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Year : 2013  |  Volume : 9  |  Issue : 3  |  Page : 447-451

Acute radiation pneumonitis after conformational radiotherapy for nonsmall cell lung cancer: Clinical, dosimetric, and associated-treatment risk factors

1 Department of Respiratory Diseases, Hôpital Ambroise Paré, 9 Avenue Charles-de-Gaulle 92100 Boulogne-Billancourt; University Versailles-Saint Quentin en Yvelines, 9 Boulevard d'Alembert, 78280 Guyancourt, France
2 Department of Radiation Oncology, Hôpital Européen Georges Pompidou, 20 rue Leblanc 75015 Paris, France
3 Department of Biostatistics, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris; University Paris Descartes, 15 rue de l'Ecole de Médecine, 75006 Paris, France
4 Department of Radiation Oncology, Hôpital Européen Georges Pompidou, 20 rue Leblanc 75015 Paris; University Paris Descartes, 15 rue de l'Ecole de Médecine, 75006 Paris, France

Date of Web Publication8-Oct-2013

Correspondence Address:
Etienne Giroux Leprieur
Department of Respiratory Diseases, Hôpital Ambroise Paré, 09 Avenue Charles de Gaulle, 92100 Boulogne-Billancourt
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.119339

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 > Abstract 

Background: Conformational thoracic radiotherapy (CTR) is a key-treatment in locally advanced nonsmall cell lung cancer (LA-NSCLC). Acute radiation pneumonitis (ARP) is one of the major complications.
Aims: To evaluate the predictors of ARP after CTR in the treatment of LA-NSCLC.
Materials and methods: A total of 47 consecutive patients (pts) were treated with CTR for LA-NSCLC and retrospectively analyzed. The mean total dose of radiation therapy (RT) was 65 Gy, with respiratory gating (RG) in 19 cases. Induction and concomitant chemotherapy was performed in 33 pts (70%) and 41 pts (87%), respectively.
Results: Eleven pts (23%) had an ARP resulting in death for one pt. In univariate analysis, age, sex, pretherapeutic value of forced expiratory volume (FEV), not-gated radiotherapy and type of concomitant chemotherapy did not appear as contributing factors in contrast to the administration of induction gemcitabine ( p = 0.03). The occurrence of ARP was significantly associated with nontumor lung volumes irradiated to 13 Gy (V13, p = 0.04), 20 Gy (V20, p = 0.02), and 25 Gy (V25, p = 0.006), the mean lung dose ( p = 0.008) and lung normal tissue complication probability (NTCP) ( p = 0.004). In multivariate logistic regression analysis, the occurrence of ARP was significantly associated with age >75 years (odds ratio (OR) = 16.72, confidence interval (CI) 95% 1.77-157.87) and administration of induction gemcitabine (OR = 18.08, CI 95% 1.09-300.08).
Conclusion: ARP is a common acute complication, requiring close posttreatment follow-up, particularly for elderly patients. The use of gemcitabine before radiation should be avoided. The benefits and risks of CTR must be carefully analyzed, according to the dosimetric parameters.

Keywords: Locally advanced stage, nonsmall cell lung cancer, pneumonitis, radiotherapy

How to cite this article:
Leprieur EG, Fernandez D, Chatellier G, Klotz S, Giraud P, Durdux C. Acute radiation pneumonitis after conformational radiotherapy for nonsmall cell lung cancer: Clinical, dosimetric, and associated-treatment risk factors. J Can Res Ther 2013;9:447-51

How to cite this URL:
Leprieur EG, Fernandez D, Chatellier G, Klotz S, Giraud P, Durdux C. Acute radiation pneumonitis after conformational radiotherapy for nonsmall cell lung cancer: Clinical, dosimetric, and associated-treatment risk factors. J Can Res Ther [serial online] 2013 [cited 2020 Jun 1];9:447-51. Available from: http://www.cancerjournal.net/text.asp?2013/9/3/447/119339

