Preliminary results of proton-beam therapy for stage III non-small-cell lung cancer.

BACKGROUND: We conducted a preliminary retrospective evaluation of the efficacy and toxicity of proton-beam therapy (pbt) for stage iii non-small-cell lung cancer. METHODS: Between January 2009 and August 2013, 27 patients (26 men, 1 woman) with stage iii non-small-cell lung cancer underwent pbt. The relative biologic effectiveness value of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned such that the 90% isodose volume of the prescribed dose encompassed the planning target volume. Of the 27 patients, 11 underwent neoadjuvant chemotherapy. Cumulative survival curves were calculated using the Kaplan-Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events. RESULTS: Median age of the patients was 72 years (range: 57-91 years), and median follow-up was 15.4 months (range: 7.8-36.9 months). Clinical stage was iiia in 14 patients (52%) and iiib in 13 (48%). The median dose of pbt was 77 GyE (range: 66-86.4 GyE). The overall survival rate in the cohort was 92.3% at 1 year and 51.1% at 2 years. Locoregional failure occurred in 7 patients, and distant metastasis, in 10. In 2 patients, initial failure was both locoregional and distant. The 1-year and 2-year rates of local control were 68.1% and 36.4% respectively. The 1-year and 2-year rates of progression-free survival were 39.9% and 21.4% respectively. Two patients experienced grade 3 pneumonitis. CONCLUSIONS: For patients with stage iii non-small-cell lung cancer, pbt can be an effective and safe treatment option.

Simultaneous intraluminal thermobrachytherapy: an in vitro study.

A multi-institutional study on simultaneous intraluminal thermobrachytherapy (SITB) for advanced esophageal cancer was conducted in Japan. In this study, brachytherapy was administered by a small radioactive source stepping through a catheter in the esophagus, and hyperthermia was also applied by an endoesophageal coil. However, experimental or clinical findings on the spatial distribution of its antitumor effects around the esophagus are not available. Therefore, we developed an in vitro model of SITB using a high-dose-rate iridium-192 stepping source and two human cancer cell lines (WiDr and A549), and determined the spatial distribution of the antitumor effects. According to this model, the antitumor effects steeply decreased as the source-cell distance increased when cells of both cell lines were irradiated with 5 Gy without heat. When WiDr cells, a more resistant cell line to radiation and heat, were simultaneously irradiated and heated for 30 min at 44 degrees C, the effects decreased much less steeply as the distance increased. For A549 cells, a more sensitive cell line, irradiation with hyperthermia even at 42 degrees C made the decrease in the effects smaller. The largest antitumor effects can be expected at 5 - 10 mm beneath the esophageal mucosa, where the endoesophageal coil can heat tissues most effectively. SITB can induce larger antitumor effects than brachytherapy alone, especially in submucosal disease, which would favor treatment of advanced cancer.

Radiation therapy for roentogenographically occult lung cancer by external beam irradiation and endobronchial high dose rate brachytherapy.

PURPOSE: We investigated the clinical usefulness of radiation therapy by external beam irradiation and endobronchial brachytherapy for the treatment of roentogenographically occult lung cancer. PATIENTS AND METHODS: From 1995 to 1996, five patients were treated with radiation therapy. We analyzed their treatment outcomes. The follow-up period varied from 3.0 to 3.8 years or until death. External beam radiation (40 Gy/20 fractions/4 weeks) was delivered to the tumor site alone, and not prophylactically given to the mediastinum. Endobronchial brachytherapy using high dose rate iridium (Ir)-192 was concurrently administered principally to a total dose of 18 Gy on the bronchial mucosa in three weekly fractions of 6 Gy each. RESULTS: Complete remission was obtained in all patients. Two patients died of intercurrent diseases at 12 and 21 months without any evidence of recurrence. The disease has been also controlled in the other three cases. With the above doses, three small tumors < 1 cm were controlled without adverse effect. In two tumors, the dose reference points were set 2-7 mm beneath the mucosa, and larger doses were administered by brachytherapy. An applicator acting as a spacer was not used in these cases. The tumors were controlled, although the irradiated bronchi showed severe stenosis in 6 months following the treatment. However, the patients were asymptomatic and did not need further intervention. CONCLUSION: External beam irradiation combined with endobronchial brachytherapy was useful for the treatment of roentogenographically occult lung cancer as an alternative to surgery. Further investigation is needed to determine the optimal doses of radiation therapy.

