Demands for therapeutic de-sensitization of HPV-positive OPC are growing

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Oropharyngeal cancer (OPC) is a type of head and neck cancer that affects structures in the throat, including the base of the tongue, back of the throat, soft palate, and tonsils.1 In the United States, OPC rates are rising every year, with an estimated 54,010 new cases in 2021.2 Known risk factors include alcohol abuse; Exposure to tobacco, including chewing tobacco, cigarettes, and pipes; and human papillomavirus (HPV) infection.

With an estimated 43 million infections in 2018, HPV is the most common sexually transmitted infection in the United States.3 HPV infection is causally linked to cancers of the anogenital region, including anal, cervical, penile, vaginal, and vulvar cancers. If HPV spreads orally, infections can also lead to the development of OPC. In the United States, more than 70% of OPC cases are caused by HPV.4th

HPV is a group of more than 100 viruses, including certain high-risk strains, that have been linked to developing cancer. The HPV-16 strain is responsible for the majority of HPV-positive (HPV +) OPC cases, with HPV-18, HPV-33, and HPV-35 also contributing, albeit significantly less than HPV-16.1 In these high-risk HPV strains, the viral genome encodes several oncogenic proteins that inhibit tumor suppressor proteins, resulting in chromosomal instability and malignancy in infected cells.

HPV + OPC is considered a genetically different form of OPC. Compared to HPV-negative (HPC–) OPC cases, HPV + OPC is associated with a favorable prognosis with improved response rates, prognosis with improved response rates to treatment and overall survival. Due to the different tumor biology, the National Comprehensive Cancer Network (NCCN) has adopted different staging criteria for HPV + and HPV– and recommends using the HPV status to stratify patients with OPC.1

The treatment landscape for localized OPC typically involves a multidisciplinary approach consisting of chemotherapy, radiation, and / or surgery. For fit patients with locally advanced OPC who can tolerate intensive therapy, simultaneous radiation with systemic high-dose cisplatin chemotherapy is the preferred treatment regimen.1 Unfortunately, treatment with OPC is associated with a high risk of treatment-related morbidity, which can cure patients of their malignancy, but with lifelong complications such as dysgeusia, dysphagia and xerostomia, but also systemic complications from cisplatin chemotherapy, including hearing loss and neurotoxicity .

Because patients with HPV + OPC are generally younger and have more favorable prognoses, clinicians have hypothesized that less intensive treatment might lead to fewer long-term treatment complications, but with persistently favorable cancer-related outcomes.5 This concept, known as deinensification, has become popular in recent years. Several strategies have been proposed to de-intensify treatment, including reducing the radiation dose; Replacing cisplatin with an alternative, less toxic agent, such as cetuximab; and surgical resection. Several phase 3 comparative studies have been conducted and more studies are ongoing.

In this phase 3 study, aptly named De-ESCALaTE (NCT01874171), patients with 334 HPV + OPC were randomized to receive radiation plus cetuximab or cisplatin.6th

Unfortunately, the study results do not speak in favor of replacing cisplatin with cetuximab. After 2 years, the incidence of severe toxicities did not differ significantly between cetuximab and cisplatin (P. = 0.98), nor do the rates of total toxicities (P. = .49). Significant differences in the 2-year overall survival and recurrence rates were observed. However, these results favored cisplatin (HR, 5.0; P. = 0.001 for overall survival; HR, 3.4; P. = 0.0007 for repetition).6th

RTOG-1016 (NCT01302834) was a second published phase 3 study comparing cetuximab with cisplatin in HPV + OPC patients.7th In this study, 805 patients who were randomized to receive radiation plus cetuximab or cisplatin were analyzed. Similar to the De-ESCALaTE study, the results of the RTOG-1016 study favored cisplatin versus cetuximab with 5-year overall survival rates of 84.6% versus 77.9%.8th

Based on the results of De-ESCALaTE and RTOG-1016, experts advise against replacing cisplatin with radiation chemotherapy in patients with localized HPV + OPC, and cisplatin plus radiation remains the preferred systemic treatment option under NCCN guidelines.1.5 As cisplatin continues to be the standard in the treatment of localized OPC, the role of deinensification for patients with HPV + OPC could be in adapting surgical strategies or radiation therapy. Treatment de-intensification should only be pursued through clinical trials, and experts encourage clinicians to conduct and analyze phase 2 studies before moving on to phase 3 studies.1.5

CONCLUSION

The cancer treatment landscape is constantly changing. Particularly with localized HPV + OPC, the difference in tumor biology represents a unique clinical area in which a reduction in treatment intensity can be justified, especially in the case of long and short-term toxicities associated with cisplatin. Interestingly, phase 3 data has shown evidence of harm in the removal of cisplatin from radiation chemotherapy for HPV + OPC; Therefore, cisplatin-based chemoradiotherapy remains the standard of care for these patients. Future studies may assist in de-intensifying treatment in ways other than removing cisplatin.

REFERENCES

1. NCCN. Guidelines for Clinical Practice in Oncology. Head and neck cancer, version 3.2021. Retrieved June 16, 2021. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf

2. Cancer statistics: oral cavity and throat cancer. National Cancer Institute. Accessed June 16, 2021. https://seer.cancer.gov/statfacts/html/oralcav.html

3. Genital HPV Infection Leaflet. CDC. Updated January 19, 2021. Accessed June 17, 2021. https://www.cdc.gov/std/hpv/stdfact-hpv.htm

4. HPV and oropharyngeal cancer. CDC. Updated September 3, 2020. Accessed June 17, 2021. https://www.cdc.gov/cancer/hpv/basic_info/hpv_oropharyngeal.htm

5. Mehanna H, Rischin D, Wong SJ et al. De-escalation according to DE-ESCALATE and RTOG 1016: a cross-group framework for head and neck cancer for future de-escalation studies. JClin Oncol. 2020; 38 (22): 2552-2557. doi: 10.1200 / JCO.20.00056

6. Mehanna H, Robinson M, Hartley A, et al .; De-escalate the HPV testing group. Radiation therapy plus cisplatin or cetuximab for low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open, randomized, controlled phase 3 study. Lancet. 2019; 393 (10166): 51-60. doi: 10.1016 / S0140-6736 (18) 32752-1

7. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin for human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomized, multicenter, non-inferiority study. Lancet. 2019; 393 (10166): 40-50. doi: 10.1016 / S0140-6736 (18) 32779-X

8. Gardasil 9. Prescribing Information. Pfizer; Accessed June 23, 2021. https://www.fda.gov/fi les / vaccines,% 20blood% 20 &% 20biologics / published / Package-Insert — Gardasil.pdf

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