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Purpose To investigate the influence of ionizing radiation on the corneal epithelium and endothelium of rabbit eyes. Methods Five healthy mature albino rabbits were unilaterally irradiated with 20 Gy of X-rays (250 kV, 12 mA). Slit-lamp biomicroscopic observation and specular microscopic examination of the corneal epithelium and endothelium were carried out before and 1, 4, 8, 12, 16, 20, 24, and 36 weeks after irradiation. We evaluated mean area of the superficial corneal epithelial cells, mean area and the percentage of hexagonal cells of the corneal endothelial cells, and corneal thickness. The statistical difference between the irradiated and control eyes was assessed using paired t-test. Results All animals developed cataract within 24 weeks. Slit-lamp biomicroscopy showed no apparent corneal abnormalities over the 36-week follow-up period. Specular microscopy revealed a significant enlargement of the superficial corneal epithelial cells from 4 to 12 weeks after irradiation (P < 0.01), which disappeared at 16 weeks post-irradiation. Specular microscopy of the corneal endothelium showed enlargement and morphological alterations of the cells beginning 8 weeks after irradiation (P<0.05). These changes persisted throughout the study period. There were no statistically significant changes in corneal thickness. Conclusion After X-ray radiation of 20 Gy, transient damage occurred in the corneal epithelium, while delayed and irreversible changes were seen in the endothelium. [ABSTRACT FROM AUTHOR]

Accidental inhalation intake of plutonium isotopes and 241Am occurred at a Pu research facility in Japan in 2017, and the five workers involved in this accident were treated by the administration of Ca/Zn-diethylenetriaminepentaacetic acid (DTPA). For the worker who was most internally exposed, the therapy was continued over 1 y after the accident. Urinary samples collected before and after each administration were subject to bioassay to evaluate the efficacy of the dose reduction. This study performed numerical analyses using a biokinetic model dealing with 241Am-DTPA with reference to the European Coordinated Network on Radiation Dosimetry approach, which assumes that the complex of actinides and Ca/Zn-DTPA is generated in the designated compartments in the biokinetic model. The results of the model prediction well captured the trend of the observed urinary excretion in the long-term bioassay and would be useful to evaluate the efficacy of the Ca/Zn-DTPA administration for the worker involved in the accident., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Seven emergency nuclear workers, who had internal exposure due to an intake of radionuclides, mainly I-131, during the emergency response operation in March 2011, after the accident at the Tokyo Electric Power Company (TEPCO) Fukushima Daiichi Nuclear Power Plant (FDNPP), visited the National Institute of Radiological Sciences (NIRS) outpatient clinic for medical evaluation. They were followed up after their first visit for 10 years. The estimated committed equivalent doses to the thyroid were distributed between 3.2 to 1.2 × 10 Sv. This group thought to be received highest exposure at the accident. None of the workers had symptoms related to abnormal thyroid function. The examinations, including thyroid function tests and ultrasound, detected no abnormalities related to radiation exposure. However, there is a need for continuous monitoring of their thyroid status for longer periods in the future., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

In Japan, the radiation-dose limit for the lens of the eye was revised in April 2021. Consequently, for workers, the numerical values of the equivalent dose to the lens of the eye are equal to those of the effective dose. Radiation workers, radiation safety officers and licensees must comply with regulations related to radiation protection and optimize protection. The new guidelines on dose monitoring of the lens of the eye developed by the Japan Health Physics Society recommend for the dose to be estimated near the eye for accurate estimation, when the dose to the lens approaches or exceeds the management criteria. However, there is limited information regarding the non-uniform exposure of nuclear power plant workers. In this study, the dose equivalents of high-dose-rate workplaces and the personal doses of 88 workers were estimated at four Japanese commercial nuclear power plant sites (RWR: 3 units and BWR: 3 units) and the dose to the lens of the eye and the exposure situations of the workers were analyzed., (© 2022 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

The dose reconstruction of populations potentially affected by the accident at the Fukushima Daiichi nuclear power plant in March 2011 is of great importance. However, it has been difficult to assess internal thyroid doses to Fukushima residents (mainly from their intake of I) due to the lack of direct measurements. For the residents, only about 1,300 data points related to I are available, and 1,080 of the data points were obtained from the screening campaign that was conducted by the Nuclear Emergency Response Local Headquarters at the end of March 2011 in Kawamata Town, Iwaki City, and Iitate Village. Here, we reassessed thyroid doses to 1,080 subjects aged ≤15 y old using new age-specific conversion factors to determine I thyroid contents from net signals of the devices used, with consideration for the possible uncertainty related to the measurements. The results demonstrated that thyroid equivalent doses to the subjects were <30 mSv (excluding outliers). We also demonstrate dose distributions of each age group from the above three municipalities and those of subjects from Minamisoma City and Fukushima City. One of the findings was that the I intake was similar among different age groups in each of the three municipalities. This was consistent with the assumption that ingestion was a dominant route of intake rather than inhalation. The range of thyroid doses to Iitate Village residents was similar to that to Iwaki City residents even though the I concentration in tap water was much higher in Iitate Village than Iwaki City. The range of thyroid doses to Minamisoma City residents was similar to that to Iitate Village and Iwaki City residents, and the range for Fukushima City residents was smallest among the five municipalities. Since the major route of intake has remained unclear, this paper presents the plausible upper and lower thyroid doses, between which the actual doses are thought to mostly exist, based on two intake scenarios: single inhalation and repeated ingestion. Further research is thus necessary to extract useful evidence from the individual evacuation behaviors for improving the present internal thyroid dose assessment.

