June 16 2021
By Sue S. Yom, MD, FASTRO
University of California San Francisco
As part of the current era of precision medicine, patients are increasingly interested in more individualized information (Hoesseini et al. 2020). Head and neck cancer (HNC) patients, who may face severe acute toxicities from their combined modality treatments, are highly motivated to take an active role in understanding various aspects of their diagnosis and care (Fakhry and D’Souza 2013). Modern-day studies show that HNC patients are willing to discuss potential trade-offs related to the use of different modalities and some may even accept small decreases in survival probabilities to avoid severe toxicities (Brotherston et al. 2013).
These questions are especially pertinent to a growing cohort of patients with HPV-associated oropharyngeal cancer (HPV+OPC) (Chaturvedi et al. 2011). These patients, who tend to be younger and healthier, have longer survival times than patients who have head and neck cancers related to traditional risk factors such as smoking and alcohol (Gillison 2007). Thus the issue of long-term toxicities is important to them. Meanwhile, there is increasing awareness that in general, in the head and neck cancer population, accrual of severe toxicities may lead to accelerated aging effects with overall survival consequences (Xiao et al. 2021).
For these reasons, NRG-HN002 was approved and developed within the NRG Head and Neck Cancer Committee in 2014. It was based on preclinical evidence indicating enhanced radiosensitivity in HPV+ cancers (Reid et al. 2020). The trial was a phase 2 study to test the feasibility and efficacy of two different regimens of reduced-dose radiation in locoregionally advanced HPV+OPC patients with T1-T3N1-N2b or T3N0 classifications under the AJCC 7th edition staging system, who had a smoking history of ≤10 pack-years. After ramp-up, accrual, and maturation of results, it was found that the arm offering 60 Gy in 30 fractions with concurrent cisplatin given at 40 mg/m2 weekly met both the pre-specified 2-year progression-free survival (PFS) endpoint and co-primary swallowing-related patient-reported outcome (PRO) (M. D. Anderson Dysphagia Inventory, MDADI) (Yom et al. 2021). The arm offering an accelerated radiation-only regimen of 60 Gy in 30 fractions in 5 weeks, given without concurrent chemotherapy, satisfied the MDADI endpoint but not the PFS endpoint.
Many complex lessons were learnt in the course of designing and developing this trial. Because this was the first head and neck cancer trial within the NCTN to have a disease-centered and co-primary PRO, the protocol needed to control for PRO effects. As a result, recommendations for ipsilateral and bilateral radiation therapy had to be specified for the first time in a national HNC protocol. Ipsilateral radiation is increasingly recognized as a major means of reducing toxicity in HNC patients but remains controversial in many common clinical scenarios (Tsai et al. 2021). The NRG Oncology specifications for ipsilateral and bilateral treatment are now standardized for further development and investigation in future HNC trials. A closely related realization resulting from this developmental work was the need to control the volumes of radiation as well as doses of radiation. Thus the CTV elective coverage in NRG-HN002 is defined specifically in relation to the involved primary site and nodal levels. It is expected that future work within NRG Oncology will continue to investigate these variables, as volume control and/or volume reduction is its own topic of increasing emerging interest. Also, because in NRG-HN002, the radiation treatment was reduced to a duration of 6 weeks, the doses to the involved and electively treated volumes of the neck needed to be translated to a 6 week course. Based on the experiences from RTOG 1016, doses of 54 Gy and 48 Gy were used which were approximately biologically equivalent but reduced in terms of physical dose and dose per fraction from what is often used in the community. This is another parameter that deserves continued controlled study.
One important finding of NRG-HN002 is that in the chemoradiation arm, the majority of patients were able to complete at least 200 mg/m2 of cumulative cisplatin dose (Yom et al. 2021). Around the time that NRG-HN005 was under design as a successor trial to NRG-HN002, the results of RTOG 1016 were issued (Gillison et al. 2019). RTOG 1016, a randomized phase III trial for patients with HPV-associated oropharyngeal cancer, showed that when combined with 70 Gy of radiation therapy over 6 weeks, weekly cetuximab failed to produce equivalent local-regional control or overall survival at 5 years compared to 2 cycles of cisplatin given every 3 weeks. One of the hallmarks of designing studies within the NRG Oncology is to maximize information gain by maintaining consistency with previously tested platforms for which there exists considerable disease outcome and quality of life data. After the results of RTOG 1016 were known, it was important to design the control arm of NRG-HN005 so that the detailed data collection from RTOG 1016 could be used to inform and power comparisons to experimental regimens. The control arm in NRG-HN005 mirrors the RTOG 1016 control arm and the single variable changed in the first experimental arm is the radiation schedule. The second experimental arm in the phase II component of the trial mirrors the arm in NRG-HN002 which did not go forward but with the addition of nivolumab.
