doi:10.1016/j.ijrobp.2006.07.1337 Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 5, pp. 1399 1407, 2006 Copyright 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$ see front matter CLINICAL INVESTIGATION Lung ANALYSIS OF CLINICAL AND DOSIMETRIC FACTORS ASSOCIATED WITH TREATMENT-RELATED PNEUMONITIS (TRP) IN PATIENTS WITH NON SMALL-CELL LUNG CANCER (NSCLC) TREATED WITH CONCURRENT CHEMOTHERAPY AND THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY (3D-CRT) SHULIAN WANG, M.D.,* ZHONGXING LIAO, M.D., XIONG WEI, M.D., HELEN H. LIU, PH.D., SUSAN L. TUCKER, PH.D., CHAO-SU HU, M.D., RODHE MOHAN, PH.D., JAMES D. COX, M.D., AND RITSUKO KOMAKI, M.D. *Department of Radiation Oncology, Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Departments of Radiation Oncology, Radiation Physics, and Biostatistics and Applied Mathematics, The University of Texas M. D. Anderson Cancer Center, Houston, TX Purpose: To investigate factors associated with treatment-related pneumonitis in non small-cell lung cancer patients treated with concurrent chemoradiotherapy. Patients and Methods: We retrospectively analyzed data from 223 patients treated with definitive concurrent chemoradiotherapy. Treatment-related pneumonitis was graded according to Common Terminology Criteria for Adverse Events version 3.0. Univariate and multivariate analyses were performed to identify predictive factors. Results: Median follow-up was 10.5 months (range, 1.4 58 months). The actuarial incidence of Grade >3 pneumonitis was 22% at 6 months and 32% at 1 year. By univariate analyses, lung volume, gross tumor volume, mean lung dose, and relative V5 through V65, in increments of 5 Gy, were all found to be significantly associated with treatment-related pneumonitis. The mean lung dose and rv5 rv65 were highly correlated (p < 0.0001). By multivariate analysis, relative V5 was the most significant factor associated with treatment-related pneumonitis; the 1-year actuarial incidences of Grade >3 pneumonitis in the group with V5 <42% and V5 >42% were 3% and 38%, respectively (p 0.001). Conclusions: In this study, a number of clinical and dosimetric factors were found to be significantly associated with treatment-related pneumonitis. However, rv5 was the only significant factor associated with this toxicity. Until it is better understood which dose range is most relevant, multiple clinical and dosimetric factors should be considered in treatment planning for non small-cell lung cancer patients receiving concurrent chemoradiotherapy. 2006 Elsevier Inc. Treatment related pneumonitis, Non small-cell lung cancer, Concurrent chemoradiotherapy, Three-dimensional conformal radiotherapy. INTRODUCTION Treatment-related pneumonitis (TRP) is one of the major acute, dose-limiting toxicities resulting from chemotherapy and thoracic radiotherapy. The diagnosis of TRP, which typically occurs 3 9 months after radiotherapy, is established by a history of chemotherapy and radiotherapy, radiographic evidence, and clinical presentation. The typical radiologic manifestation is areas of ground-glass opacity or consolidation in the irradiated lung that conforms to the Reprint requests to: Zhongxing Liao, M.D., Department of Radiation Oncology, Unit 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Tel: (713) 792-8653; Fax: (713) 745-6694; E-mail: zliao@mail.mdanderson.org Presented at the 47th annual meeting of American Society of Therapeutic Radiology and Oncology (ASTRO), October 16 20, 2005, Denver, CO, 2005. shape and size of the treatment portals (1). The symptoms of TRP are dry cough, low-grade fever, chest pain, and shortness of breath. TRP can also present as ipsilateral pleural effusion and consolidation of the lung. Treatment for TRP is largely empiric and nonspecific, consisting of oral or intravenous steroids, oxygen, and, sometimes, assisted ventilation. TRP can be lethal if patients are not responsive to treatment. The clinical symptoms of TRP can lead to a poor quality of life for lung cancer patients (2). Supported by Radiology Society of North America Research and Education Program, Grant to: Teach the Teachers from Emerging Nations. Acknowledgment The authors wish to thank Ms. Barbara E. Lewis for her excellent assistance in the preparation of this manuscript. Received Dec 21, 2005, and in revised form July 14, 2006. Accepted for publication July 14, 2006. 1399
1400 I. J. Radiation Oncology Biology Physics Volume 66, Number 5, 2006 The reported incidence of TRP ranges from 13% to 44%, with variation among reports because of inconsistencies in the criteria used to define TRP, heterogeneity in patient populations, and differences in treatment regimens and radiotherapy techniques (3 16). Several clinical factors are believed to influence the risk of TRP, including poor performance status (Eastern Cooperative Oncology Group) (17), poor pulmonary function before radiotherapy (17), chronic obstructive pulmonary disease (COPD) (14), lowerlobe tumors (18), concurrent chemotherapy (18), high total radiation dose, and high radiation dose per fraction (19). Many studies have also shown that dosimetric factors, such as mean lung dose (MLD) (4, 7, 11, 