Risk factors for radiation pneumonitis after thoracic irradiation – Nghiem Thi Minh Chau

Journal of military pharmaco-medicine n o 1-2019 138 RISK FACTORS FOR RADIATION PNEUMONITIS AFTER THORACIC IRRADIATION Nghiem Thi Minh Chau1; Duong Thuy Linh1; Nguyen Van Ba1 Tran Viet Tien1; Ryuji Hayashi2 SUMMARY Objectives: To investigate risk factors for radiation induced pneumonitis after thoracic irradiation in total of 378 patients including esophagus cancer (55 patients), lung cancer (137 patients), breast cancer (177 patients) and mediastinum tumor (9 patients). Subjects and methods: From January 2010 to January 2018, 378 patients with esophagus cancer, lung cancer, breast cancer, mediastinum tumor were treated with radiotherapy; these 378 cases were retrospectively analyzed for radiation induced pneumonitis. To explore the risk factors for radiation induced pneumonitis, the investigated factors include: Age, sex, subclinical interstitial lung disease, some irradiated underlying lung volumes of more than 15 Gy, 20 Gy (V15, V20), mean lung dose, some laboratory values KL-6, LDH, albumin, WBC, NEU, LYM, CRP. Results: Radiation induced pneumonitis was graded according to Common Terminology Criteria for Adverse Events v 4.0. Radiation induced pneumonitis was also found in CT-scans with or without fibrosis, the level of honey combing images involving of the lobe lung. While the relationships between not only the clinical factors but also the dosimetric factors and radiation induced pneumonitis were significantly associated, these parameters from laboratory tests showed the weak relationship with radiation induced pneumonitis. Conclusion: In our study, the clinical and dosimetric risk factors for radiation induced pneumonitis after irradiation were retrospectively investigated with mixed kinds of cancers consisted of numerous patients showed that radiation induced pneumonitis was induced more frequent in groups with increasing predictive risk factors such as over vs. below 70 years old, female vs. male, with vs. without interstitial lung disease as following 24.8% vs. 11.4%, 4.4% vs. 31%, 56.4% vs. 12.1%, difference was significant, p < 0.05, respectively. This study also showed that the incidence of radiation induced pneumonitis got worse after increasing V15/V20/mean lung dose in dosimetric radiotherapy. Some risk factors including age, gender, interstitial lung disease interstitial lung disease, V15/V20/mean lung dose play important roles in predicting severe radiation induced pneumonitis. * Keywords: Pneumonitis; Thoracic irradiation; Risk factors. INTRODUCTION Severe radiation pneumonitis (RP) is the most common cause of death shortly after radiotherapy. Symptoms caused by subacute radiation pneumonitis usually develop approximately 4 to 12 weeks following irradiation, whereas symptoms of late or fibrotic radiation pneumonitis develop after 6 to 12 months. 1. 103 Military Hospital 2. Toyama Hospital University, Toyama, Japan Corresponding author: Duong Thuy Linh (bsduonglinh103@gmail.com) Date received: 20/10/2018 Date accepted: 07/12/2018 Journal of military pharmaco-medicine n o 1-2019 139 Typical symptoms for both types of lung injury include dyspnea, cough, chest pain, fever and malaise. The risk factors for RP after conventional thoracic radiation therapy were reported in several studies. Therefore, investigation of factors of severe RP is important to improve the safety of thoracic radiation therapy. In this study, we retrospectively analyzed the risk factors of RP after treated radiotherapy. SUBJECTS AND METHODS 1. Subjects. 378 patients with esophagus cancer (55 patients), lung cancer (137 patients), breast cancer (177 patients), mediastinum tumor (9 patients) were treated with radiotherapy from January 2010 to January 2018. 2. Methods. - Radiotherapy: Treatment planning was performed using the Eclipse (Varian Medical System). There were only 37 patients with lung cancer treated stereotactic body radiotherapy plans, the remaining 341 patients were treated three dimensional conformal radiotherapies. The dose limitation for pulmonary parenchyma was a mean lung dose, percentages of total lung volume receiving > 20 Gy (V20) and > 15 Gy (V15) according to QUANTEC. The dose per fraction was 1.8 - 2 Gy for conventional radiotherapy, 4 - 5 Gy for stereotactic body radiotherapy. Total dose was based on type of cancer, the median prescribed dose in this study was 50 Gy (ranged 20 - 72 Gy). - Follow-up procedures: Regular follow-up visits were performed 3 - 4 month intervals for the first 2 years after completing treatment and at every 4 - 6 months thereafter. At each follow-up visit, patients