ARTICLE IN PRESS Radiotherapy and Oncology xxx (2016) xxx–xxx
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Vertebral fractures – An underestimated side-effect in patients treated with radio(chemo)therapy
Neoadjuvant or primary radio(chemo)therapy is the treatment of choice for many primary tumours in the thoracic and abdominal region [1,2]. Curative-intent radiation therapy is challenged by two competing goals: delivering a high dose to the tumour to achieve cure while sparing the surrounding tissue to reduce side effects. Traditionally, the focus has been on tissues of importance to many patients, such as lungs, heart, oesophagus, spinal cord and bowels to avoid common and severe side effects, e.g., pneumonitis, myocardial infarction, or paralysis . Thus far, vertebral bodies have not been considered as organs of risk in thoracic and abdominal irradiation. In previous studies, radiation-induced bone damage has mainly been described for stereotactic body radiotherapy [4,5]. However, also standard fractionated radiotherapy provides a risk for bone damage [6,7]. Vertebral fractures are of high clinical importance for they adversely impact the quality of life, cause pain, lead to immobility and, most importantly, they increase the overall morbidity . In the general population, vertebral fractures are predominantly caused by osteoporosis, a systemic skeletal disorder characterized by reduced bone mineral density and disruption of bone microarchitecture . Apart from age and female gender, several clinical co-conditions have been identified negatively influencing the bone stability, such as lack of calcium and vitamin D, smoking, low level of physical activity, and long-term use of systemic corticoid steroids [10,11]. These general factors may also potentially increase the likelihood of vertebral fractures in patients following radio (chemo)therapy. In previous studies it has been shown that irradiation of the pelvis, ribs and femoral bone increases the risk of bone fractures by reducing the bone mineral density [9–15]. Due to the demographic change, the number of elderly patients with aforementioned risk factors in need of radio(chemo)therapy is rising and therefore the prevention of vertebral bone fractures is of increasing importance. In the current issue of Radiotherapy and Oncology, three studies are published, which assess the frequency, association with applied dose, and further risk factors for thoracic and lumbar vertebra bone damage following irradiation [16–18]. Based on these findings, the studies developed predictive models for reduction of bone mineral density due to radio(chemo)therapy. Otani et al.  identified risk factors for vertebral compression fractures after preoperative three-dimensional conformal radiochemotherapy (50–60 Gy in 25 fractions combined with three courses of 1000 mg/m2 gemcitabine) in patients with pancreatic cancer. The authors investigated 220 patients (134 males and 86 females) with a median age of 66 (range: 33–84) years and a median follow-up of http://dx.doi.org/10.1016/j.radonc.2016.02.021 0167-8140/Ó 2016 Published by Elsevier Ireland Ltd.
17.9 months (range: 3.4–73.9 months). Follow-up computer tomography (CT) images were performed in a three-month interval, and the occurrence of vertebral fracture in the irradiated volume (covering three caudal thoracic and three cranial lumbar vertebrae) was scored by a radiation oncologist and an orthopaedist. Vertebral compression fractures were observed in 25 patients (11%) of whom 12 presented with no or only mild back pain. The authors identified female gender, higher age and high daily gemcitabine concentration during radiochemotherapy as risk factors. Combining these three risk factors with dose-volume histogram parameters in marginal probability curves, patients in the high-risk group were found to be at 5% fracture risk with a mean vertebral dose (MVD) of 22 Gy, whereas the mean dose of risk was 46.4 Gy in the intermediate-risk group. As one might expect, fractures were predominantly seen in the high-dose region. Wei et al.  retrospectively studied a cohort of 272 patients treated with (radio)chemotherapy for abdominal tumours between 1997 and 2015. Forty-two patients (27 males and 15 females) were included in this analysis, the mean age was 59.7 (range: 42–78) years. Six patients were only treated with chemotherapy and therefore served as controls. The included patients had undergone at least two post-irradiation CT scans for routine surveillance, and a radiologist reviewed these scans for vertebral fractures. Within 1 year after radiation treatment, 7.1% of the patients had developed new vertebral fractures (thoracic vertebra 7 – lumbar vertebra 5) on the CT scan. The authors demonstrated that bone mineral density reduction was significantly correlated with radiation dose to the vertebral body, starting 4–8 months after irradiation and persisting thereafter. Furthermore, they developed a predictive model for the expected value of bone mineral density in a given vertebra based on CT bone attenuation prior to irradiation, vertebral body radiation dose, and interval time from irradiation to CT scan. Uyterlinde et al.  analysed 336 patients treated with radio (chemo)therapy for locally advanced non-small cell lung carcinoma. In the majority of patients, treatment consisted of hypofractionated intensity modulated radiation therapy (66 Gy in 24 fractions) and concurrent low-dose cisplatin. Vertebral fractures were retrospectively screened from the baseline CT and followup CT/magnetic resonance imaging (MRI) scans. At a median follow-up of 12 months, the authors observed vertebral fractures in 8% of the patients, of whom 61% clinically suffered from thoracic back pain. In univariate analysis, there was no correlation between gender and vertebral fractures, whereas higher age (median: 70 vs. 63 years in the fractured versus non-fractured group, respectively; p < 0.01) was of statistical significant influence. After balancing
