Thoracic radiotherapy (TRT) improved survival in both oligo- and polymetastatic extensive stage small cell lung cancer

There has been no previous study on the efficacy of the thoracic radiotherapy (TRT) in oligometastatic or polymetastatic extensive stage small-cell lung cancer (ES-SCLC) to the overall survival (OS). In a group of 270 ES-SCLC cases retrospective study, 78 patients (28.9%) had oligometastases and 192 (71.1%) had polymetastases, among which 51 oligometastatic patients (65.4%) and 93 polymetastatic patients (51.6%) received TRT. Propensity score matching (PSM) was utilized. The 2-year OS, progression free survival (PFS) and local control (LC) in oligometastatic and polymetastatic patients were 22.8% and 4.5% (p < 0.001), 12.0% and 3.8% (p < 0.001), and 36.7% and 6.1% (p < 0.001), respectively. The 2-year OS in oligometastatic patients with the chemotherapy + radiotherapy and chemotherapy alone were 25.2% and 12.7% (p = 0.002), in contrast to 10.0% and 6.8% (p = 0.030) in polymetastatic patients. The estimated hazard ratios for survival were 2.9 and 1.7 for both oligometastatic and polymetastatic patients with radiotherapy. The polymetastatic group has a lower LC (6.1% v.s. 36.7%, (p < 0.001)), due to polymetastases patients receiving involved-sites radiotherapy with low dose schemas. TRT improved OS of patients with oligometastases and polymetastases. Our study demonstrated that aggressive TRT might be a suitable addition of chemotherapy when treating ES-SCLC patients with oligometastases and polymetastases.

SCIeNTIfIC REPORTS | 7: 9255 | DOI: 10.1038/s41598-017-09775-0 Methods Study patients and clinical data collection. This study was approved by the Regional Ethics Committee of Tianjin Medical University Cancer Institute & Hospital (NO. bc2017010). We confirm that all methods were carried out in accordance with relevant guidelines and regulations. This study is a retrospective analysis, and 270 patients from May 2010 to May 2015 with no previous ES-SCLC treatment were systemically reviewed. All the pathological types were demonstrated by morphological and immunohistochemical methods to conform with the neuroendocrine tumours of the lung diagnostic criteria 20 , and combined with clinical manifestations. Inclusion criteria include: (1) histopathological examination and immunohistochemistry were confirmed to be SCLC; (2) the state was stage IV (T any, N any and M1a/b); (3) patients did not receive prior treatment.
Staging criteria were according to American Joint Committee of Cancer (AJCC) 7 th edition manual. The pre-treatment staging examination included: complete medical history and physical examination, full blood count, serum biochemistry, chest X-ray, the computed tomography (CT) scans of the neck, chest, abdomen and pelvis, emission computed tomography (ECT)/positron emission tomography CT (PET-CT) scans and brain magnetic resonance imaging (MRI).

