Satoaki Nakamura

HIGH-DOSE-RATE INTERSTITIAL BRACHYTHERAPY AS A MONOTHERAPY FOR LOCALIZED PROSTATE CANCER: TREATMENT DESCRIPTION AND PRELIMINARY RESULTS OF A PHASE I/II CLINICAL TRIAL

PURPOSE To improve results for localized prostate cancer, a prospective clinical trial of hyperfractionated Iridium-192 high-dose-rate (HDR) brachytherapy as a monotherapy was initiated. METHODS AND MATERIALS Between May 1995 and September 1998, 22 implants were performed on 22 patients with localized prostate cancer (T1:T2:T3:T4 = 4:6:9:3) at Osaka University Hospital. Nineteen patients, who had T3-T4 tumors or pretreatment PSA >/= 20.0 ng/mL, received hormone therapy. No patient had external beam radiation. Transperineal needle implants using real-time ultrasound guidance were performed, followed by dose optimization program. Patients were irradiated twice a day, with a time interval of more than 6 h. Total dose was 48 Gy/8 fractions/5 days or 54 Gy/9 fractions/5 days. Acute toxicity was scored using the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Median follow-up time was 31 months. RESULTS HDR brachytherapy as a monotherapy was well-tolerated. No significant intra- or peri-operative complications occurred. No patient experienced acute toxicity of grade 3 or more. PSA levels normalized in 95% of patients within 20 months after irradiation. Four-year clinical and biochemical relapse-free rates were 95% and 55%, respectively. CONCLUSION Acute toxicity with this method was acceptable. Further patient accrual and longer follow-up will allow comparison to other techniques.

Comparison between definitive chemoradiotherapy and esophagectomy in patients with clinical stage I esophageal squamous cell carcinoma.

OBJECTIVES:Chemoradiotherapy (CRT) has been proposed as an alternative therapy to esophagectomy for esophageal cancer, because of its favorable survival rate and mild toxicity. However, no comparative studies of esophagectomy and CRT have been reported in patients with clinical stage I esophageal squamous cell carcinoma.METHODS:A total of 54 patients with clinical stage I esophageal squamous cell carcinoma were treated with definitive CRT and 116 patients with esophagectomy at Osaka Medical Center for Cancer and Cardiovascular Diseases between 1995 and 2008, and were included in the analysis. Overall survival and recurrence rates were evaluated.RESULTS:Complete follow-up data were available for 169 of the 170 patients (99%). The median (range) observation period was 67 (10–171) months in the esophagectomy group and 30 (4–77) months in the CRT group (P<0.0001). The 1- and 3-year overall survival rates were 97.4% and 85.5%, respectively, in the esophagectomy group and 98.1% and 88.7%, respectively, in the CRT group (P=0.78). Cox proportional hazards modeling showed that the overall survival was comparable between the two groups after adjusting for age, sex, and tumor size. The hazard ratio of CRT for overall survival was 0.95 (95% confidence interval 0.37–2.47). The incidence of local recurrence, including metachronous esophageal cancer, was significantly higher in the CRT group than in the esophagectomy group (P<0.0001). Most local recurrences in the CRT group were intramucosal carcinomas, and were cured after salvage treatment, mainly using endoscopy.CONCLUSIONS:The overall survival rate of patients with clinical stage I esophageal cancer treated with CRT was comparable to that in those treated with esophagectomy, despite a high local recurrence rate. Locally recurrent carcinoma was endoscopically treatable in most patients, with no effect on overall survival. CRT seems to be a viable alternative to esophagectomy in patients with clinical stage I esophageal cancer.