were evaluated including a medical history and physical examination, CT-scans and laboratory tests. Radiotherapy was graded according to Common Terminology Criteria for Adverse Events v4.0. Radiotherapy was also found in CT- scans with or without fibrosis, the level of honey combing images involved in the lobe lung. - The risk factors for radiation pneumonitis: The clinical risk factors for radiotherapy were investigated including age, subclinical interstitial lung diseases (ILD) and the changes of values in laboratory tests. The presence of ILD was reviewed using CT findings usually present in ILD, such as ground - glass attenuation, reticulation, patchy ground - glass abnormalities and honey combing. For dosimetric factors, the total underlying lung volume was defined as the total lung volume minus the gross tumour volume. The dosimetric parameters were calculated from the dose - volume histogram for the total underlying lung volume. The irradiated total underlying lung volumes of more than 15 Gy, 20 Gy (lung V15, V20) and mean lung dose were evaluated evaluated as risk factors for radiotherapy. The laboratory evaluation was depended on the clinical situation. The samples blood tests were collected before and after patients received thoracic irradiation. The test values were in normal ranges as followed: Journal of military pharmaco-medicine n o 1-2019 140 KL-6: 105.3 - 401.2 U/mL (Krebs von den Lungen-6); LDH: 110 - 210 U/l; albumin: 4.1 - 5.1 g/dL; WBC: 33 - 86 x 100/µL; CRP: 0.0 - 0.14 mg/dL; Neu: 42.0 - 72.3%; Lym: 20.4 - 47.5%. * Statistical analysis: The relationships among RP and the clinical factors were calculated using Chi-square probability test. The relationships between RP and dosimetric factors were analyzed using the independent samples t-test. Univariate logistic regression analyses were performed to evaluate the data using SPSS v.16.0. Differences with p-values < 0.05 were considered statistically significant. The changes of laboratory tests before and after treatment were analyzed using the paired samples test. RESULTS 1. The subjects. Table 1: The patient’s characteristics. 2. Relationships between the clinical factors and radiation pneumonitis. Table 2: Clinical factors were associated with radiation induced pneumonitis. Radiotherapy n = 63 p value Age (< 70 vs. ≥ 70 ) 26/229 vs. 37/149 0.015 Sex (male vs. female) 54/174 vs. 09/204 < 0.001 Subclinical ILD (yes vs. no) 22/39 vs. 41/339 < 0.001 Group cancer (esophagus vs. lung vs. breast vs. mediastinum) 07/55 vs. 50/137 vs. 04/177 vs. 02/09 < 0.001 By univariate analysis, all of above factors including ages, gender, ILD compared to subgroups involved in RP were significantly different (p < 0.001). Characteristics Subgroup Number of patients ILD RP ILD & RP Esophagus 55 04 07 02 Lung 137 34 50 20 Breast 177 01 04 0 Tumor type Mediastinum 09 0 2 0 Male 174 38 54 22 Gender Female 204 01 09 0 ≥ 70 149 28 37 14 Age < 70 229 11 26 08 Journal of military pharmaco-medicine n o 1-2019 141 3. Relationship between dosimetric parameters and radiotherapy. Table 3: Relationship between dosimetric factors and radiotherapy. Mean ± SEM Dosimetric factors Radiotherapy positive Radiotherapy negative p value V15 23.79 ± 1.4 11.84 ± 0.53 < 0.001 V20 19.94 ±1.19 9.81 ± 0.44 < 0.001 Mean lung dose 10.90 ± 0.58 5.72 ± 0.21 < 0.001 This table showed the relationships between the dosimetric factors and radiotherapy in all kinds of cancers. Their p values were under 0.001 meant that there was a strong difference in V15/V20/mean lung dose between 2 groups with or without radiotherapy. 4. Assessing the changes of laboratary tests before and after thoracic irradiation. Table 4: Laboratory tests before and after thoracic irradiation. Radiotherapy Before therapy After therapy p value Positive 41 623.63 ± 90.7 695.04 ± 103.41 0.54 Negative 46 406.45 ± 57.05 404.92 ± 49.32 0.97 KL6 p value 0.047 0.010 Positive 63 298.06 ± 77.4 212.53 ± 9.65 0.24 Negative 223 197.58 ± 5.9 194.38 ± 5.42 0.24 LDH p value 0.019 0.104 Positive 62 3.77 ± 0.06 4.52 ± 0.68 0.28 Negative 222 3.68 ± 0.03 4.72 ± 0.89 0.24 Albumin p value 0.201 0.859 Positive 63 70.81 ± 3.59 54.67 ± 4.15 0.001 Negative 225 63.58 ± 1.63 54.48 ± 2.08 0.00 WBC p value 0.093 0.979 Positive 55 43.93 ± 2.79 39.71 ± 4.2 0.28 Negative 203 40.77 ± 1.42 39.11 ± 1.75 0.28 Neu p value 0.318 0.896 Positive 61 21.04 ± 4.18 6.31 ± 0.5 0.001 Negative 222 17.13 ± 1.05 8.54 ± 0.33 0.00 Lym p value 0.368 0.000 Positive 60 1.61 ± 0.31 2.85 ± 0.65 0.06 Negative 185 1.28 ± 0.17 1.61 ± 0.19 0.04 CRP p value 0.360 0.016 Journal of military pharmaco-medicine n o 1-2019 142 These parameters from laboratory tests in this study were not stable between two groups with or without radiotherapy; some of tests were significantly different and others were not. The significant tests did not strongly reflect the status of radiotherapy alone which was probably in combination with other inflammations. This result was consistent with previous studies showing that they were not specific for assessing RP. There is only KL-6 value which shows significant difference between two groups with or without radiotherapy not only before treatment but also after treatment (p < 0.05). 