12, 14 16, 20) and percentage volume of lung receiving more than a threshold dose (V dose )(8, 10 13, 15, 20 22), are significant predictive factors for TRP. When these dosimetric factors are analyzed together with the clinical factors, the clinical factors lose their predictive value for TRP in most studies (8 10, 13, 16, 22); only a few factors, such as concurrent smoking (11), history of COPD (14), and induction chemotherapy with mitomycin (14), retain their predictive value. However, most studies have included patients who were treated with radiotherapy alone or with varying combinations of chemo- and radiotherapy; only in one small study were all patients treated with concurrent chemoradiotherapy (13). Treatment details, including use of chemotherapy, were not provided in other studies (4, 12). The lack of information on important variables (chemotherapy) that could influence the incidence of TRP in these studies has caused confusion concerning the actual risk of TRP after irradiation. We therefore performed a retrospective investigation to identify clinical and dosimetric factors predictive of TRP in patients with a diagnosis of locally advanced non small-cell lung cancer (NSCLC) who were treated with concurrent chemotherapy and three-dimensional conformal radiation therapy (3D-CRT), a recently developed radiotherapy technique that allows evaluation of the spatial dose distribution to irradiated tissue. This study is unique in that the population included is homogeneous and consistently treated, allowing focused analysis of a limited number of variables potentially associated with TRP. PATIENTS AND METHODS Patients We retrospectively reviewed the medical and radiation records of NSCLC patients who were treated consecutively between January 2000 and December 2003 in the Department of Radiation Oncology at The University of Texas M. D. Anderson Cancer Center. Patients were included if they had newly diagnosed and pathologically confirmed NSCLC, treatment with concurrent chemotherapy and definitive 3D-CRT, a lung dose volume histogram (DVH) that was recoverable from institutional archives, and availability of both radiographic images and symptom assessment for determining the occurrence of TRP. Patients were excluded if they had NSCLC of unknown stage, treatment with intensity-modulated radiotherapy, treatment with concurrent celecoxib or amifostine during radiotherapy, treatment with unknown concurrent chemotherapy regimens, radiotherapy with a break of more than 5 days, radiation with inconsistent doses per fraction, or total radiation doses less than 50.4 Gy. This retrospective chart review study was approved by the institutional review board and informed consent was waived. Compliance with Health Insurance Portability and Accountability Act regulations was strict. Treatments The patients chemotherapy regimens were determined by the treating medical oncologists according to M. D. Anderson Cancer Center s institutional standards. All patients had radiotherapy simulation on regular or fourdimensional (4D) computed tomography (CT) simulators in a supine position immobilized with a T bar, wing board, and Vac-lock cradle. CT scans with slices 3-mm thick were obtained from the mandible to the lower edge of the liver. When a 4D CT simulator was used, patient respiratory motion was monitored and recorded using a Varian Radiation Portal Monitor system. The gross tumor volume (GTV) was defined as the total volume of the primary and nodal tumor masses visualized on any radiographic images. The clinical target volume (CTV) was defined as the GTV plus a 0.8-cm margin, and the planning target volume (PTV) was defined as the CTV plus a 1-cm to 1.5-cm margin for setup uncertainty and respiratory motion. The regional lymph nodes were not electively irradiated. The internal target volume, which was used if the patient underwent 4D CT simulation, was determined by adding 8-mm CTV to the GTVs delineated on the maximal intensity projection image, thus creating a maximal intensity projection-gtv that combined the extension of GTVs at the 10 phases of each respiratory cycle on a 4D CT simulation scan. The PTV was internal target volume plus 1 cm in these cases. All patients 3D-CRT treatment plans were designed on a commercial treatment planning system (Pinnacle 3, Philips Medical Systems, Andover, MA) to deliver the prescribed dose to 95% of the planning target volume. Four or five fields were usually used in the treatment plan, typically anteroposterior angles in combination with oblique beams. Heterogeneity correction was applied to all dose calculations. Lung DVHs were computed from the 3D dose distributions and were extracted from the plans. DVH parameters The total normal lung volume was defined as the total lung volume minus the primary GTV and volume of the trachea and main bronchi. The following dosimetric parameters were generated from the DVH for total normal lung: lung volume, MLD, and relative and absolute volumes of lung receiving more than a threshold dose D of radiation (rvd and avd, respectively), where values of D considered were 5 80 Gy in increments of 5 Gy. We examined the association of these factors and the GTV with the occurrence of Grade 3 pneumonitis, assessed as described in the following section. Evaluation of TRP All patients were examined by their treating radiation oncologists weekly during concurrent chemoradiotherapy and 4 6 weeks after completion of treatment. The patients were then followed every 3 months for the first 3 years and every 6 months thereafter unless they had symptoms that required immediate examination or intervention. Radiographic examination by chest X-ray or CT was performed at each follow-up visit after completion of chemoradio-
