Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies.

Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.

Treatment of Relapsing HPV Diseases by Restored Function of Natural Killer Cells.

Human papillomavirus (HPV) infections underlie a wide spectrum of both benign and malignant epithelial diseases. In this report, we describe the case of a young man who had encephalitis caused by herpes simplex virus during adolescence and currently presented with multiple recurrent skin and mucosal lesions caused by HPV. The patient was found to have a pathogenic germline mutation in the X-linked interleukin-2 receptor subunit gamma gene (IL2RG), which was somatically reverted in T cells but not in natural killer (NK) cells. Allogeneic hematopoietic-cell transplantation led to restoration of NK cytotoxicity, with normalization of the skin microbiome and persistent remission of all HPV-related diseases. NK cytotoxicity appears to play a role in containing HPV colonization and the ensuing HPV-related hyperplastic or dysplastic lesions. (Funded by the National Institutes of Health and the Herbert Irving Comprehensive Cancer Center Flow Cytometry Shared Resources.).

Effects of vaginal microbiota on human papillomavirus infection and its related diseases.

With the knowledge of female reproductive tract microbiota gradually increasing, the connection between vaginal microbiota (VMB) and its related diseases is increasingly highlighted. Manifestation of VMB keeps changing with various dominated bacteria, which can affect the immune response of mucosal barrier and the entrance of pathogens. Human papillomavirus (HPV), as an oncogenic virus, is closely related to viral-associated cancer, such as cervical cancer. According to HPV infection status, VMB can transform into different types, and result in accelerating or restraining the progression of diseases, which have exposed the inner link between VMB and HPV. Therefore, probiotics therapy promises to be a new complementary therapy to rebuild a healthy VMB for patients, but there's still a long way to go before its ready for the clinic. This review focuses on composition, immune response, and application of VMB in HPV and its associated diseases and aims to provide the new ideas and directions for the research on VMB.

Trends in the treatment of human papillomavirus-associated oropharyngeal carcinoma in Slovakia.

The optimal treatment of oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) is currently a subject of clinical research. This questionnaire study investigated current trends in the treatment of HPV-associated (HPV+) OPC in Slovakia with the incorporation of deintensification of oncological treatment into routine clinical practice outside of clinical trials. The Slovak Cooperative Head and Neck Cancer Group (SCHNCG) developed a questionnaire aimed at identifying trends in the oncological treatment of HPV+ OPC intended for all radiation oncology (RO) facilities in Slovakia. Specialists in the field of RO responded to general questions about the character of their individual institutions as well as to 4 theoretical clinical scenarios (case reports) regarding the treatment of HPV+ OPC, focusing primarily on the applied dose of radiotherapy (RT), the extent of target volumes, and the type of concurrent chemotherapy (CHT). The questionnaire study involved 35 RO specialists from 14 institutions in Slovakia. Regarding primary chemoradiotherapy (CRT) in T1N1M0 HPV+ OPC, 16 respondents (45.7%) would consider de-escalation of the RT dose to <70 Gy. In the case of postoperative RT in pT1pN1M0 HPV+ OPC with negative resection margins (R0) and absent extracapsular extension (ECE), 4 physicians (11.4%) would consider de-escalation of the RT dose to <60 Gy in the tumor bed area, while the majority of the treating specialists (n=19, 54.3%) would omit concurrent CHT. In the case of primary RT in elderly patient with T2N1M0 HPV+ OPC, the same number of physicians (n=16, 45.7%) would consider de-escalation of the RT dose to <70 Gy, and 14 respondents (40.0%) would completely omit CHT. In a high-risk patient with T2N3M0 HPV+ OPC with a complete response after 3 cycles of induction chemotherapy (iCHT), none of the respondents would indicate a reduction in the RT dose to the area of the original tumor and lymphadenopathy to <60 Gy. The doses and extent of irradiated volumes in the treatment of HPV+ OPC in Slovakia vary among different institutions. The tendency to de-escalate RT doses and reduce doses of concurrent systemic therapy in Slovakia is high and there was also an observed trend to reduce the extent of radiation treatment fields.

