Upfront surgery versus definitive radiotherapy: competing risk analyses for cancer-specific and noncancer mortality in oropharyngeal cancer.

PURPOSE: The optimal treatment strategy for oropharyngeal cancer (OPC) is undetermined. We aim to compare the survival outcomes of OPC patients treated with upfront surgery versus definitive radiotherapy (RT). METHODS: A total of 8057 cases were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts. RESULTS: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 1.31; 95% confidence interval [CI], 1.05-1.64; P = 0.017) and noncancer mortality (adjusted SHR, 1.59; 95% CI 1.13-2.25; P = 0.008). In the HPV-positive cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted SHR, 1.51; 95% CI 1.23-1.85; P < 0.001) and noncancer mortality (adjusted SHR, 1.53; 95% CI 1.11-2.12; P = 0.009). CONCLUSION: Upfront surgery is a superior treatment modality compared with definitive RT in terms of lowering cancer-specific and noncancer mortality in OPC patients, regardless of HPV status. Further prospective clinical trials are needed to confirm our findings.

Successful definitive radiation treatment of refractory canine oral papillomatosis.

This case report describes a three-year-old male intact border collie diagnosed with canine papillomavirus type 1 (CPV-1+) oral papillomas resistant to standard-of-care. With time, he developed lesions consistent with squamous cell carcinoma. Malignant tumors were incompletely excised and treated with definitive external beam radiation therapy (45 Gy, 3 Gy × 15 daily). The remaining oral cavity received 27 Gy (1.8 Gy x 15 daily) to treat the disseminated oral papillomatosis. A temporary treatment delay of 2 weeks was instituted due to grade 3 mucositis. The patient remained in complete remission after 10 months from radiotherapy. No tumor recurrences were noted by the owners after >1 year from treatment.

Increasing global accessibility to high-level treatments for cervical cancers.

Human papillomaviruses (HPV)-related gynecological cancers are a major health care issue, and a leading cause of cancer death in low- and middle-income countries (LMIC). In 2020, the World Health Organization launched a program aimed at cervical cancer elimination, by screening and vaccination strategies. Offering the best possible care to women diagnosed with invasive cancer is a complementary objective. Treatment of cervical cancer as per modern standards is complex and multimodal, mainly relying on surgery, external-beam radiotherapy (+/-chemotherapy) and brachytherapy. In parallel with the pivotal role of multidisciplinary discussion, international societies provide guidance to define the most effective and least toxic anti-cancer strategy, homogenize treatment protocols and provide benchmark quality indicators as a basis for accreditation processes. The challenge is to offer the appropriate diagnostic workup and treatment upfront and to avoid non- evidence-based treatment that consumes resources, impairs quality of life (QoL), and compromises oncological outcome. Various strategies may be applied for improving treatment quality: development of surgical mentorship, companion-training programs and international cooperation. The lack of radiotherapy/brachytherapy facilities is a major concern in LMIC. Reinforcing international support in terms of education, training, research and development and technical cooperation with national projects is required to increase access to minimum requirements but also introduce modern techniques, upgrade radiotherapy/brachytherapy services, and expand access to modern systemic treatments. In countries with robust economies, compliance to standards should also be increased. Integrative cancer care and multidisciplinary approaches are needed to tackle the dual challenge of increasing cure rates while minimizing QoL impairment. Appropriate dimensioning of the resources to avoid harmful treatment delays and access to expert referral centers is also a priority.

Current considerations for radiotherapy in HPV-associated head and neck cancer.

Human papillomavirus (HPV)-mediated oncogenesis confers increased sensitivity to radiotherapy and HPV head and neck cancer is associated with improved patient outcomes. As such, management of HPV-related head and neck cancer requires a multidisciplinary approach that balances maximizing locoregional control with minimizing treatment-related toxicity. We highlight considerations in radiation dose and target delineation, as well as considerations for chemoradiation, postoperative radiotherapy, and single modality, definitive radiotherapy.

Radiation Response of Cervical Cancer Stem Cells Is Associated with Pretreatment Proportion of These Cells and Physical Status of HPV DNA.

