Tomohiko Okawa

Results of radiotherapy for inoperable locally advanced esophageal cancer

Three hundred and eleven patients with locally advanced esophageal cancer were treated by radiation therapy from 1968 to 1983 at Tokyo Womens Medical College. Of these, 288 patients with previously untreated, histologically confirmed squamous cell carcinoma but previously treated with curative intent, were eligible for analysis. The cumulative 5-year survival rate of 288 patients given radical radiotherapy was 9.0%. Sex, tumor length, and Stage (AJC) had a great influence on prognosis. The five-year survival rate in males was 5.4% and in females was 22.4%. The five-year survival rate in cases with a tumor length of 5 cm or less was 17.7% in 5-10 cm was 10.0%, and in 10 cm or above was 2.8% and they were 20.2% for Stage I, 9.9% for Stage II, and 2.6% for Stage III. There were no significant differences of survival rate among age, tumor site, and tumor type on X ray film. This data suggests that comparatively early, small-volume tumors share a significant potential for cure by radiotherapy, but potent combined therapy is necessary for the treatment of advanced cancers.

Randomized prospective clinical study of small, large and twice-a-day fraction radiotherapy for painful bone metastases

A prospective randomized clinical trial comparing small, large and twice-a-day fraction for the relief of painful bone metastases was performed from 1981 to 1986 at Tokyo Womens Medical College Hospital. Eighty patients with painful bone metastases (92 sites) were divided into three radiation methods which were conventional fraction scheme of 5 times/week at 2 Gy/day for a total of 30 Gy/15 fractions (Group I, TDF: 49), 2 times/week at 4.5 Gy/day for a total of 22.5 Gy/5 fractions (Group II, TDF: 50) and 3 times/week at 2 Gy/day twice a day at a minimum interval of 6 h for a total of 20 Gy/10 fractions (Group III). Pain was assessed using a score and response rate was 76% in Group I, 75% in Group II and 78% in Group III which were not statistically significant mutually. Group II and III regimes were found to have an earlier shorter onset of pain relief than Group I, but the dose of onset of pain relief was almost the same. Our data suggested that individualization of radiotherapy schedules based on to assess the patients condition and the expected quality of life and to consider radiation site and size of field, was more important than the fractionation regime in the treatment of painful bone metastases.

Multi-institutional randomized trial of external radiotherapy with and without intraluminal brachytherapy for esophageal cancer in Japan

PURPOSE With the aim of improving the results of treatment of esophageal cancer, we designed this multi-institutional, randomized trial to establish the optimal irradiation method in radical radiation therapy for esophageal cancer by clinically evaluating external irradiation alone and in combination with intraluminal brachytherapy. METHODS AND MATERIALS The study population consisted of patients with squamous cell carcinoma who were expected to be successfully treated with radical radiation therapy. The patients who could be given intraluminal brachytherapy at the end of external irradiation of 60 Gy were stratified into 2 groups. Patients assigned to receive external irradiation alone received boost irradiation of 10 Gy/week on a schedule similar to the previous one, and with the same or smaller irradiation field. Intraluminal brachytherapy was performed, as a rule, with the reference dose point set at a depth of 5 mm of the esophageal submucosa, and a total of 10 Gy was irradiated at a daily dose of 5 Gy, on a once-weekly schedule with low-dose-rate or high-dose-rate brachytherapy equipment. RESULTS A total of 103 patients were registered, 94 of whom were analyzable, with 8 ineligible, and 1 for whom complete information was unavailable. The overall cumulative survival rate was 20.3% at 5 years. The cause-specific survival rate was 31.8% at 5 years. The cause-specific survival rate at 5 years was 27% in the external irradiation alone group and 38% in intraluminal brachytherapy combined group. There was no significant difference between the 2 groups (p = 0.385). However, in the patients with 5 cm or less tumor length, the cause-specific survival rate was 64% at 5 years in the intraluminal brachytherapy combined group, which showed a significant improvement over 31.5% in the external irradiation alone group (p = 0.025). In the patients with Stage T1 and T2 disease, cause-specific survival rates tended to be better in the intraluminal brachytherapy combined group than in the external irradiation alone group (p = 0.088). In the patients with more than 5 cm tumor length or Stage T3-4 disease, there were no significant differences between the two groups by treatment methods (p = 0.290). The incidence of early and late complications did not differ according to whether intraluminal brachytherapy was used. CONCLUSION For the purpose of establishing the usefulness of intraluminal brachytherapy, further prospective randomized studies are necessary to evaluate the efficacy in tumors with short length and those with shallow invasion, or to assess the usefulness of intraluminal brachytherapy, as additional irradiation in large advanced tumors have been shown to have disappeared by diagnostic imaging after chemoradiotherapy with 60 Gy/6w external irradiation.

