Ipsilateral Pleura Radiotherapy Combined Intrapleural with Intravenous Chemotherapy for Patients with NSCLC Presenting Malignant Pleural Effusion

Lung cancer is the leading cause of malignant pleural effusion (MPE) [1-5]. Approximately 15% of lung cancer patients have pleural effusion at the time of initial diagnosis and 50% develop pleural effusion later in their causes [3,5,6]. Patients with pleural effusion have life short expectancy and are difficult to manage clinically [3,4]. A more definitive management strategy is often undertaken with several approaches available to physician or surgeon. These options include repeat thoracentesis, tube thoracostomy with chemical pleurodesis, placement of an indwelling, cuffed, tunned pleural catheter (ICTPC) with or without pleurodesis or medical pleuroscopy or video-assisted theracoscopic surgery (VATS) with pleurodesis [7-16]. The most common therapy for these NSCLC patients with MPE is a tube thoracostomy drainage and intrapleural instillation of a chemical sclerosing agent with or without subsequent systemic chemotherapy [17-19]. Although current mode of therapy can occasionally alleviate the symptoms, the relapse rate is as high as 50% [20].


Introduction
Lung cancer is the leading cause of malignant pleural effusion (MPE) [1][2][3][4][5]. Approximately 15% of lung cancer patients have pleural effusion at the time of initial diagnosis and 50% develop pleural effusion later in their causes [3,5,6]. Patients with pleural effusion have life short expectancy and are difficult to manage clinically [3,4]. A more definitive management strategy is often undertaken with several approaches available to physician or surgeon. These options include repeat thoracentesis, tube thoracostomy with chemical pleurodesis, placement of an indwelling, cuffed, tunned pleural catheter (ICTPC) with or without pleurodesis or medical pleuroscopy or video-assisted theracoscopic surgery (VATS) with pleurodesis [7][8][9][10][11][12][13][14][15][16]. The most common therapy for these NSCLC patients with MPE is a tube thoracostomy drainage and intrapleural instillation of a chemical sclerosing agent with or without subsequent systemic chemotherapy [17][18][19]. Although current mode of therapy can occasionally alleviate the symptoms, the relapse rate is as high as 50% [20]. MPE in patients with NSCLC portents a poor prognosis, with a median survival of 3 ~5 months [21]. On occasion, MPE can be managed by treating the underlying malignancy with contemporary antineoplastic agents and/ or radiotherapy. Unfortunately, in majority of cases, the MPE either dose not resolve or recurs after initial drainage [16]. Only one study showed that pulmonary irradiation combined with intrapleural and intravenous chemotherapy could prolong the patient's overall survival (OS) [22]. The patients with other distant metastases did not enrolled in the study except for bone metastases [22]. Because the major causes of death for patients with NSCLC and MPE include progression of pulmonary disease, pleural involvement, and organ failure resulting from distant metastases, a combined-modality approach that can effectively control pulmonary, pleural metastatic lesions appears necessary to improve the outcome of this group patients, we therefore designed and evaluated the treatment protocol consisting of ipsilateral pleura and pulmonary irradiation, i.p and i.v chemotherapy to treat patients with NSCLC presenting with symptomatic MEP. Eligibility criteria included histopathological NSCLC and symptomatic MPE at the time of initial diagnosis, Karnofsky performance status＞70, liver and kidney function were normal, and expected survival ＞3 months. From January 2006 to January 2011, 31 patients were eligible for this study. Median age was 57(33-70) years. Of the 31 cases, 15 had distant metastasis, which included bone, brain, liver and adrenal. The clinical characteristics showed in Table 1. Initial evaluation consisted of a complete history and physical examination, serum chemistry, a complete blood cell count, and serum tumor marker (CEA).