Radio- and chemoresistance of cancer stem cells (CSCs) is considered as one of the possible causes of adverse results of chemoradiotherapy for various malignancies, including cervical cancer. However, little is known about quantitative changes in the CSC subpopulation in the course of treatment and mechanisms for individual response of CSCs to therapy. The purpose of the study was to evaluate the association of radiation response of cervical CSCs with clinical and morphological parameters of disease and features of human papillomavirus (HPV) infection. The proportion of CD44+CD24low CSCs was determined by flow cytometry in cervical scrapings from 55 patients with squamous cell carcinoma of uterine cervix before treatment and after fractionated irradiation at a total dose of 10 Gy. Real-time PCR assay was used to evaluate molecular parameters of HPV DNA. Post-radiation increase in the CSC proportion was found in 47.3% of patients. Clinical and morphological parameters (stage, status of lymph node involvement, and histological type) were not significantly correlated with radiation changes in the CSC proportion. Single- and multifactor analyses revealed two independent indicators affecting the radiation response of CSCs: initial proportion of CSCs and physical status of HPV DNA (R = 0.86, p = 0.001 for the multiple regression model in the whole).

Establishment of epigenetic markers to predict irradiation efficacy against oropharyngeal cancer.

Irradiation, or chemoradiotherapy, is a curative treatment for oropharyngeal squamous cell carcinoma (OPSCC). Its invasiveness, however, can often negate its efficacy. Therefore, developing methods to predict which patients would benefit from irradiation is urgent. Promoter DNA hypermethylation was recently reported to correlate with favorable OPSCC prognosis. It is still unclear, however, whether there is an association between promoter DNA methylation and response to irradiation. In this study, we analyzed DNA methylation in the specimens from 40 OPSCC patients who had undergone irradiation, using the Infinium assay. Our results showed significant correlation between high levels of promoter DNA methylation and better response to treatment (P < 0.01). We used the 10 most differentially-methylated genes between responders and non-responders to develop a panel of predictive markers for efficacy. Our panel had high sensitivity, specificity and accuracy (92%, 93% and 93%, respectively). We conducted pyrosequencing to quantitatively validate the methylation levels of 8 of the 10 marker genes (ROBO1, ULK4P3, MYOD1, LBX1, CACNA1A, IRX4, DPYSL3 and ELAVL2) obtained by Infinium. The validation by pyrosequencing showed that these 8 genes had a high prediction performance for the training set of 40 specimens and for a validation set of 35 OPSCC specimens, showing 96% sensitivity, 89% specificity and 94% accuracy. Methylation of these markers correlated significantly with better progression-free and overall survival rates, regardless of human papillomavirus status. These results indicate that increased DNA methylation is associated with better responses to irradiation therapy and that DNA methylation can help establish efficacy prediction markers in OPSCC.

Stage I HPV-positive oropharyngeal cancer: Should all patients receive similar treatments?

BACKGROUND: Patients with clinical stage I human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (OPSCC) according to the American Joint Committee on Cancer (AJCC) eighth edition classification comprise a heterogeneous group formerly classified as stage I to stage IVA according to the seventh edition of the AJCC classification. These patients historically were treated with disparate treatment regimens, particularly with respect to the use of concurrent chemotherapy. METHODS: The National Cancer Data Base was queried for patients with AJCC eighth edition clinical stage I HPV-positive OPSCC (AJCC seventh edition stage T1-2N0-2bM0) who were diagnosed from 2010 to 2014 and underwent definitive radiotherapy. Concurrent chemotherapy with definitive radiotherapy was defined as chemotherapy administered within 7 days of the initiation of radiotherapy. RESULTS: The current analysis included 4473 patients with HPV-positive stage I OPSCC with a median follow-up of 36.3 months. A total of 3127 patients (69.9%) received concurrent chemotherapy. Concurrent chemotherapy was found to be associated with improved overall survival on multivariable analyses (hazard ratio [HR], 0.782; 95% CI, 0.645-0.948 [P = .012]). The effect of chemotherapy on survival varied based on lymph node involvement (P for interaction = .001). Specifically, chemotherapy was associated with improved survival for patients with lymph node-positive stage I disease (stage III-IVA according to the AJCC seventh edition: HR, 0.682; 95% CI, 0.557-0.835 [P < .001]), but not for patients with N0 disease (stage I-II according to the AJCC seventh edition: HR, 1.646; 95% CI, 1.011-2.681 [P = .05]). Similar results were noted among propensity score-matched cohorts. CONCLUSIONS: Treatment with concurrent chemotherapy was associated with improved overall survival for patients with lymph node-positive, but not lymph node-negative, AJCC eighth edition stage I HPV-positive OPSCC undergoing definitive radiotherapy, thereby supporting different treatment paradigms for these patients.

