The doses to Organs at risk and their Proximity to target volumes are crucial Determinants of brachytherapy toxicity

Dear Editor,

We congratulate Schweizer and colleagues for their comprehensive study investigating postoperative brachytherapy's long-term efficacy and toxicity in pT1/2pN0 oral cavity squamous cell carcinoma (OCSCC) patients [1]. The disease-free- (DFS) and overall survival (OS) rates at 60 and 180 months were 81.2 %, 75.9 %, and 77.9 %, 41.4 %, respectively. Grade 3 soft tissue necrosis (STN) and osteoradionecrosis (ORN) were each reported in 7 % of the patients. A clinical target volume (CTV) > 15 cm³ was significantly associated with both of the development of STN (p = 0.011) and ORN (p = 0.004). Although the current findings offer valuable insights, it is crucial to address two essential issues to gain a more comprehensive interpretation of the study results.

First, Schweizer and colleagues identified that a CTV > 15 cm³ is associated with significantly elevated risks of STN and ORN [1]. This observation underscores the crucial impact of the dose-volume effect, indicating that larger volumes exposed to high radiation doses can lead to increased long-term toxicity rates, including STN and ORN [2], [3]. It is crucial to emphasize that, particularly in the context of ORN, the distance of the CTV from the mandible may hold greater significance than the actual size of the CTV. This assertion is based on the observation that a narrower distance between the CTV and the mandible correlates with an increased risk of ORN development than a wider distance, as the mandible is subject to higher radiation doses in cases with a narrower distance between the CTV and the mandible, assuming that the prescribed doses remain constant for both conditions. For example, a floor-of-the-mouth tumor that is situated only 1-mm from the mandible will indisputably present a significantly higher risk of developing ORN compared to a tumor located on the mobile tongue that is 10-mm away from the mandible, assuming both tumors are receiving the same prescribed dose. Therefore, analyzing the data per the distance between the CTV and mandible and the exclusive doses received by the mandible may be valuable, potentially yielding relevant cut-offs for each parameter associated with increased ORN risk [4].

And second, while the survival endpoints were not explicitly defined, the data presented by Schweizer and colleagues indicates that the DFS rates are higher than the OS rates. For instance, at 180 months, the DFS rate was 75.9 %, compared to an OS rate of 41.4 %. However, according to statistical principles, DFS cannot have superior median survival durations or rates at specified time points [5], [6]. In this respect, the authors likely did not consider deaths as a significant event, even though this is required by the definition of DFS: as disease-free (DF) + survival (S). Therefore, the estimates presented by the authors should be interpreted as disease-free estimates rather than true DFS outcomes. Unfortunately, some other researchers also practice a comparable methodology without sufficient justification, making comparing their outcomes with existing literature challenging [7], [8]. Therefore, survival endpoint definitions must adhere to established rules to facilitate dependable comparisons among similar studies and bolster the credibility of research findings.

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.