Comparing the effects of argon plasma coagulation and interferon therapy in patients with vaginal intraepithelial neoplasia: a single-center retrospective study.

PURPOSE: This study aimed to evaluate the clinical efficacy and safety of argon plasma coagulation (APC) therapy and interferon therapy in patients with grade I and II vaginal intraepithelial neoplasia (VaIN). METHODS: A total of 112 patients with VaIN were diagnosed via colposcopy-induced biopsy and classified into the APC group (n = 77) and interferon group (n = 35). Clinical data including age, grade, symptoms, historical or concomitant neoplasia of the lower genital tract, indications for hysterectomy, pregnancy history, cytology, human papillomavirus (HPV) subtype, treatment modalities, and clinical outcomes were analyzed, retrospectively. Complications and clinical outcomes were assessed at 6- and 12-month follow-ups. RESULTS: There was no significant difference in the HPV clearance rate between the APC (53.42%) and interferon (33.33%) groups at 6 months after treatment. However, the 12-month follow-up of the APC group showed a significantly higher HPV clearance rate as compared to the interferon group (87.67% vs. 51.52%, P < 0.05). The APC group exhibited a significantly higher cure rate (79.22% vs. 40.0%) and lower persistence rate (12.99% vs. 37.14%) than the interferon group (P < 0.05). Adverse reaction analysis revealed that the primary reaction in the APC group was vaginal drainage, in contrast to the increased vaginal discharge in the interferon group; though the difference was significant (68.83% vs. 28.57%, P < 0.05), no serious complications were observed. CONCLUSIONS: Treatment with APC is a safe and more effective procedure against VaIN I and II, compared to interferon. APC may serve as a viable alternative to other physiotherapies.

The impact of distance to facility on treatment modality, short-term outcomes, and survival of patients with HPV-positive oropharyngeal squamous cell carcinoma.

PURPOSE: This study compared treatment and outcomes for patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) based on their travel distance to treatment facility. MATERIALS AND METHODS: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC in the National Cancer Database from 2010 to 2019 were identified and split into four quartiles based on distance to facility, with quartile 4 representing patients with furthest travel distances. Multivariable-adjusted logistic regression and Cox proportional hazards modeling were used to analyze the primary outcome of treatment received, and secondary outcomes of clinical stage, overall survival, surgical approach (i.e., TORS versus other), and 30-day surgical readmissions. RESULTS: 17,207 patients with HPV-positive OPSCC were evenly distributed into four quartiles. Compared to patients in quartile 1, patients in quartile 4 were 40 % less likely to receive radiation versus surgery (OR = 0.60; 95 % CI = 0.54-0.66). Among the patients who received surgery, quartile 4 had a higher odds of receiving TORS treatment compared to quartile 1 (4v1: OR = 2.38; 95 % CI = 2.05-2.77), quartile 2 (4v2: OR = 2.31, 95 % CI = 2.00-2.66), and quartile 3 (4v3: OR = 1.75; 95 % CI = 1.54-1.99). Quartile 4 had a decreased odds of mortality compared to Quartile 1 (4v1: OR = 0.87; 95 % CI = 0.79-0.97). There were no differences among the quartiles in presenting stage and 30-day readmissions. CONCLUSIONS: This study found that patients with furthest travel distance to facility were more often treated surgically over non-surgical management, with TORS over open surgery, and had better overall survival. These findings highlight potential disparities in access to care for patients with HPV-positive OPSCC.

Overall survival, disease-free survival and quality of life in patients affected by HPV mediated p16+ oropharyngeal squamous cell carcinoma treated with upfront trans-oral robotic surgery vs radiotherapy or chemoradiotherapy.