Analysis of clinical and dosimetric factors S. WANG et al. 1401 therapy. For this analysis, we reviewed all relevant dictated clinical notes by the treating physicians and all radiographic images for every patient. Treatment related pneumonitis was diagnosed by clinical presentation and any of the following radiographic abnormalities: ground-glass opacity, attenuation, or consolidation changes within the radiation field. TRP was graded according to the National Cancer Institute s Common Terminology Criteria for Adverse Events (CTC) version 3.0 (23) as follows: Grade 1 pneumonitis was asymptomatic and diagnosed by radiographic findings only; Grade 2 pneumonitis was symptomatic but did not interfere with daily activities; Grade 3 pneumonitis was symptomatic and interfered with daily activities or required administration of oxygen to the patient; Grade 4 pneumonitis required assisted ventilation for the patient; and Grade 5 pneumonitis was fatal. Statistical analysis The endpoint for this analysis was occurrence of Grade 3 pneumonitis. Time to Grade 3 pneumonitis was calculated from the end of RT. Patients without observed Grade 3 pneumonitis were censored at the date of last available follow-up. Kaplan- Meier analysis was used to calculate the actuarial incidence of TRP as a function of time from the end of 3D-CRT. The log rank test was used to perform univariate analyses of differences in times to Grade 3 pneumonitis among patients by patient-related factors (sex, age, smoking history, COPD, cardiovascular disease, and Karnofsky performance status), disease-related factors (tumor location and stage), treatment-related factors (radiation dose, use of induction chemotherapy, and chemotherapy agents), and DVHderived dosimetric parameters. A recursive partitioning technique based on the null Martingale residuals (NMRs) (24) derived from a fit of the null (constant-only) Cox proportional hazards model to the data were used to identify potential significant cut points for dividing the patient population into subgroups based on continuous factors from the DVH (lung volume, GTV, MLD, rv5 rv80, and av5 av80). Briefly, the partitioning technique consisted of considering, for each continuous factor, all possible cut points for dividing the patient population into two subgroups with at least 10% of the patients in each subgroup. The cut point selected for each factor was the one maximizing the absolute difference in mean NMRs between the two corresponding subgroups. A multivariate analysis was performed by applying this partitioning technique recursively on the subgroups until no further significant difference was found in time to Grade 3 TRP between subgroups. Pairwise Pearson correlation analysis was used to calculate the correlation between factors. p 0.05 was considered statistically significant. RESULTS A total of 223 patients satisfied the inclusion criteria. The median duration of follow-up was 10.5 months (range, 1.4 58 months). The median age of the group was 61 years (range, 35 81 years). The patients clinical characteristics are shown in Table 1. The median radiation dose was 63 Gy (range, 50.4 69.6 Gy), the median dose per fraction was 1.8 Gy (range, 1.2 2 Gy), and the median number of fractions was 35 (range, 23 58). Of the 223 patients, 132 received induction chemotherapy, and 113 of those received carboplatin plus taxanes. Table 1. Distribution of the demographic, clinical, and treatment factors and their association with time to Grade 3 treatment-related pneumonitis for 223 patients Characteristic No. of patients p value* Age 0.122 60 years 124 60 years 99 Sex 0.642 Male 116 Female 107 Chronic obstruction pulmonary disease 0.774 Yes 43 No 177 Unknown 3 Smoking history 0.095 Current smoker 53 Quit smoking 149 Never smoked 18 Unknown 3 Cardiovascular disease history 0.145 Yes 93 No 123 Unknown 7 Karnofsky performance status 0.631 60 6 70 11 80 111 90 22 Unknown 73 Affected lung 0.336 Left 96 Right 123 Mediastinum 4 Tumor location 0.421 Upper lobe 137 Middle lobe 34 Lower lobe 52 Clinical stage 0.953 II 9 IIIA 86 IIIB 114 IV 14 Induction chemotherapy 0.635 Yes 132 No 91 Chemotherapy with taxanes 0.469 Yes 172 No 51 Chemotherapy with cisplatin 0.729 Yes 55 No 168 Chemotherapy with carboplatin 0.875 Yes 166 No 57 Chemotherapy with etoposide 0.462 Yes 48 No 175 Radiation fractionation 0.947 Once daily 187 Twice daily 36 Radiation dose 0.800 60 Gy 162 60 Gy 61 * Comparison of the time to Grade 3 treatment-related pneumonitis between the subgroups with available data information (not including the subgroups with unknown data).
