Toxicity risk of non-target organs at risk receiving low-dose radiation: case report
© Shueng et al; licensee BioMed Central Ltd. 2009
Received: 8 October 2009
Accepted: 31 December 2009
Published: 31 December 2009
The spine is the most common site for bone metastases. Radiation therapy is a common treatment for palliation of pain and for prevention or treatment of spinal cord compression. Helical tomotherapy (HT), a new image-guided intensity modulated radiotherapy (IMRT), delivers highly conformal dose distributions and provides an impressive ability to spare adjacent organs at risk, thus increasing the local control of spinal column metastases and decreasing the potential risk of critical organs under treatment. However, there are a lot of non-target organs at risk (OARs) occupied by low dose with underestimate in this modern rotational IMRT treatment. Herein, we report a case of a pathologic compression fracture of the T9 vertebra in a 55-year-old patient with cholangiocarcinoma. The patient underwent HT at a dose of 30 Gy/10 fractions delivered to T8-T10 for symptom relief. Two weeks after the radiotherapy had been completed, the first course of chemotherapy comprising gemcitabine, fluorouracil, and leucovorin was administered. After two weeks of chemotherapy, however, the patient developed progressive dyspnea. A computed tomography scan of the chest revealed an interstitial pattern with traction bronchiectasis, diffuse ground-glass opacities, and cystic change with fibrosis. Acute radiation pneumonitis was diagnosed. Oncologists should be alert to the potential risk of radiation toxicities caused by low dose off-targets and abscopal effects even with highly conformal radiotherapy.
Intensity-modulated radiotherapy (IMRT) is a powerful tool which enabled us to achieve desired dose to tumor and reducing radiation doses to critical structures simultaneously. The encouraging and safety results of patients with various sites of malignancies in the thoracic region treated by IMRT have been reported recently . In addition, Gong et al. reported conventionally-fractionated image-guided intensity modulated radiotherapy (IG-IMRT) is a safe and effective treatment for cancer spinal metastasis .
Helical tomotherapy (HT) is a new CT-based rotational intensity modulated radiotherapy that can deliver highly conformal dose distributions with an ability to spare critical organs from radiation exposure . HT is also effective and feasible for patients with multiple metastatic diseases .
Radiation recall phenomenon is characterized by an inflammatory reaction within the previously treated radiation field during chemotherapy treatment . In humans, longer-range effects of radiotherapy occurring within or between tissues are referred to as abscopal, out-of-field, or distant bystander responses .
A combination of gemcitabine, 5-fluorouracil (5-FU), and leucovorin (LV) is effective in patients with unresectable or metastatic biliary tract or gallbladder adenocarcinoma . Gemcitabine chemotherapy, however, can cause radiation recall followed by standard radiation therapy .
Herein, we present a case of radiation recall pneumonitis with simultaneous abscopal effects following highly conformal HT and gencitabine-based chemotherapy for metastatic spine lesion in a patient with metastatic cholangiocarcinoma.
The contoured organs at risk (OARs), dose constraints/penalty functions and planning parameters of plan was listed as below
Max Dose Constraint [Gy]
Max Dose Penalty
DVH vol [%]
DVH dose [Gy]
DVH dose [Gy]
Min Dose Penalty
Max Dose Constraint [Gy]
Max Dose Penalty
DVH vol [%]
DVH dose [Gy]
DVH Point Penalty
Radiation therapy (RT) is a common and safe treatment to relieve pain of symptomatic osseous metastases. In addition, RT is reserved for palliation of prevention or treatment of spinal cord compression. Generally, RT focuses on limited area for symptom relief. However, RT also is safe and effective for multiple symptomatic osseous metastatic patients as multi-fractionated wide-field radiation therapy (MF-WFRT) .
Radiation pneumonitis in patients undergoing treatment for lung cancer has been shown to be associated with a V20 > 20%, where V20 represents the percentage of lung volume receiving at least 20 Gy , and a mean lung dose > 13.6 Gy . The V20 and mean lung dose in our patient were 1% and 2.7 Gy, respectively. Therefore, our plan was a safe protocol for palliative treatment of metastatic bone disease. Although the low dose around the irradiation target is usually overlooked, such as the V5 in the plan presented here (Figure 3) which was only 20%, it can potentially induce severe radiation toxicity (Figure 2).
Khan et al., reported that when rat lung was partially irradiated, micronucleus formation was observed in non-irradiated areas of the lung, indicating DNA damage at these non-irradiated sites. In humans, abscopal events such as bilateral pneumonitis have been observed in humans after unilateral irradiation . Additionally, a survival benefit of local control by simultaneous thoracic radiochemotherapy in the case of improved distant control due to chemotherapy and prophylactic cranial irradiation has been reported . These long-range bystander responses have also been studied in a lung reconstruction model in which levels of the phosphorylated histone variant γH2AX, a marker of double-strand break (DSBs), were found to be increased, reaching a maximum by 12 to 48 h after irradiation, followed by a gradual decrease over the 7-day time course . Biomolecules known to be involved in bystander responses include interleukin 6 (Il-6), Il-8, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNFα), reactive oxygen species (ROS), and reactive nitrogen species . Recently, the correlation between TGF-β1 and developing radiation pneumonitis has been reported  and the observation could also partially response to the contribution of biomolecules on bystander responses. When distant bystander responses to radiotherapy occur during cancer treatment that the potential lung injury could be happened. If subsequent treatment is radiation recall agents that it could induce nearly fatal interstitial lung disease as the case we present here.
The low dose irradiation to non-target OARs noted in this patient is not unique to tomotherapy, rather it can occur with any technique that creates a relatively large low dose volume such as multifield IMRT, volumetric arc therapies or stereotactic radiation therapy (SRT). For example, inhomogeneity corrections have a large influence on the dose delivered to the PTV and OARs for SRT of lung tumors . SRT allows for the minimization of normal tissue volume exposed to high radiation dose that is to minimize toxicity while maximizing tumor control . However, even in SRT, the large amount of low dose irradiation to non-target OARs, the incidence of lung toxicity can become high has been reported by Yamashita et al.  Oncologists should be alert to the potential risk of low dose irradiation of non-target OARs when reviewing plans in the lung. It is important to review the low dose volumes and include the low dose volumes in the dose distribution, especially if there is a plan to give chemotherapy. Also, in cases in which there is a chance of recall within the thorax, a static field Posterior-Anterior (PA) or AP/PA, or a three-dimensional conformal radiation therapy (3DCRT) approach with fewer beams and smaller irradiated volume may be preferred for palliative (or radical treatment) to avoid this problem. In addition, even with volumetric or helical arc therapy, strong penalty functions on the lung could reduce the volume of the lung receiving even low doses.
Non-target OARs can be impacted by arc therapy because of the low dose bath phenomenon. These effects can be magnified by agents known or unknown to be associated with recall effects. Optimization of planning should be considered in these situations.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors thank Hsing-Yi Lee M.S. for her assistance with radiation planning and management of images. This study was supported by grants of Far Eastern Memorial Hospital (FEMH-97-C-045), Taiwan.
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