Head and neck cancer is the seventh most common cancer in the world, with 1.1 million new diagnoses reported annually.1 In the United States, the incidence of oral and pharyngeal cancers is over 54,000 cases per year, resulting in over 11,000 yearly deaths.2 Although smoking and alcohol consumption are traditional risk factors for head and neck cancer, they are declining in many countries; on the other hand, there is a steady increase in diagnoses of human papillomavirus (HPV)-related cancers, frequently affecting the oropharynx.3
Guest Editor
Sue S. Yom, MD, PhD, MAS
Dr. Yom is the Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professor in Head and Neck Cancer Radiation Oncology and Professor in the Departments of Radiation Oncology and Otolaryngology–Head and Neck Surgery at the University of California San Francisco. Her clinical practice and academic areas of interest include head and neck and skin cancers as well as thoracic malignancies.
Head and neck cancers may vary widely in their treatment and prognosis based on anatomic site, histology, and molecular classification. This heterogeneity, daunting for clinical trial design, requires a redirection toward rationally individualized therapy. Predictive biomarkers, molecular and immunologic targets, and sophisticated understanding of patient-, tumor-, and treatment-related factors have created a discovery opportunity that is unprecedented. In addition, better understanding of etiology has led to opportunities in screening and prevention.
The ongoing starkness of cancer care disparities, both locally and globally, continues to confront the oncology profession. This year’s Head and Neck Cancer Almanac from The ASCO Post focuses on scientific highlights in HPV-related cancer prevention, treatment deintensification, and response biomarkers; systemic therapy improvements for nasopharyngeal carcinoma; and diagnostic and therapeutic advances in thyroid cancer, but also on the severe impact of health-care disparities as an ethical and oncologic issue that demands attention and resources.
Advances in HPV-Related Prevention, Diagnosis, and Treatment
As the number of HPV-related oropharyngeal cancers continues to rise, many wonder when national vaccination efforts will result in any impact. In the United States, HPV vaccination is recommended by the Centers for Disease Control and Prevention to start at age 11 to 12 but can start at age 9 and be given up to age 26, and it can also be discussed with persons aged 27 to 45 years who have not been adequately vaccinated. A cohort analysis examined incidence data from the Surveillance, Epidemiology, and End Results program in patients aged 34 to 83 years diagnosed with oropharyngeal cancers from 1992 to 2017.4 HPV vaccination data were obtained from the National Immunization Survey–Teen and National Health Interview Survey. Age-period-cohort forecasting models projected the oropharyngeal cancer incidence from 2018 to 2045 based on current levels of vaccination vs the scenario of no vaccination. Although oropharyngeal cancer incidence from 2018 to 2045 was projected to decrease dramatically in individuals aged 36 to 45 years (from 1.4 to 0.8 per 100,000 population) and decrease more modestly in those aged 46 to 55 years (from 8.7 to 7.2 per 100,000 population), incidence would continue to increase dramatically among older individuals who were 70 to 83 years of age (from 16.8 to 29.0 per 100,000 population). This is influenced by younger adults being at lowest risk of diagnosis vs older adults who are at higher risk and remain unvaccinated. Thus, providers may be facing a demographic shift of this diagnosis to an older population whose access to care, supportive care needs, and tolerance of current therapies may differ. It is worth reflecting on how national and global access to HPV vaccination may result in additional demographic shifts in the future.
Because of the improved prognosis and lengthy survival of patients with HPV-positive oropharyngeal cancer, therapy deintensification remains of high interest to decrease chronic sequelae, with one major theme being reduction in radiation therapy dose. Researchers from the University of Michigan reported an interim analysis of a single-arm phase II study.5 Patients with more than a 50% reduction in metabolic tumor volume on an FDG-PET/CT scan obtained after 2 weeks of chemoradiation treatment had reduced dose radiation to 54 Gy instead of the standard 70 Gy. At 1 month after chemoradiation, acute side effects were less in those who had reduced radiation dose, but quality-of-life measurements were not statistically different, and long-term cancer outcomes were not reported. Similarly, a phase III randomized trial from the Mayo Clinic compared a schedule of adjuvant docetaxel at 15 mg/m2 weekly with reduced-dose twice-daily radiation therapy (30–36 Gy over 2 weeks) after transoral surgery to standard adjuvant (chemo)radiation.6 Although the primary endpoint of grade 3 or higher adverse events at 6 months was not significantly different between arms, numerous other toxicity, functional, and quality-of-life metrics were improved in the reduced-dose arm, and 2-year cancer outcomes appeared similar.