In the aftermath of the 2011 Fukushima nuclear disaster, a screening survey for thyroid internal exposure from intake of radioiodine was performed on 1080 children using handheld NaI(Tl) survey meters. This article presents the design and results of a practical exercise conducted to develop the skills of personnel who would be potentially engaged in such a survey. Participants of this exercise were asked to measure manikin heads in which point sources were installed under normal (~0.05 μSv h-1) and elevated (~0.5 μSv h-1) background conditions. The results demonstrated that the measurements were less dependent on the background radiation level, and the deviation of net signals obtained by the participants were within 10-20% for dose rates above 0.2 μSv h-1. This result suggests that dose rates can be reliably obtained above a provisional operational intervention level for the device, 0.5 μSv h-1 under a real nuclear accident situation., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

As a response to the Tokyo Electric Power Company's Fukushima Daiichi nuclear power plant accident in 2011, seven TEPCO workers whose exposure doses were expected to be >250 mSv (a tentative dose limit stipulated by the Japanese central authority) attended Japan's National Institute for Radiological Sciences for additional internal dose measurements. The National Institute for Radiological Sciences examination revealed that these workers' internal doses came mainly from their intake of the radionuclide I during emergency operations. In this study, we performed numerical simulations based on individual volume-pixel (voxel) phantoms of six of the seven workers for a more sophisticated evaluation of their internal doses, taking into account the individual thyroid size and other specific parameters. The voxel phantoms were created from magnetic resonance imaging scan images. As a result, the individual thyroid volumes ranged from 6.5 to 28.2 cm and were considerably smaller than the reference value (~20 cm) adopted in the International Commission on Radiation Protection's dosimetric model for four of the six subjects. Compared to the original estimates of the thyroid absorbed dose, our preliminary evaluation revealed values that were increased by approximately 3-fold or decreased by 30% at maximum. A wide difference in the individual thyroid size would be one of the significant modifiers in the current dose estimation of subjects of the ongoing epidemiological study project. The present simulations also provided evidence that the direct thyroid measurements by the National Institute for Radiological Sciences to determine the workers' I thyroid contents were sufficiently accurate.

This article introduces the first accident of internal contamination with plutonium (Pu) or americium (Am) in Japan for which treatment was carried out. An accident of internal contamination with Pu and Am occurred at a Pu research facility at Oarai-town of Ibaraki prefecture in Japan. A plastic bag containing these radionuclides ruptured when five workers were inspecting a storage container in a hood. As a consequence, these workers were internally contaminated with Pu and Am. Although contamination on the body surface was observed in all five workers, a positive nasal swab was detected in only three of them. A chelating agent, calcium diethylenetriaminepenta-acetate (CaDTPA), was administered to all of them including the two workers without a positive nasal swab. However, bioassay detected a significant amount of Pu and Am in urine after administration of DTPA in these two workers, whereas the levels of these nuclides were below minimum detectable levels in urine before the administration. Since the prevalence of adverse reactions in DTPAs is low, the present results suggest that administration of DTPA can be used for the diagnosis of internal contamination even when a nasal swab is negative or contamination around body orifices is not detected.

Since the International Commission on Radiological Protection recommended reducing the occupational equivalent dose limit for the lens of the eye in 2011, there have been extensive discussions in various countries. This paper reviews the current situation in radiation protection of the ocular lens and the discussions on the potential impact of the new lens dose limit in Japan. Topics include historical changes to the lens dose limit, the current situation with occupational lens exposures (e.g., in medical workers, nuclear workers, and Fukushima nuclear power plant workers) and measurements, and the current status of biological studies and epidemiological studies on radiation cataracts. Our focus is on the situation in Japan, but we believe such information sharing will be useful in many other countries.

A huge earthquake struck the northeast coast of the main island of Japan on 11 March 2011, triggering a tsunami with more than 10-m-high waves hitting the area. The earthquake was followed by numerous sustained aftershocks. The earthquake and aftershocks left almost 16,000 people dead and more than 2,800 missing (as of 11 March 2014). The earthquake affected the Fukushima Daiichi Nuclear Power Plant (NPP) of Tokyo Electric Power Company (TEPCO), causing serious damage to the NPP and resulting in large amounts of radioactive materials being released into not only controlled areas but also the environment. Damage was caused to the cooling systems of the NPP, although they automatically shut down after the earthquake. The trouble with the cooling systems led to hydrogen explosions and core meltdown. The major nuclides released on land were ¹³¹I, ¹³⁴Cs, and ¹³⁷Cs. The release of these radioactive materials resulted in contamination of first responders and workers and also a high ambient dose of radiation around the NPP. The local hospital system, including that for radiation emergency medicine, was dysfunctional. Hospitals that had been designated as radiation emergency facilities were not able to function because the earthquake and tsunami had caused damage to their facilities; some of these were located within a 20-km radius of the NPP and in the evacuation areas. Local fire department personnel were also ordered to evacuate. Fukushima prefecture changed the screening level required for decontamination from 13,000 to 100,000 cpm, with decontamination by wiping being performed for over 13,000 cpm. However, as hospitals and fire departments had to abide by lower levels than that of the prefecture for receiving or transporting contaminated patients, these personnel could not accept or transport contaminated people from the NPPs. In addition, hospitals not designated as radiation emergency facilities would not receive patients from the NPPs because of concerns about the health effects of radiation. From this disaster, it was learned that basic knowledge of radiation and its effects is extremely important for health care providers.

A huge earthquake struck the northeast coast of the main island of Japan on March 11, 2011, triggering a tsunami with 14-15 meter-high waves hitting the area. The earthquake was followed by numerous sustained aftershocks. The earthquake affected the nuclear power plant (NPP) in Fukushima prefecture, resulting in large amounts of radioactive materials being released into the environment. The major nuclides released on land were ¹³¹I, ¹³⁴Cs, and ¹³⁷Cs. Therefore, almost 170,000 people had to be evacuated or stay indoors. Besides the NPP and the telecommunications system, the earthquake also affected infrastructures such as the supplies of water and electricity as well as the radiation monitoring system. The local hospital system was dysfunctional; hospitals designated as radiation-emergency facilities were not able to function because of damage from the earthquake and tsunami, and some of them were located within a 20 km radius of the NPP, the designated evacuation zone. Local fire department personnel were also asked to evacuate. Furthermore, the affected hospitals had not established their evacuation plans at that time. We have learned from this "combined disaster" that the potential for damage to lifelines as well as the monitoring systems for radiation in case of an earthquake requires our intense focus and vigilance, and that hospitals need comprehensive plans for evacuation, including patients requiring life support equipment during and after a nuclear disaster. There is an urgent need for a "combined disaster" strategy, and this should be emphasized in current disaster planning and response., (© 2013 Wiley Periodicals, Inc.)

