DE-ESCALATING INTENSITY AND PRESERVING OUTCOMES: A BAYESIAN-ML NETWORK META-ANALYSIS OF MULTIMODAL TREATMENT STRATEGIES IN HPV-POSITIVE OROPHARYNGEAL CANCER
Main
Muhammad Allam Rafi*
The study presents the first integrative Bayesian-machine learning (ML) network meta-analysis, enhanced by machine learning algorithms, to evaluate and rank de-escalation treatment strategies for HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). A total of 2,298 patients from 10 multicenter studies and randomized controlled trials were included, comprising randomized controlled trials, observational studies, and phase II investigations. Twelve distinct treatment strategies were analyzed, including TORS with de-escalated adjuvant RT, reduced-dose chemoradiotherapy, adaptive radiotherapy, and immunotherapy-based regimens. The SUCRA (Surface Under the Cumulative Ranking) scores indicated TORS + de-escalated RT as the top-ranked strategy (SUCRA = 0.91), followed by reduced-dose CRT (0.88) and adaptive RT (0.84). SHAP (SHapley Additive exPlanations) analysis from a Random Forest classifier confirmed that toxicity reduction (impact = 0.34) and quality of life (QOL) improvement (0.28) were the most critical factors driving high SUCRA rankings, with overall survival (OS) rates consistently above 90% in the top three strategies. Funnel plots suggested low publication bias, while cluster heatmaps demonstrated clear stratification of treatment profiles. The t-SNE visualization validated strong feature convergence among top-performing modalities. This analysis highlights the potential of machine learning-guided evidence synthesis to enhance clinical decision-making in personalized OPSCC therapy by balancing oncologic efficacy with functional outcomes.
Brezar, K., Prevc, A., Zakelj, M., Brožič, A., Čemažar, M., Strojan, P., & Serša, G. (2020). Synergistic effect of cisplatin chemotherapy combined with fractionated radiotherapy regimen in HPV-positive and HPV-negative experimental pharyngeal squamous cell carcinoma. Scientific Reports, 10. https://doi.org/10.1038/s41598-020-58502-9
Broughman, J. R., Xiong, D. D., Moeller, B. J., Contrera, K. J., Prendes, B., Lamarre, E., & Ward, M. C. (2020). Rethinking the 10‐pack‐year rule for favorable human papillomavirus–associated oropharynx carcinoma: a multi‐institution analysis. Cancer, 126(12), 2784-2790. https://doi.org/10.1002/cncr.32849
Bußmann, L., Laban, S., Wittekindt, C., Stromberger, C., Tribius, S., Möckelmann, N., & Busch, C. (2020). Comparative effectiveness trial of transoral head and neck surgery followed by adjuvant radio(chemo)therapy versus primary radiochemotherapy for oropharyngeal cancer (toproc). BMC Cancer, 20(1). https://doi.org/10.1186/s12885-020-07127-2
Costantino, A., Sampieri, C., Sim, N., De Virgilio, A., & Kim, S. (2024). Adjuvant Radiation Sparing after Neoadjuvant Chemotherapy and TORS in Selected HPV-Positive Oropharyngeal Cancer. The Laryngoscope. https://doi.org/10.1002/lary.31940
De Virgilio, A., Costantino, A., Mercante, G., Pellini, R., Ferreli, F., Malvezzi, L., Colombo, G., Cugini, G., Petruzzi, G., & Spriano, G. (2020). Transoral robotic surgery and intensity-modulated radiotherapy in the treatment of the oropharyngeal carcinoma: a systematic review and meta-analysis. European Archives of Oto-Rhino-Laryngology, 278, 1321 - 1335. https://doi.org/10.1007/s00405-020-06224-z
Farlow, J., Jones, A., Xie, D., Chen, D., Campbell, D., Mantravadi, A., Moore, M., Durm, G., Langer, M., Yesensky, J., & Sim, M. (2024). Adjuvant Treatment Deintensification after Transoral Surgery for Human Papillomavirus-Positive Squamous Cell Carcinoma of the Oropharynx. International Journal of Radiation OncologyBiologyPhysics. https://doi.org/10.1016/j.ijrobp.2024.01.061
