- Email: [email protected]
or Rib Fracture After Lung Stereotactic Body Radiotherapy
Int. J. Radiation Oncology Biol. Phys., Vol. 76, No. 3, pp. 796–801, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/10/$–see front matter
doi:10.1016/j.ijrobp.2009.02.027
CLINICAL INVESTIGATION
Lung
CHEST WALL VOLUME RECEIVING >30 GY PREDICTS RISK OF SEVERE PAIN AND/ OR RIB FRACTURE AFTER LUNG STEREOTACTIC BODY RADIOTHERAPY NEAL E. DUNLAP, M.D.,* JING CAI, PH.D.,* GREGORY B. BIEDERMANN, M.D.,* WENSHA YANG, PH.D.,* STANLEY H. BENEDICT, PH.D.,* KE SHENG, PH.D.,* TRACEY E. SCHEFTER, M.D.,y BRIAN D. KAVANAGH, M.D.,y AND JAMES M. LARNER, M.D.* * University of Virginia, Charlottesville, VA; and y University of Colorado Denver, Aurora, CO Purpose: To identify the dose–volume parameters that predict the risk of chest wall (CW) pain and/or rib fracture after lung stereotactic body radiotherapy. Methods and Materials: From a combined, larger multi-institution experience, 60 consecutive patients treated with three to five fractions of stereotactic body radiotherapy for primary or metastatic peripheral lung lesions were reviewed. CW pain was assessed using the Common Toxicity Criteria for pain. Peripheral lung lesions were defined as those located within 2.5 cm of the CW. A minimal point dose of 20 Gy to the CW was required. The CW volume receiving $20, $30, $40, $50, and $60 Gy was determined and related to the risk of CW toxicity. Results: Of the 60 patients, 17 experienced Grade 3 CW pain and five rib fractures. The median interval to the onset of severe pain and/or fracture was 7.1 months. The risk of CW toxicity was fitted to the median effective concentration dose–response model. The CW volume receiving 30 Gy best predicted the risk of severe CW pain and/or rib fracture (R2 = 0.9552). A volume threshold of 30 cm3 was observed before severe pain and/or rib fracture was reported. A 30% risk of developing severe CW toxicity correlated with a CW volume of 35 cm3 receiving 30 Gy. Conclusion: The development of CW toxicity is clinically relevant, and the CW should be considered an organ at risk in treatment planning. The CW volume receiving 30 Gy in three to five fractions should be limited to <30 cm3, if possible, to reduce the risk of toxicity without compromising tumor coverage. Ó 2010 Elsevier Inc. Stereotactic body radiotherapy, SBRT, lung, chest wall, dose–response, fracture.
tion of the dose and irradiated volume for SBRT are lacking. We, therefore, retrospectively reviewed the experience of patients from the Universities of Virginia and Colorado, focusing on the incidence of CW pain and/or rib fracture in patients treated with three to five fractions of SBRT for primary or metastatic peripheral lung lesions. The aim of the study was to assess the relationship between the dose–volume parameters and the development of CW pain and/or rib fracture.
INTRODUCTION The advent of stereotactic body radiotherapy (SBRT) provides a nonsurgical therapy for patients with early-stage non–small-cell lung cancer (NSCLC) or oligometastatic lesions to the lung. SBRT uses elements of three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and stereotactic targeting to allow dramatic reductions in target volume and dose escalation (1–5). However, achieving the desired doses to the target volume with adequate tumor coverage is often limited by the proximity of the target volume to critical normal tissues. Multiple Phase I and II SBRT studies of the treatment of Stage I-II NSCLC have reported chest wall (CW) pain and/ or rib fracture as a part of the toxicity profile (6–9). CW pain can be transient or can last several weeks or longer. Data from patients treated for breast cancer with external beam radiotherapy have demonstrated a relationship between the total dose and fractionation and the development of CW toxicity (10–13). However, reports of CW toxicity as a func-
METHODS AND MATERIALS Patient eligibility and treatment Between March 2005 and March 2008, 60 consecutive patients with peripheral primary NSCLC or oligometastatic lesions to the lung were treated with SBRT at the University of Virginia (n = 32) or the University of Colorado (n = 28). The patients were included in the study if they were considered to be at risk of the development of CW pain and/or rib fracture as defined by lesions within 2.5 cm of the CW receiving a >20-Gy maximal point dose to the adjacent CW.
Reprint requests: James Larner, M.D., Department of Radiation Oncology, University of Virginia, P.O. Box 800383, Charlottesville, VA 22908. Tel: (434) 924-5564; Fax: (434) 243-9789; E-mail: [email protected]
Presented at the American Society for Therapeutic Radiology and Oncology, September 2008. Conflict of interest: none. Received Nov 20, 2008, and in revised form Feb 10, 2009. Accepted for publication Feb 12, 2009. 796
Chest wall toxicity d N. E. DUNLAP et al.
All patients underwent contrast-enhanced treatment planning computed tomography in a stereotactic frame. Stereotactic coordinates of the isocenter were measured from the fiducial markers on the frame. Isocenter coordinates were used for patient setup for subsequent treatment. The gross tumor volume was identified on axial images using pulmonary windowing. The solid components and adjacent ground glass opacity were included. The planning target volume was designed to account for setup uncertainty and target motion by enlarging the gross tumor volume by 0.5 cm in the radial plane and 1.0 cm in the craniocaudal plane. Planning at the University of Virginia was performed using Hi-Art Helical Tomotherapy inverse planning software (Tomotherapy, Madison, WI) and at University of Colorado with BrainLAB planning software (BrainScan, BrainLAB AG, Heimstetten, Germany). The prescribed doses varied by institution. The normal tissue constraints adhered to the Radiation Therapy Oncology Group 0236 protocol as follows: for the heart, trachea, and ipsilateral bronchus, a 30-Gy maximal point dose; for the esophagus, a 27-Gy maximal point dose; for the brachial plexus, a 24-Gy maximal point dose; and for the spinal cord, an 18-Gy maximal point dose. The CW was not designated as a constrained structure for the original treatment plans.
Toxicity definition and follow-up Follow-up evaluations were performed 4–6 weeks after treatment completion and every 3 months thereafter. Complete physical examinations, including an assessment of performance status and evaluation of CW pain and/or rib fracture, were performed at each visit. CW pain assessment was adapted from the Common Toxicity Criteria for Adverse Events, version 3.0, for pain. Grade 0 was defined as no CW pain. Grade 1 was defined as intermittent CW pain requiring no pain medication. Grade 2 was defined as CW pain requiring non–steroidal anti-inflammatory agents or acetaminophen. Grade 3 was defined as CW pain requiring narcotic analgesics. The response of the primary tumor was assessed radiographically by computed tomography at 3-month intervals or if clinically indicated by the physician. Plain film chest radiographs were obtained only if clinically indicated. Rib fracture was documented by an independent radiologist using either plain film chest X-ray or computed tomography of the chest. Patients were excluded if the rib fracture was secondary to tumor recurrence.