PURPOSE: Treatment de-intensification for p16 + oropharyngeal squamous cell carcinoma (OPSCC) is an area of active research to reduce the side effects and improve patients' quality of life (QoL). In this paper we evaluated the Overall Survival (OS), the Disease-Free Survival (DFS) and the QoL of patients affected by p16 + OPSCC according to their prognostic stage group (PSG) and different treatments. METHODS: Patients were selected retrospectively through our Electronic Tumor Board Database according to prespecified inclusion criteria. Basic data of eligible patients were recorded and analyzed. Then, OS and DFS were evaluated according to the PSG and the treatments performed. Patients alive completed three questionnaires: the QoL Questionnaire Core 30 (QLQ-C30), the QoL Questionnaire Head & Neck 43 (QLQ-HN43) and the MD Anderson Dysphagia Inventory (MDADI) questionnaire. RESULTS: Sixty-one patients were included in this study. Eight patients died from the disease and the remaining 53 patients completed the 3 questionnaires. Fifteen (25%) patients were treated with upfront surgery, 6 (10%) patients with definitive radiotherapy and 40 (65%) patients with concomitant chemoradiotherapy. Comparing the DFS and the OS of PSG I patients by the different treatments performed, no statistically significant difference was identified. Patients treated with upfront surgery showed better outcomes in some aspects of their QoL. CONCLUSION: For p16 + OPSCC PSG I patients, upfront surgery can be considered a valid alternative to radiotherapy or chemoradiotherapy while maintaining a comparable DFS and OS and giving patients better results in terms of specific aspects of their QoL.

A Scoping Review of Complementary and Alternative Medicine for Human Papillomavirus Infections and Cervical Dysplasia.

OBJECTIVE: The goal of this scoping review is to synthesize clinically relevant scientific literature on current complementary and alternative medications that address human papillomavirus (HPV) infections and cervical dysplasia. MATERIALS AND METHODS: A systematic search of published studies was performed December 2021 for the following concepts: human papilloma virus, cervical dysplasia, and complementary and alternative medicine (CAM). Relevant publications were identified by searching Ovid MEDLINE ALL, Embase, Cochrane Library, AMED, and MEDLINE databases, in addition to clinical trial databases. Data were extracted based on specific study selection criteria and analyzed by 3 authors independently using Covidence software. RESULTS: A total of 2324 studies were identified of which 56 met inclusion criteria. Treatment outcomes measured regression of HPV, improvement of cervical cytology, and/or regression of histopathology with varied definitions of success across all studies. The CAM therapies found to have the most clinical benefit and best supporting data via randomized control trials were topical mushroom ( Coriolus versicolor) gel, oral and topical selenium therapies, and oral indol-3-carbinol. Adverse events were reported in only 28/56 (50%) of included studies. CONCLUSIONS: The evidence for treating HPV and cervical dysplasia with CAM is of low quality because of lack of standardized, clinically relevant treatment outcomes, lack of standardization of products, and minimal reporting on adverse and long-term effects. Future large, randomized control trials are needed to further assess efficacy and safety of CAM therapies to address HPV and cervical dysplasia.

Insights into the role of complement regulatory proteins in HPV mediated cervical carcinogenesis.

The persistent infection of high-risk Human papillomavirus (HR-HPV) induced cervical cancer remains a challenge in women worldwide including India. Recent advances in cancer research have paved the way for advanced cancer treatment modalities including immunotherapy by manipulating the function or number of cytotoxic T cells. It is well established that anaphylatoxins like C3a and C5a of complement system influence tumor growth by evading apoptosis leading to progression of cancer. The role of the complement system, particularly the complement regulatory proteins (CRPs) which are important determinants of immune response play a crucial role in carcinogenesis. In a tumor microenvironment (TME) assisted suppression of immune effector cells may be achieved through CRPs. However, recent advances in pharmacogenomics including drug designing and combination of these approaches have provided a holistic understanding of signaling pathways and their crosstalk, to regulate cellular communications.This review describes the role of complement system; particularly CRPs in HPV induced cervical carcinogenesis which may be used for designing anti- HPV or cervical cancer therapeutics.