The definition of oligometastases and polymetastases. The concept of oligometastases was first
proposed in Hellman's paper 12 , we further specified the ES-SCLC oligometastases as follows: (1) only one organ metastasis or metastatic lymph node metastases (able to be covered by a safe radiotherapy portal); (2) multiple brain metastases (treated with whole brain radiotherapy); or (3) continuous vertebral bone metastases treated in a single radiotherapy field. The ES-SCLC polymetastases were defined as the metastases excluding oligometastases. For total 270 patients reviewed, 169 (62.6%) patients were in the chemotherapy responsive group, and 101 (37.4%) were in the non-chemotherapy responsive group. A total of 144 patients (53.7%) received radiotherapy after chemotherapy. Among these, 15 (10.4%) patients underwent the conservative anterior-posterior field radiotherapy, while 129 (89.6%) patients received intensity-modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3DCRT). The conservative radiotherapy fields covered primary lesions, hilar and bilateral mediastinal lymph nodes. The gross tumour volume (GTV) included the primary lesion and positive metastatic lymph nodes. The clinical target volume (CTV) mainly included 0.5-0.8 cm of the primary lesion and the draining area   Table 3. Disease characteristics of patients with oligometastases with chemotherapy + thoracic radiotherapy vs. chemotherapy after Propensity Score Matching.
of positive lymph nodes. The planned target volume (PTV) was defined as the CTV plus a 0.5-1.0 cm margin and PGTV (for all polymetastatic patients) was expanded from GTV with a 0.5-1.0 cm margin. The median dose was 45 Gy with the dose range of 30-60 Gy, and the fractionated radiotherapy dose was 1.8-3 Gy.
Evaluation of the response to therapy. The response to the therapy was assessed following the response evaluation criteria in solid tumors 21 . The evaluation was performed every other cycle during the chemotherapy or 3 months after radiotherapy. The entire group of patients also received evaluation every 6-8 weeks post-treatment until disease progression.
Follow-up and statistical analysis. The endpoints of the study included OS, PFS and LC, which were measured from the date of diagnosis till the date of events or last date of follow-up. The comparison of survival curves between the different groups was examined using the log-rank method, while the comparison of categorical data was performed by chi-square method. Multivariate analysis was performed using a Cox proportional hazard model. Because of the nonrandomized nature of this study, the data were matched and analyzed using PSM   Evaluation of candidate prognostic factors. Each clinical characteristic was assessed for prognostic significance against OS using the Kaplan-Meier method and COX regression analysis to evaluate whether there was an important relationship with prognosis. Patients having female gender, smoking index <400, oligometastases, chemotherapy cycles ≥4, response to chemotherapy, TRT and prophylactic cranial irradiation(PCI), showed favorable expectation using the univariate analysis. Other clinical features, such as age, family history of malignant tumors, weight loss >5%, KPS, state of stages, brain metastases and metastatic organs did not suggest any significant relationship to OS using the univariate analysis. Patients having oligometastases, chemotherapy cycles ≥4, response to chemotherapy and TRT showed favorable expectation using the COX regression analysis.
Superior outcome with oligometastases. Patients with oligometastases were compared with those with polymetastases. The oligometastases and polymetastases groups were made comparable after PSM (see Table 2).

Superior outcome with TRT in oligometastases and polymetastases.
The authors compared oligometastatic and polymetastatic patients with chemotherapy + TRT to those with only chemotherapy. The bias due to the cofounding variables between group of chemotherapy with TRT and chemotherapy alone were reduced after PSM (see Tables 3 and 4).
The 2-year OS, PFS, and LC in oligometastatic patients treated with the chemotherapy + radiotherapy and the chemotherapy alone were 25.2% and 12.7% (p = 0.002); 19.3% and 4.8% (p = 0.006); and 57.6% and 9.6% (p < 0.001), respectively. The estimated hazard ratio for survival with chemotherapy + radiotherapy as compared  Table 4. Disease characteristics of patients with polymetastases with chemotherapy + thoracic radiotherapy vs. chemotherapy after Propensity Score Matching.
with chemotherapy alone was 2.9 (95%CI, 1.4 to 6.0). Figure 1 shows the estimated survival distribution according to treatment group. The 2-year OS, PFS, and LC in polymetastatic patients treated with the chemotherapy + radiotherapy and chemotherapy alone were 10.0% and 6.8% (p = 0.030); 5.0% and 1.4% (p < 0.001); and 32.3% and 1.6% (p < 0.001), respectively. The estimated hazard ratio for survival with chemotherapy + radiotherapy as compared with only chemotherapy was 1.7 (95%CI, 1.2 to 2.3). Figure 2 shows the estimated survival distribution according to treatment group.

