Katsuyuki Karasawa

Hypofractionated Stereotactic Radiotherapy (HypoFXSRT) for Stage I Non-small Cell Lung Cancer: Updated Results of 257 Patients in a Japanese Multi-institutional Study

Introduction: Hypofractionated stereotactic radiotherapy (HypoFXSRT) has recently been used for the treatment of small lung tumors. We retrospectively analyzed the treatment outcome of HypoFXSRT for stage I non-small cell lung cancer (NSCLC) treated in a Japanese multi-institutional study. Methods: This is a retrospective study to review 257 patients with stage I NSCLC (median age, 74 years: 164 T1N0M0, 93 T2N0M0) were treated with HypoFXSRT alone at 14 institutions. Stereotactic three-dimensional treatment was performed using noncoplanar dynamic arcs or multiple static ports. A total dose of 18 to 75 Gy at the isocenter was administered in one to 22 fractions. The median calculated biological effective dose (BED) was 111 Gy (range, 57–180 Gy) based on α/β = 10. Results: During follow-up (median, 38 months), pulmonary complications of above grade 2 arose in 14 patients (5.4%). Local progression occurred in 36 patients (14.0%), and the local recurrence rate was 8.4% for a BED of 100 Gy or more compared with 42.9% for less than 100 Gy (p < 0.001). The 5-year overall survival rate of medically operable patients was 70.8% among those treated with a BED of 100 Gy or more compared with 30.2% among those treated with less than 100 Gy (p < 0.05). Conclusions: Although this is a retrospective study, HypoFXSRT with a BED of less than 180 Gy was almost safe for stage I NSCLC, and the local control and overall survival rates in 5 years with a BED of 100 Gy or more were superior to the reported results for conventional radiotherapy. For all treatment methods and schedules, the local control and survival rates were better with a BED of 100 Gy or more compared with less than 100 Gy. HypoFXSRT is feasible for curative treatment of patients with stage I NSCLC.

Clinical Outcomes of Stereotactic Body Radiotherapy for Small Lung Lesions Clinically Diagnosed as Primary Lung Cancer on Radiologic Examination

PURPOSE Image-guided biopsy occasionally fails to diagnose small lung lesions, which are highly suggestive of primary lung cancer. The aim of the present study was to evaluate the outcome of stereotactic body radiotherapy (SBRT) for small lung lesions that were clinically diagnosed as primary lung cancer without pathologic confirmation. METHODS AND MATERIALS A total of 115 patients were treated with SBRT in 12 institutions. Tumor size ranged from 5 to 45 mm in diameter, with a median of 20 mm. RESULTS The 3-year and 5-year overall survival rates for patients with a tumor size < or =20 mm in diameter (n = 58) were both 89.8%, compared with 60.7% and 53.1% for patients with tumors >20 mm (n = 57) (p <0.0005), respectively. Local progression occurred in 2 patients (3.4%) with a tumor size < or =20 mm and in 3 patients (5.3%) with tumors >20 mm. Among the patients with a tumor size < or =20 mm, Grade 2 pulmonary complications were observed in 2 (3.4%), but no Grade 3 to 5 toxicity was observed. In patients with a tumor size >20 mm, Grades 2, 3, and 5 toxicity were observed in 5 patients (8.8%), 3 patients (5.3%), and 1 patient (1.8%), respectively. CONCLUSION In patients with a tumor < or =20 mm in diameter, SBRT was reasonably safe in this retrospective study. The clinical implications of the high local control rate depend on the accuracy of clinical/radiologic diagnosis for small lung lesions and are to be carefully evaluated in a prospective study.

Phase II clinical study on intraoperative photodynamic therapy with talaporfin sodium and semiconductor laser in patients with malignant brain tumors