Ferris, R., Flamand, Y., Weinstein, G., Li, S., Quon, H., Mehra, R., García, J., Chung, C., Gillison, M., Duvvuri, U., O'Malley, B., Ozer, E., Thomas, G., Koch, W., Gross, N., Bell, R., Saba, N., Lango, M., Mendez, E., & Burtness, B. (2021). Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311). Journal of Clinical Oncology, 40, 138 - 149. https://doi.org/10.1200/JCO.21.01752
Gebre‐Medhin, M., Brun, E., Engström, P., Cange, H. H., Hammarstedt‐Nordenvall, L., Reizenstein, J., … & Nilsson, P. (2021). Artscan iii: a randomized phase iii study comparing chemoradiotherapy with cisplatin versus cetuximab in patients with locoregionally advanced head and neck squamous cell cancer. Journal of Clinical Oncology, 39(1), 38-47. https://doi.org/10.1200/jco.20.02072
Grzywacz, V., Yan, D., Chen, S., Krauss, D., Chen, P., & Deraniyagala, R. (2021). A Novel Approach to Dose De-Escalation in HPV-Positive Oropharyngeal Chemoradiotherapy Utilizing Adaptive Planning Based on Voxel-Level FDG Response. International journal of radiation oncology, biology, physics, 111 3S, e404. https://doi.org/10.1016/j.ijrobp.2021.07.1166
Gupta, K., De, M., Athanasiou, T., Georgalas, C., & Garas, G. (2024). Quality of life outcomes comparing primary Transoral Robotic Surgery (TORS) with primary radiotherapy for early-stage oropharyngeal squamous cell carcinoma: A systematic review and meta-analysis. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, 50 7, 108434. https://doi.org/10.1016/j.ejso.2024.108434
Harrowfield, J., Isenring, E., Kiss, N., Laing, E., Lipson‐Smith, R., & Britton, B. (2021). The impact of human papillomavirus (hpv) associated oropharyngeal squamous cell carcinoma (opscc) on nutritional outcomes. Nutrients, 13(2), 514. https://doi.org/10.3390/nu13020514
Lee, N., Sherman, E., Schöder, H., McBride, S., Yu, Y., Kang, J., Tsai, C., Gelblum, D., Boyle, J., Singh, B., Cohen, M., Cracchiolo, J., Ganly, I., Dunn, L., Kriplani, A., Fetten, J., Michel, L., Wong, R., Pfister, D., & Riaz, N. (2021). The 30 ROC trial: Precision intra-treatment imaging guiding major radiation reduction in human papillomavirus related oropharyngeal cancer. Journal of Clinical Oncology, 39, 6019-6019. https://doi.org/10.1200/JCO.2021.39.15_SUPPL.6019
Miles, B., Posner, M., Gupta, V., Teng, M., Bakst, R., Yao, M., Misiukiewicz, K., Chai, R., Sharma, S., Westra, W., Kim-Schulze, S., Ccrp, B., Sobotka, S., Sikora, A., Som, P., & Genden, E. (2021). De-Escalated Adjuvant Therapy after Transoral Robotic Surgery for Human Papillomavirus-Related Oropharyngeal Carcinoma: The Sinai Robotic Surgery (SIRS) Trial. The oncologist. https://doi.org/10.1002/onco.13742
Miller, M. F., Li, Z., & Habedank, M. (2020). A randomized controlled trial testing the effectiveness of coping with cancer in the kitchen, a nutrition education program for cancer survivors. Nutrients, 12(10), 3144. https://doi.org/10.3390/nu12103144
Murakami, N., Mori, T., Machida, R., Kodaira, T., Ito, Y., Shikama, N., … & Kagami, Y. (2020). Prognostic value of epithelial cell adhesion molecules in t1‐2n0m0 glottic cancer. The Laryngoscope, 131(7), 1522-1527. https://doi.org/10.1002/lary.29348
Nauta, I. H., Heideman, D. A., Brink, A., Steen, B. v. d., Bloemena, E., Koljenović, S., & Brakenhoff, R. H. (2021). The unveiled reality of human papillomavirus as risk factor for oral cavity squamous cell carcinoma. International Journal of Cancer, 149(2), 420-430. https://doi.org/10.1002/ijc.33514
Nichols, A. C., Lang, P., Prisman, E., Berthelet, E., Tran, E., Hamilton, S., … & Palma, D. A. (2020). Treatment de-escalation for hpv-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (orator2): study protocol for a randomized phase ii trial. BMC Cancer, 20(1). https://doi.org/10.1186/s12885-020-6607-z
