Elective pelvic nodal irradiation in elderly men treated with hypofractionated radiotherapy

We thank Professor Iori and colleagues for their thoughtful commentary on our analysis of ultrahypofractionated (UHRT) versus moderately hypofractionated (MHRT) versus conventionally fractionated radiotherapy (CFRT) to the prostate in the setting of elective pelvic nodal irradiation (EPNI) for men with unfavourable prostate cancer [1]. The patients included were largely ≥70 years old [1]. With almost 6 years of follow-up, there were no differences in oncologic outcomes between the groups [1].

We observed increased late grade ≥ 2 and ≥ 3 gastrointestinal (GI) toxicity for patients treated with MHRT, where age was significantly associated with higher risk of late grade ≥ 2 GI toxicity [1]. It remains unclear why MHRT was associated with worse late GI toxicity and why there was an association with age; importantly, this was not seen in the UHRT group. Reassuringly, other phase 3 randomized studies of MHRT versus CFRT including PCS5 [2] and POP-RT [3], [4] did not demonstrate worsening late GI toxicity and no age association with toxicity, providing further reassurance of the safety of MHRT, including in elderly patients. Further efforts to reduce dose to the rectum through rectal spacers, which were not utilized in these studies, is also a consideration for patients.

We also demonstrated that UHRT was associated with worse acute grade ≥ 2 genitourinary (GU) toxicity, with no association with patient age, and no worse acute grade ≥ 3 GU toxicity [1]. This toxicity seemed to be transient, as there was no worsening of late GU toxicities [1]. Further reassuringly, an interim analysis from the PRIME trial (NCT03561961) of UHRT versus MHRT EPNI did not show differences in acute grade ≥ 2 GU toxicity [5].

While UHRT and MHRT appear safe when delivering EPNI, our study did not address the role of EPNI compared to prostate-only RT, which Iori et al address. To date, the data supporting EPNI (irrespective of fractionation) remains controversial with negative older trials including GETUG-1 [6], [7] and RTOG-9413 [8], [9]. We continue to await the results from RTOG-0924 (NCT01368588) which has completed accrual. Currently, the most relevant contemporary study testing EPNI versus prostate only RT is the POP-RT trial, which demonstrated significant improvement with EPNI, both for 5-year biochemical failure free survival (95 % with EPNI versus 81.2 % with prostate-only RT; HR 0.23), and 5-year distant metastasis-free survival (95.9 % with EPNI versus 89.2 % with prostate-only RT; HR 0.35) [4]. Based on POP-RT, patients who do not receive EPNI may be up to approximately 4 times more likely to need androgen deprivation therapy (ADT) to manage biochemical failure and/or distant metastasis, with its own side effect profile and impact on long-term prognosis.

Ultimately, we support recommendations for the use of EPNI for patients at high risk of harboring nodal disease. However, assessment of individual patients including their values, medical comorbidities, and estimates of personal risks of toxicities should guide well-informed discussions to determine a person-centred treatment plan.

Disclosures:

RMG reports honoraria from Bayer, Tolmar, Knight, and TerSera; Research funding from Astellas and TerSera.

AL reports honoraria/travel from AbbVie, Astellas, Bayer, Janssen, Knight, TerSera; Grant/research support from TerSera and Tolmar; Advisory boards/consulting for Astellas, Bayer, Janssen, Sanofi, Tolmar and TerSera; Patents/licenses for endorectal immobilization device (GU-Lok); Employment: spouse is national sales director, Sanofi Canada.

PC reports honoraria from TerSera and AstraZeneca.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.