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Radiation biology: concepts for radiation protection.

The opportunity to write a historical review of the field of radiation biology allows for the viewing of the development and maturity of a field of study, thereby being able to provide the appropriate context for the earlier years of research and its findings. The pioneering work of Muller, Sax, and McClintock, and many others, has stood the test of time. The idea that x-rays could damage the genetic material and result in interactions that could lead to gene mutations and a range of chromosomal alterations is now interpretable in terms of induced DNA damage and errors of DNA repair. The expanded idea that such genetic alterations can be induced by DNA damage that is produced by one or two tracks of ionizing radiation remains the mainstay of radiation biology. The impact of the more recent molecular approaches to unraveling the mechanism behind this simple concept has confirmed this fundamental observation. The remarkable advances have allowed for a fairly complete understanding of the specific types of DNA damage induced by ionizing radiations and the pivotal role played by the errors of repair of double-strand breaks. Given our considerably enhanced knowledge of the details of the DNA repair processes involved, misrepair is a very unlikely event. The role of potential confounders of the concept of dose-response (e.g., bystander effects, genomic instability, and adaptive responses) is taking on a growing importance to the field. The evolving need is to begin to consider mechanistically-based dose-response models for cancer risk such that any potential impact of confounders on the response at low, environmental doses can be assessed. Thus, radiation biology research has always had a focus on how best to protect human health from radiation exposures and will continue to do so.

Cell Physiological Phenomena↗

Positron emission tomography demonstrates radiation-induced changes to nonirradiated lungs in lung cancer patients treated with radiation and chemotherapy.

STUDY OBJECTIVES: To determine whether acute changes in shielded lungs can be detected by positron emission tomography (PET) after radiation therapy. DESIGN: Retrospective cohort study. SETTING: University-affiliated medical center. PATIENTS: Sixteen patients undergoing radiation therapy for lung cancer who had PET scans after receiving treatment. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Thirteen of 16 patients (81.2%) showed increased (18)fluoro-2-deoxyglucose uptake in shielded nonirradiated lung in the following four distinct patterns: (1) contralateral peripheral pleural uptake in 5 of 16 patients (31.2%); (2) ipsilateral peripheral pleural uptake in 5 of 16 patients (31.2%); (3) bilateral peripheral pleural uptake in 1 of 16 patients (6.2%); and (4) bilateral diffuse background uptake in 1 of 16 patients (6.2%). This last patient developed clinically evident radiation pneumonitis. CONCLUSIONS: Increased lung metabolic activity can be demonstrated in the nonirradiated lung in patients who have undergone radiation therapy for lung cancer and can be detected by PET scanning. PET scanning of lungs in irradiated patients may provide an early demonstrable barometer of pulmonary toxicity. If verified, this imaging tool could prove to be useful in monitoring patients receiving radiation therapy for thoracic malignancies and may have predictive value for subsequent fibrosis. PET scanning may also be an important tool in future studies to further elucidate the pathogenetic mechanism of radiation-induced lung injury.

Antineoplastic Combined Chemotherapy Protocols↗

Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro.

A long-standing dogma in the radiation sciences is that energy from radiation must be deposited in the cell nucleus to elicit a biological effect. A number of non-targeted, delayed effects of ionizing radiation have been described that challenge this dogma and pose new challenges to evaluating potential hazards associated with radiation exposure. These effects include induced genomic instability and non-targeted bystander effects. The in vitro evidence for non-targeted effects in radiation biology will be reviewed, but the question as to how one extrapolates from these in vitro observations to the risk of radiation-induced adverse health effects such as cancer remains open.

Alpha Particles↗

The effect of dose rate on radiation-induced neoplastic transformation in vitro by low doses of low-LET radiation.