Discussion
For ES-SCLC patients, chemotherapy remained the standard therapeutic modality, with a median survival of 7-12 months 3 . As of today, the first-line chemotherapy for ES-SCLC is the platinum-based combination regimen. The response rate with EP regimen was as high as 70-90% 22 . A large number of sensitive SCLC cells died after chemotherapy, and then the chemotherapy-resistance cells were promoted to proliferate increasingly. As a result, leading to relapse and metastasis, therefore patients have higher recurrence 23 . Platinum-based chemotherapy combined with TRT significantly improved OS and PFS in ES-SCLC patients 4,16,20,24,25 . In the past when applying simple platinum-based chemotherapy as a standard treatment for ES-SCLC, thoracic radiotherapy was used only to palliate local symptoms and to improve quality of life 26 . Several clinical trials have demonstrated platinum-based chemotherapy combined with TRT to improve the prognosis of ES-SCLC patients 4,16,20,24,25 . According to the previous literatures 4, 16,20,24,25 , the 2-year OS of patients with ES-SCLC who received chemotherapy plus TRT increased from 13% to 38%. For patients with a single chemotherapy regimen, when treated with additional TRT, the 2-year OS shows enhancement from 6% to 21% 4,10,16,25 . It clearly shows that radiotherapy significantly improves the prognosis of patients with ES-SCLC, however the number of tumor metastasis were not considered in the studies.
Individualized treatment of NSCLC has been widely adopted, such as the targeted therapy, or radical treatment for patients with few oligometastases [27][28][29] . Resection or radiotherapy become a treatment option that provides high local control with minimal morbidity. De Ruysscher et al. reported their result of radical treatments (chemotherapyplus radiotherapy or surgery) for NSCLC patients with less than five oligometastases 30 , and the results indicating radical treatment had long-term PFS. Recently, Endo et al. 31 reported a prospective phase II study of surgery for primary lesions (cT1-2N0-1) and surgery for synchronous or metachronous single organ metastases (e.g., brain, lung or others) with promising outcomes. Niibe et al. 32 reviewed previous studies of oligometastatic NSCLC and advocated that local treatment approaches such as surgery or ablative radiation are only indicated for isolated brain or adrenal gland metastasis in terms of the survival results, and the most favorable lesion is 12 metachronous (recurrent) metastases. Punglia et al. 33 demonstrated the hypothetical benefit of local therapy on the survival with increasing effectiveness of systemic therapy. Most reports concerning oligometastasectomy have showed that NSCLC with oligometastases can benefit from aggressive local therapy due to less biologically aggressive cancers. There was rare literature to report that the different role of TRT in oligometastatic and polymetastatic patients. Therefore, we analyzed the prognosis of ES-SCLC patients with oligometastases and polymetastases, and focused on whether TRT could improve the survival in ES-SCLC patients with different metastases. An interesting finding in this study is that the combination of platinum-based chemotherapy and TRT significantly improved the prognosis of ES-SCLC patients with oligometastases and polymetastases. Because of the high response rate (near 70%), the polymetastases maybe well treated. So TRT also significantly improves the prognosis of patients with polymetastases. The estimated hazard ratio for survival of oligometastatic patients with chemotherapy + radiotherapy was 2.9 compared with only chemotherapy; while that was 1.7 in polymetastatic patients. And the oligometastatic patients with chemotherapy + radiotherapy had superior survival benefits than polymetastatic patients. The 2-year OS in oligometastatic patients treated with the chemotherapy + radiotherapy and only chemotherapy were 25.2% and 12.7% (p = 0.002), and those were 10.0% and 6.8% (p = 0.030) in polymetastatic patients. In the meanwhile, the RTOG 0937 demonstrated a delay in progression of disease but no improve in 1-year OS with addition of consolidative extra-cranial irradiation 34 . Slotman et al. 35 also reported that patients with 0-2 distant metastases, receiving TRT had significantly longer PFS (HR = 2.02; p = 0.003), but patients with more than 2 distant metastases, receiving TRT had not significantly longer PFS (HR1.25; p = 0.14); TRT did not lead to a significant benefit in OS in patients with 0-2 distant metastases or more than 2 distant metastases.
Another interesting finding of LC is that the actual LC in oligometastatic patients was superior to that in polymetastatic patients (36.7% v.s. 6.1%, (p < 0.001)), but the LC should be similar theoretically. We usually use involved-field radiotherapy (involved-sites radiotherapy usually in polymetastases) with low dose, so this was not improved in-field control and the LC was inferior in patients with polymetastases, and the local recurrences were still higher in patients with oligometastases. So we suggested that patients with oligometastases and polymetastases should receive the more aggressive TRT.
The limitations of this study include the small number of patients and retrospective analysis method. Therefore, some large prospective studies with dedicated designed chemotherapy and radiotherapy dose schemes are needed to confirm the findings. The optimal radiotherapy fields and prescription of ES-SCLC also need to be further studied.

Conclusion
Overall, the combination of platinum-based chemotherapy and radiation therapy can improve OS and PFS in ES-SCLC patients with oligometastases or polymetastases. Patients with oligometastases compared to polymetastases benefited more from radiotherapy. The optimal options of thoracic radiotherapy in ES-SCLC need to be prospectively investigated to obtain more convincing evidence.