CRISPR/Cas9-HPV-liposome enhances antitumor immunity and treatment of HPV infection-associated cervical cancer.

Increasing evidence shows that human papillomavirus (HPV) E6/E7 deletion in cervical cancer cells may be related to the immunosuppressive tumor microenvironment and adverse reactions or resistance to immune checkpoint blockade. Here, we demonstrate that liposome delivery of CRISPR/cas9 can effectively knock out HPV, which, in turn, induces autophagy and triggers cell death-related immune activation by releasing damage-related molecular patterns. The results of in vivo experiments showed that HPV-targeting guide RNA-liposomes could promote CD8+ T cell infiltration in tumor tissues; enhance the expression of proinflammatory cytokines, such as interleukin-12, tumor necrosis factor-α, and interferon-γ, and reduce regulatory T cells and myeloid suppressor cells. The combination of HPV-targeting guide RNA-liposomes with immune checkpoint inhibitors and antiprogrammed death-1 antibodies produced highly effective antitumor effects. In addition, combination therapy induced immune memory in the cervical cancer model.

Cervical cancer treatment update: A Society of Gynecologic Oncology clinical practice statement.

Cervical cancer is the most commonly diagnosed gynecologic cancer worldwide. Although the incidence has declined with increased screening and higher uptake of human papillomavirus (HPV) vaccination in high-income countries, this disease remains the second highest cause of cancer mortality among women in low- and middle-income countries. In this clinical practice statement, we describe therapies for cervical cancer by treatment setting, as well as quality of life, financial toxicity, and disparities associated with this disease. In addition to chemotherapy and radiation, therapeutic strategies for cervical cancer include immune checkpoint blockade, antiangiogenics, and antibody-drug conjugates. Optimal treatment for recurrent cervical cancer remains an area of unmet need, necessitating further exploration of rational and innovative treatment approaches, including cell and immune-based therapies. Importantly, development of effective therapies for cervical cancer must incorporate strategies to ensure universal equitable access to HPV vaccination, screening, and treatment. Important consequences of the disease and treatment that impact quality of life must also be addressed. Patients with cervical cancer are at increased risk for financial toxicity, which can lead to downstream detrimental effects on physical, financial, and career outcomes. Underrepresentation of racial and ethnic minorities in gynecologic oncology clinical trials highlights the urgent need for collaborative and focused initiatives to bridge the significant divide and alleviate inequalities in the prevention and treatment of cervical cancer.

Evaluation and management of male genital tract infections in the setting of male infertility: an updated review.

PURPOSE OF REVIEW: Male infertility may be secondary to male genital tract infection (MGTI) in an estimated 15% of cases. In the absence of overt clinical signs, evaluation for MGTI beyond semen analysis is not well established. Therefore, we review the literature on the evaluation and management of MGTI in the setting of male infertility. RECENT FINDINGS: A set of international guidelines recommends semen culture and PCR testing, but the significance of positive results remains unclear. Clinical trials evaluating anti-inflammatory or antibiotic treatment report improvements in sperm parameters and leukocytospermia, but data on the effect on conception rates are lacking. Human papillomavirus (HPV) and the novel coronavirus (SARS-CoV-2) have been associated with poor semen parameters and decreased conception rates. SUMMARY: The finding of leukocytospermia on semen analysis prompts further evaluation for MGTI, including focused physical examination. The role of routine semen culture is controversial. Treatment options include anti-inflammatories; frequent ejaculation; and antibiotics, which should not be used in the absence of symptoms or microbiological infection. SARS-CoV-2 represents a subacute threat to fertility that should be screened for in the reproductive history along with HPV and other viruses.

De-Escalation Treatment for Human Papillomavirus-Related Oropharyngeal Cancer: Questions for Practical Consideration.