OBJECT The objective of the present study was to perform a prospective evaluation of the potential efficacy and safety of intraoperative photodynamic therapy (PDT) using talaporfin sodium and irradiation using a 664-nm semiconductor laser in patients with primary malignant parenchymal brain tumors. METHODS In 27 patients with suspected newly diagnosed or recurrent primary malignant parenchymal brain tumors, a single intravenous injection of talaporfin sodium (40 mg/m(2)) was administered 1 day before resection of the neoplasm. The next day after completion of the tumor removal, the residual lesion and/or resection cavity were irradiated using a 664-nm semiconductor laser with a radiation power density of 150 mW/cm(2) and a radiation energy density of 27 J/cm(2). The procedure was performed 22-27 hours after drug administration. The study cohort included 22 patients with a histopathologically confirmed diagnosis of primary malignant parenchymal brain tumor. Thirteen of these neoplasms (59.1%) were newly diagnosed glioblastomas multiforme (GBM). RESULTS Among all 22 patients included in the study cohort, the 12-month overall survival (OS), 6-month progression-free survival (PFS), and 6-month local PFS rates after surgery and PDT were 95.5%, 91%, and 91%, respectively. Among patients with newly diagnosed GBMs, all these parameters were 100%. Side effects on the skin, which could be attributable to the administration of talaporfin sodium, were noted in 7.4% of patients and included rash (2 cases), blister (1 case), and erythema (1 case). Skin photosensitivity test results were relatively mild and fully disappeared within 15 days after administration of photosensitizer in all patients. CONCLUSIONS Intraoperative PDT using talaporfin sodium and a semiconductor laser may be considered as a potentially effective and sufficiently safe option for adjuvant management of primary malignant parenchymal brain tumors. The inclusion of intraoperative PDT in a combined treatment strategy may have a positive impact on OS and local tumor control, particularly in patients with newly diagnosed GBMs. Clinical trial registration no.: JMA-IIA00026 (https://dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRS06/JMACTRS06.aspx?seqno=862).

Radiation therapy in early glottic carcinoma: uni- and multivariate analysis of prognostic factors affecting local control.

PURPOSE The purpose of this report is to clarify prognostic factors affecting local control of T1 and T2 glottic tumors and to define an optimal regimen for radiation therapy. METHODS AND MATERIALS Two hundred and ten patients (199 males, 11 females, age range 30 to 86 years with an average of 62 years) with previously untreated invasive squamous cell carcinoma of the glottis were treated with radiation therapy at the University of Tokyo between January 1972 and December 1989. Endoscopic microsurgery was introduced as an integral part of treatment in 1974. From 1974 to 1979 the radiation dose was gradually reduced, reaching a mean of 20 Gy in 2 weeks in 1979. From 1980 to 1983, the total dose increased to 50.4 Gy, with a fraction size of 1.8 Gy, over a mean of 5.6 weeks. From 1984 onward, the mean total radiation dose increased to 60 Gy with a fraction of 2 Gy. RESULTS Recurrence-free 5 year survival rates for T1a, T1b, and T2 were 79%, 73%, and 67%, respectively. When the relationship between radiation dose and local control rates was analyzed for each year from 1974 to 1989, total doses were strongly associated with local control for patients with T1a disease. Age, sex, daily dose, total dose, radiation machine (Co-60 or 10 MV Lineac), treatment technique (anterior wedged pair or parallel opposed fields), treatment volume, use of endoscopic microsurgery, and involvement of the anterior commissure were examined for effects upon relapse-free survival in T1a disease by uni- and multivariate analysis. Total dose was the only significant factor for T1a disease (p < 0.02). The effect of these variables upon relapse-free survival in T2 disease as well as the effect of cord mobility, and number of involved sites was examined by multivariate analysis. Total dose (p < 0.03), cord mobility (p < 0.05), and number of involved sites (p < 0.04) significantly affected relapse-free survival in T2 disease. CONCLUSION At least 50 Gy is required for treatment of T1 disease when 2 Gy is used as a daily dose, even if endoscopic microsurgery is performed. Better local control of T2 disease in patients with impaired cord mobility or more than three involved sites leads to an improved prognosis; we recommend doses of at least 70 Gy or use of hyperfractionation in such patients with these factors. Although the daily dose did not significantly affect prognosis in multivariate analyses, 1.8 Gy is not recommended for treatment of T2 tumors instead of 2 Gy.

Renal dysfunction after total-body irradiation. Significance of selective renal shielding blocks.

