*Article* **Long-Term Outcome in a Phase II Study of Regional Hyperthermia Added to Preoperative Radiochemotherapy in Locally Advanced and Recurrent Rectal Adenocarcinomas**

**Baard-Christian Schem <sup>1</sup> , Frank Pfeffer <sup>2</sup> , Martin Anton Ott <sup>3</sup> , Johan N. Wiig <sup>4</sup> , Nils Sletteskog <sup>5</sup> , Torbjørn Frøystein <sup>6</sup> , Mette Pernille Myklebust <sup>6</sup> , Sabine Leh <sup>7</sup> , Olav Dahl 6,8,\* and Olav Mella 6,8**


**Simple Summary:** Regional hyperthermia added to standard preoperative chemoradiotherapy for locally advanced and recurrent rectal cancer gives a high complete response rate and an improved long-term recurrence free survival.

**Abstract:** Hyperthermia was added to standard preoperative chemoradiation for rectal adenocarcinomas in a phase II study. Patients with T3-4 N0-2 M0 rectal cancer or local recurrences were included. Radiation dose was 54 Gy combined with capecitabine 825 mg/m<sup>2</sup> <sup>×</sup> 2 daily and once weekly oxaliplatin 55 mg/m<sup>2</sup> . Regional hyperthermia aimed at 41.5–42.5 ◦C for 60 min combined with oxaliplatin infusion. Radical surgery with total or extended TME technique, was scheduled at 6–8 weeks after radiation. From April 2003 to April 2008, a total of 49 eligible patients were recruited. Median number of hyperthermia sessions were 5.4. A total of 47 out of 49 patients (96%) had the scheduled surgery, which was clinically radical in 44 patients. Complete tumour regression occurred in 29.8% of the patients who also exhibited statistically significantly better RFS and CSS. Rate of local recurrence alone at 10 years was 9.1%, distant metastases alone occurred in 25.6%, including local recurrences 40.4%. RFS for all patients was 54.8% after 5 years and CSS was 73.5%. Patients with T50 temperatures in tumours above median 39.9 ◦C had better RFS, 66.7% vs. 31.3%, *p* = 0.047, indicating a role of hyperthermia. Toxicity was acceptable.

**Keywords:** rectal cancer; hyperthermia; chemoradiotherapy; tumour control

### **1. Introduction**

Patients presenting locally advanced rectal cancer (LARC) or primarily non-resectable rectal cancer have a dire prognosis [1]. Locally recurrent rectal cancer is difficult to control [2,3]. Preoperative radiation for advanced rectal cancer [4–6] and palliative radiotherapy for metastasized or irresectable rectal cancer [7–9] is well established.

**Citation:** Schem, B.-C.; Pfeffer, F.; Ott, M.A.; Wiig, J.N.; Sletteskog, N.; Frøystein, T.; Myklebust, M.P.; Leh, S.; Dahl, O.; Mella, O. Long-Term Outcome in a Phase II Study of Regional Hyperthermia Added to Preoperative Radiochemotherapy in Locally Advanced and Recurrent Rectal Adenocarcinomas. *Cancers* **2022**, *14*, 705. https://doi.org/ 10.3390/cancers14030705

Academic Editors: Stephan Bodis, Pirus Ghadjar and Gerard C. Van Rhoon

Received: 4 January 2022 Accepted: 25 January 2022 Published: 29 January 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The clinical benefit of superficial hyperthermia for malignant melanomas and deep pelvic hyperthermia as an adjuvant to radiotherapy for cervical cancer has been documented [10–13]. Additive effect of some chemotherapeutic drugs, including cisplatin have been shown experimentally [14]. It was therefore of interest to explore whether a preoperative combination of radiation, chemotherapy and hyperthermia could improve the results of surgery for rectal cancer. At the time the study was initiated, few clinical studies had treated primary rectal cancer by radiation combined with deep hyperthermia [13,15–17]. The combination of radiation with capecitabine was also new [18], as were the combination of hyperthermia and oxaliplatin in rectal recurrences [19] and experimental cell cultures [20,21]. Whole body hyperthermia and oxaliplatin in colorectal cancer patients was an experimental option not in general use [22]. We therefore first performed a phase I study to assess the feasibility of a combination of radiation, 5-day continuously administered 5-fluorouracil (5-FU), and weekly hyperthermia and oxaliplatin before surgery for rectal cancer [23]. Excellent local control was achieved, but acute diarrhoea was a frequent side effect. As the continuous administration of 5-FU via a central venous line was cumbersome in an outpatient setting, we replaced 5-FU with oral capecitabine in the current new phase II study. As various heating techniques had been used in earlier studies [17,24], we decided to explore the use of regional hyperthermia following the European quality assurance guidelines [25]. During the follow up of our patients, promising results have been published for LARC patients [26,27].

The present phase II study was open for patients with LARC without distant metastases and patients with local recurrences considered to be surgically curable, some with sufficient tumour shrinkage after preoperative treatment. During and after the inclusion and follow up of the study, the standard treatment has changed regarding radiation dose and inclusion of chemotherapy. We therefore waited with publication until long-term results were available. The present series of advanced and recurrent rectal cancer patients with good local control warrant consideration among the new therapeutic options. The secondary aim is the presentation of treatment-related toxicity.

#### **2. Materials and Methods**

From April 2003 to April 2008, 50 patients with histologically verified rectal adenocarcinomas were recruited. By a mistake, one patient with locally advanced tumour was examined with abdominal computed tomography (CT) the day after first treatment, which revealed multiple liver metastases, and this patient was therefore excluded due to major protocol violation.

#### *2.1. The Inclusion Criteria*

The inclusion criteria were patients with LARC (defined as T3 and T4 tumours with distance to the mesorectal facia less than 3 mm on magnetic resonance imaging (MRI), within 15 cm from the anal verge by proctoscopy) or recurrence after surgery alone. Age was below 76 years. The patients should not have evidence of distant metastases, and performance status should be 0–2. The patients should not have hypertension, cardiac failure or myocardial infarction in the previous 6 months. No chronic pulmonary or renal disease. No prior radiation or cancers, except basal cell carcinomas or stage 0 cervical cancer. Haematological tests should demonstrate Hgb > 10 g/dL, leucocytes > 3 <sup>×</sup> <sup>10</sup>9/L or thrombocytes > 100 <sup>×</sup> <sup>10</sup>9/L, and creatinine clearance > 30 mL/min. Due to the hyperthermia applicator size, maximal pelvic diameter should be less than 49 cm, and the patient should have no pacemaker or other metallic implanted object. Diagnostic procedures included clinical examination, rigid rectoscopy by a senior surgeon, biopsy confirming adenocarcinoma, CT of the pelvic area and abdomen with contrast in the rectum, and MRI of the pelvic area. Endorectal ultrasound was optional, and cystoscopy was performed if any invasion of the bladder was suspected. Blood counts included Hgb, leucocytes with differential counts, thrombocytes, analysis of Na, K, Cl, Ca, Mg and creatinine, bilirubin, ASAT, ALAT, Υ-GT, LDH and creatinine kinase.

The primary tumours were classified according to TNM 4th edition [28]. Indications for preoperative radiotherapy of LARC was based on the MRI examination showing a threatened circumferential resection margin with less than 3 mm from the mesorectal fascia (MRF) according to Norwegian national guidelines, or tumour deposits outside the MRF.

#### *2.2. Statistics and Ethics*

The outcomes were defined as local control, relapse-free survival included any local or distant recurrence with secondary colorectal cancer censored (RFS), cancer recti-specific survival (CSS) and overall survival (OS) as defined by Punt [29]. Toxicity was graded according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE), Publish Date: 9 August 2003 (https://ctep.cancer.gov/protocoldevelopment/electronic\_applications/ docs/ctcaev3.pdf, accessed on 8 September 2020) [30].