Dosimetric evaluation of CW dose The CW included the bone and soft tissue in the treated hemithorax. The CW contour was defined as a 3-cm three-dimensional expansion of the lung minus the lung volume. The mediastinal soft tissue and anterior vertebral body were excluded. Patients were divided into five groups of 12 each to calculate the risk. The absolute CW volume receiving $20, $30, $40, $50, and $60 Gy was determined. The risk of CW toxicity was then plotted as a function of the absolute volume for each analyzed dose. Patients with Grade 3 CW pain and/or rib fracture were analyzed further to determine their risk of developing toxicity according to the dose– volume parameters.
where Y is the actual risk of CW toxicity, expressed as a percentage of the maximal risk; TOP is the maximal risk (the minimal risk is zero); HillSlope is the steepness of the curve; and logEC50 represents the irradiated CW volume in which 50% of the maximal risk is observed. The model was applied to the CW volume receiving $20, $30, $40, $50, and $60 Gy. Linear regression analysis was performed to correlate the mathematical model for CW toxicity with the observed risk, as determined by the data.
RESULTS Patient and tumor characteristics A total of 60 patients with peripheral lesions were identified for analysis. Table 1 lists the patient and tumor characteristics. The median patient age included in the study was 69 years (range, 29–88). The patients were treated for either primary NSCLC or oligometastases from non–lung primary tumors. Non–lung primary tumors included adenocarcinoma of the breast in 1, melanoma in 2, squamous cell carcinoma of the head and neck in 2, penile squamous cell carcinoma in 1, thymoma in 1, and hepatocellular carcinoma in 1. Tumors were characterized by their size and distance from the CW. The median tumor diameter was 2.4 cm (range, 0.9–9.3). The median distance from the CW was 0.15 cm (range, 0–2.5). The median follow-up time was 11.1 months (range, 3–35), with a local control rate of 88%. CW pain and/or rib fracture Table 2 lists the toxicity evaluation. CW pain was classified according to the clinical symptoms. Of the 60 patients with peripheral lung lesions, 2 developed Grade 1 CW pain, 1 developed Grade 2 CW pain, and 17 developed Grade 3 CW pain. Five patients were identified radiographically as having rib fractures. The rate of all CW pain from the University of Virginia and University of Colorado was 28% and 14%, and the rib fracture rate from each institution was 9% and 7%, respectively. The median time to the onset of severe pain and/or rib fracture was 7.1 months (range, 0.6–32.3). The median time to the resolution of CW pain was 4.65 months (range, 0.67–10.5). Pain resolved in 10 of the 20 patients with any grade of CW pain and in 7 of the 17 patients with Grade 3 CW pain. At follow-up, all 5 patients with rib fracture continued to experience Grade 2 or 3 CW pain. No statistically significant difference was found in the distance of the tumor from the CW for patients who had no CW toxicity compared with those who developed CW pain and/or rib fracture (data not shown). Table 1. Patient and tumor characteristics Characteristic
Modeling CW toxicity The risk of CW toxicity as a function of the absolute irradiated CW volume was fitted to the median effective concentration (EC50) dose–response model (Eq. 1).
Y ¼ TOP=ð1 þ 10^½ðlogEC50 XÞ HillSlopeÞ
797
(1)
Age (y) Tumor diameter (cm) Tumor distance from chest wall (cm) Follow-up (mo) Total dose (Gy) Biologic equivalent dose Total fractions (n)
Median (range) 69 (29–88) 2.4 (0.9–9.3) 0.15 (0.0–2.5) 9.1 (3.0–35.0) 60 (21–60) 42–150 3 (3–5)
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Table 2. Toxicity information (n = 61) Variable Pain scale (n) Grade 0 Grade 1 Grade 2 Grade 3 Rib fracture Pain onset (mo) Median Range Resolution of pain from onset (mo) Median Range
Table 3. EC50 dose–response model data for designated dose levels Value 41 2 1 17 5 7.1 0.6–32.3 4.65 0.67–10.5
Volume–risk analysis and dose–volume relationship The absolute CW volume CW receiving $20, $30, $40, $50, and $60 Gy was determined for each of the 60 patients. The risk of severe CW toxicity was calculated using Eq. 1 and plotted as a function of volume above the dose for each dose level (Fig. 1). The EC50 model for the CW volume receiving 30 Gy correlated best with the observed data (R2 = 0.9552). The risk of CW toxicity showed a threshold of 30 cm3 before severe chest pain and/or rib fracture was noted (Fig. 1). The logEC50 for the volume receiving 30 Gy was 35 cm3 (Table 3). The CW volumes receiving 50 Gy and 60 Gy both correlated strongly with the development of CW toxicity (R2 = 0.9019 and R2 = 0.8963, respectively). The logEC50 for the 50-Gy dose level was 2.3 cm3, and the logEC50 for the 60-Gy dose level was 1.4 cm3. The risk of severe CW toxicity had an observed plateau for each predetermined dose with a maximal risk listed in Table 3. A dose–volume relationship for developing severe CW toxicity was plotted using a clinically relevant risk of 30% (Fig. 2). Similar to the EC50 dose–response model, doses of 50 and 60 Gy to relatively small volumes of the CW were required before severe CW toxicity developed. The threshold
Fig. 1. Volume–risk analysis based on median effective concentration dose–response model for designated dose levels (20, 30, 40, 50, and 60 Gy) for development of severe chest wall toxicity.
Dose to CW (Gy)
Slope (m)
20 30 40 50 60
0.12 0.28 0.28 1.30 0.60
LogEC50
Maximal risk
Correlation between expected and observed results (R2)
51 35 10 2.3 1.4
0.36 0.39 0.45 0.42 0.50
0.5575 0.9552 0.6573 0.9019 0.8963
Abbreviations: CW = chest wall; EC50 = median effective concentration.
volume of CW receiving 30 Gy was approximately 10-fold greater than the threshold volume receiving 50 Gy or 60 Gy before a 30% risk of severe CW toxicity was observed.
