INTRODUCTION
Globally, cancer is the leading cause of mortality and accounted for approximately
one in six deaths in 2020.
1
The burden of cancer mortality falls disproportionately onto low-and middle-income
countries (LMICs) which have higher cancer mortality-to-incidence ratios.
2,3
Many factors contribute to this disparity, including limited access to treatments,
more frequent advanced stages of disease at presentation, insufficient numbers of
trained physicians, and patients being unable to complete their entire planned course
of therapy.
2,4,5
This has led to many international organizations advocating for increasing investments
in health care infrastructure in LMICs, with an estimated investment of $184 billion
US dollars (USD) required.
2,6,7
Less emphasis has been placed on how LMICs can more efficiently use the resources
already available to them to increase availability and access to high-quality cancer
care, complete planned treatments, and improve oncologic outcomes. One avenue to explore
is the adoption of hypofractionated radiotherapy regimens for some of the most common
cancers.
CONTEXT
Key Objective
How would the adoption of hypofractionated radiotherapy regimens in low-and middle-income
countries (LMICs) affect access to radiotherapy, treatment compliance, and the costs
borne by patients and the health care system?
Knowledge Generated
The benefits of adopting hypofractionated radiotherapy regimens in LMICs include higher
rates of treatment compliance, decreased financial toxicity for patients, decreased
costs for health care systems, and improved access to radiotherapy.
Relevance
In LMICs, improved treatment compliance and access to radiotherapy achieved through
the adoption of hypofractionated radiotherapy regimens has the potential to narrow
the disparate oncologic outcomes observed between high-income countries and LMICs.
A multifaceted approach, including investments in radiotherapy infrastructure, clinician
and physicist-directed training programs, implementation research, and advocacy by
stakeholders and global partners, will be needed to overcome the infrastructure and
knowledge gaps which currently prohibit widespread adoption of hypofractionated treatment
regimens in LMICs.
Hypofractionated radiotherapy is a treatment approach that shortens the overall duration
of a radiotherapy treatment course by delivering fewer treatments but with a higher
dose of radiation per daily treatment. These hypofractionated treatments have become
the standard of care for patients with breast and prostate cancer in the United States
and Europe, as multiple studies have shown that they provide noninferior oncologic
outcomes and have a similar toxicity profile but can be delivered in a shorter period
of time at a lower cost to the health system.
8-14
This has enabled radiotherapy courses for patients with breast cancer to be shortened
from 5-6 weeks to 3-4 weeks or even 1 week.
8,11,12
Similarly, prostate cancer treatments have decreased from 8-9 weeks in length to 4-6
weeks or 1 week in certain circumstances.
9,10,13
Additionally, hypofractionated approaches for lung, rectal, and liver cancer have
become established treatment options.
15-19
Data are also accruing supporting the use of hypofractionated radiotherapy for head
and neck and gynecologic cancers.
20-25
More efficient utilization of resources through the adoption of hypofractionated radiotherapy
approaches for some of the most common malignancies, particularly breast and prostate
cancer, has the potential to address many of the factors contributing to the disparity
in cancer outcomes seen between LMICs and high-income countries (HICs). In this literature
review, we aim to examine the potential benefits of adopting hypofractionated treatment
approaches in LMICs and the current state of hypofractionated radiotherapy in these
settings.
METHODS
An exhaustive review of available literature was performed using the PubMed database.
Publications pertaining to hypofractionated radiotherapy and cost-effectiveness, treatment
compliance, or treatment access were included for review. Full-text papers published
in English between 2000-2022 were initially identified through a PubMed search including
the Mesh terms "Radiation” [Mesh] and (“Hypofractionation” [Mesh] OR “Hypofractionated”
[Mesh]) AND (“Accessibility” [Mesh] OR “Access” [Mesh] OR “Cost” [Mesh] OR “Compliance”
[Mesh] OR “Completion” [Mesh] OR “Benefit” [Mesh]). The initial papers identified
were then back-referenced to identify additional relevant studies. Publications were
included in this review if they addressed hypofractionated treatment regimens in LMICs.
A review of US National Library of Medicine using the search terms “hypofractionated,”
“SBRT,” “stereotactic,” “ultrahypofractionated,” “fractionated,” “moderately fractionated”
was performed to identify clinical trials using hypofractionated radiotherapy regimens.
