Effect of hyperthermia combined with external radiation therapy in primary non-small cell lung cancer with direct bony invasion.

PURPOSE: Local control in lung cancer directly invading the bone is extremely poor. Effects of regional hyperthermia combined with conventional external beam radiation therapy were evaluated. MATERIALS AND METHODS: Thirteen patients with non-small lung cancer (NSCLC) with direct bony invasion were treated with hyperthermia plus irradiation (hyperthermia group). The treatment outcome was compared with the historical treatment results in 13 patients treated with external radiation therapy alone (radiation alone group). In patients with no distant metastasis, radiation therapy at a total dose of 60-70 Gy was administered to both groups. Hyperthermia was performed for 45-60 min immediately after irradiation for two-four sessions with radiofrequency capacitive heating devices. RESULTS: For primary response, 10 of the 13 tumours responded to the treatment (3 CR, 7 PR) in the hyperthermia group, whereas seven tumours responded (1 CR, 6 PR) in the radiation alone group. The 2-year local recurrence-free survival rate for clinical M(0) patients in the hyperthermia group and that in the radiation alone group were 76.1 and 16.9%, respectively. Three patients died of distant metastases within 2 years in the hyperthermia group, but two out of three tumours histologically disappeared, even in the autopsy examination. The 2-year overall survival rate for clinical M(0) patients in the hyperthermia group and that in the radiation alone group were 44.4 and 15.4%, respectively. No severe pulmonary complication was observed in either group. CONCLUSIONS: Regional hyperthermia combined with conventional irradiation could be a tool to improve local control in patients with NSCLC deeply invading the chest wall.

Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone: patterns of recurrence, latent periods, and prognosis.

PURPOSE: A retrospective analysis was performed with emphasis on the patterns of recurrence, latent period, and prognosis in patients with cervical squamous cell carcinoma of the uterus treated with definitive radiation therapy alone. Late recurrence, which was observed more than 5 years after the initial radiation therapy, was finally focused on and discussed. MATERIALS AND METHODS: Between 1976 and 1994, 256 patients with squamous cell carcinoma of the uterine cervix without hematogenous metastasis were treated with definitive radiation therapy alone. The patients were staged as follows according to the FIGO classification: 26 in Stage I, 56 in Stage II, 124 in Stage III, 28 in Stage IVa, and 22 in Stage IVb. All the patients were treated with external beam irradiation and low-dose-rate intracavitary brachytherapy. RESULTS: A total of 74 patients had recurrence. The recurrence appeared in 67 cases (90.5%) within 5 years. Metastasis to para-aortic and/or supraclavicular nodes developed later than other types of recurrence. Among patients with lymphogenous metastasis, there were more 5-year survivors after recurrence than with other types of recurrence. Patients with early recurrence, within 2 years of the initial therapy, had a worse prognosis than those with recurrence more than 2 years after treatment. Seven patients (2.7%) in all developed late recurrence more than 5 years after the treatment. The first site of recurrence was an abdominal para-aortic or supraclavicular node in all patients, excluding one patient who developed intrapelvic lymph node metastasis. Six patients had pelvic node metastasis detected with lymphangiography at the initial treatment. Median survival after late recurrence was 16.0 months. Two of 7 patients survived more than 3 years after secondary radiation therapy, and the remainder died of recurrent disease. CONCLUSION: Patients with para-aortic and/or supraclavicular node metastasis that developed late after the initial treatment are more likely to survive due to secondary radiation therapy. Careful follow-up is emphasized for long-term survivors.

Small cell lung cancer with a brain metastasis controlled for 5 years: a case report.

We report a case of small cell lung cancer whose initial presentation was a solitary brain metastasis. On chest radiography the primary tumor was unclear and only detected by bronchofiberscopy. A small single pulmonary metastasis was noted in the right lower lobe. Subtotal resection and external irradiation were applied to the brain tumor and external irradiation was applied to the lung. Concurrently one course of systemic chemotherapy was administered. The tumors in the brain and lung had disappeared by the end of the treatment. The patient has been alive and well for 5 years without recurrence.

