Hypofractionated Radiotherapy for Prostate Cancer: An option for Africa?

Prostate cancer is the most common cancer among men in most African countries and can be effectively treated by radiotherapy. Unfortunately radiotherapy machines are extremely limited in Africa. Hypofractionated radiotherapy is delivered in fewer fractions, therfore improving hospital logistics.

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According to the World Health Organization (WHO), the numbers of cancer patients will be doubled by 2030 because of the ageing and the growth of the population. Cancer prevention strategies are limited in Africa and a shortage of medical specialists, nurses and pathology workers contributes to a late presentation in hospitals. Prostate cancer is the most common cancer among men in most African countries (1). Management options for prostate cancer include external-beam radiotherapy (EBRT), brachytherapy, radical prostatectomy, active surveillance (in men with low-risk disease), and watchful waiting (if unsuitable for radical curative treatment).

Radiotherapy machines are extremely limited in Africa, one important reason why prostate cancer is most often managed by urologists. However, for a large proportion of prostate cancer patients, EBRT will be the treatment of choice because of the limited surgical expertise in many countries and because EBRT is the most appropriate treatment for men with intermediate-and high-risk disease (2). Dose-escalated radiotherapy has been proved to significantly improve relapse-free survival, however the associated increase in radiation-induced toxic effects restricts options for further dose escalation using conventional fractionation. An important biological parameter describing the response of tissues to fractionation is the repair capacity (α/β ratio). Late responding tissues are characterized by a relatively low α/β ratio (3–4Gy), resulting in an enhanced sensitivity for large fraction doses. Acute responding healthy tissues and most tumours are characterized by a high α/β ratio (10Gy) and therefore are relatively insensitive to large fraction doses, compared to tissues with low α/β ratio. Prostate cancer has a highly atypical growth pattern in comparison with other malignancies and has a low α/β ratio (1.2-1.5Gy) lower than late responding healthy tissues (3). This disparity widens the therapeutic window by treating prostate cancer with hypofractionation. Hypofractionated radiotherapy is delivered in fewer fractions, improving patients’ convenience, hospital logistics, and reducing health-care costs.

In the past few years four large multicentric randomized, phase 3 trials, with over 6000 patients, of hypofractionated regimens have shown that moderate hypofractionation for localized prostate cancer (in low-, intermediate- and high risk patients) with fraction doses of 2.5-3.4Gy provide similar treatment outcome and toxicity compared with conventionally fractionated radiotherapy with fraction doses of 1.8-2Gy (4-7). The American Society for Radiation Oncology (ASTRO) task force for hypofractionated radiation therapy, based on a systematic literature review and strong consensus, recommended to offer moderate hypofractionation (60Gy in 20 fractions of 3Gy and 70Gy in 28 fractions of 2.5Gy) across any risk groups to patients who are candidates for EBRT for prostate cancer, and regardless of patient age, comorbidity, anatomy, or urinary function (8). Even more in the advent of the COVID-19 pandemic, professional societies including ASTRO and the National Comprehensive Cancer Network recommended adopting evidence-based hypofractionated radiotherapy.

A recently published survey in 18 African countries reported that centers are already practicing hypofractionated radiotherapy, but only 44% as a common practice. For treatment planning and contouring the survey highlighted need for additional training for radiation oncologists (9). The Lancet Oncology Commission urged for scaling up radiotherapy capacity to expand coverage (10). Hypofractionation for prostate cancer significantly reduces costs to a total of USD 606 million for prostate radiotherapy, equivalent to 49% cost minimization, and increases radiotherapy access from +0.4-36.0% (11). Adopting hypofractionated regimens as standard treatment for prostate cancer would result in substantial savings and increase radiotherapy access in Africa. Furthermore, hypofractionation offers logistical advantages increasing patient convenience, by reducing the number of visits to the cancer center (12).

Although the large randomized, phase 3 trials offer enough level I evidence to implement (moderate) hypofractionation for prostate cancer providing control and toxicity similar to that of conventionally delivered fractionation, data come only from high-income Western countries.

For this reasons, a phase II study is now being developed to run in African centers. The HYPOAFRICA trial wants to explore the feasibility of applying hypofractionation for prostate cancer in a low-income country setting, taking into consideration available techniques, quality assurance and toxicity profile. Patients with intermediate risk prostate cancer will be treated with 20 fractions of 3Gy, according to the CHHiP schedule (5), and high-risk patients with 20x3.1Gy (13). Acute and late grade ≥2 late gastro-intestinal and genitourinary toxicity will be evaluated using validated questionnaires up to 24 months after completion of radiotherapy. Also failure-free survival, relapse-free survival, overall survival, and cost-effectiveness of hypofractionation will be evaluated.