The dependence of the incidence of radiation-induced cancer on the dose rate of the radiation exposure is a question of considerable importance to the estimation of risk of cancer induction by low-dose-rate radiation. Currently a dose and dose-rate effectiveness factor (DDREF) is used to convert high-dose-rate risk estimates to low dose rates. In this study, the end point of neoplastic transformation in vitro has been used to explore this question. It has been shown previously that for low doses of low-LET radiation delivered at high dose rates, there is a suppression of neoplastic transformation frequency at doses less than around 100 mGy. In the present study, dose-response curves up to a total dose of 1000 mGy have been generated for photons from (125)I decay (approximately 30 keV) delivered at doses rates of 0.19, 0.47, 0.91 and 1.9 mGy/min. The results indicate that at dose rates of 1.9 and 0.91 mGy/min the slope of the induction curve is about 1.5 times less than that measured at high dose rate in previous studies with a similar quality of radiation (28 kVp mammographic energy X rays). In the dose region of 0 to 100 mGy, the data were equally well fitted by a threshold or linear no-threshold model. At dose rates of 0.19 and 0.47 mGy/min there was no induction of transformation even at doses up to 1000 mGy, and there was evidence for a possible suppressive effect. These results show that for this in vitro end point the DDREF is very dependent on dose rate and at very low doses and dose rates approaches infinity. The relative risks for the in vitro data compare well with those from epidemiological studies of breast cancer induction by low- and high-dose-rate radiation.

Cell Transformation, Neoplastic↗

Commentary 2 to Cox and Little: radiation-induced oncogenic transformation: the interplay between dose, dose protraction, and radiation quality.

There is now a substantial body of evidence for end points such as oncogenic transformation in vitro, and carcinogenesis and life shortening in vivo, suggesting that dose protraction leads to an increase in effectiveness relative to a single, acute exposure--at least for radiations of medium linear energy transfer (LET) such as neutrons. Table I contains a summary of the pertinent data from studies in which the effect is seen. [table: see text] This phenomenon has come to be known as the "inverse dose rate effect," because it is in marked contrast to the situation at low LET, where protraction in delivery of a dose of radiation, either by fractionation or low dose rate, results in a decreased biological effect; additionally, at medium and high LET, for radiobiological end points such as clonogenic survival, the biological effectiveness is independent of protraction. The quantity and quality of the published reports on the "inverse dose rate effect" leaves little doubt that the effect is real, but the available evidence indicates that the magnitude of the effect is due to a complex interplay between dose, dose rate, and radiation quality. Here, we first summarize the available data on the inverse dose rate effect and suggest that it follows a consistent pattern in regard to dose, dose rate, and radiation quality; second, we describe a model that predicts these features; and, finally, we describe the significance of the effect for radiation protection.

Animals↗

Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation Therapy Oncology Group Study 83-02.