High-dose radiation therapy for elderly patients with inoperable or unresectable non-small cell lung cancer.

PURPOSE: To evaluate definitive radiation therapy delivering doses in excess of 60 Gy for elderly patients aged 75 years or over with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The treatment results for 97 patients aged 75 years or older (mean age 78 years; elderly group) with inoperable or unresectable NSCLC were retrospectively analyzed and compared with those for 206 patients younger than 75 year old (mean age 64 years; younger group). The elderly patients were classified into two groups; 67 patients aged 75-79 years (the elderly A) and 30 patients aged 80 years or older (the elderly B). Most of all patients were treated with a total dose of 60 Gy or more in 2 Gy daily standard fractionation. RESULTS: The overall 2 and 5 year survival rates were 32 and 13% for the elderly A group, and 28 and 4% for the elderly B group, respectively, compared with 36 and 12% for the younger group. There was not a statistically significant difference in survival rates among three groups. In stage I-II NSCLC patients there was also no significant difference in survival curves among the three groups. In patients with stage III disease, however, the survival curve of the elderly B was inferior to those of the younger group and the elderly A group, although the difference was not statistically significant. After the treatment the deterioration rate of the performance status was only 5% in the younger group and 8% in the elderly group. Only three younger and two elderly patients died of late pulmonary insufficiency associated with high-dose irradiation to the proximal bronchus. No other treatment-related event was observed except for mild acceptable acute complications in the elderly groups. CONCLUSIONS: Definitive radiation therapy is recommended to the elderly aged 75 years or older with inoperable or unresectable NSCLC, especially early stage disease, as an acceptable choice of treatment.

Clinical application of low dose-rate brachytherapy combined with simultaneous mild temperature hyperthermia.

BACKGROUND: Recent biological research has shown that mild temperature hyperthermia (MTH) around 41 degrees C simultaneously combined with low dose-rate irradiation (LDRI) is an effective treatment modality for cancer. The aim of the study was to assess the clinical usefulness of a combination of MTH and simultaneous low dose-rate brachytherapy. MATERIALS AND METHODS: Seven superficial and 8 deep-seated tumors were included in this protocol. Two tumors had no previous treatment and the remainder were recurrent tumors which had arisen from previously treated sites. The average major diameters of superficial and deep tumors were 8.6 and 7.0 cm, respectively. The average values for Tmin in superficial and deep tumors were 41.5 and 40.7 degrees C, respectively. Brachytherapy was delivered by 137Cs and/or 192Ir LDRI sources. RESULTS: For superficial tumors, six of the seven tumors responded to the treatment (4 achieved CR, 2 PR, 1 NC) and four tumors did not recur within the follow-up period of 5-15 months. All of the deep tumors responded and 5 achieved CR, 3 PR. Four tumors recurred 4-17 months after the treatment and the remainder showed no local recurrence within the follow-up period of 4-31 months. CONCLUSION: MTH simultaneously combined with LDRI was an effective method for treating progressive and bulky tumors with a previous treatment history.

Hyperthermia-induced apoptosis in two rat yolk sac tumor cell lines with different radiothermosensitivity in vitro.

We investigated cell susceptibility to hyperthermia-induced apoptosis in two rat yolk sac tumor cell lines (RYSTs) and attempted to correlate this with the known potentially relevant molecular determinants of apoptosis, p53 protein status, Bcl-2 family of proteins and heat shock proteins (Hsp). Parent cell line, NMT-1 (carrying wild-type p53 gene) was radiosensitive but thermoresistant compared to the variant cell line, NMT-1R (mutated type p53), which was isolated from NMT-1 by repeated radiation exposure. Induction of apoptosis by hyperthermia at 43 degrees C was morphologically detected in both RYSTs using hematoxylin and eosin, and TUNEL staining and additionally confirmed by DNA ladder formation (the cleavage of DNA into oligonucleosomal fragments). Western blot analysis showed an increase in expression of p53, p21WAF1/CIP1, Hsp70 proteins in both cell lines after heat-shock at 43 degrees C for 30 min. Hsp90 expression increased in NMT-1 but was not affected by heating in NMT-1R cells, whereas hyperthermia exerted no effect on the endogenous expression of Bax. Bcl-2 protein could not be detected in either RYST. These results suggest that hyperthermia induced apoptosis in both NMT-1 and NMT-1R and apoptosis in RYSTs may be independent of p53-dependent signaling pathway.

