Treatment De-Intensification for Patients With HPV-Positive Head and Neck Cancers

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Maura L. Gillison
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Cisplatin and 70 Gy of intensity-modulated radiotherapy remain the standard of care (SoC) in HPV-positive head and neck cancer, with no data to support de-escalation as a new SoC. Cetuximab compromises locoregional tumor control and overall survival without reduced toxicity, although with different toxicity. Eliminating cisplatin and reducing radiation by 10 Gy compromise progression-free survival but not overall survival, and replacement of SoC adjuvant chemoradiotherapy with low-dose radiotherapy plus docetaxel compromises progression-free survival for patients with extracapsular extension and/or multiple cervical metastases, without significantly reducing grade 3 toxicities. The current trend toward numerous, single-institution phase II trials should be minimized, because they can be difficult to interpret. Instead, to move the field forward with more definitive outcomes, focus should be placed on taking promising concepts to multicenter, randomized phase II/III studies with clear statistical endpoints.

Based on available data on de-escalation of therapy for patients with HPV-positive head and neck cancers, cisplatin and 70 Gy of intensity-modulated radiotherapy (IMRT) remain the standard of care (SoC) for these patients. No data currently support de-escalation as a new SoC, according to Maura L. Gillison, MD, PhD, Professor of Medicine, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center.

At the NCCN 2022 Annual Conference, Dr. Gillison discussed some of the major questions around de-escalation of therapy in head and neck cancers and provided a summary of the current research by pointing out a few major takeaways. To begin, high-level evidence from randomized, multi-institutional phase III trials shows that cetuximab significantly compromises locoregional tumor control and overall survival compared with cisplatin, without reducing overall toxicity events. Of note, research has shown that cisplatin appears to be important for locoregional tumor control in the primary chemoradiotherapy (CRT) setting and the adjuvant setting, particularly in the presence of extranodal extension.

Additionally, the replacement of SoC adjuvant CRT with low-dose RT and docetaxel compromises progression-free survival (PFS) without significantly reducing grade 3 toxicity events, particularly in patients with extranodal extension or multiple involved nodes.

“Out of all these studies, I think we’re learning the most from randomized phase II multicenter studies with clear statistical endpoints or from randomized phase III studies,” said Dr. Gillison. “We’re really not learning much from a single-institution phase II trial; it’s hard to interpret them because of differences in eligibility criteria, and overall, they are being poorly designed with regard to landmark disease-control endpoints.”

Preceding the Era of De-Escalation

Around 2009, several retrospective analyses examining the effect of tumor HPV status on overall survival in head and neck cancer came to similar conclusions: patients with HPV-positive disease had an approximately 70% reduced risk of death compared with those with HPV-negative disease.14 “This was true whether it was a study of RT alone without chemotherapy or for more intensive treatments with induction chemotherapy followed by CRT,” noted Dr. Gillison.

At about the same time, a meta-analysis of Radiation Therapy Oncology Group (RTOG) trials, published by Machtay et al,5 assessed severe late toxicity after concurrent CRT for squamous cell carcinoma of the head and neck. “The result of this analysis was stunning for the field because it reported that 43% of patients had severe (grade ≥3) late toxicities >180 days after the start of RT,” Dr. Gillison explained. “The majority of [toxicities] were related to dysphagia, [gastronomy] tube dependence, and death without disease progression, raising the possibility that perhaps treatment itself increased noncancer mortality.” Dr. Gillison later summarized these data by concluding that the relative survival for patients with HPV-positive disease appeared to be independent of therapy, but it was still unknown whether the absolute survival for patients with HPV-positive disease was dependent on therapy. “But the most important question,” she added, “was this: Is cisplatin plus RT overtreatment for HPV-positive disease, or had we stumbled upon an optimal treatment of HPV-positive head and neck cancer?”