Abstract: On 11 March 2011, the Great Eastern Japan Earthquake occurred, causing the accident at the Fukushima Daiichi Nuclear Power Plant of Tokyo Electric Power Co. Residents were surveyed for contamination, and hospitalized patients within a 30-km area were transferred. In this report, the authors review the results of the survey and the effects. The screening teams measured total body contamination of each person using a Geiger-Mueller survey meter. Decontamination level was set at 100 kcpm (100,000 cpm). For levels of 13 to <100 kcpm, decontamination by wiping was planned and took place. Contamination screening during 11-21 March 2011, was carried out for 72,660 people at 200 sites. From 12 March 2011 until 10 February 2012, a total of 244,281 people were screened. As a result, there were 110 cases exceeding 100 kcpm, and 901 cases with contamination levels of 13-100 kcpm. The number of contaminated individuals screened reached a peak from 16-18 March. In the accident, contamination screening of victims and residents was performed to deal with anxiety and discrimination toward the residents. Although there was some early delay, almost all of the evacuees were relatively promptly screened. There was no external contamination at levels thought to affect the health of residents. In addition, the detection of contamination levels over 13 kcpm peaked between 15-22 March. Considering factors such as the evacuation period, this suggests that even if iodine tablets had been administered during this time, they would not have been effective., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2013 by the Health Physics Society.)

Background: Several large randomised studies from western Europe and the USA have shown that accelerated fractionation of radiotherapy might be beneficial in the treatment of squamous-cell carcinoma of the head and neck (HNSCC). The aim of this study--the International Atomic Energy Agency (IAEA) ACC trial--was to determine whether accelerated fractionation could be applied in developing countries, where there are fewer therapeutic resources and where tumour burdens can be heavier., Methods: Between Jan 6, 1999, to March 31, 2004, nine centres from Asia, Europe, the Middle East, Africa, and South America recruited patients with HNSCC of the larynx, pharynx, and oral cavity who were eligible for curative radiotherapy. Patients were randomly assigned in this open-label trial to receive an accelerated regimen of six fractions of radiotherapy per week (n=458) or to receive a conventional radiotherapy regimen of five fractions per week (n=450), receiving a total dose of 66-70 Gy in 33-35 fractions. Patients were stratified by tumour localisation, T classification, histopathological grade, and institution. Randomisation was done by a central computer-generated balanced randomisation algorithm. The primary endpoint was locoregional control, analysed for all eligible patients, irrespective of whether or not they had completed the course of radiotherapy. This trial is registered with ClinicalTrials.gov, number NCT00120211., Findings: Six patients in the accelerated group and two in the conventional group were excluded from analyses because of withdrawal of consent or missing data. The planned total radiotherapy dose was received by 418 (92%) of the 452 eligible patients in the accelerated radiotherapy group and 413 (92%) of the 448 patients in the conventional radiotherapy group. Median treatment time was 40 days in the accelerated group and 47 days in the conventional group. The 5-year actuarial rate of locoregional control was 42% in the accelerated group versus 30% in the conventional group (hazard ratio [HR] 0.63, 95% CI 0.49-0.83; p=0.004). Acute morbidity in the form of confluent mucositis was noted in 45 patients in the accelerated group and 22 patients in the conventional group (2.15, 1.27-3.35); severe skin reactions were noted in 87 patients in the accelerated group and 50 patients in the conventional group (1.91, 1.31-2.79). There were no significant differences in late radiation side-effects., Interpretation: An accelerated schedule of radiotherapy for HNSCC was more effective than conventional fractionation, and since it does not require additional resources, might be a suitable new worldwide standard baseline treatment for radiotherapy of HNSCC., Funding: International Atomic Energy Agency, Coordinated Research Project (IAEA-CRP E.3.30.18), the Danish Cancer Society, the Danish Strategic Research Council, and the Lundbeck Centre for Interventional Research in Radiation Oncology (CIRRO)., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: An International Atomic Energy Agency (IAEA)-sponsored, multi-institutional prospective randomized trial was conducted to clarify whether the combination of hyperthermia and radiotherapy improves the local response rate of locally advanced non-small cell lung cancer (NSCLC) compared with that obtained by radiotherapy alone., Methods: Between October 1998 and April 2002, 80 patients with locally advanced NSCLC were randomized to receive either standard radiation therapy alone (RT) or radiation therapy combined with hyperthermia (RT + HT). The primary endpoint was the local response rate. The secondary endpoints were local progression-free survival and overall survival., Results: The median follow-up period was 204 days for all patients and 450 days for surviving patients. There were no significant differences between the two arms with regard to local response rate (P = 0.49) or overall survival rate (P = 0.868). However, local progression-free survival was significantly better in the RT+HT arm (P = 0.036). Toxicity was generally mild and no grade 3 late toxicity was observed in either arm., Conclusion: Although improvement of local progression-free survival was observed in the RT+HT arm, this prospective randomized study failed to show any substantial benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced NSCLC.

