Hisanori Ariga

Prospective Comparison of Surgery Alone and Chemoradiotherapy With Selective Surgery in Resectable Squamous Cell Carcinoma of the Esophagus

PURPOSE Esophagectomy remains the mainstay treatment for esophageal cancer, although retrospective studies have suggested that chemoradiotherapy (CRT) is as effective as surgery. To determine whether CRT can substitute for surgery as the primary treatment modality, we performed a prospective direct comparison of outcomes after treatment in patients with resectable esophageal cancer who had received CRT and those who had undergone surgery. METHODS AND MATERIALS Eligible patients had resectable T1-3N0-1M0 thoracic esophageal cancer. After the surgeon explained the treatments in detail, the patients selected either CRT (CRT group) or surgery (OP group). The CRT course consisted of two cycles of cisplatin and fluorouracil with split-course concurrent radiotherapy of 60Gy in 30 fractions. Patients with progressive disease during CRT and/or with persistent or recurrent disease after CRT underwent salvage resection. RESULTS Of 99 eligible patients with squamous cell carcinoma registered between January 2001 and December 2005, 51 selected CRT and 48 selected surgery. Of the patients in the CRT group, 13 (25.5%) underwent esophagectomy as salvage therapy. The 3- and 5-year survival rates were 78.3% and 75.7%, respectively, in the CRT group compared with 56.9% and 50.9%, respectively, in the OP group (p = 0.0169). Patients in the OP group had significantly more metastatic recurrence than those in the CRT group. CONCLUSIONS Treatment outcomes among patients with resectable thoracic esophageal squamous cell carcinoma were comparable or superior after CRT (with salvage therapy if needed) to outcomes after surgery alone.

Radiation therapy for loco-regionally recurrent esophageal cancer after surgery

PURPOSE To evaluate the treatment outcome of radiation therapy for 33 loco-regionally recurrent esophageal cancer patients. METHODS Between 1988 and 1997, 33 patients with loco-regional recurrence of esophageal cancer after curative surgery received radiation therapy at an average total dose of 61 Gy. The site of recurrence was the supraclavicular region in 14 patients, the mediastinal region in 13 patients, and both the supraclavicular and mediastinal regions in six patients. If patients had ether distant metastasis or malignant pleural effusion, they were excluded from analysis. Patients who received prophylactic postoperative irradiation were also excluded from analysis. RESULTS The median survival period was 7 months. The survival rates at 1, 2, and 3 years were 33, 15, and 12%, respectively. In univariate analysis, patients with a short time interval between surgery and recurrence (P=0.0098) and patients with recurrence in both the supraclavicular and mediastinal regions (P=0.036) had a worse prognosis. In multivariate analysis, the time interval between surgery and recurrence (P<0.001) and age (worse prognosis in younger patients, P=0.019) were the significant prognostic factors. Complete or partial responses were observed in nine (27%) and 21 (64%) of the patients, respectively. Changes in clinical symptoms, such as dysphagia, chest pain and back pain, could be evaluated in 11 patients, and improvement in symptoms was obtained in eight (73%) patients. CONCLUSIONS The prognosis of patients who received radiation therapy for postoperative loco-regional recurrence of esophageal cancer is poor. However, there is symptomatic relief in a significant proportion of such patients, and long-term survival is possible in some patients.

Phase Ia study of a hypoxic cell sensitizer doranidazole (PR-350) in combination with conventional radiotherapy.

A phase Ia study of a 2-nitroimidazole nucleoside analog radiosensitizer doranidazole was conducted to evaluate its toxicity and pharmacokinetics in patients undergoing conventional external beam radiotherapy. Twenty-nine patients, aged 40-74 years, with a WHO performance status of 0-2 and with adequate organ functions, were entered in the study. Single administration of doranidazole was investigated first with 13 patients and then a course of five consecutive daily administrations was tested in 16 patients. Doranidazole was given i.v. 25 min before irradiation. Doranidazole doses of 400, 800, 1300 and 2000 mg/m2 were evaluated in the former study, and daily doses of 800, 1300 and 2000 mg/m2 were investigated in the latter study. All patients tolerated doranidazole administration. Although a transient decrease in the 24-h creatinine clearance rate was observed in five patients (one in the single administration study and four in the repeat administration study), this was not considered to be the dose-limiting toxicity. Other toxicities (hematological and gastrointestinal), which may not be related to doranidazole administration, were also mild and were not dose limiting. No neurotoxicity was observed. The average maximum concentration, area under the time-concentration curve and half-life of doranidazole in serum were 172-194 μg/ml, 502-582 μg·h/l and 4.2-4.6 h, respectively, at 2000 mg/m2. At the tested doses, administration of doranidaozle was tolerable and achieved serum concentrations at which reasonable radiosensitization could be expected. A phase Ib/II study to evaluate the feasibility and efficacy of up to 30 repeat administrations seems to be warranted.

Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment

OBJECT Intracranial germ cell tumors (GCTs) originating in the basal ganglia are rare. The authors investigated factors related to the diagnosis of these lesions as well as outcome in order to help decrease the time to diagnosis and improve treatment efficacy. METHODS The authors reviewed the clinical features of 142 cases of intracranial GCT in their institute. Fourteen cases of basal ganglia GCT were identified. The symptoms, neuroimaging findings, delay between symptom onset and diagnosis or treatment, initial and further treatment, and outcome were investigated. RESULTS Major symptoms were motor weakness and precocious puberty. Gadolinium-enhanced T1-weighted MR images showed enhancement in 8 of 11 patients examined, but only slight hyperintensity without enhancement in 2 patients. Ipsilateral peduncle and hemispheric atrophy were found in 3 and 4 patients, respectively. Cases of basal ganglia GCT were characterized by a longer delay from the initial neuroimaging examination to diagnosis compared with GCT in other regions. Five patients had aggravated hemiparesis in the extremities due to the delay in diagnosis. Despite good response to the initial therapy, 5 patients experienced recurrence; 2 of these 5 had malignant GCTs, and 3 had been treated only with chemotherapy or radiochemotherapy with insufficient radiation dose and field. Finally, the 2 patients with malignant GCTs died of the disease, and 1 died of aspiration pneumonia due to dissemination around the brainstem. CONCLUSIONS Early diagnosis requires MR imaging with administration of contrast medium in young patients presenting with motor weakness and/or precocious puberty. Serial neuroimaging studies should be performed if any tiny lesion is detected in the basal ganglia. Since insufficient treatment resulted in early recurrence, radiation therapy with adequate dose and field is essential.

Leptomeningeal dissemination of cerebellar malignant astrocytomas

Primary malignant astrocytomas of the cerebellum are extremely rare, and the dissemination patterns and effectiveness of postoperative radiation therapy are unclear. Five consecutive cases of histologically proven cerebellar malignant astrocytoma, two anaplastic astrocytomas, one anaplastic pilocytic astrocytoma, and two glioblastomas, were treated between 1997 and 2001. Four patients underwent surgical removal, local irradiation, and chemotherapy, and one patient with anaplastic pilocytic astrocytoma received subtotal removal followed by gamma knife radiosurgery for the residual tumor. Two patients had no recurrence at the primary site. All patients developed leptomeningeal dissemination. Four patients had supratentorial dissemination and two patients had spinal metastases. The time interval between the diagnosis of the primary cerebellar tumor and the diagnosis of leptomeningeal dissemination was 5–29 months (mean 14.6 ± 10.4 months). All patients died at 10–38 months (mean survival 22.2 ± 13.6 months). Intensive treatment including chemotherapy and radiotherapy may be required in cerebellar malignant astrocytomas, considering the high incidence of symptomatic leptomeningeal dissemination.

Long-Term Results of Radiochemotherapy for Solitary Lymph Node Metastasis After Curative Resection of Esophageal Cancer

PURPOSE To evaluate the long-term efficacy and toxicity of definitive radiochemotherapy for solitary lymph node metastasis after curative surgery of esophageal cancer. METHODS AND MATERIALS We performed a retrospective review of 35 patients who underwent definitive radiochemotherapy at Tohoku University Hospital between 2000 and 2009 for solitary lymph node metastasis after curative esophagectomy with lymph node dissection for esophageal cancer. Radiotherapy doses ranged from 60 to 66 Gy (median, 60 Gy). Concurrent chemotherapy was platinum based in all patients. The endpoints of the present study were overall survival, cause-specific survival, progression-free survival, irradiated-field control, overall tumor response, and prognostic factors. RESULTS The median observation period for survivors was 70.0 months. The 5-year overall survival was 39.2% (median survival, 39.0 months). The 5-year cause-specific survival, progression-free survival, and irradiated-field control were 43.3%, 31.0% and 59.9%, respectively. Metastatic lesion, size of the metastatic lymph node, and performance status before radiochemotherapy were significantly correlated with prognosis. Complete response and partial response were observed in 22.9% and 57.1% of the patients, respectively. There was no Grade 3 or higher adverse effect based on the Common Terminology Criteria for Adverse Events (CTCAE v3.0) in the late phase. CONCLUSIONS Based on our study findings, approximately 40% of patients with solitary lymph node metastasis after curative resection for esophageal cancer have a chance of long-term survival with definitive radiochemotherapy.

Fatal hemorrhage in irradiated esophageal cancer patients

Between 1980 and 1994, 423 patients with esophageal cancer were given curative radiation therapy. Of these patients, 31 died of massive hemorrhage and were used as the subjects of analysis in this study. The incidence of massive hemorrhage in all patients was 7% (31/423). In the 31 patients who died of massive hemorrhage, 27 had local tumors and two had no tumors at hemorrhage (two unknown cases). The mean time interval from the start of radiation to hemorrhage was 9.2 months. In 9 autopsy cases the origin of hemorrhage was a tear of the aorta in 5 cases, necrotic local tumor in 3 cases and esophageal ulcer in 1 case. The positive risk factors for this complication seemed to be excess total dose, infection, metallic stent, and tracheoesophageal fistula. Chest pain or sentinel hemorrhage proceeding to massive hemorrhage was observed in about half of the patients.

