Tomoko Kazumoto

Intraoperative irradiation after surgery for locally recurrent rectal cancer

PURPOSE: This study retrospectively evaluated the effects of intraoperative electron beam irradiation on patients with locally recurrent (pelvic) rectal cancer. METHODS: From November 1, 1975, to December 31, 1997, 51 patients underwent surgery for locally recurrent rectal or rectosigmoid cancer, and 27 patients received intraoperative electron beam irradiation. The intraoperative electron beam irradiation dose was 15 to 30 Gy. Kaplan-Meier survival estimates at three and five years were analyzed for the 47 patients who recovered postoperatively. RESULTS: Statistically significant factors related to survival included intraoperative electron beam irradiationvs. no intraoperative electron beam irradiation (P=0.0007), amount of residual tumor (slightvs. gross;P=0.0022), and symptom status (P=0.0024). Factors not associated with survival included distant metastases at reoperation, type of surgery for the recurrent tumor, external beam irradiation, pathologic grade, age, and gender. Surgical resection without intraoperative electron beam irradiation resulted in three-year and five-year survival rates of 5 and 0 percent, respectively. For patients who received intraoperative electron beam irradiation, the three-year survival rate was 43 percent and five-year survival rate was 21 percent. Intraoperative electron beam irradiation was a statistically significant factor related to survival in patients with and without distant metastasis (P=0.04 andP=0.0035, respectively), with slight residual tumor (P=0.0003), or with palliative surgery (P=0.0276). CONCLUSION: The trends seen in resection with intraoperative electron beam irradiation are encouraging with regard to improvements in survival as compared with studies not using intraoperative electron beam irradiation treatment.

INTRAOPERATIVE RADIOTHERAPY FOR UNRESECTABLE PANCREATIC CANCER: A MULTI-INSTITUTIONAL RETROSPECTIVE ANALYSIS OF 144 PATIENTS

PURPOSE To retrospectively analyze the results of intraoperative radiotherapy (IORT) with or without external beam radiotherapy (EBRT) for resected pancreatic cancer. METHODS AND MATERIALS The records of 210 patients treated with gross complete resection (R0: 147 patients; R1: 63 patients) and IORT with or without EBRT were reviewed. One hundred forty-seven patients (70.0%) were treated without EBRT and 114 patients (54.3%) were treated in conjunction with chemotherapy. The median doses of IORT and EBRT were 25 Gy (range, 20-30 Gy) and 45 Gy (range, 20-60Gy), respectively. The median follow-up of the surviving 62 patients was 26.3 months (range, 2.7-90.5 months). RESULTS At the time of this analysis, 150 of 210 patients (71.4%) had disease recurrences. Local failure was observed in 31 patients (14.8%), and the 2-year local control rate in all patients was 83.7%. The median survival time and the 2-year actuarial overall survival (OS) in all 210 patients were 19.1 months and 42.1%, respectively. Patients treated with IORT and chemotherapy had a significantly more favorable OS than those treated with IORT alone (p = 0.0011). On univariate analysis, chemotherapy use, degree of resection, carbohydrate antigen 19-9, and pathological N stage had a significant impact on OS and on multivariate analysis; these four factors were significant prognostic factors. Late gastrointestinal morbidity of NCI-CTC Grade 4 was observed in 7 patients (3.3%). CONCLUSION IORT yields an excellent local control rate for resected pancreatic cancer with few frequencies of severe late toxicity, and IORT combined with chemotherapy confers a survival benefit compared with that of IORT alone.

Prospective multi-institutional study of definitive radiotherapy with high-dose-rate intracavitary brachytherapy in patients with nonbulky (<4-cm) stage i and II uterine cervical cancer (JAROG0401/JROSG04-2)