DISCUSSION The ability to predict CW toxicity before SBRT is critical to decreasing its incidence. In patients with multiple medical comorbidities and relatively poor performance status, CW toxicity can greatly affect quality of life. The purpose of the present study was to identify the dose–volume parameters that predict the risk of CW toxicity, which can include pain and/or rib fracture, after SBRT. To our knowledge, we are the first group to report a predictive model for the development of CW toxicity after SBRT to the lung. The development of CW pain and/or rib fracture with local radiotherapy is well documented. A retrospective analysis by Pierce et al. (11) examined the incidence of radiation-induced complications in 1,624 patients treated with early-stage breast cancer. The incidence of rib fracture was reported to be 0.4–2.2% depending on the type of linear accelerator used. Meric et al. (12) reported a 0.3% incidence of rib fracture in 294 women treated with early-stage breast cancer. A similar incidence of rib fracture has been reported in the treatment of lung cancer. Quddus et al. (10) reviewed 4,531
Fig. 2. Dose–volume relationship for 30% risk of severe chest wall toxicity.
Chest wall toxicity d N. E. DUNLAP et al.
patients treated with palliative radiotherapy for NSCLC with #10 fractions and noted a rib fracture incidence of 2%. Not surprisingly, a larger dose per fraction correlates with the development of CW pain and/or rib fracture. Overgaard13 reported the development of spontaneous radiation-induced rib fractures in breast cancer patients treated after mastectomy. A total of 231 patients were treated with either a hypofractionated 12-fraction regimen or a standard 22-fraction regimen. Radiographs were taken 1–6 years after treatment and evaluated for spontaneous rib fractures. A significantly greater incidence of spontaneous rib fracture was seen in patients treated with the 12-fraction regimen compared with the 22-fraction regimen (19% vs. 6%). A dose–volume relationship was established for each fractionation schedule. Additionally, the initial clinical experiences with accelerated partial breast irradiation using proton therapy were reported by Kozak et al. (14) in a Phase I-II clinical trial of 20 patients. Patients received 32 Cobalt Gray equivalents in four fractions twice daily to the lumpectomy cavity. Three patients (10%) reported rib pain at the site of irradiation. The precise incidence of both spontaneous rib fracture and CW pain in the treatment of early-stage NSCLC with SBRT is unknown. The reports from early Phase I-II studies were from single institutions and relatively small. Norihisa et al. (15) reported a single institutional experience of 34 patients treated at 48–60 Gy with SBRT for oligometastatic lung tumors. Musculoskeletal adverse events, including rib fracture and musculitis of the CW, were observed in 2 patients (6%), and mild CW pain was observed in 6 patients (17%). Zimmermann et al. (7) reported a 3% incidence of spontaneous rib fracture in 68 inoperable patients with NSCLC treated with a mean dose of 37.5 Gy in three to five fractions. Fritz et al. (6) reported a 5% incidence of rib fracture in 40 patients treated with a single fraction of 30 Gy. The Princess Margret Hospital recently presented outcome data from the treatment of 76 patients with early-stage NSCLC with SBRT to 48–60 Gy in three to five fractions (8). Acute complications included 8% of patients developing CW pain. Also, 23% of patients experienced CW pain as a component of late toxicity and 14% developed rib fractures. The selection of fractionation and total dose for SBRT delivery are important considerations for predicting late normal tissue toxicities. The prediction of normal tissue toxicity from fractionated radiotherapy is typically determined using the classic linear-quadratic model, which provides some insight into the determination of fractionation schemes (16). However, intercomparison of conventional fractionation with hypofraction lends itself to problems when using the classic linear-quadratic model (17), making additional investigation necessary. Clinical experience with SBRT for centrally located lung lesions has indicated that fractionation might make a difference for decreasing normal tissue toxicity. A Phase II Radiation Therapy Oncology Group protocol using 60–66 Gy in three fractions reported an 11-fold increased risk of severe pulmonary toxicity for centrally located tumors (18). Others have reported that decreased fraction size using SBRT might improve severe pulmonary toxicity for centrally
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located lesions (19, 20). Similarly, the risk of CW toxicity and/or rib fraction could also be related to the fractionation scheme used. The data from our patient cohort applied to the existing logEC50 dose–response model demonstrated a clear dose and volume dependence for the development of severe CW toxicity. In the logEC50 model, the observed rates of severe CW pain and/or rib fracture correlated highly with the CW volume receiving 30, 50, or 60 Gy. Greater doses of 50 Gy and 60 Gy produced a sharp increase in the risk of severe CW toxicity when volumes as small as 1–2 cm3 were irradiated. In contrast, a moderate dose of 30 Gy to the CW showed a threshold of 30 cm3 before observing severe CW toxicity. The risk of severe CW toxicity was expected to approach 100% when given to greater than a particular volume treated at all dose levels. Unexpectedly, the risk of severe CW toxicity saturated, with the occurrence of a plateau at all dose levels, and the greater predicted risk was 50% for a dose of 60 Gy. The explanation for this observation was not completely clear. The most likely explanation was a paucity of patients receiving a particular radiation dose to large volumes. Although data points existed at large volumes, the numbers were very few. Second, the development of severe CW toxicity could have been a result of treatment of a critical CW volume to greater than a particular dose. Therefore, volumes treated to greater than the point at which maximal risk occurred would not contribute to added toxicity. Third, patients could have a genetic predisposition to developing CW toxicity, such that the development of toxicity is an all or nothing response. The mechanism by which radiation induces CW pain and/or rib fracture is not known. The proposed targets for the development of CW toxicity include muscle, connective tissue, the neurovascular bundle, and bone. In our analysis, the CW structure included all the soft tissue of the CW to account for different tissues that might sustain injury during irradiation. One proposed mechanism of local pain is injury of the peripheral nerves from local radiation. Kinsella et al. (21) reviewed the factors leading to peripheral nerve damage, including the cranial nerves and brachial plexus. Doses >60 Gy correlated with clinical symptoms of nerve dysfunction, including paresthesia, hypoesthesia, weakness, and pain. Peripheral nerve injury was also identified as the dose-limiting event for intraoperative radiotherapy. Multiple studies have demonstrated that single doses >20 Gy to pelvic nerves can cause clinically significant neuropathies, including mild to severe pain, in approximately 30% of patients (22–24). Nerves are typically considered to be a late responding tissue; therefore, the latency of neuropathy might be important. Stoll and Andrews (24) observed a typical latency of 10–22 months after irradiation. The latency period was shortened in patients treated with greater doses. The median interval to the onset of CW toxicity was 7.2 months in our patient cohort, similar to the latency reported in the intraoperative data. With a limited median follow-up of 11.1 months, additional CW toxicity might be captured with longer follow-up, affecting the latency of symptom development.