RTOG 0129 randomly assigned patients to standard fractionation radiation with high-dose cisplatin versus accelerated fractionation with concomitant boost (with the same high-dose cisplatin but just 2 vs 3 cycles).2 This was a negative trial, with similar outcomes in the 2 arms, but a retrospective analysis evaluating the impact of HPV status on survival showed that HPV status was a significant driving factor in terms of overall survival. According to Dr. Gillison, this was the first trial large enough to account for the impact of confounding prognostic factors present in previous trials (ie, good performance status and absence of comorbidities). “This analysis clearly showed that HPV status was indeed a very important prognostic factor, with an approximately 30% absolute difference in survival at 3 years,” she reported.

An additional analysis of RTOG 0129 according to known HPV status and cigarette pack-years showed that HPV status was the single greatest predictor of whether a person lived or died after a diagnosis of locoregionally advanced head and neck cancer. Prior to this analysis, cancer stage had been the single greatest predictor of prognostic outcome. “We found that smoking and stage were important, but less so,” she said. “We stratified patients with oropharyngeal cancer based on these factors into low-, intermediate-, and high-risk categories. Of course, they had dramatic differences in outcome, with the low-risk patients having HPV-positive disease, being nonsmokers, and having low N-stage disease.”

According to Dr. Gillison, these findings, along with those of Machtay et al,5 led to the era of HPV de-escalation treatment protocols. At first, proposed de-escalation strategies were largely superimposed upon the current frameworks for primary therapy for locoregionally advanced head and neck cancer: CRT platforms, transoral robotic primary surgery platforms, and induction followed by CRT therapy platforms (Figure 1).

Dr. Gillison discussed the highest-level evidence from studies designed to investigate these de-escalation strategies.

Figure 1.
Figure 1.

De-escalation framework.

Abbreviations: MSKCC, Memorial Sloan Kettering Cancer Center; RT, radiation therapy.

Citation: Journal of the National Comprehensive Cancer Network 20, 5.5; 10.6004/jnccn.2022.5010

De-Escalation Strategies in CRT

RTOG 1016 set out to answer whether cisplatin could be replaced with cetuximab, while maintaining survival outcomes and reducing toxicity.6 “Unfortunately, that study showed that cetuximab did compromise survival, so it was, in fact, inferior to cisplatin,” she noted. “Patients on the cisplatin arm had significantly fewer failures in the radiation field than those treated with cetuximab.”

These inferior outcomes regarding locoregional failure (10% vs 17% at 5 years) suggest either that cisplatin is an important radiation sensitizer for patients with HPV-positive head and neck cancer or that cetuximab is an inferior treatment—perhaps because of the high prevalence of PIK3CA-activating mutations downstream of the receptor, she said. According to Dr. Gillison, this question is currently being addressed as correlative science in RTOG 1016. The average number of grade 3 or 4 adverse effects experienced by patients showed that cetuximab was less toxic than cisplatin (with a 40% reduction in the total number of grade 3–4 events experienced per patient). However, there was no difference between the 2 arms in terms of the proportion of grade 3 or 4 adverse events.

Similar outcomes were seen in 3 other studies in this patient population, detailed in Table 1. All trials compared cisplatin with cetuximab, and all showed that locoregional tumor control appeared to be compromised with cetuximab versus cisplatin, leading to an increased hazard of death in patients treated with cetuximab. “However, we know from RTOG 1016 that the toxicity experienced by these patients [including grade 3 or 4 toxicities and long-term G-tube dependence] was dramatically reduced compared with Mitch Machtay’s analysis,5 and that was good news,” she said, adding that patients in RTOG 1016 were also treated with IMRT.

Table 1.

Cetuximab Versus Cisplatin and RT

Table 1.

“So, improvements in RT delivery, without reduction in radiation dose, may be improving the long-term quality-of-life endpoints that we’re concerned about in a de-escalation environment,” said Dr. Gillison.

Another notable trial in this arena was the HN002 trial, which randomly assigned nonsmoking or light-smoking patients with early-stage HPV-positive disease to either 60 Gy of IMRT alone over 5 weeks or 60 Gy of IMRT in 30 fractions plus weekly cisplatin.7 The study was powered to look at combined endpoints of 2-year PFS >85% and MD Anderson Dysphagia Inventory score (MDADI) ≥60. Dr. Gillison noted that the 2 study arms were compared with a landmark PFS endpoint and not with each other.