Uniformity of biological effect in high-dose rate stepping source brachytherapy: an in vitro study.

In brachytherapy with a high dose rate of iridium-192, to make a flat isodose surface that covers a target volume, the dwell times of the single stepping source are computer adjusted. However, the dose rates of the irradiation vary with the positions in the volume. To examine this effect, we developed an in vitro model of stepping source brachytherapy with a 20 cm long target volume, and determined the uniformity of the biological effect in the volume on two human cancer cell lines (WiDr and A549) plated on a multi-well plate. When the source-cell distance was 10 mm, D1 (radiation dose for 1% survival) was similar in seven positions among the target volume for both cell lines. In contrast, at the 3 mm source-cell distance for one of the two cell lines (A549), D1 in the centre of the volume was significantly higher than at the periphery, suggesting a milder antitumour effect in the centre. Considering the possible decreased effect in the centre of the target volume, where most cancers clinically exhibit their maximum tumour volume, a minimum increase in radiation dose in the centre may be clinically reasonable, especially when dose reference points are set close to the source.

Endobronchial brachytherapy for recurrent thymoma showing endobronchial polypoid growth.

The authors report a case of recurrent thymoma displaying endobronchial polypoid growth. Initially, the patient had invasive thymoma with intracaval growth into the right atrium. He was treated with multimodality therapy consisting of chemotherapy, surgical resection, and radiotherapy (50.4 Gy). Both 3 years and 6 years after the initial treatment, the tumor recurred outside the reconstructed superior vena cava. The patient was treated with repeated radiotherapy (50.4 Gy and 40 Gy), and remission was achieved. Eight years after the first therapy, an endobronchial polypoid lesion was detected in the right upper lobe bronchus and was histologically found to be thymoma. Endobronchial high-dose rate brachytherapy (20 Gy at 3 mm/5 fractions) was carried out for palliation because the recurrent tumor occurred outside of the superior vena cava area, which had been reirradiated. After the treatment, the endobronchial tumor shrunk remarkably in size without adverse effects. No tumor regrowth has been noted after a follow-up of 10 months.

Hyperthermia for bone and soft tissue sarcoma: relationship between computerized tomographic and histological findings.

Between 1983 and 1992, 38 patients with 44 tumors of bone and soft tissue sarcoma were treated by hyperthermia combined with radiotherapy or chemotherapy. The overall response rate in this series was 48% (21/44). The average time for heating to 42 degrees C and the average maximum temperature did not correlate with the local effect. The percentage of the low density area on CT images and the average maximum temperature were well correlated. When 100% necrosis was evaluated as CR and up to 50% necrosis as PR, the local response rate was elevated from 42% to > 65%. Bone and soft tissue sarcomas are good targets for hyperthermia combined with radiotherapy and chemotherapy. Some tumors indicated for this study were too large to heat with the present heating apparatus. Percent low density and percent necrosis were correlated to some degree, but adoption of this phenomenon as a criterion for evaluation should be considered carefully.

Linac-based small-field radiotherapy for brain tumors.

Small-field radiotherapy based on a 6-MeV linac and a conventional head mold is investigated as an alternative to radiosurgery with stereotactic frames. The system requires no additional device and allows fractionated treatment. The dose distributions obtained are comparable to those reported with a Gamma Unit. Overall positioning errors are within 2 mm. Using this approach, seven patients with brain tumors who could not have been treated otherwise, underwent fractionated radiotherapy with total accumulated doses ranging from 70 to 108 Gy. The treatment was tolerated well with no acute toxicity or adverse effect encountered during the follow-up period of 8-14 months. All of the patients remained free from disease progression in the treated volumes. Although the follow-up is brief, the preliminary results suggest that this is a simple and inexpensive but effective system for the treatment of small intracranial malignancies.

[Histological and biological evaluation of preoperative radiotherapy on T1N0 breast carcinoma].