Meanwhile, the most important deintensification study reported this year, ECOG 3311, was a large phase II randomized cooperative group study comparing the standard 60-Gy postoperative radiation dose against a reduced dose of 50 Gy in patients having intermediate-risk pathologic features following transoral surgery.7 Of 359 patients completing the study, 38 (10.5%) were low risk and received no further treatment after surgery, 113 (31.5%) were high risk and underwent adjuvant chemoradiation, and 208 (58%) were deemed intermediate risk and randomly assigned to receive radiotherapy at 60 Gy or 50 Gy. At 35.2 months, the primary endpoint of 2-year progression-free survival was 96% in the control arm vs 94.9% in the reduced-dose arm. Significant differences in high-grade toxicity occurred based on the intensity of adjuvant therapy; patients receiving adjuvant chemoradiation had the worst outcomes and quality of life.
Finally, personalized prognosis may become a reality with the debut of commercially available HPV detection in plasma. A team from Dana-Farber Cancer Institute collected data on 1,076 patients at 118 U.S. sites at 3 months after completion of any standard HPV-positive oropharyngeal cancer treatment, in order to determine the positive predictive value of circulating cell-free tumor tissue–modified viral HPV DNA in identifying disease persistence. Eighty (7%) of these patients tested positive, and among them, 21 (26.2%)had known disease, whereas 59 (73.8%) had no other indicator of disease at the time of testing. Of these 59 patients, 55 (93.2%) have been confirmed so far to have cancer recurrence.8
Advances in Systemic Therapy for Nasopharyngeal Carcinoma
Randomized studies from Asia continue to raise the bar for therapy efficacy in nasopharyngeal carcinoma. The standards of care have been evolving somewhat rapidly in this disease over the past several years. One important confirmatory report was the final overall survival analysis of the Chinese phase III randomized trial GEM20110714, which originally showed superiority of progression-free survival of gemcitabine/cisplatin over fluorouracil/cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. This report confirmed that after a median follow-up of 70 months, death had occurred in 81.8% of patients in the gemcitabine/cisplatin group vs 91.7% of the fluorouracil/cisplatin group, with a statistically significant hazard ratio (HR) of 0.72.9 The median overall survival was 22.1 months vs 18.6 months, and the 3- and 5-year overall survival rates were 31% vs 20.4% (P = .021), and 19.2% vs 7.8% (P < .001).
Also in the recurrent/metastatic setting, another study confirmed that this backbone of gemcitabine/cisplatin is enhanced with the addition of PD-1 inhibition. Following on the examples of the JUPITER-02 and CAPTAIN-1st clinical trials of toripalimab and camrelizumab, RATIONALE-309 was a third study of an anti–PD-1 agent developed in China, tislelizumab, combined with first-line gemcitabine/cisplatin doublet chemotherapy.10 In this study, patients received gemcitabine at 1 g/m2 plus cisplatin at 80 mg/m2 every 3 weeks for four to six cycles in combination with either tislelizumab at 200 mg intravenously or placebo; this was followed by tislelizumab or placebo every 3 weeks until disease progression. At 15.5 months, the primary endpoint of median progression-free survival was 9.6 months with the combination vs 7.4 months with chemotherapy alone (HR = 0.50). Median overall survival was not reached in the combination arm and was 23 months with chemotherapy alone (HR = 0.60).
