Vertebral fractures – An underestimated side-effect in patients treated with radio(chemo)therapy

Vertebral fractures – An underestimated side-effect in patients treated with radio(chemo)therapy

ARTICLE IN PRESS Radiotherapy and Oncology xxx (2016) xxx–xxx Contents lists available at ScienceDirect Radiotherapy and Oncology journal homepage: ...

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ARTICLE IN PRESS Radiotherapy and Oncology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Radiotherapy and Oncology journal homepage:


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 [3]. 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 [8]. 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 [9]. 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. [16] 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 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. [18] 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. [17] 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


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. [17] reported a median time to fracture of 7 months, Wei et al. [18] mentioned that bone mineral density changes can occur as early as four months from time of irradiation, and Otani et al. [16] 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. [16] identified the daily gemcitabine concentration as a risk factor. Conversely, Wei et al. [18] reported that chemotherapy had no effect on the bone mineral density, as did Uyterlinde et al. [17] 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 [30]. 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.

References [1] Huang J, Robertson JM, Margolis J, Balaraman S, Gustafson G, Khilanani P, et al. Long-term results of full-dose gemcitabine with radiation therapy compared to 5-fluorouracil with radiation therapy for locally advanced pancreas cancer. Radiother Oncol 2011;99:114–9. [2] Ezer N, Smith CB, Galsky MD, Mhango G, Gu F, Gomez J, et al. Cisplatin vs. carboplatin-based chemoradiotherapy in patients >65 years of age with stage III non-small cell lung cancer. Radiother Oncol 2014;112:272–8. [3] Chen C, Uyterlinde W, Sonke J-J, de Bois J, van den Heuvel M, Belderbos J. Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy. Radiother Oncol 2013;108:337–41. [4] Rodríguez-Ruiz ME, San Miguel I, Gil-Bazo I, Perez-Gracia JL, Arbea L, MorenoJimenez M, et al. Pathological vertebral fracture after stereotactic body radiation therapy for lung metastases. Case report and literature review. Radiat Oncol 2012;7:50. [5] Boehling NS, Grosshans DR, Allen PK, McAleer MF, Burton AW, Azeem S, et al. Vertebral compression fracture risk after stereotactic body radiotherapy for spinal metastases. J Neurosurg Spine 2012;16:379–86. [6] von Rottkay P. 2 cases of radiation-induced osteonecroses of the thoracic vertebral bodies after accelerated irradiation of bronchial carcinoma. Strahlentherapie 1985;161:704–5. [7] Wu L-A, Liu H-M, Wang C-W, Chen Y-F, Hong R-L, Ko J-Y. Osteoradionecrosis of the upper cervical spine after radiation therapy for head and neck cancer: differentiation from recurrent or metastatic disease with MR imaging. Radiology 2012;264:136–45. [8] Cooper C, Atkinson EJ, Jacobsen SJ, O’Fallon WM, Melton LJ. Population-based study of survival after osteoporotic fractures. Am J Epidemiol 1993;137:1001–5. [9] Riggs BL, Wahner HW, Dunn WL, Mazess RB, Offord KP, Melton LJ. Differential changes in bone mineral density of the appendicular and axial skeleton with aging: relationship to spinal osteoporosis. J Clin Invest 1981;67:328–35. [10] van der Klift M, de Laet CEDH, McCloskey EV, Johnell O, Kanis JA, Hofman A, et al. Risk factors for incident vertebral fractures in men and women: the Rotterdam Study. J Bone Miner Res Off J Am Soc Bone Miner Res 2004;19:1172–80. [11] Ismail AA, Cooper C, Felsenberg D, Varlow J, Kanis JA, Silman AJ, et al. Number and type of vertebral deformities: epidemiological characteristics and relation to back pain and height loss. European Vertebral Osteoporosis Study Group. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA 1999;9:206–13. [12] Pierce SM, Recht A, Lingos TI, Abner A, Vicini F, Silver B, et al. Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 1992;23:915–23. [13] Lin PP, Schupak KD, Boland PJ, Brennan MF, Healey JH. Pathologic femoral fracture after periosteal excision and radiation for the treatment of soft tissue sarcoma. Cancer 1998;82:2356–65. [14] Chen HHW, Lee BF, Guo HR, Su WR, Chiu NT. Changes in bone mineral density of lumbar spine after pelvic radiotherapy. Radiother Oncol J Eur Soc Ther Radiol Oncol 2002;62:239–42. [15] Ogino I, Okamoto N, Ono Y, Kitamura T, Nakayama H. Pelvic insufficiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy. Radiother Oncol J Eur Soc Ther Radiol Oncol 2003;68:61–7. [16] Otani K, Teshima T, Ito Y, Kawaguchi Y, Konishi K, Takahashi H, et al. Risk factors for vertebral compression fractures in preoperative chemoradiotherapy with gemcitabine for pancreatic cancer. Radiother Oncol 2016. [17] Uyterlinde W, Chen C, Belderbos J, Sonke J-J, Lange C, de Bois J, et al. Fractures of thoracic vertebrae in patients with locally advanced non-small cell lung carcinoma treated with intensity modulated radiotherapy. Radiother Oncol 2016. [18] Wei R, Jung C, Manzano W, Klempner S, Sehgal V, Ramsinghani N, et al. Bone mineral density loss in thoracic and lumbar vertebrae following radiation for abdominal cancers. Radiother Oncol 2016. [19] Lee S, Chung CK, Oh SH, Park SB. Correlation between bone mineral density measured by dual-energy X-ray absorptiometry and hounsfield units measured by diagnostic ct in lumbar spine. J Korean Neurosurg Soc 2013;54:384–9. [20] Schreiber JJ, Anderson PA, Rosas HG, Buchholz AL, Au AG. Hounsfield units for assessing bone mineral density and strength: a tool for osteoporosis management. J Bone Joint Surg Am 2011;93:1057–63. [21] Carillo V, Cozzarini C, Rancati T, Avuzzi B, Botti A, Borca VC, et al. Relationships between bladder dose–volume/surface histograms and acute urinary toxicity after radiotherapy for prostate cancer. Radiother Oncol 2014;111:100–5. [22] Cella L, D’Avino V, Palma G, Conson M, Liuzzi R, Picardi M, et al. Modeling the risk of radiation-induced lung fibrosis: irradiated heart tissue is as important as irradiated lung. Radiother Oncol 2015;117:36–43. [23] Cozzarini C, Rancati T, Carillo V, Civardi F, Garibaldi E, Franco P, et al. Multivariable models predicting specific patient-reported acute urinary symptoms after radiotherapy for prostate cancer: results of a cohort study. Radiother Oncol 2015;116:185–91. [24] Kocak-Uzel E, Gunn GB, Colen RR, Kantor ME, Mohamed AS, Schoultz-Henley S, et al. Beam path toxicity in candidate organs-at-risk: assessment of radiation emetogenesis for patients receiving head and neck intensity modulated radiotherapy. Radiother Oncol 2014;111:281–8.