Biological cell survival mapping for radiofrequency intracavitary hyperthermia combined with simultaneous high dose-rate intracavitary irradiation.

We examined the best way to combine recently developed radiofrequency intracavitary hyperthermia with simultaneous high dose-rate intracavitary brachytherapy in an original experimental model. Temperature distribution was measured with an experimental phantom which was immersed in a water bath with the temperature controlled at 37 degrees C. Radiation dose distribution was calculated with a treatment-planning computer. Cell survival was measured by colony assay with HeLa-TG cells in vitro. Radiation dose response at 1 - 7 Gy and time response with hyperthermia in the range of 40 - 46 degrees C were estimated. Radiation dose-response curves in simultaneous treatment with hyperthermia for 30 min at 37 to 46 degrees C were estimated and the surviving fractions in combined treatment were plotted against temperature. For intracavitary radiation alone, cell survival rates increased with increasing distance from the source. For intracavitary hyperthermia alone, the maximum temperature was observed at a depth of 13 mm from the surface of the applicator under suitable treatment conditions. Homogeneous cell killing from the surface of the applicator to a tumor depth of 13 mm was observed under a specific treatment condition. Our experimental model is useful for evaluating the best simultaneous combined treatment.

[Radiation therapy for head and neck cancer].

Radiation therapy is the first choice of treatment for most of the early squamous cell carcinoma of the head and neck. Conventional radiotherapy however, contributes to the high local control rates only for carcinoma of the glottic larynx and the nasopharynx. Squamous cell carcinoma of the other sites cannot be sterilized easily only by external beam radiation therapy alone. Chemoradiotherapy, conformal three-dimensional radiotherapy and multi-daily fractionation are introduced clinically to improve local control and/or survival for radioresistant tumor. In this review, consensus report of radiation therapy for carcinoma of the larynx and pharynx, which was reached an agreement in JASTRO meeting in 1998, is introduced. The role of radiation therapy in the management of head and neck cancer in present and near future is also discussed.

The effects of p53 status and human papillomavirus infection on the clinical outcome of patients with stage IIIB cervical carcinoma treated with radiation therapy alone.

BACKGROUND: It has been suggested that the p53 tumor suppressor gene regulates the radiosensitivity in human malignancies after irradiation; however, in cervical carcinoma, the role of the p53 gene is still unclear because of inactivation of functional p53 by infection with human papillomavirus (HPV). The objective of this study was to clarify the effects of p53 status and HPV infection on the clinical outcome of patients with cervical carcinoma after undergoing radiation therapy. METHODS: Fifty-two patients with International Federation of Gynecology and Obstetrics Stage IIIB squamous cell carcinoma of the cervix who received radiation therapy alone were reviewed. The combination of external beam irradiation therapy and three sessions of intracavity brachytherapy irradiation was performed for all patients. Genomic DNA extracted from paraffin embedded tissues was examined for HPV types 16, 18 and 33 by the polymerase chain reaction (PCR) method and for p53 status by PCR-single-strand conformation polymorphism (PCR-SSCP) technique. The effects of HPV infection, p53 status, and other parameters on clinical outcome were investigated by univariate analysis. RESULTS: HPV-DNA was detected in 40 patients (76.9%), and 14 patients (26.9%) had mutations of the p53 gene in the study. There was a significant correlation between the existence of HPV and p53 status (P < 0.001). Mutations of the p53 gene were detected in 6 of 12 patients (50%) who had local recurrent tumors, whereas p53 were wild type in 32 of 40 patients (80%) who achieved local control. The p53 mutation had a significant correlations with local tumor recurrence. Furthermore, p53 status caused statistical significant differences in the curves of the recurrence free survival rate and local control rate as determined by the log rank test (P = 0.02 and P = 0.03, respectively). Conversely, no obvious correlation with any clinical outcome for patients with cervical carcinoma was found concerning HPV infection. CONCLUSIONS: It is possible that the p53 gene may be used as a predictive factor in radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix.

