Robust combination of modulated electro-hyperthermia on preoperative image-guided radiotherapy 5×5 Gy in advanced rectal-sigmoid colon cancer—a case report

Introduction

Background

Colorectal cancer (CRC) ranks as the third most prevalent malignancy globally and is the second leading cause of cancer-related mortality (1). Surgical intervention remains a cornerstone in the management of rectal cancer (2,3). Emerging evidence from multiple randomized trials has established that the incorporation of preoperative short-course radiotherapy (SCRT) of 5×5 Gray (Gy) significantly mitigates the risk of local recurrence (4-7), thus becoming a standard treatment modality for rectal cancer. The timing of surgery post-SCRT, categorized into SCRT-direct surgery (where surgery is recommended within 13 days post-SCRT completion) (4-8), and SCRT-delay surgery (where surgery is advised 4–8 weeks after SCRT), has been a subject of investigation. While SCRT-delay surgery has demonstrated certain advantages over SCRT-direct surgery due to higher rates of pathological complete response (pCR) and tumor downstaging (9-12), there are risks for progression during the interval especially for patients who decline systemic treatment.

Rationale and knowledge gap

Modulated electro-hyperthermia (mEHT) has gained attention as a therapy that synergistically enhances tumor response when combined with radiotherapy (RT). This combination therapy is particularly advantageous for tumors exceeding 65 mL in volume (13). The mEHT is postulated to selectively target cancer cells, sparing normal tissue, and modulate hypoxia-inducible factor 1-alpha (HIF-1α) and its downstream genes (14,15), potentially facilitating tumor downstaging and improving surgical resection outcomes within a shorter timeframe. Despite the theoretical benefits, the clinical efficacy of integrating mEHT with SCRT in CRC remains underexplored. To our knowledge, no published case reports have documented the real-world application of this combination as a neoadjuvant treatment for advanced rectal-sigmoid colon cancer.

Objective

Here, we present a case of a 59-year-old female with advanced recto-sigmoid colon cancer (cT4bN1aM0, stage IIIC), who underwent neoadjuvant treatment with SCRT and mEHT. This case report aims to evaluate the feasibility and effectiveness of this novel combination therapy, with a focus on tumor regression, surgical outcomes, and potential implications for preoperative treatment strategies. By documenting this case, we aim to provide insight into the role of mEHT in optimizing neoadjuvant therapy and enhancing quality of life in CRC patients. We present this article in accordance with the CARE reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-24-17/rc).

Case presentation

A 59-year-old female with a notable medical history of early-stage breast cancer treated with simple mastectomy 10 years ago with complete remission and with annual follow-up. For her hypertension, and type 2 diabetes mellitus, she was on a multiple antidiabetic regimen, including linagliptin [5 mg per os (p.o.) quaque die (qd.)], repaglinide (0.5 mg p.o. qd.), and subcutaneous insulin glargine (8 IU qd) for glycemic control. Hypertension was controlled by a fixed-dose combination (Sevikar HCT p.o. qd.) containing olmesartan (40 mg), amlodipine (5 mg), and hydrochlorothiazide (12.5 mg). She was admitted to the emergency department presenting with hematochezia, decreased appetite, tenesmus, general weakness, and nausea. These symptoms contributed to a significant weight loss, from 72 to 62 kg, over the course of a month. An extensive evaluation led to the discovery of a colorectal mass accompanied by intraabdominal abscess formation. Laboratory findings indicated leukocytosis and elevated C-reactive protein levels (12.65 mg/dL, normal range: 0–1 mg/dL), signaling an inflammatory response. Tumor markers of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were also elevated (CEA 7.4 mg/dL, normal range: 0–5 mg/dL; CA19-9 80 U/mL, normal range: <27 U/mL). Diagnostic imaging with abdominal computed tomography (CT) revealed a large mass, measuring approximately 8.1 cm × 6.6 cm at the recto-sigmoid colon junction, with extra-serosal invasion into the urinary bladder. Additionally, the mass had caused perforation leading to an adjacent abscess and focal peritoneal thickening, suggestive of tumor infiltration. Several small regional lymph nodes were identified, raising concerns for lymphadenopathy. Sigmoidoscopy facilitated tumor biopsy at recto-sigmoid junction which revealed necrotic tissue and colonic mucosal tissue with highly dysplastic cells compatible with lamina propria extension, considered at least intramucosal adenocarcinoma. Laparoscopic drainage of the intraabdominal abscess along with transverse colostomy was conducted post-diagnosis. CT imaging and histopathological evaluations confirmed a diagnosis of recto-sigmoid colon adenocarcinoma, staged as cT4bN1aM0, stage IIIC (Figure 1).