26
Improved Access to Radiotherapy
Access to radiotherapy in many regions is often limited because of an insufficient
number of radiation oncology clinics, trained personnel, and treatment machines.
2,4,27,28
The consequences of limited availability of radiotherapy are best illustrated by a
report from Brazil in 2016 which found that limited access to radiotherapy was estimated
to result in more than 5,000 deaths among patients with prostate, breast, colorectal,
lung, and cervical cancer.
29
In a 2020 analysis of 46 countries, it was estimated that radiotherapy is only accessible
to approximately 62% of the patients who could benefit from it and that an additional
5,987 treatment machines would be needed in LMICs to fully meet the radiotherapy demand.
27
Accessibility varies by region, with one report indicating that access to radiation
was lowest in Africa (34%), followed by Asia-Pacific (61%) and Latin America (88%).
4
Clearly, additional investment in infrastructure is needed, but the required investment
can be reduced with optimal utilization of radiotherapy through hypofractionation,
as shown in Table 1. Adopting hypofractionated treatment approaches alone was estimated
to improve access to radiotherapy in Asia from 62% to 78% and decrease the number
of treatment machines needed in LMICs from 5,987 to 4,284, significantly reducing
the investment required to improve access to radiotherapy.
27
Another published report estimated that implementing universal hypofractionated treatments
for breast and prostate cancer would increase access to radiotherapy in Africa by
up to 25% for breast cancer and 36% for prostate cancer.
30
Using Nigeria as an example, which had seven linear accelerators (LINACs) in 2020,
it is estimated that the increase in patient throughput with the adoption of ultrahypofractionated
prostate radiotherapy would allow all eligible patients with prostate cancer in the
country to receive treatment without increasing the number of LINACs.
31
Similar results were seen when assessing the impact of adopting moderately hypofractionated
radiotherapy for prostate cancer in Brazil.
31
TABLE 1
Summary of Publications Addressing the Impact of Hypofractionated Treatments on Access
to Radiotherapy
Condensing the overall treatment time with hypofractionation allows each LINAC to
treat more patients per year, with treatment slots becoming available more frequently.
Patients who otherwise may have to wait multiple weeks for a treatment slot can then
be accommodated in a more timely fashion, preventing the delays in initiation of radiotherapy
that have been associated with worse outcomes.
34,35
A Markov model looking at the clinical implications of widespread adoption of hypofractionated
radiotherapy for breast cancer in Pakistan, which in 2017 only had 15 LINACs for a
population of 180 million people, estimated that an additional 1,098 patients with
breast cancer could be treated per year if hypofractionation was the standard of care.
32
This translated to an estimated 7% 15-year overall survival benefit among patients
with breast cancer in Pakistan illustrating how improved access to radiotherapy through
adoption of hypofractionated treatments can lead to improved oncologic outcomes.
Hypofractionation and Treatment Compliance
Improving access to radiotherapy is the first key step to eliminating the disparities
in oncologic outcomes between LMICs and HICs. However, if the radiotherapy courses
being offered cannot be feasibly completed by patients, the clinical benefits of improved
access will be limited. Two of the most cited risk factors for patients being either
unable to complete treatment or having treatment interruptions are prolonged treatment
courses and lower socioeconomic status.
36-38
Both of these risk factors may be mitigated by hypofractionated radiotherapy treatment
approaches.
Reports on the incidence of treatment interruptions vary on the basis of the primary
site and the treatment setting, but reports range from 20% to 71% while the incidence
of treatment discontinuation range from 13% to 61%.
36,38-45
Compliance with a planned radiotherapy course is crucial as multiple studies have
shown that treatment delays and interruptions are associated with worse oncologic
outcomes.
34,35
The impacts of treatment interruption or discontinuation also have knock on effects
on available resources. For instance, treatments missed may need to be made up at
the end of the treatment course, further prolonging treatment. Patients with very
protracted or incomplete treatments have a higher risk of recurrence, which could
result in the need for additional radiotherapy treatment courses in the future, further
straining resources.