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Editorial / Radiotherapy and Oncology xxx (2016) xxx–xxx
age, the percentage volume of the vertebra receiving a planned dose of P30 Gy and the mean radiation dose were identified as significant parameters for the risk of vertebral fractures. The observation that vertebral fractures are associated with absorbed radiation dose is agreed upon by all three studies [16– 18]. Remarkable is that the reported doses associated with a significant risk are much lower than frequently accepted in routine clinical practice. Similarly, the median time to discovery of the fracture was rather short in all three studies. Uyterlinde et al.  reported a median time to fracture of 7 months, Wei et al.  mentioned that bone mineral density changes can occur as early as four months from time of irradiation, and Otani et al.  disclosed vertebral fractures for 84% of the patients within 24 month after radiochemotherapy. One unresolved issue discussed by the three publications is the effect of concurrently administered chemotherapy. Otani et al.  identified the daily gemcitabine concentration as a risk factor. Conversely, Wei et al.  reported that chemotherapy had no effect on the bone mineral density, as did Uyterlinde et al.  regarding the effect of daily low dose cisplatin. The latter, however, considered that this may have been due to low number of patients not undergoing concurrent chemotherapy and therefore a lack of statistical power. Further limitations of our current knowledge summarized in the three studies [16–18] include the retrospective nature of the analyses owing lack of clinical information, e.g., correlation of back pain to the localization of the fracture, presence of local recurrent malignancy or lytic vertebral metastases potentially causing fractures. Besides, the limited number of patients suitable for these investigations and the short follow-up periods has complicated valid statistical analyses. The fact that all studies used baseline planning CT and follow-up CT/MRI scans for screening vertebral fractures did most likely not impact the reliability of findings [19,20]. Overall the findings of the three studies on vertebral fractures after radiotherapy imply that it is essential to consider the vertebral bone as an organ at risk and to delineate it for radiation treatment planning and dose evaluation purposes, in the era of highconformal dose delivery techniques. The proposed prediction models may help to identify high-risk patients and support them with prophylactic measures but need to be further refined by larger well-documented patient cohorts under consideration of clinical risk factors. It also appears very important to extent research to potential damage of other vertebra regions (e.g., after radiotherapy of head and neck cancer) and to other bones, which often receive substantial doses of radiotherapy. At a more general view, the three studies on vertebra damage demonstrate that, besides well recognized and widely investigated early and late radiation-induced normal tissue reactions including mucositis, esophagitis, pneumonitis, lung fibrosis, rectal ulceration of neurological damage (e.g., [21–29]), also ‘‘new”, not anticipated and under-researched sequelae of radiotherapy exist. Another recent example of such ‘‘new” side effects is proximal bronchial damage after high dose hypofractionated radiotherapy of lung cancer . As these side effects of radiotherapy are not anticipated, they may by their very nature easily be overseen. Databases of regular follow-up after radiotherapy, including not only assessments of symptoms by standard scoring instruments, but also, e.g., imaging investigations, are of great value for documentation of such effects. Systematic analysis of such databases for new side effects of radiotherapy, their dose–volume–response relationship and potential risk factors can then be performed whenever suspicion arises from observation of individual or few clinical cases. In contrast to many other cancer treatments, consequences of detailed information of radiation-induced side effects are often immediate as constraints for normal-tissue reactions can be taken into consideration in treatment planning and application, which reduces the risk of occurrence of damage and may increase the therapeutic gain.
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Karoline Pilz Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology, Germany Michael Baumann ⇑ Esther G.C. Troost Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden OncoRay – National Center for Radiation Research in Oncology, Dresden German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany ⇑ Address: University Hospital and Medical Faculty Carl Gustav Carus of the Technische Universität Dresden, Department of Radiation Oncology, Fetscherstraße 74, 01307 Dresden, Germany. E-mail address: [email protected]
OncoRay – National Center for Radiation Research in Oncology, Dresden German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany Aswin L. Hoffmann Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden OncoRay – National Center for Radiation Research in Oncology, Dresden
Received 14 February 2016 Accepted 18 February 2016 Available online xxxx