Patient Eligibility
A computed tomographic (CT) scan of the chest to the level of the adrenal glands, an abdominal sonographic examination, a radionuclide bone scan, and magnetic resonace imaging (MRI) of the brain were also performed for comprehensive staging. Effusion that occupied more than three-fourths of the hemithorax was classified as ' massive', between one-half and three-fourths as 'large .'and between one-fourths and one-half as moderate'moderate'and less than one-fourths as 'small' All eligible patients had a Karnofsky performance status of 70-100 and bidimensional measurable disease, but none had had prior chemo-radiotherapy or prior pleurodesis. Before treatment, all patients signed an informed consent form ( Table 1).
The treatment response of malignant effusion was evaluated according to the following criteria: i.
Complete response (CR), no fluid reaccumulation and patients were free of symptoms for at least 4 weeks determined by chest CT scan; ii.
Partial response (PR), effusion decrease more than 50% of the original effusion volume, patients were asymptomatic and no need for thoracentesis for symptom relief within 4 weeks after treatment; iii. Stable disease (SD), effusion decrease less than 50% of the original volume; iv. Progression disease (PD), recurrence of effusion greater than 50% of the original volume, patients were symptomatic and need for thoracentesis to relieve symptoms with 4 weeks of treatment. The toxicities of the therapy were evaluated according to Radiation Oncology Therapy Group (RTOG) toxicity criteria.

Intrapleural and Intravenous Chemotherapy
First, ultrasound was used to confirm puncture point. Under local anaesthesia a puncture needle was inserted. 800～1200ml pleural effusion was drained, and then 60mg cisplatin in 40ml normal saline injected into the pleural cavity. After 2 days of the thoracentesis, paclitaxel 125mg/m 2 and cisplatin75mg/m 2 were administered i.v. and followed by radiotherapy. After 3800cGy /20 factions were delivered, the second cycle chemotherapy was given, and then the radiotherapy continued.

Radiotherapy
Patients were positioned supine on the table with their arms above their head. MedTech body frame and thermoplastic body mask were utilized. CT simulation was performed for the patients using PHILIPS Brilliance Big Bore with 5 mm slice. Radiation targets included primary tumor, mediastinal, bilateral supraclavicular area, the ipsilateral pleura and 1/2 pleural effusion. The CT images were transferred to Elekta Precise 2.03 planning system to perform the forward treatment planning (FTP), which was previously described by Bai Yanling et al. [23]. The concept and method of FTP as follow: The geometric centre of the target was defined as the plan isocentre. Revolving tangential beams were designed along the chest wall to avoid direct irradiation of the normal lung tissue. The beam weights, directions, shape of MLC and other parameters were adjusted according to the dose distribution until the results meet the clinical needs. The average number of fields was 23 (18 to33) The evaluation results of FTP for all patients as follow: 90% isodose line included more than 90% GTV volume. 70% isodose line included more than 90% CTV volume under the premise of reducing the lungs dose.

Follow up
The survival time of all patients was measured from the day of registration until the date of death, living patients were censored on the date of the last follow-up examination. Failure free survival (i, e. death or disease progression). Media follow-up time 18(range, 6-54) months and the follow-up rate was 100%.

Statistical Analysis
SPSS version 17.0 (SPSS, Chicago, IL) was used for statistical analysis. The method of Kaplan-Meier was used to describe survival and failure-free survival. The differences were compared with log-rank test in the univariate analysis. P values less than or equal to 0.05 were significant. During the chemoradiation, 8 patients had still dyspnoea, who given the second aspiration of pleural fluid, and the 3/8 were given the third aspiration of pleural fluid. RTOG grade 1,2,3 and 4 of lung and esophagus acute radiation-induced toxicity was 58.1%, 19.4%, 3.2% and 0% and 48.4%9.7%, 3.2% and 0%. The rate of grade 1, 2, 3 and 4 with hematologic toxicity was 38.5%, 23.1%, 3.8%.and 0%. In general, the lung and hematologic toxicities were mild. Only one patient experienced RTOG grade 3 pneumonitis and two had grade 3 leukopenia (Table 2). Overall response of pleural effusion was 90.3% with 38.7% complete remission, 51.6% with partial remission, 6.5% stable disease, and 3.2 % progressive disease. Only one patient experienced Cancer Therapy & Oncology International Journal reaccumulation of pleural effusion. The median failure-free and overall survival was 13 and18 months, respectively. The 6, 12and 24-month OS was 90.3%, 77.3% and 19.9%, respectively. Univariate analysis showed that Karnofsky performance status (KPS), thoracic fluid volume, T and N staging, and radiation dose were prognostic factors (p=0.001, 0.000, 0.000 and 0.000) ( Table  3). Median survival time of the patients with KPS ≥80, moderate pleural effusion, N1, T1, and radiation dose ≥66.5Gy was 20, 20, 37.5, 23, and 20 months respectively.

