The ORATOR randomized trial

We need to talk about the ORATOR trial.

ORATOR is (was) the most ambitious randomized prospective study on TransOral Robotic Surgery (TORS) for oropharyngeal cancer ever attempted. If was targeted at the original decision, which is the primary treatment: primary surgery versus primary radiation therapy. That is the usual critical initial decision we need to take when managing patients with Head&Neck Cancer (HNC).

The study protocol was registered in 2012 (ClinicalTrials.gov identifier: NCT01590355) and first published in 2013(1). It was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2, randomised study funded by a Canadian Cancer Society Research Institute Grant (#701842), Ontario Institute for Cancer Research Clinician-Scientist research grant, and the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers grant.

Patients with T1–T2, N0–2 oropharyngeal squamous cell carcinoma were stratified by HPV status, and randomly assigned to surgery ( TORS plus neck dissection with or without adjuvant chemoradiotherapy, based on pathology) or radiotherapy (70 Gy, with chemotherapy if N1–2). Patients were enrolled at six hospitals in Canada and Australia.

For the management of HNC in general, and for oropharyngeal cancer in particular, we do have, in most of the circumstances, a classic dichotomy in the selection of the primary treatment: surgery or radiation therapy (both being considered acceptable standard treatment options). We would like to have high level evidence, coming from meta-analysis of clinical trials, to make an informed decision at this point. That is not possible. The treatment of HNC, especially for advanced tumours, is associated with high morbidity, often with a substantial impact on patients’ quality of life due to functional impairments. If we aim to include a patient in a clinical trial, we must also explain the randomization process. These explanations can be complex and challenging, and, in practice, the trial often becomes unfeasible, particularly when it is intended as a first-line treatment option. Nevertheless, this first choice is the most important one, because it will condition everything that happens afterwards.

The first results of the ORATOR trial were published by the end of 2019 (2). By that time the study was still active, but not recruiting. It had included 68 patients between Aug 10, 2012, and June 9, 2017. That makes 2.26 patients per hospital per year (high volume centres, not a rare diagnosis).

In 2022 the ORATOR trial published the long term results (3), and in 2024 the final results (4). No statistically significant differences were found in the evaluated outcomes (quality of life, overall survival, progression-free survival, toxicity, and dysphagia). Oncologic outcomes were excellent in both arms (88% of the patients were HPV+, oncologic outcomes would have been excellent anyway). A differential profile of adverse events was observed, and it was concluded that patients should be informed and involved in the therapeutic decision-making process, which should take place within a multidisciplinary committee (…).

From a practical standpoint, the trial did not make any significant contribution to the current state of knowledge. Twelve years, huge effort (including costs). Lessons learned from this study are indirect, and not intended in the design of the study. Now we know that probably many patients were over-treated. We need to rethink how we assess outcomes.

Evidence Based Medicine does not mean Medicine Based on Randomized Clinical Trials, but Medicine Based on the Best Possible Evidence. We do have overwhelming evidence supporting minimally invasive surgery as the optimal path (with adequate patient selection) for treatment de-escalation in oropharyngeal cancer, particularly for the HPV-related.

J Granell. Nov 4, 2024.

References

1. Nichols AC, Yoo J, Hammond JA, Fung K, Winquist E, Read N, Venkatesan V, MacNeil SD, Ernst DS, Kuruvilla S, Chen J, Corsten M, Odell M, Eapen L, Theurer J, Doyle PC, Wehrli B, Kwan K, Palma DA. Early-stage squamous cell carcinoma of the oropharynx: radiotherapy vs. trans-oral robotic surgery (ORATOR)–study protocol for a randomized phase II trial. BMC Cancer. 2013 Mar 20;13:133. doi: 10.1186/1471-2407-13-133. (open access)
2. Nichols AC, Theurer J, Prisman E, Read N, Berthelet E, Tran E, Fung K, de Almeida JR, Bayley A, Goldstein DP, Hier M, Sultanem K, Richardson K, Mlynarek A, Krishnan S, Le H, Yoo J, MacNeil SD, Winquist E, Hammond JA, Venkatesan V, Kuruvilla S, Warner A, Mitchell S, Chen J, Corsten M, Johnson-Obaseki S, Eapen L, Odell M, Parker C, Wehrli B, Kwan K, Palma DA. Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial. Lancet Oncol. 2019 Oct;20(10):1349-1359. doi: 10.1016/S1470-2045(19)30410-3.
3. Nichols AC, Theurer J, Prisman E, Read N, Berthelet E, Tran E, Fung K, de Almeida JR, Bayley A, Goldstein DP, Hier M, Sultanem K, Richardson K, Mlynarek A, Krishnan S, Le H, Yoo J, MacNeil SD, Winquist E, Hammond JA, Venkatesan V, Kuruvilla S, Warner A, Mitchell S, Chen J, Corsten M, Johnson-Obaseki S, Odell M, Parker C, Wehrli B, Kwan K, Palma DA. Randomized Trial of Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Long-Term Results of the ORATOR Trial. J Clin Oncol. 2022 Mar 10;40(8):866-875. doi: 10.1200/JCO.21.01961.
4. Nichols AC, Theurer J, Prisman E, Read N, Berthelet E, Tran E, Fung K, de Almeida JR, Bayley A, Goldstein DP, Hier M, Sultanem K, Richardson K, Mlynarek A, Krishnan S, Le H, Yoo J, MacNeil SD, Winquist E, Hammond JA, Venkatesan V, Kuruvilla S, Warner A, Mitchell S, Chen J, Johnson-Obaseki S, Odell M, Corsten M, Parker C, Wehrli B, Kwan K, Palma DA. Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Final Results of the ORATOR Randomized Trial. J Clin Oncol. 2024 Sep 20:JCO2400119. doi: 10.1200/JCO.24.00119.