Adherence to Guideline-Recommended Treatment in High-Resource Countries

Underutilization of standard-of-care radiotherapy treatments in locally advanced cervical cancer has been identified in some high-resource countries. In Australia, Japan, and France, about 50% of patients with locally advanced cervical cancer did not receive guideline-adherent treatment, with approximately 20–25% not given brachytherapy.11–13 In all studies, consideration of a patient’s general health likely contributed to non-adherence. For example, in Japan, comorbidities were cited as the most frequent reason for not providing guideline-recommended treatment.13 Clinical trials often do not include patients with high-risk comorbidities or poor performance status; these traits may be more frequently observed in clinical practice (eg, elderly patients) and contribute to lack of adherence to guideline-recommended treatment.

One approach to promote guideline-recommended radiotherapy treatment for locally advanced cervical cancer is the development of quality-of-care indicators. Quality indicators allow physicians to evaluate their practices against the guidelines and each other, encouraging optimal care for patients. To our knowledge, there is only one published set of quality indicators specifically for radiotherapy treatment of locally advanced cervical cancer, in Canada.14 Furthermore, to address underutilization in specific types of patients with locally advanced cervical cancer, such as older adults or those with certain comorbidities, we recommend development of expert consensus guidelines on management of locally advanced cervical cancer in these scenarios. Ultimately, clinical trials should be initiated in these populations to close the data gap on appropriate treatments.

While the extensive international collaboration to investigate ideal protocols for external beam radiation therapy and image-guided adaptive brachytherapy in the EMBRACE trials has led to more consistent radiation doses and techniques across institutions, some inconsistency in adherence remains.15 16 One example is the well-documented underutilization of brachytherapy for locally advanced cervical cancer treatment in some developed countries, including the USA.17 While data in Europe are lacking, brachytherapy leaders in Austria, Czech Republic, Italy, Hungary, Poland, and the UK agreed that its use is declining.18 This is concerning, as underutilization of brachytherapy has a clear adverse effect on survival in locally advanced cervical cancer.9 19

Reasons for this decline across nations with sufficient access to brachytherapy are multifactorial. The total time and labor required to execute modern brachytherapy techniques is significant compared with external beam radiation therapy in locally advanced cervical cancer treatment,20 and may contribute to the use of other boost techniques. Additionally, insufficient reimbursement systems for brachytherapy are attributed to a misunderstanding by funding institutions of the complexity and time requirement for most brachytherapy procedures; this can lead to a financial loss for radiation oncology practices performing brachytherapy.18 21 22 The American Society of Radiation Oncology has developed insurance policy coverage guidance supporting a value-based payment system that would reinforce treatment decisions based on the patients’ needs in line with clinical guidelines. However, this ideal policy has yet to be adopted by the US Medicare system.23 In Europe, the Innovative Partnership for Action Against Cancer released a comprehensive assessment of radiotherapy reimbursement plans across the continent, recommending a shift toward estimating costs of care using time-driven activity-based analysis and considering a plan that would allow adoption of emerging radiotherapy techniques.24

While brachytherapy is a mandatory component of most radiation oncology residency programs in high-resource countries, surveys indicate that many brachytherapists agree residents are not receiving adequate training, and maintenance of brachytherapy skills is a barrier to its use.18 21 25 In the USA, meeting the minimum requirement of five interstitial procedures during residency is often not enough to instill confidence in maintaining a brachytherapy practice.21 A survey of brachytherapy education in Italy found learning opportunities were heterogenous among medical schools, prompting the Italian Association of Radiotherapy and Clinical Oncology to support post-residency specialty courses and begin development of a unified curriculum.25

In response to the decline of brachytherapy use, several organizations are undertaking initiatives to enhance the image of brachytherapy and offer various types of training platforms. The American Brachytherapy Society launched a successful social media campaign in 2019 with the goal of empowering radiation oncologists to address brachytherapy underutilization.26 The American Brachytherapy Society is also starting a ‘300 in 10’ initiative, which provides an external rotation for cervical brachytherapy to senior residents in the USA at predesignated centers of excellence to further train 300 brachytherapists in 10 years.27 Increasing awareness of brachytherapy and introducing creative educational opportunities, such as the combination of didactic learning and simulation-based brachytherapy training, may increase interest in and exposure to brachytherapy.28 The International Atomic Energy Agency is currently developing a comprehensive document on the competencies needed for brachytherapy professionals, aimed at providing an international standard for assessing brachytherapy education.29

