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Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4341-4350 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.03.022 Induction and Concurrent Chemotherapy With High-Dose Thoracic Conformal Radiation Therapy in Unresectable Stage IIIA and IIIB Non–Small-Cell Lung Cancer: A Dose-Escalation Phase I TrialFrom the Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill; and the Blumenthal Cancer Center, Carolinas Medical Center, Charlotte, NC Address reprint requests to Mark A. Socinski, MD, Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, CB# 7305, Chapel Hill, NC 27599-7305; e-mail: socinski{at}med.unc.edu
PURPOSE: Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non–small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival. PATIENTS AND METHODS: Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m2, and paclitaxel 175 mg/m2 days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m2 weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTVI) and boost clinical target volume (CTVB), respectively. The CTVI received 40 to 50 Gy; the CTVB received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose.
RESULTS: Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% CONCLUSION: Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.
Lung cancer remains the leading cause of cancer death in both men and women.1 In 2004, approximately 171,900 patients will be diagnosed with lung cancer, and 157,200 deaths are expected.1 Non–small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, with 30% to 40% of these patients presenting with unresectable stage IIIA and IIIB disease.2 In patients with a good performance status (PS), combined-modality therapy using chemotherapy and thoracic radiation therapy (RT) represents the standard of care.3 Recent phase III trials have suggested that the concurrent administration of these two modalities improves long-term survival compared with sequential strategies, resulting in the general acceptance of concurrent chemoradiotherapy as a vital component of standard therapeutic paradigms.4-7 However, despite this improved survival, most patients die from their disease as a result of either locoregional or distant (or both) failure. Thoracic RT delivered with standard doses (60 to 66 Gy) using standard planning techniques results in poor local control.2 Arriagada et al8 demonstrated a local control rate of only 10% to 15% in a landmark analysis of recurrence patterns. Strategies designed to enhance local control include improved tumor targeting (three-dimensional treatment planning), escalation of thoracic RT dose, hyperfractionated or accelerated thoracic RT, and concurrent use of chemotherapy. Control of occult micrometastatic disease also remains a challenge in this population, with more than two thirds of patients developing overt metastatic disease within 2 to 3 years. It has been demonstrated that effective systemic chemotherapy can decrease the risk of overt metastasis presumably by sterilizing occult micrometastatic disease in certain patients.8 More effective systemic therapy is needed in NSCLC and should be integrated into treatment paradigms for unresectable stage III disease. Previous attempts at dose escalation of thoracic RT have been limited by fear of excessive normal tissue toxicity limiting the total dose delivered as well as skepticism that higher doses would impact survival.9 We have previously reported a phase I/II dose-escalation trial incorporating conformal or three-dimensional treatment planning (thoracic conformal RT [TCRT]) into a treatment paradigm of induction and concurrent carboplatin and paclitaxel.9,10 In this trial, we successfully escalated the dose of TCRT from 60 to 74 Gy in 62 patients with unresectable stage III NSCLC with acceptable acute and late toxicity.11 The primary acute toxicity was esophagitis; however, grade 3 and 4 esophagitis occurred in only 8% of patients. The survival profile was encouraging, with a median survival time of 24 months, and 1-, 3-, and 5-year survival rates of 71%, 39%, and 26%, respectively. Despite this more aggressive locoregional approach, local failures were noted in at least 35% of patients. An analysis of prognostic factors suggested that the postinduction chemotherapy gross tumor volume (GTV) was predictive for survival.9 We have also reported a separate analysis of 102 patients with stage III NSCLC in which the postinduction chemotherapy GTV was predictive of survival.12 This observation provided a rationale for more intense induction therapy attempting to maximally cytoreduce the bulk intrathoracic tumor before initiating combined chemoradiotherapy. Also, given the excellent tolerance of 74 Gy delivered with three-dimensional treatment planning as well as continued locoregional recurrences despite 74 Gy of TCRT, further dose escalation of the TCRT dose with concurrent chemotherapy not only seemed possible but also necessary. Given these observations, we designed a subsequent dose-escalation trial that incorporated a more intense induction regimen comprised of carboplatin, irinotecan, and paclitaxel (CIP) for two cycles.13,14 For the concurrent chemoradiotherapy aspect of treatment, weekly carboplatin and paclitaxel was administered with a planned dose escalation of TCRT from 78 Gy to 82, 86, and 90 Gy. The results of this trial form the basis of this report.