 > Introduction Top

Conformational thoracic radiotherapy (CTR) is a major treatment in the therapeutic arsenal of lung cancer, most of the time in association with chemotherapy and sometimes with surgery. [1] CTR is the main treatment of locally advanced stages (stage III), notably with mediastinal invasion. Use of CTR is mainly limited by its pulmonary and esophageal toxicity. Acute radiation pneumonitis (ARP) is defined by the apparition of a pulmonary toxic event within 6-12 weeks after the end of the radiotherapy. [2] ARP occurs in almost 10% of patients treated by CTR. [3],[4] Clinical presentation is nonspecific, with most of the time a restrictive syndrome on functional tests, with carbon monoxide (CO) diffusion abnormalities. [5] Diagnosis of ARP is often an elimination diagnosis after exclusion of other causes of pneumonitis (notably tumoral or infectious diseases). Several studies have described clinical predictive factors of ARP, with sometimes discordant results, like age or forced expiratory volume (FEV). [4],[6],[7],[8] Associated treatments could also impact the apparition of ARP, like preliminary surgery [4] or some chemotherapy drugs. [9],[10],[11],[12],[13] But most of the published works have studied dosimetric parameters, like the total administrated per fraction dose, the mean lung dose (MLD), the percentages of irradiated lung volumes more than 20 Grays (Gy) (V20) and more than 30 Gy (V30). [4] Mathematical models from dosimetric data have been created to estimate the tumor control probability (TCP) and the normal tissue complication probability (NTCP), [14] but they have not been evaluated much in clinical practice. The integration of all these clinical, tumoral, technical, and dosimetric parameters seems so necessary, in order to have a better prediction of the occurrence of ARP, responsible of 1-3% of death.

We propose in this study to search predictive factors of ARP, integrating these different parameters from a cohort of 47 patients treated by CTR for a localized but inoperable nonsmall cell lung cancer (NSCLC) in our Department.

 > Materials and Methods Top

Between May 2007 and May 2010, 444 patients have been treated for a lung cancer in the Radiation Oncology Department of the European Georges Pompidou Hospital (Paris, France). From this cohort, 47 consecutive patients with localized but inoperable NSCLC have been treated by CTR as curative intend, and have been included retrospectively in the study. From these 47 patients, 3 had an exclusive mediastinal relapse after surgery. Main clinical and tumoral data, like age, gender, histological type, TNM stage (6 th IASLC classification), tumoral topography, FEV, tobacco status, and associated oncological treatments have been recorded. Follow-up of the patients has been performed by the radiation oncologist and/or the thoracic oncologist, each week during CTR, then 1 month after the end of CTR, and then at least each 6 months during 3 years or until death of the patient.

In our study, ARP was defined according to the National Cancer Institute-Common Toxicity Adverse Events (CTAE V3). It was defined as the apparition within 12 weeks after the end of the radiotherapy of cough, dyspnea, ± fever, with radiological alveolar-interstitial abnormalities in the radiation fields. We have used the five grades classification we can suppress both of the - Acute Radiation Morbidity Scoring Criteria - (Radiation therapy Oncology group (RTOG)). We have excluded exclusively radiological late radiation fibrosis.

All included patients have been treated by CTR with a linear accelerator (Clinac Varian 2300CD ® or Clinac Varian 2100C ® ) without intensity modulation. Respiratory gating (RG) (deep inspiration breath hold after learning lessons by spirometric system Dyn'R®, or free breathing by Real Time Position Management Varian® (RPM) system) has been proposed when possible, notably in case of impaired functional tests. [15] CTR was delivered according a normo-fractionated plan (1.8-2 Gy per fraction, five fractions per week; 2.25 Gy per fraction, four fractions per week). Dosimetric planning was performed with Pinnacle/Adac® and Eclipse® software. Lung NTCP have been calculated according the Lyman-Burman model, with: TD 50 = 24.5 Gy, m = 0.18, n = 0.87 (TD 50 : t0 olerated dose for a complication probability of 50% with a uniform volume irradiation; m0 : c0 urve slope of the complication probability according to the dose; n : v0 olume dependent of the complication probability). [16]

Data are expressed as mean (± standard deviation, SD), or median (range) if nonnormally distributed variable. Data have been compared with a t test or a Mann-Whitney test, according to the distribution. Percentages have been compared with a Chi-square test or a Fisher test. P-value less than 0.05 has been considered as significant. Variables with a P value <0.10 in univariate analysis have been included in multivariate analysis (logistical regression). Statistics have been performed on the STATVIEW ® V5.0 software (SAS Intitute Inc., USA).

