Older patients with localized prostate cancer frequently have comorbidities that complicate decisions about curative treatment. Some may not be suitable candidates for surgery, while concerns about radiotherapy toxicity, prolonged androgen deprivation therapy, and competing health risks can also lead to less intensive treatment or the omission of curative-intent therapy.
A retrospective study of 226 men aged 75 years or older evaluated personalized ultra-hypofractionated radiotherapy, delivered in five fractions with or without androgen deprivation therapy, for unfavorable intermediate-, high-, or very high-risk localized prostate cancer. The findings suggest that a tailored five-fraction radiotherapy strategy may provide encouraging short- to mid-term disease control with a generally favorable safety profile in carefully selected elderly patients.
The article, titled “An overlooked opportunity? SBRT + ADT for aggressive prostate cancer in the elderly,” was published online as an article in press in Clinical and Translational Radiation Oncology on July 17, 2026.
Authors: Chiara Lorubbio, Ilaria Repetti, Federico Mastroleo, Maria Giulia Vincini, Sara Gandini, Sofia Netti, Karl Amin, Stefano Luzzago, Francesco Alessandro Mistretta, Sarah Alessi, Constantinos Zamboglou, Felipe Counago, Simon K.B. Spohn, Marcin Miszczyk, Giuseppe Petralia, Gennaro Musi, Ottavio De Cobelli, Roberto Orecchia, Giulia Marvaso, and Barbara Alicja Jereczek-Fossa.
Study Design and Patient Population
This retrospective, single-institution study included 226 men aged 75 years or older who received curative-intent ultra-hypofractionated radiotherapy for localized prostate cancer between January 2012 and December 2021. Eligible patients had histologically confirmed, clinically node-negative and nonmetastatic disease classified as unfavorable intermediate-, high-, or very high-risk according to National Comprehensive Cancer Network criteria.
The primary endpoint was biochemical relapse-free survival. Biochemical recurrence was defined according to the Phoenix criteria as an increase in prostate-specific antigen of at least 2 ng/mL above the nadir.
Secondary endpoints included clinical progression-free survival and overall survival. Clinical progression was defined as radiologically confirmed disease progression occurring after biochemical recurrence. The median age at radiotherapy was 79 years, and the median Charlson Comorbidity Index was 4.
Of the 226 patients:
- 107, or 47%, had unfavorable intermediate-risk disease;
- 111, or 49%, had high-risk disease;
- 8, or 4%, had very high-risk disease.
Common comorbidities included diabetes, peripheral vascular disease, previous malignancy, and cerebrovascular disease. Antiplatelet and anticoagulant treatments were being used by 35% and 14% of patients, respectively.
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Five-Fraction Radiotherapy and ADT
All patients received image-guided ultra-hypofractionated radiotherapy to the prostate in five fractions administered on alternate days. The total prostate dose ranged from 32.5 Gy to 36.25 Gy, corresponding to 6.5–7.25 Gy per fraction. Elective pelvic lymph-node irradiation was not performed.
When multiparametric magnetic resonance imaging was available, a simultaneous integrated boost of 37.5–40 Gy was delivered to the dominant intraprostatic lesion. This boost was administered to 98 patients, representing 43.4% of the cohort. Androgen deprivation therapy was individualized according to age, disease risk, Karnofsky Performance Score, and comorbidities, with cardiologic assessment performed for patients with significant cardiovascular comorbidities.
A total of 165 patients, or 73%, received androgen deprivation therapy for a median duration of 12 months. The remaining 61 patients did not receive hormonal treatment. According to the study discussion, ADT was frequently omitted in patients with significant comorbidities, particularly cardiovascular disease.
Biochemical and Clinical Outcomes
Median follow-up, calculated among surviving patients, was 2.3 years. Follow-up data were available for 217 of the 226 patients, of whom 44, or 20%, experienced biochemical recurrence. Among the 44 patients with biochemical recurrence, 31, or 70%, subsequently developed radiologically confirmed clinical progression. The median time to biochemical recurrence was 2.34 years.
Biochemical relapse-free survival was:
- 98% at 1 year;
- 88% at 2 years;
- 82% at 3 years.