PURPOSE To determine the efficacy of a definitive radiotherapy protocol using high-dose-rate intracavitary brachytherapy (HDR-ICBT) with a low cumulative dose schedule in nonbulky early-stage cervical cancer patients, we conducted a prospective multi-institutional study. METHODS AND MATERIALS Eligible patients had squamous cell carcinoma of the intact uterine cervix, Federation of Gynecologic Oncology and Obstetrics (FIGO) stages Ib1, IIa, and IIb, tumor size <40 mm in diameter (assessed by T2-weighted magnetic resonance imaging), and no pelvic/para-aortic lymphadenopathy. The treatment protocol consisted of whole-pelvis external beam radiotherapy (EBRT) of 20 Gy/10 fractions, pelvic EBRT with midline block of 30 Gy/15 fractions, and HDR-ICBT of 24 Gy/4 fractions (at point A). The cumulative biologically effective dose (BED) was 62 Gy(10) (α/β = 10) at point A. The primary endpoint was the 2-year pelvic disease progression-free (PDPF) rate. All patients received a radiotherapy quality assurance review. RESULTS Between September 2004 and July 2007, 60 eligible patients were enrolled. Thirty-six patients were assessed with FIGO stage Ib1; 12 patients with stage IIa; and 12 patients with stage IIb. Median tumor diameter was 28 mm (range, 6-39 mm). Median overall treatment time was 43 days. Median follow-up was 49 months (range, 7-72 months). Seven patients developed recurrences: 3 patients had pelvic recurrences (2 central, 1 nodal), and 4 patients had distant metastases. The 2-year PDPF was 96% (95% confidence interval [CI], 92%-100%). The 2-year disease-free and overall survival rates were 90% (95% CI, 82%-98%) and 95% (95% CI, 89%-100%), respectively. The 2-year late complication rates (according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer of Grade ≥ 1) were 18% (95% CI, 8%-28%) for large intestine/rectum, 4% (95% CI, 0%-8%) for small intestine, and 0% for bladder. No Grade ≥ 3 cases were observed for genitourinary/gastrointestinal late complications. CONCLUSIONS These results suggest that definitive radiotherapy using HDR-ICBT with a low cumulative dose schedule (BED, 62 Gy(10) at point A) can provide excellent local control without severe toxicity in nonbulky (<4-cm) early-stage cervical cancer.

Therapeutic Effect of Linac-based Stereotactic Radiotherapy with a Micro-multileaf Collimator for the Treatment of Patients with Brain Metastases from Lung Cancer

OBJECTIVE To assess the efficacy of hypofractionated linac-based stereotactic radiotherapy with a micro-multileaf collimator (mMLC) in lung cancer patients with brain metastases. METHODS Seventy-eight lesions of brain metastases in 49 lung cancer patients treated by stereotactic radiotherapy between September 2003 and December 2006 were analyzed. In the treatment planning, the planning target volume (PTV) was defined as an enhanced lesion plus 3 mm margin. A total dose of 39-42 Gy in three fractions was delivered to the isocenters of the PTV. RESULTS The median survival time after stereotactic radiotherapy was 17.4 months. The 1- and 2-year survival rates were 61% and 32%, respectively. The presence of extracranial tumors, the pre-treatment performance status, and the Radiation Therapy Oncology Group recursive partitioning analysis class were significant prognostic factors. The 1- and 2-year local recurrence rates were 14% and 17%, respectively, with no serious acute toxic effect. Injuries involving brain necrosis were observed in six patients. New brain metastases or meningeal carcinomatosis was seen in more than half of the patients following treatment with stereotactic radiotherapy. CONCLUSIONS Hypofactionated stereotactic radiotherapy with mMLC is considered to be an effective and safe modality for the treatment of brain metastases in lung cancer patients.

High-dose-rate Intracavitary Brachytherapy Combined with External Beam Radiotherapy for Stage IIIb Adenocarcinoma of the Uterine Cervix in Japan: A Multi-Institutional Study of Japanese Society of Therapeutic Radiology and Oncology 2006–2007 (Study of JASTRO 2006–2007)

OBJECTIVE The current study was a retrospective questionnaire survey of stage IIIb adenocarcinoma of the uterine cervix treated with high-dose-rate intracavitary brachytherapy combined with external beam radiation therapy in Japan aimed to investigate the optimal dose on the basis of the biological effective dose and prognostic factors. METHODS Between 1990 and 2000, 61 patients with stage IIIb adenocarcinoma of the uterine cervix underwent high-dose-rate intracavitary brachytherapy combined with external beam radiation therapy in 19 major hospitals in Japan. This retrospective questionnaire survey was performed by mail including survey charts to be fulfilled by radiation oncologists in these 19 major hospital. Fifty had only adenocarcinoma components and 11 had adenosquamous cell carcinoma components. All patients were treated with high-dose-rate intracavitary brachytherapy combined with external beam radiation therapy. Total biological effective dose (T-BED(10)) was calculated from the sum of the biological effective doses of the external beam radiation therapy and the intracavitary brachytherapy. Thirty-two patients underwent chemotherapy. RESULTS The 5-year overall survival rate of all patients was 20.2%. Stratified by total biological effective dose, the 5-year overall survival rate was 0% for T-BED(10) <75 Gy, 24.7% for T-BED(10) between 75 and 100 Gy and 0% for T-BED(10) >110 Gy (P = 0.15). Stratified by histopathology, the 5-year overall survival rate was 22.1% for adenocarcinoma and 13.6% for adenosquamous cell carcinoma (P = 0.43). Stratified by chemotherapy, the 5-year overall survival rate was 20.3% in patients who received chemotherapy and 20.4% in patients who did not receive chemotherapy (P = 0.96). CONCLUSIONS The 5-year overall survival rate of stage IIIb adenocarcinoma of the uterine cervix in this retrospective questionnaire survey was 20.2%. The optimal T-BED(10) and evident prognostic factors were not clear from this questionnaire survey.