Eligibility Patients eligible for this trial were required to have a cytologic or histologic diagnosis of stage IIIA or IIIB disease and be deemed appropriate candidates for combined-modality therapy. All patients were reviewed by a thoracic radiologist, pulmonologist, thoracic surgeon, radiation oncologist, and medical oncologist. Initial staging consisted of a chest x-ray and a staging chest computed tomography (CT) scan, which included full visualization of the liver and adrenal glands. Radionuclide bone scans and/or positron emission tomography (PET) scans were required as was either a CT or magnetic resonance imaging scan of the brain. Patients with supraclavicular adenopathy or pleural effusion were excluded. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 and could not have received prior chemotherapy or RT to the chest. Other required parameters were as follows: absolute neutrophil count (ANC)  1500/µL, hemoglobin 10 gm/dL, platelet count 100,000/µL, serum creatinine less than 1.5 x the institutional normal, serum bilirubin less than 1.5 x the institutional normal, and serum AST and ALT less than 2.5 x the institutional normal. Pulmonary function tests were required to document a forced expiratory volume in 1 second of greater than 800 mL. Patients underwent a bronchoscopy, mediastinoscopy, or transthoracic fine-needle aspiration for diagnosis and staging as clinically indicated. This trial was approved by the Protocol Review Committee of the Lineberger Comprehensive Cancer Center (LCCC) and the Institutional Review Board of the University of North Carolina School of Medicine and labeled LCCC 2001. All patients provided informed consent before enrollment onto this trial.
Treatment Plan
TCRT was initiated on day 43, concurrent with weekly paclitaxel and carboplatin as noted earlier. Patients underwent a planning CT after the second cycle of chemotherapy. Immobilization was not routinely used. The lungs, esophagus, heart (left ventricle), spinal cord, primary tumor, and radiographically positive lymph nodes were contoured. The prechemotherapy contrasted diagnostic CT scan was then spatially registered with the planning CT, and the initial treatment was designed from it. Spatial registration between the prechemotherapy (diagnostic) and postchemotherapy (treatment planning) scans was performed manually by a physicist without using automatic registration methods such as mutual information. Common anatomic landmarks close to the region of interest were matched; typically, these were the trachea, carina, bronchi, and vertebral bodies because these were thought to be the most stable and easily identifiable structures. This registration on the region of interest minimized the problems associated with registering a CT scan taken on a curved table with one taken on a flat table or differences in arm position, weight loss, and respiration between the two scans. For some patients, further editing of the GTV and clinical target volume (CTV) was still necessary because the patient had changed internally during the course of chemotherapy. For example, sometimes a lung would reaerate because of tumor shrinkage. Other times, changes in the mediastinum were seen because of a mediastinoscopy that was performed after the prechemotherapy scan was taken. In addition to these problems, sometimes the spinal cord doses and/or volume of lung treated exceeded acceptable values. In all of these cases, the GTV and CTV were edited to the best judgment of the radiation oncologist, in conjunction with peer review by at least two other radiation oncologists or radiologists. Most of the modifications resulted in decreasing the lateral margin of the field rather than the superior/inferior margins. In no scenario was any part of the GTV explicitly excluded. If the editing was performed because of constraints, the cases were listed as minor protocol violations. Although we have not performed a formal study to characterize pure registration error under the conditions of this trial, most of the registration error was thought to be approximately 0.5 cm or less. In cases where registration error was thought to be greater than 0.5 cm, the planning target volume was further adjusted to account for this, if possible. The registration details were not specifically stated in the protocol but were our general operating procedure. The initial CTV (CTVI) was defined as the prechemotherapy primary tumor volume, clinically positive lymph nodes, and the bilateral (elective) mediastinum. Clinically positive lymph nodes were defined as nodes
Response and Toxicity Evaluation Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria scale version 2.0. Toxicity occurring during the induction phase of the protocol was not used to establish the maximum-tolerated dose (MTD) of TCRT. Dose-limiting toxicities used to establish the MTD of TCRT were any grade 3 or 4 nonhematologic toxicity with the exception of esophagitis, which had to be grade 4, grade 4 neutropenia lasting 7 or more days, and thrombocytopenia to less than 20,000/µL.