1402 I. J. Radiation Oncology Biology Physics Volume 66, Number 5, 2006 Table 2. Induction chemotherapy regimens for 132 non small-cell lung cancer patients Chemotherapy regimen No. of patients Carboplatin plus taxanes 113 Cisplatin plus taxanes 6 Gemcitabine plus vinorelbine 4 Cisplatin plus etoposide 3 Carboplatin plus gemcitabine 1 Cisplatin plus gemcitabine 1 Docetaxel 1 Unknown 3 Carboplatin plus taxanes was the most common chemotherapy regimen for concurrent chemotherapy, followed by cisplatin and etoposide. The distributions of the induction and concurrent chemotherapy regimens are shown in Tables 2 and 3. The actuarial incidence of Grade 3 TRP was 22% (95% CI, 17 29%) at 6 months and 32% (95% CI, 26 40%) at 12 months for the whole group (Fig. 1). The majority of cases of TRP occurred 1 6 months from the end of radiotherapy. The incidence of TRP gradually reached a plateau at 12 months and remained constant thereafter. Table 1 shows the association between patient-, disease-, and treatment-related variables and incidence of TRP. Significant differences in time to Grade 3 TRP were found in subgroups of patients identified by the partitioning analysis for the following factors: GTV, lung volume, mean lung dose, and relative lung volumes rv5 rv65. Table 4 lists the cut points identified for these factors, as well as the incidence of TRP in the resulting subgroups and the results of log rank comparisons of the times to TRP in the subgroups. The other dosimetric factors considered, including av5 av80 and rv70 rv80, were not significantly associated with the time to occurrence of Grade 3 TRP. Patients with a higher mean lung dose had a higher incidence of TRP (Fig. 2). The 1-year actuarial incidence of Grade 3 TRP in patients with MLD 16.5 Gy or those with MLD 16.5 Gy was 13% vs. 36%, respectively (Fig. 3). Table 3. Concurrent chemotherapy regimens for 223 non small-cell lung cancer patients treated with concurrent chemoradiotherapy Chemotherapy regimen No. of patients Carboplatin plus taxanes 155 Cisplatin plus etoposide 43 Carboplatin plus etoposide 5 Cisplatin plus taxanes 3 Cisplatin plus irinotecan 2 Carboplatin plus gemcitabine 1 Carboplatin plus irinotecan 1 Taxanes alone 6 Cisplatin alone 3 Carboplatin alone 1 Gemcitabine alone 1 Vinorelbine alone 1 Doxorubicin alone 1 Fig. 1. Freedom from Grade 3 treatment-related pneumonitis among 223 non small cell lung cancer patients treated with concurrent chemoradiotherapy. RT radiotherapy. There were no significant differences in the times to occurrence of Grade 3 TRP for patients subdivided by the following clinical characteristics including: sex, age, COPD history, smoking history, cardiovascular disease history, and Karnofsky performance status. There was also no significant association between the time to occurrence of Grade 3 TRP and disease-related or treatment-related factors, including affected lung; tumor location, histology, and clinical stage group; use of induction chemotherapy; inclusion of taxanes, cisplatin, carboplatin, or etoposide in the induction or concurrent chemotherapy regimen; total radiation dose; and radiation fractionation. In the partitioning analysis, rv5 was the factor found to provide the cut point with the greatest corresponding difference in NMRs between patient subgroups. Patients with rv5 42% were significantly more likely to be free from Grade 3 TRP than were patients with rv5 42% at all time points (Fig. 4; p 0.001). The 6-month and 1-year actuarial incidences of Grade 3 TRP were 3% (95% CI, 0 22%) and 3% (95% CI, 0 22%) in patients with rv5 42% and 26% (95% CI, 19 33%) and 38% (95% CI, 30 47%), respectively, in patients with rv5 42%. The property of these curves identified by the partitioning analysis is that almost all of the patients with observed TRP belonged to the subgroup of patients with rv5 42%. The multivariate partitioning analysis did not identify any further significant cut points after the division based on rv5. DISCUSSION Our study included a large number of patients whose NSCLC was at a similar stage, were treated in a relatively uniform manner with concurrent chemotherapy and 3D- CRT, and were evaluated at a single institution. We investigated clinical and dosimetric factors for their association with the time to occurrence of Grade 3 TRP, measured from the end of radiotherapy. We analyzed time to TRP, instead of incidence of TRP, because of the large number of patients who succumbed to disease at less than 6 months