Survival was assessed by Kaplan-Meier estimates with 95% confidence intervals (95% CI), and differences assessed by the log-rank test. Differences with a two-tailed *p*-value less than 0.05 were considered statistically significant. IBM SPSS version 26 (IBM Corp, Armonk, NY, USA) and R (version 4.0.3, R Foundation for Statistical Computing, Vienna, Austria) were used for analyses and creating survival curves.

After oral and written information on the experimental nature of the study, all patients signed a written informed consent form. The study was conducted according to the guidelines of the Declaration of Helsinki. It was approved by the Regional Ethics Committee, Health Region West (REK III nr. 159.01) and thereby in accordance with Norwegian law and regulations.

#### **3. Treatment**

Radiation therapy was based on 3D dose planning, mostly a three-field technique with one backfield and two side fields. Tumour with regional glands received 2 Gy × 23 with a boost of 2 Gy × 4–5 against primary tumour and mesorectum or metastatic lymph nodes. Total tumour dose was therefore 54–56 Gy based on tumour size and bowel volume to be included in the boost volume, as well as comorbidity, age and acute side effects. The treatment was administered once daily, 5 days weekly. Pauses except Saturdays and Sundays were compensated for by a 6th fraction the following week(s).

Chemotherapy was administered as peroral capecitabine 825 mg/m<sup>2</sup> 5 days a week, concomitant with radiation (See Figure 1). Maximal dose was 1650 mg/day, administered in one dose the evening before radiation and the other half in the morning before radiation. Oxaliplatin was administered at a dose of 55 mg/m<sup>2</sup> each week, with a maximal dose 100 mg. Oxaliplatin was given as infusion during the hyperthermia session; at least five infusions, and if possible six infusions were administered. The drug was infused in 5% glucose, administered as a 2 h peripheral vein infusion, which started 1 h before planned start of hyperthermia.

Regional hyperthermia was administered by a BSD 2000 machine (Pyrexar Medical, Salt Lake City, UT, USA), using the Sigma-Eye applicator or the Sigma-60 applicator for patients with the highest pelvic diameters [17]. Hyperthermia was administered once a week from the first or second day of radiation, each treatment given as soon as possible after receiving the radiation fraction. Prior to radiation, catheters for Bowman temperature probes were inserted into tumour tissues using local anesthetics, and in women also in the vagina. Usually, a single catheter was inserted into the tumour, but for large tumours two catheters were used to optimize monitoring of the tumour heating. With problems of insertion of catheters or shrinkage of tumours, the probe measured rectal luminal temperature. One catheter was inserted in the urinary bladder. The positions of the catheters were verified by CT before the radiation. The treatment time was 60 min, calculated from the time the temperature probe in the tumour (or in rectal lumen if no probe was inserted in the tumour) reached 41.0 ◦C or started 30 min after initiation of the hyperthermia session. Normal tissues should be kept below 43.0 ◦C. The focus of heating was controlled by phase and amplitude steering [31]. If the awake patient reported discomfort or pain repeated

doses of fentanyl up to 0.10 mg was given intravenously. With continuous bladder temperatures > 42.5 ◦C, the bladder was irrigated by 10–30 mL of isotone saline holding room temperature for cooling. Bladder installations were kept at a minimum to avoid cooling of possible tumour near the bladder. Only tumour-tissue temperature-probe data are used for quality assessment of the hyperthermia given. The T20, T50 and T90 are defined as the temperature equal to or exceeded by 20%, 50% and 90% of the measured temperatures, respectively [32], and were calculated using the RhyThM software [33]. *Cancers* **2022**, *14*, x 4 of 16

**Figure 1.** Treatment schedule for preoperative combination treatment by radiation, chemotherapy and hyperthermia for rectal adenocarcinoma. **Figure 1.** Treatment schedule for preoperative combination treatment by radiation, chemotherapy and hyperthermia for rectal adenocarcinoma.

Regional hyperthermia was administered by a BSD 2000 machine (Pyrexar Medical, Salt Lake City, UT, USA), using the Sigma-Eye applicator or the Sigma-60 applicator for patients with the highest pelvic diameters [17]. Hyperthermia was administered once a week from the first or second day of radiation, each treatment given as soon as possible after receiving the radiation fraction. Prior to radiation, catheters for Bowman temperature probes were inserted into tumour tissues using local anesthetics, and in women also in the vagina. Usually, a single catheter was inserted into the tumour, but for large tumours two catheters were used to optimize monitoring of the tumour heating. Surgery. Rectal resections were performed according to total mesorectal excision (TME) principles. A partial, total or extended TME was carried out depending on the location. With invasion of neighbouring organs in locally advanced or recurrent tumours, a total pelvic exenteration procedures was performed. Totally 25 patients had a permanent colostomy. The resection margins were classified by the pathologists as R0 resection with a margin > 1 mm, R1 with a margin < 1 mm, and R2 in case of involved margins. The tumour regression grade (TRG) was classified by the Dworak criteria [34]. Follow up after surgery for at least 5 years followed the Norwegian national guidelines.

#### With problems of insertion of catheters or shrinkage of tumours, the probe measured rectal luminal temperature. One catheter was inserted in the urinary bladder. The **4. Results**

positions of the catheters were verified by CT before the radiation. The treatment time was 60 min, calculated from the time the temperature probe in the tumour (or in rectal lumen if no probe was inserted in the tumour) reached 41.0 °C or started 30 min after initiation of the hyperthermia session. Normal tissues should be kept below 43.0 °C. The focus of heating was controlled by phase and amplitude steering [31]. If the awake patient reported discomfort or pain repeated doses of fentanyl up to 0.10 mg was given In total 43 patients with LARC and 6 patients with recurrent rectal tumours without previous preoperative radio (chemo)therapy, 32 male and 17 female, were included. The characteristics for the patients are shown in Table 1. Fourteen tumours were locally advanced rectal adenocarcinomas, with growth into or beyond the MRF (two patients with T3N1 tumours had only 3 and 2 mm to the MRF) and were considered moderate-risk patients, while 29 patients had high-risk tumours.

intravenously. With continuous bladder temperatures > 42.5 °C, the bladder was irrigated by 10–30 mL of isotone saline holding room temperature for cooling. Bladder installations were kept at a minimum to avoid cooling of possible tumour near the bladder. Only tumour-tissue temperature-probe data are used for quality assessment of the hyperthermia given. The T20, T50 and T90 are defined as the temperature equal to or exceeded by 20%, 50% and 90% of the measured temperatures, respectively [32], and were

Surgery. Rectal resections were performed according to total mesorectal excision

a total pelvic exenteration procedures was performed. Totally 25 patients had a permanent colostomy. The resection margins were classified by the pathologists as R0 resection with a margin > 1 mm, R1 with a margin < 1 mm, and R2 in case of involved

calculated using the RhyThM software [33].


**Table 1.** Patient characteristics for patients included and treated according to the study protocol.

The median radiation dose was 54.0 Gy (range 50–56, of these, seven received 56 Gy). The median number of hyperthermia sessions was 5.4 (range 1–6) and 92% of the patients had at least four hyperthermia sessions. The temperature data measured in the tumours (*n* = 152 catheters) was mean (T-mean) 39.92 ◦C (95%CI 38.22–41.62), T-min 39.14 ◦C (95%CI 37.6–40.68), T-max 40.61 ◦C (95%CI 39.56–41.66), T20 was 40.29 ◦C (39.32–41.26), T50 39.91 ◦C (95%CI 39.06–40.76), and T90 was 39.36 ◦C (95%CI 38.58–40.14). There were no significant relation between T-stage, primary tumours versus recurrences or T size and median T50.