In the curative-intent setting for nasopharyngeal carcinoma, induction chemotherapy has become increasingly popular due to improved failure-free survival demonstrated in a prior randomized phase III trial.11 One of the goals of induction is a reduction in distant metastasis. This phase III randomized study attempted to improve failure-free survival further by comparing induction paclitaxel, cisplatin, and capecitabine (TPC) to cisplatin and fluorouracil (PF) in patients with previously untreated stage IVA to IVB nasopharyngeal carcinoma.12 At a median follow-up of 48.4 months, 3-year failure-free survival was 83.5% for TPC vs 68.9% for PF (P = .004). Importantly, 3-year distant metastasis–free survival and locoregional relapse–free survival were significantly better, even though overall survival was not. Toxicities were similar, and in fact grade 3 or 4 adverse events were lower in the TPC group.
Improvements in Diagnosis and Individualized Treatment of Thyroid Cancer
Thyroid cancers are not always included in head and neck cancer statistics, but this is an increasingly common cancer diagnosis in the head and neck region. A major need is for better risk classification of early-stage disease in order to save resources and tailor management appropriately. For example, one study of ultrasound images used deep learning to analyze radiomics, topologic data, and machine learning of thyroid imaging reporting and data system (TI-RADS) features to predict thyroid nodules as malignant with 93% to 98.7% accuracy.13 The model predicted T and N stage with 89% to 93% accuracy, extrathyroidal extension with 98% accuracy, and the presence of BRAF V600E mutation with 96% accuracy.
Furthermore, precision of therapy based on individual risk classification is another major endeavor. For low-risk differentiated thyroid cancer, a major practice-defining study this year, the French phase III trial ESTIMABL2, found that omission of radioiodine was noninferior to radioiodine ablation (1.1 GBq following injections of recombinant human thyrotropin) in patients after thyroidectomy.14 The primary endpoint was the 3-year rate of a composite endpoint of functional, structural, and biological events, including the presence of abnormal foci of radioiodine uptake on whole-body scanning requiring subsequent treatment, abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. At 3 years, the proportion of patients without an event was 95.6% in the no-radioiodine group vs 95.9% in the radioiodine group. On the other hand, for high-risk differentiated thyroid cancer, investigators from the phase III ASTRA trial attempted to demonstrate improvement in the complete remission rate from the addition of selumetinib, a MEK1/2 inhibitor, to adjuvant radioiodine.15 In theory, selumetinib can increase radioiodine avidity in radioiodine-refractory tumors, but the rate of complete remission at 18 months after radioiodine was achieved in a similar proportion of 40% of the patients receiving selumetinib vs 38% of patients in the control group.
However, for patients with known radioiodine-refractory tumors, there are promising new targeted therapies including two—apatinib and cabozantinib—with major activity against VEGFR2 vs VEGFR2 and MET, respectively.16,17 At 18.1 months, apatinib improved the median progression-free survival to 22.2 months vs 4.5 months in the Chinese phase III REALITY trial. In the phase III COSMIC-311 trial, at 8.9 months of follow-up, cabozantinib produced objective responses (all partial) in 15% of patients vs 0% in the placebo group. Although the primary endpoint of objective response rate did not meet the prespecified significance level, median progression-free survival was not reached in the cabozantinib group vs 1.9 months in the placebo group. Therefore, these two therapies, both of which improved progression-free survival, are considered to be options for patients with radioiodine-refractory cancer. Their toxicity profiles were both considered to be tolerable and, at least in the case of cabozantinib, frequently managed through dose reduction. Of note, on this basis, the U.S. Food and Drug Administration has recently approved cabozantinib for patients with previously treated radioiodine-refractory differentiated thyroid cancer.
Targeting and Combating Disparities
Despite exciting advances for so many patients with head and neck cancer, disparities remain a serious issue. An examination of the National Cancer Database between 2004 and 2017 identified multiple racial, socioeconomic, and geographic disparities in the delivery of advanced radiotherapy techniques such as intensity-modulated radiotherapy and proton-beam therapy.18 Older patients, Black patients, patients living in less-educated areas, and patients living in areas of lower census median income were less likely to receive advanced radiotherapy modalities. Underinsured patients were also less likely to receive advanced techniques. Of note, patients who lived farther and traveled distances were more likely to receive advanced treatment techniques, indicating that these patients were seeking out advanced technologies for their treatments.
