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Invited Commentary
Oncology
September 1, 2020

Characterizing the Risk of Vertebral Body Fractures in Patients Receiving Chemoradiotherapy for Esophageal Cancer

Author Affiliations
  • 1Department of Radiation Oncology, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore
JAMA Netw Open. 2020;3(9):e2014340. doi:10.1001/jamanetworkopen.2020.14340

In JAMA Network Open, Fujii et al1 report a retrospective cohort study on the rate of vertebral body fractures (VBFs) in patients with thoracic esophageal squamous cell carcinomas (eSCCs) occurring within 36 months of definitive management, with comparisons between patients treated with or without chemoradiotherapy (CRT). This study was completed within a single institution and captured 315 patients treated from 2007 to 2013. The cohorts consisted of patients undergoing surgical or endoscopic management with or without chemotherapy (n = 196) and patients undergoing definitive CRT (n = 119). Patients were followed up for a median of 40.4 (range, 0.7-124.1) months from the date of surgery or beginning of CRT.

Vertebral fractures were diagnosed on follow-up computed tomographic (CT) scans, interpreted by 2 radiation oncologists, and determined using the method of Genant et al.2 The mean dose to each thoracic vertebral body was calculated, as were the Hounsfield units for the trabecular portions of each bone, the latter of which was used as a surrogate for bone density. Univariable and multivariable analyses of the study population demonstrated that receipt of CRT, being 65 years or older, female sex, and prior fractures were associated with VBFs. Further multivariable analysis determined that the hazard ratio of a thoracic VBF for every 5-Gy increase in the mean radiation dose to a single vertebra was 1.42 (95% CI, 1.17-1.74; P = .001), and a separate model showed similar results of an association of 5-Gy increases in maximum radiation dose with the risk of thoracic VBF. Their study concluded that for patients with eSCCs, CRT was associated with VBFs and that reducing the radiation dose to the thoracic vertebrae when receiving CRT may decrease the risk of VBFs.

As described by Fujii et al,1 the development of VBFs after CRT is important given the contributions to treatment-related morbidity and associated decreases in quality of life. Vertebral body fractures can lead to pain and decreased mobility, which can negatively affect both quality and quantity of life. The risk of VBFs after abdominal and thoracic CRT has been previously reported,3 and 3 contemporary retrospective studies similar in design to that of Fujii et al1 are summarized in an excellent review by Pilz et al.4 The studies addressed in this commentary all report VBF rates ranging from 7% to 11% after CRT, which is in accordance with rates reported by Fujii et al.1 Importantly, however, only 40% to 60% of patients experiencing a VBF experienced pain; all other patients had VBFs diagnosed incidentally on follow-up imaging. Unfortunately, esophageal cancer remains a challenging disease to eradicate and still carries a high rate of distant metastatic progression.5 Metastatic disease is most frequently in the form of liver, lung, and bone metastases, the last of which can occur at rates similar to those of VBFs. For this reason, metastatic disease and VBFs need to be considered if a patient with esophageal cancer that was treated with radiotherapy presents with new-onset back pain.

There are, however, important limitations of this study that must be considered. First, although there is a benefit to this study in the sense that the comparator cohort also has the same malignant disease, comparisons between baseline characteristics are not reported. Although the univariable and multivariable analyses illustrate important and previously validated factors predisposing to the development of VBFs, it is important to know whether these were balanced between the cohorts in order to eliminate confounding baseline factors. Equally critical would be a comparison of bone density before treatment in both cohorts. Furthermore, although Fujii et al1 note the importance of malignant neoplasms in and of themselves as a contributor to the development of VBFs, there is no healthy cohort for use as a comparator in their study.

In addition, in the United States, excluding patients with very proximal cervical eSCCs and medically inoperable disease, paradigms for locally advanced eSCC (generally, stage II or greater) include neoadjuvant CRT followed by resection, based on the seminal CROSS (Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study) report.5 This differs from both paradigms reported by Fujii et al,1 and the study would benefit from an explanation of treatment decision-making. Similarly, authors of this study describe patients having primary tumors treated with a total radiation dose of 60 Gy, which is significantly higher than our national guidelines recommend based on failures of dose-escalation studies to show meaningful improvements and actually showing survival detriment.3,6

The patients in this study were treated from 2007 to 2013, and it is unclear why more contemporary patients were not included. This is relevant because all included patients were treated with 3-dimensional conformal radiotherapy; however, the use of advanced radiation modalities, such as intensity-modulated radiation therapy and proton therapy, have now been demonstrated to improve outcomes for patients with esophageal cancer.7 Both decreased prescription doses and increased conformality of radiation would likely decrease the radiation doses to thoracic vertebrae and thus portend a lower risk of VBF in patients receiving CRT today. Furthermore, VBFs were diagnosed on CT scans interpreted by 2 radiation oncologists and may have been more appropriately evaluated by diagnostic radiologists. Last, little is mentioned in this study or in prior literature as to what interventions were required for the VBFs; for instance, it would be helpful to know how many required eventual kyphoplasty or similar procedures.