In order to clarify the role of radiotherapy in breast preserving surgery for early breast cancer, histological and biological effects of preoperative radiation were evaluated. Thirty-five T1N0 patients were treated by preoperative radiotherapy with beta-tron, cumulative doses of which were ranging from 25 Gy (5 Gy x 5) to 40 Gy (8 Gy x 5) and underwent subsequent modified radical mastectomy 2 or 3 weeks after the termination of radiotherapy. Clinical tumor shrinkage more than 50% was observed in 25 out of 35 cases (71%) but did not directly correlate with histological effects. Radiotherapy was basically ineffective within 25-30 Gy, whereas histological effects more than Grade 2 were gained in 8 out of 25 patients (32%), who had received 40 Gy or more. In the preoperative radiation group, there were more ER(+), PgR(+) and histologically well-differentiated cases than in the non-radiated stage I patients. Mitotic figures were also significantly reduced after radiotherapy, whereas the expression of c-erB-2 protein was unchanged between these two groups. Our data indicate the various radiosensitivity of breast cancer cells and the indication of hormone therapy for the conservative treatment of breast carcinoma.

Radiotherapy of T1 glottic cancer with 6 MeV X rays.

We treated 154 patients with T1 glottic carcinoma with 6 MeV X rays through 16 cm2 parallel-opposing open fields on a free set-up delivering a median dose of 67 Gy in 6 2/3 weeks. Observed and relative 5-year survival rates for all patients were 87% and 100%, respectively. The local control rate at 5 years was 89%. Of 18 patients who clinically had local recurrence, 17 were salvaged by a secondary treatment. There were no complications requiring medical or surgical attention. A tendency toward increasing local control rates with increasing total doses was observed in the range between 57.5 Gy and 72.5. No significant correlation was found between local control rates and field size, daily dose, or the technique used. A tendency toward a lower local control rate was noted for patients whose anterior commissures were grossly involved; however, it is not known if this could be attributed to the use of 6 MeV X rays. The results are comparable to those obtained with 60Co as reported in the literature. It is concluded that 6 MeV X rays on a free set-up delivering 65-70 Gy in 6 1/2-7 weeks can be used satisfactorily for the treatment of early glottic carcinoma.

Stage I-II carcinoma of the anterior two-thirds of the tongue treated with different modalities: a retrospective analysis of 244 patients.

Treatment results of 244 patients with stage I-II cancer of the mobile tongue were analyzed according to the modalities employed (implantation, surgery, cryosurgery and intraoral irradiation). Overall local control rates at three years were 90 +/- 3% for implant, 89 +/- 7% for cryosurgery, and 84 +/- 9% for surgery. Local control rates in stage II patients treated with intraoral electron irradiation, however, were only 50 +/- 13%. Five-year survival rates were 72 +/- 3% with no significant differences observed in patients with either stage I or stage II regardless of treatment modality. Sixty percent (29/48) of the patients with local recurrences were salvaged by the second treatment. Since the local control and survival achieved by these modalities were similar, with the exception of patients with stage II treated by intraoral electron irradiation, we recommend interstitial implantation with iridium, intraoral electron irradiation or surgery for patients with T1 tumors, and iridium implantation or surgery for patients with T2 tumors. For those with superficial lesions measuring 5 mm or less in thickness, cryosurgery is being offered as an alternative. The patient can choose the treatment modality taking into account his/her age, sex and profession.

Dose equivalence for high-dose-rate to low-dose-rate intracavitary irradiation in the treatment of cancer of the uterine cervix.

By comparing the incidence of major radiation injury, we estimated doses clinically equivalent for high-dose-rate (HDR) to conventional low-dose-rate (LDR) intracavitary irradiation in patients with Stages IIb and IIIb cancer of the uterine cervix. We reviewed a total of 300 patients who were treated with external beam therapy to the pelvis (50 Gy in 5 weeks) followed either by low-dose-rate (253 patients) or high-dose-rate (47 patients) intracavitary treatment. The high-dose-rate intracavitary treatment was given 5 Gy per session to point A, 4 fractions in 2 weeks, with a total dose of 20 Gy. The low-dose-rate treatment was given with one or two application(s) delivering 11-52 Gy to the point A. The local control rates were similar in both groups. The incidence of major radiation injury requiring surgical intervention were 5.1% (13/253) and 4.3% (2/47) for low-dose-rate and high-dose-rate groups, respectively. The 4.3% incidence corresponded to 29.8 Gy with low-dose-rate irradiation, thus, it was concluded that the clinically equivalent dose for high-dose-rate irradiation was approximately 2/3 (20/29.8) of the dose used in low-dose-rate therapy.

A comparison of swine abdominal temperature distribution after heating with BSD-1000, an annular phased array system (APAS), and Thermotron RF-8.