Radiation therapy alone in the treatment of carcinoma of the uterine cervix: Review of experience at Tokyo Women's Medical College (1969–1983)

Three hundred thirteen patients presented with squamous cell carcinoma of the uterine cervix at Tokyo Womens Medical College from 1969 to 1983. The results are presented here. All of the patients were treated by radiotherapy with curative intent with a combination of intracavitary cesium by low-dose rate, using T.A.O. afterloading applicators, which was made of flexible tubes to adapt to the physique of Japanese women by Tazaki, E., Arai, T. and Oryu, S. and external irradiation. One hundred and sixty patients (51.1%) presented with FIGO Stage III disease, 23 patients (7.3%) presented with Stage I disease, and 75 (24.0%) with Stage II. The 5-year cumulative survival rate was 81.7% for Stage I, 76.8% for Stage II, 53.3% for Stage III, 29.2% for Stage IVa, and 10.5% for Stage IVb, respectively. The overall 5-year survival rate was 55.8%. The local regional recurrence rate according to stage was 13.6% in Stage I, 22.4% in Stage II, 41.3% in Stage IIII, and 46.7% in Stage IVa. The incidence of locoregional recurrence rate was 35.6% and distant metastasis 37.8%. The incidence of complications involving bleeding and pain which required hospitalization, was 12.2% in all patients. Only four required surgery to manage serious complications.

Phase II randomized clinical trial of LC9018 concurrently used with radiation in the treatment of carcinoma of the uterine cervix. Its effect on tumor reduction and histology

The clinical efficacy of LC9018, a biological response modifier prepared from heat‐killed Lactobacillus casei YIT9018, used in combination with radiation was studied in a randomized controlled trial on 61 patients with carcinoma of the uterine cervix of Stage IIB or III. The combination therapy with LC9018 demonstrated a significant effect on tumor reduction, compared with radiation therapy alone, at the cumulative doses of 15‐Gy and 30‐Gy external irradiation (P < 0.05). Histologic study confirmed that LC9018 also enhanced the therapeutic effect of the irradiation. Moreover, LC9018 seemed to be useful in protecting the patients from leukopenia during radiotherapy. This study suggests that LC9018, when used in combination with radiotherapy, will be an effective adjuvant immunotherapeutic agent. More studies in a large series of patients will, however, be needed to establish its long‐term efficacy, safety, and effects on both prognosis and enhancing radiotherapy.

Treatment of superficial esophageal cancer by external radiation therapy alone: results of a multi-institutional experience

PURPOSE To assess the effectiveness and toxicity of external radiation therapy for superficial esophageal cancer. METHODS AND MATERIALS During the period from March 1979 to November 1996, 78 patients with superficial esophageal cancer received radiation therapy without intracavitary irradiation at nine radiotherapy institutions in Japan. All patients had histologically-proven squamous cell carcinoma. Endoscopic ultrasonography was performed in 34 patients to discriminate mucosal from submucosal cancer. Most of the patients had received radiation therapy using conventional fractionation at an average dose of 65.5 Gy. RESULTS The survival rates at 1, 2, and 5 years were 88%, 73%, and 45%, respectively. The local control rates at 1, 2, and 5 years were 85%, 79%, and 66%, respectively. Although the difference was not significant, the survival rate of cancer patients with a tumor invading the submucosa was lower than that of the other patients. In 6 mucosal cancer patients, local recurrence was observed in 1 patient with extensive cancer. Regional lymph node recurrence and distant failure were not observed in mucosal cancer patients, while in 28 submucosal cancer patients, the 5-year survival rate and relapse free rate were only 49% and 43%, respectively. Univariate and multivariate analysis identified age as the only significant prognostic factor. Severe late injury, such as esophageal ulcer, perforation, and bleeding, was not observed. CONCLUSION External radiation therapy is effective for mucosal cancer. However, further investigation is needed to establish a better standard treatment protocol for submucosal cancer.