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC), which accounts for an increasing proportion of all head and neck cancers, represents a specific entity with distinct clinical and molecular characteristics. It is now firmly established that patients with HPV-positive oropharyngeal SCC have a significantly improved prognosis because this variant has exquisite radiosensitivity compared with HPV-negative oropharyngeal SCC; thus, it can be targeted with de-escalated approaches using reduced doses of radiation and/or chemotherapy. The overriding goal of de-escalation is to maintain the high cure and survival rates associated with traditional approaches while reducing the incidence of both short- and long-term toxicity. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, prospective studies have now been published demonstrating that de-escalated radiation can successfully maintain high rates of cure and preserve the quality of life for appropriately selected patients with this disease. However, these studies have been complicated by such factors as the relatively limited sample sizes, as well as the variability in treatment, inclusion criteria, and follow-up. How treatment paradigms will evolve, particularly in the era of precision medicine, is a provocative question and is the subject of this review.

Management of Recurrent HPV-Positive Oropharyngeal Squamous Cell Carcinoma: a Contemporary Review.

PURPOSE OF REVIEW: To review the impact of contemporary treatment strategies on salvage outcomes in patients with recurrent human papilloma virus-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC). RECENT FINDINGS: Secondary to HPV, changes in disease biology have impacted primary treatments and subsequent approaches to patients with recurrence. With treatment strategies more inclusive of upfront surgery, the characteristics of patients with recurrence HPV + OPSCC have been further redefined. Less invasive endoscopic surgical approaches such as transoral robotic surgery (TORS), and the continued refinement of conformal radiotherapy techniques, have improved treatment options for patients with recurrent HPV + OPSCC. Systemic treatment options have continued to expand including potentially effective immune-based therapies. Effective surveillance with systemic and oral biomarkers offers hope of earlier detection of recurrence. Management of patients with recurrent OPSCC remains difficult. Modest improvements in salvage treatment have been observed within the HPV + OPSCC cohort largely reflecting disease biology and improved treatment techniques.

Immunotherapy in HPV-Related Oropharyngeal Cancers.

OPINION STATEMENT: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) incidence has been increasing in recent decades. Treatment of the locally advanced HPV-related OPSCC includes a multidisciplinary approach. Immunotherapy with immune checkpoint inhibitors is used in the treatment of patients with recurrent/metastatic head and neck squamous cell carcinomas (HNSCC), including HPV-related OPSCC patients. There is increasing knowledge of the role of HPV in the tumor immune microenvironment. Therefore, HPV status of OPSCC plays an essential role in the design of immunotherapy clinical trials in both curative intent and metastatic settings. Moreover, HPV has become a potential therapeutic target, with vaccines and adoptive T-cell therapies being developed against HPV for the treatment of OPSCC. Several novel studies are designed to target HPV in combination with immune checkpoint inhibitors. Thus, HPV-related OPSCC remains a unique subgroup in the immunotherapy era.

Human papillomavirus independent status on pathologic response and outcomes in locally advanced cervical cancer managed with chemoradiotherapy followed by surgery.

