SUVmax-based Parameters of FDG-PET/CT Reliably Predict Pathologic Complete Response After Preoperative Hyperthermo-chemoradiotherapy in Rectal Cancer.

BACKGROUND/AIM: To determine the most reliable predictor for pathologic complete response (pCR) in patients who underwent preoperative chemoradiotherapy and regional hyperthermia (HCRT) for rectal cancer. PATIENTS AND METHODS: Thirty-six patients were enrolled. The local control status of the patients was assessed using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), magnetic resonance imaging (MRI), and colonoscopy before and after HCRT. The relationships between various parameters of these clinical examinations and pCR were analyzed. RESULTS: Ten (28%) patients achieved pCR. The accuracies of predicting pCR using FDG-PET/CT, MRI, and colonoscopy were 78%, 61%, and 75%, respectively. FDG-PET/CT was the only independent predictive modality for pCR (p=0.021). The maximum standardized uptake value (SUVmax) and SUVmax normalized to liver uptake (SLR) after HCRT showed the highest sensitivity (90%) and the decreasing rate of SUVmax and SLR demonstrated the highest specificity (89%) for pCR. CONCLUSION: SUVmax-based parameters of FDG-PET/CT after HCRT were the most reliable predictors for pCR.

Chemoradiotherapy and concurrent radiofrequency thermal therapy to treat primary rectal cancer and prediction of treatment responses.

The present study aimed to evaluate a previously reported predictive formula of output-limiting symptoms induced by radiofrequency (RF) to determine the efficacy of this neoadjuvant chemoradiation (NACR) and concurrent RF thermal therapy. The present study included 81 consecutive patients with confirmed diagnoses of rectal adenocarcinoma that was localized in the mid-low rectum (up to 12 cm from the anal verge) who received NACR [intensity-modulated radiotherapy (IMRT), 50 Gy/25 fractions, capecitabine 1,700 mg/m2/day for 5 days/week)] with concurrent thermal therapy (Thermotron-RF8, once a week for 5 weeks with 50 min irradiation). Patients with progressive disease (PD) did not receive RF outputs higher than the predicted value. Some patients who were predicted to receive more output in fact received more than the predicted output. In patients who were predicted to receive moderately higher outputs, 37.5% of the patients experienced pathological complete responses, which was the highest rate, while in those who did not receive more than the predicted output, 66.7% of the patients experienced PD, which was the highest rate in the present study. We speculate that RF thermal therapy may offset the chemoradiation effects in some patients. Adding thermal therapy as a multimodality therapy to NACR potentially affects patients with lower predicted outputs and actual observed outputs slightly higher than the predictive value. Our predictive equation for initial energy output, in which output­limiting symptoms can be used to predict treatment efficacy, consequently, can be used to decide whether to continue this treatment modality.

Radiofrequency thermal treatment with chemoradiotherapy for advanced rectal cancer.

We previously reported that patients with a clinical complete response (CR) following radiofrequency thermal treatment exhibit significantly increased body temperature compared with other groups, whereas patients with a clinical partial response or stable disease depended on the absence or presence of output limiting symptoms. The aim of this study was to evaluate the correlation among treatment response, Hidaka radiofrequency (RF) output classification (HROC: termed by us) and changes in body temperature. From December 2011 to January 2014, 51 consecutive rectal cancer cases were included in this study. All patients underwent 5 RF thermal treatments with concurrent chemoradiation. Patients were classified into three groups based on HROC: with ≤9, 10-16, and ≥17 points, calculated as the sum total points of five treatments. Thirty-three patients received surgery 8 weeks after treatment, and among them, 32 resected specimens were evaluated for histological response. Eighteen patients did not undergo surgery, five because of progressive disease (PD) and 13 refused because of permanent colostomy. We demonstrated that good local control (ypCR + CR + CRPD) was observed in 32.7% of cases in this study. Pathological complete response (ypCR) was observed in 15.7% of the total 51 patients and in 24.2% of the 33 patients who underwent surgery. All ypCR cases had ≥10 points in the HROC, but there were no patients with ypCR among those with ≤9 points in the HROC. Standardization of RF thermal treatment was performed safely, and two types of patients were identified: those without or with increased temperatures, who consequently showed no or some benefit, respectively, for similar RF output thermal treatment. We propose that the HROC is beneficial for evaluating the efficacy of RF thermal treatment with chemoradiation for rectal cancer, and the thermoregulation control mechanism in individual patients may be pivotal in predicting the response to RF thermal treatment.

