Seminars in Radiation Oncology

The Cost-Effectiveness and Value Proposition of Brachytherapy

Brachytherapy is an effective treatment modality for a wide range of malignancies. However, brachytherapy utilization for both prostate and gynecologic malignancies has significantly declined over the last 20 years in favor of external beam radiation techniques. The cause of this decline is multifactorial, with logistical challenges, lower reimbursement, and inadequate training contributing to the preference of many radiation oncologists to more frequently recommend external beam radiation therapy. While the authors recognize the application of brachytherapy to a wider range of disease presentations among which include breast, skin, head and neck, and connective tissue cancers, in this review, we will review the analyses supporting brachytherapy as a cost-effective component of the management in patients with prostate, cervix, and endometrial cancer.

Prevention and Screening of HPV Malignancies

It is estimated that 5% of the global cancer burden, or approximately 690,000 cancer cases annually, is attributable to human papillomavirus (HPV). Primary prevention through prophylactic vaccination is the best option for reducing the burden of HPV-related cancers. Most high-income countries (HICs) have introduced the HPV vaccine and are routinely vaccinating adolescent boys and girls. Unfortunately, although they suffer the greatest morbidity and mortality due to HPV-related cancers, many lower- and middle-income countries (LMICs) have been unable to initiate and sustain vaccination programs. Secondary prevention in the form of screening has led to substantial declines in cervical cancer incidence in areas with established screening programs, but LMICs with absent or inadequate screening programs have high incidence rates. Meanwhile, HICs have seen incidence rates of anal and oropharyngeal cancers rise owing to the limited availability of organized screening for anal cancer and no validated screening options for oropharyngeal cancer. The implementation of screening programs for individuals at high risk of these cancers has the potential to reduce the burden of cervical cancer in LMICs, of anal and oropharyngeal cancers in HICs, and of anal cancer for highly selected HIV+ populations in LMICs. This review will discuss primary prevention of HPV-related cancers through vaccination and secondary prevention through screening of cervical, anal, and oropharyngeal cancers. Areas of concern and highlights of successes already achieved are included.

Why De-Intensification is not Possible in HPV-Associated Cervical Cancer

Prognostic and Predictive Clinical and Biological Factors in HPV Malignancies

Human papillomavirus (HPV) causes the majority of oropharyngeal, cervical, and anal cancers, among others. These HPV-associated cancers cause substantial morbidity and mortality despite ongoing vaccination efforts. Aside from the earliest stage tumors, chemoradiation is used to treat most HPV-associated cancers across disease sites. Response rates are variable, and opportunities to improve oncologic control and reduce toxicity remain. HPV malignancies share multiple commonalities in oncogenesis and tumor biology that may inform personalized methods of screening, diagnosis, treatment and surveillance. In this review we discuss the current literature and identify promising molecular targets, prognostic and predictive clinical factors and biomarkers in HPV-associated oropharyngeal, cervical and anal cancer.

Epidemiology of HPV Related Malignancies

Human papillomavirus is the most common sexually transmitted infection in the world and had been linked to both anogenital and oropharyngeal cancers. It causes nearly 100% of cervical cancers and an increasing portion of oropharyngeal cancers. The geographical burden of cervical HPV infection and associated cancers is not uniform and is mainly found in low middle income countries in South America, Africa, and Asia. However, HPV-positive oropharyngeal cancer is rapidly becoming more prevalent in high middle income countries. With the development of vaccines which prevent HPV infection, the World Health Organization has designated the extirpation of HPV and its associated cancers a priority. Countries that have implemented adequate vaccine programs have shown a decrease in HPV prevalence. Understanding the epidemiology of HPV and its associated cancers is fundamental in improving vaccine programs and other health programs.

