## Introduction

Cancer incidence continues to increase and malignancy now represents the second most common cause of death and disability-adjusted life years worldwide after cardiovascular disease1. Prostate carcinoma is the third most prevalent type of cancer worldwide, with over 1,400,000 cases in 2020 and is the most common cancer in men; ~375,000 deaths from prostate were expected in the same year worldwide2. Prostate cancer incidence is rising owing to increased prostate-specific antigen (PSA) screening, longer life expectancy and growing awareness in men’s health. Although the incidence of prostate cancer remains highest in developed countries, the mortality rate is disproportionately higher in low-income and middle-income countries (LMICs). A 2016 analysis of global prostate cancer burden reported age-standardized incidence rates of 68 cases and 14.5 cases per 100,000 in developed and developing countries, respectively, and the respective mortality rates were 10 (15%) and 6.6 (46%) per 100,000 (ref.3).

Only a minority (~5%) of patients present with metastatic disease at the time of diagnosis4. Most patients have localized disease that is amenable to curative-intent treatment, with various management alternatives available, including surgery, external beam radiotherapy (EBRT) and brachytherapy. Radiation treatment and surgery have been shown to have equivalent long-term oncological outcomes, with differences only in the rates and types of associated adverse effects5. An analysis of patient-reported outcomes from the PROTECT trial (NCT02044172) — the largest and most influential randomized evidence comparing patients with localized prostate cancer to active surveillance, EBRT and radical prostatectomy — revealed higher rates of sexual dysfunction and urinary incontinence in patients who underwent prostatectomy, whereas EBRT was associated with a higher risk of gastrointestinal (GI) toxicity6. Notably, although the trial outcomes showed equivalence in oncological end points, the majority of patients were low risk, with >75% of patients having Gleason 6 disease and 90% having a PSA levels of <10 ng/ml (ref.7).

Traditionally, curative-intent EBRT has been delivered using conventional fractionation schedules, treating patients with 1.8–2.0 Gy per day. Initial studies have established that total doses of radiotherapy of 76–78 Gy, compared with lower doses of 68–70 Gy, improve disease control rates by approximately 10–15% at 5 years8,9,10. However, such treatment, albeit effective, entails a treatment course that spans over 7–8 weeks’ duration. The time and financial costs to both the patient and the treatment centre can be substantial. In limited-resource settings, alternative treatment options are necessary and hypofractionation presents that opportunity.

The American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO) and American Urological Association (AUA) recognize that moderate hypofractionation is a compelling option in men with prostate cancer across all risk groups receiving EBRT to the prostate alone as endorsed in their 2018 joint guideline22. In moderate hypofractionation, the per fraction dose ranges between 2.4 and 3.4 Gy; the most commonly used regimen is 60 Gy in 20 fractions over 4 weeks. The joint guideline also makes a conditional recommendation for the use of ultra-hypofractionation in low-risk and intermediate-risk prostate cancer. The guideline defines ultra-hypofractionation as EBRT with a per fraction dose of ≥5 Gy. Usual regimens include 36.5 Gy in 5 fractions, 42.7 Gy in 7 fractions or 35 Gy in 5 fractions22. Furthermore, with the use of IMRT technology, ultra-hypofractionated radiotherapy can be delivered with increased precision and a sharp dose fall-off to surrounding normal tissues in a technique referred to as stereotactic body radiotherapy (SBRT).

This Review will acknowledge and contextualize the advantages that these shorter treatment courses could have for health-care systems, patients and caregivers, particularly in LMICs. We describe the evidence supporting the use of these treatment schemes, their technological requisites and the economic impacts of hypofractionation as they pertain to developing nations.

## Framing the issue: global necessity and disparities

Radiotherapy is extensively used in the management of prostate cancer23. The optimal radiotherapy utilization rate in patients with prostate cancer — that is, the ideal number of patients who should receive it within the clinical context — has been estimated at ~60%24,25. This value is corroborated by the use of population-based data to verify estimates of need models in which 61% of prostate cancer patients were estimated to require radiation within 5 years of diagnosis26.

In Brazil, an upper-middle-income country, close to 110,000 patients (about 20% of cancer diagnoses) requiring radiotherapy were estimated to miss out on receiving this treatment. As a result, >5,000 deaths were attributable to the lack of adequate treatment for the five most common cancers, namely prostate, breast, colorectal, lung and cervical cancers31. Part of the issue is antiquated technology; a 2019 Brazilian federal census showed that 34% of the radiotherapy machines in Brazil were obsolete, with this proportion projected to grow to 51% in 2022 if replacements are not acquired32.

Even in high-income countries disparities exist in access to radiotherapy. A study from Sweden, a high-income country, found that patients with a low income and who were unmarried had a higher likelihood of not receiving standard-of-care radiotherapy management for their cancer33. Often, the reason for this discrepancy is geographical, with patients living in rural areas being disproportionately affected34. The use of shorter treatment courses with hypofractionation can mitigate this latter issue by reducing travel expenses and increasing patient convenience35,36.

Thus, radiotherapy access is a global concern. However, the effects of this lack of access are most pronounced in the developing world, where the greatest disparity exists. The 2015 report by the Lancet Oncology Commission called for an action plan that aimed to increase radiotherapy treatment capacity by 25% in 2025 compared with capacity in 2015 (ref.37). Progress on these goals involving capacity-building in radiotherapy access is being actively investigated by the senior author of this Review and is pending publication. Hypofractionation offers the opportunity to increase treatment capacity for a single radiotherapy machine by simply reducing the number of treatment sessions required per patient, thereby expanding machine capacity for a disease that is becoming more and more common as the developing world advances.

## Clinical evidence

A number of clinical trials have evaluated the benefits and outcomes associated with moderate and ultra-hypofractionation in men with prostate cancer as well as the role of concurrent androgen deprivation therapy (ADT).