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Muscle injury also contributes to localized pain syndromes after irradiation. A potential explanation for the development of CW pain is fibrosis of the soft tissue adjacent to the intercostal nerves, resulting in compression. Complications from the use of intraoperative radiotherapy to treat abdominal and pelvic malignancies using single fractions of 10–20 Gy showed an increased risk of pelvic pain secondary to fibrosis (21). Fibrosis was thought to be causing compression of the lumbosacral plexus. The National Cancer Institute reviewed 145 cases of treatment of soft-tissue sarcomas. Doses >63 Gy resulted in increased amounts of pain and muscle dysfunction at the site of irradiation (25). Radiation-induced damage to bone is also a well-described source of pain. The total dose and fractionation schedule have correlated with the risk of spontaneous fracture (13, 14, 26). The effect of local irradiation on fracture load to bone has also been examined in animal models. The results indicated that the fracture load was significantly reduced after single doses of 40 and 60 Gy (15). Bone injury primarily occurs through bone atrophy, resulting in a reduction of the number of structural components in the tissue, without a reduction in
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overall size. Proposed mechanisms of injury have included Haversian channel injury, leading to sclerotic bone marrow elements, a reduction of osteoblasts, leading to decreased collagen production and increased alkaline phosphatase activity, and, finally, vascular injury, causing alterations in blood flow (27, 28).
CONCLUSION The development of CW toxicity is clinically relevant, and the CW should be considered an organ at risk in treatment planning. Our data have demonstrated that the CW volume receiving 30 Gy in three to five fractions should be limited to <30 cm3, if possible, to reduce the risk of toxicity without compromising tumor coverage. In cases in which an unacceptable risk of CW toxicity is predicted using our doseresponse model, the question of how to minimize that risk remains. Options could include lowering the prescription dose, increasing the fractionation, or replanning using alternative beam arrangements to remove the dose from the CW.
REFERENCES 1. Blomgren H, Lax I, Na¨slund I, et al. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator: Clinical experience of the first thirty-one patients. Acta Oncol 1995;34:861–870. 2. Hof H, Herfarth KK, Mu¨nter M, et al. Stereotactic single-dose radiotherapy of stage I non–small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 2003;56:335–341. 3. Nagata Y, Negoro Y, Aoki T, et al. Clinical outcomes of 3D conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2002;52:1041–1046. 4. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: Results of a Phase I study in medically inoperable Stage I non-small cell lung cancer. Chest 2003;124: 1946–1955. 5. Zimmermann FB, Geinitz H, Schill S, et al. Stereotactic hypofractionated radiation therapy for stage I non-small cell lung cancer. Lung Cancer 2005;48:107–114. 6. Fritz P, Kraus H, Blaschke T, et al. Stereotactic, high singledose irradiation of stage I non-small cell lung cancer (NSCLC) using four-dimensional CT scans for treatment planning. Lung Cancer 2008;60:193–199. 7. Zimmerman FB, Geintz H, Schill S, et al. Stereotactic hypofractionated radiotherapy in stage I (T1-2 N0 M0) nonsmall cell lung cancer (NSCLC). Acta Oncol 2006;45: 796–801. 8. Dahele M, Pearson S, Purdie T, et al. Improving outcomes for early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT). Curr Oncol 2008;15: 155–161. 9. Collins BT, Erickson K, Reichner CA, et al. Radical stereotactic radiosurgery with real-time tumor motion tracking in the treatment of small peripheral lung tumors. Radiat Oncol 2007;2:39. 10. Quddus AM, Kerr GR, Price A, et al. Long-term survival in patients with non-small cell lung cancer treated with palliative radiotherapy. Clin Oncol (R Coll Radiol) 2001;13:95–98.
11. Pierce SM, Recht A, Lingos TI, et al. Long-term radiation complications following conservative surgery and radiation therapy in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 1992;23:915–923. 12. Meric F, Buchholz TA, Mirza NQ, et al. Long-term complications associated with breast-conservation surgery and radiotherapy. Ann Surg Oncol 2002;9:543–549. 13. Overgaard M. Spontaneous radiation-induced rib fractures in breast cancer patients treated with postmastectomy irradiation: A clinical radiobiological analysis of the influence of fraction size and dose-response relationships on late bone changes. Acta Oncol 1988;27:117–122. 14. Kozak KR, Smith BL, Adams J, et al. Accelerated partial-breast irradiation using proton beams: Initial clinical experience. Int J Radiat Oncol Biol Phys 2006;66:691–698. 15. Norihisa Y, Nagata Y, Takayama K, et al. Stereotactic body radiotherapy for oligometastatic lung tumors. Int J Radiat Oncol Biol Phys 2008;1:398–403. 16. Jones B, Dale RG, Finst P, et al. Biological equivalent dose assessment of the consequences of hypofractionated radiotherapy. Int J Radiat Oncol Biol Phys 2000;47: 1379–1384. 17. Astrahan M. Some implications of linear-quadratic-linear radiation dose-response with regard to hypofractionation. Med Phys 2008;35:4161–4172. 18. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24: 4833–4839. 19. Song SY, Choi W, Shin SS, et al. Fractionated stereotactic body radiation therapy for medically inoperable stage I lung cancer adjacent to central large bronchus. Lung Cancer. In press. 20. Joyner M, Salter BJ, Papanikolaou N, et al. Stereotactic body radiation therapy for centrally located lung lesions. Acta Oncol 2006;45:802–807.
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21. Kinsella TJ, Sindelar WF, Deluca AM, et al. Tolerance of peripheral nerve to intraoperative radiotherapy (IORT). Int J Radiat Oncol Biol Phys 1985;11:1579–1585. 22. Stinson SF, DeLaney TF, Greenberg J, et al. Acute and longterm effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1991;21:1492–1499. 23. Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus injury: Follow-up of two different fractionation schedules. Radiother Oncol 1990;18:213–220. 24. Stoll BA, Andrews JT. Radiation-induced peripheral neuropathy. BMJ 1966;1:834–837.
