Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma: NRG Oncology/GOG Study 279.

PURPOSE: To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery. METHODS: Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m2 and G 50 mg/m2 were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0. RESULTS: Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment. CONCLUSION: Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.

Computational and AI-driven 3D structural analysis of human papillomavirus (HPV) oncoproteins E5, E6, and E7 reveal significant divergence of HPV E5 between low-risk and high-risk genotypes.

There are over 220 identified genotypes of Human papillomavirus (HPV), and the HPV genome encodes 3 major oncogenes, E5, E6, and E7. Conservation and divergence in protein sequence and function between low-risk versus high-risk oncogenic HPV genotypes has not been fully characterized. Here, we used modern computational and structural folding algorithms to perform a comparative analysis of HPV E5, E6, and E7 between multiple low risk and high risk genotypes. We first identified significantly greater sequence divergence in E5 between low- and high-risk genotypes compared to E6 and E7. Next, we used AlphaFold to model the structure of papillomavirus proteins and complexes with high confidence, including some with no established consensus structure. We observed that HPV E5, but not E6 or E7, had a dramatically different 3D structure between low-risk and high-risk genotypes. To our knowledge, this is the first comparative analysis of HPV proteins using Alphafold artificial intelligence (AI) system. The marked differences in E5 sequence and structure in high-risk HPVs may contribute in important and underappreciated ways to the development of HPV-associated cancers.

Examining the Effect of Direct Patient Care for Medical Physicists: A Randomized Prospective Phase III Trial.

PURPOSE: Our purpose was to investigate the effect of physicist-patient consults on patient anxiety and patient satisfaction with a randomized prospective phase III clinical trial. METHODS AND MATERIALS: Sixty-six patients were randomly assigned to the physics direct patient care (PDPC) arm or the control arm of the trial. Patients assigned to the PDPC arm received 2 physicist-patient consults to educate them on the technical aspects of their radiation therapy, while patients assigned to the control arm received the standard of care (ie, standard radiation therapy workflow without any additional physicist-patient consults). Questionnaires were administered to all patients at 4 time points (after enrollment, after the simulation, after the first treatment, and after the last treatment) to assess anxiety and satisfaction. RESULTS: The decrease in anxiety for the PDPC arm, compared with the control arm, was statistically significant at the first treatment (P = .027) time point. The increase in technical satisfaction for the PDPC arm, compared with the control arm, was statistically significant at the simulation (P = .005), first treatment (P < .001), and last treatment (P = .002) time points. The increase in overall satisfaction for the PDPC arm, compared with the control arm, was statistically significant at the first treatment (P = .014) and last treatment (P = .001) time points. CONCLUSIONS: Physicist-patient consults improved the patient experience by decreasing anxiety and increasing satisfaction. Future work is needed to modify current radiation oncology workflows and medical physics responsibilities to allow all patients to benefit from this advancement in patient care.

Incomplete cisplatin regimens in chemoradiation and its effect on outcomes for locally advanced cervical cancer.

OBJECTIVE: To identify factors associated with receipt of incomplete cisplatin during chemoradiation for locally advanced cervical cancer and its impact on outcomes. METHODS: Patients with locally advanced cervical cancer treated with chemoradiation at our institution between November 2015 and August 2020 were retrospectively identified. Patients who received ≤4 cycles were identified as the 'incomplete' cohort and those who received 5-6 cycles as the 'complete' cohort. The primary endpoint of incomplete chemotherapy was evaluated with multivariable logistic regression. Secondary endpoints of locoregional failure, overall survival, and distant failure were evaluated in multivariable Cox and Fine-Gray models. RESULTS: Of 140 patients with locally advanced cervical cancer that underwent chemoradiation, 22 (15.7%) received an incomplete cisplatin regimen (8 with 0 cycles, 14 with 1-4 cycles). The most common reasons for receiving incomplete treatment were comorbidities/infections (41%), unmet laboratory parameters (27%), and cisplatin intolerance (14%). In multivariable models, only poor (2-4) Eastern Cooperative Oncology Group performance status was a significant predictor as these patients were 41 times more likely to receive incomplete chemotherapy (odds ratio (OR), 95% confidence interval (CI) 4.57 to 375.15, p<0.001). Median follow-up time was 20 months (range 4-64). In multivariable models, receipt of incomplete cisplatin was significantly associated with higher recurrence (locoregional failure hazard ratio (HR) 3.02, 95% CI 1.08 to 8.45, p=0.03; distant failure HR 2.71, 95% CI 1.13 to 6.47, p=0.02) and worse survival (overall survival HR 4.91, 95% CI 1.27 to 18.98, p=0.02). CONCLUSION: Incomplete cisplatin regimen was associated with worse oncologic outcomes. Poor performance status was the only factor associated with receiving an incomplete regimen. This notable proportion of patients may be a target for better tolerated novel targeted anticancer agents in order to improve outcomes.

