American Journal of Clinical Oncology:
Original Article: Thoracic
Chemotherapy Significantly Increases the Risk of Radiation Pneumonitis in Radiation Therapy of Advanced Lung Cancer
Parashar, Bhupesh MD*; Edwards, Alison MS†; Mehta, Rajeev BA‡; Pasmantier, Mark MD§; Wernicke, A. Gabriella MD*; Sabbas, Albert PhD*; Kerestez, Roger S. MD¶; Nori, Dattatreyudu MD*; Chao, K. S. Clifford MD*
From the *Department of Radiation Oncology, Stich Radiation Center, Weill Cornell Medical Center, New York, NY; †Department of Public Health, Division of Biostatistics and Epidemiology, Weill Cornell Medical Center, New York, NY; ‡Northwestern University Feinberg School of Medicine, Evanston, IL; §Department of Medical Oncology, Weill Cornell Medical Center, New York, NY; and ¶Department of Hematology and Oncology, State University of New York, Stony Brook, NY.
Presented at the American Society for Therapeutic Radiology and Oncology, 2007.
Reprints: Bhupesh Parashar, MD, Department of Radiation Oncology, Stich Radiation Center, Weill Cornell Medical Center, New York, NY 10021. E-mail: firstname.lastname@example.org.
Introduction: The reported rate of developing radiation pneumonitis (RP) in patients receiving definitive radiation therapy (RT) for lung cancer is 5% to 36%. However, this incidence is probably underreported because of the nonspecific symptoms of RP that may be erroneously attributed to another cardiovascular or respiratory disorder. The objective of this study was to evaluate the incidence of RP in lung cancer patients receiving RT or chemoradiation therapy.
Methods: Of the 110 patients that were reviewed, 86 were chosen for a retrospective analysis. A diagnosis of RP was made based on clinical assessment in the first 6 to 12 months after RT. Radiation pneumonitis was graded as per Radiation Therapy Oncology Group grading criteria.
Results: The incidence of developing grade 2 or higher RP was significantly associated with addition of chemotherapy. The incidence of RP in patients receiving chemotherapy was 62.7% (42/67) versus 15.8% (3/19) in patients receiving no chemotherapy (P < 0.001). However, there was no significant effect of the type or sequence of chemotherapy on the incidence of RP. The risk of developing RP is 5 times greater in patients receiving chemotherapy when compared with those not receiving this treatment (hazard ratio: 5.0; 95% confidence interval 1.5, 16.1). In addition, patients in age group 61 to 70 years had a significantly increased risk of developing RP compared with patients of age 60 or younger (hazard ratio: 3.0; 95% confidence interval: 1.4, 6.5). Histology and radiation dose were not significant factors in development of RP.
Conclusion: The incidence of RP in patients receiving external-beam RT is significantly increased with addition of chemotherapy and 61 to 70 year age group.
Lung cancer is the leading cause of cancer death among men and women.1 In the United States, non-small cell lung cancer (NSCLC) comprises about 85% of lung cancer diagnosis and approximately 85% to 90% present with stage III (A/B) disease.2 On the basis of the results of several randomized trials,3–8 carboplatin/paclitaxel and radiation (RT) has been the standard of care of treatment of such patients. Small cell lung cancers are also treated with chemoradiation therapy (CRT), although cisplatin and etoposide is used as the chemotherapy standard.9,10
Radiation pneumonitis (RP) represents the acute phase in the development of radiation-induced lung injury. Onset of RP usually occurs after completion of RT, peaks at around 2 months, and stabilizes or resolves at 6 to 12 months. Diagnosis of RP is based on nonspecific symptoms such as dyspnea, cough, fever, and chest pain with or without an alteration in pulmonary functions. Radiographic changes in RP may reveal infiltration inside or outside the radiation field. Most commonly reported predictive factors to the development of RP include tumor location,11 pulmonary dysfunction before RT,12,13 age,14 V20, V30, mean lung dose, normal tissue complication probability,15–18 and addition of systemic agents.13,19
The reported incidence of moderate-to-severe RP in patients receiving RT/CRT has been reported to be 10% to 20%.20 However, this incidence is probably underreported because of the nonspecific symptoms of acute RP that may be erroneously attributed to another cardiovascular or respiratory disorder, and the time interval between completion of radiation and the development of symptoms. In addition, RP scoring is nonstandardized and may vary from one scoring system to another.
The objective of this study was to determine the incidence of clinical RP in lung cancer patients treated with RT/CRT and to determine the effects of chemotherapy, age, radiation dose, and histology in its incidence.
Between 2003 and 2008, 110 patients with lung cancer received 3-dimensional (3D) conformal radiation therapy. RT was delivered in conventional fractionation (1.8–2 Gy per fraction). Of the 110 patients, 86 patients with adequate follow-up and documentation were included in the retrospective analysis. Our study was performed in accordance with the guidelines of the institutional review board that approved the study. Informed consent was not required because of the retrospective chart analysis. The initial analysis included the complete history and physical examination and the imaging studies performed prior to and subsequent to completion of RT.