### Evidence supporting moderate hypofractionation

The joint guideline recognizes that moderate hypofractionation should be offered to men with low-risk, intermediate-risk and high-risk prostate cancer; common fractionation schedules typically administer 60–72 Gy over 4–6 weeks12,13,14,16,17,18,38. The bulk of current evidence supports equivalent results with the use of 60 Gy in 20 fractions over 4 weeks to the prostate with or without the inclusion of seminal vesicles and omission of pelvic lymph nodes compared with conventional fractionation22. This schedule was evaluated across patients with predominantly low-risk and intermediate-risk disease in two phase III trials in the presence or absence of ADT16,18.

Seven prospective randomized control trials (RCTs), including close to 6,500 patients in total, have been performed from 2013 to 2019, and demonstrate that moderate hypofractionation renders comparable disease control rates to conventional fractionated regimens12,13,14,16,17,18,38. The largest of these include the CHHiP and PROFIT trials16,18. The former trial enrolled 3,200 patients of all risk groups, although >70% of patients fell into the intermediate risk category. Patients were randomized to one of three arms: the conventional arm of 74 Gy in 34 fractions or one of two hypofractionation arms, of either 60 Gy in 20 fractions or 57 Gy in 19 fractions. After a median follow-up of approximately 5 years, 60 Gy in 20 fractions were found to be non-inferior to 74 Gy in 34 fractions in terms of clinical or biochemical failure, with 90.6% and 88.3% of patients being failure free in the hypofractionated and conventional arms, respectively (p = 0.0018). Similarly, long-term toxicity did not differ between the arms16. The PROFIT trial enrolled 1,200 patients with intermediate-risk disease and randomized them to conventional 78 Gy in 39 fractions versus hypofractionated 60 Gy in 20 fractions. At 5 years, the biochemical recurrence-free survival (BCFS) was 85% in both arms. Grade 3 or greater late toxicity did not differ significantly between the two arms18. (Table 1).

Overall, the data from these RCTs suggest that the efficacy of moderate hypofractionation is not influenced by patient comorbidity, age, anatomy or urinary function. Late GI and genitourinary (GU) toxic effects are comparable between the two fractionation schemes, although RTOG 0415 and HYPRO did report a higher incidence of late toxicity with hypofractionation14,15. Acute GU toxicity was also similar in both groups; however, moderate hypofractionation might be correlated with a higher risk of acute GI toxicity. In the CHHiP trial, grade 2 or greater acute GI toxicity was observed in 38% of patients who received 60 Gy in 20 fractions compared to 25% of patients in the conventional arm (p <0.0001)16. Similarly, Aluwini et al. observed a grade 2 or greater acute GI toxicity incidence of 42% versus 31.2% in the hypofractionated and conventional arms, respectively (p = 0.0015)39. The increase in toxicity observed in the hypofractionated arms of these studies could be explained in part by the higher biological equivalent dose (BED) used. BED is a function of total dose and is a proportional dose per fraction. It has been proposed that BEDs of >180 Gy are associated with a greater risk of toxicity40. Some patient characteristics (prostate volume, age, and baseline GI and/or GU symptoms) are correlated with an increased risk of toxicity despite conventional or hypofractionation schedules22. Similarly, a Cochrane meta-analysis of 10 RCTs with a total of 8,278 patients showed no difference in overall survival (HR 0.94, 95% CI 0.83–1.07) and equivalent prostate cancer-specific survival (HR 1.00, 95% CI 0.72–1.39) between hypofractionation and conventional fractionation. In this Cochrane review, only acute GI toxicity was found to be higher in moderate hypofractionation compared with conventional schedules (RR 1.45, 95% CI 1.19–1.75)41.

### Evidence for ultra-hypofractionation

The 2018 joint guideline presents a conditional recommendation for ultra-hypofractionation as an alternative to conventional EBRT in patients with low-risk and intermediate-risk disease22. When the guideline was released, these recommendations were conditional on new data becoming available from ongoing randomized trials. The National Comprehensive Cancer Network (NCCN) lists SBRT as an appropriate treatment option for patients with localized prostate cancer in all risk groups42. Two key phase III trials, both of which were published after the joint guideline, support ultra-hypofractionation19,20 (Table 1). HYPO-RT-PC randomized 1,200 patients with intermediate-risk and high-risk disease to 78 Gy in 39 fractions versus 42.7 Gy in 7 fractions20. After 5 years, failure-free survival in patients who received SBRT was non-inferior to conventional fractionation, at 85% in both arms (p = 0.99). However, patients in the ultra-hypofractionation arm experienced significantly more grade ≥2 GU and GI toxic effects after radiotherapy up to 3 months post treatment than patients in the conventional therapy arm. However, these differences dissipated with longer follow-up duration, except for GU toxicity alone, which, at 1 year, was significantly higher for ultra-hypofractionation at 6% compared with 2% in the conventional therapy arm (p = 0.004). PACE-B was a non-inferiority trial of 874 patients with low-risk and intermediate-risk prostate cancer who were randomized to 78 Gy in 39 fractions, 62 Gy in 20 fractions or 36.25 Gy in 5 fractions19. No differences were observed in grade 2 or worse acute GI toxicity between the conventional or moderate hypofractionation versus the SBRT arms, with an incidence of 12% and 10%, respectively (p = 0.38). Similarly, grade ≥2 acute GU toxic effects between these same groups was at 27% versus 23% (p = 0.16). Oncological outcomes are still eagerly awaited. The promising early toxicity data from PACE-B compared with HYPO-RT-PC suggest that the lower BED in this trial might be preferable. Additionally, all patients in PACE-B were treated with SBRT rather than non-intensity-modulated techniques, whereas this proportion was only 20% in HYPO-RT-PC.