Scale-up of radiotherapy for cervical cancer in the era of human papillomavirus vaccination in low-income and middle-income countries: a model-based analysis of need and economic impact.

BACKGROUND: Radiotherapy is standard of care for cervical cancer, but major global gaps in access exist, particularly in low-income and middle-income countries. We modelled the health and economic benefits of a 20-year radiotherapy scale-up to estimate the long-term demand for treatment in the context of human papillomavirus (HPV) vaccination. METHODS: We applied the Global Task Force on Radiotherapy for Cancer Control investment framework to model the health and economic benefits of scaling up external-beam radiotherapy and brachytherapy for cervical cancer in upper-middle-income, lower-middle-income, and low-income countries between 2015 and 2035. We estimated the unique costs of external-beam radiotherapy and brachytherapy and included a specific valuation of women's caregiving contributions. Model outcomes life-years gained and the human capital and full income net present value of investment. We estimated the effects of stage at diagnosis, radiotherapy delivery system, and simultaneous HPV vaccination (75% coverage) up to a time horizon set at 2072. FINDINGS: For the period from 2015 to 2035, we estimated that 9·4 million women in low-income and middle-income countries required treatment with external-beam radiotherapy, of which 7·0 million also required treatment with brachytherapy. Incremental scale-up of radiotherapy in these countries from 2015 to meet optimal radiotherapy demand by 2035 yielded 11·4 million life-years gained, $59·3 billion in human capital net present value (-$1·5 billion in low-income, $19·9 billion in lower-middle-income, and $40·9 billion in upper-middle-income countries), and $151·5 billion in full income net present value ($1·5 billion in low-income countries, $53·6 billion in lower-middle-income countries, and $96·4 billion in upper-middle-income countries). Benefits increased with advanced stage of cervical cancer and more efficient scale up of radiotherapy. Bivalent HPV vaccination of 12-year-old girls resulted in a 3·9% reduction in incident cases from 2015-2035. By 2072, when the first vaccinated cohort of girls reaches 70 years of age, vaccination yielded a 22·9% reduction in cervical cancer incidence, with 38·4 million requiring external-beam radiotherapy and 28·8 million requiring brachytherapy. INTERPRETATION: Effective cervical cancer control requires a comprehensive strategy. Even with HPV vaccination, radiotherapy treatment scale-up remains essential and produces large health benefits and a strong return on investment to countries at different levels of development. FUNDING: None.

Characterization and radiosensitivity of HPV-related oropharyngeal squamous cell carcinoma patient-derived xenografts.

Background: Oropharyngeal squamous cell carcinomas (OPSCC) are rising rapidly in incidence due to Human Papillomavirus (HPV) and/or tobacco smoking. Prognosis is better for patients with HPV-positive disease, but may also be influenced by tobacco smoking and other factors. There is a need to individualize treatment to minimize morbidity and improve prognosis. Patient-derived xenografts (PDX) is an emerging pre-clinical research model that may more accurately reflect the human disease, and is an attractive platform to study disease biology and develop treatments and biomarkers. In this study we describe the establishment of PDX models, compare PDX tumors to the human original, and assess the suitability of this model for radiotherapy research and biomarker development. Material and methods: Tumor biopsies from 34 patients with previously untreated OPSCC were implanted in immunodeficient mice, giving rise to 12 squamous cell carcinoma PDX models (7 HPV+, 5 HPV-). Primary and PDX tumors were characterized extensively, examining histology, immunohistochemistry, cancer gene sequencing and gene expression analysis. Radiosensitivity was assessed in vivo in a growth delay assay. Results: Established PDX models maintained histological and immunohistochemical characteristics as well as HPV-status of the primary tumor. Important cancer driver gene mutations, e.g., in TP53, PIK3CA and others, were preserved. Gene expression related to cancer stem cell markers and gene expression subtype were preserved, while gene expression related to hypoxia and immune response differed. Radiosensitivity studies showed high concordance with clinical observations. Conclusion: PDX from OPSCC preserves important molecular characteristics of the human primary tumor. Radiosensitivity were in accordance with clinically observed treatment response. The PDX model is a clinically relevant surrogate model of head and neck cancer. Perspectives include increased understanding of disease biology, which could lead to development of novel treatments and biomarkers.