35
Treatment delays and treatment discontinuation can occur because of clinic-based factors
(machine downtime, understaffed centers being unable to accommodate all patients,
or insufficient medical supplies or resources) or for patient-based reasons (financial,
logistical, or personal). In regard to patient-specific factors, a shorter treatment
course can make compliance with a planned radiotherapy course more feasible by reducing
housing and transportation costs, and decreasing time away from work and family.
45
Unfortunately, there is currently no data available quantifying the impact hypofractionated
radiotherapy may have on treatment compliance in LMICs.
However, there are some limited data on this topic as it relates to breast cancer
in the setting of HICs, as shown in Table 2. A study from Saudi Arabia analyzed the
factors affecting treatment interruptions in a population of 286 patients receiving
postoperative radiotherapy for breast cancer, of whom half received a hypofractionated
3-4.5 week course and half received a standard 5-7 week course, with length depending
on inclusion of a lumpectomy cavity boost.
40
Overall, 20% of patients had a treatment interruption of at least one day, but patients
treated with conventional fractionation were twice as likely to have a treatment interruption
(27% v 14%, P = .007). Additionally, patients treated with conventional fractionation
had significantly longer treatment interruptions (3 v 2 days, P = .02) compared with
patients treated with a hypofractionated course.
TABLE 2
Summary of Publications Addressing the Impact of Hypofractionated Treatments on Treatment
Compliance
Three studies from the United States, including one institutional study and two National
Cancer Database (NCDB) studies, reported similar findings.
44,46,47
The institutional study reported on 743 patients with breast cancer, 56 of which were
treated with hypofractionated therapy and reported on rates of on-time completion
(defined as treatment completion assuming treatment is given 5 days per week with
an additionally 7-day buffer) and timely completion (similar to on-time but with a
30-day buffer) of radiotherapy. Hypofractionation was associated with higher rates
of on-time completion (46.5% v 17.8%, P < .001) and timely completion (75% v 52%,
P < .001) of radiotherapy.
46
The two NCDB studies were consistent with these results and reported higher overall
completion rates (99.3% v 79.7%, P < .0001) and timely completion rates (94.5% v 74.8%,
P < .0001) which was defined as treatment completion within 5 weeks of initiation
of hypofractionated radiotherapy or 7 weeks for conventionally fractionated treatments.
44,47
Importantly, racial and socioeconomic disparities in treatment completion rates and
tumor control were narrowed when a hypofractionated radiotherapy approach was used
because of higher rates of treatment compliance and completion.
47
This gives some hope that the implementation of hypofractionated radiotherapy may
allow more patients to complete their recommended treatment course and help to narrow
the differences in cancer mortality-to-incidence ratios between LMICs and HICs.
Reduced Costs
Multiple studies have shown that hypofractionated radiotherapy for patients with breast
and prostate cancer is the most cost-effective radiotherapy regimen.
48-52
Although dependent on a country's health care system, reimbursement often scales with
the number of fractions, making fractionation the largest contributing factor to the
cost of radiotherapy treatments.
50
However, most cost-effectiveness data have been reported from HICs, with only five
studies focused on LMICs, as shown in Table 3. The first of these studies reported
that reducing breast cancer treatments from 25 to 15 fractions across Africa would
save an estimated $1.1 billion USD between 2019 and 2025 while reducing prostate cancer
treatments from 39 to 20 fractions would save an additional $606 million USD over
the same time period.
30
This represents a significant amount of capital which could then be invested in health
care infrastructure.
TABLE 3
Summary of Publications Addressing the Impact of Hypofractionated Treatments on Treatment
Cost
Four country-level studies have evaluated cost-effectiveness. The first reported that
25-fraction moderately hypofractionated intensity-modulated radiation therapy (IMRT)
for prostate cancer in Hungary was more cost-effective (absolute savings of €1,141
Euros) than a 35-39-fraction three-dimensional radiation therapy (3DCRT) course, despite
the extra planning and technology costs and requirements associated with IMRT.
33
Additionally, moderately hypofractionated radiotherapy resulted in a 10% increase
in the number of patients who could be treated because of to increased machine capacity.
33
Adoption of moderately hypofractionated radiotherapy for prostate cancer was predicted
to save the Nigerian health care system approximately $13 million USD annually after
accounting for required LINAC upgrades to deliver IMRT and image-guided radiation
therapy (IGRT), consumable resources, construction, machine maintenance, and educational
and personnel costs.