A key aspect to note in these randomized trials is that the majority of patients enrolled had low-risk or intermediate-risk disease. Only 11% of patients in HYPO-RT-PC (NCT03274687) had high-risk disease as defined by T-stage or Gleason grade, suggesting that extrapolation of ultra-hypofractionation to this patient population should be done with caution20. Furthermore, the majority (95%) of patients in the PACE-B (NCT01584258) trial had prostate volumes of <80 cc (ref.19). A 2015 dosimetric analysis of prostate volumes in prostate cancer patients receiving SBRT reported that patients with a V100 (volume receiving 100% of the prescription dose) of >120 cc had the greatest decline in urinary quality of life (QoL)43. Prostate size was not reported in HYPO-RT-PC and, therefore, this detail could further explain the differences in acute toxicities between the two trials. Nevertheless, the results of these trials support the non-inferiority of disease control of ultra-hypofractionation in comparison to moderate hypofractionation and conventional schedules with similar toxicity profiles19,20.

A 2019 systematic review and meta-analysis assessed >6,000 patients treated with SBRT in 38 prospective trials with a median follow-up period of 39 months44. In this meta-analysis, the majority of patients had intermediate-risk disease (n = 2,901), with 78% of included studies containing some proportion of this patient population. Of the 38 trials in the meta-analysis, 92% included patients with low-risk disease and only 38% included patients with high-risk disease. Using data from 2,343 patients in 14 studies, the meta-analysis calculated the overall 5-year BCFS at 95.3% (95% CI 91.3–97.5; p <0.001); in patients with intermediate-risk disease, the 5-year BCRFS was slightly lower, at 92.1% (95% CI 89.2–94.3), whereas BCRFS was 96.7% (95% CI 95.2–97.8) in patients with low-risk disease. Trials including patients with high-risk prostate cancer rarely described the BCRFS results and, therefore, quantitative synthesis was not performed in this patient subset. The estimated incidences of late grade ≥3 GI and GU events were 1.1% (95% CI 0.6–2.0) and 2.0% (95% CI 1.4–2.8), respectively. QoL outcomes measured using the Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire were reported in 25 studies and 3,293 patients. Both GU and GI EPIC-26 scores returned to pre-radiotherapy baseline 2 years after treatment and remained non-significantly different at 5 years compared with the 2-year scores (p = 0.5 and p = 0.8 for GU and GI, respectively). This meta-analysis provides evidence that SBRT for localized prostate cancer is associated with excellent disease control, minimal toxicity and negligible effects on QoL44. Notably, these data largely pertain to patients with low-risk and intermediate-risk disease and, therefore, cannot routinely be applied to patients with high-risk disease.

### Role of ADT in hypofractionation

ADT plays an essential role in the management of high-risk and unfavourable intermediate-risk (UIR) prostate cancers treated with radiotherapy. Several trials have established the benefit of the addition of 18–36 months of ADT in patients with high-risk disease and of 4–6 months of ADT in patients with intermediate-risk disease treated with conventionally fractionated radiotherapy schedules45,46,47,48,49,50,51,52. The AUA/ASTRO/Society of Urologic Oncology (SUO) Guideline on the management of clinically localized prostate cancer recommends the use of concurrent ADT in these risk groups in the setting of definitive radiotherapy53.

However, the benefit of ADT is not as well defined in the setting of hypofractionation given that no comparative, randomized trials have directly evaluated this question. The use of ADT was heterogeneous in the moderate hypofractionation trials discussed in this current Review and ranged from none of the patients in the study to the entire cohort, making the contribution of ADT difficult to determine. Nevertheless, the oncological outcomes between the hypofractionated arms of these trials do not seem to drastically differ12,14,16,17,18,38 (Table 1).

Interestingly, none of the patients in the PACE-B or HYPO-RT-PC ultra-hypofractionation trials received ADT, although PACE-B excluded patients with high-risk disease and only a minority of patients had high-risk disease in HYPO-RT-PC19,20.

Thus, ADT was not strongly indicated for the majority of patients enrolled in these trials.

## Summary of evidence

The NCCN42 and 2018 joint22 guidelines suggest moderate hypofractionated radiotherapy as a standard of care in patients with all risk categories of prostate cancer. These guidelines also recognize that, with appropriate expertise and technology, ultra-hypofractionation is a reasonable option for patients with localized disease in patients with low-risk or intermediate-risk disease22,42. In light of the COVID-19 pandemic, SBRT is being encouraged as the schedule of choice for eligible patients in order to minimize hospital visits and, therefore, infection exposure58.

Given that improvement in overall survival has never been observed with any treatment scheme, whether it be hypofractionation, SBRT or conventional dose escalation, other factors need to be considered when determining the optimal management option for patients. Consequently, patient convenience and cost-effectiveness are of utmost importance when determining the best therapy option for patients with localized disease.

## Technical considerations

As radiotherapy precision evolves, so too do the technical requirements to necessitate its delivery. At a minimum, modern prostate radiotherapy involves CT-based simulation to guide subsequent treatment using megavoltage linear accelerators (LINACs). Additional upgrades are necessary for advanced methods such as intensity modulation and image-guided treatment delivery.

### Treatment simulation

Standard treatment simulation for patients with prostate cancer who will undergo either moderate hypofractionation or SBRT uses CT in the first instance. CT simulation requires several considerations to ensure simulation quality and reproducibility of treatment set-up, particularly relating to intra-patient variability in rectal and bladder filling and prioritizing dose reduction to these structures as critical organs at risk (OARs). To minimize rectal filling discrepancies, patients are instructed to empty their bowels before simulation, using enemas, suppositories and probiotics, although no single rectal management method has been deemed optimal59.