Figure 1 Histopathological findings of colorectal carcinoma (H&E, 100×). Histopathological findings showed highly atypical tall columnar cells with pseudostratified nuclei arranged in cribriform or garland growth pattern and abundant intraluminal necrosis. The features were characteristic of a primary colorectal adenocarcinoma. H&E, hematoxylin and eosin.

Given the tumor’s advanced stage, a tailored treatment strategy was devised, comprising a short course of direct RT (25 Gy in 5 fractions) utilizing image-guided helical tomotherapy (HT), paired with mEHT (EHY-2030, Oncotherm, Hungary, Germany) twice in a week. The patient received surgery within 13 days post-SCRT completion that would be categorized as SCRT-direct surgery. The mEHT treatment employed capacitive-coupling with an amplitude-modulated 13.56-MHz radiofrequency, which the patient tolerated well without significant adverse events. The mEHT procedure was usually administered twice weekly with each session scheduled for 60 minutes, following a gradual escalation protocol to optimize treatment efficacy. The stepwise power adjustment starts at 80 W for the initial 10 minutes, progressively increasing to 100 W for the subsequent 10 minutes, and further escalating to 180 W for another 10 minutes. During the final 30 minutes of treatment, the power output was modulated based on the patient’s tolerance and subjective discomfort, ensuring safety while maintaining therapeutic efficacy, with a maximum threshold of 240 W.

Subsequent CT imaging demonstrated a remarkable tumor response, with the initial volume of 492.33 mL reducing to 291.77 mL, a 40.7% decrease. Hematochezia also subsided in the following week after start of the mEHT procedure. Thirteen days after the neoadjuvant mEHT therapy, an anterior resection and partial cystectomy were successfully performed. The pathological examination of the resected specimen revealed moderately differentiated adenocarcinoma penetrating through the muscularis propria into the peri-colorectal tissues, without evidence of regional lymph node metastasis. The clearances of proximal, distal, and radial margins were confirmed, classifying the postoperative tumor stage as ypT3N0M0, stage IIA. Figure 2 shows a clinical timeline of key events from diagnosis to treatment and follow-up. After surgery, the patient’s symptoms significantly improved. General weakness improved and the patient gained weight after nutritional support. Her appetite recovered within 2 weeks after surgery. CEA level returned to normal range (3.2 mg/dL, normal range, 0–5 mg/dL) 1 month after surgery. Although CA19-9 level was still slightly above normal range (36.9 U/mL, normal range: <27 U/mL), but both tumor markers remained stable during follow-up. CT imaging at 3 months after surgery showed no evidence of local recurrence or metastasis. Colonoscope performed at 2 months post-operation also showed fair healing and ecchymosis of anastomosis site with no other abnormality. Thus, colostomy closure was arranged and the patient tolerated the whole process smoothly. Follow-up of CT images at 6 months and 1 year after colostomy closure showed no evidence of local recurrence. No focal lesions were seen in the chest or abdomen. The patient returned to normal life and kept regular follow-up at our out-patient department. A visual timeline of the patient’s clinical course is shown in Figure 2.

Figure 2 Visual timeline summarizing the clinical course. The timeline illustrates key events from initial diagnosis to neoadjuvant therapy and surgical management. H&E, 100×. CT, computed tomography; H&E, hematoxylin and eosin; IGRT, image-guided radiotherapy; M, metastasis; mEHT, modulated electro-hyperthermia; N, node; OP, operation; T, tumor.

Ethical considerations

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case report illustrates the significant benefits of integrating mEHT with short-course image-guided radiotherapy (IGRT) as a neoadjuvant treatment for advanced recto-sigmoid colon cancer. The observed substantial reduction in tumor size following the combined mEHT and IGRT intervention resulted in downstaging the cancer from stage IIIC to stage IIA. This outcome is particularly significant as it facilitated a more straightforward surgical procedure, suggesting that the synergistic use of mEHT and IGRT can enhance surgical operability and improve patient prognosis.

Preoperative SCRT has been recognized for its role in reducing the local recurrence rate of rectal cancer, thus becoming a standard of care (4-7). HT employs a specialized intensity-modulated radiotherapy (IMRT) system, enabling the delivery of highly conformal dose distributions via helical volumetric IMRT (16,17). This method is notably effective in sparing critical organs, thanks to its precision and the use of image-guided (IG) techniques. Comparative dosimetric studies have demonstrated that HT significantly reduces the volume of normal tissue exposed to high-dose RT in patients with lower gastrointestinal cancers, as opposed to traditional three-dimensional (3D)-conformal RT (18,19) or IMRT (20). This precision in targeting the tumor site is associated with decreased rates of both acute and late severe gastrointestinal toxicities (21,22).