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25. Giese WL, Kinsella TJ. Radiation injury to peripheral and cranial nerves. In: Gutin PH, Leibel SA, Sheline GE, editors. Radiation injury to the nervous system. New York: Raven Press; 1991. p. 383–403. 26. Tepper JE, Gunderson LL, Orlow E, et al. Complications of intraoperative radiation therapy. Int J Radiat Oncol Biol Phys 1984;10:1831–1839. 27. Hopewell JW. Radiation-therapy effects on bone density. Med Pediatr Oncol 2003;41:208–211. 28. Nyaruba MM, Yamamoto I, Kimura H, et al. Bone fragility induced by X-ray irradiation in relation to cortical bone-mineral content. Acta Radiol 1998;39:43–61.
doi:10.1016/j.ijrobp.2009.02.027
CLINICAL INVESTIGATION
Lung
CHEST WALL VOLUME RECEIVING >30 GY PREDICTS RISK OF SEVERE PAIN AND/ OR RIB FRACTURE AFTER LUNG STEREOTACTIC BODY RADIOTHERAPY NEAL E. DUNLAP, M.D.,* JING CAI, PH.D.,* GREGORY B. BIEDERMANN, M.D.,* WENSHA YANG, PH.D.,* STANLEY H. BENEDICT, PH.D.,* KE SHENG, PH.D.,* TRACEY E. SCHEFTER, M.D.,y BRIAN D. KAVANAGH, M.D.,y AND JAMES M. LARNER, M.D.* * University of Virginia, Charlottesville, VA; and y University of Colorado Denver, Aurora, CO Purpose: To identify the dose–volume parameters that predict the risk of chest wall (CW) pain and/or rib fracture after lung stereotactic body radiotherapy. Methods and Materials: From a combined, larger multi-institution experience, 60 consecutive patients treated with three to five fractions of stereotactic body radiotherapy for primary or metastatic peripheral lung lesions were reviewed. CW pain was assessed using the Common Toxicity Criteria for pain. Peripheral lung lesions were defined as those located within 2.5 cm of the CW. A minimal point dose of 20 Gy to the CW was required. The CW volume receiving $20, $30, $40, $50, and $60 Gy was determined and related to the risk of CW toxicity. Results: Of the 60 patients, 17 experienced Grade 3 CW pain and five rib fractures. The median interval to the onset of severe pain and/or fracture was 7.1 months. The risk of CW toxicity was fitted to the median effective concentration dose–response model. The CW volume receiving 30 Gy best predicted the risk of severe CW pain and/or rib fracture (R2 = 0.9552). A volume threshold of 30 cm3 was observed before severe pain and/or rib fracture was reported. A 30% risk of developing severe CW toxicity correlated with a CW volume of 35 cm3 receiving 30 Gy. Conclusion: The development of CW toxicity is clinically relevant, and the CW should be considered an organ at risk in treatment planning. The CW volume receiving 30 Gy in three to five fractions should be limited to <30 cm3, if possible, to reduce the risk of toxicity without compromising tumor coverage. Ó 2010 Elsevier Inc. Stereotactic body radiotherapy, SBRT, lung, chest wall, dose–response, fracture.
tion of the dose and irradiated volume for SBRT are lacking. We, therefore, retrospectively reviewed the experience of patients from the Universities of Virginia and Colorado, focusing on the incidence of CW pain and/or rib fracture in patients treated with three to five fractions of SBRT for primary or metastatic peripheral lung lesions. The aim of the study was to assess the relationship between the dose–volume parameters and the development of CW pain and/or rib fracture.
INTRODUCTION The advent of stereotactic body radiotherapy (SBRT) provides a nonsurgical therapy for patients with early-stage non–small-cell lung cancer (NSCLC) or oligometastatic lesions to the lung. SBRT uses elements of three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and stereotactic targeting to allow dramatic reductions in target volume and dose escalation (1–5). However, achieving the desired doses to the target volume with adequate tumor coverage is often limited by the proximity of the target volume to critical normal tissues. Multiple Phase I and II SBRT studies of the treatment of Stage I-II NSCLC have reported chest wall (CW) pain and/ or rib fracture as a part of the toxicity profile (6–9). CW pain can be transient or can last several weeks or longer. Data from patients treated for breast cancer with external beam radiotherapy have demonstrated a relationship between the total dose and fractionation and the development of CW toxicity (10–13). However, reports of CW toxicity as a func-
METHODS AND MATERIALS Patient eligibility and treatment Between March 2005 and March 2008, 60 consecutive patients with peripheral primary NSCLC or oligometastatic lesions to the lung were treated with SBRT at the University of Virginia (n = 32) or the University of Colorado (n = 28). The patients were included in the study if they were considered to be at risk of the development of CW pain and/or rib fracture as defined by lesions within 2.5 cm of the CW receiving a >20-Gy maximal point dose to the adjacent CW.
Reprint requests: James Larner, M.D., Department of Radiation Oncology, University of Virginia, P.O. Box 800383, Charlottesville, VA 22908. Tel: (434) 924-5564; Fax: (434) 243-9789; E-mail: [email protected]
Presented at the American Society for Therapeutic Radiology and Oncology, September 2008. Conflict of interest: none. Received Nov 20, 2008, and in revised form Feb 10, 2009. Accepted for publication Feb 12, 2009. 796
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All patients underwent contrast-enhanced treatment planning computed tomography in a stereotactic frame. Stereotactic coordinates of the isocenter were measured from the fiducial markers on the frame. Isocenter coordinates were used for patient setup for subsequent treatment. The gross tumor volume was identified on axial images using pulmonary windowing. The solid components and adjacent ground glass opacity were included. The planning target volume was designed to account for setup uncertainty and target motion by enlarging the gross tumor volume by 0.5 cm in the radial plane and 1.0 cm in the craniocaudal plane. Planning at the University of Virginia was performed using Hi-Art Helical Tomotherapy inverse planning software (Tomotherapy, Madison, WI) and at University of Colorado with BrainLAB planning software (BrainScan, BrainLAB AG, Heimstetten, Germany). The prescribed doses varied by institution. The normal tissue constraints adhered to the Radiation Therapy Oncology Group 0236 protocol as follows: for the heart, trachea, and ipsilateral bronchus, a 30-Gy maximal point dose; for the esophagus, a 27-Gy maximal point dose; for the brachial plexus, a 24-Gy maximal point dose; and for the spinal cord, an 18-Gy maximal point dose. The CW was not designated as a constrained structure for the original treatment plans.
Toxicity definition and follow-up Follow-up evaluations were performed 4–6 weeks after treatment completion and every 3 months thereafter. Complete physical examinations, including an assessment of performance status and evaluation of CW pain and/or rib fracture, were performed at each visit. CW pain assessment was adapted from the Common Toxicity Criteria for Adverse Events, version 3.0, for pain. Grade 0 was defined as no CW pain. Grade 1 was defined as intermittent CW pain requiring no pain medication. Grade 2 was defined as CW pain requiring non–steroidal anti-inflammatory agents or acetaminophen. Grade 3 was defined as CW pain requiring narcotic analgesics. The response of the primary tumor was assessed radiographically by computed tomography at 3-month intervals or if clinically indicated by the physician. Plain film chest radiographs were obtained only if clinically indicated. Rib fracture was documented by an independent radiologist using either plain film chest X-ray or computed tomography of the chest. Patients were excluded if the rib fracture was secondary to tumor recurrence.
