Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment

Bone sarcoma as a second malignancy is rare but highly fatal. The present knowledge about radiation-absorbed organ dose–response is insufficient to predict the risks induced by radiation therapy techniques. The objective of the present study was to assess the treatment-induced risk for bone sarcoma following a childhood cancer and particularly the related risk of radiotherapy. Therefore, a retrospective cohort of 4,171 survivors of a solid childhood cancer treated between 1942 and 1986 in France and Britain has been followed prospectively. We collected detailed information on treatments received during childhood cancer. Additionally, an innovative methodology has been developed to evaluate the dose–response relationship between bone sarcoma and radiation dose throughout this cohort. The median follow-up was 26 years, and 39 patients had developed bone sarcoma. It was found that the overall incidence was 45-fold higher [standardized incidence ratio 44.8, 95 % confidence interval (CI) 31.0–59.8] than expected from the general population, and the absolute excess risk was 35.1 per 100,000 person-years (95 % CI 24.0–47.1). The risk of bone sarcoma increased slowly up to a cumulative radiation organ absorbed dose of 15 Gy [hazard ratio (HR) = 8.2, 95 % CI 1.6–42.9] and then strongly increased for higher radiation doses (HR for 30 Gy or more 117.9, 95 % CI 36.5–380.6), compared with patients not treated with radiotherapy. A linear model with an excess relative risk per Gy of 1.77 (95 % CI 0.6213–5.935) provided a close fit to the data. These findings have important therapeutic implications: Lowering the radiation dose to the bones should reduce the incidence of secondary bone sarcomas. Other therapeutic solutions should be preferred to radiotherapy in bone sarcoma-sensitive areas.     

Protection against solar ultraviolet radiation in childhood

In the last decade, awareness of the harmful effects of solar ultraviolet radiation has increased. Modern lifestyles, outdoor occupations, sports and other activities make total sun avoidance impossible. Children spend more time outdoors than adults and there is compelling evidence that childhood is a particularly vulnerable time for the photocarcinogenic effects of the sun. Sun exposure among infants and pre-school age children is largely depend on the discretion of adult care providers. It is important to learn safe habits about sun-safety behaviours during the childhood. Children deserve to live and play in safe environments, and it is the responsibility of every adult to help children stay safe. Protecting children from excessive sun exposure is protection from sunburn today and other forms of sun damages, especially skin cancers, in the future.     

Thyroid neoplasia following low-dose radiation in childhood

The thyroid gland is highly sensitive to the carcinogenic effects of ionizing radiation. Previously, we reported a significant increase of thyroid cancer and adenomas among 10,834 persons in Israel who received radiotherapy to the scalp for ringworm. These findings have now been extended with further follow-up and revised dosimetry. Overall, 98 thyroid tumors were identified among the exposed and 57 among 10,834 nonexposed matched population and 5392 sibling comparison subjects. An estimated thyroid dose of 9 cGy was linked to a fourfold (95% Cl = 2.3-7.9) increase of malignant tumors and a twofold (95% Cl = 1.3-3.0) increase of benign tumors. The dose-response relationship was consistent with linearity. Age was an important modifier of risk with those exposed under 5 years being significantly more prone to develop thyroid tumors than older children. The pattern of radiation risk over time could be described on the basis of a constant multiplication of the background rate, and an absolute risk model was not compatible with the observed data. Overall, the excess relative risk per cGy for thyroid cancer development after childhood exposure is estimated as 0.3, and the absolute excess risk as 13 per 10(6) PY-cGy. For benign tumors the estimated excess relative risk was 0.1 per cGy and the absolute risk was 15 per 10(6) PY-cGy.     

Microbeam radiation therapy: Clinical perspectives

Microbeam radiation therapy (MRT), a novel form of spatially fractionated radiotherapy (RT), uses arrays of synchrotron-generated X-ray microbeams (MB). MRT has been identified as a promising treatment concept that might be applied to patients with malignant central nervous system (CNS) tumours for whom, at the current stage of development, no satisfactory therapy is available yet. Preclinical experimental studies have shown that the CNS of healthy rodents and piglets can tolerate much higher radiation doses delivered by spatially separated MBs than those delivered by a single, uninterrupted, macroscopically wide beam. High-dose, high-precision radiotherapies such as MRT with reduced probabilities of normal tissue complications offer prospects of improved therapeutic ratios, as extensively demonstrated by results of experiments published by many international groups in the last two decades. The significance of developing MRT as a new RT approach cannot be understated. Up to 50% of cancer patients receive conventional RT, and any new treatment that provides better tumour control whilst preserving healthy tissue is likely to significantly improve patient outcomes.     

Fallout,radiation doses near Dounreay,and childhood leukaemia.