Improved survival in cervical cancer patients receiving care at National Cancer Institute-designated cancer centers.

BACKGROUND: Locally advanced cervical cancer (CC) remains lethal in the United States. We investigate the effect of receiving care at an National Cancer Institute-designated cancer center (NCICC) on survival. METHODS: Data for women diagnosed with CC from 2004 to 2016 who received radiation treatment were extracted from the California Cancer Registry (n = 4250). Cox proportional hazards regression models assessed whether (1) receiving care at NCICCs was associated with risk of CC-specific death, (2) this association remained after multivariable adjustment for age, race/ethnicity, and insurance status, and (3) this association was explained by receipt of guideline-concordant treatment. RESULTS: Median age was 50 years (interquartile range [IQR] 41-61 years), with median follow-up of 2.7 years (IQR 1.3-6.0 years). One-third of patients were seen at an NCICC, and 29% died of CC. The hazard of CC-specific death was reduced by 20% for those receiving care at NCICCs compared with patients receiving care elsewhere (HR = .80; 95% CI, 0.70-0.90). Adjustment for guideline-concordant treatment and other covariates minimally attenuated the association to 0.83 (95% CI, 0.74-0.95), suggesting that the survival advantage associated with care at NCICCs may not be due to receipt of guideline-concordant treatment. CONCLUSIONS: This study demonstrates survival benefit for patients receiving care at NCICCs compared with those receiving care elsewhere that is not explained by differences in guideline-concordant care. Structural, organizational, or provider characteristics and differences in patients receiving care at centers with and without NCI designation could explain observed associations. Further understanding of these factors will promote equality across oncology care facilities and survival equity for patients with CC.

Disparities in time to start of definitive radiation treatment for patients with locally advanced cervical cancer.

BACKGROUND: Chemoradiation or radiation therapy alone are curative standards for patients with locally advanced cervical cancer. OBJECTIVE: To investigate factors that influence time to initiation of chemoradiation or radiation and the subsequent impact of time to treatment on recurrence and survival outcomes. METHODS: Patients with locally advanced cervical cancer treated with definitive chemoradiation or radiation at our institution between November 2015 and August 2020 were retrospectively identified. Time to treatment initiation was defined as the number of days from date of diagnosis (via biopsy) to the start date of radiation. The cohort was stratified by the median time to treatment into early (<75 days) and delayed (≥75 days) cohorts. Multivariable logistic regression was conducted to examine factors associated with delayed time to treatment. RESULTS: We identified 143 patients with locally advanced cervical cancer who underwent definitive chemoradiation or radiation. Median follow-up time was 18 months (range 2-62). A total of 71 (49.7%) patients had time to treatment <75 days and 72 (50.3%) patients had time to treatment ≥75 days. The delayed cohort had a higher proportion of Hispanic patients (51.4% vs 31.0%, p=0.04). In multivariable modeling, Hispanic women were 2.71 times more likely (p=0.04) to undergo delayed time to treatment than non-Hispanic white women. Additionally, patients with stage >IIB disease were less likely to undergo delayed time to treatment (OR 0.26, p=0.02) than patients with stage

Global challenges of radiotherapy for the treatment of locally advanced cervical cancer.