All patients had at least one oxaliplatin dose, 94% had four and more doses, and 71% had all six scheduled courses. One patient had only three weeks with capecitabine, two only four weeks, while 94% had the scheduled 5–6 weeks of oral chemotherapy together with radiation.

A total of 41 of the 43 patients with locally advanced tumours had the scheduled surgery at a median time of 84 days (range 69–216) after the start of radiation. The longest delay was for a very advanced tumour, which first had an exploratory laparotomy finding that the tumour was irresectable, and a new attempt later with the successful removal of a seemingly large tumour, however showing no vital tumour cells when examined by microscopy. Two patients were not operated as planned preoperative examinations revealed distant metastases. All six patients with local recurrences were operated as scheduled. The resections were recorded as R0 in 41 (87%) of the operated patients, R1 in 3 (6%) and R2 in 3 (6%) patients. The pathological assessment of TRG showed no malignant cells, complete regression (TRG4, pCR) in 14 (29.8%) of the specimens, 22 (46.9%) with TRG 3, 7 (14.9%) with moderate response, TRG 2, and only 4 (8.5%) with minimal regression, TRG 1.

The rate of local recurrence alone at 5 and 10 years was 9.1% (95%CI 4.4–13.8) and at 15 years the local recurrence rate was 12.3% (95%CI 0.8–23.8) for all included patients. Distant metastases only occurred in 25.6% (95%CI 12.3–38.9) of the patients after 5 years, 40.4% (95%CI 26.4–54.4) including concurrent local recurrences. For all patients, 5-year RFS was 54.8% (95%CI 40.8–68.8), Figure 2. There was no difference in RFS according to presentation as locally advanced tumours or recurrences. CSS for all patients at 5 years was 73.5% (95%CI 61.2–85.8) and at 10 years 62.5% (95%CI 48.9–76.2), Figure 3. CSS was similar

for LARC patients and patients with recurrence. OS was 73.5% (95%CI 61.2–85.8) at 5 years, and dropped to 55.1% (95%CI 41.3–68.9) after 10 years (Figure A1). (46.9%) with TRG 3, 7 (14.9%) with moderate response, TRG 2, and only 4 (8.5%) with

Classification of tumour response as TRG 4 (pCR) among the 47 operated patients yielded better RFS compared with the other groups (*p* = 0.032), see Figure 4. For patients with TRG 4 the 5-year CSS was 92.9% (95%CI 79.4–100.0) versus 72.7% (95%CI 57.5–87.9) for patients with residual tumour cells, and 10-year CSS 83.6 % (95%CI 62.5–100) versus 57.4% (95%CI 40.0–74.8), (*p* = 0.063), respectively. Thus the CSS differences were not statistically significant. minimal regression, TRG 1. The rate of local recurrence alone at 5 and 10 years was 9.1% (95%CI 4.4–13.8) and at 15 years the local recurrence rate was 12.3% (95%CI 0.8–23.8) for all included patients. Distant metastases only occurred in 25.6% (95%CI 12.3–38.9) of the patients after 5 years, 40.4% (95%CI 26.4–54.4) including concurrent local recurrences. For all patients, 5-year

When evaluating outcome in relation to the thermometry data, we were only able to retrieve the original disk recordings for 39 patients, thus data were unavailable for 10 patients. It was found that the RFS was significantly better, 66.7% (95%CI 40.6–86.7) for patients with recordings above 39.9 ◦C (T50, median of all recordings) versus 31.3% (95%CI 9.3–53.3), *p* = 0.047, in the lower group, see Figure 5. RFS was 54.8% (95%CI 40.8–68.8), Figure 2. There was no difference in RFS according to presentation as locally advanced tumours or recurrences. CSS for all patients at 5 years was 73.5% (95%CI 61.2–85.8) and at 10 years 62.5% (95%CI 48.9–76.2), Figure 3. CSS was similar for LARC patients and patients with recurrence. OS was 73.5% (95%CI 61.2–85.8) at 5 years, and dropped to 55.1% (95%CI 41.3–68.9) after 10 years (Figure A1).

**Figure 2.** Relapse-free survival (RFS) for 49 rectal cancer patients with locally advanced or recurrent rectal adenocarcinoma. **Figure 2.** Relapse-free survival (RFS) for 49 rectal cancer patients with locally advanced or recurrent rectal adenocarcinoma.

**Figure 3.** Cancer specific survival (CSS) for 49 patients, 43 with locally advanced and 6 patients with local recurrences of rectal adenocarcinomas. **Figure 3.** Cancer specific survival (CSS) for 49 patients, 43 with locally advanced and 6 patients with local recurrences of rectal adenocarcinomas. *Cancers* **2022**, *14*, x 8 of 16

**Figure 4.** RFS according to histopathology classification according to Dworak's TRG grades for 47 patients operated for rectal adenocarcinomas after preoperative radiochemotherapy with hyperthermia. TRG4 means pCR. **Figure 4.** RFS according to histopathology classification according to Dworak's TRG grades for 47 patients operated for rectal adenocarcinomas after preoperative radiochemotherapy with hyperthermia. TRG4 means pCR.

When evaluating outcome in relation to the thermometry data, we were only able to retrieve the original disk recordings for 39 patients, thus data were unavailable for 10

patients with recordings above 39.9 °C (T50, median of all recordings) versus 31.3%

(95%CI 9.3–53.3), *p* = 0.047, in the lower group, see Figure 5.

(95%CI 9.3–53.3), *p* = 0.047, in the lower group, see Figure 5.

hyperthermia. TRG4 means pCR.

**Figure 5.** RFS according to quality of heating divided above or below 39.91 ◦C, the median of the T50 measured in the tumours during all heating sessions among 39 patients.

**Figure 4.** RFS according to histopathology classification according to Dworak's TRG grades for 47 patients operated for rectal adenocarcinomas after preoperative radiochemotherapy with

When evaluating outcome in relation to the thermometry data, we were only able to retrieve the original disk recordings for 39 patients, thus data were unavailable for 10 patients. It was found that the RFS was significantly better, 66.7% (95%CI 40.6–86.7) for patients with recordings above 39.9 °C (T50, median of all recordings) versus 31.3%

Toxicity. Table 2 shows that most patients who had the scheduled treatment including surgery, had some acute side effects: 23% had grade 1, 34% had grade 2, 40% had grade 3, and only one (2%) recorded as grade 4 due to reduced general condition caused by several side effects. The most frequent side effects were diarrhoea due to chemotherapy and radiation, skin toxicity due to radiation and nausea related to chemotherapy. Fever reaction without infection after oxaliplatin was recorded in 40% of the patients. Twenty-seven patients (57%) experienced no long-term toxicity. Grade 1 occurred in two patients (4%, subileus and an accidentally fixed urether catheter), grade 2 in four patients (8%, one slight vaginal athresia and one abdominal pain possibly related to the oncological treatment, one patient had surgery for a ventral hernia, and one patient was not operated on due to liver metastases presented a Guillain Barre syndrome, probably unrelated to the treatment). Grade 3 was recorded in six patients (12%), two patients with bladder symptoms (irritation and paresis), one hip arthrosis and one subileus after several years, and one stoma surgery due to local pain. Grade 4 was observed in five patients (10%): two with stenotic ureters, two patients had ileus, one of them also hip surgery and one pelvic pain. One Grade 5 patient died 2 weeks after surgery due to sepsis and adult respiratory distress syndrome, considered a complication after major surgery. In summary the side effects were as expected for the present cohort of locally advanced tumours with some elderly patients, and no obvious unexpected toxicity related to the hyperthermia treatment was observed.