The mEHT, on the other hand, operates through a distinct mechanism. It disrupts the tumor microenvironment, induces the production of heat shock proteins, and enhances immune responses. These processes collectively facilitate tumor regression. Experimental evidence from studies involving the HT29 human colon cancer cell line, xenografted into BALB/c nu/nu immunocompromised mice, has shown that a single 30-minute session of mEHT can induce significant levels of apoptosis, DNA fragmentation, and the formation of apoptotic bodies (23). Similarly, in the CT26 aggressive CRC cell line, when transplanted into BALB/c mice, mEHT has been observed to cause significant pathomorphological changes and DNA fragmentation, indicative of massive apoptosis (24). This body of evidence suggests that mEHT, even as a stand-alone therapy, holds substantial potential for contributing to the treatment of CRC.

The efficacy of mEHT in augmenting the effects of RT is underpinned by its capacity to selectively target tumor cells while sparing normal tissue, thereby enhancing the tumor’s sensitivity to radiation (14,15). There is a growing body of evidence indicating that hyperthermia serves as a viable method for effectively escalating the radiation dose. Incremental temperature increases induced by mEHT have been correlated with a linear enhancement in the equivalent radiation dose during RT treatment, resulting in notable apoptosis and a reduction in tumor volume in vivo (15). Furthermore, the addition of hyperthermia has been observed to facilitate a dose escalation, achieving a clinically significant increase in the average equivalent radiation dose by approximately 10 Gy, even under conservative estimations (25).

The Lyon R96-02 randomized study (26) investigated the impact of radiation dose escalation on pCR rates in advanced rectal cancer, revealing that patients treated with HT and a simultaneous integrated boost (SIB), without accompanying chemotherapy and followed by delayed surgery, experienced a downstaging rate from cT4 to pT3 of 37.5% (22). Similarly, the KROG 10-01 phase II trial examined the effects of preoperative SCRT delivered by HT in conjunction with chemotherapy, followed by delayed surgery in the treatment of locally advanced rectal cancer, and found a tumor volume reduction rate of 62.5% (27). Although the tumor regression volumes were not specified in previous literature on neoadjuvant SCRT alone in CRC, studies such as the Stockholm III Trial have reported a 16.7% favorable regression within 6 weeks with SCRT alone (28). However, delaying surgery after SCRT may present challenges, including the potential for tumor progression or early recurrence during the waiting period. In our presented case, the combination of SCRT via HT with mEHT resulted in a 40.7% reduction in tumor volume and downstaging from stage IIIC to stage IIA within 2 weeks. Addition mEHT to SCRT may provide an additional tumor-sensitizing effect that leads to more rapid tumor shrinkage and increased response rates that allows earlier surgical intervention without compromising outcomes. These outcomes prompt further exploration of mEHT in conjunction with SCRT as synergistic components within treatment protocols of direct surgery, potentially mirroring the tumor volume reduction rates observed from delayed surgery strategies.

While SCRT with immediate surgery appears to have a higher rate of early postoperative complications, this may be due to masked radiation toxicity rather than an actual increase in surgical risk. Approximately 6% of patients undergoing SCRT with delay developed grade 3–4 radiation-induced toxicity, necessitating hospitalization (29). In our case, the patient tolerated the combination of SCRT and mEHT well, with only mild and transient skin erythema at the electrode site and no severe gastrointestinal or hematologic toxicities. No significant postoperative complications such as infection, bleeding or obstruction were noted. This may be attributed to the integration of EHT, which improves balance between tumor regression and normal tissue preservation, allowing for timely surgical intervention without increasing toxicity. However, larger studies with longer follow-ups are needed to determine whether this combination influences late-onset toxicities or functional outcomes in CRC patients.

This case report highlights the first documented integration of mEHT with SCRT-direct surgery in advanced recto-sigmoid colon cancer, demonstrating rapid tumor regression and favorable surgical outcomes with no significant adverse events. However, this study has several limitations. As a single-case report, the findings may not be generalizable, and larger prospective studies are needed to confirm the efficacy of neoadjuvant mEHT + SCRT in CRC. Additionally, the lack of a direct comparison with SCRT alone limits our ability to quantify the exact contribution of mEHT to tumor regression. Although the short-term outcomes seemed favorable, long-term survival, recurrence rates, and potential late toxicities remains to be elucidated in extended follow-up time and further clinical evaluation.

Conclusions

The preoperative integration of SCRT and mEHT presents a potentially promising modality for the management of advanced CRC, evidenced by a significant reduction in tumor volume. This combined approach may offer a strategic advantage in treating complex cancer cases, potentially leading to improved outcomes and enhanced quality of life for patients. However, the preliminary nature of these findings necessitates long-term follow-up to ascertain their validity and sustainability.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-24-17/rc

Funding: This work was supported by grants from the Far Eastern Memorial Hospital (No. FEMH-2024-C-033).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-24-17/coif). C.H.H. serves as an unpaid editorial board member of Therapeutic Radiology and Oncology from October 2024 to December 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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