Nichols, D., Zhao, J., Boyce, B., Amdur, R., Mendenhall, W., Danan, D., Hitchcock, K., Ning, K., Keyes, K., Lee, J., & Dziegielewski, P. (2020). HPV/p16-positive oropharyngeal cancer treated with transoral robotic surgery: The roles of margins, extra-nodal extension and adjuvant treatment. American journal of otolaryngology, 42 1, 102793. https://doi.org/10.1016/j.amjoto.2020.102793
Palma, D., Prisman, E., Berthelet, E., Tran, E., Hamilton, S., Wu, J., Eskander, A., Higgins, K., Karam, I., Poon, I., Husain, Z., Enepekides, D., Hier, M., Sultanem, K., Richardson, K., Mlynarek, A., Johnson-Obaseki, S., Eapen, L., Odell, M., Bayley, A., Dowthwaite, S., Jackson, J., Dzienis, M., O'Neil, J., Chandarana, S., Banerjee, R., Hart, R., Chung, J., Tenenholz, T., Krishnan, S., Le, H., Yoo, J., Mendez, A., Winquist, E., Kuruvilla, S., Stewart, P., Warner, A., Mitchell, S., Chen, J., Parker, C., Wehrli, B., Kwan, K., Theurer, J., Sathya, J., Hammond, J., Read, N., Venkatesan, V., MacNeil, D., Fung, K., & Nichols, A. (2021). A Randomized Trial of Radiotherapy vs. Trans-Oral Surgery for Treatment De-Escalation in HPV-Associated Oropharyngeal Squamous Cell Carcinoma (ORATOR2). International Journal of Radiation Oncology Biology Physics. https://doi.org/10.1016/j.ijrobp.2021.09.013
Palma, D., Prisman, E., Berthelet, E., Tran, E., Hamilton, S., Wu, J., Eskander, A., Higgins, K., Karam, I., Poon, I., Husain, Z., Enepekides, D., Hier, M., Sultanem, K., Richardson, K., Mlynarek, A., Johnson-Obaseki, S., Odell, M., Bayley, A., Dowthwaite, S., Jackson, J., Dzienis, M., O’Neil, J., Chandarana, S., Banerjee, R., Hart, R., Chung, J., Tenenholtz, T., Krishnan, S., Le, H., Yoo, J., Mendez, A., Winquist, E., Kuruvilla, S., Stewart, P., Warner, A., Mitchell, S., Chen, J., Parker, C., Wehrli, B., Kwan, K., Theurer, J., Sathya, J., Hammond, J., Read, N., Venkatesan, V., MacNeil, S., Fung, K., & Nichols, A. (2022). Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial. JAMA oncology. https://doi.org/10.1001/jamaoncol.2022.0615
Park, D., Lee, M., Kim, S., & Lee, S. (2020). Comparative safety and effectiveness of transoral robotic surgery versus open surgery for oropharyngeal cancer: A systematic review and meta-analysis. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. https://doi.org/10.1016/j.ejso.2019.09.185
Petrelli, F., Luciani, A., Ghidini, A., Cherri, S., Gamba, P., Maddalo, M., Bossi, P., & Zaniboni, A. (2022). Treatment de‐escalation for HPV+ oropharyngeal cancer: A systematic review and meta‐analysis. Head & Neck, 44, 1255 - 1266. https://doi.org/10.1002/hed.27019
Price, K., Van Abel, K., Moore, E., Patel, S., Hinni, M., Chintakuntlawar, A., Graner, D., Neben-Wittich, S., Garces, Y., Price, D., Janus, J., Foster, N., Ginos, B., Foote, R. (2022). Long-term Toxicity, Swallow Function, and Quality of Life on MC1273, a Phase II Study of Dose De-escalation for Adjuvant Chemoradiation in HPV-Positive Oropharyngeal Cancer (HPV-OPC).. International journal of radiation oncology, biology, physics. https://doi.org/10.1016/j.ijrobp.2022.05.047
Rosenberg, A., Agrawal, N., Pearson, A., Seiwert, T., Gooi, Z., Blair, E., Ginat, D., Howard, A., Chin, J., Kochanny, S., Izumchenko, E., Juloori, A., Haraf, D., & Vokes, E. (2021). Nivolumab, nabpaclitaxel, and carboplatin followed by risk/response adaptive de-escalated locoregional therapy for HPV-associated oropharyngeal cancer: OPTIMA II trial. Journal of Clinical Oncology, 39, 6011-6011. https://doi.org/10.1200/JCO.2021.39.15_SUPPL.6011
Sadeghi, N., Subramaniam, T., Richardson, K., Mascarella, M., Zeitouni, A., Shenouda, G., Sultanem, K., Mlynarek, A., Caglar, D., Esfahani, K., Joshi, A., Siegel, R., Goodman, J., Thakkar, P., Lee, E., Golabi, N., Ramanakumar, A., Hier, M., & Bouganim, N. (2024). Neoadjuvant Chemotherapy and Transoral Robotic Surgery for Human Papillomavirus-Related Oropharyngeal Cancer. JAMA otolaryngology-- head & neck surgery. https://doi.org/10.1001/jamaoto.2024.3303