**Table 2.** Acute toxicity observed during preoperative therapy and first month after surgery in 47 patients.


#### **5. Discussion**

Since this study was done, the surgical techniques used in combination with radiation and delivery of radiation have evolved and have reduced the local recurrence rate to about 5% for operable rectal cancer [35,36]. We therefore were initially not too enthusiastic of our achievement with the use of hyperthermia. However, most of the patients could be resected 12 weeks after the preoperative treatment in our series. We obtained a R0 resection rate of 87%, which seems better than 61% in a previous national study including locally advanced T4 rectal cancer patients [37]. Pathological assessment of the operation specimens revealed no residual tumour cells (TRG 4) in 29.8% of the patients, which is higher than the standard 10–20% pCR as reported after preoperative radiochemotherapy for rectal cancer [38–42], but some report even higher percentages [39,43,44]. In general the TRG4 rate is influenced by the initial tumour stage, the given treatment, as well as the timing between preoperative treatment and surgery. The high TRG4 rate in the present cohort of advanced rectal cancers is very promising. The most important aspect of the TRG4 is that no viable tumour cells after preoperative treatment is a predictor of higher RFS as demonstrated in Figure 4 in accordance with the findings in other series [40,45–48]. In the pCR group, 11 of 14 patients had no recurrence versus 14 of 33 in the other categories (*p* < 0.05). In our cohort the 5-year CSS was 92.9% for patients with pCR versus 72.7% with residual tumour cells, but this did not reach statistical significance, possibly due to the small sample size.

The isolated local recurrence rate at 5 years was 9% in this series of locally advanced rectal cancer patients. This is the same as observed in 2005 in a series of 3388 Norwegian patients with operable rectal cancer treated for cure by surgery alone including 5% preoperative and 5% postoperative radiation [48]. In a previous Norwegian series of LARC patients defined as T4 tumours, the local recurrence rates at 5 years were 18% (95%CI 14–23) for patients with a R0-resection and 40% (95%CI 26–52) if the procedure was classified as R1 [35]. We observed two local recurrences after about 10 years. Whether these recurrences are true local recurrences or de novo development of new primary tumours cannot be determined, and we have therefore recorded them as local recurrences. Habr-Gama has reported adenomas after pCR for rectal cancer [49]. Thus, new primary cancer at the tumour bed may develop from such residual adenomas.

For comparison, the 5-year relative survival rate for all operated rectal cancers in Norway was 79% in 2004-06 [35]. The overall survival at 5 years in our series was 73.5%, clearly improved from 29% in the previous Norwegian series where 5-year survival was 49% after R0 resection and 20% after a R1 resection. In a more recent randomized trial, the 5-year overall survival for locally advanced rectal cancer was 66% after preoperative radiochemotherapy and 53% after preoperative radiation alone [1]. However, after 10-years there was no significant difference between radiation alone or radiochemotherapy in this trial [49].

The current study was designed to assess a possible role of hyperthermia. When 86 rectal cancer patients, treated with preoperative radiotherapy followed by surgical resection and adjuvant 5-FU and hyperthermia once or twice a week, were compared with predicted outcomes from a nomogram based on randomised European trials without hyperthermia, the observed OS (87.3%) versus predicted OS (75.5%), distant metastasis free survival (87.3%) vs. predicted (75.5%), and local control (95.8% vs. 95.8%, respectively), was better after hyperthermia [50]. Recently a series of 112 patients with locally advanced and recurrent rectal cancer had preoperative radiation (55.8–59.4 Gy) and regional hyperthermia with 5FU or capecitabine and oxaliplatin in locally advanced patients [51]. They reported a local recurrence rate of 2.3% with hyperthermia vs. 21.3% without hyperthermia and DFS of 89.1% vs. 70.4%, respectively. In another study including 78 LARC patients also using a similar regimen as our study with radiation 50.4 Gy combined with 5-FU and hyperthermia twice per week, pCR was seen in 14% with combined TRG 4 and TRG 3 in 50% of the patients [52]. DFS and OS were also in accord with our data. They also report that those patients achieving best quality hyperthermia had best tumour response. These studies therefore also support a role of hyperthermia in rectal cancer. Currently there has not been published a prospectively randomized study demonstrating the effect of deep hyperthermia added to preoperative treatment in rectal cancer patients.

It proved difficult to achieve the temperature aim stated in our protocol in most patients, mainly due to local pain and discomfort limiting power output, despite the use of fentanyl. However, achieving a temperature above median of T50 for the patients where temperature was recorded in tumours, resulted in a significant better RFS. Our findings support general reviews demonstrating that hyperthermia in addition to its own effect, is a sensitizer for radiation [27,53–55] as well as a chemosensitizer [53]. For further details on mechanism of action of hyperthermia, see references [12,53,56]. In addition, hyperthermia may also have positive immunological effects [57,58].

The role of oxaliplatin in the preoperative treatment of rectal cancer is controversial. Some authors report only increased toxicity (diarrhoea) [59], while others showed improved pCR, local control and distant metastases, but no effect on OS [60]. Other authors have reported improved outcomes in patients treated with oxaliplatin [61–63]. Avoiding the last scheduled dose of oxaliplatin significantly reduced pathological response in a recent study [64]. We cannot assess the contribution of oxaliplatin in our cohort, but we notice that oxaliplatin is part of current total neoadjuvant therapy for rectal cancer where induction chemotherapy is used before radiation [65–68]. Giving more chemotherapy before surgery was recently documented in two large randomized studies and several phase II studies, yielding pCR rates around 30% for total neoadjuvant therapy versus 14% for standard radiochemotherapy in a meta-analysis [69–71]. Although the disease free survival (DFS) at 3 years seems promising [71], the 4.6 year local recurrence rate was 8.3% in the experimental arm versus 6% after standard radiochemotherapy in the Rapido trial [69]. It should be noted that the time from diagnosis to surgery was 10 weeks longer in the experimental arm, which may have favoured this group. Distant metastases were recorded for 20.0% in the experimental group compared with 26.8% in the standard group in this trial, and diseaserelated treatment failure was 23.7% in the experimental group versus 30.4% (*p* = 0.019) in the standard of care group, but there was no difference in OS. Therefore, the effect of this more intense preoperative chemotherapy treatment on reduction of distant metastases must be further validation in new studies to assess the impact of more intense chemotherapy over longer time. Preoperative chemotherapy with mFOLFIRINOX may be an alternative option as pCR was 27.5% after chemotherapy alone versus 11.7% after standard preoperative chemoradiation followed by adjuvant chemotherapy, and 3-year DFS was 75.7% and 68.5%, respectively [72].

Surgery alone or after preoperative radiation has been the traditional treatment of local recurrences of rectal cancer [73,74]. Radiotherapy alone yields poor local control after surgery for rectal cancer [2], while radiochemotherapy followed by surgery seems better [49]. Currently carbon-ion radiotherapy seems to offer even better local control, but distant failures remain a problem [75,76]. Our data and the recent phase II studies imply a role of hyperthermia in recurrent rectal cancer [51,52].

In the present study, there was no unexpected long-term toxicity associated with addition of hyperthermia and the overall acute and long-term toxicity seems to be in line with current use of preoperative radiochemotherapy for rectal cancer [1,77,78]. No negative effects on quality of life with addition of hyperthermia to neoadjuvant radiochemotherapy was reported in this setting [79]. We must however admit that side effects recorded in the patient's journal and retrospectively collected as done in our study, are a weakness of our study.

#### **6. Conclusions**

This study of radiochemotherapy combined with deep regional hyperthermia showed, after long follow-up, good local control and survival, and no indications of increased treatment-related long-term side effects. The achieved temperatures during hyperthermia were relatively low, indicating a possibility for even better tumour effects with improvement of heating technology.