Hyperfractionated and Hypofractionated Radiation Therapy for Human Malignant Glioma Xenograft in Nude Mice

Xenografts of a human malignant glioma subcutaneously transplanted into nude mice were irradiated with graded single doses (2, 5, 10 or 20 Gy) or five types of fractionation schedules in two weeks: conventional [20 Gy in 10 fractions (fr)], hyperfractionated [24 Gy in 20 fr (two fractions per day)], and hypofractionated‐1, 2, 3 [20 Gy, 18 Gy, 16 Gy in 4 fr]. All of the fractionated irradiation groups showed tumor regression. The hypofractionation‐1 group (20 Gy in 4 fr) demonstrated the most prominent tumor regression, while the hyperfractionation group (24 Gy in 20 fr) showed the least effect. The hypofractionation‐2 group (18 Gy in 4 fr) showed similar regression to the conventional fractionation group (20 Gy in 10 fr). Histologically, tumors in the control groups consisted of a homogenous population of small anaplastic cells, and only a small number of tumor cells were glial fibrillary acidic protein (GFAP)‐positive. Following irradiation, the population of small anaplastic cells decreased and the percentage of GFAP‐positive cells increased. Cellular pleomorphism became much more prominent after irradiation in all of the fractionated irradiation groups as compared with the graded single dose irradiation groups. In this study, hyperfractionation was not effective against human glioma xenografts compared with conventional fractionation and hypofractionation. This indicates that care is needed in applying hyperfractionation regimens to human malignant gliomas.

Concurrent chemoradiotherapy followed by consolidation chemotherapy with bi-weekly docetaxel and carboplatin for stage III unresectable, non-small-cell lung cancer: clinical application of a protocol used in a previous phase II study.

PURPOSE To assess the clinical applicability of a protocol evaluated in a previously reported phase II study of concurrent chemoradiotherapy followed by consolidation chemotherapy with bi-weekly docetaxel and carboplatin in patients with stage III, unresectable, non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Between January 2000 and March 2006, 116 previously untreated patients with histologically proven, stage III NSCLC were treated with concurrent chemoradiotherapy. Radiation therapy was administered in 2-Gy daily fractions to a total dose of 60 Gy in combination with docetaxel, 30 mg/m(2), and carboplatin at an area under the curve value of 3 every 2 weeks during and after radiation therapy. RESULTS The median survival time for the entire group was 25.5 months. The actuarial 2-year and 5-year overall survival rates were 53% and 31%, respectively. The 3-year cause-specific survival rate was 60% in patients with stage IIIA disease, whereas it was 35% in patients with stage IIIB disease (p = 0.007). The actuarial 2-year and 5-year local control rates were 62% and 55%, respectively. Acute hematologic toxicities of Grade ≥3 severity were observed in 20.7% of patients, while radiation pneumonitis and esophagitis of Grade ≥3 severity were observed in 2.6% and 1.7% of patients, respectively. CONCLUSIONS The feasibility of the protocol used in the previous phase II study was reconfirmed in this series, and excellent treatment results were achieved.