 > Results Top

Patients' characteristics are resumed in [Table 1]. The cohort contained 47 patients (women, n = 10; men, n = 37), aged 70 years (mean, range 53-87), treated for a localized NSCLC, without malignant pleural effusion. Mediastinal invasion was found on computed tomography (CT)-scan and positron emission tomography (PET)-scan in 35 patients, without evident primitive lesion in 3 patients. All patients but three were smoker (93%). Twenty-three patients (59%) had a FEV ≥70% of theoretical value before the beginning of CTR.
Table 1: Patients' characteristics

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Concerning CTR, the mean total dose was 65 Gy (±2.13 Gy), delivered in 54 days (±13 days). RG was performed for 19 patients (14 patients (30%) with deep breath hold technic and 5 patients with RPM technic). Mean and median volumes of the planning target volume (PTV) were 514 ml (±262 ml) and 539 ml (range 63-1161 ml), respectively. Percentages of mean and median V20 were 30% (±7%) and 30% (range 13-48%), respectively. MLD was 17 Gy (range 7.3-26.9). MLD outside PTV was 14 Gy (range 6.5-22.7). Lung NTCP was 15% for all the patients.

Thirty-three patients (70%) have received induction chemotherapy before CTR (with platinum-drug, n = 32; with gemcitabine, n = 4). Delay between the last cycle of chemotherapy and the beginning of CTR was always more than 3 weeks. Concomitant chemotherapy has been performed in 41 patients (87%) (with platinum-drug, n = 31; with a taxane, n = 13) [Table 1]. Gemcitabine was never used during radiotherapy. No patient received maintenance treatment.

Eleven patients (23%) developed ARP (grade 2 : n = 3; grade 3 : n = 7; grades 4-5 : n = 1 (cf below)). It concerned four women (40%) and seven men (19%, p = 0.21). Systemic corticotherapy was administered for seven patients, in association with antibiotics for one patient. ARP leaded to death for one patient who developed a multi-factorial acute respiratory failure (pneumonitis due to Pseudomonas aeruginosa with pneumothorax), occurring few days after the end of CTR. This patient was a man, aged 63 years, with a cT4N1 large cell carcinoma of the right upper lobe. He received three cycles of induction chemotherapy (cisplatin and vinorelbine), and then a CTR at 65 Gy (2.25 Gy per fraction, four fractions per week), without RG, and associated to paclitaxel (50 mg/m², each week). His pretherapeutic FEV was 82% of theoretical value. His dosimetric analysis showed a V20 at 36%, a MLD at 20.5 Gy, and a lung NTCP at 17%.

Results of univariate analysis are shown in [Table 2]. Age more than 75 years tended to be associated with ARP ( p = 0.06). Age more than 70 years was not a related factor of ARP ( p = 0.09). Pretherapeutic FEV was not different between patients with ARP (78% ±15) and other patients (67% ±19; p = 0.09). Concomitant chemotherapy type or RG were not statistically associated with the occurrence of ARP. However, ARP was more frequent in patients who received induction chemotherapy with gemcitabine ( p = 0.03). ARP was also correlated to nontumoral irradiated lung volumes at 13 (V13, p = 0.04), 20 (V20, p = 0.02), and 25 (V25, p = 0.006) Gy. Other significant dosimetric factors were MLD ( p = 0.008) and lung NTCP ( p = 0.004).
Table 2: Predictive factors of acute radiation pneumonitis (ARP) in a 47 patient cohort. Univariate analysis

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Results of multivariate analysis are shown in [Table 3]. Statistical factors associated with ARP were aged more than 75 years (odds ratio (OR) = 16.72, CI 95% 1.77-157.87) and administration of induction gemcitabine (OR = 18.08, CI 95% 1.09-300.08).
Table 3: Predictive factors of acute radiation pneumonitis (ARP) in a 47 patient cohort. Multivariate analysis

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After the end of the treatment, tumor response was evaluated on 45 patients (2 patients were lost to follow-up) according to Response Evaluation Criteria In Solid Tumors (RECIST) . Twenty patients has an objective response (complete response: n = 4; partial response: n = 16), 15 patients had a stabilization, and a progression occurred in ten patients. One year after the end of the treatment, nine patients were dead: five patients from tumor progression and four patients from infectious disease (notably under chemotherapy).

 > Discussion Top

The retrospective analysis of 47 consecutive patients treated by CTR in our Department has shown a rate of ARP of 23%. Several factors seem to be correlated with ARP : 0 induction use of gemcitabine, high V13, V20 and V25, the MLD and the lung NTCP. In multivariate analysis, only age more than 75 years and use of induction gemcitabine were independently associated with ARP.