Purpose: AK-2123, a nitrotriazole hypoxic cell sensitizer, has reportedly improved results in head and neck cancers, uterine cervical cancers and other solid tumours when added to radical radiotherapy. A prospectively randomised trial was initiated by the International Atomic Energy Agency (IAEA) evaluating AK-2123 and radiotherapy in treatment of uterine cervical cancer stage III and IV., Patients and Methods: A total of 462 patients were randomised from 8 centres. Patients from four centres were excluded due to lack of accrual, closing of the centre and insufficient documentation and reporting. The final study population consisted of 333 patients who were randomised between May 1995 and December 1998. Patients were randomised to either standard radical treatment (radiation therapy alone, RT) or standard radical radiotherapy and additional administration of AK-2123 (RT+AK-2123). The total dose of 45-50.8 Gy was delivered by 20-28 fractions in an overall time of 4-5 1/2 weeks, with further dose escalation by brachytherapy or external beam. In the study arm, patients received 0.6 g/sqm AK-2123 by intravenous administration before external beam radiotherapy, treating with AK-2123 on alternate days (e.g. Monday-Wednesday-Friday) during the entire course of external beam therapy. Following exclusion of 7 patients who did not undergo treatment, a total of 326 patients remained for evaluation., Results: The rate of local tumour control was significantly higher in the group after radiotherapy and additional administration of AK-2123. Local tumour control was 61% (95/155) after AK-2123 and 46% (79/171) after radiotherapy alone (p=0.006). The actuarial survival at 60 months was 57% after RT+AK-2123, compared to 41% after RT (Log Rank p=0.01). AK-2123 did neither increase gastro-intestinal toxicity nor was it attributed to any haematological toxicity. A mild peripheral toxicity (Grade 1: 13% and Grade 2: 2%) usually completely reversible was infrequently seen after AK-2123 administration., Conclusion: We conclude that the addition of AK-2123 to radical radiotherapy significantly increases local tumour control and survival in advanced squamous cell cancer of the uterine cervix without the addition of any major toxicity.

Purpose: AK-2123, a nitrotriazole hypoxic cell sensitizer has reportedly improved results in head and neck cancers, uterine cervical cancers and other solid tumours when added to radical radiotherapy. A prospectively randomised trial was initiated by the International Atomic Energy Agency (IAEA) evaluating AK-2123 and radiotherapy in treatment of uterine cervical cancer stage IIIA and IIIB., Materials and Methods: A total of 333 patients were randomised between May 1995 and December 1998. Patients were randomised to either standard radical treatment (radiation therapy alone, RT) or standard radical radiotherapy and additional administration of AK-2123 (RT+AK-2123). The total dose of 45-50.8 Gy was delivered in 20 to 28 fractions over 4 to 5 1/2 weeks. The dose to the central disease was escalated to a radiobiologically equivalent dose of 70 Gy by external beam or brachytherapy, in accordance with each centres individual practice. In the study arm, patients received 0.6 g/sqm AK-2123 by intravenous administration before external beam radiotherapy, treating with AK-2123 on alternate days (e.g. Monday-Wednesday-Friday) during the entire course of external beam therapy., Results: After a median follow up of 57 months (range 30-73 months) the rate of local tumour control was significantly higher in the group who received radiotherapy and additional administration of AK-2123. Local tumour control at the last follow up was 61% after combined radiotherapy and AK-2123 and 46% after radiotherapy alone (p = 0.005). AK-2123 neither increased gastro-intestinal toxicity nor gave any haematological toxicity. A mild peripheral neuropathy (Grade 1:11% and Grade 2:3%) was seen infrequently after AK-2123 administration and was usually completely reversible. Crude survival rates were 41% after radical treatment compared to 57% after combined therapy (p = 0.007)., Conclusion: We conclude that the addition of AK-2123 to radical radiotherapy significantly increases response rates and local tumour control in advanced squamous cell cancer of the uterine cervix without any increase in major toxicity. Further analysis and follow up are needed to evaluate if this benefit will translate into prolonged survival. We strongly suggest that our initially very promising study should lead other centres to further studies of AK-2123 in randomised clinical trials.

Purpose: Hyperthermia can be used to enhance the effects of radiation, and a combined treatment may, in some circumstances, be an advantage. Uterine cervical cancer is very common in developing countries. The control of locally advanced pelvic tumors is difficult with conventional treatment modalities. Based upon the biologic rationale and in view of the recent advances in heating and thermometry techniques, radiotherapy in combination with hyperthermia was investigated in a multi-institutional prospective randomized trial sponsored by the International Atomic Energy Agency. The primary purpose was to clarify whether the combination of hyperthermia and radiotherapy improves the rate of local control, compared with radiotherapy alone., Methods and Materials: A total of 110 patients with biopsy-proven, locally advanced carcinoma of the uterine cervix were randomized to treatment by radiotherapy with or without hyperthermia. The patients were stratified by institution, stage, and histologic type. Each patient received external beam radiation therapy and brachytherapy. For the patients randomized to receive hyperthermia, a minimum of five sessions (60 min each, once per week) were administered, employing a radiofrequency (RF) capacitive heating device. Intratumoral temperature was measured at the first hyperthermic treatment, and at least once more during the course of treatment. The equipment and the policies and procedures at each participating institution except one (Pusan) were personally inspected at least once by the corresponding author, to ensure that quality assurance procedures were in place and were followed for treatment according to the protocol guidelines. The median follow-up period was 466 days for all the patients and 512 days for the surviving patients., Results: The two arms were well balanced with regard to the patient factors, tumor factors, and treatment factors. The overall survival rate at 3 years was 73.2%, and the local control rate was 68.5%. There were no significant differences between the patients treated with or without hyperthermia, either with regard to the survival (p = 0.1893) or the rate of local control (p = 0.58). The survival was significantly worse among the patients with Stage IIb disease who received hyperthermia (p = 0.0162) although there was no difference in their rate of local control (p = 0.7988). Further analysis is necessary to determine if the difference in survival is due to a greater incidence of distant metastases or some other cause. Acute Grade 2-3 toxicity was seen in 10/55 patients (18%) treated by hyperthermia and in 2/55 of the patients (4%) treated without hyperthermia (p = 0.01). There was no significant difference in the late toxicity observed in the two arms., Conclusion: This prospective randomized study failed to show any benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced carcinoma of the uterine cervix. The acute toxicity was significantly greater among the patients receiving hyperthermia, and the survival was significantly worse among the Stage IIb patients receiving hyperthermia even though there was no difference in the local control rate.