Shorter brachytherapy regimens may help reduce the overall time and personnel required for brachytherapy treatment. During the coronavirus disease 2019 (COVID-19) pandemic, hypofractionated radiotherapy regimens have been used with some success.30 Datta et al recently identified a combination of hypofractionated radiotherapy ± longer working hours to improve overall radiotherapy coverage with existing facilities in 43 countries in Asia, where economic development has been significantly impacted by the pandemic.31 Shorter brachytherapy regimens may also help patient compliance, as there is evidence to suggest that significant psychological distress is associated with current recommended regimens.32 Two ongoing phase II trials in Mexico (NCT04070976) and Canada (HEROICC-Trial (NCT04583254)) are evaluating the efficacy and safety of hypofractionated radiotherapy doses in concurrent chemoradiotherapy for locally advanced cervical cancer.

Limited Access to Radiotherapy in Low- and Middle-Income Countries

For low- and middle-income countries, there is a deficit of radiotherapy facilities based on the estimated need. While some high-resource countries have a surplus of radiotherapy coverage, some low- and middle-income countries may have no facilities, with coverage increasing linearly with gross national income.33 In 2014, 55 of 139 low- and middle-income countries had no radiotherapy facilities; Africa and Oceania were the most affected.34 In Latin America, only three countries met the International Atomic Energy Agency recommendation of one megavoltage machine per 250 000 population, and there was only one brachytherapy machine per 2.4 million people for the entire region, with ~50% of machines located in Brazil and Mexico.35 No countries with radiotherapy facilities in Africa met International Atomic Energy Agency recommendations for megavoltage machines, and only one brachytherapy machine per 15.4 million people was available for the entire continent, with >70% of all machines in only six countries.35 In 2017, India reported a deficit of radiotherapy machines at 1 per 2.1 million people, with a growing need that would only widen this gap.36 A map of the distribution of megavoltage and brachytherapy units as of February 2021 (Figure 3) shows that disparities between and within geographical regions and individual countries are still prevalent.

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Figure 3

Distribution of megavoltage (A) and brachytherapy (B) equipment per the International Atomic Energy Agency Directory of Radiotherapy Centres (DIRAC) as of February 2021. Data are voluntarily submitted to DIRAC by several sources including individuals working in a radiotherapy center, national DIRAC coordinators, the International Atomic Energy Agency/World Health Organization mailed dosimetry audit program, third-party organizations, and other sources. The International Atomic Energy Agency DIRAC website (https://dirac.iaea.org/) was accessed on March 28, 2021. Distribution of megavoltage and brachytherapy units across the globe were generated by the website and were current as of February 28, 2021.

For countries that have a higher proportion of radiotherapy facilities, there can be disparity in the regional density of facilities within a country. For example, although China has made strides in increasing the overall ratio of radiotherapy facilities per million people (0.75 in 2006 to 1.49 in 2015), these resources are limited in rural areas like Ningxia (0.87 radiotherapy facilities per million people); by contrast, in modern cities like Beijing (3.07 radiotherapy facilities per million people), advanced treatment is available and delivered in an appropriate timeframe.37 Similar trends in regional density of facilities have been reported in Argentina and India.38 39

Multiple factors contribute to the shortage of radiotherapy facilities. Overuse of limited facilities can lead to frequent maintenance requirements, which temporarily further reduces the radiotherapy capacity of a region. Timely investment by low- and middle-income countries in radiotherapy facilities and required personnel is critical to achieve the WHO goal of appropriately treating 90% of all patients with cervical cancer. The International Atomic Energy Agency has been a key resource in bringing radiotherapy to low- and middle-income countries over the years through many initiatives and multiple guidance documents.29 40 41 The initiation or scale-up of radiotherapy programs requires a level of readiness in low-resource countries or regions, which is supported by strong national commitments to building infrastructure that includes adequate radiotherapy facilities and supporting systems (eg, electricity, transportation) with appropriate equitable distribution. Facilitators of successful experiences in creating high-quality radiotherapy programs in low- and middle-income countries include significant political support, development of a costed cancer plan, multiple funding sources, adoption of evidence-based practice, strategic partnerships (such as with the International Atomic Energy Agency), focus on patient-centered care, and availability of supportive technologies.42