The gold standard technique for hypofractionation includes image-guided radiotherapy (IGRT) with 3-4 implanted gold fiducials, though this is not mandatory (5). CT scan-based treatment planning with MRI fusion allows for accurate volume delineation and may be used. Inversely planned intensity modulated radiotherapy (IMRT) is the ideal for treatment delivery. In resource-constrained settings, a reasonable option when IMRT techniques are not available, is modified forward planning with the field-in-field technique, or three-dimensional (3-D) conformal therapy with higher energies. Position verification prior to every fraction with electronic kilovoltage or megavoltage portal imaging or X-ray volumetric imaging ensures accurate delivery. A technical protocol (delineation, dose constraints, dose requirements), including quality assurance, will be provided when performing the trial.

In summary, several randomised clinical trials have shown the efficacy and safety of hypofractionated EBRT for prostate cancer. Hypofractionation offers economic and logistic advantages, reducing the burden of the very limited radiotherapy resources in most African countries and it increases patient convenience. The answer to the question is therefore, yes, hypofractionated radiotherapy for prostate cancer is an option for Africa, pending trials in the local setting.

 References

  1. Parkin DM, Bray F, Ferlay J, Jemal A. Cancer in Africa 2012. Cancer Epidemiol Biomarkers Prev 2014;23:953–966. https://doi.org/10.1158/1055-9965.EPI-14- 0281.
  2. Wolff RF, Ryder S, Bossi A, et al. A systematic review of randomised controlled trials of radiotherapy for localised prostate cancer. Eur J Cancer 2015;51:2345–67.
  3. Brenner DJ, Martinez AA, Edmundson GK, Mitchell C, Thames HD, Armour EP. Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52:6–13.
  4. Incrocci L, Wortel RC, Ghidey AW, Aluwini S, Schimmel E, Krol S, van der Toorn PP, de Jager H, Heemsbergen W, Heijmen B, Pos F. Hypofractionated versus conventionally fractionated radiotherapy for localized prostate cancer; five-year relapse-free survival from the randomised phase III HYPRO trial. Lancet Oncol 2016;17:1061-9.
  5. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomized, non-inferiority, phase 3 CHHip trial. Lancet Oncol 2016:17:1047-60.
  6. Lee WR, Dignam JJ, Amin MB, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol 2016;34;2325-2332.
  7. Catton CN, Lukka H, Gu CS, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol 2017:35;1-7.
  8. Morgan SC, Hoffman K, Loblaw DA et al. Hypofractionated radiation therapy for localized prostate cancer: Executive summary of an ASTRO, ASCO, and AUA evidence-based guideline. Practical Rad Oncol 2018;8:354-360.
  9. Swanson W, Kamwa F, Samba R, et al. Hypofractionated radiotherapy capacity in African cancer centers. Front Oncol 2020; doi: 10.3389/fonc.2020.618641.
  10. Atun R, Jaffray DA, Barton MB, et al. Expanding global access to radiotherapy. Lancet Oncol 2015;16: 1153–86.
  11. Irabor OC, Swanson W, Shaukat F, et al. Can the adoption of hypofractionation guidelines expand global radiotherapy access? An analysis for breast and prostate radiotherapy. J Glob Oncol 2020;6:667-78.
  12. Incrocci L, Heijmen B, Kupelian P, Simonds HM. Hypofractionation and prostate cancer: A good option for Africa? South Afr J Oncol 2017;1(0);1-3.
  13. Arcangeli G, Saracino B, Arcangeli S, et al. Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial. J Clin Oncol 2017;35:1891-1897.

Prof. Luca Incrocci

MD PhD, Erasmus MC

Luca Incrocci is Professor of Genito-Urinary Radiotherapy at the Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands. He received his MD in 1992 at the University of Pisa, Italy, and then joined the University Hospital Rotterdam to complete residencies in the Departments of Urology and Radiation Oncology.

His current research is focused on Quality of Life of cancer patients and on the development of radiation techniques to improve treatment outcome and to decrease side effects of radiation therapy for genito-urinary malignancies.

He is actively involved in international programs to provide education and improve radiation therapy access in African countries. He has been a member of the UICC’s Global Task Force on Radiotherapy for Cancer Control and an advisor for developing radiotherapy facilities and PhD programs in Ethiopia. He is part of the Win-Win initiative of the Harvard Global Health Catalyst, and he recently launched his foundation (www.LucaIncrocciFoundation.org) to improve cancer care in Ethiopia.

Prof. Incrocci is member of several scientific societies, he is actively involved in teaching and supervising fellows and PhD students and is author of more than 150 peer-reviewed papers, reviews, book chapters.