31
A study on the cost effectiveness of hypofractionated compared with conventionally
fractionated postmastectomy breast radiation in China found that it was associated
with an 11% cost reduction and was determined to be cost-effective.
54
Another study from China reported that neoadjuvant 10-fraction hypofractionated radiation
for esophageal cancer resulted in a 41% reduction in radiotherapy costs over a 20-fraction
moderately hypofractionated regimen.
53
Reducing the treatment costs patients incur is equally important to reducing the costs
for the overall health care system. The cost associated with traveling, finding housing,
and missing work can carry staggering consequences for patients. For instance, the
majority of Nigerian patients with breast or cervical cancer reported a moderate or
major loss of revenue because of not being able to work (68%) with one third of patients
also reporting that their family members had moderate or major losses in revenue (32%).
55
Given these financial challenges, it is not surprising that 23% of Nigerian patients
from this cohort reported taking out loans to cover the cost of their medical care
and daily needs. Similar challenges were faced by Argentinian patients with cervical
cancer who experienced reduced hours worked (45%), more work interruptions (25%),
a loss of family income (39%), reduced amounts of food consumed by their family (37%),
delays in paying for essential services such as electricity (43%), the sale of property
or use of savings to cover basic need (38%), and disruptions in children's schooling
(28%).
37
This highlights how the burden of prolonged treatments can negatively affect entire
families. Additionally, patients who lost household income as a result of their cancer
treatments were less likely to be compliant with their scheduled radiotherapy, further
hinting at the interplay between socioeconomic factors and oncologic outcomes.
37
There are minimal data quantifying how using shortened hypofractionated treatment
courses would affect a patient's out-of-pocket expenses in LMICs. A study found that
when accounting for traveling expenses alone, Canadian patients had an additional
$1,930 Canadian dollars of out-of-pocket expenses when treated with a 39-fraction
radiotherapy regimen for prostate cancer compared with a 5-fraction regimen.
56
This is further supported by an American study which reported that the cost to the
patient in nonmedical expenses was approximately 50% less when using a 16-fraction
treatment approach compared with a 25-fraction treatment approach for breast cancer,
largely because of decreased traveling expenses and lost wages because of daily travel
requirements.
57
However, even this study does not fully account for either the cost of prolonged periods
of missed work when patients must relocate to receive radiotherapy or the lost productivity
after completion of treatment, which may account for approximately one third of the
true economic cost of a patient's cancer treatment.
58
Despite the lack of data from patients in LMICs, these findings are likely applicable
to patients in these settings as a shortened treatment course decreases the need for
housing, time away from work, and minimizes expenses related to traveling for daily
treatments. These benefits may not be accounted for when assessing the value of hypofractionated
radiotherapy from a health care system's perspective but are likely highly valued
by patients.
State of Hypofractionation in LMICs
Despite the benefits associated with hypofractionated radiotherapy, the adoption rate
of hypofractionated treatments has varied widely between countries. A recently published
European Society for Radiotherapy and Oncology's Global Impact of Radiotherapy in
Oncology (ESTRO-GIRO) survey, completed by 2,316 radiation oncologists around the
world, evaluated adoption rates of hypofractionated radiation for bone metastases
and breast, prostate, and cervical cancer.
59
They found that while hypofractionation was widely adopted for palliative radiotherapy,
accounting for approximately 75% of palliative treatments, the utilization for definitive
indications varied significantly by region. For example, low-risk prostate cancer
was treated with hypofractionated radiotherapy at higher rates in North America (94%)
compared with Europe (67%), Latin America (44%), Asia-Pacific (42%), Middle East (31%),
and Africa (19%). Although the absolute difference in utilization between these regions
decreased for intermediate-and high-risk prostate cancer, the disparate utilization
rates still persisted. Similar trends were seen for node-negative postlumpectomy breast
cancer, with hypofractionated regimens being more common in North America (97%) compared
with Europe (89%), Latin America (77%), Middle East (76%), Asia-Pacific (72%), and
Africa (40%).
To assess the current state of hypofractionated radiotherapy utilization across the
world, we analyzed which countries had ongoing clinical trials involving hypofractionated
radiotherapy using the US National Library of Medicine database, as shown in Figure
1. The majority of the trials involving hypofractionation are being performed in HIC
(82%), followed by middle-income countries (12%), with no registered ongoing clinical
trials in low-income countries.
