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Phase II Radiation Therapy Oncology Group trial of conventional radiation therapy followed by treatment with recombinant interferon-beta for supratentorial glioblastoma: results of RTOG 9710.

PURPOSE: The aim of this study was to determine whether recombinant human interferon beta-1a (rhIFN-beta), when given after radiation therapy, improves survival in glioblastoma. METHODS AND MATERIALS: After surgery, 109 patients with newly diagnosed supratentorial glioblastoma were enrolled and treated with radiation therapy (60 Gy). A total of 55 patients remained stable after radiation and were treated with rhIFN-beta (6 MU/day i.m., 3 times/week). Outcomes were compared with the Radiation Therapy Oncology Group glioma historical database. RESULTS: RhIFN-beta was well tolerated, with 1 Grade 4 toxicity and 8 other patients experiencing Grade 3 toxicity. Median survival time (MST) of the 55 rhIFN-beta-treated patients was 13.4 months. MST for the 34 rhIFN-beta-treated in RPA Classes III and IV was 16.9 vs. 12.4 months for historical controls (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 0.89-1.81). There was also a trend toward improved survival across all RPA Classes comparing the 55 rhIFN-beta treated patients and 1,658 historical controls (HR = 1.24, 95% CI = 0.94-1.63). The high rate of early failures (54/109) after radiation and before initiation of rhIFN-beta was likely caused by stricter interpretation of early radiographic changes in the current study. Matched-pair and intent-to-treat analyses performed to try to address this bias showed no difference in survival between study patients and controls. CONCLUSION: RhIFN-beta given after conventional radiation therapy was well tolerated, with a trend toward survival benefit in patients who remained stable after radiation therapy. These data suggest that rhIFN-beta warrants further evaluation in additional studies, possibly in combination with current temozolomide-based regimens.

Antineoplastic Agents↗

Untargeted effects of ionizing radiation: implications for radiation pathology.

The dogma that genetic alterations are restricted to directly irradiated cells has been challenged by observations in which effects of ionizing radiation, characteristically associated with the consequences of energy deposition in the cell nucleus, arise in non-irradiated cells. These, so called, untargeted effects are demonstrated in cells that have received damaging signals produced by irradiated cells (radiation-induced bystander effects) or that are the descendants of irradiated cells (radiation-induced genomic instability). Radiation-induced genomic instability is characterized by a number of delayed adverse responses including chromosomal abnormalities, gene mutations and cell death. Similar effects, as well as responses that may be regarded as protective, have been attributed to bystander mechanisms. Whilst the majority of studies to date have used in vitro systems, some adverse non-targeted effects have been demonstrated in vivo. However, at least for haemopoietic tissues, radiation-induced genomic instability in vivo may not necessarily be a reflection of genomically unstable cells. Rather the damage may reflect responses to ongoing production of damaging signals; i.e. bystander responses, but not in the sense used to describe the rapidly induced effects resulting from direct interaction of irradiated and non-irradiated cells. The findings are consistent with a delayed and long-lived tissue reaction to radiation injury characteristic of an inflammatory response with the potential for persisting bystander-mediated damage. An important implication of the findings is that contrary to conventional radiobiological dogma and interpretation of epidemiologically-based risk estimates, ionizing radiation may contribute to malignancy and particularly childhood leukaemia by promoting initiated cells rather than being the initiating agent. Untargeted mechanisms may also contribute to other pathological consequences.

Animals↗

Device selection in the treatment of in-stent restenosis with and without radiation (from the Gamma Radiation Trials).