Purpose:A retrospective analysis was conducted on the outcome of total-body irradiation (TBI) followed by bone marrow transplantation (BMT) on leukemia patients. Also studied was the risk of renal dysfunction after TBI/BMT with or without the use of selective renal shielding blocks.Patients and Methods:The cases of 109 leukemia patients who received TBI as a component of the conditioning regimen for their BMT were reviewed. They received 12 Gy of TBI in six fractions over 3 consecutive days. Doses to eyes and lungs were reduced to 7 Gy and 8 Gy, respectively, by customized organ shielding blocks. After March 1999, renal shielding blocks were used to constrain the renal dose to 10 Gy. The patients were followed for a median period of 16.6 months (range: 0.3–180.1 months).Results:The 2-year and 5-year overall survival rates were 55.4% and 43.2%, respectively. Renal dysfunction-free rates were different between those with and without renal shielding blocks: 100% and 78.5%, respectively, at 2 years. Overall survivals were not significantly different among these patients: 60.4% and 52.9%, respectively, at 2 years in patients with and without renal shielding blocks (p = 0.53).Conclusion:The use of selective renal shielding blocks provided evidence for reducing radiation-induced renal toxicities without decreasing the overall survival rate.Ziel:Retrospektive Analyse des Outcome der Ganzkörperbestrahlung („total body irradiation“: TBI) vor Knochenmarktransplantation (KMT) bei Leukämiepatienten. Untersucht wurde auch das Risiko von Nierenfunktionsstörungen nach TBI/KMT mit oder ohne Einsatz selektiver Abschirmung der Nieren.Patienten und Methodik:Ausgewertet wurden 109 Leukämiepatienten, die eine TBI im Rahmen der Vorbereitung ihrer KMT erhalten hatten. Sie erhielten eine TBI von 12 Gy in 6 Fraktionen an 3 aufeinanderfolgenden Tagen. Die Bestrahlungsdosen an Augen und Lunge wurden durch individuelle Abschirmung auf 7 bzw. 8 Gy reduziert. Ab März 1999 wurden auch die Nieren abgeschirmt, um die Strahlendosis auf 10 Gy zu vermindern. Die Patienten wurden im Median 16,6 Monate (Bereich: 0,3–180,1 Monate) nachbeobachtet.Ergebnisse:Die 2- and 5-Jahres-Gesamtüberlebensraten betrugen 55,4% bzw. 43,2%. Der Anteil der Patienten ohne Nierenfunktionsstörung lag in den Gruppen mit oder ohne Nierenabschirmung bei 100% bzw. 78,5% nach 2 Jahren. Beim Gesamtüberleben wurden mit 60,4% bzw. 52,9% nach zwei Jahren keine signifikanten Unterschiede zwischen den Gruppen mit und ohne Nierenabschirmung festgestellt (p = 0,53).Schlussfolgerung:Die selektive Abschirmung der Nieren verminderte strahleninduzierte Nierenschädigungen, ohne die Gesamtüberlebensrate zu beeinträchtigen.

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.

Thermoradiotherapy in the treatment of locally advanced nonsmall cell lung cancer

PURPOSE To improve the treatment results of locally advanced non-small cell lung cancer (NSCLC), we have been conducting a clinical trial using regional hyperthermia combined with radiotherapy. METHODS AND MATERIALS Between 1985 and 1990, 19 patients were treated. All cases except one were regarded as initially unresectable. There were 10 Stage IIIA cases and nine Stage IIIB cases. In 10 cases thermoradiotherapy was used definitively, and in the other nine cases preoperatively. Radiotherapy was administered with conventional fractionation. Total dose ranged from 42 to 80 Gy (mean 62.9 Gy) for definitive treatment cases, and 38 to 47 Gy (mean 40.6 Gy) for preoperative cases. Radiofrequency (RF) capacitive hyperthermia was administered twice weekly, immediately after radiotherapy. Total sessions of hyperthermia ranged from 5 to 16 times (mean 9.0) for definitive treatment cases and 3 to 8 times (mean 6.7) for preoperative cases. RESULTS The results of thermoradiotherapy group (HTRT group) were compared with our historical control group (RT group); initially unresectable Stage III NSCLC irradiated definitively with 50 Gy or more (26 cases), or became resectable after radiotherapy and operated (4 cases). As for initial response, there were 5 complete responses (CRs), 13 partial responses (PRs), and 1 no change (NC) (CR rate 26%, response rate 95%) in the HTRT group, whereas there were no CR, 21 PRs, and 9 NCs in the RT group (CR rate 0%, p < 0.005, response rate 70%, p < 0.05). Overall 3-year local relapse-free survival and survival rate for the HTRT group was 73% and 37%, respectively, and 20% and 6.7%, respectively, for the RT group (p < 0.01, p < 0.01). The rate of death from uncontrolled primary disease for the HTRT group was significantly lower than for the RT group (21% vs. 53%, p < 0.03). CONCLUSION Although the number of cases is rather small, thermoradiotherapy in the treatment of locally advanced NSCLC is promising in raising resectability, local control, and, thus, long-term survival.