Preoperative chemoradiation reduces the risk of pancreatic fistula after distal pancreatectomy for pancreatic adenocarcinoma

BACKGROUND Pancreatic fistula (PF) is a common complication after pancreatectomy. Previous reports indicate that preoperative irradiation decreases the risk of PF after pancreatoduodenectomy. In this context, the impact of preoperative chemoradiation therapy (CRT) on PF formation after distal pancreatectomy is of interest. METHODS Fifty-eight patients with pancreatic adenocarcinoma who underwent distal pancreatectomy, including 28 patients with preoperative gemcitabine-based CRT and 30 patients without preoperative treatment, were assessed in this study. The incidence and severity of postoperative PF, assessed according to the definition of the International Study Group on Pancreatic Fistula, were compared between the 2 groups. RESULTS In the CRT group, 86% of patients did not develop PF, whereas grades A and B PF were observed in 1 and 3 patients, respectively. In the non-CRT group, 33% of patients did not develop a PF, whereas grades A and B PF were observed in 9 and 11 patients, respectively. The incidence of clinically significant PF, defined as either grade B or grade C PF, was less in the CRT group (P = .031). The amylase activities in the draining fluid on postoperative days 1 and 3 were both less in the CRT group (P = .003 and P = .006, respectively). CONCLUSION Preoperative CRT significantly decreases the incidence of PF after distal pancreatectomy, which potentially provides another benefit to patients in addition to its original advantages (ie, locoregional effect and patient selection effect), allowing more opportunities for the immediate initiation of postoperative adjuvant treatment.

Comparison Between Radical Esophagectomy and Definitive Chemoradiotherapy in Patients with Clinical T1bN0M0 Esophageal Cancer

BackgroundEsophagectomy remains the mainstay treatment for clinical T1bN0M0 esophageal cancer because pathologic lymph node metastases in these patients are not negligible. Recently, chemoradiotherapy (CRT), which can preserve the esophagus, has been reported to be a promising therapeutic alternative to esophagectomy. However, to our knowledge, no comparative studies of esophagectomy and CRT have been reported in clinical T1bN0M0 esophageal cancer.MethodsA total of 173 patients with clinical T1bN0M0 squamous cell carcinoma of the thoracic esophagus were enrolled in this study, 102 of whom were treated with radical esophagectomy (S group) and 71 with definitive CRT (CRT group). Treatment results of both groups were retrospectively compared.ResultsNo statistically significant difference was found in overall survival, but the S group displayed significantly better progression-free survival than the CRT group. Disease recurrence was observed in 12 S group patients and 20 CRT group patients. The incidence of distant recurrence was similar, while local recurrence and lymph node recurrence were significantly more frequent in the CRT group. In the S group, 20 patients had pathologic lymph node metastasis. The progression-free survival of patients with pathologic lymph node metastasis did not differ from those without nodal metastasis. In the CRT group, local recurrence could be controlled by salvage esophagectomy, but treatment results of lymph node recurrence were poor; only 4 of 12 patients with lymph node recurrences were cured.ConclusionsSelection of patients at high risk of pathologic lymph node metastasis is essential when formulating treatment decisions for clinical T1bN0M0 esophageal cancers.

Human equilibrative nucleoside transporter 1 level does not predict prognosis in pancreatic cancer patients treated with neoadjuvant chemoradiation including gemcitabine

BackgroundGemcitabine is a key drug for the treatment of pancreatic cancer. Human equilibrative nucleoside transporter 1 (hENT1) is a major transporter responsible for gemcitabine uptake into cells. This study was conducted to elucidate the association between expression level of hENT1 and outcome for pancreatic cancer patients treated with neoadjuvant therapy including gemcitabine.MethodsSixty-three patients who underwent neoadjuvant chemoradiation followed by curative surgery for pancreatic ductal adenocarcinomas were included. Immunohistochemistry was performed using resected specimens and the staining intensity of hENT1 was scored as having no staining, low staining, or high staining; the former two were defined as negative expression of hENT1. The association between expression level of hENT1 and overall survival was evaluated by Cox proportional regression model.ResultsExpression level of hENT1 was evaluated as positive in 22 (35%) patients, and as negative in 41 (65%) patients. Univariate analysis showed that regional lymph node metastasis, vascular permeation, and perineural invasion are prognostic factors; however, expression level of hENT1 did not reach statistical significance. Multivariate analysis showed only vascular permeation as a prognostic factor.ConclusionsExpression level of hENT1 was not associated with prognosis for pancreatic cancer patients who were treated with neoadjuvant chemoradiation including gemcitabine.

