Relationships between thermal dose parameters and the efficacy of definitive chemoradiotherapy plus regional hyperthermia in the treatment of locally advanced cervical cancer: data from a multicentre randomised clinical trial.

PURPOSE: To evaluate the contribution of the thermal dose parameters during regional hyperthermia (HT) treatment to the clinical outcomes in patients with cervical carcinoma (CC) who received chemoradiotherapy (CRT) plus HT. MATERIALS AND METHODS: Data from a multicentre randomised clinical trial of concurrent CRT + HT vs. CRT alone were used to evaluate the efficacy and safety of this combination therapy in the CC patients. The intrarectal temperatures of patients undergoing HT were recorded. The complete thermal data of 47 (92%) of the 51 patients in the CRT + HT group were available for the thermal analysis. Thus, 47 patients who received CRT + HT were included in the present study. RESULTS: Among the patients who received CRT + HT, a higher CEM43T90 (≥1 min) value (a thermal dose parameter) was significantly associated with better local relapse-free survival in both univariate (p = 0.024) and multivariate (p = 0.0097) analyses. The disease-free survival of the patients with higher CEM43T90 (≥1 min) values tended to be better in comparison to patients with lower CEM43T90 (<1 min) value (p = 0.071). A complete response tended to be associated with the CEM43T90 (p = 0.056). Disease-free survival, local relapse-free survival and complete response rate for patients with higher CEM43T90 (≥1) were significantly better than those for patients with CRT alone (p = 0.036, p = 0.036 and p = 0.048). CONCLUSIONS: Dose-effect relationships between thermal dose parameters and clinical outcomes were confirmed in the CC patients treated with a combination of CRT + HT. This study also confirmed that HT with lower CEM43T90 is insufficient to achieve a significant hyperthermic sensitisation to CRT.

A multicentre randomised clinical trial of chemoradiotherapy plus hyperthermia versus chemoradiotherapy alone in patients with locally advanced cervical cancer.

PURPOSE: To evaluate the effectiveness of whole-pelvic hyperthermia (HT) added to standard chemoradiotherapy (CRT) in locally advanced cervical cancer (CC), by investigating the clinical response and survival of patients treated with cisplatin-based CRT vs. CRT with HT (CRT + HT). MATERIALS AND METHODS: This study was conducted at five hospitals in Japan between September 2001 and March 2015 in patients with the International Federation of Gynecology and Obstetrics stage IB (bulky)-IVA CC undergoing definitive CRT. After giving a written informed consent, patients were randomly allocated to two treatment groups: CRT and CRT + HT group. Overall survival (OS), disease-free survival (DFS), local relapse-free survival (LRFS), complete response (CR) rate and tolerability were evaluated. RESULTS: In total, 101 patients were treated. Patient characteristics, total dose of cisplatin and radiotherapy were similar for both groups. Although not statistically significant, the 5-year OS, DFS and LRFS in the CRT + HT group (77.8%, 70.8% and 80.1%, respectively) were better than those in the CRT group (64.8%, 60.6% and 71.0%, respectively). CR was significantly more likely to be achieved in patients in the CRT + HT group than in the CRT group (88% vs. 77.6%; adjusted odds ratio, 3.993; 95% confidence interval, 1.018-15.67; p = .047). CRT + HT was well tolerated and caused no additional acute or long-term toxicity compared with CRT alone. CONCLUSIONS: HT combined with CRT improved the CR rate of CRT in patients with locally advanced CC, however, could not improve survival outcomes. Further studies in larger samples are warranted.

Investigation of whether in-room CT-based adaptive intracavitary brachytherapy for uterine cervical cancer is robust against interfractional location variations of organs and/or applicators.

This study investigates whether in-room computed tomography (CT)-based adaptive treatment planning (ATP) is robust against interfractional location variations, namely, interfractional organ motions and/or applicator displacements, in 3D intracavitary brachytherapy (ICBT) for uterine cervical cancer. In ATP, the radiation treatment plans, which have been designed based on planning CT images (and/or MR images) acquired just before the treatments, are adaptively applied for each fraction, taking into account the interfractional location variations. 2D and 3D plans with ATP for 14 patients were simulated for 56 fractions at a prescribed dose of 600 cGy per fraction. The standard deviations (SDs) of location displacements (interfractional location variations) of the target and organs at risk (OARs) with 3D ATP were significantly smaller than those with 2D ATP (P < 0.05). The homogeneity index (HI), conformity index (CI) and tumor control probability (TCP) in 3D ATP were significantly higher for high-risk clinical target volumes than those in 2D ATP. The SDs of the HI, CI, TCP, bladder and rectum D2cc, and the bladder and rectum normal tissue complication probability (NTCP) in 3D ATP were significantly smaller than those in 2D ATP. The results of this study suggest that the interfractional location variations give smaller impacts on the planning evaluation indices in 3D ATP than in 2D ATP. Therefore, the 3D plans with ATP are expected to be robust against interfractional location variations in each treatment fraction.