Radiotherapy for superficial esophageal cancer

PURPOSE The results of definitive radiotherapy for superficial esophageal cancer is presented. METHODS AND MATERIALS Twenty-one patients with superficial squamous cell carcinoma of the esophagus were treated by definitive radiotherapy with megavoltage x-rays in Tokyo Womens Medical College from 1975 to December 1990. Eight patients refused surgery and 13 patients were considered to be unsuitable for surgery due to advanced age or morbid conditions such as severe pulmonary dysfunction, myocardial infarction, liver cirrhosis, and other cancer. Radiotherapy was performed using 1.8-2.2 Gy fraction dose, 5 times a week and with a total dose of 50-76 Gy/5-7 weeks (median; 70 Gy). Three patients received intraluminal radiotherapy in addition. Combined chemotherapy was performed in four cases, and three cases received it before radiotherapy and one case after radiotherapy. RESULTS Overall survival rate was 40.8%, and the cause-specific 5-year survival rate was 61.7%. The 5-year survival rate of the group with morbid conditions was 17.5%, but that of the group without morbid conditions was 60.6%. Seven patients developed recurrence (primary site: 3, lymph nodes: 3, lung: 1) and one patient revealed multicentric cancer of the hypopharynx with wide submucosal spread of the esophagus at 28 months after radiotherapy. No patient developed severe side effect due to radiotherapy. CONCLUSION Definitive radiotherapy with or without chemotherapy can be applied as an alternative therapy to surgery for superficial esophageal cancer, even for the operable patients under good general condition.

Comparison of radiation dose to the left anterior descending artery by whole and partial breast irradiation in breast cancer patients

Purpose Breast conserving surgery (BCS) followed by whole breast irradiation (WBI) is the standard of care for breast cancer patients. However, there is a risk of coronary events with WBI therapy. In this study, we compared the radiation dose in the left anterior descending artery (LAD) in patients receiving partial breast irradiation (PBI) with WBI. Material and methods We evaluated consecutive patients who underwent adjuvant radiotherapy after BCS between October 2008 and July 2014. Whole breast irradiation patients received 50 Gy in fractions of 2 Gy to the entire breast. Partial breast irradiation was performed using multicatheter brachytherapy at a dose of 32 Gy in eight fractions. The mean and maximal cumulative doses to LAD were calculated. The radiotherapeutic biologically effective dose of PBI was adjusted to WBI, and radiation techniques were compared. Results Of 379 consecutive patients with 383 lesions receiving radiotherapy (151 WBI and 232 PBI lesions), 82 WBI and 100 PBI patients were analyzed. In WBI patients, the mean and maximal cumulative doses for left-sided breast cancer (2.13 ± 0.11 and 8.19 ± 1.21 Gy, respectively) were significantly higher than those for right-sided (0.37 ± 0.02 and 0.56 ± 0.03 Gy, respectively; p < 0.0001). In PBI patients with left-sided breast cancer, the doses for tumors in inner quadrants or central location (2.54 ± 0.21 and 4.43 ± 0.38 Gy, respectively) were significantly elevated compared to outer quadrants (1.02 ± 0.17 and 2.10 ± 0.29 Gy, respectively; p < 0.0001). After the adjustment, the doses in PBI patients were significantly reduced in patients with tumors only in outer quadrants (1.12 ± 0.20 and 2.43 ± 0.37 Gy, respectively; p = 0.0001). Conclusions Tumor control and dose to LAD should be considered during treatment since PBI may reduce the risk of coronary artery disease especially in patients with lateral tumors in the left breast.