Outcome and toxicity of stereotactic body radiotherapy with helical tomotherapy for inoperable lung tumor: analysis of Grade 5 radiation pneumonitis

To analyze outcomes and toxicities of stereotactic body radiotherapy with helical tomotherapy (HT-SBRT) for inoperable lung tumors, the medical records of 30 patients with 31 lung tumors treated with HT-SBRT were reviewed. The 3-year local control, cause-specific survival and overall survival rates (LC, CCS and OS, respectively) were analyzed using the Kaplan–Meier method. Toxicities were graded using Common Terminology Criteria for Adverse Events ver. 4. To investigate the factors associated with Grade 5 radiation pneumonitis (G5 RP), several parameters were analyzed: (i) patient-specific factors (age, gross tumor volume and PTV, and the interstitial pulmonary shadow on pretreatment CT); and (ii) dosimetry-specific factors (conformity index, homogeneity index, mean lung dose, and V5, V10, V15, V20 and V25 of the total lungs). The median duration of observation for all patients was 36.5 months (range, 4–67 months). The 3-year LC, CCS and OS were 82, 84 and 77%, respectively. Regarding Grade 3 or higher toxicities, two patients (6.7%) developed G5 RP. GTV was significantly associated with G5 RP (P = 0.025), and there were non-significant but slight associations with developing G5 RP for V5 (P = 0.067) and PTV (P = 0.096). HT-SBRT led to standard values of LC, CCS and OS, but also caused a markedly higher incidence of G5 RP. It is essential to optimize patient selection so as to avoid severe radiation pneumonitis in HT-SBRT.

Carotid blowout syndrome in pharyngeal cancer patients treated by hypofractionated stereotactic re-irradiation using CyberKnife: A multi-institutional matched-cohort analysis

BACKGROUND AND PURPOSE Although reirradiation has attracted attention as a potential therapy for recurrent head and neck tumors with the advent of modern radiotherapy, severe rate toxicity such as carotid blowout syndrome (CBOS) limits its potential. The aim of this study was to identify the risk factors of CBOS after hypofractionated stereotactic radiotherapy (SBRT). METHODS AND PATIENTS We conducted a matched-pair design examination of pharyngeal cancer patients treated by CyberKnife reirradiation in four institutes. Twelve cases with CBOS were observed per 60 cases without CBOS cases. Prognostic factors for CBOS were analyzed and a risk classification model was constructed. RESULTS The median prescribed radiation dose was 30 Gy in 5 fractions with CyberKnife SBRT after 60 Gy/30 fractions of previous radiotherapy. The median duration between reirradiation and CBOS onset was 5 months (range, 0-69 months). CBOS cases showed a median survival time of 5.5 months compared to 22.8 months for non-CBOS cases (1-year survival rate, 36% vs.72%; p=0.003). Univariate analysis identified an angle of carotid invasion of >180°, the presence of ulceration, planning treatment volume, and irradiation to lymph node areas as statistically significant predisposing factors for CBOS. Only patients with carotid invasion of >180° developed CBOS (12/50, 24%), whereas no patient with tumor involvement less than a half semicircle around the carotid artery developed CBOS (0/22, 0%, p=0.03). Multivariate Cox hazard model analysis revealed that the presence of ulceration and irradiation to lymph nodes were statistically significant predisposing factors. Thus, we constructed a CBOS risk classification system: CBOS index=(summation of risk factors; carotid invasion >180°, presence of ulceration, lymph node area irradiation). This system sufficiently separated the risk groups. CONCLUSION The presence of ulceration and lymph node irradiation are risk factors of CBOS. The CBOS index, including carotid invasion of >180°, is useful in classifying the risk factors and determining the indications for reirradiation.

