Abstract Background: The importance of tumour hypoxia for the outcome of radiotherapy has been under investigation for decades. Numerous clinical trials modifying the hypoxic radioresistance in ...squamous cell carcinoma of the head and neck (HNSCC) have been conducted, but most have been inconclusive, partly due to a small number of patients in the individual trial. The present meta-analysis was, therefore, performed utilising the results from all clinical trials addressing the specific question of hypoxic modification in HNSCC undergoing curative intended primary radiotherapy alone. Methods: A systematic review of published and unpublished data identified 4805 patients with HNSCC treated in 32 randomized clinical trials, applying, normobaric oxygen or carbogen breathing (5 trials); hyperbaric oxygen (HBO) (9 trials); hypoxic radiosensitizers (17 trials) and HBO and radiosensitizer (1 trial). The trials were analysed with regard to the following endpoints: loco-regional control (32 trials), disease specific survival (30 trials), overall survival (29 trials), distant metastases (12 trials) and complications to radiotherapy (23 trials). Results: Overall hypoxic modification of radiotherapy in head and neck cancer did result in a significant improved therapeutic benefit. This was most dominantly observed when using the direct endpoint of loco-regional control with an odds ratio (OR) of 0.71, 95% cf.l. 0.63–0.80; p < 0.001), but this was almost mirrored in the disease specific survival (OR: 0.73, 95% cf.l. 0.64–0.82; p < 0.001), and to a lesser extent in the overall survival (OR: 0.87, 95% cf.l. 0.77–0.98; p = 0.03). The risk of distant metastases was not significantly influenced although it appears to be less in the tumours treated with hypoxic modification (OR: 0.87, 95% cf.l. 0.69–1.09; p = 0.22), whereas the radiation related late complications were not influenced by the overall use of hypoxic modifications (OR: 1.00, 95% cf.l. 0.82–1.23; p = 0.96). The improvement in loco-regional control was found to be independent of the type of hypoxic modification. The trials have used different fractionation schedules, including large doses per fraction, which may result in relatively more hypoxia and greater benefit. However, analysis of HNSCC trials using conventional fractionation only, showed that the significant effect of hypoxic modification was maintained. Conclusion: The meta-analysis thus demonstrates that there is level 1a evidence in favour of adding hypoxic modification to radiotherapy of squamous cell carcinomas of the head and neck.
Since observations from the beginning of the last century, it has become well established that solid tumors may contain oxygen-deficient hypoxic areas and that cells in such areas may cause tumors to ...become radioresistant. Identifying hypoxic cells in human tumors has improved by the help of new imaging and physiologic techniques, and a substantial amount of data indicates the presence of hypoxia in many types of human tumors, although with a considerable heterogeneity among individual tumors. Controlled clinical trials during the last 40 years have indicated that this source of radiation resistance can be eliminated or modified by normobaric or hyperbaric oxygen or by the use of nitroimidazoles as hypoxic radiation sensitizers. More recently, attention has been given to hypoxic cytotoxins, a group of drugs that selectively or preferably destroys cells in a hypoxic environment. An updated systematic review identified 10,108 patients in 86 randomized trials designed to modify tumor hypoxia in patients treated with curative attempted primary radiation therapy alone. Overall modification of tumor hypoxia significantly improved the effect of radiotherapy, with an odds ratio of 0.77 (95% CI, 0.71 to 0.86) for the outcome of locoregional control and with an associated significant overall survival benefit (odds ratio = 0.87; 95% CI, 0.80 to 0.95). No significant influence was found on the incidence of distant metastases or on the risk of radiation-related complications. Ample data exist to support a high level of evidence for the benefit of hypoxic modification. However, hypoxic modification still has no impact on general clinical practice.