Analysis of clinical and dosimetric factors S. WANG et al. 1403 Table 4. Incidence of Grade 3 TRP in patient subgroups defined by univariate partitioning analysis of MLD, GTV, lung volume, and rv5 through rv65 Variable Median (range) Group No. of patients Incidence of TRP at 1 year (95% CI) p value* MLD 22.4 Gy (5.1 44.6 Gy) 16.5 Gy 30 13% (4 35%) 0.018 6.5 Gy 193 36% (28 44%) GTV 143 cc (1.5 1186 cc) 310 cc 181 28% (21 36%) 0.003 310 cc 42 54% (37 73%) Lung volume 3349 cc (1639 7871 cc) 5040 cc 200 35% (28 44%) 0.024 5040 cc 23 6% (1 33%) rv5 57% (12 98%) 42% 32 3% ( 1 22%) 0.001 42% 191 38% (30 47%) rv10 47% (18 76%) 33% 25 5% (1 28%) 0.007 33% 198 37% (29 45%) rv15 43% (9 90%) 31% 26 4% (1 27%) 0.005 31 197 37% (29 46%) rv20 38% (8 78%) 28% 30 4% (1 24%) 0.003 28% 193 37% (30 46%) rv25 34% (7 71%) 27% 33 3% ( 1 22%) 0.001 27% 190 38% (30 47%) rv30 32% (7 66%) 22% 28 10% (3 35%) 0.014 22% 195 36% (28 44%) rv35 29% (6 59%) 24% 56 12% (5 28%) 0.001 24% 167 39% (31 49%) rv40 27% (6 56%) 22% 54 12% (5 28%) 0.001 22% 169 39% (31 48%) rv45 24% (1 52%) 20% 61 14% (6 28%) 0.001 20% 162 39% (31 49%) rv50 21% (0 48%) 14% 35 15% (6 37%) 0.021 14% 188 36% (28 44%) rv55 18% (0 46%) 15% 75 16% (8 31%) 0.001 15% 148 40% (31 50%) rv60 15% (0 45%) 10% 44 16% (7 35%) 0.018 10% 179 36% (29 45%) rv65 10% (0 43%) 11% 119 25% (17 36%) 0.021 11% 104 40% (30 52%) Abbreviations: TRP treatment-related pneumonitis; MLD mean lung dose; GTV gross tumor volume. * Log rank test of differences in time to TRP. of follow-up and thus could not be assessed for occurrence of TRP. Although 6 months after treatment is generally used as a cutoff for diagnosing TRP, there were some patients in the present cohort who experienced this end point at times up to about 14 months after the end of treatment (Fig. 1). Of the clinical factors investigated, we found that lung volume and GTV were the patient- and disease-related factors that were associated with the incidence of CTC 3.0 Grade 3 TRP, suggesting that the remaining volume of functional lung is critical for patients well being after chemoradiation. Of the dosimetric factors investigated, the MLD and relative V5 V65, in increments of 5 Gy, were all found to be significantly associated with the incidence of CTC 3.0 Grade 3 TRP. The dosimetric factors were highly correlated (p 0.0001). In multivariate analysis, rv5 was highly predictive of Grade 3 TRP, with a 1-year actuarial incidence of Grade 3 TRP of 3% vs. 38% in the subgroups of patients having rv5 42% vs. rv5 42% (p 0.001). Although rv5 was the only factor selected by the multivariate recursive partitioning analysis, many of the other dosimetric factors investigated in our study, including MLD and rv10 rv65, were significantly associated with the incidence of Grade 3 TRP; these factors are highly correlated with one another and with rv5 (Table 5). The high level of correlation makes it impossible to reach a definitive conclusion as to which dose level is most strongly associated with the risk of Grade 3 TRP. Although the partitioning analysis suggests that very low doses, near 5 Gy, might be most relevant, we investigated the significance of differences in time to Grade 3 TRP in all possible partitions of the patient cohort by dose (5 80 Gy in increments of 1 Gy) and relative volume (1% to 99%) in which each subset included at least 10% of the patients. Figure 5 illustrates all partitions considered (small dots) as well as the dose volume cut points (solid circles) for which the comparison of time to Grade 3 TRP in the corresponding subgroups reached statistical significance (p 0.05, log rank test). As shown in Fig. 5, there is a wide variety in the dose volume criteria corresponding to significant differences in time to Grade 3 TRP. In view of the high