Statistical Design
Patient Characteristics Twenty-nine patients were entered onto this trial (Table 1). The median age was 59 years (range, 40 to 81 years). Eighteen patients (62%) were male, and 13 (45%) had stage IIIA (N2) disease, whereas 16 (55%) had stage IIIB disease (only three of these patients had T4N0-1 disease, whereas the remainder had N3 disease). Eleven patients (38%) had an ECOG PS of 0, whereas the remainder had a PS of 1. Eleven patients (38%) had more than 5% weight loss before initiating therapy. Only nine patients (31%) had a PET scan. One patient withdrew consent before receiving any therapy, whereas two patients withdrew consent during the first cycle of induction therapy. Twenty-six patients started the combined-modality portion of the protocol; however, one patient died 3 days into TCRT from an abdominal aortic thrombotic event. Twenty-five (86%) of 29 patients were considered assessable for evaluating the tolerability and toxicity of this aggressive combined-modality approach.
Induction Chemotherapy Fifty-four cycles of induction chemotherapy with CIP were administered to the 28 patients who received at least one dose. The hematologic and nonhematologic toxicities are listed in Table 2. In general, induction CIP with filgrastim support was well tolerated. Rates of all grade 3 and 4 toxicities were less than 10%. In fact, other than nausea and vomiting, no other grade 3 or 4 nonhematologic toxicities were noted. Hematologic toxicity was also minimal, with only 8% of cycles complicated by grade 3 or 4 neutropenia. Twenty-five (96%) of 26 patients initiated chemoradiotherapy on day 43, with one patient requiring a 2-week delay because of neutropenia.
Twenty-six patients were assessable for response to induction CIP. Twelve patients (46.2%; 95% CI, 27% to 67%) had an objective partial response, whereas the remaining 14 patients (53.8%; 95% CI, 33% to 74%) had stable disease. No disease progression was noted during the two cycles of induction CIP. The median preinduction chemotherapy GTV was 66 mL (range, 13 to 281 mL). The median postinduction chemotherapy GTV was 28 mL (range, 7 to 281 mL), representing a median reduction in the GTV of 58%.
Concurrent Chemoradiotherapy The hematologic and nonhematologic toxicities encountered during the concurrent chemoradiotherapy portion of the trial are listed in Table 3. Five patients were entered at the 78-Gy dose level. One patient developed grade 3 esophagitis and fatigue/malaise at 50 Gy and refused further therapy after 60 Gy. One patient developed a bronchoesophageal fistula at 74 Gy in the setting of a dramatic tumor response. The remaining three patients completed therapy to 78 Gy without grade 3 or 4 nonhematologic toxicity.