Intraoperative radiotherapy and bypass surgery for unresectable pancreatic cancer.

BACKGROUND/AIMS: Conflicting results have been reported concerning the usefulness of radiotherapy for unresectable pancreatic cancer. We evaluated the clinical efficacy of intraoperative radiotherapy and/or external beam radiotherapy in combination with bypass surgery. METHODOLOGY: Twenty-six patients with unresectable pancreatic cancer (16 in Stage II-III and 10 in Stage IV) were treated with intraoperative radiotherapy plus external beam radiotherapy (16 patients) or intraoperative radiotherapy alone (10 patients). The dose of intraoperative radiotherapy was either 25 or 30 Gy and the external beam radiotherapy dose was 31-60 Gy. The feasibility and clinical outcome were analyzed. RESULTS: The median survival time for Stage II-III and Stage IV were 11.5 and 6.5 months, respectively. The difference between Stage II-III and Stage IV in survival patterns was statistically significant (P < 0.05). For Stage II-III patients, the survival curves between the groups of intraoperative radiotherapy plus external beam radiotherapy and intraoperative radiotherapy alone were not significantly different, and only performance status was a significant factor in the prognosis (P < 0.05). Gastrointestinal bleeding was noted in 8%, but did not occur in the patients treated with an external beam radiotherapy dose less than 50 Gy. Palliative radiation was successfully performed to relieve pain, jaundice and appetite-loss and to shorten the hospital stay. CONCLUSIONS: The combination therapy with intraoperative radiotherapy and bypass surgery is considered to be tolerable and effective for unresectable pancreatic cancer, and also may improve the quality of life of the patients.

[Study on evaluation method of patient dose in diagnostic radiology required for introducing the guidance level: investigation of entrance surface dose of patient using direct measurement by TLD].

Using direct measurement, we investigated entrance surface doses of patients for routine radiographs in attempt to develop evaluation methods of patient dose in order to establish the guidance level in Japan. To date, patient doses have been evaluated by calculations based on radiographic conditions, or model experiments using phantoms. Their patient doses are then evaluated based on several assumptions. Direct measurement of patient dose is difficult to perform in many patients due to its time requirement, level of expertise required and difficulty in providing an explanation of the procedure to the patient. However, such direct measurement is essential since it incorporates all aspects of radiography from the radiographic equipment used, to the actual conditions of each patient without assumption. In this study, we examined the (1) need for introducing the guidance level, (2) controversial points in the calculation method for patient dose evaluation, (3) evaluation accuracy required for introducing the guidance level, and (4) necessity for a standardized method.

[Recent advances of radiation therapy for non-small cell lung cancer].

Radiation therapy(RT) has been frequently used for patients with inoperable or unresectable non-small cell lung cancer(NSCLC). In our series of NSCLC patients without progression of disease at the end of two years after RT, the majority of squamous cell carcinoma patients were alive well after 5 years from RT. On the other hand, half of adenocarcinoma patients had distant failures later. The recent data have indicated that the prognosis for selected favorable patients with unresectable disease will be improved by systemic chemotherapy combined with RT. Furthermore recent innovations in RT have shown promise in the treatment of NSCLC, especially squamous cell carcinoma. For future improvement of the treatment results of NSCLC, it is important that the role of RT be established.

Experimental induction of apoptosis by a combination of etoposide and radiation treatment.