Improvement in treatment results of glioblastoma over the last three decades and beneficial factors.

BACKGROUND: The purpose of this study is to elucidate the trend of glioblastoma outcome and scrutinize the factors contributing to better outcome over three decades. METHODS: Survival time and the influencing factors were retrospectively analyzed in 223 newly diagnosed primary glioblastoma patients during 1980-2010. Appraised factors included age, sex, tumor site, year of surgery, extent of resections, use of surgery supporting system, Karnofsky Performance Status (KPS), chemotherapy, conventional external beam radiotherapy (EBRT), and CyberKnife stereotactic radiotherapy (CK-SRT) use. RESULTS: The median survival time (MST) in all patients was 13.6 months. The MSTs for 4 periods were 9.8 (1980-1990), 13.7 (1991-2000), 12.9 (2001-2005), and 15.8 months (2006-2010), respectively (p=0.0047). Total resection, subtotal resection, partial resection, and biopsy had MSTs of 31.8, 13.9, 11.4, and 7.0 months, respectively (p<0.0001). Regarding chemotherapy, MSTs of the temozolomide base group and nimustine hydrochloride (ACNU) base group were 16.9 and 14.6 months, respectively, whereas the MST of patients without chemotherapy was only 9.8 months (p<0.0001). The MSTs for 40-Gy EBRT plus CK-SRT and 60-Gy EBRT were 19.1 and 10.7 months, respectively (p<0.0001). But in sub-selected patients, treated during 2001-2010, whose resection rate was total resection or subtotal resection, EBRT was completed and postoperative KPS was greater than or equal to 70, the MST with and without CK-SRT was 26.6 and 18.3 months, respectively (p=0.1529). According to the Cox proportional hazards model, degree of resection, KPS, ACNU use, temozolomide use, bevacizumab use, EBRT dose, and CK-SRT use were good prognostic factors. Use of neuronavigation and use of intraoperative magnetic resonance imaging were related to higher resection rate, but not determined as prognostic factors. CONCLUSIONS: We observed a gradual improvement in glioblastoma outcome, presumably because of improvements in therapeutic modalities for surgery, anticancer agents, and radiation, but the efficacy of CK-SRT remains unclear.

The usefulness of neoadjuvant chemoradiation therapy for locally advanced esophageal cancer with multiple lymph-node metastases.

BACKGROUND: The prognosis of patients with esophageal squamous-cell cancer (ESCC) and multiple lymph-node metastases is quite poor. We examined whether neoadjuvant chemoradiation therapy (CRT) has a beneficial effect in such patients. METHODS: A total of 50 consecutive patients with T3-4 tumors and without organ metastases were prospectively enrolled. Of those patients, 20, who had four or more nodal metastases, underwent neoadjuvant CRT (CRT group), and the remaining 30 patients, who had three or fewer nodal metastases, underwent surgery alone (surgery group). CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The groups' clinical outcomes were compared. RESULTS: Surgery was performed in 48 patients: all enrolled patients except for 2 who had organ metastasis after CRT. In the CRT group, the number of patients with pathological complete response was observed in 8 patients (44 %), mean nodal metastases number was changed from 8.2 to 2.6 and 9 patients had pN0. The 3-year survival rate was 76 % in the CRT group (4 patients relapsed) and 68 % in the surgery group (8 patients relapsed), which is not a statistically significant difference (P = 0.61). CONCLUSIONS: Neoadjuvant CRT is beneficial for locally advanced ESCC with four or more lymph-node metastases.

Prognostic factors in esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiation therapy.