Both retrospective and prospective series have found significant associations between rectal distension and decreased disease control, although this association can be reduced by daily cone-beam CT (CBCT) imaging60,61. Furthermore, in addition to bowel preparation, patients are commonly asked to empty their bladder and to drink a standardized quantity of fluids before they undergo simulation to maintain consistent pelvic anatomy between treatments and to reduce the amount of bladder and bowel inside the treatment field, decreasing the likelihood and severity of toxic effects. A treatment-planning study investigating the effect of bladder filling on radiation dose showed that the median effective dose received by the bladder differed by 20 Gy between a full and empty bladder scan for a radical prostate plan62.

In centres with the capacity to also perform MRI simulation, data support an overall reduction of contoured prostate volume of approximately 26% when comparing combined CT–MRI co-registered treatment planning for target delineation with CT simulation alone and is possibly associated with reductions in acute GU toxicity63. Evidence also suggests that combined CT–MRI can better delineate and spare dosing to erectile tissue, although whether this dose reduction translates into decreased erectile toxicity has yet to be established64. POTEN-C (NCT03525262) is a phase II RCT currently accruing to evaluate the outcomes of neurovascular bundle sparing in prostate SBRT. The trial is expected to complete accrual in June 2024, with a target of 120 patients randomized 1:1 to neurovascular-sparing and non-sparing arms65.

However, much of the evidence to date for hypofractionation has not relied exclusively on MRI guidance for treatment planning; for example, in HYPO-RT-PC and PACE-B, MR-fusion during the simulation process was highly recommended but not mandated. We would recommend the routine addition of MR-fusion if available for ultra-hypofractionation treatment planning; however, it is not essential if not available given that much of the evidence base was developed without it.

Precise target localization before the delivery of each fraction is critical in SBRT owing to the high radiotherapy doses used. For prostate SBRT, transrectal ultrasonography-guided insertion of fiducial seed markers is often performed before simulation to improve target localization. Typically, patients are simulated 7 days after marker insertion to allow for possible seed migration, although some evidence suggests that, in the absence of oedema, seed positions do not vary substantially between insertion and simulation66,67,68. Fiducial marker implantation facilitates the targeting of radiotherapy and increases the accuracy of CBCT matching by up to 91% in the lateral direction and 64% in both the anterior–posterior and superior–inferior directions, respectively, compared with soft-tissue matching alone69,70. Fiducial markers are typically created from a radio-opaque metal such as gold and 3–4 fiducials are usually inserted inside the prostate at different levels of the gland in non-coplanar positions71. Insertion is performed as a 5–10-minute outpatient procedure under local anaesthesia and is commonly well tolerated. Severe adverse events are uncommon: a small number of patients experience urinary urgency (16%), haematuria (13%) or haematospermia (10%). In rare instances, systemic infection could occur in about 3% of patients72. Although recommended, fiducial placement is not mandatory if daily CBCT is available and implemented73,74.