Output-limiting symptoms induced by radiofrequency hyperthermia. Are they predictable?

BACKGROUND: During radiofrequency (RF) hyperthermia treatment, hot-spot phenomena may occur and prevent treatment continuation if the output is not lowered. We previously reported a significant correlation between the initial energy output at which output-limiting symptoms occurred and patient status. Patients with a complete clinical response had significantly increased temperature, while some patients with partial clinical response and stable disease had increased temperature, depending on the occurrence of output-limiting symptoms. To predict the initial energy output at which output-limiting symptoms occur, we performed multiple regression analysis with the parameters of patients' physical status. MATERIALS AND METHODS: Hyperthermia alone or concomitant with chemotherapy and/or radiotherapy was applied in 62 patients with malignant disease for a total of 310 treatments with a Thermotron RF-8 between December 2011 and April 2014. RESULTS: No output-limiting symptoms were shown in 65.5% of 310 treatments. Pain (29.7%), micturition desire (1.9%), skin discomfort (0.6%), subcutaneous induration (1.6%), cold sensation (0.6%), and nausea (0.3%) were reported in the 310 treatments. A good predictive equation for initial energy output at which output-limiting symptoms occur was determined with two parameters, initial time of an output-limiting symptom onset, and thickness of the fat of the abdominal wall. Multiple regression analysis showed an adjusted R(2 )= 0.99 and variance inflation factor < 2. CONCLUSIONS: We present a good predictive equation for initial energy output at which output-limiting symptoms occur. It is critical to prevent RF hyperthermia-induced output-limiting symptoms and establish new prevention strategies.

A novel strategy of radiofrequency hyperthermia (neothermia) in combination with preoperative chemoradiotherapy for the treatment of advanced rectal cancer: a pilot study.

The safety of weekly regional hyperthermia performed with 8 MHz radiofrequency (RF) capacitive heating equipment has been established in rectal cancer. We aimed to standardize hyperthermia treatment for scientific evaluation and for assessing local tumor response to RF hyperthermia in rectal cancer. Forty-nine patients diagnosed with rectal adenocarcinoma were included in the study. All patients received chemoradiation with intensity-modulated radiation therapy 5 days/week (dose, 50 Gy/25 times) concomitant with 5 days/week for five times of capecitabine (1700 mg/m(2) per day) and once a week for five times of 50 min irradiations by an 8 MHz RF capacitive heating device. Thirty-three patients underwent surgery 8 weeks after treatment. Three patients did not undergo surgery because of progressive disease (PD) and 13 refused. Eight (16.3%) patients had a pathological complete response (ypCR) after surgery. Among patients without surgery, 3 (6.1%) had clinical complete response (CR) and 3 (6.1%) had local CR but distant PD (CRPD). Ninety percent of ypCR + CR patients were shown in 6.21 W min(-1) m(-2) /treatment or higher group of average total accumulated irradiation output with 429°C min(-1) m(-2) or higher group of total accumulated thermal output. However, a patient with CRPD was in the higher total accumulated thermal output group. We propose a new quantitative parameter for the hyperthermia and demonstrated that patients can benefit from mild irradiation with mild temperature. Using these parameters, the exact output, optimal thermal treatment, and contraindications or indications of this modality could be determined in a multi-institutional, future study.

Expression of hypoxia-inducible factor 1α predicts clinical outcome after preoperative hyperthermo-chemoradiotherapy for locally advanced rectal cancer.