Radiation Techniques and Radiation Parameters
Radiotherapy was planned using standard 3D conformal techniques for all patients >95% of the planning target volume receiving the prescribed dose. Radiation therapy was administered using photon beams, with energy between 6 and 15 MV. Target volume consisted of the original and boost volumes if the radiation dose went beyond 50 Gy. Original volume was based on a planning CT scan taken before chemotherapy in the chemotherapy group, and included primary lesion, any grossly involved nodal sites, plus ipsilateral hilum, and mediastinum with a margin of 2 cm. Even if the primary tumor was in the lung periphery, only one radiation field was used to cover it and mediastinum. All radiotherapy plans and field arrangements were reviewed in quality assurance meetings in which consensus was obtained according to each patient's clinical circumstances. The mean lung dose, lung volume irradiated to 20 Gy (V20), and volume of lung irradiated to 30 Gy (V30) were used as dosimetric parameters to estimate the lung volume irradiated. The right lung and the left lung were contoured separately and then taken into consideration as a single structure called “total lung,” which was defined as follows, as in the study of Graham et al15: (Right lung + Left lung) − PTV. All treatment plans were approved if conventional dosimetric lung constraints were respected: V20 of 35% or lower, V30 of 18% or lower, and mean lung dose of 20 Gy or lower; moreover, the dose delivered to the spinal cord was limited to less than 45 Gy.
Evaluation of RP and Follow-Up
During or after completion of RT, patients were followed for a period 2 to 3 months till the acute reactions subsided and were then followed every 4 to 6 months in the Department of Radiation Oncology/Medical Oncology or cardiothoracic surgery. A diagnosis of RP was made based on clinical symptoms/radiographic changes in the first 6–12 months after RT. RP was graded as per the Radiation Therapy Oncology Group grading criteria (Table 1).
Patient and treatment characteristics were compared between those who were diagnosed with RP and those who did not develop the disease. All variables were considered as categorical, and were tested for associations with the outcome using Fisher exact test. Factors' associations with RP were examined using Cox proportional hazards models and were included in the final multivariable model if they were significantly associated with the outcome at the 0.1 level. For the survival analysis, patients were censored if they were lost to follow-up without being diagnosed with RP. The final model included age as a categorical predictor and chemotherapy. The association between chemotherapy and RP was further examined using the Kaplan-Meier product-limit survival function, taking into account those patients who were lost to follow-up. The log-rank test was used to test the magnitude of the association of this predictor with the outcome by comparing survival rates across time. All analyses were performed using SAS software version 9.1 (SAS Institute Inc, Cary, NC).
There were 37 men and 49 women with a median age of 68 years (range, 40–91 years). Cancer stage was determined in all except one patient as per the 2006 Joint Committee on Cancer guidelines. Of the total 86 patients, 2 patients had stage I NSCLC, 3 had stage II NSCLC, 64 had stage III/IV NSCLC, 12 had limited stage SCLC, 2 had extensive stage SCLC, 2 patients had recurrent NSCLC, and 1 patient's stage was not known, although the patient was considered to have localized cancer. Radiation therapy was delivered using 3D conformal treatment planning. Radiation doses used are summarized in Table 2.
In patients who received chemotherapy as a part of the treatment, of the 86 patients, only 15 (17.4%) patients received induction chemotherapy, 44 (51.2%) received concurrent chemotherapy, and 25 (29.1%) patients received adjuvant chemotherapy. The chemotherapy regimens that were used were carboplatin/paclitaxel, cisplatin/etoposide, docetaxel (9), gemcitabine (2), pemetrexed (1), topotecan (2), erlotinib (3), irinotecan (1), Vinorelbine (1), or a combination. The agents and the sequence of chemotherapy used are summarized in Table 3. Of the 86 patients, 45 (52.32%) developed grade 2 or higher RP. Only 1 of 86 patient developed grade 4 RP and 1 patient developed grade 5 toxicity.
The median study time for patients developing RP was 2 months, whereas the median follow-up time for patients not experiencing the event was 11 months.
Univariate and Multivariate Analysis of Potentially Prognostic Factors
The incidence of developing grade 2 or higher RP was significantly associated with addition of chemotherapy. Approximately 78% (67/86) of patients received chemotherapy. The incidence of RP in patients receiving chemotherapy was 62.7% (42/67) in comparison to 15.8% (3/19) in patients receiving no chemotherapy (P < 0.001). However, there was no effect of the type or sequence of chemotherapy (Table 3).