Possible explanations for the recently reported increased incidence of childhood leukaemia around Dounreay were examined in the light of changes in the national incidence of leukaemia that occurred during the period of exposure to fallout from international testing of nuclear weapons in the atmosphere. It was concluded that the increase could not be accounted for by an underestimate of the risk of leukaemia per unit dose of radiation at low doses and low dose rates, nor by an underestimate of the relative biological efficiency of high as compared with low linear energy transfer radiation. One possible explanation was underestimation of doses to the red bone marrow due to the discharges at Dounreay relative to the dose from fallout, though investigation of ways in which this might have occurred did not suggest anything definite. Other possible explanations included a misconception of the site of origin of childhood leukaemia, outbreaks of an infectious disease, and exposure to some other, unidentified environmental agent. These findings weigh heavily against the hypothesis that the recent increase in childhood leukaemia near Dounreay might be accounted for by radioactive discharges from nuclear plants, unless the doses to the stem cells from which childhood leukaemia originates have been grossly underestimated.     

Background gamma radiation and childhood cancer in Germany: an ecological study

The relationship of low-dose background gamma radiation and childhood leukaemia was investigated in a number of studies. Results from these studies are inconclusive. Therefore, in the present study 25 years of German childhood cancer data were analyzed using interpolated background annual gamma dose rate per community in an ecological study. The main question was leukaemia; as exploratory questions we investigate central nervous system (CNS) tumours, thyroid carcinomas and diagnoses less likely to be related to radiation. A Poisson regression model was applied and a fractional polynomial model building procedure. As the main sensitivity analysis a community deprivation index was included as a potential confounder. It was found that outdoor background gamma annual dose rates in Germany range roughly from 0.5–1.5 mSv/a with an average of 0.817 mSv/a. No association of annual ambient gamma dose rates with leukaemia incidence was found. Amongst the exploratory analyses, a strong association was found with CNS tumour incidence [rate ratio for 1.5 vs 0.5 mSv/a: 1.35; 95% confidence interval (1.17, 1.57)]. The community level deprivation index was not a confounder. It is concluded that the present study did not confirm an association of annual outdoor ambient gamma dose rate and childhood leukaemia, corresponding to some studies and contrasting others. An association with CNS incidence was found in the exploratory analyses. As this is an ecological study no causal interpretation is possible.     

Intensity-modulated radiation therapy

Intensity-modulated radiation therapy (IMRT) is an increasingly popular technical means of tightly focusing the radiation dose around a cancer. As with stereotactic radiotherapy, IMRT uses multiple fields and angles to converge on the target. The potential for total dose escalation and for escalation of daily fraction size to the gross cancer is exciting. The excitement, however, has greatly overshadowed a range of radiobiological and clinical concerns.     

FLASH radiotherapy: an emerging approach in radiation therapy

FLASH radiotherapy (RT) is a technique involving the delivery of ultra-high dose rate radiation to the target. FLASH-RT has been shown to reduce radiation-induced toxicity in healthy tissues without compromising the anti-cancer effects of treatment compared to conventional radiation therapy. In the present article, we review the published data on FLASH-RT and discuss the current state of knowledge of this novel approach. We also highlight the technological constraints and complexity of FLASH-RT and describe the physics underlying this modality, particularly how technology supports energy transfer by ionising radiation (e.g., beam on/off sequence, pulse-energy load, intervals). We emphasise that current preclinical experience is mostly based on FLASH electrons and that clinical application of FLASH-RT is very limited. The incorporation of FLASH-RT into routine clinical radiotherapy will require the development of devices capable of producing FLASH photon beams.     

Tracheal cancer: Role of radiation therapy

Purpose

To assess the results of tracheal cancer patients treatment and factors influencing prognosis.

Background

Primary malignant neoplasms of the trachea are rare. The treatment of choice for tracheal carcinomas is resection. Radiation therapy is recommended as a part of radical treatment or for palliation of symptoms.

Materials and methods

Between 1962 and 2006, 50 patients diagnosed with tracheal cancer were treated at the Centre of Oncology in Krakow. The analysis focused on locoregional recurrence-free survival (LRRFS), disease free survival (DFS) and overall survival (OS). Survival rates, univariate and multivariate analyses of prognostic factors were performed using the Kaplan–Meier method, the log rank test and Cox''s proportional hazard method, respectively.For over 40 years, patients were treated using different modalities: surgery followed by radiotherapy (6%), radiotherapy (78%), chemoradiotherapy (8%), and symptomatic treatment (8%).

Results

The 5-year LRRFS was 18%, DFS was 15% and OS was 17%. gender (favoured females) was the only prognostic factor for LRRFS. For OS, the independent prognostic factors were performance status (favoured Karnofsky higher than 80), stage and year of start of the treatment (later than 1988 vs. earlier – 5-year OS 20% vs. 12%).5-year OS in the following (strongly differentiated over the time) treatment modalities were: surgery followed by radiotherapy (66%), radiotherapy (16%), chemoradiotherapy (0%), and symptomatic treatment (0%).Of 44 patients treated with radiotherapy symptomatic partial response was observed in 32 patients and follow-up imaging studies revealed complete response in 5 patients, partial response in 25, stable disease in 4 or progressive disease in 4.

Conclusions

Radical treatment in patients in early stage and good performance status seems to be correlated with the improvement of survival. However, despite the fact that results of treatment are poor, radiotherapy offers symptomatic improvement.     