1404 I. J. Radiation Oncology Biology Physics Volume 66, Number 5, 2006 Fig. 2. Actuarial 1-year incidence of treatment-related pneumonitis (TRP) in each of five approximately equal patient subgroups defined by mean lung dose (MLD) (n 44, 45, 45, 45, and 44). Data points show average MLD per patient subgroup and actuarial 1-year TRP estimates for that group. The vertical error bars show the standard errors of the actuarial 1-year TRP estimates; the horizontal error bars show the standard deviations of MLD in each group. correlation among relative lung volumes exposed to different doses (Table 5), it is not yet possible to conclusively determine which dose range is most important in inducing Grade 3 TRP. Despite its retrospective nature, our study is unique because the patient population is quite homogeneous compared with most published studies to date: 96% of the patients had Stage III or IV NSCLC, 65% had Karnofsky performance status 70, 96% received platinum-based concurrent chemotherapy, and 79% had no COPD. The homogeneity of the study population probably minimized variation in patient-, disease-, and treatment-related variables that might be associated with risk of TRP, allowing a relatively pure analysis of dosimetric factors. Our findings are consistent with the results of many other studies published after the introduction of 3D-CRT (11, 12, 15, 20, 22). Some of the dose volume parameters identified in our study were also reported by Willner et al. (20) (rv10, V20, V30, and V40) or Fay et al. (22) (rv30, V40, and V50) Fig. 3. Effect of mean lung dose on freedom from Grade 3 treatment-related pneumonitis. RT radiotherapy. Fig. 4. Effect of rv5 on freedom from Grade 3 treatment-related pneumonitis. RT radiotherapy. to be significantly associated with the incidence of TRP. In addition, all of the dose volume parameters were highly correlated (25), suggesting that the shape of the DVH is perhaps more important than single points on the DVH curve such as rv20, rv5, or MLD in predicting the probability of TRP. In clinical practice, the total radiation dose that can be tolerated depends on the volume of tissue irradiated. Indeed, preclinical and clinical studies have shown that morbidity from TRP depends on the volume (26, 27) and region of the normal lung irradiated (25, 28, 29). In our study, the rv5 was the factor most strongly associated with Grade 3 TRP in a multivariate recursive partitioning analysis. This finding suggests that damage to the lung, which has functional subunits arranged in parallel, may be more dependent on the volume irradiated than on the radiation dose. Delivery of a small dose of radiation as low as 5 Gy to a large lung volume is not safe. This finding is consistent with a recent report from our group that volume of lung spared from 5 Gy was the most significant predictive factor for postoperative pulmonary complication after concurrent chemoradiation in patients with esophageal cancer (30). This finding is further supported by Gopal et al. (31), who observed a sharp loss in the diffusing capacity for carbon monoxide of normal lung exposed to as little as 13 Gy. The investigators concluded that a small dose of radiation to a large volume of lung could be much worse than a large dose to a small volume in functional lung damage. Yorke et al. (12) also reported that the risk of complications rises steeply above an MLD of 10 Gy, indicating a need to limit widespread irradiation of normal lung tissue, even at low doses. In contrast, Willner et al. (20) reported that logistic regression curves for rv10, rv20, rv30, and rv40 demonstrated sharper increases in risk of TRP at higher doses, and the investigators concluded that a small dose, such as 10 Gy, to a large volume of normal lung is preferable to a large dose, such as 40 Gy, to a small volume. We believe that the volume of normal lung receiving low-dose irradiation should be minimized to avoid severe TRP. The low- and high-dose volumes are highly correlated, so we need to consider multiple dosimetric factors for an individual treatment plan.
