Despite evidence supporting its effectiveness, HT remains infrequently used for rectal cancer treatment, even in the era of advanced multimodal therapies such as TNT. For decades, HT has been recognized for its potential to enhance the efficacy of radiotherapy and chemotherapy. Specifically, HT enhances the efficacy of treatments by increasing drug uptake and by inhibiting DNA repair mechanisms and heat-dependent immunological reactions, e.g., through heat-shock proteins and other apoptotic pathways [26, 27]. However, its integration into routine clinical practice has been limited, likely due to logistical challenges, insufficient clinical data, and lack of standardized protocols. This limited use highlights a significant gap in achieving the full therapeutic potential of HT, particularly in improving outcomes for patients with LARC.

For many years, HT in combination with radiotherapy and/or chemotherapy was not considered for neoadjuvant treatment. In oncology, the efficacy of HT was demonstrated for high-risk soft-tissue sarcomas in a randomized phase III trial, which showed that adding deep HT to standard chemotherapy was beneficial. This approach significantly and sustainably improved local control and OS in patients [23]. The R0 resection rate, a measure of local response, was also increased from 42% with neoadjuvant chemotherapy to 51% with HT [23].

In rectal cancer, the potential role of regional HT is increasing, as recently demonstrated in several clinical trials. A phase II study added regional HT to standard preoperative CRT, resulting in a high CR rate and improved long-term recurrence-free survival [24]. The present study demonstrated an overall CR rate of 39%, which is approximately 10% higher than the rate observed in a comparable approach without deep HT (ARO 04). Schroeder et al. [21] also demonstrated in their analysis that the addition of effective HT increases the rates of CR by approximately 10%. In both patient collectives, CR was associated with improved survival. Due to limited follow-up data, a correlation of increased CR rates with improved DFS and OS was not considered in our analysis.

In the TNT concept, the CAO/ARO/AIO-12 trial compared CRT plus induction or consolidation chemotherapy for LARC [18]. This trial is of special interest since the treatment regimen of arm B (additional HT) was comparable to the treatment applied in our study population. Taking into account the limited comparability between studies, the cCR rate (18%, 95% CI: 8–29%) significantly exceeded historical CAO/ARO/AIO-12 benchmarks (3%, p = 0.005), indicating superior clinical complete response. Overall CR rates showed numerical improvement (39% vs. 28%, p = 0.122), while pCR rates were comparable to controls (20% vs. 25%, p = 0.425). Moreover, observed pCR rates in our population were comparable to those from the UNICANCER-PRODIGE 23 trial (28%) that investigated neoadjuvant chemotherapy with FOLFIRINOX followed by chemoradiotherapy, surgery, and adjuvant chemotherapy in LARC [5]. Similarly, the RAPIDO trial evaluating short-course radiotherapy followed by chemotherapy before total mesorectal excision showed pCR rates of 28% in the experimental group, indicating the increased efficacy of preoperative chemotherapy in LARC [6]. Both trials showed lower frequency of cCR rates followed by watch-and-wait strategies (1% and 3%, respectively). Although our study primarily focused on early efficacy endpoints and survival data remain immature, patients achieving cCR demonstrated sustained disease-free status. These findings highlight the durable efficacy of TNT incorporating HT. However, these findings are based on a small cohort and should be interpreted with caution, as the data are preliminary and limited by the duration of follow-up.

The results of our study are consistent with other studies showing that the addition of HT can improve complete remission rates by about 10%. Furthermore, Gani et al. [28] and Ott et al. [19] showed the feasibility of HT, with high efficacy and comparably minimal acute and late toxicities.

Nevertheless, the addition of HT treatment leads to increased tumor regression and increases the rates of sphincter-preserving operations by about 20% [20]. The decision to preserve the sphincter using surgical techniques or to follow a watch-and-wait approach is challenging and depends on the surgeon’s expertise and mindset. Since five patients in our study had rectal extirpation after achieving pCR, it is important to discuss whether a watch-and-wait approach or surgery is more beneficial in terms of quality of life, recurrence, and OS. This requires careful, individual, case-by-case decision-making and should be evaluated in prospective studies.

All these studies suggest that HT, when combined with chemotherapy and radiation, may enhance treatment efficacy in rectal carcinoma. In a recently published systematic review and meta-analysis, including 12 studies and 760 cases of locally advanced rectal cancer, neoadjuvant CRT in combination with deep regional HT achieved a pCR rate of 19%. With classic neoadjuvant CRT using 5‑FU or capecitabine, pCR rates of approximately 10% can be achieved [29]; adding HT could thus increase pCR rates by approximately 10%. In conclusion, better response rates and higher downstaging rates are associated with a better prognosis [11].

Moreover, the frequency and mean temperature during HT may influence the therapy outcome in patients with LARC [28]. In patients with fewer than six HT sessions (n = 7), the CR rate was slightly reduced (29%); however, this is limited by the low number in our study population. Schroeder et al. [24] found that at least four HT treatments in combination with neoadjuvant RCT achieved a significantly increased pCR rate of 22.5% compared to treatment without HT (p = 0.043). Interestingly, our data showed that higher mean temperatures during HT treatment were associated with higher rates of sphincter preservation. The positive effect of higher HT temperatures on LARC outcomes is consistent with a study that showed improved recurrence-free survival rates depending on the HT treatment temperature [28]. It is suggested that higher cumulative thermal exposures in terms of frequency or mean temperature could improve patient outcomes. Nevertheless, the findings of our study should be interpreted with caution due to the limited sample size and the potential influence of outliers and confounding factors.

The present study has several important limitations. As a single-center retrospective analysis with a limited number of patients it is subjected to selection bias and limited external validity. The limited availability of long-term follow-up data on OS and DFS, as well as tumor regrowth rate, restricts the assessment of long-term outcomes. Furthermore, the variability among surgeons performing the procedures may have introduced inconsistencies in surgical technique and patient outcomes. Moreover, the absence of a standardized watch-and-wait protocol could influence the outcomes. Additionally, the limited availability of detailed tumor biology data, including molecular and genetic characteristics, may confine the identification of potential prognostic and predictive factors. This analysis was restricted to short-term toxicity, and late toxic events were not evaluated. Future analyses with prolonged follow-up data are needed in order to consider tumor regrowth, DFS, and OS as important clinical endpoints.