Nonsmall-cell lung cancer (NSCLC) is a major cause of cancer death. Definite thoracic radiotherapy (TRT), with or without concurrent chemotherapy, is the treatment of choice for patients with unresectable locally advanced NSCLC.1 One of the most common treatment-related toxicities is radiation pneumonitis, which typically occurs between 1 month and 6 months after the completion of radiotherapy.2,3 The clinical manifestations include cough, shortness of breath, and fever, with or without changes in pulmonary function. Radiation recall pneumonitis (RRP) is a special form of radiation pneumonitis (RP), which is an inflammatory reaction in a previously irradiated area of lung tissue after application of a pharmacological agent such as chemotherapy.4,5
In recent years, studies have shown that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), gefitinib, erlotinib, and afatinib can provide significant benefits to patients with advanced NSCLC.6–9 Patients with tumors that had sensitive EGFR mutations and had been treated with EGFR-TKI experienced longer progression-free survival and a higher quality of life compared with those who had been treated with standard chemotherapy.10–12 A major concern during EGFR-TKI treatment is the development of interstitial lung disease (ILD), which Inoue et al13 first reported in 2003. Although rare, ILD is a potentially life-threatening complication of EGFR-TKI treatment. Studies have suggested that prior radiotherapy is a risk factor for the development of ILD.13,14
Both in vitro and in vivo studies have suggested that EGFR-TKI not only enhances the antitumor activity of radiation but also increases pulmonary toxicity.15–18 Furthermore, case reports have discussed RRP after treatment with EGFR-TKI.19–21 Previous studies have focused mostly on EGFR-TKI-induced ILD; however, the incidence of EGFR-TKI-related RRP remains unclear, and therefore requires further investigation.
2.1. Patients and clinical data
We retrospectively reviewed the medical and radiation therapy records of patients with NSCLC who were treated between 2002 and 2011 at Taipei Veterans General Hospital, Taipei, Taiwan. Patients with advanced NSCLC who had received TRT and EGFR-TKI (within 5 years after radiotherapy) were screened. However, patients who had received concurrent EGFR-TKI and radiotherapy or EGFR-TKI before radiotherapy were excluded. The following demographic data of patients were retrieved: age, sex, smoking history, Eastern Cooperative Oncology Group performance status, pulmonary function, histology type, and clinical stage. Serial chest images of each patient were reviewed. The patients were followed-up until October 31, 2013, or death. This study was approved by the Institutional Review Board of Taipei Veterans General Hospital and was conducted in accordance with the Declaration of Helsinki.
2.2. Radiotherapy parameters
The following dosimetric parameters were generated from the dose-volume histogram of the patients’ radiotherapy treatment planning: (1) the mean lung dose (MLD), which is the average radiation dose of the whole-lung volume; and (2) the V5 and V20, which correspond to the percentages of the lung volume receiving a radiation dose of more than 5 Gy and 20 Gy, respectively, during the entire course of radiotherapy. The MLD, V5, and V20 are the most commonly applied parameters for evaluating the possibilities of radiotherapy-induced pneumonitis. These parameters were calculated according to the dose distribution in the bilateral whole-lung volume minus the planned target volume. All the data were obtained and manipulated using the Eclipse Treatment Planning System (Varian Medical Systems, Palo Alto, CA, USA).
2.3. Definition of EGFR-TKI-related RRP and classical EGFR-TKI-induced ILD
The diagnosis of EGFR-TKI-related RRP was based on the following criteria: (1) use of EGFR-TKI treatment after the completion of TRT (after at least 7 days); (2) new onset of respiratory symptoms during EGFR-TKI treatment; (3) acute radiographic changes including ground-glass opacity or consolidation within the prior radiation area; and (4) the radiological examination of the chest before EGFR-TKI treatment showing no pneumonitis change. All information was independently reviewed by two pulmonologists and one radiologist, and consensus was reached to confirm the diagnosis. The grade of RRP was classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0: Grade 1 pneumonitis is asymptomatic and diagnosed according to radiographic findings only; Grade 2 pneumonitis is symptomatic and requires medical intervention; Grade 3 pneumonitis is severely symptomatic, limiting self-care daily activities, and necessitates oxygen; Grade 4 pneumonitis is life-threatening and requires urgent intervention (tracheostomy or intubation); and Grade 5 pneumonitis is lethal. The diagnosis of classical EGFR-TKI-induced ILD was based on previously published criteria: (1) new onset of respiratory symptoms during EGFR-TKI treatment; (2) characteristic radiological findings on chest plain film or computed tomography scan; and (3) exclusion of pulmonary infection, lymphangitis carcinomatosis, and RP.22 Preexisting ILD was defined as peripheral reticulation at the bilateral lung base on chest computed tomographic images, which were obtained before radiotherapy.