Patients were divided into 4 age groups. These were ≤60, 61–70, 71–80, and ≥81 years. Table 4 describes results from univariable Cox proportional hazards models. Patients in age group 61 to 70 had a significantly increased risk of developing RP when compared with the youngest age group (hazard ratio [HR]: 3.0; 95% confidence interval [CI]: 1.4, 6.5). Of patients in this age group, 77% (20/26) developed grade 2 or higher RP. More than 44% of RP patients were between 61 and 70 years of age. In comparison, 22.2% in ≤60 years, 22.2% of 71 to 80 years, and 11.1% of ≥81years developed RP. Chemotherapy was also a significant predictor of RP in the univariable analysis. Patients who received any chemotherapy had a 5 times greater risk of developing RP than in patients who did not receive this treatment (HR: 5.0; 95% CI: 1.5, 16.1). Histology of lung cancers and radiation dose were not significant predictors of developing RP (Table 4).
The results of the final multivariable model suggest that age and chemotherapy history are significant predictors of RP at the 0.05 level (P = 0.04 and 0.02 for age and chemotherapy, respectively). As shown in Table 5, the risk of developing RP is 2.9 times greater for patients between 61 and 70 years of age as compared with those 60 or younger, regardless of their chemotherapy treatment status. After adjusting for age, patients who received chemotherapy were at a greater risk of RP than those who did not (HR: 4.6; 95% CI: 1.3, 16.5).
Kaplan-Meier survival curves (Fig. 1) were statistically different based on chemotherapy status (P = 0.0012) with chemotherapy patients having a lower event-free survival rate throughout the duration of the study than those who did not receive chemotherapy as a form of treatment. Taking into account patients lost to follow-up, the cumulative incidence of RP was 65.9% (95% CI: 54.1, 77.3) for the chemotherapy group and 17.9% (95% CI: 6.1, 46.1) for those patients who did not have chemotherapy. All cases of RP occurred within 6 months for the chemotherapy group and within 3 months for the others.
Our study has shown a significant incidence of radiation RP in patients receiving chemotherapy. In addition, 61 to 70 year age group was significantly associated with increased RP rates. The sequence or the type of chemotherapy was not a significant factor in RP development. Histology and radiation dose were not significantly associated with the development of RP. A patient who is 61 to 70 years has a 2.9 times higher risk for developing RP than patients who are 60 years or younger. The risk of developing RP is 4.6 times higher for patients receiving chemotherapy than the patients not receiving chemotherapy.
RP is a common dose-limiting toxicity that occurs after thoracic radiation therapy. The reported risk overall of developing RP is between 5% and 36%. However, this incidence underreported because of nonspecific symptoms associated with RP and the difference in RP scoring criteria. In addition, RP may not be symptomatic and may not be reported to the treating physician, or patients may expire early, thereby artificially reducing the true estimated incidence of RP.
There are numerous studies that have linked RP to various patient and treatment related factors (see introduction). A recent study evaluated the fusion of methodologically different nonlinear multivariate models that were trained to predict radiation-induced pneumonitis on a database of 219 lung cancer patients treated with radiotherapy. Five features that were extracted as the consensus among all 4 models in predicating RP were chemotherapy, equivalent uniform dose for exponent a = 1.2 to 3, equivalent uniform dose for a = 0.5 to 1.2, lung volume receiving >2 to 30 Gy, female gender, and squamous cell histology.21
An association between dose volume histogram parameters and RP risk has been demonstrated in the literature although the ideal dose volume histogram metric with excellent operating characteristics, either alone or in a model with other predictive variables, for RP risk prediction has not yet been identified.22 In the study of Graham et al,15 half of the patients were treated with radiotherapy and half with radiochemotherapy. The incidence of RP was up to 20% at 24 months but just 7%, if the V20 value was 31% or lower. In the experience of Hernando et al,23 the global rate of pulmonary toxicity was 19%, but it was only 6% when V30 was 18% or lower.
Regarding the addition of systemic agents, a phase I study using S-1, a newly developed 5-FU derivative, and cisplatin with thoracic radiotherapy showed excellent response rates but no grade 2 or higher RP.24 In contrast, a phase III study evaluating consolidation Docetaxel after cisplatin, etoposide, and RT showed a 9.6% rate of grade 3 to 5 RP and no improvement in median survival.25 A phase II study evaluating continuous infusion Topotecan with RT showed it to be well tolerated with 6 of 20 (30%) patients developing grade 3 RP.26
Other patient related factors have been shown to be important in the development of RP. In 1 study, levels of TGF-beta1 and mean long dose have been shown to predict the severity of acute RP.27 Monson et al28 showed an increased risk of clinical RP in lung cancer patients with a history of smoking. A study evaluating the influence of prognosis and the incidence of RP failed to show any correlation between the 2.29
Our study has shown that the rate of clinical RP in patients receiving CRT is fairly high. However, most of the patients developed grade 2/3 RP that was easily controlled with steroids and only 1 of 86 patients developed grade 4 RP requiring assisted ventilation and 1 of 86 developed grade 5 (fatal) RP. This information should be taken into account during overall management and patient counseling.
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