Dosimetric evaluation of CW dose The CW included the bone and soft tissue in the treated hemithorax. The CW contour was defined as a 3-cm three-dimensional expansion of the lung minus the lung volume. The mediastinal soft tissue and anterior vertebral body were excluded. Patients were divided into five groups of 12 each to calculate the risk. The absolute CW volume receiving $20, $30, $40, $50, and $60 Gy was determined. The risk of CW toxicity was then plotted as a function of the absolute volume for each analyzed dose. Patients with Grade 3 CW pain and/or rib fracture were analyzed further to determine their risk of developing toxicity according to the dose– volume parameters.
where Y is the actual risk of CW toxicity, expressed as a percentage of the maximal risk; TOP is the maximal risk (the minimal risk is zero); HillSlope is the steepness of the curve; and logEC50 represents the irradiated CW volume in which 50% of the maximal risk is observed. The model was applied to the CW volume receiving $20, $30, $40, $50, and $60 Gy. Linear regression analysis was performed to correlate the mathematical model for CW toxicity with the observed risk, as determined by the data.
RESULTS Patient and tumor characteristics A total of 60 patients with peripheral lesions were identified for analysis. Table 1 lists the patient and tumor characteristics. The median patient age included in the study was 69 years (range, 29–88). The patients were treated for either primary NSCLC or oligometastases from non–lung primary tumors. Non–lung primary tumors included adenocarcinoma of the breast in 1, melanoma in 2, squamous cell carcinoma of the head and neck in 2, penile squamous cell carcinoma in 1, thymoma in 1, and hepatocellular carcinoma in 1. Tumors were characterized by their size and distance from the CW. The median tumor diameter was 2.4 cm (range, 0.9–9.3). The median distance from the CW was 0.15 cm (range, 0–2.5). The median follow-up time was 11.1 months (range, 3–35), with a local control rate of 88%. CW pain and/or rib fracture Table 2 lists the toxicity evaluation. CW pain was classified according to the clinical symptoms. Of the 60 patients with peripheral lung lesions, 2 developed Grade 1 CW pain, 1 developed Grade 2 CW pain, and 17 developed Grade 3 CW pain. Five patients were identified radiographically as having rib fractures. The rate of all CW pain from the University of Virginia and University of Colorado was 28% and 14%, and the rib fracture rate from each institution was 9% and 7%, respectively. The median time to the onset of severe pain and/or rib fracture was 7.1 months (range, 0.6–32.3). The median time to the resolution of CW pain was 4.65 months (range, 0.67–10.5). Pain resolved in 10 of the 20 patients with any grade of CW pain and in 7 of the 17 patients with Grade 3 CW pain. At follow-up, all 5 patients with rib fracture continued to experience Grade 2 or 3 CW pain. No statistically significant difference was found in the distance of the tumor from the CW for patients who had no CW toxicity compared with those who developed CW pain and/or rib fracture (data not shown). Table 1. Patient and tumor characteristics Characteristic
Modeling CW toxicity The risk of CW toxicity as a function of the absolute irradiated CW volume was fitted to the median effective concentration (EC50) dose–response model (Eq. 1).
Y ¼ TOP=ð1 þ 10^½ðlogEC50 XÞ HillSlopeÞ
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(1)
Age (y) Tumor diameter (cm) Tumor distance from chest wall (cm) Follow-up (mo) Total dose (Gy) Biologic equivalent dose Total fractions (n)
Median (range) 69 (29–88) 2.4 (0.9–9.3) 0.15 (0.0–2.5) 9.1 (3.0–35.0) 60 (21–60) 42–150 3 (3–5)
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Table 2. Toxicity information (n = 61) Variable Pain scale (n) Grade 0 Grade 1 Grade 2 Grade 3 Rib fracture Pain onset (mo) Median Range Resolution of pain from onset (mo) Median Range
Table 3. EC50 dose–response model data for designated dose levels Value 41 2 1 17 5 7.1 0.6–32.3 4.65 0.67–10.5
Volume–risk analysis and dose–volume relationship The absolute CW volume CW receiving $20, $30, $40, $50, and $60 Gy was determined for each of the 60 patients. The risk of severe CW toxicity was calculated using Eq. 1 and plotted as a function of volume above the dose for each dose level (Fig. 1). The EC50 model for the CW volume receiving 30 Gy correlated best with the observed data (R2 = 0.9552). The risk of CW toxicity showed a threshold of 30 cm3 before severe chest pain and/or rib fracture was noted (Fig. 1). The logEC50 for the volume receiving 30 Gy was 35 cm3 (Table 3). The CW volumes receiving 50 Gy and 60 Gy both correlated strongly with the development of CW toxicity (R2 = 0.9019 and R2 = 0.8963, respectively). The logEC50 for the 50-Gy dose level was 2.3 cm3, and the logEC50 for the 60-Gy dose level was 1.4 cm3. The risk of severe CW toxicity had an observed plateau for each predetermined dose with a maximal risk listed in Table 3. A dose–volume relationship for developing severe CW toxicity was plotted using a clinically relevant risk of 30% (Fig. 2). Similar to the EC50 dose–response model, doses of 50 and 60 Gy to relatively small volumes of the CW were required before severe CW toxicity developed. The threshold
Fig. 1. Volume–risk analysis based on median effective concentration dose–response model for designated dose levels (20, 30, 40, 50, and 60 Gy) for development of severe chest wall toxicity.
Dose to CW (Gy)
Slope (m)
20 30 40 50 60
0.12 0.28 0.28 1.30 0.60
LogEC50
Maximal risk
Correlation between expected and observed results (R2)
51 35 10 2.3 1.4
0.36 0.39 0.45 0.42 0.50
0.5575 0.9552 0.6573 0.9019 0.8963
Abbreviations: CW = chest wall; EC50 = median effective concentration.
volume of CW receiving 30 Gy was approximately 10-fold greater than the threshold volume receiving 50 Gy or 60 Gy before a 30% risk of severe CW toxicity was observed.
