherapy was weekly paclitaxel + carboplatin in 91%. OMC was started at a median of 2.6 months (IQR 2.3–2.8) from CRT completion. Grade 3 or higher toxicities occurred in 18 patients (24%) in the OMC arm and 9 (12%) in the observation arm; P = 0.071. Median PFS was 25 months (95% CI, 17–58) in the OMC arm and was not attained [NA] (95% CI, 25–NA) in the observation arm; HR, 1.51, 95% CI, 1–2; P = 0.073. Median OS was 36 months (95% CI, 23–NA) in the OMC arm, and not attained (95% CI, NA–NA) in the observation arm; HR, 1.77; 95% CI, 1–2.9; P = 0.023.

Conclusion

Oral metronomic methotrexate and celecoxib in patients who have not progressed radiologically and have no endoscopic evidence of disease following radical CRT for locally advanced esophageal/GEJ SCC does not improve outcomes and may lower survival. [Funded by the TMC-Research Administration Council (TRAC); CHROME study (CHemoRadiotherapy followed by Oral Metronomic therapy in Esophageal cancer); ctri.nic.in number: CTRI/2015/09/006204].

Trial registration number

CTRI/2015/09/006204.

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Data availability

The data collected for the study, including deidentified individual participant data and a data dictionary defining each field in the set, will be made available to others, on reasonable request. Additionally, the study protocol, statistical analysis plan and the informed consent form will be made available, on reasonable request. These data will be made available, on reasonable request, starting from the time of publication. The data are available on reasonable request from Dr. Vanita Noronha (vanita.noronha@gmail.com) or Dr. Kumar Prabhash (kumarprabhashtmh@gmail.com). Data will be made available, on reasonable request for additional analyses or other scientific purposes, with investigator support and with a signed data access agreement.

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Acknowledgements

We greatly appreciate the statistical analysis help provided by Ms. Smruti Mokal, Mr. Sanjay Talole, and Ms. Rohini Hawaldar.

Funding

This work was supported by the Tata Memorial Center Research Administration Council (TRAC) (grant number not applicable).

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Parel, Mumbai, India

    V. Noronha, V. M. Patil, N. S. Menon, A. Joshi, S. Goud, S. More, D. Nakti, A. Yadav, S. Shah, S. D. Banavali & K. Prabhash

  2. Department of Biostatistics, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India

    S. Kannan & A. Pawar

  3. Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India

    A. Mahajan & A. Janu

  4. Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India

    R. Kumar

  5. Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India

    A. Tibdewal, N. Mummudi & J. P. Agarwal

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  1. V. Noronha
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  2. V. M. Patil
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  4. A. Joshi
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  6. S. More
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  18. S. D. Banavali
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  19. K. Prabhash
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Corresponding author

Correspondence to K. Prabhash.

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Ethical Statement

The study was approved by the Institutional Ethics Committee (IEC) of the Tata Memorial Center (Project number 155, approved by IEC-III).

Conflict of interest

Unrelated to the current study, Dr. Vanita Noronha has received research funding from Amgen, Sanofi India Ltd., Dr. Reddy’s Laboratories Inc., Intas Pharmaceuticals and Astra Zeneca Pharma India Ltd. (all research grants paid to the institution). Unrelated to the current study, Dr. Kumar Prabhash has received research funding from Dr. Reddy’s Laboratories Inc., Fresenius Kabi India Pvt. Ltd., Alkem Laboratories, Natco Pharma Ltd., BDR Pharmaceuticals Intl. Pvt. Ltd, and Roche Holding AG (all research grants paid to the institution). All the other authors declared no conflicts of interest.

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Noronha, V., Patil, V.M., Menon, N.S. et al. Oral metronomic chemotherapy after definitive chemoradiation in esophageal squamous cell carcinoma: a randomized clinical trial. Esophagus 19, 670–682 (2022). https://doi.org/10.1007/s10388-022-00923-8

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  • DOI: https://doi.org/10.1007/s10388-022-00923-8

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