For the whole group of patients, the results showed that PCI group had a lower incidence of BM, 3 patients (15.7%) developed brain metastasis in PCI group, and the BM rate of non-PCI group was 33.3%(11 patients), P = .041. In addition, The BM rate for patients with pathologic stages I, II, and III were 11.7%, 30%, 36%. Specifically, in PCI group, the incidence of brain metastasis was 0% (0/5) in patients with p-stage I disease, 20.0% (1/5) in p-stage II patients, and it was 22.2% (2/9) in patients with p-stage III. In non-PCI group, the incidence of brain metastasis was 16.6% (2/12) in patients with p-stage I disease, 40.0% (2/5) in p-stage II patients, and it was 43.8% (7/16) in patients with p-stage III.
The 2-year BMFS rate in PCI group was significantly better than non-PCI group (89.0% vs 53.0%, P = .026); Fig. 3). Further subgroup analysis showed that 2-year BMFS benefits of PCI therapy were significant in patients with stage III disease (83.6% vs 51.3%, P = .030); however, the difference of the patients with stage I (P = .325) or II (P = .520) disease was not statistically significant.
3.4 Prognostic factors
The results of univariate and multivariate analysis were shown in Table 2. Pathologic stage (HR: 2.442, 95%CI: 1.406–4.242, P = .002) and PCI (HR: 0.330, 95%CI: 0.114–0.954, P = .041) were independently prognostic factor for the OS.
SCLC is characterized by highly malignant, early recurrence and metastasis. Especially, brain metastasis is 1 of the main reasons for its failure of treatment. As early as the 1970 s, people realized the importance of PCI in controlling brain metastases. In 1999, 987 SCLC patients who achieve a CR were analyzed by a meta-analysis which had shown a significant survival benefit of PCI, a 5.4% increase of 3-year survival rate (20.7% vs 15.3%, P = .01) and a 25.3% decrease of 3-year survival cumulative incidence of BM (33.3% vs 58.6%, P < .001). Owning to this study, the important role of PCI in the comprehensive treatment of patients with limited SCLC was determined.
In recent years, there are still many controversies in the application of PCI. The efficacy of PCI on patients who received definitive surgery for surgically resected SCLC is undefined, According to the article published in recent years, the incidence of BM in patients with stage I, II, and III SCLC were 6.25% to 14%, 13% to 38%, and 11% to 36%.[12–16] Patients with complete resection and incomplete resection had significant differences in the incidence of BM (20.5% vs 42.9%, P = .028). In this study, the BM in overall patients with complete resection of stage I, II, and III were 11.7%, 30%, and 36%, respectively.
Gong et al study included 126 patients who underwent surgical resection with SCLC, the results showed that the 5-year OS rate of patients with stage I, II, and III were 54.8%, 35.6%, and 14.1%, respectively, P = .001. Another retrospective study analyzed 193 patients with completely surgical resection SCLC. The 2-year and 5-year OS rates in PCI group were significantly better than those of non-PCI group (92.5%, 54.9% and 63.2%, 47.8%, P = .005). But the patients with p-stage I couldn’t get the survival benefit from PCI, P = .601. Therefore, the authors suggested that PCI might confer survival advantage in completely surgically resected patients with p-stage II/III SCLC, but not for p-stage I disease because of its lower incidence of BM.
A large study by Xu et al analyzed 349 patients with completely surgically resected SCLC, 115 patients were allocated to PCI group versus 234 in no-PCI group. The MST in PCI group was significantly better than non-PCI group (36.4 months vs 25.62 months, P = .023). PCI could confer OS advantage for stage II (36.40 months vs 24.05 months, P = .047) or III (29.34 months vs 21.16 months, P = .009) SCLC patients, but not for patients of stage I (P = .282). In terms of the cumulative incidence of BM, the patients who received PCI had lower 2-year BM (13% vs 22.6%, P = .009). Subgroup analysis shows that the cumulative incidence of BM in PCI group patients with stage III were significantly reduced (14% vs 27.8%, P = .018), while stage I (10.5% vs 13.6%, P = .389), and stage II (12.8% vs 22.4%, P = .094) were not.
PCI could improve the OS and BMFS of patients with completely surgically resected SCLC in our study. Patients who received PCI had a longer 5-year survival rate (46.7% vs 29.8%, P = .023) and 2-year BMFS rate (89.0% vs 53.0%, P = .026). The 2-year and 5-year survival rates for patients with pathologic stages I, II, and III were 83.0%, 58.1%, 40.6% and 65.3%, 34.3%,21.1% respectively, P = .011. However, in a further subgroup analysis, we found that PCI can improve 5-year survival rates in patients with stage III patients (24.7% vs 16.8%, P = .031) but not for I (P = .924) and II (P = .094). Similarly, PCI was associated with 2-year BMFS benefit in stage III patients (83.6% versus 51.3%, P = .030) but not I (P = .325) and II (P = .520). The small overall sample size for stage I/ II patients might affect the statistical analysis.
The incidence of BM of patients with stage I in this study was 11.7%. Patients with stage I have a lower incidence of BM compared with stage II, III patients, PCI is not recommended for patients with stage I in many studies, but there are still some studies hold different views. A small retrospective study analyzed 39 patients who underwent completely surgical resection with stage I and II SCLC. In this study, no-BM occurred in 21 patients of PCI group and 22.2% (4/18) of the patients who did not receive PCI developed BM at follow-up of 8 to 27 months. Additionally, the BMFS (P = .01) and OS (P = .01) of PCI group were significantly better than non-PCI group. So the researchers suggested that PCI might be considered for all completely surgically resected patients with stage I and II. Another large sample study which based on the National Cancer Database (NCDB) enrolled 954 patients with stage I disease. The results showed that PCI group could confer better survival than any other group in this study, (P < .01). Although patients of stage I have a much lower risk of BM than stage II and III patients, the stage I patients who received PCI could get survival benefit if the sample size big enough.