MRI for Radiation Therapy Planning in Human Papillomavirus-associated Gynecologic Cancers.

Locally advanced human papillomavirus (HPV)-associated gynecologic cancers, including cervical, vaginal, and vulvar cancers, are treated primarily with radiation therapy (RT). Cervical cancer remains a leading cause of cancer death among women worldwide. The superior soft-tissue resolution of MRI compared with other imaging modalities makes it an ideal modality for RT planning, execution, and follow-up of these malignancies. This superiority has been corroborated in the literature when comparing MRI-based RT planning to radiography-based conventional treatment planning approaches. In 2005, the Groupe Européen de Curiethérapie and the European Society for Radiation Therapy and Oncology guidelines underscored the central role of MRI for successful implementation of three-dimensional image-based cervical cancer brachytherapy. The delineation of both gross tumor volume and clinical tumor volume for brachytherapy is performed at the time of each brachytherapy application, on the basis of the findings depicted on anatomic MR images. Contemporary knowledge concerning the role of MRI for RT planning in HPV-associated gynecologic cancers warrants an understanding of the epidemiology and clinical manifestations of these cancers, as well as knowledge of MRI protocol for cancer staging, selection of RT candidates, brachytherapy implant assessment, posttreatment surveillance, and delineation of treatment-related complications. Technical requirements, patient preparation, and image acquisition protocols are detailed in this review, and imaging-based treatment protocols are summarized. Knowledge of these fundamental concepts enables the radiologist to play an important role in diagnosis, staging, and posttreatment follow-up, helping to guide radiation oncologists and other clinicians in the management of these malignancies.©RSNA, 2019.

Tumor volume as a prognostic marker in p16-positive and p16-negative oropharyngeal cancer patients treated with definitive intensity-modulated radiotherapy.

PURPOSE: To investigate the impact of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) in oropharyngeal squamous cell carcinoma (OPSCC) and the difference in their role between human papillomavirus (HPV)-positive and HPV-negative patients. METHODS: The patient cohort consists of 91 OPSCC patients treated with definitive radiochemotherapy or radiotherapy using intensity-modulated radiotherapy (IMRT). All patients had a minimum follow-up of 31 months. Volume measurements were made from computer tomography (CT) scans and HPV status was assessed by p16 immunohistochemistry. The end points were as follows: overall survival (OS), disease-free survival (DFS) and locoregional control (LRC). RESULTS: pGTV was a significant independent prognostic factor for overall survival (OS; p = 0.020) in p16-negative patients. nGTV of p16-negative tumors had significant prognostic value in all end points in multivariate analyses. High-stage (III-IVc) p16-negative tumors were only associated with significantly poorer OS (p = 0.046) but not with poorer LRC or DFS when compared with the low-stage (I-II) tumors. nGTV of p16-positive tumors was an independent prognostic factor for DFS (p = 0.005) and LRC (p = 0.007) in multivariate analyses. CONCLUSION: pGTV may serve as an independent prognostic factor in p16-negative patients and nGTV may serve as an independent prognostic factor both in p16-positive and p16-negative patients treated with radiochemotherapy or radiotherapy using IMRT. Tumor volume may have an impact on selecting patients for de-escalation protocols in the future, both in p16-positive and p16-negative patients.

Human Papilloma Virus as a Biomarker for Personalized Head and Neck Cancer Radiotherapy.