Novel Radiosensitization Strategies in Uterine Cervix Cancer

The clinical, molecular, and genetic heterogeneity of uterine cervix cancers makes the discovery of effective therapies a challenge. Optimal evaluation of effective radiotherapy-agent combinations requires sophisticated trial strategies from the United States National Cancer Institute and its pharmaceutical collaborators. One strategy involves the phase 0 trial, which falls under the United States Food and Drug Administration Exploratory Investigational New Drug Guidance, or xIND. As currently envisioned for radiotherapy-based trials, the phase 0 trial provides a platform for study of pharmacodynamic effects linked to pharmacokinetic exposures, designed to screen a new experimental agent's dose or schedule, in combination with standard radiotherapy regimens, in a very small number (10-15) of subjects. In the phase 0 trial, radiotherapy-agent combinations are intended to be biologically active, but a new experimental agent's low dose or infrequent schedule is considered nontoxic and nonbeneficial. The phase 0 trial primary endpoint is an individual subject's pharmacodynamic response. Regimens move on from phase 0 trial development if and when a predetermined all-subject pharmacodynamic response rate is crossed. An initial safety experience during and after the radiotherapy-agent combination determines future feasibility. For this article, the clinical example of women with abdominopelvic lymph node-positive uterine cervix cancer is used to elaborate the phase 0 trial approach to the discovery of novel radiosensitizing oncological agents. It is expected that phase 0 radiotherapy-agent trials will become more prevalent in near-term clinical development.

Meeting the Global Need for Radiation Therapy in Cervical Cancer—An Overview

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women. The discrepancy in cervical cancer incidence and mortality between developed and developing nations has become increasingly apparent with 84% of the incidence and 88% of the mortality of cervical cancer occurring in low income countries. Access to comprehensive cancer care is a challenge and in particular the radiotherapy facilities. The radiotherapy infrastructure requirement is grossly inadequate with only 30% of the needs available and is even worst in LIC's with only 3% facilities. Additionally, lack of brachytherapy facilities and expertise in LIC's and LMIC's compounds the issue further. Even with continued HPV vaccination programs, there will still be a substantial burden of cervical cancer patients for treatment. Introspection and review in international and national policies, augmentation of (i) infrastructure - affordable & sustainable, (ii) manpower and rigorous training in accessible regions would be vital. International and National collaborative efforts among global organizations and societies, periodic peer reviews, resource stratified treatment guidelines and research, and health education would contribute further to women health. The amalgamation of palliative and hospice care services and radiotherapy facilities seamlessly would be a major step for comprehensive management of cervical cancer patients.

Automated Radiation Treatment Planning for Cervical Cancer

The radiation treatment-planning process includes contouring, planning, and reviewing the final plan, and each component requires substantial time and effort from multiple experts. Automation of treatment planning can save time and reduce the cost of radiation treatment, and potentially provides more consistent and better quality plans. With the recent breakthroughs in computer hardware and artificial intelligence technology, automation methods for radiation treatment planning have achieved a clinically acceptable level of performance in general. At the same time, the automation process should be developed and evaluated independently for different disease sites and treatment techniques as they are unique from each other. In this article, we will discuss the current status of automated radiation treatment planning for cervical cancer for simple and complex plans and corresponding automated quality assurance methods. Furthermore, we will introduce Radiation Planning Assistant, a web-based system designed to fully automate treatment planning for cervical cancer and other treatment sites.

Aiming for 100% Local Control in Locally Advanced Cervical Cancer: The Role of Complex Brachytherapy Applicators and Intraprocedural Imaging

The use of brachytherapy for the treatment of gynecologic malignancies, particularly cervical cancer, has a long and rich history that is nearly as long as the history of radiation oncology itself. From the first gynecologic brachytherapy treatments in the early 20th century to the modern era, significant transformation has occurred driven largely by advancements in technology. The development of high-dose rate sources, remote afterloaders, novel applicators, and 3-dimensional image guidance has led to improved local control, and thus improved survival, solidifying the role of brachytherapy as an integral component in the treatment of locally advanced cervical cancer. Current research efforts examining novel magnetic resonance imaging sequences, active magnetic resonance tracking, and the application of hydrogel aim to further improve local control and reduce treatment toxicity.