Cervical cancer represents a significant portion of the global cancer burden for women, with low- and middle-income countries carrying the bulk of this burden. Additionally, underserved populations in countries with sufficient resources may have a higher incidence of cervical cancer and poorer outcomes. Concurrent chemoradiotherapy is the standard-of-care treatment for locally advanced cervical cancer, which includes patients with stage IB3 to IVA disease, and it is effective for many patients; however, cervical cancer-related mortality remains high. The critical nature of cervical cancer treatment is underscored by the recent launch of the World Health Organization global initiative to accelerate the elimination of cervical cancer using a triple-intervention strategy of increased vaccination, screening, and treatment. The initiative calls for 90% of all patients diagnosed with cervical cancer to receive the appropriate treatment, but to reach this global goal there are significant barriers related to radiotherapy that must be addressed. We discuss and review evidence of the lack of adherence to guideline-recommended treatment, brachytherapy underutilization, limited access to radiotherapy in low- and middle-income countries, as well as regional limitations within high-income countries, as the major barriers to radiotherapy treatment for locally advanced cervical cancer. We further review ways these barriers are currently being addressed and, in some cases, make additional recommendations to address these issues. Finally, despite receiving recommended treatments, many patients with locally advanced cervical cancer have a poor prognosis. With effective administration of current standards of care, the global community will be able to shift focus to advancing treatment efficacy for these patients. We review several types of therapies under clinical investigation that are additions to concurrent chemoradiotherapy, including immune checkpoint inhibitors, antiangiogenic agents, DNA repair inhibitors, human papillomavirus vaccines, and radiosensitizing nanoparticles.

Immunotherapy and radiation therapy sequencing: State of the data on timing, efficacy, and safety.

Radiation therapy exerts a tumoricidal local effect as well as both local and systemic immunomodulation. Immune checkpoint blockade has become a widely used treatment modality across cancer types with a rapidly growing list of agents and US Food and Drug Administration-approved indications. Moreover, there may be synergy between radiation therapy and immune checkpoint blockade. Various strategies have been used, but the optimal sequencing of these therapies is unclear. In this review, the authors discuss the major mechanisms of available immune checkpoint inhibitors and explore the available preclinical and clinical evidence regarding treatment sequencing. They also review safety considerations and conclude with possible future directions.

Brachytherapy utilization for cervical cancer in Western United States border counties: seeking to understand referral patterns for outcome improvement.

PURPOSE: Standard of care for definitive treatment of locally advanced cervical cancer (LACC) is concurrent chemoradiation followed by a brachytherapy boost. Only 55.8% of women in the United States receive brachytherapy, with even lower proportions in San Diego and Imperial Counties. The purpose of this study was to investigate brachytherapy practice and referral patterns in Western United States border region. MATERIAL AND METHODS: A short survey was sent to 28 radiation oncologists in San Diego and Imperial Counties, who treat patients with gynecologic malignancies. Descriptive statistics were used for analysis. RESULTS: Seventeen (61%) physicians responded to the survey. All physicians reported some training in cervical cancer brachytherapy during residency, with median 6 months. Only two physicians reported personally treating all cervical cancer patients with brachytherapy; however, 92% of remaining physicians would recommend brachytherapy for patients if given time and access. The most common reason for referral (78%) was patients deemed to require hybrid or interstitial brachytherapy implants. Barriers to referral included patients' preference, insurance status, their resources, or logistics. No changes were reported for brachytherapy practices during the COVID-19 pandemic, except the addition of pre-procedural testing for SARS-CoV-2. Ninety-two percent of physicians identified inadequate maintenance of skills as a barrier to performing brachytherapy, but 77% were not interested in additional training. External beam radiation therapy boosts were rarely recommended in case scenarios describing potentially curable patients. CONCLUSIONS: The importance of brachytherapy is widely recognized for conferring a survival benefit, but barriers to implementation include inadequate training or maintenance of skills, and larger systematic issues related to reimbursement policy, social support, and financial hardship. As most established providers were uninterested in additional brachytherapy training, future approaches to improve patients' access should be multidimensional and reflect the value of brachytherapy in definitive treatment of patients with LACC.