Patterns of Radiotherapy Practice for Pancreatic Cancer in Japan: Results of the Japanese Radiation Oncology Study Group (JROSG) Survey

PURPOSE To determine the patterns of radiotherapy practice for pancreatic cancer in Japan. METHODS AND MATERIALS A questionnaire-based national survey of radiotherapy for pancreatic cancer treated between 2000 and 2006 was conducted by the Japanese Radiation Oncology Study Group (JROSG). Detailed information on 870 patients from 34 radiation oncology institutions was accumulated. RESULTS The median age of all patients was 64 years (range, 36-88), and 80.2% of the patients had good performance status. More than 85% of patients had clinical Stage T3-T4 disease, and 68.9% of patients had unresectable disease at diagnosis. Concerning radiotherapy (RT), 49.8% of patients were treated with radical external beam RT (EBRT) (median dose, 50.4 Gy), 44.4% of patients were treated with intraoperative RT (median dose, 25 Gy) with or without EBRT (median dose, 45 Gy), and 5.9% of patients were treated with postoperative radiotherapy (median dose, 50 Gy). The treatment field consisted of the primary tumor (bed) only in 55.6% of the patients. Computed tomography-based treatment planning and conformal RT was used in 93.1% and 83.1% of the patients treated with EBRT, respectively. Chemotherapy was used for 691 patients (79.4%; before RT for 66 patients; during RT for 531; and after RT for 364). Gemcitabine was the most frequently used drug, followed by 5-fluorouracil. CONCLUSION This study describes the general patterns of RT practice for pancreatic cancer in Japan. Most patients had advanced unresectable disease, and radical EBRT, as well as intraoperative RT with or without EBRT, was frequently used. Chemotherapy with gemcitabine was commonly used in conjunction with RT during the survey period.

Recommendations for high-risk clinical target volume definition with computed tomography for three-dimensional image-guided brachytherapy in cervical cancer patients

Abstract Our purpose was to develop recommendations for contouring the computed tomography (CT)-based high-risk clinical target volume (CTVHR) for 3D image-guided brachytherapy (3D-IGBT) for cervical cancer. A 15-member Japanese Radiation Oncology Study Group (JROSG) committee with expertise in gynecological radiation oncology initiated guideline development for CT-based CTVHR (based on a comprehensive literature review as well as clinical experience) in July 2014. Extensive discussions occurred during four face-to-face meetings and frequent email communication until a consensus was reached. The CT-based CTVHR boundaries were defined by each anatomical plane (cranial–caudal, lateral, or anterior–posterior) with or without tumor progression beyond the uterine cervix at diagnosis. Since the availability of magnetic resonance imaging (MRI) with applicator insertion for 3D planning is currently limited, T2-weighted MRI obtained at diagnosis and just before brachytherapy without applicator insertion was used as a reference for accurately estimating the tumor size and topography. Furthermore, utilizing information from clinical examinations performed both at diagnosis and brachytherapy is strongly recommended. In conclusion, these recommendations will serve as a brachytherapy protocol to be used at institutions with limited availability of MRI for 3D treatment planning.

High-dose-rate Intra-cavitary Brachytherapy Combined with External Beam Radiation Therapy for Under 40-Year-old Patients with Invasive Uterine Cervical Carcinoma: Clinical Outcomes in 118 Patients in a Japanese Multi-institutional Study, JASTRO

BACKGROUND The current study was designed to evaluate the clinical outcomes of curative intent radiation therapy for young patients with invasive uterine cervical carcinoma in Japan. METHODS One hundred and eighteen patients aged ≤40 were registered in the multi-institutional study of the Japanese Society of Therapeutic Radiology and Oncology (JASTRO) from 26 major institutions in Japan. The age range was 24-39 years and the maximum tumor diameter was 2.0-9.2 cm. The International Federation of Gynecology and Obstetrics clinical stages were Ib, IIa, IIb, IIIa, IIIb and IVa in 17, 6, 40, 2, 50 and 3, respectively. Curative intent radiation therapy consisted of the combination of external beam radiation therapy and high-dose rate intra-cavitary brachytherapy. The total dose of external beam radiation therapy ranged between 44 and 68 Gy. Both the median and mode of total high-dose-rate intra-cavitary brachytherapy dose to point A were 24 Gy in four fractions. Ninety-six patients (58%) received chemotherapy. RESULTS The 5-year overall survival rate and local control rate of all patients were 61 and 65%, respectively. The 5-year overall survival rates of International Federation of Gynecology and Obstetrics Stage Ib, IIa, IIb, IIIa, IIIb and IVa were 88, 100, 75, 100, 37 and 0%, respectively. The 5-year local control rates of International Federation of Gynecology and Obstetrics Stage Ib, IIa, IIb, IIIa, IIIb and IVa were 82, 75, 75, 100, 51 and 0%, respectively. Sixteen patients experienced grade 3 or greater late radiation morbidity. CONCLUSIONS The 5-year overall survival rate of young patients with Stage IIIb was comparatively low at 37%.