Our study did not show the value of postoperative adjuvant chemotherapy and radiotherapy clinical. We analyzed the reasons as follow:
- The 26.9% (14/52) patients received postoperative adjuvant radiotherapy in this study, and the number of receiving radiotherapy patients was insufficient or could affect the statistical analysis.
- The study showed that radiation was not associated with a significant survival advantage even had lower OS compared with simple surgery when used alone or combined chemotherapy. Patients of stage I and II accounted for 28.5% (4/14) received postoperative adjuvant radiotherapy in our study, which may affect the outcome.
- In our study, although 84.6% of patients received postoperative adjuvant chemotherapy, only 38.5% (20/52) of patients received ≥4 cycles of chemotherapy after surgical resection. The study showed that the 2-year and 5-year OS of patients undergoing adjuvant chemotherapy and non-adjuvant chemotherapy group were 52.0%, 31.3% and 38.0%, 26.2%. The survival of adjuvant chemotherapy group was better than non-adjuvant chemotherapy group, due to the small sample size which could not show the statistical differences.
There are several limitations in our study as follow:
- retrospective study of its own characteristics, the bias of treatment options may affect the conclusions.
- The small sample size of the subgroup analysis might affect the statistical analysis.
- Failure to assess the acute toxicity of both groups of patients.
In conclusions, the OS benefits of PCI were significant in limited SCLC patients treated with definitive surgery, especially for those with stage III diseases. It is difficult to determine whether the patients with stage I, II could benefit from PCI or not due to the small number of sample. Accumulate enough cases to identify high-risk patients for PCI warrants further study.
6 Additional information
The authors declare that they have no competing interests.
Conceptualization: Xiao Hu.
Data curation: Meng-yuan Chen.
Formal analysis: Meng-yuan Chen.
Methodology: Ming Chen.
Resources: Ming Chen.
Software: Ming Chen.
Supervision: Xiao Hu, Yu-jin Xu.
Validation: Xiao Hu, Ming Chen.
Writing – original draft: Meng-yuan Chen.
Writing – review & editing: Meng-yuan Chen, Ming Chen.
. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. Clin Oncol 2006;24:4539–44.
. Bayman NA, Sheikh H, Kularatne B, et al. Radiotherapy for small-cell lung cancer—where are we heading. Lung Cancer 2009;63:307–14.
. Socha J, Kepka L. Prophylactic cranial irradiation for small-cell lung can- cer: how, when and for whom. Expert Rev Anticancer Ther 2012;12:505–17.
. Seute T, Leffers P, ten Velde GP, et al. Neurologic disorders in 432 con- secutive patients with small cell lung carcinoma. Cancer 2004;100:801–6.
. Arriagada R, Le Chevalier T, Rivie[Combining Grave Accent]re A, et al. Patterns of failure after prophylactic cranial irradiation in small-cell lung cancer: analysis of 505 randomized patients. Ann Oncol 2002;13:748–54.
. Komaki R, Cox JD, Whitson W. Risk of brain metastasis from small carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer 1981;65:811–4.
. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in com- plete remission: a meta-analysis of individual data from 987 patients. New Engl J Med 1999;341:476–84.
. Patel S, Macdonald OK, Suntharalingam M. Evaluation of the use of prophylactic cranial irradiation in small cell lung cancer
. Cancer 2009;115:842–50.
. Halthore A, Goenka A, Sharma R, et al. Prophylactic cranial irradiation for resectable small cell lung cancer
. Clin Lung Cancer 2018;19:115–9.
. Schild SE, Foster NR, Meyers JP, et al. Prophylactic cranial irradiation in small-cell lung cancer: findings from a North Central Cancer Treatment Group pooled analysis. Ann Oncol 2012;23:2919–24.
. Bloom BC, Augustyn A, Sepesi B, et al. Prophylactic cranial irradiation following surgical resection
of early-stage small-cell lung cancer: a review of the literature. Front Oncol 2017;7:228.
. Nakamura H, Kato Y, Kato H, et al. Outcome of surgery for small-cell lung cancer-response to induction chemotherapy predicts survival. Thorac Cardiovasc Surg 2004;52:206–10.
. Tsuchiya R, Suzuki K, Ichinose Yet, et al. Phase II trial of postoperative adjuvant cisplatin and etoposide in patients with completely resected stage I–IIIA small-cell lung cancer: The Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). J Thorac Cardiovasc Surg 2005;129:977–83.
. Gong L, Wang QI, Zhao L, et al. Factors affecting the risk of brain metastasis in small cell lung cancer
with surgery: is prophylactic cranial irradiation necessary for stage I-III disease. Int J Radiat Oncol 2013;85:196–200.
. Hui Z, Hongbo G, Fang S, et al. Prophylactic cranial irradiation improved the overall survival of patients with surgically resected small cell lung cancer
, but not for stage I disease. Lung Cancer 2014;86:334–8.
. Xu J, Yang H, Fu X, et al. Prophylactic cranial irradiation for patients with surgically resected small cell lung cancer
. J Thorac Oncol 2016;26:1556–864.
. Bischof M, Debus J, Herarth K, et al. Surgery and chemotherapy for small-cell lung cancer in stages I–II with or without radiotherapy. Strahlenther Onkole 2007;183:679–84.
. Chi-Fu JY, Derek Y, Paul J, et al. Role of adjuvant therapy in a population-based cohort of patients with early-stage small-cell lung cancer. J Clin Oncol 2016;34:1057–64.
Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
brain metastases; PCI; prognosis; small cell lung cancer; surgical resection