Current Status of Clinical Trials for Cervical and Uterine Cancer Using Immunotherapy Combined With Radiation.

Novel therapies combined with radiation continue to be of significant interest in the developmental treatment paradigm of gynecologic cancers. Clinical implementation of immunotherapy in oncology has rapidly changed the treatment landscape, options, paradigm, and outcomes through clinical trials. Immunotherapy has emerged as a therapeutic pillar in the treatment of solid tumors with demonstrable synergistic activity when combined with radiation therapy and chemoradiotherapy by an alteration or enhancement of the immune system. In solid tumors, radiation therapy induces migration of dendritic cells, T cell activation, and proliferation, and increases in tumor-infiltrating lymphocytes. These immunomodulatory effects in conjunction with immune checkpoint blockade are currently under active investigation in the adjuvant, definitive, and metastatic settings. Results from early phase trials demonstrate promising efficacy and overall tolerable toxicity profiles of combined modality treatment. There is significant interest in optimizing the treatment for patients with locally advanced cervical cancer beyond the standard of care-chemoradiation-which has been in place for the last 30 years. The majority of cervical cancer emerges after persistent infection with a high-risk subtype of the human papillomavirus, where viral oncoproteins lead to cellular changes and immortalization. As a result, immune tolerance can develop, resulting in cancer. Knowledge of the mechanism of human papillomavirus-related oncogenesis suggests that immune therapy or checkpoint blockade can reinvigorate an antitumor immune response. Current clinical trials are exploring the therapeutic potential of these approaches. Uterine cancers have been grouped into 4 molecular subclasses by their driver mutations, mutational burden, and copy-number alterations. Of these subgroups, the polymerase epsilon-mutated and microsatellite-unstable may represent up to 40% of endometrial cancers, and they have been shown to be immunogenic. Because of the inherent immunogenicity of these MSI-high tumors, combined immune modulation strategies, including chemotherapy, radiation, and immunotherapy and immune checkpoint inhibitor therapy, are being explored to improve treatment outcomes. In this review, we explore current immunomodulatory and multimodality therapeutic approaches in the treatment of cervical and uterine cancer through ongoing clinical trials investigating the combination of immunotherapy and radiation therapy.

Immunotherapy With Radiotherapy and Chemoradiotherapy for Cervical Cancer.

Outcomes for women with node-positive, recurrent, and metastatic cervical cancer remain poor. Persistent infection by the human papilloma virus is related to disordered interactions with the immune system and development of cervical cancer, making the resultant malignancy an attractive target for immunotherapy. Various types of immunomodulatory treatments have been studied, including a bacterial vaccine vector and T cell therapy. Immune checkpoint blockade has shown promise in the recurrent or metastatic settings, and in combination with chemoradiotherapy for definitive treatment with acceptable toxicity profiles. Ongoing trials are investigating timing, dosing, and combinations of immunomodulatory treatments, with potential to improve survival and advance our understanding of the immune system's role in combating cervical cancer.

Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929).

PURPOSE: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti-CTL antigen-4 (anti-CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment. PATIENTS AND METHODS: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot. RESULTS: Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival. CONCLUSIONS: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

Radiation Therapy for Cervical Cancer: Executive Summary of an ASTRO Clinical Practice Guideline.