DISCUSSION The ability to predict CW toxicity before SBRT is critical to decreasing its incidence. In patients with multiple medical comorbidities and relatively poor performance status, CW toxicity can greatly affect quality of life. The purpose of the present study was to identify the dose–volume parameters that predict the risk of CW toxicity, which can include pain and/or rib fracture, after SBRT. To our knowledge, we are the first group to report a predictive model for the development of CW toxicity after SBRT to the lung. The development of CW pain and/or rib fracture with local radiotherapy is well documented. A retrospective analysis by Pierce et al. (11) examined the incidence of radiation-induced complications in 1,624 patients treated with early-stage breast cancer. The incidence of rib fracture was reported to be 0.4–2.2% depending on the type of linear accelerator used. Meric et al. (12) reported a 0.3% incidence of rib fracture in 294 women treated with early-stage breast cancer. A similar incidence of rib fracture has been reported in the treatment of lung cancer. Quddus et al. (10) reviewed 4,531
Fig. 2. Dose–volume relationship for 30% risk of severe chest wall toxicity.
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patients treated with palliative radiotherapy for NSCLC with #10 fractions and noted a rib fracture incidence of 2%. Not surprisingly, a larger dose per fraction correlates with the development of CW pain and/or rib fracture. Overgaard13 reported the development of spontaneous radiation-induced rib fractures in breast cancer patients treated after mastectomy. A total of 231 patients were treated with either a hypofractionated 12-fraction regimen or a standard 22-fraction regimen. Radiographs were taken 1–6 years after treatment and evaluated for spontaneous rib fractures. A significantly greater incidence of spontaneous rib fracture was seen in patients treated with the 12-fraction regimen compared with the 22-fraction regimen (19% vs. 6%). A dose–volume relationship was established for each fractionation schedule. Additionally, the initial clinical experiences with accelerated partial breast irradiation using proton therapy were reported by Kozak et al. (14) in a Phase I-II clinical trial of 20 patients. Patients received 32 Cobalt Gray equivalents in four fractions twice daily to the lumpectomy cavity. Three patients (10%) reported rib pain at the site of irradiation. The precise incidence of both spontaneous rib fracture and CW pain in the treatment of early-stage NSCLC with SBRT is unknown. The reports from early Phase I-II studies were from single institutions and relatively small. Norihisa et al. (15) reported a single institutional experience of 34 patients treated at 48–60 Gy with SBRT for oligometastatic lung tumors. Musculoskeletal adverse events, including rib fracture and musculitis of the CW, were observed in 2 patients (6%), and mild CW pain was observed in 6 patients (17%). Zimmermann et al. (7) reported a 3% incidence of spontaneous rib fracture in 68 inoperable patients with NSCLC treated with a mean dose of 37.5 Gy in three to five fractions. Fritz et al. (6) reported a 5% incidence of rib fracture in 40 patients treated with a single fraction of 30 Gy. The Princess Margret Hospital recently presented outcome data from the treatment of 76 patients with early-stage NSCLC with SBRT to 48–60 Gy in three to five fractions (8). Acute complications included 8% of patients developing CW pain. Also, 23% of patients experienced CW pain as a component of late toxicity and 14% developed rib fractures. The selection of fractionation and total dose for SBRT delivery are important considerations for predicting late normal tissue toxicities. The prediction of normal tissue toxicity from fractionated radiotherapy is typically determined using the classic linear-quadratic model, which provides some insight into the determination of fractionation schemes (16). However, intercomparison of conventional fractionation with hypofraction lends itself to problems when using the classic linear-quadratic model (17), making additional investigation necessary. Clinical experience with SBRT for centrally located lung lesions has indicated that fractionation might make a difference for decreasing normal tissue toxicity. A Phase II Radiation Therapy Oncology Group protocol using 60–66 Gy in three fractions reported an 11-fold increased risk of severe pulmonary toxicity for centrally located tumors (18). Others have reported that decreased fraction size using SBRT might improve severe pulmonary toxicity for centrally
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located lesions (19, 20). Similarly, the risk of CW toxicity and/or rib fraction could also be related to the fractionation scheme used. The data from our patient cohort applied to the existing logEC50 dose–response model demonstrated a clear dose and volume dependence for the development of severe CW toxicity. In the logEC50 model, the observed rates of severe CW pain and/or rib fracture correlated highly with the CW volume receiving 30, 50, or 60 Gy. Greater doses of 50 Gy and 60 Gy produced a sharp increase in the risk of severe CW toxicity when volumes as small as 1–2 cm3 were irradiated. In contrast, a moderate dose of 30 Gy to the CW showed a threshold of 30 cm3 before observing severe CW toxicity. The risk of severe CW toxicity was expected to approach 100% when given to greater than a particular volume treated at all dose levels. Unexpectedly, the risk of severe CW toxicity saturated, with the occurrence of a plateau at all dose levels, and the greater predicted risk was 50% for a dose of 60 Gy. The explanation for this observation was not completely clear. The most likely explanation was a paucity of patients receiving a particular radiation dose to large volumes. Although data points existed at large volumes, the numbers were very few. Second, the development of severe CW toxicity could have been a result of treatment of a critical CW volume to greater than a particular dose. Therefore, volumes treated to greater than the point at which maximal risk occurred would not contribute to added toxicity. Third, patients could have a genetic predisposition to developing CW toxicity, such that the development of toxicity is an all or nothing response. The mechanism by which radiation induces CW pain and/or rib fracture is not known. The proposed targets for the development of CW toxicity include muscle, connective tissue, the neurovascular bundle, and bone. In our analysis, the CW structure included all the soft tissue of the CW to account for different tissues that might sustain injury during irradiation. One proposed mechanism of local pain is injury of the peripheral nerves from local radiation. Kinsella et al. (21) reviewed the factors leading to peripheral nerve damage, including the cranial nerves and brachial plexus. Doses >60 Gy correlated with clinical symptoms of nerve dysfunction, including paresthesia, hypoesthesia, weakness, and pain. Peripheral nerve injury was also identified as the dose-limiting event for intraoperative radiotherapy. Multiple studies have demonstrated that single doses >20 Gy to pelvic nerves can cause clinically significant neuropathies, including mild to severe pain, in approximately 30% of patients (22–24). Nerves are typically considered to be a late responding tissue; therefore, the latency of neuropathy might be important. Stoll and Andrews (24) observed a typical latency of 10–22 months after irradiation. The latency period was shortened in patients treated with greater doses. The median interval to the onset of CW toxicity was 7.2 months in our patient cohort, similar to the latency reported in the intraoperative data. With a limited median follow-up of 11.1 months, additional CW toxicity might be captured with longer follow-up, affecting the latency of symptom development.