Purpose: To investigate long-term changes in the cornea after ionizing irradiation in rabbits., Methods: Mature albino rabbits (n = 4) were unilaterally irradiated with 20 Gy of x-rays. The contralateral eye served as a control. The rabbits were examined with slit-lamp biomicroscopy for 5 years. The eyes were then enucleated for histopathologic examinations with light microscopy and transmission electron microscopy., Results: On biomicroscopy, there was no corneal abnormality during the 5-year follow-up period. On histopathology, no abnormality was observed in the corneal epithelium. In the endothelium, a vacuole-like structure was recognized by light microscopy, and transmission electron microscopy revealed marked enlargement of intercellular space and anamorphosis of the nuclei., Conclusion: Moderate x-ray irradiation to rabbit eye did not induce any long-term damage to the corneal epithelium, but the endothelium demonstrated persistent and irreversible damage, which was observed even 5 years after irradiation.

Background and Purpose: Single agent mitomycin c (MMC) has been shown to improve the outcome of radiotherapy in single institution trials. In order to confirm these findings in a broader worldwide setting, the International Atomic Energy Agency (IAEA) initiated a multicentre trial randomising between radiotherapy alone versus radiotherapy plus MMC., Material and Methods: Patients with advanced head and neck cancer were treated with primary curative radiotherapy (66 Gy in 33 fractions with five fractions per week) +/-a single injection (15 mg/m(2)) of MMC at the end of the first week of radiotherapy. Stratification parameters were tumour localization, T-stage, N-stage, and institution. A total of 558 patients were recruited in the trial from February 1996 to December 1999. Insufficient accrual and reporting led to the exclusion of three centres. The final study population consisted of 478 patients from seven centres. Patients had stage III (n=223) or stage IV (n=255) squamous cell carcinoma of the oral cavity (n=230), oropharynx (n=140), hypopharynx (n=65) or larynx (n=43). Prognostic factors like age, gender, site, size, differentiation and stage were well balanced between the two arms., Results: The haematological side effects of MMC were very modest (<5% grade 3-4) and did not require any specific interventions. Furthermore, MMC did not enhance the incidence or severity of acute and late radiation side effects. Confluent mucositis and dry skin desquamation was common, occurring in 56% and 62% of patients, respectively. The overall 3-year primary locoregional tumour control, disease-specific and overall survival rates were 19, 36 and 30%, respectively. Gender, haemoglobin drop, tumour site, tumour and nodal stage were significant parameters for loco-regional tumour control. There was no significant effect of MMC on locoregional control or survival, except for the 161 N0 patients, where MMC resulted in a better loco-regional control (3-year estimate 16% vs. 29%, P=0.01)., Conclusions: The study did not show any major influence of MMC on loco-regional tumour control, survival or morbidity after primary radiotherapy in stage III-IV head and neck cancer except in N0 patients where loco-regional control was significantly improved.

Purpose: To provide recommendations for the implementation of high dose rate (HDR) 192Ir brachytherapy technology in developing countries., Methods: An Advisory Group Meeting of the International Atomic Energy Agency (IAEA) met to address the implementation of HDR 192Ir brachytherapy technology in developing countries. These recommendations reflect only the personal opinions of the authors and do not necessarily represent the opinion of the IAEA., Results: An HDR treatment system should be purchased as a complete unit that includes the 192Ir radioactive source, source loading unit, applicators, treatment planning system, and control console. Infrastructure support may require additional or improved buildings and procurement of or access to new imaging facilities. A supportive budget is needed for quarterly source replacement and the annual maintenance necessary to keep the system operational. The radiation oncologist, medical physicist, and technologist should be specially trained before HDR can be introduced. Training for the oncologist and medical physicist is an ongoing process as new techniques or sites of treatment are introduced. Procedures for quality assurance (QA) of patient treatment, and the planning system must be introduced. Emergency procedures with adequate training of all associated personnel must be in place., Conclusions: The decision to select HDR in preference to alternate methods of brachytherapy is influenced by the ability of the machine to treat a wide variety of clinical sites. In departments with personnel and budgetary resources to support this equipment appropriately, economic advantage becomes evident only if large numbers of patients are treated. Intangible benefits of source safety, personnel safety, and easy adaptation to fluctuating demand for treatments also require consideration when evaluating the need to introduce this treatment system.

AK-2123, is a nitrotriazole with a potential to sensitize hypoxic tissue to radiation. Cancer of cervix in advanced stages are predominantly treated with radiation. These are the tumours which harbour a large hypoxic core. This is an Indian experience of the multicentric trial. Patients were randomized to control and AK-2123 arm. 49 patients were randomized to each group. Patients received external radiation with telecobalt to a dose of 50 Gy in five weeks. Those in the study arm received 600 mg/m2, on alternate days. The patients were further treated with intracavitory radiation a dose of 20 Gy. The total dose of 70 Gy was achieved. Patients in the study arm had a complete response of 71.43% (35 of 49) while only 21 of 49 (42.86%) responded in the control group. The overall survival at two years was 72.2% for the study group and 32.43% for control. Neuropathy, a drug related toxicity was transient except, in one patient, which has persisted. AK-2123, has shown significant radiation sensitizing potential.