In-stent restenosis (ISR) is a major limitation of coronary stenting and is associated with high recurrence rates after intervention with all available devices. Intracoronary gamma (gamma) radiation was proved to reduce the recurrence rate after conventional therapy. The purpose of this study was to compare the different devices utilized for the treatment of ISR with and without gamma radiation. To search for the optimal device for the treatment of ISR, 685 patients from the radiation trials for ISR who were randomized to either iridium-192 gamma radiation (559 patients) or placebo (126 patients) following intervention were evaluated. Devices used included balloon percutaneous transluminal coronary angioplasty, excimer laser coronary angioplasty (ELCA), rotational atherectomy, and additional stent implantation. Baseline clinical and angiographic characteristics were similar between the gamma radiation and placebo groups. One- and 6-month clinical and angiographic outcomes were compared. The use of stenting compared with other devices was associated with increased late loss. Device selection used as adjunctive therapy did not influence the 30-day outcome. Patients treated with gamma radiation and placebo therapy had similar rates of composite major adverse coronary events (MACE) (death, Q-wave myocardial infarction, target vessel revascularization) (3% vs 2%, p = NS). At 6 months, MACE rates in irradiated patients were similar among POBA (29%), ELCA (28%), rotational atherectomy (18%), and additional stent implantation (30%, p = NS), and were significantly lower compared with placebo for the entire cohort and for each device subgroup. The overall recurrence rate of ISR was lower in patients treated with gamma radiation using iridium-192 compared with placebo. Device selection did not influence late clinical outcomes in irradiated and nonirradiated groups.

Aged↗

Gemcitabine-induced radiation recall dermatitis following whole pelvic radiation therapy.

OBJECTIVES: Radiation recall dermatitis secondary to gemcitabine use has been reported in isolated cases of patients treated for breast and lung cancers. There have been no reports of radiation recall dermatitis from gemcitabine after whole pelvic radiation therapy employed as a treatment of a gynecologic cancer. CASE: A 67-year-old woman was treated with whole pelvic radiation for palliation of lower extremity swelling and pain due to recurrent ovarian adenocarcinoma. Three months later, the patient was treated with gemcitabine for three courses. Therapy was discontinued secondary to severe cellulitis and edema of the skin of the anterior abdominal wall in the field of her prior radiation therapy. CONCLUSIONS: Radiation recall dermatitis secondary to gemcitabine should be considered in any patient with pelvic or lower abdominal skin abnormalities after pelvic radiation and subsequent gemcitabine therapy.

Adenocarcinoma↗

Plastic scintillation dosimetry for radiation therapy: minimizing capture of Cerenkov radiation noise.

Over the last decade, there has been an increased interest in scintillation dosimetry using small water-equivalent plastic scintillators, because of their favourable characteristics when compared with other more commonly used detector systems. Although plastic scintillators have been shown to have many desirable dosimetric properties, as yet there is no successful commercial detector system of this type available for routine clinical use in radiation oncology. The main factor preventing this new technology from realizing its full potential in commercial applications is the maximization of signal coupling efficiency and the minimization of noise capture. A principal constituent of noise is Cerenkov radiation. This study reports the calculated capture of Cerenkov radiation by an optical fibre in the special case where the radiation is generated by a relativistic particle on the fibre axis and the fibre axis is parallel to the Cerenkov cone. The fraction of radiation captured is calculated as a function of the fibre core refractive index and the refractive index difference between the core and the cladding of the fibre for relativistic particles. This is then used to deduce the relative intensity captured for a range of fibre core refractive indices and fibre core-cladding refractive index differences. It is shown that the core refractive index has little effect on the amount of radiation captured compared to the refractive index difference. The implications of this result for the design of radiation therapy plastic scintillation dosimeters are considered.

Anisotropy↗

Hyperfractionated radiation therapy for hypopharyngeal carcinoma compared with conventional radiation therapy: local control, laryngeal preservation and overall survival.