A lot of various factors of ARP have been studied in the literature. Concerning clinical factors, like age, results are discordant. Some studies, like our work, have suggested a link between age and ARP. A prospective study of 96 patients treated by 3-D CTR for a stage I-III NSCLC has shown in univariate analysis a correlation between age more than 60 years and ARP, with an OR at 2.73 (CI 95% 1.07-6.98). [4] Cellular aging induces molecular dysfunctions, with telomere length shortening, alteration of deoxyribonucleic acid (DNA) reparation mechanisms, and altered protein accumulation. There is an imbalance between the oxidative stress and the antioxidative system. [17] Thus, the cellular regeneration capacity in elderly patients receiving an outside aggression (like radiotherapy) is decreased. However, we note that several other studies did not find this association between age and ARP, [7],[18],[19],[20] and the impact of elevated age on the occurrence of ARP is still controversial. Data on induction treatment are more consistent. Gemcitabine is classically known as responsible for increased radiation toxicity, [21] and a minimal delay of 3-4 weeks between the last cycle and the beginning of radiotherapy is recommended. Despite that delay, we noted a 10-times higher rate of ARP in patients who received gemcitabine (27.3%) compared with other patients (2.9%, p0 = 0.03). Multivariate analysis confirmed this association, with an OR of ARP in case of use of gemcitabine at 18.08 (CI 95% 1.09-300.08). Then, the use of gemcitabine, at usual doses (1250 mg/m² D1, D8, D21, in association with platinum), even in case of exclusive induction use, seems to be proscribed if a CTR is considered. We can note, nevertheless, promising results in term of tolerance and efficacy of a CTR associated with gemcitabine at adapted doses, in phase I-II trials. [22] We did not find any over-risk of ARP with taxanes. This over-risk had been evocated in several studies with paclitaxel in radiotherapy for breast cancer, [11],[12] but was not found in concomitant use in radiotherapy for NSCLC. [23] Data from the literature with docetaxel objectivize a high toxicity profile, with a questionable survival benefit. [13],[24]

Dosimetric parameters correlated with ARP in multivariate analysis are a high V13, V20 and V25, and a high MLD. These factors are classically described as good predictors of toxicity, with a threshold at 30% for V20. [4] Thresholds for V13 and V25 are not currently clearly defined. Concerning MLD, several studies have already shown an impact on the occurrence of ARP. [7],[25],[26] The main difficulty is to define the maximal threshold. Indeed, values for MLD vary according to studies, and its interpretation is difficult. For example, in several retrospective studies, MLDs were reported at 20.7 Gy (SD 7.07), [7] 23.8 Gy (range 15-34), [25] and 30.5 Gy (SD 1.4). [26] So, the analysis of "composite" factors, including dosimetric factors and others related to irradiation, is promising. NTCP reflects the complication probability on healthy tissue, according to doses distribution. Some studies have already shown its potential interest. [25],[27] Hernando et al. [7] retrospectively studied 201 patients treated by CTR. NTCP belonged to major dosimetric factors associated with ARP : 0 patients with ARP had a lung NTCP (mean) at 19.6%, versus 12% for other patients ( p0 = 0.006). Interestingly, this factor is associated in our work with an over-risk of ARP. Patients with ARP had a lung NTCP at 22%, versus 6% for other patients (p0 = 0.004). In the same way, ipsilateral lung NTCP was 99.5%, versus 55% (p0 = 0.007). Unfortunately, multivariate analysis failed to show significant association, probably due to a lack of power of the study.

New radiotherapy techniques have been recently developed in order to limit lung toxicity. RG allows overcoming breath movements, with a better tumoral targeting. A French multicentric randomized trial has tested gating on 401 patients treated by CTR for a lung cancer. Pulmonary, cardiac, and esophageal toxicities were statistically lower with gating, notably with deep inspiration breath-hold technique. [28] We failed to show an impact of gating in our study, probably due to the low number of concerned patients (n = 19).

Our work has several limits. This is a retrospective study, with a little number of patients. However, all consecutive patients treated by CTR for a localized NSCLC have been included. This nonselected cohort is representative of the daily practice of an academic Radiation Oncology Department.

In conclusion, ARP is a nonrare event after CTR. Some factors seem to be particularly associated with its occurrence, like age more than 75 years, a high V13, V20, V25, a high MLD, and an induction use of gemcitabine. Development of new markers, notably biological markers, like TGF-β, interleukine (Il)-6, and Il-10, is necessary to better individualize the risk of ARP. Several works have shown promising results. Arpin et al. analyzed blood levels of pro- and antiinflammatory cytokines, during and after CTR. An inverse correlation has been found in multivariate analysis, between blood levels of Il-6 and Il-10 during the 15 first days of CTR and the apparition of ARP. [29] Other works have shown that an absence of decrease of TGF-β level during CTR was associated with an over-risk of ARP. [30],[31] Some additional studies are needed to validate these preliminary results.

 > References Top

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  [Table 1], [Table 2], [Table 3]

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