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**Author Contributions:** Conceptualization, B.-C.S., O.M. and O.D.; methodology, B.-C.S., O.M., T.F., F.P., J.N.W., M.A.O. and N.S.; software, O.D.; validation, S.L.; formal analysis, O.D.; resources, O.M.; data curation, O.D. and M.P.M.; writing—original draft preparation, O.D.; writing—review and editing, all authors; visualization, B.-C.S., M.P.M. and O.D.; supervision, O.M.; project administration, O.M.; funding acquisition, O.D. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was supported by an unrestricted grant from the Trond Mohn Foundsation, earlier Bergen Research Foundation, BFS2015PAR02, and the Norwegian Cancer Society (Hyperthermia equipment). The sponsors had no influense on the study design.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Regional Ethics Committee of Western Norway, protocol code REK III nr. 159.01, date of approval 7 November 2001.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study. *Cancers* **2022**, *14*, x 12 of 16

> **Data Availability Statement:** Anonymous data may be disclosed upon any reasonable relevant request according to EU General Data Protection Regulation (GDPR) and Norwegian legislation. **Data Availability Statement:** Anonymous data may be disclosed upon any reasonable relevant request according to EU General Data Protection Regulation (GDPR) and Norwegian legislation.

> **Acknowledgments:** The study were supported by an unrestricted grant from Trond Mohn Foundation and the Norwegian Cancer Society. **Acknowledgments:** The study were supported by an unrestricted grant from Trond Mohn Foundation and the Norwegian Cancer Society.

**Conflicts of Interest:** The authors declare no conflict of interest. **Conflicts of Interest:** The authors declare no conflict of interest.

#### **Appendix A Appendix A**

**Figure A1.** Overall survival for 49 rectal cancer patients, 43 with locally advanced and 6 with recurrent adenocarcinomas. **Figure A1.** Overall survival for 49 rectal cancer patients, 43 with locally advanced and 6 with recurrent adenocarcinomas.

3. Temple, W.J.; Saettler, E.B. Locally recurrent rectal cancer: Role of composite resection of extensive pelvic tumors with strategies

4. Dahl, O.; Horn, A.; Morild, I.; Halvorsen, J.F.; Odland, G.; Reinertsen, S.; Reisæter, A.; Kavli, H.; Thunold, J. Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a randomized multicenter trial in western

5. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: A systematic overview of 8507 patients from

6. Krook, J.E.; Moertel, C.G.; Gunderson, L.L.; Wieand, H.S.; Collins, R.T.; Beart, R.W.; Kubista, T.P.; Poon, M.A.; Meyers, W.C.; Mailliard, J.A.; et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. *N. Engl. J. Med.* **1991**, *324*, 709–715. 7. Bjerkeset, T.; Dahl, O. Irradiation and surgery of primarily inoperable rectal adenocarcinoma. *Dis. Colon Rectum* **1980**, *23*, 298–

8. Mella O, Dahl O, Horn A et al. Radiotherapy and resection for apparently inoperable rectal adenocarcinoma. *Dis. Colon. Rectum*

rectal cancer treated with surgery alone as the initial treatment. *Radiat. Oncol. J.* **2017**, *35*, 71–77.

1. Braendengen, M.; Tveit, K.M.; Berglund, Å.; Birkemeyer, E.; Frykholm, G.; Påhlman, L.; Wiig, J.N.; Byström, P.; Bujko, K.; Glimelius, B. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable

### **References**


## *Article* **Intensity-Modulated Radiotherapy with Regional Hyperthermia for High-Risk Localized Prostate Carcinoma**

**Sota Nakahara <sup>1</sup> , Takayuki Ohguri 1,\* , Sho Kakinouchi <sup>1</sup> , Hirohide Itamura <sup>1</sup> , Takahiro Morisaki <sup>1</sup> , Subaru Tani <sup>1</sup> , Katuya Yahara <sup>2</sup> and Naohiro Fujimoto <sup>3</sup>**


**Simple Summary:** Several randomized controlled trials have shown that concurrent use of deep regional hyperthermia and radiotherapy results in a significant increase in local control of cervical and rectal cancer. Intensity-modulated radiotherapy (IMRT) plus androgen deprivation therapy (ADT) has recently become standard treatment for high-risk localized prostate carcinoma; however, as there is room for improvement in outcomes, we have been using hyperthermia to improve the effect of IMRT. This retrospective analysis shows that addition of regional hyperthermia to IMRT plus ADT is a promising approach as it improves clinical outcomes with acceptable toxicity. Importantly, a higher thermal dose was significantly correlated with better biochemical disease-free survival. Further investigations, including prospective trials with detailed treatment protocols, are needed.

**Abstract:** Background: The purpose of this study was to evaluate the efficacy and toxicity of adding regional hyperthermia to intensity-modulated radiotherapy (IMRT) plus neoadjuvant androgen deprivation therapy (ADT) for high-risk localized prostate carcinoma. Methods: Data from 121 consecutive patients with high-risk prostate carcinoma who were treated with IMRT were retrospectively analyzed. The total planned dose of IMRT was 76 Gy in 38 fractions for all patients; hyperthermia was used in 70 of 121 patients. Intra-rectal temperatures at the prostate level were measured to evaluate thermal dose. Results: Median number of heating sessions was five and the median total thermal dose of CEM43T90 was 7.5 min. Median follow-up duration was 64 months. Addition of hyperthermia to IMRT predicted better clinical relapse-free survival. Higher thermal dose with CEM43T90 (>7 min) predicted improved biochemical disease-free survival. The occurrence of acute and delayed toxicity ≥Grade 2 was not significantly different between patients with or without hyperthermia. Conclusions: IMRT plus regional hyperthermia represents a promising approach with acceptable toxicity for high-risk localized prostate carcinoma. Further studies are needed to verify the efficacy of this combined treatment.

**Keywords:** hyperthermia; intensity-modulated radiotherapy; prostate cancer; thermal dose

#### **1. Introduction**

Radiation therapy with androgen deprivation therapy (ADT) is the main treatment modality for patients with high-risk localized prostate cancer [1]. External radiation, such as intensity-modulated radiotherapy (IMRT), stereotactic body radiation therapy, and proton therapy, has been increasingly used in recent years to optimize dose concentration in tumors and reduce exposure to at-risk organs. The 5-year biochemical disease-free survival for external beam radiotherapy was reported to be 80–90% in the low-risk group, 70–80%

**Citation:** Nakahara, S.; Ohguri, T.; Kakinouchi, S.; Itamura, H.; Morisaki, T.; Tani, S.; Yahara, K.; Fujimoto, N. Intensity-Modulated Radiotherapy with Regional Hyperthermia for High-Risk Localized Prostate Carcinoma. *Cancers* **2022**, *14*, 400. https:// doi.org/10.3390/cancers14020400

Academic Editors: Stephan Bodis, Pirus Ghadjar, Gerard C. Van Rhoon and Alessio Giuseppe Morganti

Received: 20 November 2021 Accepted: 11 January 2022 Published: 13 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

in the intermediate-risk group, and 50–70% in the high-risk group [2]. Clinical outcomes in the high-risk group can be improved, unlike in the low- to intermediate-risk groups.

Hyperthermia is known to be cytotoxic to cancer cells and acts as a radiosensitizer [3,4]. Radiation therapy-resistant tumor cells that are hypoxic, of low pH, nutritionally deprived, and in the S-phase are more sensitive to hyperthermia [3,5,6]. The clinical efficacy of radiotherapy plus hyperthermia have been demonstrated in randomized clinical trials in patients with advanced head and neck cancer, locally recurrent breast cancer, malignant melanoma, bladder cancer, rectal cancer, and cervical cancer [1]. In patients with prostate cancer, previous phase I/II clinical trials and retrospective studies have described the use of three-dimensional conformal radiation therapy in combination with regional hyperthermia to be both promising and feasible. Additionally, it does not cause severe toxicity [7–13].