A dramatic increase in the incidence of HPV-related oropharyngeal cancer has been reported in some parts of the western world over the past 30 years. They constitute a clinically distinct subgroup of cancers in terms of molecular biology, patient characteristics, and treatment outcome. This chapter describes the molecular characteristics, epidemiology, and demographics of the HPV-related head and neck cancers and discuss available methods to detect HPV-related tumours. The impact of HPV-related biomarkers in clinical studies on radiotherapy only, altered fractionation, modulation of hypoxia, and concurrent chemo- or bio-radiotherapy are reviewed as well as the perspectives of de-escalation and immune-modulation are discussed.

Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy.

Single nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110 and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1,008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank p < 0.0001 and p < 0.0001, respectively) and an approximately threefold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2-4.6; and HR, 3.1; 95% CI, 2.2-4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, p < 0.0001 and p < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR, 12.9; 95% CI, 3.8-43.6; and HR, 8.1; 95% CI, 3.6-18.6, respectively), whereas no significant associations were found for FAS1377 and FASLG124 polymorphisms. Our findings suggest that FAS670 and FASLG844 polymorphisms modulate the risk of recurrence of SCCOP, particularly in patients with HPV16-positive tumors. Larger studies are needed to validate these results.

Improved survival in HPV/p16-positive oropharyngeal cancer patients treated with postoperative radiotherapy.

INTRODUCTION: In the literature, HPV infection and/or p16 positivity have been consistently demonstrated to correlate with improved response rates in oropharyngeal squamous cell carcinoma (OPSCC) patients treated with primary radiotherapy (RT) alone and in combination with chemotherapy. However, the exact role of HPV/p16 positivity in patients treated with postoperative RT is still unclear. METHODS: We analyzed tumor samples for HPV-DNA and p16 expression and correlated these variables with treatment outcome in a series of 63 consecutively treated oropharyngeal cancer patients (95% stage III/IV). HPV and p16 analysis were performed using validated test systems. Survival was estimated by the Kaplan-Meier method. Cox proportional hazard regression models were applied to compare the risk of death among patients stratified according to risk factors. RESULTS: Expression of p16 or high-risk HPV-DNA was detected in 60.3% and 39.6% of the tumors, respectively. p16 expression [overall survival (OS) at 2 years: 91%] as well as HPV infection (OS at 2 years: 95%) was associated with improved OS. Mean survival in p16-positive patients was 112 months compared to 64.6 months in case of p16 negativity. All HPV-positive tumors stained positive for p16. In a multivariable analysis, p16 positivity was associated with improved OS and with disease-free survival. CONCLUSION: p16 expression and HPV infection are strongly associated with the outcome of postoperatively irradiated OPSCC patients. HPV and p16 double-negative OPSCC patients should be regarded as a distinct "very high-risk patient group" that may benefit from intensified or novel treatment combinations.

miR-375 Modulates Radiosensitivity of HR-HPV-Positive Cervical Cancer Cells by Targeting UBE3A through the p53 Pathway.

BACKGROUND: Prediction of radioresistance of HR-HPV-positive (+) cervical cancer, especially before the course of radiotherapy, is quite beneficial to develop an optimal treatment strategy for individual patients. Unfortunately, the mechanisms responsible for radioresistance of cervical cancer are still largely unexplored. HR-HPV infection leads to a series of changes to normal biophysical process, including miRNAs expression. In this study, we explored the association between miR-375 and radioresistance in HR-HPV (+) cervical cancer. MATERIAL AND METHODS: qRT-PCR analysis was performed to determine miR-375 expression in HR-HPV-positive (+) cervical cancer patients and in HPV-16-positive SiHa and HPV-18-positive HeLa cervical cancer cell lines. The influence of miR-375 on radiosensitivity and the downstream regulative network were further explored in the cell line models. RESULTS: The results verified a putative binding site between miR-375 and UBE3A. miR-375 overexpression could significantly reduce UBE3A expression. UBE3A knockdown led to significantly reduced cell survival under radiation treatment. miR-375 promoted radiosensitivity of HR-HPV (+) cancer through decreasing p53 degradation and thereby increasing radiation-induced apoptosis. CONCLUSIONS: The miR-375-UBE3A axis is important in modulating radiosensitivity of HR-HPV (+) cervical cancer.

Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis.

BACKGROUND AND PURPOSE: Human Papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) respond favourably to radiotherapy as compared to HPV-unrelated HNSCC. We investigated DNA damage response in HPV-positive and HPV-negative HNSCC cell lines aiming to identify mechanisms, which illustrate reasons for the increased sensitivity of HPV-positive cancers of the oropharynx. METHODS: Radiation response including clonogenic survival, apoptosis, DNA double-strand break (DSB) repair, and cell cycle redistribution in four HPV-positive (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) cell lines was evaluated. RESULTS: HPV-positive cells were more radiosensitive (mean SF2: 0.198 range: 0.22-0.18) than HPV-negative cells (mean SF2: 0.34, range: 0.45-0.27; p = 0.010). Irradiated HPV-positive cell lines progressed faster through S-phase showing a more distinct accumulation in G2/M. The abnormal cell cycle checkpoint activation was accompanied by a more pronounced increase of cell death after x-irradiation and a higher number of residual and unreleased DSBs. CONCLUSIONS: The enhanced responsiveness of HPV-related HNSCC to radiotherapy might be caused by a higher cellular radiosensitivity due to cell cycle dysregulation and impaired DNA DSB repair.

Translational risk-adapted approaches to de-escalated radiation for human papillomavirus-positive oropharyngeal cancer: Past, present, and future.

Interest in the use of de-escalated radiation to treat patients with newly diagnosed human papillomavirus (HPV)-positive oropharyngeal cancer has grown dramatically with the publication of prospective trials demonstrating the efficacy of such an approach. While the rationale for de-escalation--- namely to decrease treatment-related toxicity while maintaining the excellent rates of disease control historically observed in patients with this disease-is inherently obvious, uncertainty exists regarding how to best select patients for de-escalation. Consequently, risk-adapted strategies using a variety of translational and clinical platforms have been increasingly popularized to better refine treatment. These have integrated contemporary methods of mid-treatment response assessment using advanced technologies and molecular assays to customize the radiation dose. By monitoring the response as patients actively proceed through treatment, risk-adapted protocols have the potential to provide insight into the biological behavior of tumors and make individualized therapy possible. The purpose of this review is to summarize the evidence to date on risk-adapted approaches to de-escalated radiation-- highlighting the clinical, radiological, and biological data which may ultimately help usher the principles of precision medicine into practice for patients with HPV-positive oropharyngeal cancer.

De-escalated radiation for human papillomavirus virus-related oropharyngeal cancer: Who, why, what, where, when, how, how much and what next?

The emergence of treatment de-escalation as a feasible option for patients with newly diagnosed human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma has generated considerable excitement among both providers and patients alike. Since HPV-positive oropharyngeal carcinoma has been shown to be a unique entity with distinct clinical and molecular characteristics, the rationale for customizing treatment for patients with this disease is compelling. Indeed, evidence has accumulated demonstrating that patients with HPV-positive oropharyngeal cancer have a significantly improved prognosis as a result of their exquisite radiosensitivity compared to their HPV-negative counterparts and thus might possibly be targeted with de-escalated approaches. The fundamental goal of de-escalation is to maintain the high cure and survival rates associated with traditional approaches while reducing the intensity of treatment and thus the incidence of both short- and long-term toxicity. Given the rapidly increasing incidence of this disease, particularly among younger patients who are generally healthy, the focus on quality of life seems germane. Although the exact reason for the improved sensitivity of HPV-positive oropharyngeal carcinoma to treatment is uncertain, prospective studies have now been published demonstrating that de-escalated radiation can successfully maintain the high rates of cure and preserve quality of life for appropriately selected patients with this disease. However, these studies have been fairly heterogeneous in design, and it remains questionable how to apply their findings to real-world practice. The potential of integrating translational approaches into clinical paradigms is also just starting to become recognized. Consequently, multiple uncertainties continue to exist with respect to de-escalation for HPV-positive oropharyngeal cancer, and these questions comprise the crux of this review.

Radiation Therapy for HPV-Positive Oropharyngeal Squamous Cell Carcinoma: An ASTRO Clinical Practice Guideline.