Renal Dysfunction after Total-Body Irradiation

Purpose:A retrospective analysis was conducted on the outcome of total-body irradiation (TBI) followed by bone marrow transplantation (BMT) on leukemia patients. Also studied was the risk of renal dysfunction after TBI/BMT with or without the use of selective renal shielding blocks.Patients and Methods:The cases of 109 leukemia patients who received TBI as a component of the conditioning regimen for their BMT were reviewed. They received 12 Gy of TBI in six fractions over 3 consecutive days. Doses to eyes and lungs were reduced to 7 Gy and 8 Gy, respectively, by customized organ shielding blocks. After March 1999, renal shielding blocks were used to constrain the renal dose to 10 Gy. The patients were followed for a median period of 16.6 months (range: 0.3–180.1 months).Results:The 2-year and 5-year overall survival rates were 55.4% and 43.2%, respectively. Renal dysfunction-free rates were different between those with and without renal shielding blocks: 100% and 78.5%, respectively, at 2 years. Overall survivals were not significantly different among these patients: 60.4% and 52.9%, respectively, at 2 years in patients with and without renal shielding blocks (p = 0.53).Conclusion:The use of selective renal shielding blocks provided evidence for reducing radiation-induced renal toxicities without decreasing the overall survival rate.Ziel:Retrospektive Analyse des Outcome der Ganzkörperbestrahlung („total body irradiation“: TBI) vor Knochenmarktransplantation (KMT) bei Leukämiepatienten. Untersucht wurde auch das Risiko von Nierenfunktionsstörungen nach TBI/KMT mit oder ohne Einsatz selektiver Abschirmung der Nieren.Patienten und Methodik:Ausgewertet wurden 109 Leukämiepatienten, die eine TBI im Rahmen der Vorbereitung ihrer KMT erhalten hatten. Sie erhielten eine TBI von 12 Gy in 6 Fraktionen an 3 aufeinanderfolgenden Tagen. Die Bestrahlungsdosen an Augen und Lunge wurden durch individuelle Abschirmung auf 7 bzw. 8 Gy reduziert. Ab März 1999 wurden auch die Nieren abgeschirmt, um die Strahlendosis auf 10 Gy zu vermindern. Die Patienten wurden im Median 16,6 Monate (Bereich: 0,3–180,1 Monate) nachbeobachtet.Ergebnisse:Die 2- and 5-Jahres-Gesamtüberlebensraten betrugen 55,4% bzw. 43,2%. Der Anteil der Patienten ohne Nierenfunktionsstörung lag in den Gruppen mit oder ohne Nierenabschirmung bei 100% bzw. 78,5% nach 2 Jahren. Beim Gesamtüberleben wurden mit 60,4% bzw. 52,9% nach zwei Jahren keine signifikanten Unterschiede zwischen den Gruppen mit und ohne Nierenabschirmung festgestellt (p = 0,53).Schlussfolgerung:Die selektive Abschirmung der Nieren verminderte strahleninduzierte Nierenschädigungen, ohne die Gesamtüberlebensrate zu beeinträchtigen.

Efficacy of novel hypoxic cell sensitiser doranidazole in the treatment of locally advanced pancreatic cancer: Long-term results of a placebo-controlled randomised study

Novel hypoxic cell radiosensitiser doranidazole was tested for unresectable pancreatic cancer administered at intraoperative radiotherapy. Short-term survival was not different. However, difference has been observed concerning 3-year survival (doranidazole group vs. placebo; 23% vs. 0%, p=0.0192). This sensitiser might be effective in improving long-term survival for pancreatic cancer.

Phase III Trial of Radiosensitizer PR-350 Combined With Intraoperative Radiotherapy for the Treatment of Locally Advanced Pancreatic Cancer

Abstract: A randomized, controlled trial was conducted to clarify the effect of novel radiosensitizer, PR-350, accompanied by intraoperative radiology (IOR) on locally advanced pancreatic cancer. Between July 1999 and March 2002, 48 patients were enrolled in this clinical trial and received either PR-350 or placebo. Any differences between the PR-350 group (n = 22) and control group (n = 25) were not statically significant. All patients were evaluated, and none of them showed toxicity, with the exception of 1 patient from the control group, and the PR-350 compound was considered to be safe. The efficacy of IOR with PR-350 was evaluated using CT examination. The committee responsible for evaluating efficacy reported that 47.4% of the PR-350 group showed the effective response, compared with 21.7% of the control group (P = 0.1067, Fisher analysis). At 6 months following treatment, the tumor mass reduction rate in the PR-350 group was significantly improved (P = 0.0274). By the time of the last follow-up in July 2003, 17 PR-350 patients and 24 control patients group had died of the disease. The median survival period of the PR-350 group was thus 318.5 days and that of the control group is 303.0 days. One-year survival rates of the PR-350 group and control group were 36.4% and 32.0%, respectively. Although the PR-350 group did not demonstrate significantly better survival than the control group, 4 of 22 PR-350 patients were still living more than 2 years after the end of the trial, compared with only 1 of 25 patients from the control group. The mechanism of this increased therapeutic response to radiotherapy using PR-350 must be clarified to establish more effective strategy for pancreatic cancer treatment.