In Japan, the safety and efficacy of hyperthermia in combination with radiotherapy using the 8-MHz capacitive device has been demonstrated since the 1980s, including in prospective phase I/II studies of patients with deep-seated malignant pelvic tumors [14–18]. Based on these results, and since the 1990s, electromagnetic hyperthermia for malignant tumors has been covered by public health insurance, irrespective of the type and stage of the malignant tumor. In Japan, all the people are covered by public health insurance. The patient is free to choose the medical institution and can receive advanced medical treatment at a low cost. In clinical practice, electromagnetic hyperthermia is mainly used in locally advanced cancers wherein further improvement of the antitumor effects of radiotherapy and/or chemotherapy is required, although only a limited number of hospitals are able to carry out the procedure. Hence, in our institution, combination therapy using IMRT and regional hyperthermia was initiated in 2011 to improve the clinical outcomes in patients with high-risk localized prostate cancer. To the best of our knowledge, there are no reports on clinical outcomes after such combination therapy; thus, the purpose of this study was to evaluate the efficacy and toxicity of IMRT plus regional hyperthermia for high-risk localized prostate carcinoma.

#### **2. Materials and Methods**

#### *2.1. Patients*

In the current study, we explained to the patients that the standard treatment for National Comprehensive Carcinoma Network (NCCN) high-risk prostate cancer combining IMRT and hormonal therapy results in biochemical recurrence in approximately 20–40% of patients, thereby requiring additional treatment. Furthermore, the possibility of improving the radiotherapeutic effect by performing hyperthermia and the possible side effects (mainly heat sensation, fatigue, and subcutaneous fat burns) were fully clarified. Finally, hyperthermia treatment can only be carried out after the patient had understood the advantages and disadvantages of and consented to the treatment by signing informed consent documents.

This retrospective study was conducted with the permission of the Institutional Review Board of the authors' university. All personal data, such as names and addresses, were anonymized so that the subjects could not be identified and stored in a locked vault together with their correspondence, under the strict control of the Principal Investigator, when investigating data from electronic medical records and treatment devices.

High-risk prostate carcinoma patients (*n* = 123), defined according to the NCCN, were treated with definitive IMRT between March 2011 and December 2018, at an institutional hospital. During the same period, according to our institution's treatment protocol aimed at improving clinical outcomes, a subset of the patients (70/123; 57%) were provided regional hyperthermia along with definitive IMRT (Figure 1); the remaining 53 patients were treated with definitive IMRT alone. Primary indications against the use of regional hyperthermia were as follows: patient refusal (*n* = 21), cerebral disease (*n* = 12), cardiovascular disease (*n* = 8), orthopedic disease (*n* = 5), presence of other disease (*n* = 4), and advanced age (*n* = 3). Two of the 123 patients were not able to complete the planned IMRT dose (76 Gy in 38 fractions) and were excluded from the study. Therefore, data from 70 patients treated with definitive IMRT plus regional hyperthermia, and 51 patients treated with definitive IMRT alone, were retrospectively analyzed (Figure 1). Patients with postoperative prostate carcinoma were not included in this study.

**Figure 1.** Patient flow diagram.

Patient baseline characteristics and treatments are listed in Table 1. All patients had pathologically confirmed prostate adenocarcinoma and initially underwent neoadjuvant ADT for a median duration of 9 months (interquartile range, 7–11 months). Adjuvant ADT was continued in 22 patients after completion of IMRT for a median duration of 24 months (interquartile range, 22–33 months). Median total duration of neoadjuvant plus adjuvant ADT was 10 months (interquartile range, 8–18 months).





PSA, prostate-specific antigen; IMRT, intensity-modulated radiotherapy; ADT, androgen deprivation therapy.

#### *2.2. IMRT*

Radiation treatment was provided to all patients with definitive intent using a 10-MV linear accelerator (ONCOR Impression Plus, Siemens Medical Systems, Concord, CA). The clinical target volume (CTV) included the entire prostate, gross extracapsular disease, and proximal seminal vesicles. The planning target volume (PTV) was delineated by contouring the CTV with a margin of 7 mm in all directions except posteriorly, where it was only 4 mm. Our dose prescription policy was based on D95 of the PTV, i.e., percentage of the prescribed dose covering 95% of the volume. The total planned dose for all patients was 76 Gy, with a fractional dose of 2.0 Gy once a day, five times/week. Patients were immobilized using Vac-Lok cushions in the supine position and were treated with step-and-shoot IMRT. A megavoltage cone beam CT system was used to match the patient's position. Dose-volume constraints for at-risk organs were as follows: rectum V50 Gy < 25%, V65 Gy < 17%; bladder V40 Gy < 50%, V65 Gy < 25%; femoral head Dmax < 50 Gy, and small intestine Dmax < 60 Gy.

#### *2.3. Hyperthermia*

Regional hyperthermia was provided using a 8 MHz radiofrequency capacitive device (Thermotron RF-8, Yamamoto Vinita Co., Osaka, Japan). The physical features of this instrument and its thermal distribution in a phantom model and the human body have been described previously [14,19]. Briefly, both the upper and lower electrodes were 30 cm in diameter and were placed on opposite sides of the pelvis with the patient in the prone position. The treatment goal was at least 30 min of continuous heating after the radiofrequency output was increased to the patient's tolerance threshold. Patients were carefully instructed to report any unpleasant sensations that were suggestive of a hot spot. Radiofrequency output was increased to the maximum level tolerated by the patient after appropriately adjusting treatment settings. The liquid in the regular boluses adhering to the metal electrode was 5% NaCl or 5% potassium sulfate, both having similar conductivity. To reduce any preferential heating of subcutaneous fat tissue, overlay boluses were applied in addition to regular boluses. Circulating liquid (0.5% NaCl or 0.5% potassium sulfate; both show similar conductivity) inside the overlay boluses was cooled by the RF-8 circulatory system during heating. Superficial cooling was performed using circulating liquid set at 5 ◦C in the overlay boluses. A gauze soaked in 10% NaCl was inserted in the intergluteal cleft to improve temperature distribution in the prostate. Exceptions occurred in 4 patients

provided hyperthermia in 2012; they were included in a previous prospective clinical trial on optimization of deep heating area using this heating device and mobile insulator sheets [20].

Hyperthermia was provided once or twice a week, after radiotherapy. We directly measured intra-rectal temperature in all patients and during all hyperthermia sessions using a 4-point microthermocouple sensor that was inserted into the rectum at the level of the prostate. The thermal dose corresponding to the cumulative equivalent minutes at 43 ◦C for the T90 (CEM43T90) was obtained based on these intra-rectal temperatures during all hyperthermia sessions. The T90 is an index temperature that indicates either achieving or surpassing 90% of intra-rectal measurement points; similarly, T25 indicates either achievement of target temperature or that it has exceeded 25% of intra-rectal measurement points. The CEM43T90 has been extensively and successfully used in clinical trials to assess efficacy of heating [21–23] and provides data on the thermal isoeffect dose expressed in cumulative equivalent minutes at a reference temperature of 43 ◦C based on the lower end of temperature distribution (T90). The CEM43T90 is calculated from the time-temperature data as follows:

$$\text{CEM43T90} = \sum\_{i=0}^{n} t\_i R^{(43 - T90i)}$$

When the temperature is higher than 43 ◦C, R = 0.5. When the temperature is lower than 43 ◦C, R = 0.25. In this protocol, *t<sup>i</sup>* is the time interval of the *ith* sample (*t<sup>i</sup>* = 1.0 min). Temperatures exceeding T90 of the intra-rectal measurement points during the *ith* minute was designated as T90i. We then used the CEM43T90 to convert each T90i into an equivalent time at 43 ◦C, and these were added over the entire treatment duration of "n" min.