ARTICLE IN PRESS Editorial / Radiotherapy and Oncology xxx (2016) xxx–xxx [25] Mitra D, Nout R, Catalano PJ, Creutzberg C, Cimbak N, Lee L, et al. Rectal bleeding after radiation therapy for endometrial cancer. Radiother Oncol 2015;115:240–5. [26] Schytte T, Bentzen SM, Brink C, Hansen O. Changes in pulmonary function after definitive radiotherapy for NSCLC. Radiother Oncol 2015;117:23–8. [27] van der Laan HP, Bijl HP, Steenbakkers RJ, van der Schaaf A, Chouvalova O, Vemer-van den Hoek JG, et al. Acute symptoms during the course of head and neck radiotherapy or chemoradiation are strong predictors of late dysphagia. Radiother Oncol 2015;115:56–62. [28] Wijsman R, Dankers F, Troost EG, Hoffmann AL, van der Heijden EH, de GeusOei LF, et al. Multivariable normal-tissue complication modeling of acute esophageal toxicity in advanced stage non-small cell lung cancer patients treated with intensity-modulated (chemo-)radiotherapy. Radiother Oncol 2015;117:49–54. [29] Wu AJ, Williams E, Modh A, Foster A, Yorke E, Rimner A, et al. Dosimetric predictors of esophageal toxicity after stereotactic body radiotherapy for central lung tumors. Radiother Oncol 2014;112:267–71. [30] Cannon DM, Mehta MP, Adkison JB, Khuntia D, Traynor AM, Tome WA, et al. Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer. J Clin Oncol 2013;31:4343–8.

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] (E.G.C. Troost)

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