The NRG Oncology Head and Neck Cancer Committee continues the exploration of reduced-dose radiation in conjunction with defined and controlled radiation volumes for HPV-associated oropharyngeal cancer patients in our currently accruing phase II trial, NRG-HN005 (https://clinicaltrials.gov/ct2/show/NCT03952585), which will continue into a seamless phase III study with the possibility of changing the standard of care. Regardless of the phase II or III trial results, the outcomes of NRG-HN005 will provide an important and considerable understanding, in conjunction with the results of NRG-HN002 and RTOG 1016, of how to continue to personalize radiation therapy treatments for head and neck cancer patients. The goal of these investigations is the proper deintensifying or intensifying of therapy as needed to achieve patients’ best outcomes both in terms of survivorship and quality of life.
Thank you to Dr. Quynh Le and Dr. Erich Sturgis for their comments.
Brotherston DC, Poon I, Le T, Leung M, Kiss A, Ringash J, Balogh J, Lee J, Wright JR. 2013. Patient preferences for oropharyngeal cancer treatment de-escalation. Head Neck. 35(2):151–159. https://doi.org/10.1002/hed.22930
Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber M, Cozen W, et al. 2011. Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States. J Clin Oncol. 29(32):4294–4301. https://doi.org/10.1200/JCO.2011.36.4596
Fakhry C, D’Souza G. 2013. Discussing the diagnosis of HPV-OSCC: Common questions and answers. Oral Oncol. 49(9):863–871. https://doi.org/10.1016/j.oraloncology.2013.06.002
Gillison ML. 2007. Current topics in the epidemiology of oral cavity and oropharyngeal cancers. Head Neck. 29(8):779–792. https://doi.org/10.1002/hed.20573
Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, Jordan RCK, Zhao W, Sturgis EM, Burtness B, et al. 2019. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. The Lancet. 393(10166):40–50. https://doi.org/10.1016/S0140-6736(18)32779-X
Hoesseini A, Dronkers EAC, Sewnaik A, Hardillo JAU, Baatenburg de Jong RJ, Offerman MPJ. 2020. Head and neck cancer patients’ preferences for individualized prognostic information: a focus group study. BMC Cancer. 20(1):399. https://doi.org/10.1186/s12885-020-6554-8
Reid P, Staudacher AH, Marcu LG, Olver I, Moghaddasi L, Brown MP, Bezak E. 2020. Influence of the human papillomavirus on the radio-responsiveness of cancer stem cells in head and neck cancers. Sci Rep. 10(1):2716. https://doi.org/10.1038/s41598-020-59654-4
Tsai CJ, Galloway TJ, Margalit DN, Bakst RL, Beadle BM, Beitler JJ, Chang S, Chen A, Cooper J, Koyfman SA, et al. 2021. Ipsilateral radiation for squamous cell carcinoma of the tonsil: American Radium Society appropriate use criteria executive summary. Head Neck. 43(1):392–406. https://doi.org/10.1002/hed.26492
Xiao C, Miller AH, Peng G, Levine ME, Conneely KN, Zhao H, Eldridge RC, Wommack EC, Jeon S, Higgins KA, et al. 2021. Association of epigenetic age acceleration with risk factors, survival, and quality of life in patients with head and neck cancer. Int J Radiat Oncol.:S036030162100362X. https://doi.org/10.1016/j.ijrobp.2021.04.002
Yom SS, Torres-Saavedra P, Caudell JJ, Waldron JN, Gillison ML, Xia P, Truong MT, Kong C, Jordan R, Subramaniam RM, et al. 2021. Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002). J Clin Oncol. 39(9):956–965. https://doi.org/10.1200/JCO.20.03128