Background and Purpose: The acquisition of radiotherapy by countries in transition (CITs) is an evolutionary process from having no resources whatsoever, to meeting the standards adopted by well-developed countries. The influence of the economic ability of a country to acquire and sustain this technology has intuitively been accepted as a major factor but has not before been subjected to analysis for a large group of countries. This information has been analysed to provide guidance to countries commencing and expanding radiotherapy services., Material and Methods: The number of linear accelerators and (60)Co megavoltage teletherapy machines in 72 CITs, those with gross national income per capita (GNI/cap)<$12000 per annum (pa) and a sample of 12 countries with GNI/cap>$12000 pa were expressed as machines per million population (MEV/mil) and used as an index of the ability of the country to provide a service. This figure was related to GNI/cap. The average populations of 24 further countries without radiotherapy were compared with 21 countries with radiotherapy facilities having the same range of GNI/cap., Results: The relationship log(10) MEV/mil=-2.90+0.85 log(10) GNI/cap was identified between the machines and income. Also verified was that small low income countries were less likely to have the technology than those with large populations., Conclusions: The increase in the number of teletherapy machines is closely linked to the GNI/cap of a country. Our sample of well developed countries failed to demonstrate a levelling off of equipment acquisition with income. In the lower income group, smaller countries were less likely to have radiotherapy services than those with large populations.

Background/aims: We estimated the capacity for exfoliative mechanical clearance which could occur in shrinkage of esophageal tumors following radiotherapy; both mechanical clearance and phagocytotic biological clearance of another clearance mechanism could participate in primary diseases located on outer tissue surfaces, whereas only biological clearance can participate in lymph node metastases surrounded by normal tissues which prevent mechanical clearance., Methodology: Twenty-one patients with primary esophageal cancer and lymph node metastasis both treated by radiotherapy with the same dose were reviewed. The extent of tumor shrinkage was estimated by measuring the size on computed tomography scans before and after radiotherapy. The capacity for biological clearance plus mechanical clearance (primary disease) or biological clearance alone (lymph node metastasis) was defined as the slope of a tumor shrinkage curve. The capacity for mechanical clearance was estimated by intra-patient subtraction., Results: Extent of tumor shrinkage was consistently greater in primary disease than in lymph node metastasis for each patient, showing significant correlation in extent of shrinkage between them. The capacity was smaller for mechanical clearance than for biological clearance as a whole, showing no correlation between them., Conclusions: Mechanical clearance is highly likely to participate extra in the shrinkage of tumors located on outer tissue surfaces; therefore, these tumors will normally respond more highly than parenchymal tumors.

Purpose: Resources for radiation therapy in Asian and Pacific countries were analyzed to obtain a better understanding of the status of radiation oncological practice in the region., Methods and Materials: The data were obtained mainly through surveys on the availability of major equipment and personnel which were conducted through an International Atomic Energy Agency regional project. The study included 17 countries in South Asia, South East Asia, East Asia and Australasia. Data were related to national populations and economic and a general health care indices., Results: Large differences in equipment and personnel among countries were demonstrated. The availability of both teletherapy and brachytherapy was related to the economic status of the countries. The shortage of teletherapy machines was evident in more countries than that of brachytherapy. Many departments were found to treat patients without simulators or treatment planning systems. The number of radiation oncologists standardized by cancer incidence of a country did not correlate well with economic status., Conclusions: There were significant deficiencies in the availability of all components of radiation therapy in the analyzed countries. The deficiencies were linked predominantly to the economic status of the country. Cognisance should be taken of the specific shortfalls in each country to ensure that expansion or any assistance offered appropriately match its needs and can be fully utilized. The information on the resources currently available for radiation oncological practice in the region presented in this paper provides a valuable basis for planning of development aid programs on radiation therapy.

Background/aims: Pancreatic cancer is extremely refractory even to aggressive treatments including surgery, resulting in early metastasis and/or local recurrence. We investigated changes in serum tumor marker CA 19-9 levels during preoperative radiotherapy in conjunction with initial treatment failure., Methodology: Twenty-three patients presenting with localized disease and an increased serum CA 19-9 level, who were slated to undergo pancreatectomy and/or intraoperative radiotherapy following preoperative radiotherapy were reviewed. CA 19-9 response, the ratio of post-radiotherapy level before laparotomy to pre-radiotherapy level, was analyzed in relation to disease-control time and survival., Results: Eleven patients revealed metastasis at restaging or laparotomy; 12 patients (52%) completed aggressive treatments. Initial failure was identified at the liver (52%), peritoneum (52%), or local site (26%) with a median disease-control time of 91 days; 7 patients showed combined failure. All but 1 patient died of cancer with a median survival time of 264 days. CA 19-9 response (range: 0-1185%) did not correlate with disease-control time or survival; 8 progressive-disease patients (> 140% response), however, showed significantly shorter disease-control time than 15 nonprogressive-disease patients (< or = 140% response)., Conclusions: CA 19-9 monitoring is useful in preoperative radiotherapy for identifying patients who will not benefit by succeeding aggressive treatments by predicting early metastasis.

Although tumor clearance is a common criterion in assessing the impact of radiotherapy (RT), it is not always reliable. Patterns of tumor clearance were determined using 91 metastatic lymph nodes (LNs) from 51 patients with head and neck tumors treated by definitive RT (61-80 Gy) or preoperative RT (43-65 Gy). Clearance rate (CR) was estimated as a daily volume decrement expressed as a ratio to the pre-RT LN volume. CR was greater for the so-called radioresponsive nasopharyngeal subgroups and more poorly differentiated than those of oral cavity and well-differentiated, respectively. Histologically, LNs that were removed following RT consisted mainly of fibrous tissues, necrotic tissues, and few cancer cells. There was no difference in CR between the cancer-cell-positive group (n = 21) and the cancer-cell-negative group (n = 31). Although the CR may reflect inherent radiosensitivity of tumor cells, tumor persistence predicts the amount of oncologically inactive materials rather than that of remaining cancer cells.