Analysis of clinical and dosimetric factors S. WANG et al. 1405 Table 5. Pearson correlation coefficients between dosimetric factors; p 0.001 in each case MLD rv5 rv15 rv25 rv35 rv45 rv55 rv65 MLD 1.000 rv5 0.783 1.000 rv15 0.891 0.847 1.000 rv25 0.944 0.759 0.915 1.000 rv35 0.954 0.696 0.832 0.938 1.000 rv45 0.925 0.601 0.726 0.849 0.952 1.000 rv55 0.824 0.411 0.556 0.693 0.802 0.901 1.000 rv65 0.656 0.211 0.361 0.493 0.597 0.673 0.823 1.000 Abbreviation: MLD mean lung dose. Techniques that decrease the volume of lung covered by a threshold dose include intensity-modulated radiotherapy and proton therapy; the latter seems more promising than the former in treating lung cancer, because proton therapy reduces the volume of lung irradiated with a low dose, whereas intensity-modulated radiotherapy involves a greater volume of the lung in low dose region if more than five beam angles are used (32). Consistent with other studies (4, 7, 8, 11, 16), the current study showed that MLD is an important dosimetric factor associated with the incidence of severe TRP and that a dose near 20 Gy (16.5 Gy) is a critical MLD cut point in predicting the incidence of TRP. It has been reported that when the MLD exceeds 20 Gy, the incidence of TRP is more than 20% (Table 6), although different grading systems for TRP were used in the aforementioned studies. Also, Oetzel et al. (4) and Willner et al. (20) found that the MLD of the ipsilateral lung is more important than the MLD of the total lung in predicting the risk of TRP. The incidence of Grade 2 TRP, as diagnosed using CTC Fig. 5. Comparison of time to Grade 3 treatment-related pneumonitis (TRP) in patients subgroups divided according to magnitude (%) of relative volume of lung receiving more than a threshold dose D of radiation, for D 5 to 80 Gy. Small dots indicate comparisons for which each subset of the cohort included at least 10% of the patients; solid circles indicate comparisons for which the comparison of time to Grade 3 TRP in the corresponding subgroups reached statistical significance p 0.05 (log rank test). 2.0, in patients treated with concurrent chemoradiation was 27.3% at 6 months and 31.2% at 12 months in a report by Tsujino et al. (13). Only 1% of the 71 patients in that study developed CTC 2.0 Grade 3 TRP, compared with 22% at 6 months and 32% at 12 months in the current study. In another study, the incidence of TRP was higher in patients who were treated with concurrent chemoradiation than in those treated with radiation only (33), indicating that chemotherapy might have sensitized the patients normal lungs to radiation. It is difficult to compare the incidence of TRP in the current study with incidences in other studies because some included both lung cancer and esophageal cancer patients, who tend to have a low incidence of TRP (4), and most of the studies included both patients who were treated with and without chemotherapy or patients who were treated with sequential and concurrent chemotherapy (8, 11, 14, 16, 17, 22). Nonetheless, the 22% incidence of CTC 3.0 Grade 3 TRP in the current study seems high compared with the 1% incidence of CTC 2.0 Grade 3 TRP in the study by Tsujino et al. This discrepancy might be explained by a difference in the scoring criteria: CTC 2.0 was used in their study, and CTC 3.0 was used in the current study. There was also a difference in the radiation techniques used: in their study, patients were treated with anteroposterior fields followed by oblique fields; in the current study, patients were treated with all planned beams daily, and more than two fields a day were treated, which may have increased the volume of lung receiving low-dose radiation on a daily basis. We plan to investigate the association between number of fields treated daily and incidence of TRP. The severity of lung damage by radiation is believed to depend on four factors: the total radiation dose, the volume of lung irradiated, the radiation dose per treatment (or fraction size), and the use of concurrent chemotherapy (26, 34). In the current study, the majority of patients were irradiated with a conventional dose schedule (1.8 2.0 Gy per fraction, once daily), and 36 patients were treated with hyperfraction radiation (1.2 Gy per fraction, twice daily). There was no difference in the incidence of TRP in patients between the two treatment groups. However, because of the imbalance in the numbers of patients on the two fractionation schedules, it is difficult to draw conclusions. There are no data on whether different lung dosi-