5. Risk factors between the death-induced radiotherapy group and the alive patients group. Table 5: Assessing the difference of risk factors between the death-induced radiotherapy group and the alive patients group, who was diagnosed with lung cancer and had radiotherapy after radiation therapy. Mean ± SEM Dosimetric factors Death-induced RP (n = 5) Survivors (n = 45) p value ILD 03 17 V15 27.26 ± 5.6 24.32 ± 1.61 0.638 V20 20.62 ± 6.4 21.11 ± 1.38 0.943 MLD 12.60 ± 2.29 11.36 ± 0.71 0.629 Before treatment KL6 686.6 ± 120.23 601.31 ± 104.85 0.603 LDH 284.2 ± 44.54 320.18 ± 107.92 0.759 Albumin 3.9 ± 0.15 3.84 ± 0.05 0.726 WBC 79.22 ± 13.89 69.10 ± 3.61 0.515 Neu 51.4 ± 12.32 41.57 ± 2.47 0.475 Lympho 20.2 ± 4.33 22.14 ± 5.76 0.790 CRP 2.11 ± 0.82 1.38 ± 0.35 0.457 After treatment KL6 1436.0 ± 630.84 677.67 ± 109.4 0.05 LDH 295.8 ± 56.87 207.1 ± 11.08 0.196 Albumin 3.54 ± 0.41 4.30 ± 0.74 0.374 WBC 83.52 ± 26.57 54.28 ± 4.74 0.336 Neu 77.35 ± 35.32 39.77 ± 4.26 0.033 Lympho 4.9 ± 1.23 6.8 ± 0.68 0.203 CRP 3.32 ± 1.71 2.79 ± 0.82 0.792 Journal of military pharmaco-medicine n o 1-2019 143 There were 5 deaths due to radiotherapy in the total of 50 patients had been RP after treatment. However, this result showed that there was not any clear difference between two groups about these parameters. The time of occurring radiotherapy early is the common feature in the death induced radiotherapy group. 3 patients had radiotherapy during treatment with radiotherapy and died after finishing the course treatment about 18 days to 1 month. 2 patients suffered from radiotherapy occurred in after treatment 2 months to 3 months and died after 1.5 month to 2 months. DISCUSSION Radiotherapy includes stereotactic body radiotherapy and conventional therapy have been widely used as a safe and effective treatment for many kinds of cancers indicated with thoracic irradiation. One of the most common causes of toxicity after radiotherapy either stereotactic body radiotherapy or conventional therapy is radiotherapy, especially for patients with lung cancer. Although most of radiotherapy was in grade 1 or 2, a few cases had the potential to be severe or mortal [1, 2, 3]. In our study, we focused on 4 types of cancers: esophagus, lung, breast and mediastinum cancers and assessed predictive risk factors for complication after radiotherapy. Many factors affect the risk for radiotherapy including the method of irradiation, the volume of irradiated lung, the total dosage and frequency of irradiation, associated chemotherapy, and possibly the genetic background of the patient, gender, age, ILD [4]. In our study, the clinical and dosimetric risk factors for radiotherapy after irradiation were retrospectively investigated with combined kinds of cancers on a great number of patients. The results showed that radiotherapy was induced more frequent in groups with increasing predictive risk factors such as over vs. below 70 years old, female vs. male, with vs. without ILD with the corresponding rate of 24.8% vs. 11.4%, 4.4% vs. 31%, 56.4% vs. 12.1%, difference was significant, p < 0.05, respectively. Our study showed that the incidence of radiotherapy got worse after increasing V15/V20/mean lung dose in dosimetric radiotherapy. These results were consistent with previous studies [5], which proved that irradiated underlying lung volumes of more than 15 Gy, 20 Gy (V15, V20), mean lung dose play important role in predicting severe radiotherapy. Laboratory tests were sometimes not consistent with status of radiotherapy which showed the tests were not specific for radiotherapy due to diverse conditions. However, there was only KL-6 value which shows significant difference between two groups with or without radiotherapy not only before treatment but also after treatment (p < 0.05). KL-6 is a mucinous high molecular weight glycoprotein, expressed on type 2 pneumocytes. It is generally regarded as the lung epithelium-specific protein KL-6. Previous studies suggested that KL-6 is a useful marker for the clinical diagnosis of pneumonitis [6]. 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