BACKGROUND: Recent randomized trials have revealed the effectiveness of hyperfractionated radiation therapy for treating head and neck carcinomas, especially in their local control. Because the hypopharynx is located near the larynx, increasing local control of hypopharyngeal carcinomas achieves greater laryngeal preservation, which is very important for patients' quality of life. In consideration of this, our facility adopted hyperfractionated radiation therapy for hypopharyngeal carcinoma in 1996. In this study we compared the results of this therapy with those of conventional radiation therapy. METHODS: Forty-two patients with hypopharyngeal carcinoma whose tumors were inoperable or who refused surgery were treated with curative intended radiation therapy between April 1975 and January 2002 at Tokyo Metropolitan Komagome Hospital. Of these patients, 23 were treated with hyperfractionated radiation therapy (the HF group) and 19 were treated with conventional fractionated radiation therapy (the CF group). In the HF group, the numbers of patients at each clinical stage were as follows: stage I, 2; stage II, 5; stage III, 6; stage IV, 10. The fraction size was 1.2 Gy and the mean total dose was 73.4 Gy (range, 66-79.2 Gy). In the CF group, the corresponding numbers were as follows: stage I, 3; stage II, 1; stage III, 5; stage IV, 10. The fraction size was 1.8-2.0 Gy and the mean total dose was 65.4 Gy (range, 60-70 Gy). RESULTS: The 3-year local control rates for the HF group and the CF group were 61.5 and 18.4%, respectively (P = 0.016). The 3-year pharyngolaryngectomy-free survival rates for the HF group and the CF group were 64.7% and 5.3%, respectively (P = 0.0008). The 3-year overall survival rates for the HF group and the CF group were 69.3 and 31.6%, respectively (P = 0.075). CONCLUSION: This study suggests that hyperfractionated radiation therapy for hypopharyngeal carcinoma is promising with a better local control rate, a greater laryngeal preservation rate and a relatively better overall survival rate.

Adult↗

Dose-volumetric parameters for predicting severe radiation pneumonitis after three-dimensional conformal radiation therapy for lung cancer.

PURPOSE: To retrospectively evaluate dose-volumetric parameters for association with risk of severe (grade >/=3) radiation pneumonitis (RP) in patients after three-dimensional (3D) conformal radiation therapy for lung cancer. MATERIALS AND METHODS: The study was approved by the institutional review board, which did not require informed consent. Data from 76 patients (66 men, 10 women; median age, 60 years; range, 35-79 years) with histologically proved lung cancer treated curatively with 3D conformal radiation therapy between August 2001 and October 2002 were retrospectively analyzed. Twenty patients underwent surgery before radiation therapy; 57 patients received chemotherapy. Median total radiation dose of 60 Gy (range, 54-66 Gy) was delivered in 30 (range, 27-33) fractions over 6 weeks. RP was scored by using Radiation Therapy Oncology Group criteria. Clinical parameters were analyzed. Dose-volumetric parameters analyzed were percentage of lung volume that received a dose of 20 Gy or more (V20), 30 Gy or more (V30), 40 Gy or more (V40), or 50 Gy or more (V50); mean lung dose (MLD); normal tissue complication probability (NTCP); and total dose. Fisher exact test was performed to compare clinical parameters between patients who developed severe RP and those who did not. Univariate and multivariate logistic regression analyses were performed to evaluate data for association between dose-volumetric parameters and severe RP. Pearson chi(2) test was used to assess data for correlations among dose-volumetric parameters. P < or = .05 was considered to indicate statistically significant difference. RESULTS: Of 76 patients, 30 (39%) did not develop RP; 23 (30%) developed RP of grade 1; 11 (14%), grade 2; 11 (14%), grade 3; and 1 (1%), grade 4. None had grade 5 RP. Age (< 60 vs > or =60), sex, Karnofsky performance status (< 70 vs > or =70), forced expiratory volume in 1 second, presence of weight loss, preexisting lung disease, history of thoracic surgery, and history of chemotherapy did not significantly differ between patients who developed severe RP and those who did not. In univariate analyses, MLD, V20, V30, V40, V50, and NTCP were associated with severe RP (P < .05). In multivariate analysis, MLD was the only variable associated with severe RP. CONCLUSION: MLD is a useful indicator of risk for development of severe RP after 3D conformal radiation therapy in patients with lung cancer.

Adult↗

The transcription of the XRCC1 gene in the heart of radiation-resistant and radiation-sensitive mice after ionizing irradiation.