#### *2.4. Follow-Up*

The length of follow-up was calculated from the IMRT start date. Patients were followed up at intervals of 1–3 months during the first year and at 3–6 months thereafter. At each follow-up visit, PSA was measured, and potential gastrointestinal (GI) and genitourinary (GU) morbidity were accessed. Biochemical relapse was defined as per the Phoenix definition [24]. The presence of bone metastasis was confirmed by bone scintigraphy, CT, or MRI, while soft tissue metastasis was confirmed by CT or MRI. Toxicity of the therapy was evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The highest toxicity level for each patient during and after IMRT was used for toxicity analysis. Toxicity was classified as either acute (occurring during therapy or up to 3 months after therapy) or delayed (occurring more than 3 months after completion of therapy).

#### *2.5. Statistical Analyses*

The Chi-squared test or the Mann–Whitney U test was used to evaluate differences in clinical characteristics between patients with and without hyperthermia. Biochemical disease-free survival (bDFS) (Phoenix definition), clinical relapse-free survival (RFS), and overall survival (OS) rates were calculated from IMRT initiation using the Kaplan–Meier method. Any significant differences between the actuarial curves were assessed using the log-rank test. Hazard ratio and 95% confidence interval were calculated using the Wald test. Multivariate analyses using a Cox proportional hazards model were also performed to identify prognostic factors for the survivals. The Fisher's exact probability test was used to compare grade 2 or higher toxicity between patients with and without hyperthermia.

#### **3. Results**

#### *3.1. Thermal Data*

The number of heating sessions in each patient ranged from 1–7 (median, 5) and the median duration of heating per session was 50 min (range, 30–55 min). The thermal dose of CEM43T90 ranged from 0.1 to 32.1 min (median 7.5 min). Figure 2a shows CEM43T90 for each heating session with median values for the first, 2nd, 3rd, 4th, 5th, 6th, and 7th

sessions being 0.9, 1.4, 1.3, 1.4, 1.9, 1.8, and 1.2 min, respectively. The CEM43T90 of the first session tended to be lower than of later sessions. Median T90 values for sessions 1–7 were 40.3, 40.5, 40.5, 40.3, 40.4, 40.4, and 40.2 ◦C, respectively, (Figure 2b) while those for T25 were 41.1, 41.2, 41.3, 41.3, 41.2, 41.2, and 40.9 ◦C, respectively (Figure 2c). Average heating time for each session is shown in Figure 2d.

**Figure 2.** Thermal dose of CEM43T90 (**a**) median T90 (**b**) median T25 (**c**) and heating time (**d**) in each of the HT treatment sessions.

#### *3.2. Efficacy and Prognostic Factors*

Median follow-up time was 64 months (interquartile range, 49–83 months). Table 1 provides data on differences in patient characteristics between the two groups, and no significant differences were detected.

The 3-year and 5-year bDFS rates were 92.2% and 86.9%, respectively, for all 121 patients and biochemical relapse occurred in 6 patients in each group. Table 2 shows the results of univariate analyses of select factors affecting bDFS, and hyperthermia was not significant predictor of bDFS. Further, 5-year bDFS rate for patients with and without hyperthermia was similar at 89.8% and 82.9%, respectively (*p* = 0.2170, Figure 3a). However, the 5-year bDFS rate was 96.4% in the 39 patients with a CEM43T90 > 7 min, which was significantly better than 82.4% in the remaining 82 patients with a CEM43T90 ≤ 7 min or no hyperthermia treatment (Table 2). Table 3 lists the results of univariate analyses of factors affecting bDFS in 70 patients treated with IMRT plus regional hyperthermia, and a higher thermal dose of CEM43T90 > 7 min was a significant predictor of bDFS. Figure 3b shows that the 5-year bDFS rate of 96.4% in 39 patients with CEM43T90 > 7 min was significantly better than 81.5% in 31 patients with the CEM43T90 ≤ 7 min (*p* = 0.0316) and 82.9% in 51 patients not provided hyperthermia (*p* = 0.0370).


**Table 2.** Univariate analyses of certain factors for bDFS in 121 patients treated with IMRT with or without regional hyperthermia.

\* Hazard ratio and 95% confidence interval were calculated using the Wald test.

**Figure 3.** bDFS and clinical RFS rates. (**a**) bDFS with and without hyperthermia treatment. (**b**) bDFS among patients administered a thermal dose of CEM43T90 > 7 min, CEM43T90 ≤ 7 min, or no hyperthermia treatment. (**c**) Comparison of clinical RFS between the groups with and without hyperthermia treatment. (**d**) Comparison of clinical RFS among the patients with thermal dose CEM43T90 > 7 min, CEM43T90 ≤ 7 min, and no hyperthermia treatment.


**Table 3.** Univariate analyses of certain factors for bDFS in 70 patients treated with IMRT plus regional hyperthermia.

\* Hazard ratio and 95% confidence interval were calculated using the Wald test.

Clinical relapse occurred in one patient treated with hyperthermia and in 4 patients without hyperthermia, and the sites of first clinical relapse were lymph node (*n* = 2), lymph node and lung (*n* = 2), and bone and lymph node (*n* = 1). The 3-year and 5-year clinical RFS rates were 97.4% and 93.9%, respectively, for all 121 patients. Table 4 shows the results of univariate and multivariate analyses of factors related to clinical RFS and additional hyperthermia was significant predictor of clinical RFS in both univariate and multivariate analyses. The 5-year clinical RFS rate was 98.0% for patients provided hyperthermia but 88.6% among patients without hyperthermia (*p* = 0.0229, Figure 3c). Further, 5-year clinical RFS rate was 100% in the 39 patients with CEM43T90 > 7 min and 95.0% in 31 patients with CEM43T90 ≤ 7 min (Figure 3d). The 5-year OS rate was 100% for patients who underwent hyperthermia and 95.9% among patients who did not undergo hyperthermia.

**Table 4.** Univariate and multivariate analyses of certain factors for clinical relapse-free survival in 121 patients treated with IMRT with or without regional hyperthermia.


\* Log-rank test. \*\* Hazard ratio and 95% confidence interval were calculated using the Wald test. CI, confidence interval; PSA, prostate-specific antigen; ADT, androgen deprivation therapy.

#### *3.3. Toxicity*

Acute toxicity (≥Grade 2) occurred in 70 patients treated with IMRT and hyperthermia and included grade 2 (*n* = 11, 15.7%) and grade 3 (*n* = 2; 2.8%) GU toxicity. In 51 patients treated with IMRT alone, acute toxicities were grade 3 GU toxicity in 3 (5.9%) patients and grade 2 GU toxicity in 6 (11.8%). The occurrence of acute toxicities ≥ grade 2 was not significantly different between patients with or without hyperthermia treatment. Skin burn, as a subcutaneous induration, was seen in two (2.9%) patients and it spontaneously disappeared after completion of combined therapy. Delayed toxicity ≥ grade 2 among 70 patients treated with IMRT with hyperthermia included grade 3 GI toxicity in one (1.4%) patient and grade 3 GU in one (1.4%) patient. Among 51 patients treated with IMRT alone, delayed toxicity ≥ grade 2 did not occur. Between patients with or without hyperthermia, the occurrence of delayed toxicity ≥ grade 2 was not significantly different.