Finally, evolving evidence suggests that MRI-LINACs can feasibly administer a course of SBRT without fiducial placement95,96,97. These machines, which have become commercially available since 2018, have adaptive day-to-day online imaging capabilities, enabling treatment adaptation in the event of plan deviations98,99. However, like CK systems, these novel machines are expensive, costing CAD$8.5–10 million100, and have more limited operational capacity than gantry-based LINACs given their comparatively longer treatment durations (typically ~45 minutes as opposed to typically 20 minutes)101. MR-LINACs are, therefore, not well suited for implementation in the developing world. ### Treatment delivery and quality assurance Intensity modulation has been used in many trials and is becoming more commonly implemented for localized prostate cancer treatment given its superior ability to conform to the target volume and to spare nearby normal tissues (Figs 1,2). Only one prospective study has been designed to compare IMRT and 3D-conformal radiotherapy (3D-CRT)102. In this trial, 215 patients treated with 70 Gy in 25 fractions were randomized to receive treatment with either IMRT or 3D-CRT. After 4.6 years’ median follow-up duration, IMRT was associated with lower toxicity rates than 3D-CRT (RTOG grade ≥2 late GU toxicity 3.7% and 12.3%, respectively (p = 0.02); RTOG grade ≥2 late GI toxicity 6.4% and 21.7%, respectively (p = 0.001); RTOG grade ≥2 early GI toxicity 7% and 24%, respectively (p = 0.001); RTOG grade ≥2 early GU toxicity 9% and 27%, respectively (p = 0.001)). The 5-year rate of BCFS was not different for the IMRT and 3D-CRT groups, at 95.4% and 94.3% (p = 0.678), respectively102. A secondary analysis of the RTOG 0126 trial, which compared IMRT and 3D-CRT in patients with prostate cancer, mirrored these findings, with the IMRT arm experiencing significantly less acute GI and GU toxicity than the 3D-CRT arm (10% and 15%, respectively; p = 0.042) as well as grade ≥2 late GI toxicity (15% and 22%, respectively; p = 0.039). These data suggest that IMRT is superior to 3D-CRT for use in hypofractionated prostate radiotherapy delivery, although 3D-CRT is associated with acceptable toxicity rates and oncological outcomes if IMRT is not available103 The management of inter-fraction and intra-fraction variation is one of the main technical challenges in treatment delivery. A robust quality assurance programme combined with a suitable target margin according to the image-guidance approach is critical in ensuring the safe and effective delivery of moderate hypofractionated and SBRT for localized prostate cancer treatment. Target localization can vary and can be dependent on rectal and bladder filling, even while the treatment is being delivered104. Thus, confirmation of the anatomy is crucial before the delivery of each fraction to avoid a reduction in treatment efficacy and an increase in toxic effects105. Where IGRT is absent, such as in low-resource settings where LINAC upgrades can be cost prohibitive, a larger margin is required, resulting in much higher doses to nearby structures and organs such as the rectum (Figs 3,4). Several options are available to assess prostate displacement during treatment: cine-MRI, electromagnetic transponders such as Calypso system by Varian106, CBCT, fiducial markers and ultrasonography. Each method has advantages and limitations in terms of cost, precision and treatment time22, but the overall goal with all of these systems is to ascertain the inter-fraction and intra-fraction movement of the prostate to enable the application of smaller PTV margins. Moderate hypofractionation does not require as stringent image guidance as SBRT given the lower dose per fraction and reduced risk of serious adverse effects if one fraction is sub-optimally targeted. This less-stringent approach is reflected in the PTV margin used (5–10 mm), which is often similar to that of conventionally fractionated plans. As such, alternate image guidance approaches can be considered. The use of CBCT and orthogonal kV–kV with fiducials as image-guidance modalities have been compared in a retrospective study of PTV margin definition. The study showed no difference in the accuracy of target delineation and determined that PTV margins can be kept at 5–8 mm with daily imaging regardless of modality used107. Furthermore, more than half of patients in the seminal CHHiP trial16 were not treated with IGRT techniques yet grade 2+ toxicity was only ~12% in the hypofractionated groups despite the lack of image guidance. These data suggest that moderate hypofractionation can be safely and effectively delivered without strict IGRT requirements, improving access in centres in LMICs in which the costs of IGRT upgrades can be prohibitive. However, daily IGRT should be encouraged for facilities with this capability, even for moderate hypofractionation. Techniques to limit inter-fraction variation include controlling bladder and bowel filling with the intake of a defined volume of water108, the use of laxatives109, a strict diet throughout the course of treatment110 and immobilization of the prostate using an endorectal balloon111. Hydrogel spacers can improve rectal dose and toxicity112. However, despite all these alternatives, the joint AUA/ASCO/ASTRO guideline recommends that, until data from phase III trials are available, each centre should define its IGRT protocol22. A number of clinical and technical considerations apply to moderate and ultra-hypofractionated treatments (Table 2). As per the 2018 joint guidelines, ultra-hypofractionation should be restricted to patients with a prostate volume of <100 cc, International Prostate Symptom Score (IPSS) of <20 and non-high-risk disease as the majority of published prospective evidence supports these specifications22. Trials that are currently in progress, such as the RTOG/NRG GU005 (NCT03367702) trial and the HEAT trial (NCT01794403), further restrict the criterion of prostate volume to be <70 cc and <80 cc, respectively113,114. From a technological perspective, most of the available data for ultra-hypofractionation are derived from patients treated with IMRT. This is due, in part, to the temporal association between the adoption of intensity modulation in localized prostate trials and the novelty of ultra-hypofractionation. IGRT was mandated in both randomized trials of ultra-hypofractionation as were smaller PTV expansions in comparison to moderate hypofractionation studies, which did not have these requirements19,20,22. For centres in LMICs considering the transition to hypofractionation, several key points must be considered. First, the appropriate treatment machine must be acquired and commissioned. Gantry-based LINAC systems, the most readily available and affordable radiotherapy machines, can be effective for both moderate and ultra-hypofractionated therapies. Newer technologies such as CK or MR-LINACs, although tempting due to their novelty, are not the most economical investment for a department owing to their high initial start-up costs as well as longer treatment duration. Secondly, clear patient preparation and simulation protocols can provide cost-effective methods to improve treatment outcomes. Stringent pre-treatment patient protocols to ensure bladder filling and rectal emptying are inexpensive to establish, easy to implement and can drastically improve target localization, reducing treatment margins and decreasing overall toxicity. Next, the choice of image guidance, if any, must be determined. An option in departments with multiple LINACs is to equip one with onboard CBCT capabilities and subsequently distribute patient load so that interval IGRT can be performed for all patients, for example, on a weekly basis. However, centres interested in ultra-hypofractionation must keep in mind that IGRT is mandatory for each fraction. If initial upgrade costs for IGRT capabilities are prohibitive, moderate hypofractionation can still be performed with reasonable outcomes16. Finally, treatment planning protocols, including target volume margins and normal tissue tolerances, must be adapted based on IGRT frequency and quality to ensure efficacy and safety. ## Cost and cost-effectiveness Despite the clinical and logistical advantages of hypofractionation, cost and sustainability remain the driving force behind the clinical implementation of new treatment methodologies. Several financial considerations beyond the initial machine purchase cost must be examined by a radiotherapy department prior to developing a hypofractionation programme, including machine commissioning, maintenance, power, staffing and training expenses. Economic evaluations are helpful in providing guidance and long-term cost comparisons between different radiotherapy techniques and modalities. ### Economic evaluation studies Developments in radiotherapy, from standard 3D-CRT, IMRT and incorporation of IGRT, have increased the associated costs for each treatment course. These costs are largely associated with the increased labour required to plan, check and administer IMRT treatments and, therefore, the cost is variable amongst health-care systems. In general, the cost of a conventional course of 3D-CRT for localized prostate cancer has been estimated to be approximately CAD$ 13,500 for each patient, whereas IMRT costs approximately CAD$14,520 for each patient in Canada115,116. In the USA, this cost differential was greater than in Canada, in that 3D-CRT was US$ 13,013 per course, whereas IMRT cost US$27,084 (ref.117). A British study reported a cost of £ 4,799.31 and £ 5,920.93 for a conventional course of 3D-CRT and IMRT, respectively118. Although IMRT has a higher nominal cost than 3D-CRT, the incremental cost-effectiveness ratio (ICER) of IMRT was shown to be under the generally accepted range of US$ 50,000/quality-adjusted life years (QALY) in the USA119 and Canada115 owing to the eventual health economic savings of this modality, which are due, in general, to lower rates of toxicity120. Likewise, despite higher initiation costs than conventional radiotherapy and moderate hypofractionation, SBRT shows promise for prostate cancer treatment in terms of both the long-term cost savings associated with this modality and the potential radiobiological benefits for disease control with larger fraction sizes21.