Patterns of radiologic response of 10 thymomas treated by preoperative radiotherapy (RT) (18-20 Gy/2 weeks) were determined in conjunction with histologic response. Changes in tumor volume were evaluated with CT scans obtained 5 to 36 days before and 14 to 24 days after the initiation of RT and before surgery. The extent of tumor volume reduction (TR) varied widely (40-78%), while the mean daily volume decrement expressed as a percentage of the pre-RT tumor volume correlated significantly with the pre-RT tumor volume. Histologically, the tumors, all of which were resected 17 to 33 days after RT initiation, generally consisted of predominant fibrous tissues, rare necrotic foci, and few epithelial cells. The TR did not correlate with pre-RT tumor volume, observation period, histologic subtype, or quantity of remaining epithelial cells. The TR of thymomas does not predict RT impact on tumor cells but does reflect the quantity of inherent tumor stroma.

Purpose: To determine the preserved functional capacity of the liver as a probable determinant of radiation tolerance in patients with cirrhosis and hepatocellular carcinoma, who underwent proton beam radiotherapy., Materials and Methods: We reviewed computed tomographic (CT) scans of 26 patients with cirrhosis and hepatocellular carcinoma during a period of 12-27 months after proton beam radiotherapy. Tumors were treated with focused proton beams with target doses of 140-186 TDF (time, dose, and fractionation). We measured the degree of hypertrophy of the untreated liver volume by measuring the total liver volume and the treated liver volume which was radiologically identified on contrast-enhanced CT scans. The risk of radiation-induced liver failure was estimated using the prediction score (PS) originally used for estimating posthepatectomy liver failure, substituting the planned treated liver volume for the resection liver volume., Results: The degree of hypertrophy ranged from -19% to 51%, and was significantly positively correlated with the ratio of the planned treated liver volume to the functional liver volume. The PS agreed well with observed radiation tolerance in 21 patients, but underestimated the tolerance in 5. This underestimation was diminished when the PS was recalculated using the identified untreated liver volume in lieu of the planned untreated liver volume., Conclusion: As in surgical treatment, radiation tolerance of the cirrhotic liver after focused treatment is closely related to the preserved functional capacity of the identified untreated liver volume, which shows compensatory hypertrophy following radiotherapy.

Clearance of a parenchymal tumor following radiotherapy was determined by using follow-up CT scans of 18 hepatocellular carcinoma tumors treated with focused proton beams. Regression analysis of the daily decrement (DD) and the diameter (D) of a tumor mass in each CT observation interval, DD = a*Db, showed that the exponent b was 3.0 or larger in early periods and 2.0 or smaller in late periods. This suggests that the clearance depends initially on the tumor volume, subsequently on the tumor surface area, and then it becomes much more moderate, possibly due to radiation damage to the parenchymal tissues.

Purpose: To determine the capacity of biological clearance in tumor regression following radiotherapy by using metastatic brain tumors as a clinical model in which mechanical clearance is negligible., Methods and Materials: Thirty-eight tumors (19 nonsmall cell lung cancer, 11 small cell lung cancer, and 8 nonlung cancer) in 23 patients were followed with computed tomography (CT) scans over 3 months or more following initiation of radiotherapy, with doses ranging between 34 and 66 Gy. The tumor regression rate (RR; mm3/day), which represented the capacity of biological clearance, was calculated for each CT observation period. The complete response (CR) rate was calculated. The relationship between RR and tumor diameter was determined with regression analysis in conjunction with the pattern of contrast enhancement and the type of primary disease. The change of the RR also was examined., Results: The CR rate was 60.5% for the total group; it was lower for ring-enhanced tumors (41.7%) than diffusely enhanced tumors (69.2%), which included mostly small cell lung cancer metastases. The RR correlated significantly with the tumor diameter (D), with a regression curve of exponential function (RR = 0.035 *D2.5). The RR varied widely and was rather large until 40 days following initiation of radiotherapy, especially for the subgroups of diffusely enhanced tumors and the small cell lung cancer tumors, and became rather constant thereafter., Conclusion: A tumor diameter exponent in the regression curve of smaller than 3.0 indicates that the larger the tumor volume is, the smaller the capacity of biological clearance. The capacity of biological clearance also is dependent on vascularity and cellularity of the tumor components expressed by the pattern of contrast enhancement.

Purpose: To compare the biological effects of a 135 MeV/u carbon-ion beam and 13 MeV fast neutron beam using human osteosarcoma cells., Methods and Materials: We have studied the clonogenic cell survival, recovery of potentially lethal damage (PLD) in plateau phase cells, and spheroid cure in multicellular spheroid after irradiation at various positions in the plateau and spread out Bragg peak (SOBP) of a 135 MeV/u carbon-ion beam and with 13 MeV neutrons. The carbon beam had a 4-cm range in water and a range filter was used to produce a 3-cm extended-peak region. The reference radiation was 137Cs gamma-rays., Results: The relative biological effectiveness (RBE) values for 10% survival level of plateau phase cells for carbon-ions at the position of plateau, proximal peak, midpeak, and distal peak within the SOBP, and neutrons were 1.71, 2.48, 2.63, 3.47, and 2.29, respectively. Corresponding RBE values at 1% level were 1.64, 1.93, 2.06, 2.49, and 2.05. The extent of recovery from PLD was reduced after carbon-ions at proximal peak, midpeak, and distal peak, and neutrons, although not substantially reduced after carbon-ions at plateau. The RBE values for 50% spheroid cure level of spheroids for carbon-ions at the position of plateau, proximal peak, midproximal peak, middistal peak, and distal peak within the SOBP, and neutrons were 1.69, 1.88, 1.87, 1.94, 2.03, and 1.90, respectively., Conclusions: The biological parameters measured all indicate an approximately comparable biological effectiveness between 75-80 KeV/microns carbon-ions of the SOBP and 13 MeV neutrons in the human tumor model studied in vitro.

The radiation tolerance of the liver was investigated in 12 patients, 11 of them with liver cirrhosis, treated for hepatocellular carcinoma by partial liver irradiation with doses between 50 and 77 Gy. The tolerance was assessed by the complication probability (Lyman's model), which concerned the injured tissue itself, and by a prediction score used for postsurgical liver failure, which concerned the preserved functional capacity, assuming that the > or = 30 Gy volume was equivalent to the resected volume. The prediction score corresponded better with the observed risk of fatal liver failure than the complication probability. The liver volume after radiotherapy correlated largely with the untreated volume and the low-dose volume. Thus the preserved functional capacity gives a better expression of the radiation tolerance than direct measures of the extent of injured tissue.