Treatment outcome of medium-dose-rate intracavitary brachytherapy for carcinoma of the uterine cervix: comparison with low-dose-rate intracavitary brachytherapy.

PURPOSE To evaluate and compare the efficacy of medium-dose-rate (MDR) and low-dose-rate (LDR) intracavitary brachytherapy (ICBT) for uterine cervical cancer. METHODS AND MATERIALS We evaluated 419 patients with squamous cell carcinoma of the cervix who were treated by radical radiotherapy with curative intent at Tokyo Womens Medical University from 1969 to 1999. LDR was used from 1969 to 1986, and MDR has been used since July 1987. When compared with LDR, fraction dose was decreased and fraction size was increased (1 or 2 fractions) for MDR to make the total dose of MDR equal to that of LDR. In general, the patients received a total dose of 60 to 70 Gy at Point A with external beam radiotherapy combined with brachytherapy according to the International Federation of Gynecology and Obstetrics stage. In the LDR group, 32 patients had Stage I disease, 81 had Stage II, 182 had Stage III, and 29 had Stage IVA; in the MDR group, 9 patients had Stage I disease, 19 had Stage II, 55 had Stage III, and 12 had Stage IVA. RESULTS The 5-year overall survival rates for Stages I, II, III, and IVA in the LDR group were 78%, 72%, 55%, and 34%, respectively. In the MDR group, the 5-year overall survival rates were 100%, 68%, 52%, and 42%, respectively. No significant statistical differences were seen between the two groups. The actuarial rates of late complications Grade 2 or greater at 5 years for the rectum, bladder, and small intestine in the LDR group were 11.1%, 5.8%, and 2.0%, respectively. The rates for the MDR group were 11.7%, 4.2%, and 2.6%, respectively, all of which were without statistical differences. CONCLUSION These data suggest that MDR ICBT is effective, useful, and equally as good as LDR ICBT in daytime (about 5 hours) treatments of patients with cervical cancer.

Efficacy of single-stage breast-conserving treatment using multicatheter partial breast brachytherapy evaluated by GEC-ESTRO phase 3 trial

Purpose The GEC-ESTRO has reported the equivalent outcomes of partial breast irradiation (PBI) using multicatheter interstitial brachytherapy (MCB) to whole breast irradiation (WBI) in breast-conserving therapy (BCT). We performed single-stage BCT with partial breast brachytherapy by intraoperative catheter placement. After the categorization of patients into inclusion and exclusion criteria on this trial, our databases were evaluated in order to translate it to Japanese patients. Material and methods Patients undergoing BCT were retrospectively examined between November 2007 and December 2015. The technique is an open-cavity implant with a dose of 32 Gy in 8 fractions. The 4-year clinical outcomes of MCB-PBI were evaluated in the 2 distinct categories, and the comparison of the outcomes of MCB-PBI with WBI was performed in patients with unfavorable features. Results Of a total of 501 lesions undergoing BCT, 301 lesions were treated with MCB-PBI and 200 lesions with WBI. At the median follow-up time of 52 months, the 4-year rate of ipsilateral breast tumor recurrence (IBTR)-free, disease-free (DFS), and overall survival (OS) in patients with MCB-PBI and WBI were 98.9% vs. 98.0% (p = 0.56), 97.0% vs. 95.3% (p = 0.78), and 99.6% vs. 98.2% (p = 0.38), respectively. Although in exclusion cohort treated with MCB-PBI, IBTR-free, and disease-free survival were significantly worse than in inclusion cohort, non-significantly worse outcomes was demonstrated than in exclusion cohort with WBI; IBTR-free survival (95.0% vs. 97.2%, p = 0.24), and disease-free survival (95.0% vs. 95.8%, p = 0.31). Conclusions Single-stage BCT using MCB-PBI offered similar tumor control rates compering to WBI. However, further research is needed to define the benefit for patients with an exclusion criteria.