Targeted Therapy as a Potential De-Escalation Strategy in Locally Advanced HPV-Associated Oropharyngeal Cancer: A Literature Review

Abstract

The treatment landscape of locally advanced HPV-oropharyngeal squamous cell carcinoma (OPSCC) is undergoing transformation. This is because the high cures rates observed in OPSCC are paired with severe treatment-related, long-term toxicities. These significant adverse effects have led some to conclude that the current standard of care is over-treating patients, and that de-intensifying the regimens may achieve comparable survival outcomes with lower toxicities. Consequently, several de-escalation approaches involving locally advanced OPSCC are underway. These include the reduction of dosage and volume of intensive cytotoxic regimens, as well as elimination of invasive surgical procedures. Such de-intensifying treatments have the potential to achieve efficacy and concurrently alleviate morbidity. Targeted therapies, given their overall safer toxicity profiles, also make excellent candidates for de-escalation, either alone or alongside standard treatments. However, their role in these endeavors is currently limited, because few targeted therapies are currently in clinical use for head and neck cancers. Unfortunately, cetuximab, the only FDA-approved targeted therapy, has shown inferior outcomes when paired with radiation as compared to cisplatin, the standard radio-sensitizer, in recent de-escalation trials. These findings indicate the need for a better understanding of OPSCC biology in the design of rational therapeutic strategies and the development of novel, OPSCC-targeted therapies that are safe and can improve the therapeutic index of standard therapies. In this review, we summarize ongoing research on mechanism-based inhibitors in OPSCC, beginning with the salient molecular features that modulate tumorigenic processes and response, then exploring pharmacological inhibition and pre-clinical validation studies of candidate targeted agents, and finally, summarizing the progression of those candidates in the clinic.

Tumor-Infiltrating Lymphocytes in Head and Neck Cancer: Ready for Prime Time?

“…De-escalation strategies are currently being considered in several malignancies. The goals of de-escalation are reducing therapy-related toxicity, increasing or maintaining survival outcomes, and improving patients quality of life [46]. Indeed, the multimodal therapeutic approaches applied in HNSCC, including surgery, radiotherapy, and/or chemotherapy, are correlated with both acute and long-term toxicity.…”

Role and Clinical Utility of Cancer/Testis Antigens in Head and Neck Squamous Cell Carcinoma

“…However, treatment-related morbidities and quality of life issues remain major concerns for survivors [1]. Long-term morbidities include dysphagia, xerostomia, ototoxicity, and trismus [6]. Head and neck cancer survivors have the second-highest suicide rate, surpassed only by pancreatic cancer, and are almost twice as likely to die from suicide compared to survivors of other cancers [7].…”

GA-OH enhances the cytotoxicity of photon and proton radiation in HPV+ HNSCC cells

“…Cetuximab has thus far been regarded as the most promising cisplatin substitute for HNSCC treatment in conjunction with radiation. However, in various recent clinical trials, cetuximab has shown inferior survival outcomes as compared to cisplatin, and this has dampened the hope of incorporating its use into de-intensified regimens for HPV-related HNSCC (15)(16)(17)(18). Together, these observations further underscore the need for greater efforts to discover and develop more robust and selective targeted agents.…”

“…However, because HPV-associated OPSCC has excellent outcomes, many now believe that the current standard dose is resulting in overtreatment of the HPV + patient cohort. Numerous endeavors to de-escalate the radiation treatment regimens are already underway with a goal of lowering toxicity without compromising clinical outcomes (3,11,(15)(16)(17)(18). Most de-escalation attempts thus far have revolved around limiting the toxicity inflicted by photon-based radiotherapy.…”