The present study was undertaken to investigate cell death (particularly apoptosis) induced by etoposide, radiation, and both, and to examine p53 protein expression in relation to cell death. Nude mice transplanted with a human tumor (ependymoblastoma) were treated with etoposide (5-40 mg/kg) or 1-2 Gy X-ray irradiation or both. The tumor was excised at different points after treatment, and tumor tissue specimens were used to check for apoptosis and p53 protein expression by TUNEL, p53 protein staining, etc. Induction of p53-dependent apoptosis was observed in the etoposide treatment group, the X-ray irradiation group, and the combined (etoposide + X-ray irradiation) group. Etoposide 10 mg/kg was found to be approximately equivalent to 1 Gy X-ray irradiation in ability to induce apoptosis. When etoposide treatment was combined with X-ray irradiation at intervals of 3-6 hours, an approximately additive effect was observed.

Caffeine enhanced radiosensitivity of rat tumor cells with a mutant-type p53 by inducing apoptosis in a p53-independent manner.

The radiosensitizing effects of caffeine on two rat yolk sac tumor cell lines with a different p53 status were investigated. A reduction of radiation-induced G(2) arrest was caused by caffeine at a concentration of 2 mM in both cell lines. The reduction of survival was observed in a combination of radiation and 2 mM caffeine only in a lower radiation dose range, but not in a higher dose range in NMT-1 with a wild type p53. Radiosensitization of caffeine was recognized even in a higher dose range for cells with a mutant-type p53. Apoptosis, which was not prominent after irradiation alone or caffeine treatment alone, was induced by irradiation in combination with caffeine in cells with a mutant-type p53 through a p53-independent pathway.

Radiation therapy for elderly patient with squamous cell carcinoma of the uterine cervix.

OBJECTIVE: The purpose of this study was to profile cervical squamous cell carcinoma in elderly patients undergoing radiation therapy and to study the treatment outcome and side effects of therapy. MATERIALS AND METHODS: A retrospective analysis was carried out from the records of 380 patients with squamous cell carcinoma of the uterine cervix who had been given radiation therapy between 1970 and 1994. The patients were divided into three age groups: under 70 years (youngest group; n = 215), 70 to 79 years (intermediate group; n = 124), and 80 years or older (oldest group; n = 41). Radiation therapy was performed by a combination of external beam therapy and three brachytherapy fractions using low-dose-rate sources. RESULTS: The 5-year overall survival rates in the youngest, intermediate, and oldest groups were 58, 50, and 33%, respectively, while cause-specific survival rates were 68, 70, and 65%, respectively. For the patients with stage III, the 5-year overall survival rates in the youngest, intermediate, and oldest groups were 59, 48, and 36%, respectively, while cause-specific survival rates were 72, 70, and 70%, respectively. There was no statistical significance in the 5-year intrapelvic recurrence rates among the three groups. Grade 3 or 4 complications occurred in 6.5% of the youngest, 11.3% of the intermediate, and 7.3% of the oldest groups. CONCLUSION: Radiation therapy with external beam combined with three fractions of low-dose-rate brachytherapy proved both highly effective and safe for senior patients with cervical squamous cell carcinoma.

Induction of p53-dependent apoptosis in vivo by nedaplatin and ionizing radiation.

p53 protein expression, apoptosis and growth delay induced by nedaplatin, a novel platinum compound, were investigated in vivo, and compared with those induced by ionizing radiation. A human ependymoblastoma with wild-type p53 was transplanted subcutaneously to the thighs of nude mice. The incidences of p53 protein-positive cells and apoptosis in tumors increased following exposure to ionizing radiation. In tumors treated with nedaplatin, they also increased, but the incidences of p53 protein-positive cells and apoptosis induced by 32 mg/kg nedaplatin, 1/2 LD50, were lower than those induced by 1 Gy irradiation. However, growth-delay assay showed no significant difference between the efficacy of 32 mg/kg nedaplatin and that of 1 Gy irradiation. These results suggest that the main antineoplastic activity caused by nedaplatin may be mediated through different mechanisms than those of the p53-dependent early apoptosis.