Hypoxia-inducible factor 1α (HIF-1α) is an intrinsic marker of tumor hypoxia. It has been considered that hypoxic conditions reduce radiosensitivity, but the role of HIF-1α in patients treated with preoperative therapy for rectal cancer is still unclear. The aim of this study was to evaluate the predictive value of tumor response to preoperative hyperthermo-chemoradiotherapy (HCRT) and the prognostic significance of HIF-1α expression in patients with locally advanced rectal cancer. Between 2003 and 2006, 50 patients with histologically proven rectal adenocarcinoma who underwent HCRT followed by surgery were investigated. HIF-1α expression was immunohistochemically evaluated using pre-treatment biopsies. The total radiation dose was 40-50 Gy and chemotherapy consisted of 5-FU and LV administered by continuous infusion on Day 1-5, Day 15-19, and Day 29-33 during radiotherapy. Hyperthermia treatment was performed for once a week for 2-5 sessions. The surgical operation was performed 8 weeks after HCRT and each resected specimen was graded by histological criteria of the Japanese Classification of Colorectal Carcinoma. The effects of HIF-1α on clinical outcomes were analyzed by univariate and multivariate analysis. Positive HIF-1α expression was recognized in 42.0% of samples (21/50). Resected specimens that showed pathological grades 1, 2, and 3 numbered 17, 24, and 9 cases, respectively. There were no significant differences between the HIF-1α-positive group and HIF-1α-negative group for pathological grading and pCR. Overall survival (OS) rate at 3 years in the HIF-1α-negative group was 85.2%, which was significantly better than the 60.6% in the HIF-1α-positive group. Recurrence-free survival (RFS) rate at 3 years in the HIF-1α-negative group was 82.8%, being significantly better than 47.6% in the HIF-1α-positive group. In addition, elevated HIF-1α expression was significantly correlated with recurrence-free survival and metastasis-free survival rate in multivariate analysis. HIF-1α expression might be predictive of recurrence-free survival and metastasis-free survival rate for rectal cancer patients treated with HCRT.

L-type amino-acid transporter 1 expression predicts the response to preoperative hyperthermo-chemoradiotherapy for advanced rectal cancer.

AIM: To evaluate whether expression of L-type amino acid transporter 1 (LAT1) in pretreatment rectal cancer biopsies is predictive of tumour response to neoadjuvant hyperthermo-chemoradiotherapy (HCRT). PATIENTS AND METHODS: Forty-four patients with rectal adenocarcinoma who received neoadjuvant HCRT were investigated. LAT1 expression was immunohistochemically evaluated using pretreatment biopsies. The operation was performed after 2-3 months following HCRT and each resected specimen was graded by the histological criteria of the Japanese Classification of Colorectal Carcinoma. RESULTS: A positive LAT1 expression was recognized in 50.0% (22/44) of patients. Resected specimens were divided into 2 groups according to the histological grading criteria: good response (n=29) and poor response (n=15). LAT1-negative tumours had an 81.8% probability of good response and 18.2% probability of poor response. LAT1 expression showed marginally significant association with response to HCRT (p=0.05). CONCLUSION: LAT1 may be a useful predictive marker of response to HCRT in rectal cancer.

Combined effect of hyperthermia at 42 degrees C and irradiation dose of 2 Gy on two rat yolk sac tumor cell lines with different radio-thermosensitivity in vitro.

BACKGROUND: Two rat yolk sac tumor cell lines, NMT-1 and NMT-1R, are of the same origin and of different sensitivity to irradiation and to heat. The aim of this study was to investigate the sensitivities of these two cell lines to combined treatments of low-dose irradiation at 2 Gy and hyperthermia at 42 degrees C. MATERIALS AND METHODS: The cell survival was assayed by soft agar clonogenic assay. After the survival curves of radiation alone and of heat alone at various temperatures were estimated, not only the effect of irradiation on heat, but the effect of heat on irradiation were evaluated with sequential treatments in both cell lines. These effects on survival curves were evaluated by the enhancement ratios at isosurvival levels of 37%, 10% and 1%, respectively. RESULTS: NMT-1 was more sensitive to radiation but more resistant to heat than NMT-1R. For 1% survival level, radiosensitivity in NMT-1 was 1.32 times that in NMT-1R, while thermal sensitivity at 42 degrees C in NMT-1R was 2.73 times that in NMT-1. For sequential treatment, thermosensitization by a radiation dose of 2 Gy in radiosensitive NMT-1 was greater than that in radioresistant NMT-1R. Following heat at 42 degrees C for 1 hour, increased radiosensitivity in NMT-1R was significant, whereas the same heat treatment produced an increase in the radiation sensitivity of NMT-1 with a reduction of the survival curve shoulder but with less slope modification. There was no difference in the surviving fraction in the time-course of a combination of heat and irradiation at various intervals within 6 hours for NMT-1 except for heating immediately after irradiation. However a significant increase in survival was observed when heat was applied more than 3 hours after 2 Gy irradiation for NMT1-R. CONCLUSION: These results from our cell lines with the same origin were useful for investigation into the interaction of irradiation with heat.