Discussion
MPE is a common complication in patients with NSCLC, which is difficult to manage clinically. The most common therapy for these patients is a tube thoracostomy drainage and intrapleural instillation of a chemical sclerosing agent with or without subsequent systemic chemotherapy. MPE in patients with NSCLC portents a poor prognosis, with a median survival of 3 ~5 months, which estimated 1, 2-year survival 12.6% ~24.8% and 5.4%~11.3% [22]. Most patients with NSCLC and MPE die of intrapulmonary progression, intractable intrapleural effusion, systemic metastasis, or a combination of these. We therefore injected cisplatin into the pleural cavity to enhance killing tumor cells seeding the pleurae. Paclitaxel, an effective firstline agent for NSCLC, was given intravenously two cycles during the chemoradiation to control systemic disease. Ipsilateral pleura radiotherapy was introduced to enhance local control of intrapulmonary diseases, pleural involvement, tumor cells in pleural fluid. The overall response rate in measurable lesions to this combined modality treatment was 87.1%, and the control rate of pleural effusion was 90.3% through the whole clinical course. The median failure-free and overall survival was 13 and 18 months. 1,2-year survival rate was 70.3%, and 19.9%, which were higher than the results reported by Wu-Chu Su et al. [22]. Wu-Chu Su`s study only included patients with bone metastasis. Before radiotherapy, 4 cycles intrapleural and intravenous chemotherapy were given, and one month after radiotherapy 7020cGy/39F, 3-6 cycle chemotherapy were administered i.v.
The median failure-free and overall survival was 8 and 16 months, and 1-year survival rate was 63.0%. 22 The clinical results of the multiple cycle chemotherapy (4 times i.p. and 6-9 cycles i.v.) combined with pulmonary irradiation was not as good as that of less cycle chemotherapy (1-time i.p and 2 cycles i.v.) combined with ipsilateral pleurae radiotherapy in our study. The main difference between the two studies was that ipsilateral pleurae radiotherapy was introduced in our study and did not in Su`s study. MPE occurs mostly because of impaired lymphatic drainage, anywhere from tumor occlusion of parietal pleura stomata to enlarged mediastinal lymph nodes. 19 In patients with lung cancer, MPEs are usually caused by pulmonary artery invasion and embolization of tumor cells to the visceral pleura or direct invasion from peripheral tumours [24]. So, the ipsilateral pleurae radiotherapy was an effective method for patients with NSCLC and MPE.
Morgensztern et al. [21] study showed a significant prognostic role for MPE, which was associated with a decreased median OS from 5 months to 3 months in patients with stage M1b disease [21]. Our study found that there was not difference between OS of patients with distant(M1b) and no distant metastases (20 months versus 18 months) ( Table 3). This mainly was because the distant metastatic lesions in our study were given radiotherapy. Univariate analysis in our study also found that predictors for poor outcomes were KPS＜80, massive amount of pleural effusion, advanced T and N stage, and lower radiation dose (Table 3).
Radiotherapy was rarely used for treating patients with NSCLC and MPE, mainly because the conventional radiation techniques increase radiation damage of normal lung tissue [25]. Thorax cancer of patients who received radical radiotherapy approximately 13% to 37% occurred radiation pneumonitis( RP) [26]. In our study, the forward treatment planning (FTP) and boost radiation technique were used for the patients with NSCLC and MPE, which not only increased tumor radiation dose, but also lung radiation side effects were acceptable. Of the 31 patients, 6(19.4%) and 1(3.2%) experienced grade 2 and 3 acute pulmonary toxicity respectively. In conclusion ipsilateral pleura radiotherapy combined with intrapleural and intravenous Chemotherapy for patients with NSCLC presenting malignant pleural effusion is feasible, effective, and provides an alternative treatment modality for them.

Author Disclosures of Potential Conflicts of Interest
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