BACKGROUND: Efforts to improve local control and survival by increasing the dose of once-daily radiation therapy beyond 70 Gray (Gy) for patients with malignant gliomas has yet been unsuccessful. Hyperfractionated radiation therapy (HF) should allow for delivery of a higher total dose without increasing normal tissue late effects, whereas accelerated hyperfractionated radiation therapy (AHF) may minimize tumor repopulation by shortening overall treatment time. The Radiation Therapy Oncology Group (RTOG) conducted a randomized Phase I/II study of escalating doses of HF and AHF either carmustine (bis-chlorethyl nitrosourea [BCNU]) fro adults with supratentorial glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). Primary study endpoints were overall survival and acute and chronic treatment-related toxicity. METHODS: From 1983 to 1989, 786 patients with supratentorial gliomas (81% with GBM and 19% with AA) were stratified by histology, age, and performance status and randomized to receive partial brain irradiation, utilizing either HF (1.2 Gy twice daily to doses of 64.8, 72, 76.8, or 81.6 Gy) of AHF (1.6 Gy twice daily to doses of 48 or 54.4 Gy). All patients received carmustine. The distinction of pronistic factors was similar on all arms. RESULTS: There were 747 eligible and analyzable patients among 786 enrolled patients (95%). Two patients had a Grade 5 and 65 patients had a Grade 4 chemotherapy toxicity. Two patients in the 81.6 Gy arm experienced late Grade 4 radiation toxicity and there was 1 late radiation-associated death in the 54.4 Gy arm. The rate of Grade 3 of worse radiation toxicity at 5 years, calculated by the delivered does level, was 3% in the lowest total dose arms (48 and 54.4 Gy), 4% in the intermediate dose arms (64.8 and 72 Gy), and 5% in the highest dose arms (76.8 and 81.6 Gy) (p = 0.54). Survival rates at 2 and 5 years were: 21% and 11%, and 4%, respectively, for GBM patients. There were no significant differences between the treatment arms with regard to median survival time (MST), when analyzed by the originally assigned dose. The MST for all patients varied between 10.8 months and 12.7 months (P = 0.59); between 9.6 months and 11 months for patients with GBM (P = 0.43); and between 30.4 months and 85.8 months for patients with AA (P = 0.78). Analysis of the survival rates for all patients by dose received rather than by dose assigned revealed a 14% 5-year survival rate for the lower HF doses (64.8 and 73 Gy), 11% for the higher doses (76.8 and 81.6 Gy), and 10% for the AHF doses (48 and 54.4 Gy) (P = 0.1). The subgroup a AA patients had a better MST (49.9 months) in the lower received HF doses than in the higher HF doses (34.6 months) (P = 0.35). In contrast, GM patients who received the higher HF doses had survival superior to the patients in the AHF arms (MST of 11.6 months and 10.2 months, respectively, P = 0.04). CONCLUSIONS: The use of HF with BCNU and dose escalation up to 81.6 Gy is both feasible and tolerable, although late toxicity increases slightly with increasing dose. The best MST with the least toxicity were observed for AA in the lower received HF doses (72 and 64.8 Gy). Accordingly, 72 Gy in two 1.2 Gy fractions was used as the investigational arm of a completed Phase III trial (RTOG 90-06). In contrast, for GBM patients, longer survival times were noted in the higher received HF doses (78.6 and 81.6 Gy), suggesting the role for further dose escalation. The low toxicity rate with AHF arms suggest that further dose escalation is possible and is currently occurring in RTOG 94-11.

Adolescent↗

Hydroxyurea plus pelvic radiation versus placebo plus pelvic radiation in surgically staged stage IIIB cervical cancer.

Forty-five evaluable patients with stage IIIB carcinoma of the uterine cervix were entered into a prospective, double-blind, randomized study to evaluate the possible radiation-potentiating properties of hydroxyurea. All patients were documented to be without para-aortic lymph node metastasis by pretherapy staging para-aortic lymphadenectomy. The original plan of therapy was for continuous therapy (200 rads/day) of 6,000 rads of pelvic radiation for 6 weeks plus intrauterine radium. However, 16 patients received 6,000 rads in 8 weeks by split-course therapy (2-week rest after 3,000 rads) plus radium. Twenty-nine patients received the planned continuous therapy. The median dose of pelvic radiation for patients who received continuous therapy or split-course radiation was 6,000 rads. Leukopenia (WBC less than 2,500/mm3) was significantly increased in the patients given hydroxyurea as compared to those given placebo (P less than .001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation skin reaction, diarrhea, or radiation-induced complications requiring surgical correction. The estimated 5-year progression-free survival rate for the combined, continuous, and split-course radiation therapy hydroxyurea patients was 60%, and its was 52% for the corresponding placebo patients (P = .49). However, the estimated 5-year progression free survival rate for the correctly treated patients (continuous therapy) was 91% for the hydroxyurea group and 60% for the placebo group (P less than .06).

Adult↗

Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma--possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: report of the Radiation Therapy Oncology Group Protocol 8302.