A number of economic evaluations have compared conventional, hypofractionated and ultra-hypofractionated treatment for localized prostate cancer121,122,123,124,125,126 (Table 3). A 2012 study by Hodges et al.125 performed a cost–utility comparison between SBRT and conventional IMRT for a model 70-year-old man with localized prostate cancer. In their model, both modalities resulted in a mean QALY of 7.9 years but SBRT was associated with a higher total cost of US$22,152 versus US$ 35,431 for conventional IMRT. Sensitivity analysis showed that up to a 6% decrease in efficacy and 4% decrease in toxicity outcomes for SBRT was allowed to maintain an ICER of approximately US$50,000 per QALY, which is a commonly accepted willingness-to-pay threshold. Another 2012 US-based study compared the cost utility of conventional IMRT, SBRT and proton therapy. SBRT was found to be the least costly modality with a lifetime cost of US$ 24,873 versus IMRT (US$33,068) and proton therapy (US$ 69,412) and resulted in the most QALYs at 8.11 years versus 8.05 and 8.06 years for the same modalities, respectively126. In 2014, Sher et al.124 compared conventional IMRT versus CK-based SBRT and non-CK-based SBRT using a 65-year-old man with low-risk prostate cancer as a model patient. The authors concluded astounding ICERs of US$285,000 per QALY and US$ 591,100 per QALY for IMRT over non-CK-based and CK-based SBRT, respectively, suggesting a considerable cost benefit of SBRT over conventional IMRT.

Moderate hypofractionation and SBRT have also been evaluated. A Canadian cost–utility analysis compared conventional, moderate hypofractionated and SBRT treatment schedules in a model 70-year-old man with low-risk prostate cancer. SBRT was ultimately demonstrated to be the most cost-effective option, with a cost of CAD$4,368–6,333 per QALY, compared with CAD$ 4,956–6,462 and CAD$5,935–7,992 per QALY for moderate hypofractionated and conventional treatment, respectively123. In a secondary analysis of a randomized trial, Voong et al.122 reported a difference of US$ 7,000 at a median of 6 years with conventional (US$30,241) versus hypofractionated IMRT (US$ 22,957), with no threshold reported within the sensitivity analysis wherein conventional treatment would be less costly. Finally, a Hungarian cost–utility analysis comparing 3D-CRT with conventional and moderately hypofractionated IMRT concluded that, compared with conventional 3D-CRT, conventional IMRT and hypofractionated IMRT resulted in ICERs of €1,624 and €5,600 less per QALY, respectively121.

Furthermore, these observations are supported by real world data. A 2019 Surveillance, Epidemiology, and End Results (SEER) database analysis estimated an annual cost saving of US$160–360 million with the exclusive use of moderate hypofractionation in the USA compared with conventional fractionation127. In LMICs, these cost savings could translate to more money being available for equipment acquisition and upgrades, personnel training, and an opportunity to expand the treatment capacity of the centre127. ### Hardware costs Image-guidance is necessary to decrease toxicity and improve treatment delivery and, for certain techniques such as SBRT, high-quality image guidance is essential. A 2014 comparison of various image-guided radiotherapy strategies estimated the individual costs of distinct IGRT techniques128. In this analysis, the daily costs for cine-MRI, electromagnetic transponders, CBCT, fiducial and ultrasonography were US$ 3,000–4,000/scan, US$64–141/day, US$ 143/day, US$87/day and US$ 67/day, respectively, according to the Medicare fee schedule. The cost of a transponder placement was estimated at US$1,200/patient and fiducial marker placement cost was estimated at US$ 391/patient.

The additional costs of adjunct technologies for radiotherapy delivery must also be taken into consideration. In 2017, the average price of a LINAC was US$1,976,000 and the inclusion of the equipment required for CBCT cost an additional US$ 350,000, representing an increase of ~18% in the cost of the machine129. As a result, some centres, whether in high-income countries or LMICs, can find the initial cost prohibitive beyond funding of the basic LINAC, restricting the use of hypofractionated strategies such as SBRT, which require additional equipment130.

In 2012, in order to address the radiotherapy shortage, the Brazilian government spearheaded a national project to expand LINAC capacity within the country131. The initial goal was to expand 32 existing radiotherapy centres and build 48 new centres with a total goal of adding 80 LINACs nationally; however, 8 years after the initiation of the project, only 38 LINACs have been installed and only 29 are operational. Additionally, the goal is now to expand to 100 LINACs total (adding 20 more LINACs to the initial goal of 80) by November 2021, a goal which has been hampered by the COVID-19 pandemic. In Brazil’s radiotherapy expansion project, the estimated cost to upgrade a multi-leaf collimator (MLC) from 80 to 120 leaves to enable increased precision in dose shaping and to add IMRT licenses is US$350,000. The upgrade to CBCT capability would add another US$ 350,000. Acquisition of these upgrades, which are necessary in order to provide SBRT, would result in a total cost that is much higher than a basic LINAC.