PURPOSE: This guideline reviews the evidence and provides recommendations for the indications and appropriate techniques of radiation therapy (RT) in the treatment of nonmetastatic cervical cancer. METHODS: The American Society for Radiation Oncology convened a task force to address 5 key questions focused on the use of RT in definitive and postoperative management of cervical cancer. These questions included the indications for postoperative and definitive RT, the use of chemotherapy in sequence or concurrent with RT, the use of intensity modulated radiation therapy (IMRT), and the indications and techniques of brachytherapy. 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: The guideline recommends postoperative RT for those with intermediate risk factors, and chemoradiation for those with high-risk factors. In the definitive setting, chemoradiation is recommended for stages IB3-IVA, and RT or chemoradiation is conditionally recommended for stages IA1-IB2 if medically inoperable. IMRT is recommended for postoperative RT and conditionally recommended for definitive RT, for the purposes of reducing acute and late toxicity. Brachytherapy is strongly recommended for all women receiving definitive RT, and several recommendations are made for target dose and fractionation, the use of intraoperative imaging, volume-based planning, and recommendations for doses limits for organs at risk. CONCLUSIONS: There is strong evidence supporting the use of RT with or without chemotherapy in both definitive and postoperative settings. Brachytherapy is an essential part of definitive management and volumetric planning is recommended. IMRT may be used for the reduction of acute and late toxicity. The use of radiation remains an essential component for women with cervical cancer to achieve cure.

COVID-19 impact on timing of brachytherapy treatment and strategies for risk mitigation.

PURPOSE: The purpose of this study was to highlight the importance of timely brachytherapy treatment for patients with gynecologic, breast, and prostate malignancies, and provide a framework for brachytherapy clinical practice and management in response to the COVID-19 pandemic. METHODS AND MATERIALS: We review amassing evidence to help guide the management and timing of brachytherapy for gynecologic, breast, and prostate cancers. Where concrete data could not be found, peer-reviewed expert opinion is provided. RESULTS: There may be a significant negative impact on oncologic outcomes for patients with gynecologic malignancies who have a delay in the timely completion of therapy. Delay of prostate or breast cancer treatment may also impact oncologic outcomes. If a treatment delay is expected, endocrine therapy may be an appropriate temporizing measure before delivery of radiation therapy. The use of shorter brachytherapy fractionation schedules will help minimize patient exposure and conserve resources. CONCLUSIONS: Brachytherapy remains a critical treatment for patients and may shorten treatment time and exposure for some. Reduced patient exposure and resource utilization is important during COVID-19. Every effort should be made to ensure timely brachytherapy delivery for patients with gynecologic malignancies, and endocrine therapy may help temporize treatment delays for breast and prostate cancer patients. Physicians should continue to follow developing institutional, state, and federal guidelines/recommendations as challenges in delivering care during COVID-19 will continue to evolve.

Clinical feasibility of MR-assisted CT-based cervical brachytherapy using MR-to-CT deformable image registration.

PURPOSE: The purpose of this study is to evaluate the feasibility of using deformable image registration algorithms to improve high-dose-rate high-risk clinical target volume (HR-CTV) delineation between preapplicator implantation MRI (pre-MRI) and postapplicator implantation CT (post-CT) in the treatment of locally advanced cervical cancer (LACC). METHOD AND MATERIALS: Twenty-six patients were identified for the study. Regions of interest were segmented on MRI and CT. A HR-CTV was delineated on pre-MRI and compared with the previously contoured HR-CTV on the post-CT. Two commercially available algorithms, ANACONDA (anatomically constrained) and MORFEUS (biomechanical model based) with various controlling structure settings, including the cervix, uterus, etc., were used to deform pre-MRI to post-CT. MRI-to-CT deformed targets are denoted as HR-CTV'. Quantitative deformation metrics include Dice index, distance to agreement, and center of mass displacement. Qualitative clinical usefulness of deformations was scored based on HR-CTV identification on CT images. RESULTS: For ANACONDA and MORFEUS deformations, using a cervix controlling region of interest resulted in the highest Dice, lowest distance to agreement, and lowest center of mass displacement for HR-CTV'. With MORFEUS deformations, the deformed HR-CTV' proved clinically useful in 23 patients. CONCLUSIONS: Prebrachytherapy implantation MRI can aid target contours for CT-based brachytherapy through ANACONDA or MORFEUS algorithms with appropriate parameter selection for LACC patients.