26
Breast, prostate, and bladder represented the majority of the disease sites. Of the
LMICs doing these clinical trials, the largest portion of these are being done in
China (46%), Brazil (13%), and India (9%).
FIG 1
World map of countries color coded on the basis of the number of ongoing clinical
trials involving hypofractionated radiotherapy regimens.
60
These hypofractionated approaches have increasingly been recommended by professional
societies since the COVID-19 pandemic as a way to limit patient's risk of infection
by decreasing their exposure to the medical system.
21,61,62
Early reports indicate that radiation oncologists from LMICs have increased their
utilization of hypofractionated regimens since the beginning of the COVID-19 pandemic
with one report from India finding that 9% of radiation oncologists had implemented
hypofractionated treatments for the first time.
63-66
Similarly, multiple institutions have reported that patients on average are being
treated with fewer fractions per treatment course since the beginning of the COVID-19
pandemic, suggesting increased adoption of hypofractionated treatment regimens.
67,68
Despite these recent advances in the adoption of hypofractionated radiotherapy regimens,
the results of the ESTRO-GIRO survey indicate that the regions that would most benefit
from the widespread adoption of hypofractionated treatments also have the lowest utilization
rates. The reason why hypofractionation is not more widely used varied by region,
but surprisingly, technology was only cited as a significant barrier by 24% of respondents
from Latin America, 23% of respondents from the Middle East, 19% of respondents from
Africa, 16% of respondents from Asia-Pacific, 11% of respondents from Europe, and
3% of respondents from North America.
59
Most respondents were more likely to cite a lack of long-term data (18%-61%), fear
of inferior local control (14%-32%), or concern for increased toxicity (23%-56%) as
being significant barriers to adoption. This may indicate that a knowledge gap exists
surrounding hypofractionation, limiting implementation.
Although less than a quarter of ESTRO-GIRO survey respondents reporting that technology
represented a barrier to implementing hypofractionated treatments, there is a well-documented
technological gap between the radiotherapy resources available in LMICs and HICs.
This technology and infrastructure gap likely contributes to the disparity in hypofractionation
utilization as the infrastructure, technological capabilities, and expertise required
to deliver hypofractionated treatments is not insubstantial, as shown in Table 4.
It has been postulated that the minimum requirements for implementing hypofractionated
radiotherapy include a LINAC capable of delivering 3DCRT (minimum 10 MV beam) with
5-mm multileaf collimators, computed tomography (CT) treatment simulation (maximum
3-mm slice thickness), forward and inverse treatment planning systems, appropriate
immobilization devices, a regimented quality assurance protocol, and well-trained
radiation oncologists, physicists, radiation therapists, and dosimetrists.
31,69,70
Although these represent minimal standards, treatment with IMRT (minimum 6 MV beam)
with image guidance and motion tracking systems is preferred but requires additional
equipment and expertise. In Brazil's radiotherapy expansion project, the estimated
cost to upgrade LINACs to deliver IMRT, including licensing costs, was $350,000 USD,
with an additional estimated $350,000 USD to upgrade LINACs to provide IGRT capabilities
with cone beam computed tomography.
31
However, institutions will also face recurring maintenance and software licensing
costs, further driving up the long-term investment required to acquire and maintain
the infrastructure required to delivery hypofractionated radiotherapy. Costs for maintenance
contracts should be factored into the initial investment costs and budget impact analyses.
TABLE 4
Summary of Published Guidelines on the Required Minimum Infrastructure for Adoption
of Moderately Hypofractionated Radiotherapy and SBRT in Low-and Middle-Income Countries
Meeting these infrastructure standards may currently be out of reach for many cancer
centers in LMICs, as a 2018 survey of middle-income countries revealed that 49% of
patients are still treated with two-dimensional techniques and only 3% of patients
are being treated with IMRT.
28
This concern is further supported by a survey of 18 radiation oncology clinics in
Africa which found that none of the clinics had advanced motion tracking systems (four-dimensional
CT, infrared light-emitting diodes, and speckle-texture projection) and only one clinic
used fiducials in their practice.