Medulloblastoma: developmental mechanisms out of control

Medulloblastoma, which is a highly aggressive central nervous system neoplasm, represents an intriguing example of how deregulated developmental mechanisms can lead to tumour development. Recent advances in the understanding of the role of Sonic Hedgehog, Wnt and Notch signalling pathways in the development of the cerebellum have shed new light on medulloblastoma pathogenesis.     

Reduction mammaplasty following radiation therapy for breast cancer.

This report describes an unusual case in which reduction mammaplasty was performed following radiation therapy for breast cancer. While healing was significantly prolonged (compared with the nonirradiated contralateral breast), the final result was satisfactory from both the functional and the aesthetic standpoint. Women with prior radiation therapy may be considered candidates for reduction mammaplasty. Patients should be warned of the increased risks of wound complications, the likelihood of delayed healing, and the possibility of pigmentation changes in the grafted nipple-areola complex. We elected to transpose the nipple as a full-thickness graft, but consideration also might be given to use of an inferiorly based pedicle flap.     

Preoperative radiation therapy for rectal cancer. personal experience

PURPOSE: Comparison of the effectiveness of preoperative and "sandwich" (preoperative and postoperative) radiation therapy in the treatment of midrectum and lower rectum carcinoma, based on a prospective clinical trial. MATERIAL AND METHOD: Over the period between 1990 and 1997, we treated 115 patients suffering from mid-rectum and lower rectum carcinoma at the Budapest Oncoradiological Centre, using sandwich therapy (22.5 Gy preoperative-27.5 Gy postoperative) in the case of 36 patients and 36 Gy preoperative radiation therapy in the case of 79 patients with external-beam megavoltage therapy with mostly telecobalt radiation and to a smaller number of cases 6 MV energy. The external-beam radiation therapy was nearly always applied with a 4-field box technique, and radical surgery was performed within 10 days following the preoperative radiation treatment. Effectiveness was evaluated in terms of a Log-Rank and Peto-Wilcoxon tests and the Kaplan-Meier survival curve. RESULTS: The effectiveness of the different therapies was compared in terms of the percentage of local failure and the rate of disease-free survival. The results show that when using the "sandwich" radiation therapy local failure is expected to occur in 13.8% of all cases, compared with 17.7%, when only preoperative radiation therapy is used. In terms of five-year disease-free survival, the sandwich therapy seems to be better, but for a higher number of years, namely 7.5, the preoperative radiation therapy yielded better results. CONCLUSION: In terms of local failure, the effectiveness of the preoperative and the "sandwich" radiation therapies for the treatment of mid-rectum and lower rectum carcinoma was nearly identical, while preoperative radiation therapy provided longer disease-free survival. Further trials using multivariation analysis need to be performed to evaluate the two types of radiation treatments, taking into account other parameters, such as grading, age and lymphatic spread.     

Intraoperative radiation therapy in uterine cervical cancer: A review

Locally advanced uterine cervical cancer continues to present a high number of pelvic relapses. Intraoperative radiation therapy (IORT) allows a precise therapeutic intensification in the surgical area in cases in which removal of the tumour recurrence is feasible. At the same time, IORT excludes the radiosensitive organs from the field of irradiation. While the first gynecological IORT took place in 1905, procedures have been limited over the years and the series are retrospective, including few patients. At the same, time recurrences are located at different pelvic areas. Both heterogeneity and the long recruiting time make it difficult to correctly interpret the published results. Despite this, we have reviewed the most relevant publications. Some institutions indicated IORT as a boost on the surgical bed of the excised tumor recurrence. In others, IORT permits an extra radiation dose after radical surgery of the primary tumor, usually in stage IIB. Most studies conclude that the addition of IORT increases the local control but probably with little impact on survival. On the other hand, there is a controversy in the indication of IORT in surgically resectable primary tumours. No clear advantage over the usual scheme of chemoradiation and brachytherapy has been detected. Randomized studies that allow a breakthrough in the conclusions are highly unlikely to be performed in this area.     

Radiotherapy of childhood haemangiomas: From active treatment to radiation risk estimates

Childhood skin haemangiomas have been subjected to many different kinds of active treatment. From the beginning of the twentieth century and up to 1960–1970, radiotherapy maintained a dominating place in this treatment, although during the latter part of this period its role was more and more questioned. Starting in 1958, I felt that, based on the scientific literature and on my own observations at Malmö University Hospital, active therapy including radiotherapy should be abandoned since it had turned out to be unnecessary and, furthermore, could be harmful. This viewpoint resulted from an increased knowledge of the natural history of the disease. I then got the possibility to establish a follow-up study cohort at Sahlgrenska University Hospital in Göteborg with the aim of gaining information on early and late radiation effects following childhood radiotherapy. Later, the study cohort was enlarged by pooling with similar cohorts originating from Stockholm and Paris. A summary of the results of the epidemiological studies is also presented here. This historical overview reflects half a century of radiation therapy and radiation protection philosophy. It contains a basic message pointing to the value of proper and reliable collection of medical data and to the importance of local, regional and national registers, to preserve the information.