Machine upkeep and maintenance costs are additional financial considerations for a radiotherapy programme, which can be particularly burdensome to low-resource centres. A 2021 survey of 28 African countries reported that LINAC downtime in these countries is associated with failures of the vacuum pump, power instability and malfunction of the MLCs132. Recurring costs have been estimated to account for a further 5.5–15% of the initial machine investments133. LINAC maintenance and quality assurance (QA) have been estimated to have a median annual cost of US$41,390, with further annual electrical costs of US$ 2,800 for machine operation. The median cost per fraction of radiotherapy has been calculated as US11.02 for LINAC machines, which further illustrates the cost benefits of hypofractionation in minimizing these added costs134. ### Personnel and training costs Finally, the stringent dosimetric constraints, complex planning requirements and treatment monitoring involved in hypofractionation will require advanced training and departmental protocol development that meets internationally accepted standards set by trial protocols and are in line with the International Commission of Radiation Units and Measures (ICRU)135. Radiology departments will be required to fund the additional training required to ensure proper treatment setup and delivery themselves as well as covering the costs of equipment maintenance and QA. Skilled personnel training has been identified as a particular challenge in LMICs, in which human resources are often limited. A 2014 study of radiation therapy infrastructure and human resources in LMICs estimated deficits of 39%, 68% and 67% in radiation oncologists, medical physicists and radiation therapists, respectively; in 2020, they estimated that these same needs would grow to be 103%, 292% and 270%, respectively, of the 2014 capacity29. Often, training must be sought in well-established cancer centres in industrialized countries, which presents further issues. The first of these is the cost of training. The cost of a European-trained team of four radiation oncologists, three medical physicists and seven therapists has been estimated at €1.85–2.516 million, which is prohibitive to most radiation oncology centres in LMICs. Nevertheless, the International Atomic Energy Agency (IAEA) provides grant support for candidates from low-income countries and partial coverage for trainees from middle-income countries to train abroad27. The second issue is of ‘brain drain’, whereby trained professionals opt to emigrate to more industrialized countries after training for better opportunities, resources and QoL. This phenomenon has been identified as a particular issue for medical physicists as they seek support in countries where they are not identified as health professionals, which is commonplace in LMICs136. The brain drain phenomenon has been identified as a major concern in the global oncology community and a call to action has been made for developed countries to help LMIC institutions to retain personnel after training by abolishing policies such as merit-based immigration, which involves setting educational and skill requirements for prospective immigrants137. ## Obstacles and opportunities for LMICs Despite the advantages of hypofractionation, adoption in LMICs remains low compared with high-income countries138. A 2021 international ESTRO survey of over 2,300 radiation oncologists reported that radiation oncologists from LMICs (OR 0.54; p <0.001) and Asia-Pacific regions (OR 0.47; p <0.001) were significantly less likely to use hypofractionation on multivariable analysis than Europeans. In prostate cancer treatment specifically, respondents practicing in the Middle East and Africa reported the lowest rates of hypofractionation utilization (18–30%) despite also being nations in which resource limitations are high. The authors of the study raise concerns that a knowledge gap existed, particularly in Africa, where respondents had the lowest acceptance of hypofractionation but, conversely, the highest support for controversial indications such as elective pelvic irradiation138. Provider education is an important consideration in the implementation and acceptance of a hypofractionation programme and, as such, just as critical to the development of a hypofractionation programme as the technical infrastructure. ### Opportunities for improvement As global access to the internet expands, e-learning approaches provide a promising and robust platform for educational opportunities between developed and developing countries. For example, the Africa Radiation Oncology Network (AFRONET) coordinated by the IAEA, enables radiation oncology trainees from Anglophone African countries to learn from international experts in the field139. Several other professional organizations, including ASTRO and the American Association of Physicists in Medicine (AAPM), have developed online training modules specifically geared towards LMICs in order to extend opportunities for education, cancer care, research and outreach to developing nations140. The radiation oncology community is encouraged to take advantage of information and communication technologies (ICTs) in order to extend opportunities for education, cancer care, research and outreach to developing nations141. In particular, ICT platforms can enable educational sessions and resources to be shared from established oncology centres in developed countries with developing centres in LMICs. In 2019, experts from the UK and Canada, in consultation with the IAEA, led a 4.5-day web-based programme on the target volume delineation in the treatment of prostate cancer. It was attended by 22 participants from 11 African LMICs. Participants were able to participate in 1:1 tutorials to consolidate their learning and, in some cases, produce acceptable target volume and normal tissue contours, with only minor revision required142. Furthermore, in day-to-day operations, cloud-based technology could be used for plan review, whereby experts from established centres can offer aid and opinions on more complex plans remotely141,143. Several other ICT-powered programmes are currently in existence144. BOTSOGO is a collaborative effort between Harvard Medical School and the oncology community of Botswana, which includes monthly tumour boards as well as guidance on developing a local research infrastructure145. Radiating Hope, a non-profit organization dedicated to updating and providing radiotherapy equipment to developing countries, has developed a remote platform to enable treatment planning QA and technical support144,146. The Quality Assurance Review Centre (QARC) is a US-based programme from the University of Massachusetts Medical School that provides remote radiotherapy plan QA as well as clinical trial support for developing countries144. Global RT is an online forum for the education and discussion of the essential nature of radiotherapy for the global community, which also lists global oncology opportunities for interested volunteers147. As machine learning (ML) and artificial intelligence technologies evolve, the development of machine-assisted planning also offers an opportunity for LMICs. In 2019, the first patient with localized prostate cancer was treated with IMRT via a machine-generated plan as part of a clinical trial in Canada148. Since then, substantial focus has been directed towards advancing these technologies in the field of radiation oncology. Not only does the use of ML-based planning algorithms expand the capacity for patient treatment but it might also support the training of inexperienced personnel and guide them through the planning process without the need for direct supervision. Furthermore, ML can facilitate plan QA, a process in most centres in which new radiotherapy plans are reviewed by the departmental group for safety and quality. In this way, centres with limited personnel can focus their human resources on reviewing only on the cases with the most complex concerns necessitating group discussion149. A 2020 perspective piece by Australian radiation therapists urged that ML education be incorporated in radiation therapy training programmes as its role in patient care expands and is substantiated150; however, at the time of writing, the field of ML and its application to radiotherapy is still in its infancy. Further refinement of these technologies is required before regular practice implementation can occur in developed countries with sufficient personnel oversight and, subsequently, in LMICs. ## Modelling the impact of prostate hypofractionation The potential for increasing access to radiotherapy by using moderate hypofractionation and/or SBRT in the treatment of localized prostate cancer can be illustrated with a real-life working example. A 2013 analysis of African radiotherapy resources by the IAEA identified Nigeria as needing the most additional machines (138 machines) to adequately service their population28. Thus, the potential benefits of hypofractionation in Nigeria can be used to model the effects of hypofractionation rollout in other LMICs. ### Capacity This model begins with a number of assumptions. According to the IAEA directory of radiotherapy centres, as of 2020, Nigeria has seven linear accelerators to service the entire country151. Each radiotherapy unit is estimated to treat 400–600 patients a year for all indications37,152. Given that a course of conventional radiotherapy for prostate cancer tends be longer than most other radiotherapy treatments153, usually requiring 38–39 daily fractions, the lower end of 400 patients is a reasonable capacity estimate per radiotherapy machine per year. By contrast, moderate hypofractionation will be assumed to be 20 daily fractions and SBRT to be 5 daily fractions as per CHHiP/PROFIT and PACE-B schedules. According to the GLOBOCAN database, a total of 15,306 cases of prostate cancer were reported in Nigeria in 2020 (ref.2), which, when considering previous series reporting that nearly 60% of patients presenting for care in southwestern Nigeria had metastatic stage at presentation154,155, means that 6,122 (40%) patients annually would require radical treatment for localized prostate cancer. For the purposes of this example, we assume that all patients will be eligible for radical radiotherapy and that prostatectomy will not be considered as a competing treatment modality. Considering all assumptions, a total of 2,800 prostate cancer patients (46% of all incident prostate cancers per year) can be treated annually with conventional treatment using Nigeria’s current machine capacity, before even considering the use of the machine to treat other malignancies that ‘compete’ for radiotherapy resources. The implementation of hypofractionation would translate into a twofold increase in capacity, without any additional investment. SBRT has the most drastic effect, with a treatment course that requires only one-eighth of the fractions needed for a conventional course. The implementation of SBRT would, therefore, mean that nearly all patients would be able to access curative therapy. Thus, the benefit of using hypofractionation to increase the proportion of patients who will be able to receive curative intent radiotherapy is clear. ### Cost According to a 2016 economic analysis that directly compared the costs of a conventional, hypofractionation and ultra-hypofractionated schedule, the total cost of treating all 2,800 patients with arc-based conventional fractionation would be CAD 16,618,000 (US$12.6 million)123. By contrast, hypofractionation and SBRT with the same arc-based system would cost CAD$ 13,876,800 and CAD$12,230,400, respectively, for these same 2,800 patients. This difference amounts to a total cost-saving of almost CAD$ 3 million and CAD$4.5 million with hypofractionation and ultra-hypofractionation, respectively, compared with a conventional fractionation schedule. However, the start-up costs associated with machine upgrade and personnel training must also be considered, although personnel training can be covered by the IAEA programme for trainees from LMICs. Assuming that each LINAC requires MLC and CBCT upgrades (which are estimated to cost US$ 700,000 as per the Brazilian report131) to provide optimal hypofractionation treatment, the cost would total US$4.9 million (CAD$ 6.25 million). Thus, using moderate hypofractionation the initial capital invested in upgrading these LINACs would break even in a little over 2 years and the costs would be recouped in less than 2 years for SBRT. Notably, although IMRT and CBCT capabilities are ideal for moderate hypofractionation, they are not mandatory and, therefore, represent an area of initial cost-savings that could lead to faster recoupment of overall costs. Thus, by lobbying government agencies for increased funding and device manufacturers to lower acquisition costs for LINACs, the necessary infrastructure can be established in LMICs such as Nigeria, and these countries could expect to offer curative treatment options to more patients with localized prostate cancer in a sustainable manner.