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Muscle injury also contributes to localized pain syndromes after irradiation. A potential explanation for the development of CW pain is fibrosis of the soft tissue adjacent to the intercostal nerves, resulting in compression. Complications from the use of intraoperative radiotherapy to treat abdominal and pelvic malignancies using single fractions of 10–20 Gy showed an increased risk of pelvic pain secondary to fibrosis (21). Fibrosis was thought to be causing compression of the lumbosacral plexus. The National Cancer Institute reviewed 145 cases of treatment of soft-tissue sarcomas. Doses >63 Gy resulted in increased amounts of pain and muscle dysfunction at the site of irradiation (25). Radiation-induced damage to bone is also a well-described source of pain. The total dose and fractionation schedule have correlated with the risk of spontaneous fracture (13, 14, 26). The effect of local irradiation on fracture load to bone has also been examined in animal models. The results indicated that the fracture load was significantly reduced after single doses of 40 and 60 Gy (15). Bone injury primarily occurs through bone atrophy, resulting in a reduction of the number of structural components in the tissue, without a reduction in
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overall size. Proposed mechanisms of injury have included Haversian channel injury, leading to sclerotic bone marrow elements, a reduction of osteoblasts, leading to decreased collagen production and increased alkaline phosphatase activity, and, finally, vascular injury, causing alterations in blood flow (27, 28).
CONCLUSION The development of CW toxicity is clinically relevant, and the CW should be considered an organ at risk in treatment planning. Our data have demonstrated that the CW volume receiving 30 Gy in three to five fractions should be limited to <30 cm3, if possible, to reduce the risk of toxicity without compromising tumor coverage. In cases in which an unacceptable risk of CW toxicity is predicted using our doseresponse model, the question of how to minimize that risk remains. Options could include lowering the prescription dose, increasing the fractionation, or replanning using alternative beam arrangements to remove the dose from the CW.
REFERENCES 1. Blomgren H, Lax I, Na¨slund I, et al. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator: Clinical experience of the first thirty-one patients. Acta Oncol 1995;34:861–870. 2. Hof H, Herfarth KK, Mu¨nter M, et al. Stereotactic single-dose radiotherapy of stage I non–small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 2003;56:335–341. 3. Nagata Y, Negoro Y, Aoki T, et al. Clinical outcomes of 3D conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2002;52:1041–1046. 4. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: Results of a Phase I study in medically inoperable Stage I non-small cell lung cancer. Chest 2003;124: 1946–1955. 5. Zimmermann FB, Geinitz H, Schill S, et al. Stereotactic hypofractionated radiation therapy for stage I non-small cell lung cancer. Lung Cancer 2005;48:107–114. 6. Fritz P, Kraus H, Blaschke T, et al. Stereotactic, high singledose irradiation of stage I non-small cell lung cancer (NSCLC) using four-dimensional CT scans for treatment planning. Lung Cancer 2008;60:193–199. 7. Zimmerman FB, Geintz H, Schill S, et al. Stereotactic hypofractionated radiotherapy in stage I (T1-2 N0 M0) nonsmall cell lung cancer (NSCLC). Acta Oncol 2006;45: 796–801. 8. Dahele M, Pearson S, Purdie T, et al. Improving outcomes for early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT). Curr Oncol 2008;15: 155–161. 9. Collins BT, Erickson K, Reichner CA, et al. Radical stereotactic radiosurgery with real-time tumor motion tracking in the treatment of small peripheral lung tumors. Radiat Oncol 2007;2:39. 10. Quddus AM, Kerr GR, Price A, et al. Long-term survival in patients with non-small cell lung cancer treated with palliative radiotherapy. Clin Oncol (R Coll Radiol) 2001;13:95–98.
11. Pierce SM, Recht A, Lingos TI, et al. Long-term radiation complications following conservative surgery and radiation therapy in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 1992;23:915–923. 12. Meric F, Buchholz TA, Mirza NQ, et al. Long-term complications associated with breast-conservation surgery and radiotherapy. Ann Surg Oncol 2002;9:543–549. 13. Overgaard M. Spontaneous radiation-induced rib fractures in breast cancer patients treated with postmastectomy irradiation: A clinical radiobiological analysis of the influence of fraction size and dose-response relationships on late bone changes. Acta Oncol 1988;27:117–122. 14. Kozak KR, Smith BL, Adams J, et al. Accelerated partial-breast irradiation using proton beams: Initial clinical experience. Int J Radiat Oncol Biol Phys 2006;66:691–698. 15. Norihisa Y, Nagata Y, Takayama K, et al. Stereotactic body radiotherapy for oligometastatic lung tumors. Int J Radiat Oncol Biol Phys 2008;1:398–403. 16. Jones B, Dale RG, Finst P, et al. Biological equivalent dose assessment of the consequences of hypofractionated radiotherapy. Int J Radiat Oncol Biol Phys 2000;47: 1379–1384. 17. Astrahan M. Some implications of linear-quadratic-linear radiation dose-response with regard to hypofractionation. Med Phys 2008;35:4161–4172. 18. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24: 4833–4839. 19. Song SY, Choi W, Shin SS, et al. Fractionated stereotactic body radiation therapy for medically inoperable stage I lung cancer adjacent to central large bronchus. Lung Cancer. In press. 20. Joyner M, Salter BJ, Papanikolaou N, et al. Stereotactic body radiation therapy for centrally located lung lesions. Acta Oncol 2006;45:802–807.
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21. Kinsella TJ, Sindelar WF, Deluca AM, et al. Tolerance of peripheral nerve to intraoperative radiotherapy (IORT). Int J Radiat Oncol Biol Phys 1985;11:1579–1585. 22. Stinson SF, DeLaney TF, Greenberg J, et al. Acute and longterm effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1991;21:1492–1499. 23. Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus injury: Follow-up of two different fractionation schedules. Radiother Oncol 1990;18:213–220. 24. Stoll BA, Andrews JT. Radiation-induced peripheral neuropathy. BMJ 1966;1:834–837.
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25. Giese WL, Kinsella TJ. Radiation injury to peripheral and cranial nerves. In: Gutin PH, Leibel SA, Sheline GE, editors. Radiation injury to the nervous system. New York: Raven Press; 1991. p. 383–403. 26. Tepper JE, Gunderson LL, Orlow E, et al. Complications of intraoperative radiation therapy. Int J Radiat Oncol Biol Phys 1984;10:1831–1839. 27. Hopewell JW. Radiation-therapy effects on bone density. Med Pediatr Oncol 2003;41:208–211. 28. Nyaruba MM, Yamamoto I, Kimura H, et al. Bone fragility induced by X-ray irradiation in relation to cortical bone-mineral content. Acta Radiol 1998;39:43–61.