70
These 18 clinics had significant differences in their capabilities with five of the
18 clinics reporting being capable of delivering IMRT while five clinics did not have
the equipment necessary to perform CT treatment simulations. If these 18 clinics are
representative of the region, it may be that delivering safe hypofractionated radiotherapy
is only possible at a minority of treatment centers in Africa, one of the regions
with the most to gain from its implementation.
4,30
Building Capacity for Hypofractionated Treatments
A multifaceted approach will be needed to overcome the infrastructure and knowledge
gaps which may be prohibiting more widespread adoption of hypofractionated treatment
regimens. The need for investments in infrastructure cannot be ignored. Of particular
importance for hypofractionated radiotherapy are the capability to perform a CT treatment
simulation, create treatment immobilization devices, deliver IGRT, and perform regimented
quality assurance practices.
69,70
One of the challenges to acquiring and maintaining the necessary infrastructure for
hypofractionated radiotherapy is the limited financial resources earmarked for radiotherapy.
This is likely due to competing interests, both within the health care system and
outside of it. Strong commitment from policymakers and the political will to address
this issue is essential.
Although there are significant costs associated with upgrading infrastructure to support
delivery of hypofractionated radiotherapy, there is economic justification to support
the investment. A recent model developed by the Global Task Force on Radiotherapy
for Cancer Control found that for every $1 USD invested in radiation oncology services
in LMICs, there was a $2.95 USD return on investment. These results were consistent
across all regions and income levels and represent a very compelling economic argument
justifying focused investments in radiation therapy infrastructure. Stakeholders will
need to work with large organizations, such as the International Atomic Energy Agency,
Rays of Hope, and Radiating Hope, or academic institutions in the United States, Europe,
or Asia, to ensure that policymakers and government officials are aware of these benefits
and advocate for increasing investments in radiotherapy infrastructure.
Facilities in LMICs that already have the necessary resources to provide hypofractionated
treatments, but have not yet integrated them into their clinical practice, should
consider implementation research to identify how to effectively introduce hypofractionated
treatments.
71
Publishing these implementation studies will create a framework for the adoption of
hypofractionated treatments that other LMIC cancer centers can rely on once they develop
the infrastructure needed to deliver these treatments. Appropriately implementing
this hypofractionated radiotherapy into clinical practice is critical, as attempting
to do so without adequate infrastructure or training can compromise treatment outcomes
and lead to increased treatment toxicity.
72
The knowledge gap that exists regarding hypofractionated treatments and the required
quality assurance protocols could potentially be bridged through web-based learning
programs and conferencing platforms which are currently used in many LMICs through
the International Atomic Energy Agency and other international organizations.
73-75
These web-based programs could give clinicians from LMICs the opportunity to present
cases and treatment plans to regional or international physicians who are aware of
the local resources available and have experience with hypofractionation.
76,77
Similar networks should be created for physicists, dosimetrists, and radiation therapists
to receive additional training on the appropriate quality assurance protocols needed
when delivering hypofractionated treatments.
These training programs will need to be continually updated as novel targeted therapies
are brought to market which may interact with radiotherapy and increase the potential
toxicity of hypofractionated treatments.
78,79
There are still significant unknowns regarding the potential for radiosensitization
when using targeted therapies, with one survey finding that only 11% of radiation
oncologists from the Netherlands felt there was sufficient information and resources
available to allow for adequate decision making when combining these two treatment
modalities.
80
Given the inherent uncertainty regarding these multimodality treatments, physicians
should be cautious when combining hypofractionated radiotherapy with new targeted
therapies.
In conclusion, the potential benefits of hypofractionated radiotherapy for patients
and health care systems in LMICs include higher rates of treatment compliance, decreased
financial toxicity for patients, decreased costs for health care systems, and improved
access to radiotherapy. A number of barriers exist, both in regards to infrastructure
and clinician training, that will need to be overcome before achieving more widespread
adoption of hypofractionation. Infrastructure and training investments should be directed
toward increasing the capacity for hypofractionated radiotherapy, as these treatments
have the potential to address some of the most significant factors contributing to
the disparate oncologic outcomes between LMICs and HICs. Further study in LMICs is
warranted to identify the minimum infrastructure requirements for the safe delivery
of hypofractionated radiotherapy and identify effective processes to help build capacity
for adoption of hypofractionation in that setting.