1406 I. J. Radiation Oncology Biology Physics Volume 66, Number 5, 2006 Table 6. Effect of MLD on incidence of TRP Author, year (ref. no.) Treatment Criteria, grade Incidence of TRP for the whole group% MLD, Gy Observed rate of TRP for MLD subgroup% Oetzel et al., 1995 (4) 28% 3D-CRT, chemotherapy not mentioned Kwa et al., 1998 (7) 100% 3D-CRT, 14% chemotherapy Graham et al., 1999 (8) 100% 3D-CRT 42%, chemotherapy Hernando et al., 2001 (11) 100% 3D-CRT 18%, concurrent chemotherapy, 51% surgery Kim et al., 2005 (16) 100% 3D-CRT, 58% concurrent chemotherapy, 26% surgery Current study 2005 100% 3D-CRT, 100% concurrent chemotherapy RTOG 1 15 15 0 17.5 20 13 22.5 25 21 27.5 43 SWOG 2 16 0 8 5 8 16 11 16 24 24 24 36 25 RTOG 2 14 at 6 months 20 8 20 24 Symptomatic CTC 2.0 1 19 10 10 10 20 16 21 30 27 30 44 RTOG 3 16 10 0 10 14.9 11 15 45 CTC 3.0 3 22 at 6 months 16.5 13 16.5 36 Abbreviations: TRP treatment-related pneumonitis; MLD mean lung dose; RTOG Radiotherapy Oncology Group; SWOG Southwest Oncology Group; 3D-CRT three-dimensional conformal radiation therapy; CTC National Cancer Institute s Common Terminology Criteria for Adverse Events. metric parameters and cut points should be used for evaluating treatment plans in which different fractionation schedules are used, although it is well known that latereacting tissues such as lung tissue are sensitive to the fractionation dose. Roach et al. (19) found a higher incidence of TRP in patients treated with fractionation doses greater than 2.67 Gy, and twice-daily irradiation seemed to reduce the risk if the same total daily dose was given as a single fraction. Because the majority of patients in our study were treated with a conventional fraction dose, further study is needed to determine the effect of hyperfractionated radiation on the risk of TRP. In summary, our findings suggest that lung volume, GTV and multiple dosimetric factors that define the shape of the DVH, rather than a single factor, should be considered in the evaluation of treatment planning for NSCLC patients treated with definitive concurrent chemotherapy and 3D- CRT. Our results provide crucial information on lung tolerance, as defined by CTC 3.0, in NSCLC patients treated with concurrent chemoradiotherapy. REFERENCES 1. Choi YW, Munden RF, Erasmus JJ, et al. Effects of radiation therapy on the lung: Radiologic appearances and differential diagnosis. Radiographics 2004;24:985 998. 2. Movsas B, Raffin TA, Epstein AH, et al. Pulmonary radiation injury. Chest 1997;111:1061 1076. 3. Martel MK, Ten Haken RK, Hazuka MB, et al. Dose-volume histogram and 3-D treatment planning evaluation of patients with pneumonitis. Int J Radiat Oncol Biol Phys 1994;28:575 581. 4. Oetzel D, Schraube P, Hensley F, et al. Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 1995;33:455 460. 5. Marks LB, Munley MT, Bentel GC, et al. Physical and biological predictors of changes in whole-lung function following thoracic irradiation. Int J Radiat Oncol Biol Phys 1997;39: 563 570. 6. Armstrong J, Raben A, Zelefsky M, et al. Promising survival with three-dimensional conformal radiation therapy for nonsmall cell lung cancer. Radiother Oncol 1997;44:17 22. 7. Kwa SL, Lebesque JV, Theuws JC, et al. Radiation pneumonitis as a function of mean lung dose: An analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys 1998;42:1 9. 8. Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1999;45:323 329. 9. Sunyach MP, Falchero L, Pommier P, et al. Prospective evaluation of early lung toxicity following three-dimensional conformal radiation therapy in non-small-cell lung cancer: Preliminary results. Int J Radiat Oncol Biol Phys 2000;48:459 463. 10. Fu XL, Huang H, Bentel G, et al. Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V(30) and transforming growth factor beta. Int J Radiat Oncol Biol Phys 2001;50: 899 908. 11. Hernando ML, Marks LB, Bentel GC, et al. Radiation-induced pulmonary toxicity: A dose-volume histogram analysis in 201 patients with lung cancer. Int J Radiat Oncol Biol Phys 2001; 51:650 659. 12. Yorke ED, Jackson A, Rosenzweig KE, et al. Dose-volume
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