#### **4. Discussion**

The results of the present study demonstrate the feasibility of combining IMRT (total 76 Gy in 38 fractions) and regional hyperthermia. This strategy appears to have promising efficacy in patients with high-risk localized prostate carcinoma as the addition of hyperthermia resulted in a significant improvement in clinical RFS. The strengths of this study are that total dose and fractionation of IMRT were identical in all patients, and that neoadjuvant hormone therapy was administered to all patients. Thus, this cohort of patients was suitable for evaluating the radio-sensitizing effect of hyperthermia and for reducing bias due to differences in treatment protocols for NCCN-defined high-risk localized prostate carcinoma. Additionally, temperature in the rectum of the dorsal prostate during heating was monitored in all patients, which permitted adequate analyses of the thermal dose provided.

IMRT is the standard radiation modality used in the treatment of high-risk localized prostate cancer. A recent study with IMRT at a dose of 76–80 Gy plus ADT, which was administrated in 78.5% of the patients with NCCN high-risk localized prostate carcinoma, reported 5-year bDFS and metastasis-free survival rates of 80.6% and 92.5%, respectively [25]. Simizu et al. (2017) have described clinical outcomes after IMRT (72.6–74.8 Gy in 2.2 Gy per fraction) plus ADT administrated to 61% of the patients with high-risk prostate carcinoma and report 5-year bDFS and clinical RFS rates of 77% and 87%, respectively [26]. Marvaso et al. (2018) conducted ultra-hypofractionated radiotherapy using image-guided IMRT (32.5 or 35 Gy in 5 fractions) plus ADT in 21 (75%) of the 28 patients with NCCN high-risk localized prostate carcinoma and report 3-year bDFS and clinical RFS rates of 66% and 87%, respectively [27]. We report higher and more promising 5-year bDFS and clinical RFS rates of 89.8% and 98.0%, respectively, after IMRT with 76Gy in 38 fractions plus regional hyperthermia and ADT (Figure 3a,c).

Previous reports of high-dose IMRT describe the occurrence of acute ≥ grade 2 toxicities to be 28% and that of delayed ≥ grade 2 GI and GU toxicities to be 4% and 15%, respectively, in 772 patients with prostate carcinoma [28]. We have previously reported that addition of regional hyperthermia to 3D-CRT (70 Gy in 35 fractions) did not increase the occurrence of acute or delayed toxicity in patients with prostate carcinoma [13]. Similarly, we now show that acute and delayed toxicities were comparable when regional hyperthermia was added to IMRT.

Maluta et al. (2007) have reported on the clinical outcomes of a prospective phase II study for locally advanced prostate carcinoma in a cohort of 144 patients treated with three-dimensional radiotherapy (74 Gy in 37 fractions) plus regional hyperthermia; additional ADT was administered to more than 60% of the patients [11]. In that study, 5-year OS was 87%, and 5-year bDFS was 49% and no severe toxicities were recorded. Hurwitz et al. (2011) also describe the results of a prospective phase II study for locally advanced prostate carcinoma in 37 patients treated with three-dimensional radiotherapy (66 Gy, daily dose of 1.8–2.0 Gy) plus two transrectal ultrasound hyperthermia treatments and ADT [12,29]; specifically, 5-year OS and bDFS were 93.5% and 60.6%, respectively. Although we only included patients with NCCN high-risk and not very high-risk, IMRT

with 76 Gy in 38 fractions plus regional hyperthermia and ADT demonstrated a favorable clinical outcome, indicating that our treatment strategy is promising.

Several clinical randomized trials conducted in the 1990s have demonstrated that adding hyperthermia to radiotherapy improves local control and complete response rates in patients with superficial tumors, such as those involving recurrent breast carcinoma and malignant melanoma [30,31]. Importantly, detailed analyses of thermal data from those randomized trials of breast carcinoma as well as malignant melanoma treated with radiotherapy, with or without hyperthermia, showed significant improvements in local control rates in patients who achieved higher intra-tumor temperatures [32,33]. Previous clinical studies on deep-seated tumors, including cervical carcinoma of the uterus and rectal carcinoma that were treated with hyperthermia plus deep regional hyperthermia, also state that thermal parameters correlate with clinical outcomes [34–36]. For prostate carcinoma, we have previously demonstrated that the addition of regional hyperthermia with a higher thermal dose (CEM43T90 ≥ 1 min/heating session) for 3D-conformal radiotherapy improves bDFS [13]. Here, bDFS was significantly higher in patients treated with a higher combined thermal dose of CEM43T90 ≥ 7 min (Figure 3b).

Recent investigations on hyperthermia treatment planning have aimed to simulate temperature patterns as well as specific absorption rate (SAR) distributions, while helping operators visualize the effects of different steering strategies in modern locoregional radiofrequency hyperthermia treatments [37–39]. We have previously investigated the use of electromagnetic field numerical simulations for reducing subcutaneous fat overheating, which is a major drawback of deep heating using a capacitively coupled heating system [40]. Hence, optimization of temperature distribution in the deep regional hyperthermia in the pelvis is needed [40] and we used recommended optimal settings in the numerical simulation study, such as use of overlay boluses, electrical conductivity of the circulating coolant, prone position during hyperthermia, and intergluteal cleft gauze, which resulted in improved bDFS among patients who received a good thermal dose. Further improvements in heating methods and selection of patients suitable for hyperthermia represent future research directions.

The efficacy of brachytherapy combined with external beam radiotherapy and ADT as another method of improving the therapeutic effect of IMRT and ADT has been reported in prostate cancer. The ASCENDE-RT trial found that additional low-dose rate brachytherapy improved bDFS, but at the cost of higher, acute and late genitourinary toxicity [41]. Our proposed combination therapy with hyperthermia seems to be a promising method of improving the efficacy of external beam radiotherapy, given its noninvasiveness and the lack of a significant increase in side effects.

Despite these promising results, our study has a few limitations. As this was a retrospective study, the possibility of selection bias with respect to prognostic factors cannot be ruled out. However, as dose prescription for IMRT was constant and there were no differences in the major prognostic factors between patients with and without hyperthermia, the influence of selection bias can be presumed to be relatively small. The duration of ADT was a potential confounding factor. Although no significant difference was found in the duration of ADT between the patients with and without hyperthermia treatment, the duration of ADT was shorter in the hyperthermia group. Therefore, we speculate that the duration of ADT is unlikely to be a confounding factor in the results of this study. A formal prospective clinical trial is needed to determine the efficacy and prognostic factors associated with this approach of combined therapy in patients with high-risk localized prostate carcinoma.

#### **5. Conclusions**

To the best of our knowledge, this is the first report to assess efficacy, in terms of clinical outcomes, of a combination of IMRT and regional hyperthermia in patients with high-risk localized prostate carcinoma. We demonstrate that the use of definitive IMRT, combined with regional hyperthermia, is a promising treatment modality that is not

associated with severe toxicity. Our results support further evaluation such as clinical trials evaluating IMRT with or without regional hyperthermia in patients with high-risk localized prostate carcinoma.

**Author Contributions:** Conceptualization, T.O. and S.N.; Data curation, T.O., S.N., S.K., H.I., T.M. and S.T.; Formal analysis, S.N. and T.O. Investigation, S.N., T.O., S.K., H.I., T.M. and S.T.; Methodology, T.O.; Project administration, T.O.; Validation, T.O.; Writing—original draft, S.N. and T.O.; Writing review and editing, S.N., T.O., K.Y. and N.F. All authors have read and agreed to this tentative abstract. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by JSPS KAKENHI Grant Number JP20K08146.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of University of Occupational and Environmental Health (protocol code UOEHCRB19-073 and 13 February 2020).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Conflicts of Interest:** Author T.O. received scholarship donation from Yamamoto Vinita Co., Ltd., Osaka, Japan.

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