2.4. Statistical analysis
Statistical analyses were conducted and plots constructed using SPSS statistics 18.0 (SPSS Inc., Chicago, IL, USA). The association between the potential factors and the occurrence of RRP was analyzed using Fisher's exact test. Radiotherapy dosimetric parameters were compared between groups using the Mann–Whitney U test. A p value < 0.05 was considered statistically significant.
A total of 763 patients who had received TRT for advanced NSCLC between 2002 and 2011 in this institute were identified. Of those patients, 160 received EGFR-TKI treatment after the completion of radiotherapy. Demographic data of these patients are summarized in Table 1. Most of the patients were men (64.4%), approximately half were nonsmokers (50.6%), and some of them had pre-existing ILD (15%). Of the 160 patients, 150 received three-dimensional conformal radiotherapy. The median radiation dose was 60 Gy (range, 20–76 Gy). A total of 58 patients (36.3%) underwent radiotherapy with concurrent chemotherapy. The median interval between the completion of radiotherapy and EGFR-TKI was 7.4 months (range, 0.2–55 months). Radiotherapy dosimetric parameters (MLD, V5, and V20) were available for 139 patients (87%).
In total, acute interstitial pneumonitis after TRT was identified in 20 patients. Based on the radiographic features, clinical manifestations, and treatment history, six patients were identified as having chemotherapy-related RRP. In 14 patients with interstitial pneumonitis during EGFR-TKI treatment, the pneumonitis was confined to the prior radiation field and was then considered EGFR-TKI-related RRP in seven cases (4.4%). The pneumonitis was bilateral and randomly distributed in the remaining seven patients (4.4%), who were then diagnosed with classical EGFR-TKI-induced ILD (Fig. 1). The demographics and clinical characteristics of the patients with EGFR-TKI-related RRP are listed in Tables 2 and 3, respectively. The median duration of EGFR-TKI treatment at the occurrence of RRP was 43 days (range, 18–65 days); for the development of classical ILD, it was 24 days (range, 10–52 days). A representative case of EGFR-TKI related RRP was shown in Fig. 2.
Four patients (57%) with Grades 1 and 2 RRP and three with Grade 3 RRP required hospitalization. Systemic steroids were administered to patients with Grade 3 RRP; EGFR-TKI treatment was aborted in two and continued in one patient. In all patients, symptoms and radiographic abnormalities improved in 2 weeks. In four patients with Grades 1 and 2 RRP, only supportive care was provided. EGFR-TKI treatment was discontinued in one patient and continued in three patients whose symptoms and radiographic changes remained stable. None of these seven patients succumbed to RRP during the study period. One patient with Grade 3 RRP was rechallenged with the same EGFR-TKI after the episode and developed bilateral interstitial pneumonitis. In patients with classical EGFR-TKI-induced ILD, six of the seven patients developed severe pneumonitis and required hospitalization. The mortality rate was 71.4% despite aggressive medical treatment.
The occurrence of EGFR-TKI-related RRP was not associated with sex, age, performance status, smoking history, preexisting ILD, baseline pulmonary function, or type of EGFR-TKI (all p > 0.05; Table 4). Regarding the timing of EGFR-TKI treatment, EGFR-TKI-related RRP was more common in patients treated with EGFR-TKI within 90 days after the completion of radiotherapy compared with those who began receiving treatment later (20% vs. 2.1%; p = 0.005). Development of classic EGFR-TKI-induced ILD after radiotherapy showed borderline significant associations with male sex (p = 0.051), poor performance status (p = 0.051), and pre-existing ILD (p = 0.069).
Regarding the radiotherapy dosimetric parameters, no difference was observed between patients with and without EGFR-TKI-related RRP or classical ILD except that patients with EGFR-TKI-related RRP had a slightly lower V20 (p = 0.051) than those without. By contrast, the occurrence of chemotherapy-related RRP seemed to be associated with higher V5 (p = 0.012) and MLD (p = 0.068; Fig. 3).
Although uncommon, ILD is a potentially fatal complication of EGFR-TKI treatment. In this study, we showed that EGFR-TKI might also induce another form of interstitial pneumonitis, RRP, in patients who had received prior TRT. In patients with mild symptoms, only supportive management was required, whereas in those with moderate symptoms, hospitalization and systemic steroid treatment were necessary.