The XRCC1 (X-Ray Repair Cross Complementing) gene was described to play a role for the sensitivity of mammalian cell lines toward ionizing irradiation. Cells with a mutation of this gene present with decreased single strand break repair and reduced recombination repair, they show increased double strand breaks, and sister chromatid exchange is increased up to 10-fold. The goal of our study was to investigate the transcription of this gene in the heart after ionizing irradiation in the mouse. Furthermore, we intended to examine whether radiation-sensitive mice would show a transcriptional pattern different from radiation-resistant mice. Radiation-sensitive BALB/c/J Him mice and radiation-resistant C3H He/Him mice were whole body irradiated with x-ray at 2, 4, and 6 Gy and killed 5, 15, and 30 min after irradiation. mRNA was isolated from the heart and hybridized with probes for XRCC1 and beta-actin as a housekeeping gene control. Irradiation at 2 Gy showed increased transcription of XRCC1 at 5 min in the C3H He/Him group, approached XRCC1 transcription of BALB/c J/Him mice at 15 min, and was lower in the latter at 30 min after irradiation. Irradiation at 4 Gy showed double the transcription at 5 min and an about 3-fold rapid increase of mRNA XRCC1 in the radiation-resistant group at 15 min after irradiation, returning to the transcriptional level of sensitive animals at 30 min. Irradiation at 6 Gy seemed to overwhelm the system in both groups, but resistant mice still showed higher levels of XRCC1 transcription. We conclude that radiation-resistant mice show a higher transcription level for the XRCC1 gene in the heart early after x-ray whole body irradiation. This findings is the first in vivo study on XRCC1 of this kind and may in part explain the differences in the radiation sensitivity between the two strains studied.

Animals↗

Interaction of hyperthermia and radiation: radiation quality.

Cell-survival data were collected to determine the survival response of asynchronous CHO cells subjects to radiation and hyperthermia. The irradiation was at room temperature 100 minutes before exposure to hyperthermia at 42 degrees C. The survival response to the combination of these two agents is expressed by means of a survival surface, a three-dimensional concept relating cell survival to heat dose and radiation dose. The survival surface could be approximately described by a survival model comprising three components of cell killing: the unperturbed radiation component, the unperturbed hyperthermia component, and the interaction component. The dependence of the radiation component and the interaction component on radiation quality were investigated by irradiating with either 60Co gamma rays, 250 kV X rays or 14.7 MeV neutrons. An analysis suggests that the interaction component and the radiation component exhibit similar dependencies on radiation quality both for the deposition of damage and the repair or accumulation of that damage.

Animals↗

SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro.

In recent decades, radiation research has concentrated primarily on the cancer cell compartment. Much less is known about the effect of ionizing radiation on the endothelial cell compartment and the complex interaction between tumor cells and their microenvironment. Here we report that ionizing radiation is a potent antiangiogenic agent that inhibits endothelial cell survival, proliferation, tube formation and invasion. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor were able to reduce the radiosensitivity of endothelial cells. Yet, it is also found that radiation induces angiogenic factor production by tumor cells that can be abrogated by the addition of antiangiogenic agents. Receptor tyrosine kinase inhibitors of Flk-1/KDR/VEGFR2, FGFR1 and PDGFR beta, SU5416, and SU6668 enhanced the antiangiogenic effects of direct radiation of the endothelial cells. In a coculture system of PC3 prostate cancer cells and endothelial cells, isolated irradiation of the PC3 cells enhanced endothelial cell invasiveness through a Matrigel matrix, which was inhibited by SU5416 and SU6668. Furthermore, ionizing radiation up-regulated VEGF and basic fibroblast growth factor in PC3 cells and VEGFR2 in endothelial cells. Together these findings suggest a radiation-inducible protective role for tumor cells in the support of their associated vasculature that may be down-regulated by coadministration of angiogenesis inhibitors. These results rationalize concurrent administration of angiogenesis inhibitors and radiotherapy in cancer treatment.

Angiogenesis Inhibitors↗

[Risk of radiation-related cancer following exposure to diagnostic radiation].