OBJECTIVE: While human papillomavirus (HPV) has been shown to play a significant role in cervical cancer carcinogenesis (HPV associated cases), a considerable percentage of cervical cancers occur independently of HPV status (HPV independent). METHODS: In this retrospective study of 254 locally advanced cervical cancer patients treated with chemoradiotherapy and radical surgery, HPV genotypes were determined using the Anyplex II HPV28 kit that uses multiplex, real time polymerase chain reaction technology. The primary endpoints of this study were to evaluate the complete response to chemoradiotherapy (pathologic complete response), the presence of microscopic (<3 mm, pathologic micro partial response, group 1) and macroscopic (>3 mm, pathologic macro partial response, group 2) residual carcinoma in the cervix, and the persistence of metastatic lymph nodes (group 3) in HPV independent cervical cancers. Secondary endpoints were evaluation of disease-free survival and overall survival. RESULTS: Of 254 patients studied, 21 cases (8.3%) of cervical cancer were determined to be HPV independent. The percentage of pathologic complete response was found to be higher in the HPV associated group compared with the HPV independent group (p<0.001). In the HPV associated cervical cancer group, 5 year disease free survival was found to be 80.8% versus 59.9% in the HPV independent group (p=0.014). Overall survival was also higher in the HPV associated group (87.9%) compared with the HPV independent patients (69.4%) (p=0.023). In the multivariate analysis, the International Federation of Gynecology and Obstetrics (FIGO) stage and HPV genotypes maintained their relevant impact on pathologic complete response to chemoradiotherapy: FIGO stages IIIC1 and IIIC2 were associated with a 13-fold increased risk for the presence of metastatic lymph nodes compared with group 1 (p<0.001). HPV independent cervical cancers showed the highest risk for the development of macroscopic/stable disease (p=0.007), and persistence of metastatic lymph nodes (p=0.004) versus group 1, respectively. CONCLUSIONS: This study showed that HPV status at diagnosis could be a relevant factor for clinical outcomes in locally advanced cervical cancer patients.

The significance of nonsurgical therapies for cervical infection of high-risk human papilloma virus: A systematic review and meta-analysis.

OBJECTIVE: To assess whether nonsurgical therapies were related with clearance of cervical infection of high-risk human papilloma virus (hr-HPV) or regression of mild abnormal cytology related with hr-HPV. METHODS: Until March 2023, we identified a total of 10 424 women with cervical infection of hr-HPV and 1966 women with mild abnormal cytology related with hr-HPV from 44 studies that met the inclusion criteria. RESULTS: After systematically retrieving literature, we identified 2317 citations and 44 randomized controlled studies (RCT) were enrolled. Cumulative results suggested women with cervical infection of hr-HPV might benefit from nonsurgical therapies. Both the clearance of hr-HPV (OR: 3.83, I2 = 99%, p < 0.00001) and regression of mild abnormal cytology related with hr-HPV (OR: 3.12, I2 = 63%, p < 0.00001) were significantly higher than control group. Subgroup analysis stratified by systematic therapy, topical therapy, traditional Chinese medicines (TCMs), and presistent hr-HPV got consistent results. There was substantial heterogeneity between trials (I2 = 87% for clearance of hr-HPV and 63% for regression of cytology), sensitivity analysis was performed by excluding single study one by one, and found the cumulative results were stable and dependable. Both the funnel plots for clearance of hr-HPV and regression of abnormal cytology were asymmetrical, significant publication bias might exist. CONCLUSION: Nonsurgical therapies might benefit women who had a cervical infection of hr-HPV with/without mild abnormal cytology related with hr-HPV. Both the clearance of hr-HPV and regression of abnormal cytology were significantly higher than control group. More studies with less heterogeneity were needed urgently to draw concrete conclusion.

Comparison of different treatments for HPV+ oropharyngeal carcinoma: a network meta-analysis.

INTRODUCTION: Treatment of human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is rapidly evolving. Despite either surgery or radiotherapy (RT), with or without chemotherapy (CT), being acceptable in intermediate and locally advanced diseases, there is uncertainty regarding the best treatment option for these patients. Therefore, we performed a network meta-analysis (NMA) to compare the relative efficacy of different treatments for HPV+ oropharyngeal carcinoma. MATERIAL AND METHODS: Randomized clinical trials that enrolled adults with non-metastatic HPV+ oropharynx cancer and provided data about overall survival (OS) and/or progression-free survival (PFS) and/or locoregional control and distant metastases (LRC and DM) were included. Fixed- or random-effects models were fit using a Bayesian approach to NMA. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (CrIs). The primary outcome was OS. RESULTS: A total of 844 citations were screened; 11 randomized clinical trials were included (HPV+ stage III-IV cancer, mainly oropharynx carcinomas). Nine treatment arms were compared. Radiotherapy (altered or standard fractionation) + triweekly cisplatin (HR 3.8; 95% CrIs 0.29-65 and 0.3; 95% CrIs 0.03-2.51) was superior to RT in term of OS (P score = 0.42 and 0.16). Radiotherapy with low and high cisplatin doses appeared similar (HR 1.57; 95% CrIs 0.19-12.72). Altered fractionation or standard RT + 3-weekly cisplatin are the 2 highest-ranked options in terms of PFS (P score = 0.35 and 0.34). CONCLUSIONS: This meta-analysis confirms the role of cisplatin added to RT as the best option for HPV+ oropharyngeal carcinoma. RT+ 3-weekly cisplatin is likely to be the best radical treatment in terms of OS and PFS.