RP is a common side effect of TRT, and the incidence of RP correlates with radiation dose. A previous report showed that V20 greater than 30% was significantly associated with Grade 2 or greater RP in lung cancer patients who received concurrent chemoradiation.23 Oh et al24 also reported that MLD was the only significant factor predictive of RP and the risk of RP was high if the MLD > 16.1 Gy. The diagnosis of RP alone is less likely in our seven patients because none of the patients had V20 > 25% or MLD > 15 Gy. Radiation recall is a special form of RP characterized by acute inflammation confined to a previously irradiated area, occurs months or years after radiation treatment, and is triggered by the administration of certain pharmacologic agents.4 Several precipitating agents have been reported to be responsible for radiation recall. Chemotherapeutics are the most common; however, others, such as antibiotics and lipid-lowering agents, have also been mentioned.25,26 EGFR-TKI is an effective treatment for patients with advanced NSCLC and is being used increasingly nowadays. When radiotherapy is followed by EGFR-TKI, subclinical damage from irradiation may be uncovered and manifest clinically as RRP. Previous case reports have shown that EGFR-TKI could also induce RRP.19–21 To our knowledge, this study is the first to systematically evaluate the incidence and risk factors of EGFR-TKI-related RRP.
Several patient-specific factors (e.g., age, smoking history, performance status, preexisting lung disease, and pulmonary function) and treatment-specific factors (e.g., MLD, V5, and V20) have been proposed as potential predictors of RP.2 However, no factor has been consistently reported to be associated with RRP. In this study, we found no factors significantly associated with EGFR-TKI-related RRP. However, interestingly, it seemed that higher normal lung radiation exposure (represented by V5 and MLD) was associated with an increased risk of chemotherapy-related RRP.
The mechanism of RRP remains unclear. Stem cells in the irradiated area may have increased sensitivity or may display a “remembered” reaction to subsequent treatment. Vascular reactions and idiosyncratic drug hypersensitivity phenomena are also possible hypotheses.4,27 The difference in action between cytotoxic chemotherapy and EGFR-TKI may provide a clue to elucidate the mechanism of RRP. Further study is necessary to investigate this issue.
Although RRP seems unpredictable, previous studies suggest that the risk is higher if the time interval between the completion of radiotherapy and initiation of chemotherapy is short.4 Our study results were in agreement with this notion. In this series, the incidence of EGFR-TKI-related RRP was up to 20% in patients who began receiving EGFR-TKI within 90 days after radiotherapy. By contrast, it was only 2.1% in patients who were treated with EGFR-TKI 90 days after radiotherapy. Moreover, two other patients developed classical EGFR-TKI-induced ILD during this period. Together, six out of 20 patients (30%) who received EGFR-TKI < 90 days after radiotherapy developed some type of acute interstitial pneumonia. Therefore, because of the potential morbidity and mortality, physicians should carefully evaluate the risks and benefits of initiating EGFR-TKI treatment for patients who have just completed TRT in the past 3 months.
Management of radiation recall depends on the affected organ system and the severity of the reaction. In some cases, radiation recall may resolve spontaneously and only a close observation may be required.4 Withhold of the precipitating agents and administration of systemic steroid may be needed if pneumonitis of Grade 3 or above develops. Ding et al5 reported an improvement in symptoms and in chest images for all 12 patients with chemotherapy-induced RRP after aborting treatment with precipitating agents and administering systemic steroids. In our study, four of the seven patients with RRP continued to be treated with EGFR-TKI, with or without a short course of systemic steroid treatment. All patients recovered from the episodes, which is in agreement with previous reports that concluded that the prognosis of RRP is generally favorable when it is diagnosed at an early stage.5,20,21 By contrast, classical EGFR-TKI-induced ILD has a relatively high mortality rate.28,29
In patients who had radiation recall, rechallenge with the precipitating drug did not always elicit a reaction.4 The evidence of rechallenge in lung cancer patients with RRP is scarce. In Ding et al's5 series, four patients were rechallenged with the same chemotherapy drugs with concomitant steroid treatment, and none showed recurrence. However, one patient in our series was rechallenged with the same EGFR-TKI, and pneumonitis recurred and progressed to bilateral lungs. Therefore, physicians should find a balance between the severity of the underlying malignancy and the efficacy and the potential toxicity of the agents considered (Fig. 3).
The study has several limitations. Firstly, it was a retrospective study and some selection bias might have existed. However, to the best of our knowledge, it is the only study to estimate the incidence of EGFR-TKI-related RRP in patients with NSCLC after TRT. Secondly, our definitions of EGFR-TKI-related ILD and RRP are arbitrary. To the best of our knowledge, there is no published criterion to differentiate these two types of interstitial pneumonitis objectively. Our definition of RRP, which was regularly used in previous reports, is a pneumonitis that is elicited by some pharmacological agent and is confined to a previously irradiated area. However, classic EGFR-TKI related ILD is usually diffusely distributed in both lungs and is not related to radiotherapy. Also, based on our study, the severities of these two types of pneumonitis are different. All patients with RRP recovered from the episodes, but EGFR-TKI-induced ILD carried a high mortality rate. More clinical studies are necessary to verify our results.