Seven patients were entered at the 82-Gy dose level, with all seven completing treatment to 82 Gy. A single patient developed grade 3 esophagitis. No other grade 3 or 4 nonhematologic toxicities occurred. Seven patients were entered at the 86-Gy level, with five completing treatment to 82 Gy. One patient developed grade 4 nausea/vomiting and grade 3 esophagitis, whereas another experienced grade 3 malaise/fatigue. Both patients received a total TCRT dose of 70 Gy. No other grade 3 or 4 nonhematologic toxicities occurred. Six patients were entered at the 90-Gy dose level, and all six completed treatment to 90 Gy. One patient developed grade 3 esophagitis. No other grade 3 or 4 nonhematologic toxicities occurred. The hematologic toxicity encountered on the concurrent portion of treatment was generally mild. Grade 3 or 4 neutropenia occurred in six (24%) of 25 patients. No cases of febrile neutropenia were observed. Grade 3 thrombocytopenia occurred in two patients (4%). Three patients (6%) developed grade 3 or 4 anemia, whereas 16 patients (64%) experienced grade 2 or greater anemia. As a general measure of tolerance, the median change in weight of the patients comparing their baseline weight with their weight at the end of concurrent chemoradiotherapy was –4%, (range, –15% to +8%). Also, the median days of delay noted during the concurrent course of therapy was zero (range, 0 to 15 days). The dose-intensity of the concurrent carboplatin and paclitaxel was an AUC of 1.81/wk and 40.0 mg/m2/wk, respectively.
Late Toxicity
Overall Response, Survival, and Recurrence Patterns The median time of follow-up for survivors was 25 months (range, 10 to 35 months). The median survival was 24 months, with 1- and 2-year survival probabilities of 0.69 (95% CI, 0.51 to 0.87) and 0.46 (95% CI, 0.37 to 0.76), respectively (Fig 1). Eleven patients experienced disease recurrence or progression, with two patients having only local progression (one patient at 86 Gy and one at 90 Gy), three having locoregional progression, one having locoregional and distant progression, and five having distant-only progression (two had brain-only failures).
Unresectable, locally advanced, stage III NSCLC remains a therapeutic challenge to both medical and radiation oncologists. Because treatment strategies have become more aggressive, cure is possible in a minority of well-staged patients.11,17-19 The current standard of care for thoracic RT in unresectable stage III NSCLC was defined by the Radiation Therapy Oncology Group (RTOG) in RTOG 73-01.20 This trial compared 40 Gy (both split and continuous), 50 Gy, and 60 Gy in 378 patients using standard planning techniques. Despite identical 5-year survival rates, 60 Gy emerged as the winner based on a suggestion that early survival and locoregional control rates were superior for this arm of the trial. As previously noted, local control rates at 60 Gy are poor. Also, retrospective analyses of cooperative-group trials suggests that tumor-targeting errors are common, and uncertainty exists in at least one third of cases as to the exact tumor location and coverage when using standard planning techniques.9 We have adhered to this standard set forth in RTOG 73-01 for over two decades, with subsequent efforts in radiation oncology escalating the dose of thoracic RT to only 66 or 69 Gy bid in certain trials.18,19 The incorporation of three-dimensional treatment planning has the ability to improve the therapeutic index of TCRT by more accurately targeting the tumor and reducing the amount of normal tissue included in the radiation field, thereby reducing toxicity. This has allowed significant TCRT dose escalation (with or without chemotherapy) and improved the toxicity of combined-modality therapy at standard doses of TCRT.21 There are very few examples in the phase III setting where more aggressive RT has been evaluated. One example is the continuous hyperfractionated accelerated RT (CHART) trial by Saunders et al.22 In this trial, 563 patients with either stage III (60%) or medically inoperable stages I or II (40%) NSCLC were randomly assigned to either standard thoracic RT (60 Gy in 6 weeks) or CHART (54 Gy in 12 consecutive days, 3 fractions/d). There was a significant benefit in locoregional control, metastasis-free survival, and overall survival in favor of CHART. The 4-year survival rate was 7% for the standard arm versus 12% for the CHART arm (P = .008). This survival benefit came at the cost of increased acute toxicity consisting mainly of esophagitis. The ECOG recently reported preliminary results of a similar trial limited to stage III NSCLC patients.23 Sequential carboplatin and paclitaxel was used followed by a randomization to either standard thoracic RT (64 Gy) or hyperfractionated accelerated