Saito, Y., Hayashi, R., Iida, Y., Mizumachi, T., Fujii, T., Matsumoto, F., … & Yane, K. (2020). Optimization of therapeutic strategy for p16‐positive oropharyngeal squamous cell carcinoma: multi‐institutional observational study based on the national head and neck cancer registry of japan. Cancer, 126(18), 4177-4187. https://doi.org/10.1002/cncr.33062
Sher, D., Pham, N., Shah, J., Sen, N., Williams, K., Subramaniam, R., Moore, W., Chorley, R., Ahn, C., & Khan, S. (2020). Prospective phase II study of radiotherapy dose and volume de-escalation for elective neck treatment of oropharyngeal and laryngeal cancer. International journal of radiation oncology, biology, physics. https://doi.org/10.1016/j.ijrobp.2020.09.063
Stone, L., Kasten, B., Rao, S., Gonzalez, M., Stevens, T., Lin, D., Carroll, W., Greene, B., Moore, L., Fuson, A., James, S., Hartman, Y., McCammon, S., Panuganti, B., Nabell, L., Li, Y., Li, M., Bailey, L., Rosenthal, E., Jeyarajan, H., Thomas, C., & Warram, J. (2024). Interim Phase II Results Using Panitumumab-IRDye800CW During Transoral Robotic Surgery in Patients with Oropharyngeal Cancer.. Clinical cancer research: an official journal of the American Association for Cancer Research. https://doi.org/10.1158/1078-0432.CCR-24-0940
Swain, M., Kannan, S., Srinivasan, S., Agarwal, J., & Gupta, T. (2022). Concurrent Cetuximab-based bioradiotherapy versus Cisplatin-based Chemoradiotherapy in the Definitive Management of Favourable Biology Human Papillomavirus-associated Oropharyngeal Squamous Cell Carcinoma: Systematic Review and Meta-analysis. Clinical oncology (Royal College of Radiologists (Great Britain)). https://doi.org/10.1016/j.clon.2022.03.009
Tsai, C., McBride, S., Riaz, N., Kang, J., Spielsinger, D., Waldenberg, T., Gelblum, D., Yu, Y., Chen, L., Zakeri, K., Wong, R., Dunn, L., Pfister, D., Sherman, E., & Lee, N. (2022). Evaluation of Substantial Reduction in Elective Radiotherapy Dose and Field in Patients With Human Papillomavirus-Associated Oropharyngeal Carcinoma Treated With Definitive Chemoradiotherapy. JAMA oncology. https://doi.org/10.1001/jamaoncol.2021.6416
Tsai, C., McBride, S., Riaz, N., Kang, J., Spielsinger, D., Waldenberg, T., Yu, Y., Chen, L., Zakeri, K., Wong, R., Dunn, L., Sherman, E., & Lee, N. (2021). Dose and Volume De-Escalation for Elective Nodal Regions in Patients With Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer (OPC) Undergoing Curative-Intent Concurrent Chemoradiation (CCRT).. International journal of radiation oncology, biology, physics, 111 3S, S142-S143. https://doi.org/10.1016/j.ijrobp.2021.07.321
Yang, M., Liu, Y., Sui, J., Jin, F., Li, D., Zhang, L., Wang, N., Xie, Y., Wang, Y., & Wu, Y. (2022). Reduced-dose radiation in human papillomavirus-associated oropharyngeal carcinoma can improve outcome: a systematic review and meta-analysis. Annals of Translational Medicine, 10. https://doi.org/10.21037/atm-22-5935
Yom, S., Torres-Saavedra, P., Caudell, J., Waldron, J., Gillison, M., Xia, P., Truong, M., Kong, C., Jordan, R., Subramaniam, R., Yao, M., Chung, C., Geiger, J., Chan, J., O'Sullivan, B., Blakaj, D., Mell, L., Thorstad, W., Jones, C., Banerjee, R., Lominska, C., & Le, Q. (2021). Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002). Journal of Clinical Oncology, 39, 956 - 965. https://doi.org/10.1200/JCO.20.03128
Yver, C., Shimunov, D., Weinstein, G., Rajasekaran, K., Cannady, S., Lukens, J., Lin, A., Swisher-McClure, S., Cohen, R., Aggarwal, C., Bauml, J., Loevner, L., Newman, J., Chalian, A., Rassekh, C., Basu, D., O'Malley, B., & Brody, R. (2021). Oncologic and survival outcomes for resectable locally-advanced HPV-related oropharyngeal cancer treated with transoral robotic surgery. Oral oncology, 118, 105307. https://doi.org/10.1016/j.oraloncology.2021.105307