Comparison of effects of doxorubicin and radiation on p53-dependent apoptosis in vivo.

The effects of doxorubicin and radiation on apoptosis, p53 expression, and tumor growth in human tumor xenografts were investigated. Human ependymoblastoma (NNE), primitive neuroectodermal tumor (YKP), glioblastoma (KYG) and small cell lung carcinoma (GLS) that are all transplantable to nude mice were treated with doxorubicin (8 mg/kg) or radiation (1 Gy). The histological study was performed by using TUNEL and p53 staining. Cytotoxic effects of doxorubicin and radiation were compared with no-treatment group by the growth curves and apoptotic index of tumor to each treatment. In NNE with wild-type p53, doxorubicin induced growth delay of tumors (tumor volume doubling time; 13.7+/-3.3 days in control group vs 30.4+/-1.5 days in doxorubicin group), but no growth delay of tumors in KYG and GLS with mutant type p53. While radiation-induced apoptosis appeared most frequently at 6 h after irradiation, doxorubicin-induced apoptosis had a tendency to appear later. Furthermore, although the frequency of doxorubicin-induced apoptosis was lower than that of apoptosis by 1 Gy irradiation, apoptotic cells appeared for many hours after the treatment. Doxorubicin-induced apoptosis may be correlated with p53 phenotype because apoptosis was induced only in tumor with wild-type p53, but it appeared less frequently and later than radiation-induced apoptosis.

Experimental study of the effects on apoptosis of docetaxel alone and in combination with irradiation.

The effects of docetaxel alone and in combination with irradiation were experimentally investigated in terms of induction of apoptosis. A human ependymoblastoma was transplanted into nude mice, and they were intravenously injected with docetaxel, followed or preceded by irradiation with a single dose of 2 Gy. Apoptosis was less common in the docetaxel-alone group than in the irradiation-alone group. When administration of docetaxel was followed by irradiation, apoptosis was equal to or less common than in the irradiation-alone group. Apoptosis was most common in the irradiation-followed-by-docetaxel group. The incidence of mitosis was lower in the irradiation-alone group and the irradiation-followed-by-docetaxel group than in the docetaxel-alone group and the docetaxel-followed-by-irradiation group. The combined effect of irradiation and docetaxel appears to be useful in inducing apoptosis, but the sequence of irradiation and docetaxel is important.

Limited field irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer.

The outcome of limited field irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer (NSCLC) was analyzed to discuss the elective irradiation of regional lymph nodes. From 1976 through 1994, 36 patients with peripheral stage I NSCLC were treated with definitive radiation therapy (RT) alone at Gunma University hospital. The total dose ranged from 60 to 81 Gy with a 2 Gy-daily standard fractionation, although only one patient received 48 Gy. Ten patients received elective irradiation of the regional lymph nodes with a total dose of 40 Gy or more. The overall response rate was 97% with 31% complete responses. The overall survival rates at 3 and 5 years were 42 and 23%, and disease-specific survival rates were 56 and 39% at 3 and 5 years, respectively. In 26 patients without the elective regional irradiation, disease-specific survival rates at 3 and 5 years were 53 and 40%, respectively, whereas they were 64 and 39% in 10 patients with the regional nodal irradiation. The cumulative 5-year local progression rate was 28%, and the overall progression rate was 60% at 5 years. Four patients had a local recurrence as the only site of initial tumor progression. Combined local and regional progression was seen in two patients, and one patient had a local recurrence in combination with distant metastasis. Twelve patients had distant failure without evidence of local or regional progression. Only one patient without regional nodal irradiation developed an isolated regional failure. No patient had serious complications related to RT. High-dose limited field RT is justified for medically inoperable patients with peripheral stage I NSCLC. The regional nodal irradiation can be omitted in these pulmonary compromised patients because of the low regional relapse rate. Dose-escalation by a conformal RT with a small target volume can be expected to provide a better local control rate and better survival.