Abstract Background and purpose: Radiotherapy for breast cancer both decreases loco-regional recurrence rates and improves overall survival. However, radiotherapy has also been associated with ...increased second cancer risk at exposed sites. In this meta-analysis, we estimated the risk of second non-breast cancers after radiotherapy for breast cancer. Material and methods: The databases Medline/Pubmed, Cochrane, Embase and Cinahl were systematically searched, for cohort studies on second cancer after radiotherapy for breast cancer, from inception to August 1st 2013. Included studies were to report the relative risk (RR) of second cancers comparing irradiated female breast cancer patients to unirradiated patients. Primary endpoints were all second non-breast-cancers and second cancers of the lung, esophagus, thyroid and second sarcomas. RRs were pooled using random-effects meta-analysis. Results: Thirteen studies comprising 762,468 breast cancer patients were included in the meta-analysis. Five or more years after breast cancer diagnosis radiotherapy was significantly associated with an increased risk of second non-breast cancer RR 1.12 (95% confidence interval CI 1.06–1.19), second cancer of the lung RR 1.39 (95% CI 1.28–1.51), esophagus RR 1.53 (95% CI 1.01–2.31) and second sarcomas RR 2.53 (95% CI 1.74–3.70). The risk increased over time, and was highest 15 or more years after breast cancer diagnosis, for second lung RR 1.66 (95% CI 1.36–2.01) and second esophagus cancer RR 2.17 (95% CI 1.11–4.25). There was no significant association between radiotherapy and second thyroid cancer. Conclusions: Radiotherapy for breast cancer is significantly associated with increased risks of second non-breast cancer, overall and in organs adjacent to the previous treatment fields. Despite a relative small absolute risk, the growing number of long-time survivors after breast cancer warrants the need for normal tissue sparing radiotherapy techniques.
Since the initial observations made at the beginning of the last century, it has been established that solid tumors contain regions of low oxygenation (hypoxia). Tumor cells can survive in these ...hypoxic conditions and are a major factor in tumor radioresistance. This significance has resulted in hypoxia becoming the most cited biological topic in translational radiation oncology. Identifying hypoxic cells in human tumors has become paramount, and the ability to do this has been improved by the help of new imaging techniques and the use of predictive gene profiles. Substantial data confirm the presence of hypoxia in many types of human tumors, although with considerable heterogeneity among individual tumors. Various approaches have been investigated for eliminating the hypoxic population. These include increasing oxygen availability, directly radiosensitizing or killing the hypoxic cells, indirectly affecting them by targeting the tumor vascular supply, increasing the radiation dose to this resistant population, or by using radiation with a high linear energy transfer, for which hypoxia is believed to be less of an issue. Many of these approaches have undergone controlled clinical trials during the last 50 years, and the results have shown that hypoxic radiation resistance can indeed be overcome. Thus, ample data exists to support a high level of evidence for the benefit of hypoxic modification. However, such hypoxic modification still has no impact on general clinical practice. In this review we summarize the biological rationale, and the current activities and trials, related to identifying and overcoming hypoxia in modern radiotherapy.
It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced ...heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients with early-stage node-positive breast cancer.
In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients with left-sided disease were allocated to no IMNI because of the risk of radiation-induced heart disease. The primary end point was overall survival. Secondary end points were breast cancer mortality and distant recurrence. Analyses were by intention to treat.
A total of 3,089 patients were included. Of these, 1,492 patients were allocated to IMNI, whereas 1,597 patients were allocated to no IMNI. With a median of 8.9 years of follow-up time, the 8-year overall survival rates were 75.9% with IMNI versus 72.2% without IMNI. The adjusted hazard ratio (HR) for death was 0.82 (95% CI, 0.72 to 0.94; P = .005). Breast cancer mortality was 20.9% with IMNI versus 23.4% without IMNI (adjusted HR, 0.85; 95% CI, 0.73 to 0.98; P = .03). The risk of distant recurrence at 8 years was 27.4% with IMNI versus 29.7% without IMNI (adjusted HR, 0.89; 95% CI, 0.78 to 1.01; P = .07). The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease.
In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer.
Technological advances and clinical research over the past few decades have given radiation oncologists the capability to personalize treatments for accurate delivery of radiation dose based on ...clinical parameters and anatomical information. Eradication of gross and microscopic tumours with preservation of health-related quality of life can be achieved in many patients. Two major strategies, acting synergistically, will enable further widening of the therapeutic window of radiation oncology in the era of precision medicine: technology-driven improvement of treatment conformity, including advanced image guidance and particle therapy, and novel biological concepts for personalized treatment, including biomarker-guided prescription, combined treatment modalities and adaptation of treatment during its course.
