In this study, we show that the incidental pelvic nodal doses are very low with IMRT and VMAT techniques in patients with nonmetastatic MIBC receiving TMT with bladder-only irradiation. However, it is noteworthy that the rate of regional failure in our cohort is quite low despite inadequate incidental nodal doses for microscopic disease eradication.

Trimodality therapy, as an organ-preserving approach, is currently one of the most commonly applied treatments in eligible patients and includes maximal TUR followed by definitive CRT [15]. Although there is currently no prospective randomized study comparing radical cystectomy with TMT, it has been stated that both treatment modalities provide similar survival rates based on the results of several studies [3, 4, 11, 16]. Although TMT is currently recommended by many centers for patients who met the eligibility criteria for an organ-sparing approach, TMT protocols also vary widely between centers. The benefits of concurrent CHT for medically fit patients and maximal TUR before CRT are well defined for patients receiving TMT and do not vary much worldwide [11]. On the contrary, there is no optimal standard protocol for simulation, target volume delineation, and dose prescription. Previously, we have reported our gemcitabine-based TMT outcomes without ENI for patients with non-metastatic MIBC [13]. However, the RT techniques employed in that study were either 3DCRT or IMRT/VMAT.

In a dosimetric study of 20 patients, pelvic lymphatics received high radiation doses incidentally in patients undergoing 3DCRT, even without ENI [12]. Approximately 35% of the failure patterns in patients treated with TMT are locoregional recurrences ± distant metastasis [17]. Among the underlying reasons why the survival benefit of ENI has not yet been proven in any studies and its role in TMT is controversial, there is the possibility of incidental irradiation of pelvic lymphatics in patients receiving bladder-only irradiation [18, 19]. In the results of a recently published large National Cancer Database study from the United States, ENI did not improved OS as compared with bladder-only irradiation for 2104 patients with T2-T4N0M0 MIBC. However, it should be taken into consideration when evaluating these results that 83.7% of the patients who received bladder-only irradiation were treated with a 3DCRT technique, and incidental nodal doses may be sufficient for microscopic disease eradication, at least in a significant portion of patients. On the other hand, IMRT and VMAT provide better OAR preservation as compared to 3DCRT, and incidental nodal doses may not be as high as in 3DCRT with IMRT and VMAT techniques.

The largest bladder-sparing trial to date, the Bladder Cancer 2001 (BC2001) trial from the United Kingdom, demonstrated the benefit of addition of CHT to RT for both locoregional control and disease-free survival [10]. Unlike most of the RTOG studies, ENI was not performed in the BC2001 trial and bladder-only irradiation was administered to the patients. The regional failure rate was found to be approximately 5% [20, 21]. However, the RT technique used in the BC2001 trial was also 3DCRT. Thus, the possibility of incidental nodal irradiation should be taken into consideration when interpreting the results. Currently, no data exist comparing IMRT- or VMAT-based bladder-only irradiation vs. bladder + ENI approaches. To the best of our knowledge, our study is the first to investigate incidental nodal doses with bladder-only irradiation in the era of IMRT and VMAT. The results of our study show that incidental nodal doses with bladder-only irradiation applied with modern techniques are lower than in historical 3DCRT series. Despite low incidental nodal doses, the regional failure rate was only 2.5% in our study. On the other hand, the only lymphatic recurrence developed from a low-dose-painted area. In the study by Baumann et al. [22], the 5‑year pelvic recurrence rate was reported as 28% in patients with ≥ pT3 tumors and as 8% in patients with ≤ pT2 tumors after radical cystectomy. They proposed that in cases of stage ≥ pT3 with negative margins, RT should include targeting the iliac and obturator nodes at a minimum. Additionally, for cases of stage ≥ pT3 with positive margins, coverage of the presacral nodes and cystectomy bed may be required. On the other hand, since patients treated with TMT generally have T2 tumors, it remains uncertain from the current literature whether there is a particular lymph node level that requires a higher radiation dose. Although there is no universally accepted standard definition of radiation dose for microscopic disease eradication, there are studies demonstrating the effectiveness of doses ranging from 30 to 50 Gy in various tumor types [23, 24]. Hence, in our study, we also analyzed the volumes of V40 Gy, revealing that even in the obturator lymphatic region, where this ratio peaks, it remained below 50% of the prescribed dose with IMRT and VMAT.

In addition to ENI, there are also surgical studies examining the role of treatment intensification towards lymphatics on oncological outcomes. The role of extended pelvic lymphadenectomy (EPL) during radical cystectomy was evaluated in a recent phase III randomized controlled trial, SWOG-1011, the results of which were presented at the American Society of Clinical Oncology 2023 Annual Meeting (NCT01224665). In standard lymphadenectomy, the obturator, external iliac, and internal iliac lymphatics were removed. In EPL, the common iliac, presciatic, and presacral lymphatics were also removed in addition to the standard lymphadenectomy. In the results, EPL did not improve OS and DFS as compared with standard lymphadenectomy. In addition, EPL was also associated with higher rates of toxicity.

Although our study is the first to show that high incidental nodal doses are not valid in the era of IMRT/VMAT, and current margin concepts for patients receiving TMT with bladder-only irradiation, it also has some limitations. First, the small retrospective cohort size with a short follow-up limits the generalizability of our findings. Secondly, various clinical and pathological features that may be related to regional recurrence could not be evaluated, and the low regional recurrence rate in our findings requires careful interpretation due to the focus on dosimetric analyzes of the study.