Between January 1983 and November 1987, the Radiation Therapy Oncology Group conducted a prospective, randomized, multi-institutional, dose searching Phase I/II trial to evaluate hyperfractionated radiation therapy in the treatment of supratentorial malignant glioma. Patients with anaplastic astrocytoma, or glioblastoma multiforme, age 18-70 years with a Karnofsky performance status of 40-100 were stratified according to age, Karnofsky performance status, and histology, and were randomized. Initially randomization was to one of three arms: 64.8 Gy, 72.0 Gy, and 76.8 Gy. Fractions of 1.2 Gy were given twice daily, 5 days per week, with intervals of 4 to 8 hr. All patients received bis-chlorethyl nitrosourea (BCNU) 80 mg/m2 on days 3, 4, 5 of radiation therapy and then every 8 weeks for 1 year. After acceptable rates of acute and late effects were found, the randomization was changed to 81.6 Gy and 72.0 Gy with a weighting of 2:1. Out of 466 patients randomized, 435 were analyzed. The distribution of prognostic factors was comparable among the 76.8 Gy arm, 81.6 Gy arm, and the final randomization of the 72 Gy arm. The 64.8 Gy arm and the initial randomization of the 72 Gy arm had somewhat worse prognostic variables. Late radiation toxicity occurred in 1.3-6.8% of the patients, with a modest increase with increasing radiation dose. The best survival occurred in those patients treated with 72 Gy (median survival of 12.8 months overall, and 14 months for the final 72 Gy randomization). The Cox proportional hazards model confirmed the prognostic variables of age, histology and Karnofsky performance status. In addition, the longer interval of 4.5-8 hr was associated with a worse prognosis than the 4-4.4 hr interval (p = 0.0011). The difference in survival between the 81.6 Gy arm and the lower three arms approached significance (p = 0.078) with inferior survival observed in the 81.6 Gy arm. When therapy was evaluated by radiation therapy dose received (60-74.4 Gy compared with 74.5-84.0 Gy), the p value was 0.062 in favor of the lower dose range. Patients with anaplastic astrocytoma treated with 72 Gy by hyperfractionation + BCNU had at least as good a survival as those treated with 60 Gy by conventional fractionation + BCNU on Radiation Therapy Oncology Group protocols 7401 and 7918. This suggests that 72 Gy delivered by 1.2 Gy twice daily is no more toxic than 60 Gy delivered by conventional fractionation.

Adult↗

Postoperative radiation therapy for surgically staged endometrial cancer: impact of time factors (overall treatment time and surgery-to-radiation interval) on outcome.

PURPOSE: To evaluate the impact of prolonged overall radiation treatment (RT) time and surgery-to-radiation interval on local control (LC) and disease-specific survival (DSS) of surgically staged endometrial cancer patients in relation to known prognostic factors. METHODS AND MATERIALS: Between 1971 and 1993, 195 endometrial cancer patients received postoperative RT at the Fox Chase Cancer Center. All patients underwent total abdominal hysterectomy (TAH), with 38% also having lymph node sampling. All patients received whole pelvic external beam RT to a median dose of 45 Gy (range 40 to 60 Gy). Sixty-nine percent received a vaginal cuff boost with either low dose rate or high dose rate brachytherapy. Tumor and treatment factors were analyzed for impact on LC and DSS. Median follow-up was 47 months (range: 6 to 187 months). RESULTS: The overall actuarial 5-year LC rate was 85%. In multivariate analysis, tumor grade, pathologic stage, external radiation dose, and surgical lymph node evaluation were independent prognostic variables for improved LC. Surgery-to-radiation interval of greater than 6 weeks was a marginally significant factor for decreased LC (p = 0.06). Overall RT time and external beam treatment time did not appear to impact LC rates. The overall actuarial 5-year DSS rate was 86%. In multivariate analysis, depth of myometrial invasion, tumor grade, and pathologic stage were independent prognostic variables for DSS. In addition, a surgery-to-radiation interval of greater than 6 weeks was significantly associated with decreased DSS (p < 0.005). CONCLUSIONS: Surgery-to-radiation interval of greater than 6 weeks is a significant independent prognostic variable for decreased DSS and a marginally significant variable for decreased LC in patients irradiated postoperatively for endometrial cancer. Other time factors (overall RT time and external beam treatment time) did not appear to impact outcome. Based on this analysis, postoperative radiation therapy for endometrial cancer should be initiated within 6 weeks following surgery.