RT (57.6 Gy over 2.5 weeks, 3 fractions/d without weekends). Unfortunately, this trial was closed prematurely because it failed to reach its accrual goal and, therefore, is far from definitive. However, the 3-year survival for both the standard thoracic RT (14%) and the hyperfractionated accelerated RT (23%) arms were strikingly similar to the original CHART trial.22 Both of these experiences suggest that the current standard of care regarding thoracic RT is suboptimal and new strategies are needed. Our previous phase I/II trial (LCCC 9603) used induction carboplatin and paclitaxel followed by concurrent low-dose weekly carboplatin and paclitaxel with TCRT escalated from 60 to 74 Gy.10 The escalation of the TCRT dose to 74 Gy was accomplished without dose-limiting toxicity. This aggressive approach yielded a median survival of 24 months and a 5-year survival of 26% (95% CI, 15% to 38%) with acceptable acute and late toxicity.11 Analysis of recurrence patterns from that trial suggested that distant and locoregional failure occurred with equal frequency (34% and 25%, respectively). Clearly, novel strategies addressing both these issues were needed. The use of induction therapy in unresectable stage III NSCLC remains a standard paradigm based on the results of several phase III trials.17-19 It was originally established by Cancer and Leukemia Group B trial 8433 and was intended to address the issue of micrometastatic disease present in the majority of these patients. The use of this strategy was shown in a large randomized phase III trial to significantly reduce the risk of metastatic disease compared with using thoracic RT alone.8 We also recently reported that the GTV after induction chemotherapy was predictive of survival.12 This seems intuitive in that at any given radiation dose, smaller volumes of disease are theoretically more likely to be controlled compared with larger volumes.24 This also seems to be consistent with the observation that significant downstaging has been a consistent prognostic factor in most surgical series. Given these observations, the use of more aggressive induction therapy seemed appropriate. We previously developed a triplet regimen (CIP) in stage IV NSCLC demonstrating promising activity and good tolerability in fit patients.13,14 Although triplet regimens do not seem to enhance survival in the palliative setting in general, they seem to have higher response rates.25 We incorporated CIP as induction therapy, opting to use growth factor support because the primary toxicity in advanced NSCLC was neutropenia (78% grade 3 or 4, with a 20% rate of fever or neutropenia). We found this strategy to be well tolerated in this trial, with a 46% objective response rate and no early progression of disease during induction therapy. This is in contrast to our previous experience with carboplatin and paclitaxel,10 in which 13% of patients progressed during induction therapy with the majority progressing locally. Obviously, this trial cannot address what additional benefits triplet regimens may have over doublet regimens, but it suggests that they can be as well tolerated in this setting as they seem to be in the preoperative setting.26-28 The primary objective of this trial was to escalate the dose of TCRT from 78 to 90 Gy with concurrent weekly carboplatin and paclitaxel. This objective was accomplished with acceptable acute toxicity. It is of interest that those patients who developed severe acute toxicity did so by 50 to 70 Gy. It should be noted that the radiation parameters of the patients treated on this trial were favorable. Our previous experience9 suggested that the risk of severe acute esophagitis was significantly increased if the length of the esophagus receiving more than 60 Gy exceeded 13.5 cm (Spearman's correlation coefficient of 0.4, P = .008). However, the median length of the esophagus receiving more than 60 Gy was 6.5 cm, making our population a good-risk one from an acute esophagitis point of view. Likewise, most patients had a V20 less than 35%, although three patients had V20 values of 36% to 40%. We observed grade 3 radiation pneumonitis in one patient (4%). Certainly, within the TCRT planning constraints outlined in this population, escalation of the TCRT dose to 90 Gy with concurrent chemotherapy is possible with acceptable acute toxicity. The more troubling issue is related to the development of late toxicities. We did observe typical late toxicities of radiation including grade 2 esophageal strictures in three patients (12%) and the single case of grade 3 radiation pneumonitis just previously noted. Unusual toxicities were also observed in the form of bronchial stenosis in two patients and fatal hemoptysis in two patients. Bronchial stenosis is a known