Focal dose escalation using FDG-PET-guided intensity-modulated radiation therapy boost for postoperative local recurrent rectal cancer: a planning study with comparison of DVH and NTCP

BackgroundTo evaluate the safety of focal dose escalation to regions with standardized uptake value (SUV) >2.0 using intensity-modulated radiation therapy (IMRT) by comparison of radiotherapy plans using dose-volume histograms (DVHs) and normal tissue complication probability (NTCP) for postoperative local recurrent rectal cancerMethodsFirst, we performed conventional radiotherapy with 40 Gy/20 fr. (CRT 40 Gy) for 12 patients with postoperative local recurrent rectal cancer, and then we performed FDG-PET/CT radiotherapy planning for those patients. We defined the regions with SUV > 2.0 as biological target volume (BTV) and made three boost plans for each patient: 1) CRT boost plan, 2) IMRT without dose-painting boost plan, and 3) IMRT with dose-painting boost plan. The total boost dose was 20 Gy. In IMRT with dose-painting boost plan, we increased the dose for BTV+5 mm by 30% of the prescribed dose. We added CRT boost plan to CRT 40 Gy (summed plan 1), IMRT without dose-painting boost plan to CRT 40 Gy (summed plan 2) and IMRT with dose-painting boost plan to CRT 40 Gy (summed plan 3), and we compared those plans using DVHs and NTCP.ResultsDmean of PTV-PET and that of PTV-CT were 26.5 Gy and 21.3 Gy, respectively. V50 of small bowel PRV in summed plan 1 was significantly higher than those in other plans ((summed plan 1 vs. summed plan 2 vs. summed plan 3: 47.11 ± 45.33 cm3 vs. 40.63 ± 39.13 cm3 vs. 41.25 ± 39.96 cm3(p < 0.01, respectively)). There were no significant differences in V30, V40, V60, Dmean or NTCP of small bowel PRV.ConclusionsFDG-PET-guided IMRT can facilitate focal dose-escalation to regions with SUV above 2.0 for postoperative local recurrent rectal cancer.

Three-dimensional summation of rectal doses in brachytherapy combined with external beam radiotherapy for prostate cancer

BACKGROUND AND PURPOSE To determine the dose constraints for rectal bleeding in brachytherapy (BRT) combined with external beam radiotherapy (EBRT). MATERIALS AND METHODS Post-BRT, pelvic computed tomography images were used for subsequent EBRT planning and BRT postplans in 37 patients. The physical doses for each plan were converted to biologically effective doses, and corresponding voxel doses were integrated to plot the summed dose-volume histogram (sum-DVH). Between 5 patients with (bled-pts) and 32 without (spared-pts) grade 2 or 3 rectal bleeding, the differences in the mean minimal dose (rDn) covering the rectal volume of 0.5-10.0 cc and the rectal volume (rVn) receiving the calculated dose of 20-150Gy were compared. RESULTS The differences in the summed-rDn were determined by BRT exposure, while those of the summed-rVn were determined in the low-dose range and superimposed in the high-dose range by EBRT exposure. Of the 13 patients with rV150 of >1.2 cc, 4 were bled-pts (30.8%). Of the 24 patients with rV150 of ≤ 1.2cc, 1 was a bled-pts (4.2%) (p=0.024; odds ratio, 10.2; CI (95%), 1.0-104.3). CONCLUSIONS The mono-scale DVH analysis is a promising method for exploring the threshold for rectal bleeding in combined radiotherapy.

Evaluation of radiation-induced myocardial damage using iodine-123 β-methyl-iodophenyl pentadecanoic acid scintigraphy

We evaluated radiation-induced myocardial damage using iodine-123 β-methyl-iodophenyl pentadecanoic acid (I-123 BMIPP) scintigraphy. Between May 2010 and April 2011 we performed I-123 BMIPP scintigraphy for patients who had maintained complete response to curative radiotherapy (RT) for esophageal cancer for more than six months. We compared the area of the myocardium in the RT fields with that of reduced I-123 BMIPP uptake using a 15-segment model that is based on axial computed tomography (CT) images. We classified the segments into three categories: segments receiving 40 Gy (Segment 40 Gy), segments receiving 60 Gy (Segment 60 Gy) and segments out of the radiation fields (Segment 0 Gy). A segment with reduced uptake in the RT fields was defined as positive. A total of 510 segments in 34 patients were used for analysis. The median interval from completion of RT to I-123 BMIPP scintigraphy was 22 months (range, 6–103 months). The numbers of Segment 0 Gy, Segment 40 Gy and Segment 60 Gy were 324, 133 and 53, respectively. Reduced uptake was detected in 42.9% (57/133) of Segment 40 Gy, 67.9% (36/53) of Segment 60 Gy and 13.3% (43/324) of Segment 0 Gy. The odds ratios of 40 Gy and 60 Gy compared with regions out of the RT fields were 5.2 (95% confidence interval [CI]: 3.7–7.4) and 15.4 (95% CI: 6.9–34.6), respectively. Reduced myocardial I-123 BMIPP uptake in RT fields, suggesting RT-induced myocardial damage, was frequently observed. I-123 BMIPP myocardial scintigraphy may be useful for identifying RT-induced myocardial damage.