Actuarial Analysis↗

Recurrences of rectal cancers: results of a multimodal approach with intraoperative radiation therapy. French Group of IORT. Intraoperative Radiation Therapy.

PURPOSE: Prognosis of recurrent rectal cancer remains poor, mainly because of the difficulties of achieving a satisfactory local control. Intraoperative radiation therapy (IORT) allows for the delivery of a complementary single dose to the tumor residues or to the tumor bed and could be useful jn a multimodal treatment. In an attempt to evaluate this interest, a retrospective analysis of patients treated with IORT in six French hospitals has been performed. METHODS AND MATERIALS: Data have been collected in 73 patients (41 men), with a mean age of 62 years, treated with IORT. Initial rectal tumors were large (mean diameter: 45 mm), partially or totally fixed to the contiguous structures in 39%, and with nodal involvement in 50% of the cases. Initial surgery had been a sphincter-sparing surgery in 67%; external radiation therapy had been delivered in 52%, and a chemotherapy had been given in 10% of the patients. Recurrences were isolated (without metastases) in 86%, and were posterior or posterolateral in 55% of the cases. Surgery allowed for a complete macroscopical resection in 57%, a partial resection with gross residual disease in 29%, and no resection in 14% of the recurrences. Intraoperative radiation therapy was delivered in a dose of 10 to 25 Gy (mean 18.5) through localizators of a mean diameter of 75 mm (60 to 110). External radiation therapy, either preoperative or postoperatively was given to 30 patients without prior radiation therapy. Ten patients received additional chemotherapy with 5-fluorouracil. RESULTS: Four postoperative deaths occurred. Postoperative morbidity occurred in 16 patients and some complications were probably related to the IORT procedure. Four long-term complications were observed. Overall actuarial survival occurred in 72.4% of the patients at 1 year, in 44.6% at 2 years, and in 30.6% at 3 years. Twenty-one local failures have been observed. Actuarial local control occurred in 71.3% of the patients at 1 year, 47.7% at 2 years, and 31.3% at 3 years. CONCLUSION: Intraoperative radiation therapy is a complementary treatment for recurrences of rectal cancer. It provides encouraging results, particularly in some selected situations, when patients have not previously been treated with external radiation therapy. Further studies of multimodal treatments are necessary.

Adult↗

Phase III randomized pilot study comparing interferon alpha-2b in combination with radiation therapy versus radiation therapy alone in patients with stage III-B carcinoma of the cervix.

This randomized pilot study was designed to determine whether the addition of interferon alpha-2b to standard radiation therapy offered an advantage in loco-regional control and survival over radiation therapy alone in a homogeneous group of patients with stage IIIB carcinoma of the cervix. Thirty-six patients were treated with a combination of interferon alpha-2b plus radiation therapy, and 38 patients were treated with radiation therapy alone. Patients with evidence of ureteral obstruction were excluded from the study. Evaluation of loco-regional response was determined by pelvic examination, cervical cytology, biopsies and CT scans when indicated. Survival time was measured from initiation of treatment to date of death or last follow-up. Patient characteristics were comparable between both study arms. The objective complete response rate was 67% in the combined therapy group and 55% in the radiation alone group (P = 0.454). With a median follow-up of 17 months for all patients and 31 months for live patients, 50% of the combined group survived vs. 39.5% of the radiation alone group (P = 0.424). We conclude that the addition of interferon alpha-2b to standard radiation therapy did not significantly improve loco-regional response or survival, although such a trend was noted. We encourage the design of a larger randomized study with sufficient power to detect meaningful differences to prove whether the tendency observed in the present investigation holds any promise to improve the outcome of these patients.

Adult↗

Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer.

BACKGROUND: We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation. METHODS: Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy. RESULTS: After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease. CONCLUSIONS: These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.