“In that study, we saw an analogous finding to what we saw in RTOG 1016,” she reported. “Which was that the elimination of cisplatin compromised locoregional control, suggesting again that cisplatin is a good radiation sensitizer, and that patients with HPV-positive disease benefit from it with regard to locoregional control.”

According to Dr. Gillison, the compromise in locoregional tumor control, as well as the morbidity associated with a salvage resection, can be considerable. To that end, the RT-alone arm was abandoned in the HN002 trial. The randomized phase II/III HN005 trial is currently enrolling, in which the SoC is 70 Gy + 2 cycles of high-dose cisplatin and is being compared with investigational arms of 60 Gy with either 2 cycles of high-dose cisplatin or nivolumab for 6 cycles (ClinicalTrials.gov identifier: NCT03952585). “Those that exceed the landmark PFS and MDADI scores could move forward in a randomized phase III trial,” she said.

Can Adjuvant Therapy Be Altered After Primary Surgical Resection?

ECOG 3311 was the first published trial that set out to answer whether adjuvant therapy can be altered for HPV-positive oropharyngeal cancer eligible for transoral robotic surgery.8 This phase II trial randomly assigned patients with intermediate-risk disease to postoperative RT at 50 or 60 Gy. Both study arms met the landmark 2-year PFS endpoint, both demonstrating that the lower bound of the confidence interval was >90.

“Given this population with extremely low-volume, low-risk disease, a lot of these patients will be treated with 60 Gy of RT alone,” she said. “My question for this trial is this: is the addition of surgical resection really dose escalation in this patient population?” Given that the population was somewhat similar to HN002, these data suggest that locoregional control can be maintained with either primary surgical resection or the addition of cisplatin to primary RT.

According to Dr. Gillison, data from the DART trial, presented at the 2021 Annual Meeting of the American Society for Radiation Oncology,9 further demonstrated that “in the adjuvant setting, patients with extranodal extension and multiple nodes seem to rely on and benefit from the radiation sensitization conferred by the addition of cisplatin to radiation. In addition, it appears better with cisplatin than with 2 doses of docetaxel,” she explained. Once again, the data support the conclusion that patients with HPV-positive cancer do benefit from radiosensitization with cisplatin.

De-Escalation Recommendations for the Future

Currently, a variety of frameworks are being investigated in terms of how better to select patients for de-escalation, taking into account clinical features, postoperative pathologic features, and response to systemic therapy, as well as a newer selection of approaches considering dynamic imaging responses and molecular selection. A number of these strategies are briefly summarized in Figure 2.

Figure 2.
Figure 2.

Patient selection framework.

Abbreviations: cfHPV, cell-free HPV; CR, complete response; ENE, extranodal extension; LVI, lymphovascular invasion; PNI, perineural invasion; PR, partial response.

Citation: Journal of the National Comprehensive Cancer Network 20, 5.5; 10.6004/jnccn.2022.5010

As research thus far has identified that de-escalation approaches frequently put patients at increased risk for locoregional failure—and potentially compromise their survival endpoints—a number of experts in the field have suggested some general approaches to consider before de-escalating therapy in patients with head and neck cancers.10

To begin, focus on harm reduction versus de-escalation. “For instance, we’ve seen that IMRT seems to significantly reduce toxicity endpoints versus prior radiation mechanisms. Now we’ll see whether a randomized phase III trial comparing IMRT with proton therapy will result in harm reduction,” she noted.

Until patient selection is improved via predictive biomarkers, focus should be placed on enrolling patients in multicenter, randomized phase II/III trials, with data safety monitoring boards with a minimum 2-year follow-up of locoregional failure and PFS, as well as stringent stopping criteria to avoid harm. “Given that our overall goal is to preserve survival while reducing toxicities,” she added, “we should focus on the inclusion of long-term toxicity outcomes to a minimum of 5 years.”

References

  • 1.

    Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100:261269.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Ang KK, Harris J, Wheeler R. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:2435.

  • 3.