As this study demonstrates, it is critical as we develop advanced technologies and medicines for patients with head and neck cancer that we analyze their availability and distribution to all of our patients, with the goal of assuring equity of care for our most vulnerable populations.
DISCLOSURE: Dr. Yom has received research funding (institutional) from BioMimetix, Bristol Myers Squibb, EMD Serono, Genentech, and Merck; and reported patents, royalties, and other intellectual property with Springer and UpToDate.
REFERENCES
1. Mody MD, Rocco JW, Yom SS, et al: Head and neck cancer. Lancet 398:2289-2299, 2021.
2. Siegel RL, Miller KD, Fuchs HE, et al: Cancer statistics, 2022. CA Cancer J Clin 72:7-33, 2022.
3. Mehanna H, Beech T, Nicholson T, et al: Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer—Systematic review and meta-analysis of trends by time and region. Head Neck 35:747-755, 2013.
4. Zhang Y, Fakhry C, D’Souza G: Projected association of human papillomavirus vaccination with oropharynx cancer incidence in the US, 2020-2045. JAMA Oncol 7:e212907, 2021.
5. Allen SG, Rosen BS, Cao Y, et al: Early toxicity and patient reported outcomes from a phase 2 trial of FDG-PET response-based de-escalated definitive radiotherapy for p16+ oropharynx cancer. 2022 Multidisciplinary Head and Neck Cancers Symposium. Abstract 1. Presented February 24, 2022.
6. Ma DJ, 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. 2021 ASTRO Annual Meeting. Abstract LBA-1. Presented October 25, 2021.
7. 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 40:138-149, 2022.
8. Berger B, Hanna GJ, Posner M, et al: Detection of occult recurrence using circulating HPV tumor DNA among patients treated for HPV-driven oropharyngeal squamous cell carcinoma. 2022 Multidisciplinary Head and Neck Cancers Symposium. Abstract 3. Presented February 24, 2022.
9. Hong S, Zhang Y, Yu G, et al: Gemcitabine plus cisplatin versus fluorouracil plus cisplatin as first-line therapy for recurrent or metastatic nasopharyngeal carcinoma: Final overall survival analysis of GEM20110714 phase III study. J Clin Oncol 39:3273-3282, 2021.
10. Zhang L, Yang Y, Pan JJ, et al: RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer. 2022 ASCO Plenary Series. Abstract 384950.
11. Sun Y, Li WF, Chen NY, et al: Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase 3, multicentre, randomised controlled trial. Lancet Oncol 17:1509-1520, 2016.
12. Li WZ, Lv X, Hu D, et al: Effect of induction chemotherapy with paclitaxel, cisplatin, and capecitabine vs cisplatin and fluorouracil on failure-free survival for patients with stage IVA to IVB nasopharyngeal carcinoma. JAMA Oncol 8:706-714, 2022.
13. Paul R, Juliano A, Faquin W, et al: An artificial intelligence ultrasound platform for screening and staging of thyroid cancer. 2022 Multidisciplinary Head and Neck Cancers Symposium. Abstract 10. Presented February 25, 2022.
14. Leboulleux S, Bournaud C, Chougnet CN, et al: Thyroidectomy without radioiodine in patients with low-risk thyroid cancer. N Engl J Med 386:923-932, 2022.
15. Ho AL, Dedecjus M, Wirth LJ, et al: Selumetinib plus adjuvant radioactive iodine in patients with high-risk differentiated thyroid cancer: A phase III, randomized, placebo-controlled trial (ASTRA). J Clin Oncol 40:1870-1878, 2022.
16. Lin Y, Qin S, Li Z, et al: Apatinib vs placebo in patients with locally advanced or metastatic, radioactive iodine–refractory differentiated thyroid cancer: The REALITY randomized clinical trial. JAMA Oncol 8:242-250, 2022.
17. Brose MS, Robinson B, Sherman SI, et al: Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): A randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 22:1126-1138, 2021.
18. McCall NS, Liu Y, Janopaul-Naylor J, et al: Standard but not equal: Disparities in advanced radiotherapy techniques for head and neck cancer in the United States. 2022 Multidisciplinary Head and Neck Cancers Symposium. Abstract 17. Presented February 25, 2022.