PURPOSE: Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct disease from other head and neck tumors. This guideline provides evidence-based recommendations on the critical decisions in its curative treatment, including both definitive and postoperative radiation therapy (RT) management. METHODS: ASTRO convened a task force to address 5 key questions on the use of RT for management of HPV-associated OPSCC. These questions included indications for definitive and postoperative RT and chemoradiation; dose-fractionation regimens and treatment volumes; preferred RT techniques and normal tissue considerations; and posttreatment management decisions. The task force did not address indications for primary surgery versus RT. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: Concurrent cisplatin is recommended for patients receiving definitive RT with T3-4 disease and/or 1 node >3 cm, or multiple nodes. For similar patients who are ineligible for cisplatin, concurrent cetuximab, carboplatin/5-fluorouracil, or taxane-based systemic therapy are conditionally recommended. In the postoperative setting, RT with concurrent cisplatin (either schedule) is recommended for positive surgical margins or extranodal extension. Postoperative RT alone is recommended for pT3-4 disease, >2 nodes, or a single node >3 cm. Observation is conditionally recommended for pT1-2 disease and a single node ≤3 cm without other risk factors. For patients treated with definitive RT with concurrent systemic therapy, 7000 cGy in 33 to 35 fractions is recommended, and for patients receiving postoperative RT without positive surgical margins and extranodal extension, 5600 to 6000 cGy is recommended. For all patients receiving RT, intensity modulated RT over 3-dimensional techniques with reduction in dose to critical organs at risk (including salivary and swallowing structures) is recommended. Reassessment with positron emission tomography-computed tomography is recommended approximately 3 months after definitive RT/chemoradiation, and neck dissection is recommended for convincing evidence of residual disease; for equivocal positron emission tomography-computed tomography findings, either neck dissection or repeat imaging is recommended. CONCLUSIONS: The role and practice of RT continues to evolve for HPV-associated OPSCC, and these guidelines inform best clinical practice based on the available evidence.

Association of follow-up imaging frequency with temporal incidence and patterns of distant failure following (chemo) radiotherapy for HPV related oropharyngeal cancer.

OBJECTIVES: Emerging data supports radical intent therapy for oligometastatic (OM) relapsed human papilloma virus (HPV+) related oropharyngeal cancer (OPC). We assess the association of follow-up imaging frequency amongst HPV + OPC, with temporal and spatial patterns of distant relapse, to inform rationalisation of routine post-treatment imaging. MATERIALS AND METHODS: A retrospective single centre cohort study was carried out of consecutive HPV + OPC patients treated with radical intent (chemo)radiotherapy ((CT)RT) between 2011 and 2019. OM state was defined as ≤ 5 metastasis, none larger than 3 cm (OMs) or, if interval from last negative surveillance imaging > 6-months, then ≤ 10 metastasis, none larger than 5 cm, (OMp). Patients not meeting OMs / OMp criteria were deemed to have incurable diffuse metastatic disease (DMdiffuse). RESULTS: 793 HPV-OPC patients were identified with median follow-up 3.15years (range 0.2-8.9). 52 (6.6 %) patients had radiologically identified DM at first failure and were considered for analysis. The median time to recurrence was 15.1 months (range: 2.6-63 months). 87 % of distant metastasis (DM) occurred in the first two years after treatment. Twenty-seven (52 %) patients had OM (OMs or OMp) at time of failure, with 31 % having OMs. The median time from completion of treatment to diagnosis of DMdiffuse vs OM was 22.2 months (range: 2.6-63.1 months) vs 11.6 months (range: 3.5-32.5 months). The probability of being diagnosed with OM vs DMdiffuse increased with reducing interval from last negative surveillance scan to imaging identifying DM (≤6 months 88.9 %, 7-12 months 71.4 %, 13-24 months 35 %, > 24 months 22.2 %). CONCLUSION: We demonstrate that a reduced interval between last negative imaging and subsequent radiological diagnosis of DM is associated with increased likelihood of identification of OM disease. Consideration of increased frequency of surveillance imaging during the first two years of follow up is supported, particularly for patients at high risk of distant failure.