    Settle K, Posner MR, Schumaker LM, et al. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila) 2009;2:776781.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27:19921998.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 2008;26:35823589.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet 2019;393:4050.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Yom SS, Torres-Saavedra P, Caudell JJ, et al. Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002). J Clin Oncol 2021;39:956965.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Ferris RL, Flamand Y, Weinstein GS, et al. 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). J Clin Oncol 2022;40:138149.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Ma DM, Price K, Moore EJ, et al. MC1675, a phase III evaluation of de-escalated adjuvant radiation therapy (DART) vs. standard adjuvant treatment for human papillomavirus associated oropharyngeal squamous cell carcinoma [abstract]. Presented at the 2021 ASTRO Annual Meeting; October 24–27, 2021. Abstract LBA-1.

    • Search Google Scholar
    • Export Citation
  • 10.

    Mehanna H, Rischin D, Wong SJ, et al. De-escalation after DE-ESCALATE and RTOG 1016: a Head and Neck Cancer InterGroup framework for future de-escalation studies. J Clin Oncol 2020;38:25522557.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Rischin D, King M, Kenny L, et al. Randomized trial of radiation therapy with weekly cisplatin or cetuximab in low-risk HPV-associated oropharyngeal cancer (TROG 12.01) - a Trans-Tasman Radiation Oncology Group study. Int J Radiat Oncol Biol Phys 2021;111:876886.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Gebre-Medhin M, Brun E, Engström P, et al. ARTSCAN III: a randomized phase III study comparing chemoradiotherapy with cisplatin versus cetuximab in patients with locoregionally advanced head and neck squamous cell cancer. J Clin Oncol 2021;39:3847.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Disclosures: Dr. Gillison has disclosed receiving consulting fees from Bayer HealthCare, Bristol-Myers Squibb Company, Eisai Inc., EMD Serono, Ipsen, Merck & Co., Inc., Nektar Therapeutics, and Roche Laboratories, Inc.; and receiving grant/research support from Bristol-Myers Squibb Company, Gilead Sciences, Inc., and Kura Oncology, Inc.

Correspondence: Maura L. Gillison, MD, PhD, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030. Email: mgillison@mdanderson.org
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    Figure 1.

    De-escalation framework.

    Abbreviations: MSKCC, Memorial Sloan Kettering Cancer Center; RT, radiation therapy.

  • View in gallery
    Figure 2.

    Patient selection framework.

    Abbreviations: cfHPV, cell-free HPV; CR, complete response; ENE, extranodal extension; LVI, lymphovascular invasion; PNI, perineural invasion; PR, partial response.

  • 1.

    Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100:261269.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Ang KK, Harris J, Wheeler R. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:2435.

  • 3.

    Settle K, Posner MR, Schumaker LM, et al. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila) 2009;2:776781.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27:19921998.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 2008;26:35823589.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet 2019;393:4050.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Yom SS, Torres-Saavedra P, Caudell JJ, et al. Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002). J Clin Oncol 2021;39:956965.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Ferris RL, Flamand Y, Weinstein GS, et al. 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). J Clin Oncol 2022;40:138149.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Ma DM, Price K, Moore EJ, et al. MC1675, a phase III evaluation of de-escalated adjuvant radiation therapy (DART) vs. standard adjuvant treatment for human papillomavirus associated oropharyngeal squamous cell carcinoma [abstract]. Presented at the 2021 ASTRO Annual Meeting; October 24–27, 2021. Abstract LBA-1.

    • Search Google Scholar
    • Export Citation
  • 10.

    Mehanna H, Rischin D, Wong SJ, et al. De-escalation after DE-ESCALATE and RTOG 1016: a Head and Neck Cancer InterGroup framework for future de-escalation studies. J Clin Oncol 2020;38:25522557.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Rischin D, King M, Kenny L, et al. Randomized trial of radiation therapy with weekly cisplatin or cetuximab in low-risk HPV-associated oropharyngeal cancer (TROG 12.01) - a Trans-Tasman Radiation Oncology Group study. Int J Radiat Oncol Biol Phys 2021;111:876886.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Gebre-Medhin M, Brun E, Engström P, et al. ARTSCAN III: a randomized phase III study comparing chemoradiotherapy with cisplatin versus cetuximab in patients with locoregionally advanced head and neck squamous cell cancer. J Clin Oncol 2021;39:3847.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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