Clinical progression-free survival was:
- 99% at 1 year;
- 92% at 2 years;
- 86% at 3 years.
Patients who developed clinical progression predominantly had high-risk or unfavorable intermediate-risk disease. Among the 31 patients who developed clinical progression, 19, or 61%, had oligoprogressive disease. Nine progression events involved the irradiated treatment field. At the last follow-up, 76.1% of patients were alive and disease-free, while 19% were alive with disease. A total of 2.7% had died, with all deaths attributed to causes unrelated to prostate cancer. Five patients, or 2.2%, were lost to follow-up.
ADT and Radiation Dose
No statistically significant association was identified between biochemical relapse-free survival or clinical progression-free survival and ADT use, ADT duration, simultaneous integrated boost, or the other evaluated clinical and treatment variables. Among evaluable patients, biochemical recurrence occurred in 19.5% of those who received ADT and 22.4% of those who did not.
However, ADT was not randomly assigned. Its use and duration were based on clinical judgment, disease risk, age, performance status, comorbidities, and cardiovascular health. The absence of a statistically significant association should therefore not be interpreted as evidence that ADT provides no oncological benefit. No significant difference in oncological outcomes was observed between patients treated with 35 Gy and those treated with 36.25 Gy.
The 14 patients who received 32.5 Gy were excluded from the formal dose comparison because of the small subgroup size. Seven developed biochemical recurrence and four developed clinical progression. Although these rates suggested a possible dose-response relationship, the small number of patients prevented a definitive conclusion.
Treatment-Related Toxicity
The five-fraction treatment was generally well tolerated. A total of 91% of patients experienced no acute gastrointestinal toxicity, while 56% experienced no acute genitourinary toxicity. Grade 2 or higher acute genitourinary toxicity occurred in 19 patients, while six patients experienced grade 2 acute gastrointestinal toxicity. No acute grade 3 or higher gastrointestinal toxicity was reported.
Grade 3 or higher toxicity was uncommon. Two acute grade 3 or higher genitourinary events were reported and had resolved by the final follow-up. One late grade 3 gastrointestinal event due to actinic proctitis was also reported. Overall, late toxicity was generally favorable.
Older age and a higher Charlson Comorbidity Index were significantly associated with an increased risk of acute genitourinary toxicity. Larger prostate clinical target volumes were significantly associated with acute gastrointestinal toxicity. No evaluated clinical or treatment-related factor was significantly associated with late genitourinary or gastrointestinal toxicity. Antiplatelet and anticoagulant therapy were not significantly associated with either acute or late grade 2 or higher toxicity.
Androgen deprivation therapy was also reported to be well tolerated. No toxicity above grade 1 was documented during hormonal treatment, with hot flashes and fatigue among the mild symptoms described.
Limitations
The study was retrospective and conducted at a single institution, creating a risk of selection bias and incomplete or nonuniform reporting. Treatment was heterogeneous, including differences in radiotherapy dose, use of an intraprostatic boost, and the administration and duration of ADT.
Imaging practices also changed during the study period. Prostate-specific membrane antigen positron emission tomography was introduced at the institution in 2019, meaning that some patients treated earlier may have been understaged.
The median follow-up of 2.3 years was relatively short for localized prostate cancer, limiting conclusions about long-term disease control, delayed oncological events, and very late toxicity. The study also lacked prospectively collected patient-reported outcomes and a formal quality-of-life assessment.
Takeaway
Personalized five-fraction ultra-hypofractionated radiotherapy, with or without androgen deprivation therapy, provided encouraging short- to mid-term disease control with a generally favorable safety profile in elderly patients with unfavorable intermediate-, high-, or very high-risk localized prostate cancer.
The findings suggest that advanced age and comorbidities should not automatically exclude carefully selected patients from curative-intent radiotherapy.
However, the retrospective design, individualized treatment selection, limited follow-up, and small number of events prevent definitive conclusions regarding the optimal radiotherapy dose or the use and duration of ADT. Prospective studies with longer follow-up and quality-of-life assessment are needed.
The full article is available in Clinical and Translational Radiation Oncology.