These data are in line with a modelling analysis on the cost savings of switching from conventional to moderate hypofractionation in African countries, which predicted an even greater financial benefit of hypofractionation. This study used an activity-based costing model, which comprehensively accounted for optimal allocation algorithms to treatment machines as well as personnel salaries, consumable resources, and costs of construction and maintenance. Over a span of 5 years (2019–2025), Nigeria would be expected to save US$91.2 million in total (about US$ 13 million a year) if considering factors beyond machine and treatment costs such as maintenance and education156.

The population level benefits of hypofractionation can also extend to upper-middle income countries. In 2016, in the Brazilian public health system, 27,757 patients with intermediate-risk and high-risk prostate cancer were in need of definitive treatment with radiotherapy. Nevertheless, only 53.4% of this population are estimated to have received radiotherapy in this system, resulting in a projected death of 562 patients with intermediate-risk prostate cancer and of 298 with high-risk disease in the 10–13 years from diagnosis31. Considering that, in 2016, all patients in the Brazilian public health system were treated using a conventionally fractionated radiotherapy regimen (74 Gy in 37 fractions), almost the entire prostate cancer population (98.8%) requiring radiotherapy in that year could have been treated by the adoption of moderate hypofractionation radiotherapy (60 Gy in 20 fractions).

## Conclusions

Evolving evidence supports the efficacy and safety of moderate hypofractionation and ultra-hypofractionation in the management of localized prostate cancer. With resource allocation being a key consideration in LMICs, abbreviating treatment times can alleviate health-care burden and costs to both providers and patients. Hypofractionated regimens can be delivered without substantial added costs to current radiotherapy programmes and, in the long term, have proven more cost-effective. As the world population ages and prostate cancer becomes more prevalent, radiotherapy providers should be encouraged to consider the timely adoption of these treatment schedules.