BACKGROUND: Definitive evaluation of surgical specimens obtained after neoadjuvant chemoradiation therapy (CRT) is important for assessing additional treatment or prognosis in patients with esophageal squamous cell carcinoma (ESCC). In this study, we examined the histological prognostic factors for ESCC patients treated with CRT and determined an appropriate strategy for their evaluation. PATIENTS AND METHODS: The present study involved 38 consecutive ESCC patients who underwent CRT followed by curative operation. CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. We examined histological variables as follows: CRT effect on primary tumor (T-effect: T-effective/T-ineffective), tumor depth (pT), lymph node metastases (pN: pN0/N1), number of lymph node metastases (number-pN), lymphatic invasion, and venous invasion. Univariate and multivariate analyses were performed to examine the independent prognostic factors. Survivals and mode of recurrence were then evaluated according to the independent prognostic factors. RESULTS: In the univariate analyses, T-effect, pN, number-pN, lymphatic invasion, and venous invasion were found to be prognostic factors with p < 0.01, and pT was a factor with p < 0.05. In the multivariate analysis, pN and T-effect were independent prognostic factors. The five-year survival rate of pN0 patients was more than 75%, even though the T-effect was poor. The 5-year survival rate of patients judged as pN1/T-effective was 50%, whereas all of the pN1/T-ineffective patients died within 2 years with relapse disease. CONCLUSION: The evaluation method using both pN status and T-effect is useful for assessing prognosis of ESCC patients treated with neoadjuvant CRT.

[A case of pancreatic cancer with liver metastasis controlled effectively by chemotherapy based on chemosensitivity test and stereotactic body radiotherapy].

A 5 5-year-old woman was admitted to our hospital for pancreatic cancer with liver metastasis. We performed pancreatoduodenectomy, D2 dissection, and partial liver resection. Tissue from a resected liver metastasis was submitted to a chemosensitivity test. Based on the test results, we performed systemic chemotherapy with paclitaxel and hepatic artery infusion with gemcitabine for lung and liver metastasis after surgery. Furthermore, we added stereotactic body radiation therapy(SBRT)(48 Gy/4 Fr)for 3 liver metastases that showed enlargement after chemotherapy. Effective control of recurrent tumors was possible for 2 years and 5 month, and she maintained normal daily activities. She died of peritoneal dissemination 3 years and one month after surgery. Combined modality therapy with anticancer agents based on a chemosensitivity test and SBRT may be one useful therapy for pancreatic cancer with distant metastases.

A phase II study of oral S-1 with concurrent radiotherapy followed by chemotherapy with S-1 alone for locally advanced pancreatic cancer.

BACKGROUND/PURPOSE: S-1 is a new oral fluoropyrimidine anticancer agent shown to be effective for pancreatic cancer. In a previous phase I trial, we evaluated the safety of S-1 combined with radiotherapy to determine the maximum tolerated dose and dose-limiting toxicity in patients with unresectable pancreatic cancer. The recommended dose of S-1 for phase II trials of chemoradiotherapy was determined as 80 mg/m(2)/day given on days 1-21 of a 28-day cycle. This phase II study was conducted to further evaluate the efficacy and toxicity of radiotherapy combined with S-1 (UMIN000004794). METHODS: Eligible patients had locally advanced and unresectable pancreatic cancer without distant metastases, an Eastern Cooperative Oncology Group performance status of 0-1, adequate organ and marrow functions, and no prior anticancer therapy. Patients initially received 4 weeks of chemoradiotherapy. S-1 was given orally at a dose of 80 mg/m(2)/day twice daily on days 1-21. Radiotherapy was delivered in fractions of 1.25 Gy twice daily, 5 days per week for 4 weeks (total dose: 50 Gy in 40 fractions). One month after the completion of chemoradiotherapy, S-1 was administered for 14 days followed by a 14-day rest period. This cycle was repeated as maintenance therapy until disease progression or unacceptable toxicity. RESULTS: Fifty patients were enrolled in this phase II study. Median follow-up was 14.6 months (range 5.4-58.9 months). Forty-three patients (86%) completed the scheduled course of chemoradiotherapy. There was no treatment-related death or grade 4 toxicity. The major toxic effects were leukopenia and nausea. The objective tumor response according to the Response Evaluation Criteria in Solid Tumours criteria was partial response in 15 patients (30%) (95% confidence interval (CI), 18-45%), stable disease in 23 (46%), and progressive disease in 12 (24%). Median progression-free survival and median overall survival were 6.7 months (95% CI, 4.7-11.2 months) and 14.3 months (95% CI, 10.8-20.8 months), respectively. Survival rates at 1 and 2 years were 62 and 27%, respectively. CONCLUSIONS: Combination therapy with S-1 and radiation in patients with locally advanced and unresectable pancreatic cancer is considered a promising, well-tolerated regimen that can be recommended as an effective treatment for locally advanced pancreatic cancer.

Comparison of hyper-fractionated accelerated and standard fractionated radiotherapy with concomitant low-dose gemcitabine for unresectable pancreatic cancer.