Adult↗

Radiation dose to otologic structures during head and neck cancer radiation therapy.

BACKGROUND: Otologic structures are often contained within head and neck cancer radiation treatment ports. The dosimetry to otologic structures has not been routinely analyzed and radiation treatment planning does not currently attempt to specifically avoid the inner ear structures when dosimetry is calculated. Recent studies demonstrate that up to 30% of patients experience sensorineural hearing loss on multimodality therapy with cisplatin and radiation. METHODS: In the current case series, radiation dosimetry to otologic structures was calculated from computed tomogram treatment plans on patients. Fifteen nasopharyngeal, oral cavity, oropharyngeal, and hypopharyngeal cancer patients were analyzed. RESULTS: Between 8% and 102% of the total dose is delivered to the petrous bone/cochlea, with 4 of 15 patients getting more than 50% of the dose to at least one cochlea The mastoid air cells received between 3% and 75% of the total dose, with higher doses being delivered to patients with bulky high neck metastases or nasopharyngeal tumors. The eustachian tubes received between 20% and 102% of the total dose, with 10 of 15 patients receiving more than 50% of the dose to this anatomic site. CONCLUSION: We conclude that the cochlea and eustachian tubes receive significant radiation during treatment, particularly in nasopharyngeal cancer patients. Careful design of radiation treatment ports may allow for the reduction of radiation to hearing structures.

Carcinoma, Squamous Cell↗

Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials.

PURPOSE: We evaluated the effect of external-beam radiation therapy on disease-specific survival (death from causes related to prostate cancer) and overall survival in men with clinically localized prostate cancer. METHODS: From 1975 to 1992, 1,465 men with clinically localized prostate cancer received radiation therapy on four Radiation Therapy Oncology Group phase III randomized trials and were pooled for this analysis. No one received androgen-deprivation therapy with his initial treatment. All original histology had central pathologic review for grading using the Gleason classification system. Total delivered radiation dose ranged from 60 to 78 Gy (median, 68.4 Gy). The median follow-up time was 8 years. RESULTS: A Cox regression model revealed that Gleason score was an independent predictor of disease-specific survival and overall survival. The 10-year disease-specific survival rates by Gleason score were as follows: score of 2 through 5, 85%; score of 6, 79%; score of 7, 62%; and score of 8 through 10, 43%. Stratifying outcome by this important prognostic factor revealed that higher radiation dose was a significant predictor for improved disease-specific survival and overall survival only for those patients whose cancers had Gleason scores of 8 through 10 (P <.05). After adjusting for clinical T stage, nodal status, and age, treating with a higher radiation dose was associated with a 29% lower relative risk of death from prostate cancer and 27% reduced mortality rate (P <.05). CONCLUSION: These data demonstrate that higher-dose radiation therapy can significantly reduce the risk of dying from prostate cancer in men with clinically localized disease. This survival benefit is restricted to men with poorly differentiated cancers.

Aged↗

Stage IA non-Hodgkin's lymphoma of the Waldeyer's ring. Limited chemotherapy and radiation therapy versus radiation therapy alone.

Seventeen patients with stage IA non-Hodgkin's lymphoma of the Waldeyer's were treated with radiation therapy with or without chemotherapy. All lesions were judged as having intermediate grade malignancy in the Working Formulation. Eight patients received combined treatment with three cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and radiation therapy with 30 to 40 Gy. Another 9 patients were treated with radiation therapy 40 to 60 Gy alone. After a median follow-up of 69 months, all 8 patients, treated with combined modality were alive and relapse-free, whereas 4 of the 9 treated with irradiation alone had relapsed. All relapses occurred trans-diaphragmatically. Two of the 4 relapsing patients were saved, but the other two died of the disease. The 5-year relapse-free and cause-specific survival rates were 100% and 100% in the combined modality group, and 56% and 76% in the radiation therapy alone group (relapse-free: p = 0.04, cause-specific: p = 0.16). There were no serious complications related to the treatment, although most patients complained of mouth dryness and most patients given CHOP had paresthesia. Our opinion was that the total impact of these two side-effects on quality of life was less pronounced after combined modality than after radiation therapy alone. Limited chemotherapy and radiation therapy seemed to be more beneficial than radiation therapy alone not only in relapse-free survival but also in quality of life after treatment.