Introduction: Cervical Cancer

Intensified Systemic Therapy Regimens in Combination With Definitive Radiation for Treatment of Cervical Cancer

Definitive standard chemoradiation for locoregionally advanced carcinomas of the uterine cervix includes multimodality therapy consisting of concurrent cisplatin based chemoradiation comprising of external-beam radiotherapy with systemic chemotherapy followed by intracavitary brachytherapy. New developments in radiotherapy, such as intensity-modulated radiotherapy, which aim to improve tumor control rates and reduce associated toxicity have reopened the discussion regarding the benefit of intensification of concomitant or sequential systemic therapy in the treatment of cervical cancer. Intensification of systemic chemotherapy used in standard chemoradiation for cervical cancer is an attractive approach to improve disease control, but given the concerns regarding toxicity deserves further evaluation to ensure their safe use in patients. This is a review of published and ongoing studies investigating intensification of systemic chemotherapy in the treatment of locally advanced cervical cancer.

Knowledge-Based Planning for Intact Cervical Cancer

Cervical cancer radiotherapy is often complicated by significant variability in the quality and consistency of treatment plans. Knowledge-based planning (KBP), which utilizes prior patient data to correlated achievable optimal dosimetry with patient-specific anatomy, has demonstrated promise as a quality control tool for controlling this variability, with consequences for patient outcomes, as well as for the reliability of data from multi-institutional clinical trials. In this article we highlight the application of KBP-based quality control to cervical cancer radiotherapy. We discuss the potential impact of KBP on multi-institutional clinical trials to standardize cervical cancer treatment planning across diverse clinics, and discuss challenges and progress in the implementation of KBP for brachytherapy treatment planning. Additionally, we briefly discuss secondary applications of KBP for cervical cancer. The emerging picture from these studies indicates several exciting opportunities for increasing the utilization of KBP in day-to-day cervical cancer radiotherapy.

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.

Incorporating Magnetic Resonance Imaging (MRI) Based Radiation Therapy Response Prediction into Clinical Practice for Locally Advanced Cervical Cancer Patients

In recent years, magnetic resonance imaging (MRI) has become one of the standard imaging tools to define the macroscopic gross tumor volume in locally advanced cervical cancer patients based on T2-weighted sequence. Recent data suggest that functional MRI could be used to potentially improve the delineation of target volumes based on physiologic features, defining radioresistant subvolumes that may require higher doses to achieve local cure. Functional imaging can be used to predict tumor biology and outcome, as well as for assessment of tumor response during radiotherapy. The concept of adaptive radiotherapy relies on the possibility of monitoring variations in target volumes structures to guide treatment-plan modification during radiotherapy, taking into account not only internal movements but also tumor response. With integrated MRI in radiotherapy linear accelerators, motion monitoring during treatment delivery has become available. MRI can be also used to accurately evaluate cervical tumor residual volume after chemoradiotherapy, and therefore allowing a personalized treatment planning for brachytherapy boost, based on tumor radiosensitivity. In this review, we discuss how MRI tumor response assessment could be included into clinical practice during radiation therapy in locally advanced cervical cancer patients.

Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk.

Image-Guided Gynecologic Brachytherapy for Cervical Cancer

The incorporation of magnetic resonance imaging in brachytherapy has resulted in an increased use of interstitial catheters in order to create a comprehensive treatment plan that covers the visualized tumor. However, the insertion with passive, image-guidance requires estimating the location of the tumor during the insertion process, rather than visualizing and inserting the catheters directly to the desired location under active tracking. In order to treat residual disease, multiparametric MR sequences can enhance the information available to the clinician. The precision availed by MR-guided brachytherapy results in substantial improvements in needle positioning, and resulting treatment plans.