The paper on the risk of radiation-related cancer following exposure to diagnostic X-ray, appeared in the issue of Jan 31, 2004 of the Lancet, and described an attributable risk estimate of 3.2% from the current medical exposure among the cancer incidences in Japan. While the fact that Japan is known as a country with the highest level of medical exposure, the quantification of radiation-related cancer risk have made quite an impact on medical society. The risk estimate based on the linear-non-threshold (LNT) dose response that remains unresolved scientifically need further research, but the radiation risk has been a useful tool not only for decision-making by risk-benefit analysis such as justification of medical use of radiation, but also for comparison with other risks. Recent radiation biology suggests that a bystander effect and adaptive response might modify the estimated cancer risk based on the LNT model at low doses. The risk from most diagnostic X-rays may be so small that excess cancer due to radiation can not be statistically detected. However, a diagnosis giving a relatively higher dose such as computer tomography in children should be carefully justified using a risk estimate. Raising awareness of low-dose cancer risk should involve not only understanding the process of risk estimation including data and assumption but also understanding there is indirect evidence for risk of lower level radiation exposure in medical procedures.

Adult↗

Radiation necrosis of the brain and radiation-induced cerebrovasculopathy.

Thirteen patients with radiation necrosis and 6 patients with occlusive radiation-induced cerebrovasculopathy were reviewed. Computed tomography (CT) demonstrated low attenuation with a mass effect and irregular contrast enhancement in the radiation necrosis. The mass effect and the contrast enhancement decreased gradually. Angiography showed an avascular mass, generalized narrowing of the ipsilateral arteries and slow blood circulation in 3 cases. Radiation-induced vasculopathy appeared as localized stenosis and irregular walls of the arteries within the irradiated area. In cases with radiation vasculopathy accompanied by sufficient collateral blood flow brain damage was rarely demonstrated by CT. In patients with radiation-induced vasculopathy the lesion was not associated with signs of radiation necrosis.

Adult↗

[Possibility of biological indication of radiation injury from the blood levels of deoxynucleosides and deoxynucleotides in combined radiation-mechanical injuries].

A study was made of the dependence of a total content of deoxynucleosides and deoxynucleotides in blood serum and blood clot leukocytes upon radiation dose and time lapsed after radiation- and radiation-mechanical affection. It was established that after radiation-mechanical affection this dependence was different from that observed after the effect of radiation alone. From the analysis of the data obtained it was inferred that deoxynucleosides and deoxynucleotides could be used for biological indication of radiation damage in conditions of radiation-mechanical affection.

Animals↗

Quality assurance in radiation therapy: clinical and physical aspects. Radiation protection.

One usually thinks of radiation safety as keeping patient and personnel exposure as low as reasonably achievable; however, radiation protection activities play an important role in quality assurance for both the clinical and physical aspects. Radiation protection has several aspects: The first step is the design of the irradiation device and its shielding. While this step is out of the hands of the user, the location and level of leakage radiation must be verified by the user. Periodic leak testing of sealed sources is required. Room shielding design is based on the leakage levels specified by the manufacturer and on levels of scatter and primary radiation impinging on the radiation barriers. The addition of shielding for photoneutrons should be planned for accelerators producing photons above 10 MeV. Integrity and adequacy of shielding should be verified by survey after unit installation. Installation and periodic testing of interlocks are necessary to assure that nonirradiation conditions can be restored as soon as necessary. Personnel monitoring serves two purposes; to provide a record of personnel exposures and to alert one to unsuspected changes that may have taken place in procedure, shielding integrity, or source location. Area monitoring and survey on a periodic basis also provides knowledge of unsuspected changes in procedure, shielding integrity, or source location. Brachytherapy and the transport of small radiation sources require additional precautionary actions. Protection of patient anatomy not being treated reduces the chance of normal tissue damage and the possibility of carcinogenic effects.

Humans↗

Changes of immune functions after radiation, burns and combined radiation-burn injury in rats.

The changes of several immune functions were observed in rats after they were inflicted with 6 Gy gamma rays irradiation, 15% TBSA full thickness brun and the combination of the 2 injuries. It was found that the functions of thymocytes and splenoctyes suffered the most severe suppression in the 24th to 72nd hour after radiation injury and began to recover on the 7th day. In the rats with burn injury, the suppression on thymocytes and splenocytes were significantly less severe than that after radiation and recovered more rapidly. The effects of combined radiation-burn injury showed several characteristics. The suppression on the thymocytes was more severe with slower recovery as compared with that after single radiation injury only. The suppression on the splenocytes as a whole was similar to that after single radiation injury, but in the early stage after combined injury, the suppression was far more severe than that after radiation. Escharectomy and skin grafting on the burn wounds on the 1st day after combined injury could accelerate the recovery on both the thymocytes and splenocytes. Our findings indicated that the severity of the suppression on the immune functions due to combined radiation-burn injury might depend on the size of the burn wounds.