Adult↗

[A comparison of the effects of 180kv X-ray radiation and cobalt-60 radiation on the jaws of the guinea pigs]

OBJECTIVE: Study of the effects of 180kv x-ray and cobalt-60 radiation on jaws and enhance the understanding of pathology of osteroradionecrosis of jaws(ORNJ).METHODS: 128 guinea pigs were grouped according to different irradiation sources and doses.Fractioned radiation from both sources was delivered in right mandible.The teeth extractions were conducted one week prior to radiation and 1,3,5 months after radiation respectively.Following radiation,the guinea pigs were examined by gross observation, x-ray film and histopathological examination at regular interval. RESULTS: Bone resorption occured within 1 month after irradiation as result of osteoblast inhibition and osteoclast activation.From 2 to 4 month afterwards,the number of osteocytes reduced and pyknosis, empty lacunae as well as obliteration of small vessels in periodontal membrane were commonly seen.The teeth extractions conducted at 3 months,5 months after radiation lead to ORNJ in 7 amimals (14.6%).CONCLUSION: 180kv x-ray radiation was far more damaging to jaws than cobalt-60 radiation.The dental extraction is an important factor inducint the development of ORNJ.

Journal Article↗

Interaction between radiation and drug damage in mammalian cells. IV. Radiation response of adriamycin-resistant V79 cells.

Adriamycin-resistant variants derived from V79 Chinese hamster cells were examined for their radiation response properties. A stable resistant cell line (77A) demonstrated a significant reduction in the extrapolation number of the single-dose radiation survival curve. Second-step mutants from 77A cells exhibited a spectrum of radiation response states including decreased D0 values and large extrapolation numbers. A highly Adriamycin-resistant line (LZ) was found to be radiation sensitive with increased capacity for the accumulation of sublethal radiation injury. LZ cells are known to contain double-minute chromosomes and an amplified gene for the multidrug phenotype and to exhibit multidrug resistant properties. These cells require the presence of Adriamycin in their growth medium to maintain their pleiotropic characteristics. LZ cells became more resistant to radiation following reversion to an intermediate Adriamycin response as the consequence of growth in Adriamycin-free medium. Reverted cells also lost their large capacity for sublethal damage. It is suggested that detailed study of these mutants may provide insight into the identification of radiation-sensitive sites and their relationship to the genetic changes characterizing Adriamycin-resistant cell lines.

Animals↗

Molecular Biology to Radiation Oncology: A Model for Translational Research? Opportunities in basic and translational research. From a workshop sponsored by the National Cancer Institute, Radiation Research Program, January 26-28, 1997, Bethesda, Maryland.

Many exciting discoveries are being made that are providing new insights into how molecules, cells and tissues respond to ionizing radiation. There remains a need, however, to translate these findings into more effective treatments for cancer patients, including those treated with radiation therapy. This complex task will require the collaboration of scientists studying molecular, cellular and tissue responses, and those performing clinical trials of emerging therapies. The Radiation Research Program of the National Cancer Institute sponsored a workshop entitled "Molecular Biology to Radiation Oncology: A Model for Translational Research?" to bring together basic scientists and clinicians to exchange ideas and fundamental concepts and to identify opportunities for future research and collaboration. Four broad topics were addressed: signal transduction and apoptosis, the cell cycle, repair of radiation damage, and the microenvironment. The development, selection and use of appropriate experimental models is crucial to finding and developing new therapies, and opportunities exist in this area as well. This paper and the accompanying paper by Coleman and Harris that provides the viewpoint of radiation oncologists (Radiat. Res. 150, 134-147, 1998) summarize the background concepts and opportunities for translational research identified by the workshop participants.

Apoptosis↗