Despite its limitations, this study raises attention to an important treatment-related morbidity that can be overlooked by radiation oncologists and has implications for future radiotherapy planning and patient counseling and survivorship. This study once again highlights the inherent risk of bone density changes resulting from CRT, warranting counseling specific to this treatment-related toxic effect. Because this study validates previously reported factors predisposing to VBFs, patients exhibiting these characteristics at the time of treatment in particular should receive counseling with the potential for medical and nutritional interventions to ensure that overall bone density can be optimized. In select patients (and as has demonstrated benefit in women with breast cancer8), this may include interventions such as vitamin supplementation, bisphosphonate use, or a guided exercise program and could include formal bone-mineral density assessments before receiving CRT.

This study adds to the previously mentioned body of literature that carries implications specifically for radiation oncologists in terms of the importance of minimizing exposure to the bones and bone marrow. Because advanced radiation modalities are increasingly used, physicians will have the capability to deliver highly conformal plans and may have the ability to significantly decrease radiation exposure to the vertebral bodies, if it is an established planning goal. In conclusion, although there are limitations to the work by Fujii et al,1 it contributes to a body of literature describing a consistent rate of VBFs after receipt of CRT and continues to draw the attention of radiation oncologists to minimize the vertebral body radiation dose and to monitor bone density and health throughout follow-up and survivorship clinics.

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Article Information

Published: September 1, 2020. doi:10.1001/jamanetworkopen.2020.14340

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 DeCesaris C et al. JAMA Network Open.

Corresponding Author: Avani D. Rao MD, Department of Radiation Oncology, University of Maryland Marlene and Stewart Greenebaum Cancer Center, 22 S Greene St, Baltimore, MD, 21201 (avani0814@gmail.com).

Conflict of Interest Disclosures: None reported.

References
1.
Fujii  K, Sakanaka  K, Uozumi  R,  et al.  Association of chemoradiotherapy with thoracic vertebral fractures in patients with esophageal cancer.   JAMA Netw Open. 2020;3(9):e2013952. doi:10.1001/jamanetworkopen.2020.13952Google Scholar
2.
Genant  HK, Wu  CY, van Kuijk  C, Nevitt  MC.  Vertebral fracture assessment using a semiquantitative technique.   J Bone Miner Res. 1993;8(9):1137-1148. doi:10.1002/jbmr.5650080915 PubMedGoogle ScholarCrossref
3.
Ajani  JA, D’Amico  TA, Chair  V, et al. NCCN Guidelines Version 2.2020 Esophageal and Esophagogastric Junction Cancers Continue; 2020.
4.
Pilz  K, Hoffmann  AL, Baumann  M, Troost  EGC.  Vertebral fractures: an underestimated side-effect in patients treated with radio(chemo)therapy.   Radiother Oncol. 2016;118(3):421-423. doi:10.1016/j.radonc.2016.02.021 PubMedGoogle ScholarCrossref
5.
Shapiro  J, van Lanschot  JJB, Hulshof  MCCM,  et al; CROSS study group.  Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.   Lancet Oncol. 2015;16(9):1090-1098. doi:10.1016/S1470-2045(15)00040-6 PubMedGoogle ScholarCrossref
6.
Minsky  BD, Pajak  TF, Ginsberg  RJ,  et al.  INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy.   J Clin Oncol. 2002;20(5):1167-1174. doi:10.1200/JCO.2002.20.5.1167 PubMedGoogle ScholarCrossref
7.
Lin  SH, Merrell  KW, Shen  J,  et al.  Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer.   Radiother Oncol. 2017;123(3):376-381. doi:10.1016/j.radonc.2017.04.013 PubMedGoogle ScholarCrossref
8.
Lüftner  D, Niepel  D, Steger  GG.  Therapeutic approaches for protecting bone health in patients with breast cancer.   Breast. 2018;37:28-35. doi:10.1016/j.breast.2017.10.007PubMedGoogle ScholarCrossref
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