In conclusion, this study showed that in patients with NSCLC who have a history of TRT, treatment with EGFR-TKI may induce not only interstitial lung disease but also RRP. The RRP risk is 10-fold higher when the interval between the completion of radiotherapy and the initiation of EGFR-TKI is < 90 days. Physicians should be aware of both of these unexpected adverse events and consider them when evaluating the risks and benefits of EGFR-TKI after TRT.
This study was supported by grant V103A-007 from Taipei Veterans General Hospital. We thank Mr. Bill Thornton (Wallace Academic Editing) for English editing.
1. Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, et al. NCCN Non-Small Cell Lung Cancer Panel Members. Non-small cell lung cancer. J Natl Compr Canc Netw
2. Mehta V. Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Phys
3. Wang S, Liao Z, Wei X, Liu HH, Tucker SL, Hu CS, et al. 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). Int J Radiat Oncol Biol Phys
4. Burris HA 3rd, Hurtig J. Radiation recall with anticancer agents. Oncologist
5. Ding X, Ji W, Li J, Zhang X, Wang L. Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer. Radiat Oncol
6. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet
7. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med
8. Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol
9. Chen YM. Update of epidermal growth factor receptor-tyrosine kinase inhibitors in non-small-cell lung cancer. J Chin Med Assoc
10. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med
11. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicenter, open-label, randomized, phase 3 study. Lancet Oncol
12. Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol
13. Inoue A, Saijo Y, Maemondo M, Gomi K, Tokue Y, Kimura Y, et al. Severe acute interstitial pneumonia and gefitinib. Lancet
14. Hotta K, Kiura K, Tabata M, Harita S, Gemba K, Yonei T, et al. Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib: an analysis of risk factors and treatment outcomes in Okayama Lung Cancer Study Group. Cancer J
15. Chinnaiyan P, Huang S, Vallabhaneni G, Armstrong E, Varambally S, Tomlins SA, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res
16. Huang SM, Li J, Armstrong EA, Harari PM. Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res
17. Okamoto I, Takahashi T, Okamoto H, Nakagawa K, Watanabe K, Nakamatsu K, et al. Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Lung Cancer
18. Nanda A, Dias-Santagata DC, Stubbs H, O’Hara CJ, Zaner KS, Lynch TJ, et al. Unusual tumor response and toxicity from radiation and concurrent erlotinib for non-small-cell lung cancer. Clin Lung Cancer
19. Miya T, Ono Y, Tanaka H, Koshiishi Y, Goya T. Radiation recall pneumonitis induced by Gefitinib (Iressa): a case report. Nihon Kokyuki Gakkai Zasshi
20. Onal C, Abali H, Koc Z, Kara S. Radiation recall pneumonitis caused by erlotinib after palliative definitive radiotherapy. Onkologie
21. Togashi Y, Masago K, Mishima M, Fukudo M, Inui K. A case of radiation recall pneumonitis induced by erlotinib, which can be related to high plasma concentration. J Thorac Oncol
22. Ando M, Okamoto I, Yamamoto N, Takeda K, Tamura K, Seto T, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol
23. Tsujino K, Hirota S, Endo M, Obayashi K, Kotani Y, Satouchi M, et al. Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys
24. Oh D, Ahn YC, Park HC, Lim do H, Han Y. Prediction of radiation pneumonitis following high-dose thoracic radiation therapy by 3 Gy/fraction for non-small cell lung cancer: analysis of clinical and dosimetric factors. Jpn J Clin Oncol
25. Taunk NK, Haffty BG, Goyal S. Radiation recall 5 years after whole-breast irradiation for early-stage breast cancer secondary to initiation of rosuvastatin and amlodipine. J Clin Oncol
26. Wernicke AG, Swistel AJ, Parashar B, Myskowski PL. Levofloxacin-induced radiation recall dermatitis: a case report and a review of the literature. Clin Breast Cancer
27. Azria D, Magne N, Zouhair A, Castadot P, Culine S, Ychou M, et al. Radiation recall: a well-recognized but neglected phenomenon. Cancer Treat Rev
28. Hotta K, Kiura K, Takigawa N, Yoshioka H, Harita S, Kuyama S, et al. Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese Patients with non-small cell lung cancer: the Okayama Lung Cancer Study Group experience. J Thorac Oncol
29. Chang SC, Chang CY, Chang SJ, Yuan MK, Lai YC, Liu YC, et al. Gefitinib-related interstitial lung disease in Taiwanese patients with non-small-cell lung cancer. Clin Lung Cancer