External hyperthermia for deep-seated tumors is still a difficult problem. We compared the abdominal temperature distribution in a pig after heating with BSD-1000, an annular phased array system (APAS), and Thermotron RF-8. Thirty elastic tubes were inserted into the upper abdomen of the pig and a thermocouple was inserted into each of the tubes. After heating, these thermocouples were moved at 1-cm intervals and the three-dimensional temperature distribution was obtained. The temperature distribution after heating with APAS and Thermotron RF-8 was compared by using the distribution on the longitudinal center line of each sagittal plane at 1-cm intervals from the center. The temperature was much higher and its distribution more homogeneous with APAS than Thermotron RF-8.

[Radiotherapy for endobronchially invading recurrence of esophageal cancer after resective surgery].

Sixty-eight patients with endobronchially invading recurrence of esophageal cancer after resective surgery were treated with radiotherapy from 1966 to 1988. The mean interval between resective surgery and diagnosis of recurrence was 11.1 months, that was significantly shortened in a3 group. The dose of radiation for recurrence ranged from 2 to 70.3 Gy, with a mean dose of 42.6 Gy. The mean survival time after treatment of recurrence was 4.9 months. The dose of radiation was found to have a positive correlation with survival time. The cause of death was bleeding in 20 patients, and respiratory failure in 36. High dose of radiation was thought to induce high incidence of bleeding. The results indicated that external beam radiotherapy with conventional fractionation was not so much effective for the recurrence.

[Control of aftereffects due to intraoperative radiotherapy].

In cases of treating a pancreatic cancer, an aneurysm and thrombus of the abdominal aorta, necrosis of the vertebral body, and damage to the peripheral nerves can be caused by intraoperative radiotherapy (IORT). These aftereffects have been observed in tests conducted in experimental animal reported by Colorado State University. Similarly, our clinical experiences have led us to set safety guidelines to prevent damage due to IORT. The safety level of a radiation dose for IORT alone is limited to 30 Gy, and for IORT combined with external beam radiotherapy, from 20 Gy (IORT) plus 50 Gy (EBRT). Using these parameters, among 58 cases of a pancreatic tumor treated by IORT, only one case subsequently developed a pseudoaneurysm at the stump of splenic artery.

Carcinoma of the uterine cervix treated by irradiation alone. Results of treatment at the National Cancer Center, Tokyo.

Six hundred and twelve patients with previously untreated invasive carcinoma of the uterine cervix were treated by irradiation alone at the National Cancer Hospital from 1972 to 1983. The number of patients was 7, 39, 43, 127, 15, 319, 28 and 34 in stages IA, IB, IIA, IIB, IIIA, IIIB, IVA and IVB respectively. Low-dose-rate intracavitary irradiation with or without external irradiation was used in 383 patients, high-dose-rate intracavitary irradiation with or without external irradiation in 130, external irradiation alone in 98, and external irradiation combined with radon-222 seed implantation in one patient. Five-year-survival rates were 85, 65, 57, 41, 14 11% for stages IB, IIA, IIB, IIIB, IVA, and IVB respectively. The rate of complications was rather high in the present series, and so we have been investigating whether it is possible to reduce the dose. Low-dose-rate intracavitary irradiation has been replaced by high-dose-rate irradiation by using a remotely controlled afterloading system.

Local effect of hyperthermia for superficial and shallow-seated tumors.

In approximately seven years, 134 patients with 161 tumors were treated by hyperthermia combined with radiation or chemotherapy at our department. The primary tumors were breast cancer, head and neck cancer, and soft tissue tumors in most patients. Adenocarcinoma was the most frequent, followed by squamous cell carcinoma and soft tissue sarcoma. The local response rates for primary inoperable advanced, metastatic, and local recurrence of breast cancer were 88% (7/8), 50% (10/15), and 86% (18/21), respectively. The local response rate of 39 tumors of neck lymph nodes was 49% (19/39). A total of 26 tumors of bone and soft tissue were treated. Five tumors showed CR and six PR, for a total response rate of 42%. Among 20 patients with malignant melanoma, CR and PR were 25% (5/20) and 30% (6/20), respectively. The local response rate for all patients with superficial and shallow-seated tumors was 58% (94/161). In some tumors classified as showing NR, complete disappearance of tumor cells was demonstrated by a post-treatment histological examination. The efficacy of hyperthermia, when evaluated solely on the basis of tumor size, is likely to be underestimated.