The survival of patients with glioblastoma multiforme is extremely poor, the 5-year survival rate being almost zero. The cause of failure is almost exclusively local progression of tumor, the remainder is due to complications of treatment. Although this tumor is clearly radiation resistant, there is evidence of a dose response relationship. Using a thin slice CT scan of the entire head of a patient with glioblastoma multiforme, 3-dimensional radiation treatment plans were developed for treatment to a dose of 90 cobalt-Gray-equivalent (CGE). Dose distributions using protons were compared to those using x-rays. The results showed advantages for the proton beam technique. Namely the proton plan irradiated less non-target brain than the x-ray plan; this was especially so in the decrease of coverage of deep-seated structures. The volume of non-target brain that received more than 70 CGE was 175 ml for the x-ray plan and 94 ml for the proton plan. This study indicates that for a subpopulation of patients with glioblastoma multiforme, at least 90 CGE could be delivered with proton beam techniques to the target with only small volumes of normal brain structures receiving more than 70 CGE.

The low tolerance of the central nervous system (CNS) limits the radiation dose which can be delivered in the treatment of many patients with brain and head and neck tumors. Although there are many reports concerning the tolerance of the CNS, few have examined individual substructures of the brain and fewer still have had detailed dose information. This study has both. A three dimensional planning system was used to develop the combined proton beam/photon beam treatments for 27 patients with skull-base tumors. The cranial nerves and their related nuclei were delineated on the planning CT scans and the radiation dose to each was determined from three dimensional dose distributions. In the 594 CNS structures (22 structures/patient in 27 patients), there have been 17 structures (in 5 patients) with clinically manifest radiation injury, after a mean follow-up time of 74 months (range 40-110 months). From statistical analyses, dose is found to be a significant predictor of injury. Using logistic regression analysis, we find that, for each cranial nerve, at 60 Cobalt Gray Equivalent (CGE) the complication rate is 1% (0.5-3% with 95% confidence) and that the 5% complication rate occurs at 70 CGE (64-81 CGE with 95% confidence). The slope of the dose response curve (at 50%) is 3.2 (2.2-5.4 with 95% confidence). No significant relationship between dose and latency period for nerve injury was found.

To assess the usefulness of proton beams for treatment of patients with rectal cancer, we have performed comparative 3D treatment planning for proton beam and x-ray beam therapy. Three common x-ray techniques (AP-PA, 3-field, and 4-field box), a proton beam only plan, and a proton boost plan were compared. The plan which would have been treated without the aid of the 3D planning system was also simulated. Dose distributions were analyzed and dose-volume histograms computed for the target volumes and critical normal tissues. Analyses of these plans demonstrate that the proton beam techniques reduce the volume of small bowel irradiated. This may allow higher doses to be delivered to the tumor, with a probable increase in local control, or a reduction in normal tissue complications probability. All the plans developed with the 3D planning system treated significantly less bowel than the one planned without it.

Using proton beam therapy, high doses have been delivered to chordomas and chondrosarcomas of the base of skull and cervical spine. Dose inhomogeneity to the tumors has been accepted in order to maintain normal tissue tolerances, and detailed attention to patient immobilization and to precise positioning has minimized the margins necessary to ensure these dose constraints. This study examined the contribution of precise positioning to the better dose localization achieved in these treatments. Three patients whose tumors represented different anatomic geometries were studied. Treatment plans were developed which treated as much of the tumor as possible to 74 Cobalt-Gray-Equivalent (CGE) while maintaining the central brain stem and central spinal cord at less than or equal to 48 CGE, the surface of the brain stem, surface of the spinal cord, and optic structures at less than or equal to 60 CGE, and the temporal lobes at less than or equal to 5% likelihood of complication using a biophysical model of normal tissue complication probability. Two positioning accuracies were assumed: 3 mm and 10 mm. Both proton beam plans and 10 MV X ray beam plans were developed with these assumptions and dose constraints. In all cases with the same positioning uncertainties, the proton beam plans delivered more dose to a larger percentage of the tumor volume and the estimated tumor control probability was higher than with the X ray plans. However, without precise positioning both the proton plans and the X ray plans deteriorated, with a 12% to 25% decrease in estimated tumor control probability. In all but one case, the difference between protons with good positioning and poor positioning was greater than the difference between protons and X rays, both with good positioning. Hence in treating these tumors, which are in close proximity to critical normal tissues, attention to immobilization and precise positioning is essential. With good positioning, proton beam therapy permits higher doses to significantly more of the tumor in these sites than do X rays.

Balb/c mice were irradiated on the leg in the area of the spread out Bragg peak (SOBP) of a 30 MeV proton beam. The proton beam was modulated to different ranges in order to determine the early skin reaction versus beam quality at different portions of the SOBP. The respective 50% moist desquamation doses of 1, 3, and 8.5 mm penetration were 25.9, 30.0, and 30.4 Gy. Irradiation of the superficial layer with the distal portion of the SOBP produced a significantly more severe reaction than did whole layer irradiation.

Proton beam treatment techniques provide a powerful approach to improving dose distribution (decrease treatment volume towards target volume) and hence increasing dose to target with resultant higher tumor control rates and lesser morbity. To achieve these dose distributions in patients requires use of modern imaging techniques, rigid immobilization systems, confirmation of target position vis a vis the proton beam at each treatment session, treatment planning which feature beam's eye view, displays of uncertainty, dose at each anatomic point, boli based on accurate assessment of density along each pixel, etc. Experience at MGH/MEEI/HCL has yielded a disease-free survival of 78% for patients with chordoma/chondrosarcoma of base of skull. Local control is achieved by 98% of patients treated for choroidal melanoma.