toxicity with brachytherapy29 but is not documented as a common toxicity with standard doses of external-beam thoracic RT. The cases of fatal hemoptysis are more concerning, particularly when no tumor was seen in the chest at the time of autopsy. Fatal hemoptysis has been described as a complication of brachytherapy and aggressive external-beam approaches.30-33 In our previous trial, initial locoregional failures occurred in 35% of patients who experienced treatment failure despite the dose escalation of TCRT up to 74 Gy. We designed the current trial to evaluate the feasibility of further dose escalation with concurrent chemotherapy given the fact that bulky, intrathoracic disease would likely require doses of TCRT commonly used in cancers in other anatomic sites such as head and neck, prostate, and cervical cancer.9 Other investigators have also pursued dose escalation of TCRT using several different strategies and patient populations.34-40 The trials outlined in Table 4 included varying percentages of stage III NSCLC patients (41% to 100%). Elective nodal regions were irradiated in some trials10,34,38,39 but not others.35-37,40 Our decision to deliver elective nodal irradiation was based on the acceptable acute toxicity seen in our previous trial,10 the general acceptance of its use for the past three decades,20 and the potential for higher volume micrometastatic disease to be harbored at these sites.41,42 As has been demonstrated in early-stage NSCLC, standard staging studies that include PET and CT fail to identify up to 10% of patients with mediastinal-node involvement,41,42 and pathologic complete responses of up to 18% have been obtained with 45 Gy of radiation delivered with concurrent chemotherapy.43 Despite combined-modality therapy being a standard of care,3 not all trials routinely used induction chemotherapy and none of them, with the exception of this study and another of our previous studies,10 used concurrent chemotherapy. The dose-escalation schemes in some of the trials were dictated by the volume of irradiated lung,36 the V20,37,38 or the relative mean lung dose.40 As is shown in Table 4, the doses of TCRT attained were generally in excess of 74 Gy, with acceptable rates of esophagitis and pneumonitis. Taken together, these nine trials suggest that TCRT doses ranging from 74 to 90 Gy are feasible when dedicated treatment planning parameters using three-dimensional techniques are used.
Our trial differed from all the other previously noted dose-escalation trials in several ways. All the patients who entered had stage III NSCLC. All of the patients received concurrent weekly chemotherapy, which, in general, increases the risk of acute toxicity, particularly esophagitis. Also, the use of sequential or induction therapy was not as consistent among the other trials as it was in our study. In our trial, the majority of patients had V20 values of 20% to 35%. As demonstrated, we were able to successfully escalate the TCRT dose from 78 to 90 Gy with concurrent carboplatin and paclitaxel, with acceptable acute toxicity. In summary, because locoregional control rates with standard doses of thoracic RT and standard planning techniques remain poor,8 novel approaches are needed to enhance locoregional control, particularly in the unresectable patient. This report and the data presented in Table 4 clearly establish the safety of dose-escalated approaches in selected stage III NSCLC patients, although this strategy is not without its risks. Because improvements in locoregional control could improve survival, as has been shown in both NSCLC44,45 and small-cell lung cancer,46 the strategy of dose-escalated TCRT needs to be further explored in unresectable stage III NSCLC. We believe the current standard of 60 Gy as defined in RTOG 73-0120 is inadequate. Although our trial and others10,34-40 establish the feasibility of doses in excess of 74 Gy using three-dimensional treatment planning, the potential risk of severe toxicity exists, and this treatment could only be justified if a survival benefit was realized at higher doses. For these reasons, we believe it is reasonable and timely to address this issue in a randomized phase III trial comparing 60 Gy of radiation with a dose of 74 Gy or greater.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Mark A. Socinski, Bristol-Myers Squibb.
Presented at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Salt Lake City, UT, October 19-23, 2003; the 10th World Conference in Lung Cancer (Innovations in Chemoradiation), Vancouver, Canada, August 10-14, 2003; and the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
20 Gy (V20), spinal cord received 50 Gy, and brachial plexus received 66 Gy. No dose limits were used for the esophagus, trachea, or heart. 