Abstract Background Several epidemiological studies have reported increased risks of second lung cancers after breast cancer irradiation. In this study we assessed the effects of the delivered ...radiation dose to the lung and the risk of second primary lung cancer. Methods We conducted a nested case–control study of second lung cancer in a population based cohort of 23,627 early breast cancer patients treated with post-operative radiotherapy from 1982 to 2007. The cohort included 151 cases diagnosed with second primary lung cancer and 443 controls. Individual dose-reconstructions were performed and the delivered dose to the center of the second lung tumor and the comparable location for the controls were estimated, based on the patient specific radiotherapy charts. Results The median age at breast cancer diagnosis was 54 years (range 34–74). The median time from breast cancer treatment to second lung cancer diagnosis was 12 years (range 1–26 years). 91% of the cases were categorized as ever smokers vs. 40% among the controls. For patients diagnosed with a second primary lung cancer five or more years after breast cancer treatment the rate of lung cancer increased linearly with 8.5% per Gray (95% confidence interval = 3.1–23.3%; p < 0.001). This rate was enhanced for ever smokers with an excess rate of 17.3% per Gray (95% CI = 4.5–54%; p < 0.005). Conclusions Second lung cancer after radiotherapy for early breast cancer is associated with the delivered dose to the lung. Although the absolute risk is relative low, the growing number of long-time survivors after breast cancer treatment highlights the need for advances in normal tissue sparing radiation techniques.
Abstract Background and purpose To analyze the long-term risk of second primary solid non-breast cancer in a national population-based cohort of 46,176 patients treated for early breast cancer ...between 1982 and 2007. Patients and methods All patients studied were treated according to the national guidelines of the Danish Breast Cancer Cooperative Group. The risk of second primary cancers was estimated by Standardised incidence ratios (SIRs) and multivariate Cox regression models were used to estimate adjusted hazard ratios (HR) among irradiated women compared to non-irradiated. All irradiated patients were treated on linear accelerators. Second cancers were a priori categorized into two groups; radiotherapy-associated- (oesophagus, lung, heart/mediastinum, pleura, bones, and connective tissue) and non-radiotherapy-associated sites (all other cancers). Results 2358 second cancers had occurred during the follow-up. For the radiotherapy-associated sites the HR among irradiated women was 1.34 (95% CI 1.11–1.61) with significantly increased HRs for the time periods of 10–14 years (HR 1.55; 95% CI 1.08–2.24) and ⩾ 15 years after treatment (HR 1.79; 95% CI 1.14–2.81). There was no increased risk for the non-radiotherapy-associated sites (HR 1.04; 95% CI 0.94–1.1). The estimated attributable risk related to radiotherapy for the radiotherapy-associated sites translates into one radiation-induced second cancer in every 200 women treated with radiotherapy. Conclusions Radiotherapy treated breast cancer patients have a small but significantly excess risk of second cancers.
To examine the importance of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER-2), and constructed subtypes in a large study randomly assigning ...patients to receive or not receive postmastectomy radiotherapy (PMRT).
The present analysis included 1,000 of the 3,083 high-risk breast cancer patients randomly assigned to PMRT in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c. Tissue microarray sections were stained for ER, PgR, and HER-2. Median follow-up time for patients alive was 17 years. End points were locoregional recurrence as isolated first event, distant metastases, and overall survival. For statistical analyses four subgroups were constructed from hormonal receptors (Rec). Rec+ was defined as ER+ and/or PgR+. Rec-as both ER-and PgR-. The four subgroups were Rec+/HER-2-, Rec+/HER-2+, Rec-/HER-2-(triple negative), and Rec-/HER-2+.
A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall survival improvement after PMRT was found among patients with an a priori poor prognosis, the hormonal receptor-negative and HER-2+ patients, and in particular the Rec-/HER-2+ subtype. Furthermore, comparing hazard ratios and 95% CIs, significantly smaller improvements in locoregional recurrence control after PMRT were found for ER-and PgR-tumors compared with the ER+ and PgR+ tumors (P = .003 and .04, respectively), and for the triple-negative (P = .02), and the Rec-/HER-2+ subtypes (P = .003) compared with the Rec+/HER-2-subtype.
Hormonal receptor status, HER-2, and the constructed subtypes may be predictive of locoregional recurrence and survival after postmastectomy radiotherapy.
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