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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.

SUBMITTER: Chitsike L

PROVIDER: S-EPMC8418093 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PURPOSE:To report a small substudy of an ongoing large, multi-arm study using functional imaging to assess pre-/intratreatment hypoxia for all head and neck cancer, in which we hypothesized that pre- and early-treatment hypoxia assessment using functional positron emission tomography (PET) imaging may help select which human papillomavirus (HPV)-positive (HPV(+)) oropharyngeal cancer (OPC) patients can safely receive radiation de-escalation without jeopardizing treatment outcomes. METHODS AND MATERIALS:Patients with HPV(+) oropharyngeal carcinoma were enrolled on an institutional review board-approved prospective study of which de-escalation based on imaging response was done for node(s) only. Pretreatment (18)F-fluorodeoxyglucose and dynamic (18)F-FMISO (fluoromisonidazole) positron emission tomography (PET) scans were performed. For patients with pretreatment hypoxia on(18)F-FMISO PET (defined as a >1.2 tumor to muscle standard uptake value ratio), a repeat scan was done 1 week after chemoradiation. Patients without pretreatment hypoxia or with resolution of hypoxia on repeat scan received a 10-Gy dose reduction to metastatic lymph node(s). The 2-year local, regional, distant metastasis-free, and overall survival rates were estimated using the Kaplan-Meier product-limit method. A subset of patients had biopsy of a hypoxic node done under image guidance. RESULTS:Thirty-three HPV(+) OPC patients were enrolled in this pilot study. One hundred percent showed pretreatment hypoxia (at primary site and/or node[s]), and among these, 48% resolved (at primary site and/or node[s]); 30% met criteria and received 10-Gy reduction to the lymph node(s). At the median follow-up of 32 months (range, 21-61 months), the 2-year locoregional control rate was 100%. One patient failed distantly with persistence of hypoxia on (18)F-FMISO PET. The 2-year distant metastasis-free rate was 97%. The 2-year OS rate was 100%. Hypoxia on imaging was confirmed pathologically. CONCLUSIONS:Hypoxia is present in HPV(+) tumors but resolves within 1 week of treatment in 48% of cases either at the primary site and/or lymph node(s). Our 100% locoregional control rate suggests that intratreatment functional imaging used to selectively de-escalate node(s) to 60 Gy was confirmed safe using our stringent imaging criteria. Intratreatment functional imaging warrants further study to determine its ultimate role in de-escalation treatment strategies.

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

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