Post-therapeutic surveillance of HPV-driven oropharyngeal cancers: are we ready to change our practices?

PURPOSE: Although HPV-positive and negative oropharyngeal cancers are two distinct diseases, Post-Therapeutic Surveillance (PTS) modalities are similar. Adjusting PTS strategies to HPV status will represent a massive practice change that raises the issue of its acceptability, by both physicians and patients. METHODS: Two distinct surveys were designed and submitted, respectively, to HPV-positive patients and physicians (surgeons, radiation and medical oncologists) involved in head and neck cancer treatment. RESULTS: 133 patients and 90 physicians have participated to the study. Most patients were reluctant to embrace new PTS options (remote consultations, nurse consultations and smart phone applications). However, 84% of patients would be favorable to use HPV Circulating DNA (HPV Ct DNA) measurement to guide surveillance modalities. 57% of physicians acknowledged that our current PTS strategy is improvable and most of them would accept the use of new monitoring options from the third year of follow-up. 87% of physicians would be interested to participate to a trial comparing the current PTS strategy to a new approach, where monitoring modalities (number of visits, imaging prescription) would depend on HPV Ct DNA level. CONCLUSIONS: Patients and physicians are aware that PTS modalities should depend on HPV status. Their adhesion is a prerequisite to any potential changes. Strategies based on HPV Ct DNA measurement should be assessed within a randomized clinical trial.

Concurrent immunoradiation for HPV-associated oropharyngeal squamous cell carcinoma.

OBJECTIVES: Current trials for HPV-associated oropharyngeal SCCs (OP-SCCs) are evaluating treatment de-escalation including use of concurrent immunotherapy with radiation therapy (I-RT). Given limited prospective data following I-RT, we aimed to examine this question utilizing the National Cancer Data Base (NCDB). METHODS: The NCDB was queried for patients with HPV-associated OP-SCCs eligible for current de-escalation studies with AJCC 7th edition T1-T2/N1-N2b and T3/N0-N2b disease. Patients were stratified into I-RT, concurrent chemoradiation (C-RT), and radiation therapy alone (RT) arms. Kaplan-Meier analysis was utilized to compare overall survival (OS) between treatment arms followed by a Cox multivariate (MVA) proportional hazards model controlling for tumor and patient characteristics and propensity-score analyses with inverse probability treatment weighting (IPTW). RESULTS: We identified 4768 patients; 313 received I-RT, 3660 patients received C-RT, and 795 received RT. Median age was 62 years (range 27-90) with a median Charlson-Deyo co-morbidity score of 0 (range: 0-3). The vast majority were cN1-N2a (88.8%) and 26.5% were cT3. On MVA, inferior 3-year and 8-year OS was noted following I-RT (81.6% and 70.5%) vs. C-RT (90.6% and 79.4%) (HR = 1.69 (95% CI: 1.29-2.21); p < 0.0001) with no significant difference vs. RT (88.1% and 75.8%) (HR = 1.07; p = 0.80). This was also maintained on IPTW-analysis (HR = 1.62 (95% CI: 1.23-2.15); p = 0.001). CONCLUSIONS: I-RT was associated with significantly poorer OS vs. C-RT with no benefit compared to RT for HPV-associated OP-SCCs. I-RT is not recommended outside of currently accruing clinical trials.