Given the limited ability of low- and middle-income countries to train additional radiation oncologists to meet the growing need for radiotherapy facilities, a deficit of 8900 full-time equivalent employees is projected in 2030.43 Without properly trained staff, quality and safety of radiotherapy treatment is at risk.29 40 Effective training and increased numbers of radiation technologists, nurses, medical physicists, and radiation oncologists are needed to ensure quality care in low- and middle-income countries. Successful initiatives to bring education and training to low-resource countries include several e-learning programs.41 42 The web-based Chartrounds facilitates training and chart review of cases, connecting radiation specialists and local practitioners. In the first year of implementation in India, 76% of participants agreed that the sessions would contribute to a change in their radiation oncology practice.44 Train-the-trainer-style series from organizations such as Radiating Hope and Royal Australian and New Zealand College of Radiologists, European Society for Radiotherapy and Oncology, and International Atomic Energy Agency are another avenue for disseminating current knowledge and practical advice. Partnerships between medical institutions in high- and low-resource countries can also facilitate development of radiation oncology expertise.

While many low- and middle-income countries are working toward improved access to cervical cancer treatments, the most effective treatments may not be available. Therefore, several organizations have provided cervical cancer treatment guidelines targeted to regions with various levels of treatment availability; however, recommendations are often based on expert consensus as opposed to strong clinical evidence (Table 2). Until adequate radiotherapy resources become available, patients with locally advanced cervical cancer treated per these limited-resource recommendations will continue to have poorer prognoses compared with those treated with an ideal concurrent chemoradiotherapy regimen.

Future Directions in Concurrent Chemoradiotherapy for Locally Advanced Cervical Cancer

More than half of patients with locally advanced cervical cancer who are treated with concurrent chemoradiotherapy will develop recurrent disease or distant metastasis; thus, continued research for improved treatment is needed. Importantly, recent results from the phase III OUTBACK trial showed adjuvant chemotherapy following concurrent chemoradiotherapy did not provide a survival benefit at 5 years compared with concurrent chemoradiotherapy alone in patients with locally advanced cervical cancer, and there were significantly more adverse events in the adjuvant chemotherapy group.45 Combinations of concurrent chemoradiotherapy with immunotherapies, targeted therapies, or other novel therapies are actively being investigated (Table 3).

Combining concurrent chemoradiotherapy and programmed death-1/programmed death ligand-1 blockade with immune checkpoint inhibitors can enhance CD8 +T cell immune response and recruitment to the tumor site. This combination has provided improved outcomes in patients with advanced non-small cell lung cancer in the PACIFIC trial of durvalumab given after concurrent chemoradiotherapy, which led to its approval in the USA for this indication.46 More recently, the phase III KEYNOTE-826 trial of pembrolizumab given in combination with platinum-based chemotherapy with or without bevacizumab reported improved progression-free survival and overall survival for patients with programmed death ligand-1-positive recurrent/metastatic cervical cancer.47 Ongoing studies of concurrent chemoradiotherapy in combination with immune checkpoint inhibitors in patients with locally advanced cervical cancer are assessing the sequence of treatments and overall efficacy and safety (Table 3).48–50

Other unique concurrent chemoradiotherapy combinations are being tested. Although decreasing tumor vasculature with antiangiogenic agents appears counterintuitive with concurrent chemoradiotherapy, since chemotherapy and radiation depend on a functioning vascular system, antiangiogenic agents may enhance chemoradiation through normalization of the vasculature surrounding the tumor.51 DNA repair inhibitors, such as triapine, and inorganic radiosensitizing nanoparticles, such as AGuIX, are being combined with concurrent chemoradiotherapy with the rationale that these agents would enhance the effects of chemoradiation-mediated cell death.52 53 Finally, stimulation of T-cell responses by therapeutic human papillomavirus vaccines, such as PDS0101, may enhance the effects of concurrent chemoradiotherapy for treatment of locally advanced cervical cancer.