Animals↗

[A case of radiation neuropathy following radiation therapy for metastasis of breast cancer].

We report a 49-year-old woman with radiation neuropathy, which occurred 7 years after radiation therapy for supraclavicular lymph node metastasis of breast cancer. The patient had noticed a hard induration in the right breast twelve years previously and had a radical operation for right breast cancer. After surgery, she remained well until 7 years ago when she noted a right supraclavicular mass. Based on a diagnosis of metastasis of breast cancer at the right supraclavicular lymph node, she received radiation therapy at 50 Gy in 25 fractions to the lesion. Seven years after radiation therapy, the patient noted muscle weakness of II-V fingers of the right hand, followed by muscle atrophy of the right forearm. We diagnosed her condition as radiation neuropathy based on the absence of a mass lesion in the right supraclavicular region, no RI deposits in that region on Ga and bone scintigraphy, findings supportive of a lesion in the right brachial plexus on EMG and the history of radiation therapy for supraclavicular lymph node metastasis of breast cancer 7 years previously. We treated the patient with pulse therapy with high-dose oral prednisolone. Subsequently, the muscle weakness and atrophy of the right forearm and fingers have improved gradually. We suggest that pulse therapy with high-dose oral prednisolone for radiation neuropathy should be evaluated in a clinical trial, since few therapies are available for this condition.

Breast Neoplasms↗

Evaluation of cisplatin response in three radiation resistant and three radiation sensitive cell lines.

The cisplatin response was studied in three radiation sensitive mutant cell lines each paired with normally responding or radiation resistant cell lines of parental or similar origin. The radiation sensitive cell lines V3 (CHO), AT5BI (human fibroblast) and HT144 (melanoma) also showed reduced or lack of ability to repair sublethal radiation damage. Also, V3 did not repair radiation induced DNA double strand breaks and AT5BI was excision repair deficient. None of these cell lines show any cross sensitivity to cisplatin treatment. Instead the response was more like the paired normally radiation responding cell lines, except for AT5BI which showed cisplatin resistance. Thus the mechanisms causing radiation sensitivity in the three cell lines are not involved in cisplatin sensitivity.

Animals↗

Radiation exposure and radiation protection of the physician in iodine-131 Lipiodol therapy of liver tumours.

Intra-arterial iodine-131 labelled Lipiodol therapy for liver cancer has been investigated for safety and efficacy over a number of years, but data on radiation exposure of personnel have remained unavailable to date. The aim of this study was to assess the radiation exposure of the physician during intra-arterial 131I-Lipiodol therapy for liver malignancies and to develop appropriate radiation protection measures and equipment. During 20 intra-arterial administrations of 131I-Lipiodol (1110-1924 MBq), radiation dose equivalents (RDE) to the whole body, fingers and eyes of the physician were determined for (a) conventional manual administration through a shielded syringe, (b) administration with an automatic injector and (c) administration with a lead container developed in-house. Administration by syringe resulted in a finger RDE of 19.5 mSv, an eye RDE of 130-140 microSv, and a whole-body RDE of 108-119 microSv. The injector reduced the finger RDE to 5 mSv. With both technique (a) and technique (b), contamination of angiography materials was observed. The container allowed safe transport and administration of the radiopharmaceutical from 4 m distance and reduced the finger RDE to <3 microSv and the eye RDE to <1 microSv during injection. During femoral artery compression, radiation exposure to the fingers reached 170 microSv, but the whole-body dose could be reduced from a mean RDE of 114 microSv to 14 microSv. No more contamination occurred. In conclusion, radiation exposure was high when 131I-Lipiodol was administered by syringe or injector, but was significantly reduced with the lead container.

Humans↗