Transitioning from conventional radiotherapy to intensity-modulated radiotherapy for localized prostate cancer: changing focus from rectal bleeding to detailed quality of life analysis

With the advent of modern radiation techniques, we have been able to deliver a higher prescribed radiotherapy dose for localized prostate cancer without severe adverse reactions. We reviewed and analyzed the change of toxicity profiles of external beam radiation therapy (EBRT) from the literature. Late rectal bleeding is the main adverse effect, and an incidence of >20% of Grade ≥2 adverse events was reported for 2D conventional radiotherapy of up to 70 Gy. 3D conformal radiation therapy (3D-CRT) was found to reduce the incidence to ∼10%. Furthermore, intensity-modulated radiation therapy (IMRT) reduced it further to a few percentage points. However, simultaneously, urological toxicities were enhanced by dose escalation using highly precise external radiotherapy. We should pay more attention to detailed quality of life (QOL) analysis, not only with respect to rectal bleeding but also other specific symptoms (such as urinary incontinence and impotence), for two reasons: (i) because of the increasing number of patients aged >80 years, and (ii) because of improved survival with elevated doses of radiotherapy and/or hormonal therapy; age is an important prognostic factor not only for prostate-specific antigen (PSA) control but also for adverse reactions. Those factors shift the main focus of treatment purpose from survival and avoidance of PSA failure to maintaining good QOL, particularly in older patients. In conclusion, the focus of toxicity analysis after radiotherapy for prostate cancer patients is changing from rectal bleeding to total elaborate quality of life assessment.

Patterns of Failure Associated with Involved Field Radiotherapy in Patients with Clinical Stage I Thoracic Esophageal Cancer

OBJECTIVE To analyze the patterns of the first sites of failure in patients with clinical stage I thoracic esophageal cancer after involved field radiotherapy and to determine whether elective nodal irradiation is necessary for these patients. MATERIALS AND METHODS Between 2000 and 2007, 68 patients aged 43-84 years with clinical stage I thoracic esophageal cancer received definitive radiotherapy. The radiation field included the primary tumor with a 3-cm margin in the cranio-caudal direction. Patterns of lymph node failure were classified according to the first sites of failure. In-field, regional and distant lymph node failures were defined as lymph node failures within the irradiated area, within the mediastinum or perigastric area beyond the irradiated area, and outside the regional lymph nodes, respectively. RESULTS The 3 year overall and disease-free survival rates were 76 and 66%, respectively (median follow-up: 42 months). Twenty-two of the 68 patients exhibited treatment failure. Local failure with or without recurrence in other sites was observed in 11 patients, lymph node failure in 10 patients, and distant metastasis in 1. Of the 10 patients with lymph node failure, sites of failure were in-field in 1 patient, in-field and distant in 1, regional in 3, distant in 2 and distant and regional in 3. CONCLUSIONS Involved field radiotherapy did not result in significant incidence of regional lymph node failure in clinical stage I thoracic esophageal cancer patients. However, further investigation is needed to establish the optimal radiotherapy field for clinical stage I thoracic esophageal cancer.

Significance of Endoscopic Screening and Endoscopic Resection for Esophageal Cancer in Patients with Hypopharyngeal Cancer

OBJECTIVE The efficacy of endoscopic screening for esophageal cancer in patients with hypopharyngeal cancer remains controversial and its impact on prognosis has not been adequately discussed. We studied the use of endoscopic screening to detect esophageal cancer in hypopharyngeal cancer patients by analyzing the incidence, stage and prognosis. METHODS We included 64 patients with hypopharyngeal cancer who received radical radiotherapy at our institute. Chromoendoscopic esophageal examinations with Lugol dye solution were routinely performed at and after treatment for hypopharyngeal cancer. RESULTS Twenty-eight esophageal cancers were detected in 28 (41%) patients (18 synchronous and 10 metachronous cancers). Of the 28 cancers, 23 were stage 0 or I cancer and 15 of these were treated with endoscopic resection. Local control was achieved in all of these 23 stage 0 or I cancers. The 5-year overall survival rates with esophageal cancer were 83% in stage 0, 47% in stage I and 0% in stage IIA-IVB. CONCLUSIONS This study showed a strikingly high incidence of esophageal cancer in hypopharyngeal cancer patients. We suppose that the combination of early detection by chromoendoscopic examination and endoscopic resection for associated esophageal cancer in hypopharyngeal cancer patients improve prognosis and maintain quality of life.