BACKGROUND: Concurrent chemoradiotherapy with gemcitabine improves median survival for patients with unresectable pancreatic cancer. Recently, hyperfractionated accelerated radiotherapy (HART) has been used to treat these patients; however, the safety and efficacy are not well defined. PATIENTS AND METHODS: The standard-fractionated radiotherapy (SFRT) group (n=17) received 50.4 Gy in 28 fractions of 1.8 Gy/day. The HART group (n=18) received 50 Gy in 40 fractions of 1.25 Gy twice/day. Concurrent gemcitabine was administered to both groups. RESULTS: Median survival times were 11.3 months (SFRT) and 12.9 months (HART). One- and two-year survival rates were 37.5% and 18.8% (SFRT) and 47.1% and 17.6% (HART), respectively. The response rates did not differ significantly. The HART regimen required significantly fewer treatment days (35.5) than did the SFRT regimen (41.3). The toxicity profiles were similar. CONCLUSION: The HART/gemcitabine regimen has equivalent efficacy and a shorter treatment time as compared with the SFRT/gemcitabine regimen for patients with unresectable pancreatic cancer.

Variation of clinical target volume definition among Japanese radiation oncologists in external beam radiotherapy for prostate cancer.

BACKGROUND: We investigated the interobserver variation in the prostate target volume and the trend toward the use of diagnostic computed tomography (CT) or magnetic resonance (MR) images for treatment planning. METHODS: Twenty-five radiation oncologists were asked to draw the external contour of the prostate on CT images (0.3 cm spacing) of a patient with localized prostate cancer. They also answered a questionnaire regarding the use of diagnostic CT or MR images for the contouring. RESULTS: Of the 25 physicians, 28% rarely or never referred to the diagnostic CT images. In contrast, the physicians tended to refer to the MR images more frequently. Approximately 50% of the physicians believed in the usefulness of contrast-enhanced images for the delineation of the prostate. As for the variation of the prostate contouring, the median craniocaudal prostate length was 36 mm (range, 21-54 mm), and the median prostate volume was 43.5 cm(3) (range, 23.8-98.3 cm(3)). The interobserver variability was not significant in the duration as a radiation oncologist, the board certification status as radiation oncologists, and the number of treatment plans developed for prostate cancer during the last 1 year. CONCLUSION: A wide variety of the definitions of the prostate was found among Japanese radiation oncologists.

[An effective treatment by chemoradiation therapy after stent insertion for advanced esophageal cancer with esophago-pulmonary fistula--report of a case].

We report the case of a 56-year-old male who was diagnosed as advanced esophageal cancer with esophago-pulmonary fistula and lung abscess. He received radiation therapy in combination with chemotherapy using cisplatin and 5-FU after insertion of a self-expanding metallic stent. He had sufficient food intake during the chemoradiotherapy (CRT). CRT was very effective for not only primary tumor but also lymph node metastasis, with resulting partial response. We could not detect any relapses and metastases for 8 months after CRT. The CRT after insertion of self-expanding metallic stent is one of the useful and palliative treatments for advance esophageal cancer with esophago-pulmonary fistula.

External-beam radiation therapy for age-related macular degeneration: two years' follow-up results at a total dose of 20 Gy in 10 fractions.

PURPOSE: The efficacy of external-beam radiation therapy (RT) was evaluated in the treatment of eyes with subfoveal or juxtafoveal choroidal neovascularization in age-related macular degeneration (ARMD). MATERIALS AND METHODS: Twenty-one eyes of 18 patients with occult or mixed-type ARMD received a total dose of 20 Gy of 6 MV X-rays in 10 fractions. The follow-up time was 24 months. Fifteen non-treated eyes of 13 patients who had been followed served as a control. RESULTS: In the RT group, visual acuity was improved in three eyes, maintained in 14 eyes, and worsened in four eyes. In the control group, it was not improved in any eyes, was maintained in six eyes, and worsened in nine eyes. The improved or maintained rate in visual acuity was 81% in the RT group and 40% in the control group (p=0.0342). In the RT group, fundoscopic and angiographic findings were improved in five eyes, unchanged in seven eyes, and worsened in nine eyes, while they were not improved in any eyes, unchanged in two eyes, and worsened in 13 eyes in the control group(p=0.0342). CONCLUSION: RT at a total dose of 20 Gy in 10 fractions is effective for ARMD for at least two years. RT may be effective treatment for occult or mixed-type ARMD compared with the classic type.