Journal of Clinical and Translational Research 2021; 7(1): 34-48 Journal of Clinical and Translational Research Journal homepage: http://www.jctres.com/en/home REVIEW ARTICLE The current role of surgery and SBRT in early stage of small cell lung cancer Núria Farré1*, José Belda-Sanchis2, Mauro Guarino2, Laura Tilea1, Jady Vivian Rojas Cordero1, Elisabeth Martínez-Téllez2 1 Department of Radiation Oncology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, 2Department of Thoracic Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, ARTICLE INFO ABSTRACT Article history: Background: Early stage small cell lung cancer (T1-2N0M0SCLC) represents 7% of all SCLC. Received: September 9, 2020 The standard treatment in patients with intrathoracic SCLC disease is the use of concurrent Revised: November 13, 2020 chemoradiotherapy (CRT). Nowadays, the recommended management of this highly selected group is Accepted: December 13, 2020 surgical resection due to favorable survival outcomes. For medically inoperable patients or those who Published online: February 17, 2021 refuse surgery, there is an increasing interest in evaluating the role of Stereotactic Body Radiotherapy (SBRT) for T1-2N0SCLC, transferring the favorable experience obtained on inoperable NSCLC Keywords: (Non-Small-cell Lung Cancer). In the era of multimodality treatment, adjuvant systemic therapy plays chemoradiotherapy an important role even in the management of early SCLC, increasing the disease-free survival (DFS) chemotherapy and Overall Survival (OS). The benefit of Prophylactic Cranial Irradiation (PCI), that currently has a early stage small cell lung cancer Category I recommendation for localized stage SLCL, remains controversial in this selected subgroup prophylactic cranial irradiation of patients due to the lower risk of brain metastasis. radiotherapy Aim: This review summarizes the most relevant data on the local management of T1-2N0M0SCLC small cell lung cancer (surgery and radiotherapy), and evaluates the relevance of adjuvant treatment. stereotactic ablative radiotherapy Relevance for patients: Provides a critical evaluation of best current clinical management options stereotactic body radiotherapy for T1-2N0M0 SCLC. surgery *Corresponding author: Núria Farré 1. Introduction Department of Radiation Oncology, Hospital de Small cell lung cancer (SCLC) accounts for 15-20% of all lung cancers [1-3]. It is strongly la Santa Creu i Sant Pau, Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain associated with cigarette smoking and the most aggressive subtype with a median overall E-mail: nfarre@santpau.cat survival time of 7 months and 5-year relative survival rates of 5-7% [4,5]. SCLC is most often diagnosed at advanced stages. Using the Veterans Administration Lung Cancer Study © 2021 Farré, et al. This is an Open Group stage system, roughly 60% of the patients present with limited-stage disease while Access article distributed under the terms 40% present with extensive stage [1]. Early-stage SCLC (T1-2N0SCLC), defined as Stages of the Creative Commons Attribution- I and II according to the American Joint Committee on Cancer Staging [6,7], comprises 7% NonCommercial 4.0 International License (http://creativecommons.org/licenses/by- of all SCLC and 0.29% of all lung cancers [8]. nc/4.0/), permitting all non-commercial use, Even for this selected subgroup of patients, the 5-year overall survival (OS) remains distribution, and reproduction in any medium, poor, <35%, despite an intensive treatment. At this moment, the international guidelines provided the original work is properly cited. recommend a local therapy as the first option for early SCLC. Surgical resection for fit patients has shown favorable survival outcomes in several studies [9,10], whereas definitive radiotherapy (RT) treatment is recommended for inoperable patients in addition to systemic therapy. Recently, the development of a highly conformal RT treatment, Stereotactic Body Radiotherapy (SBRT) with excellent results in early NSCLC, has led to an increased interest in its use in early well-staged SCLC patients [11,12]. The authors present a literature review of the current role of surgery and SBRT in early stage small cell lung cancer to provide a critical evaluation of the available data from existing DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 35 studies. A comprehensive search was conducted in the NHS and an overall 5-year survival of 10% [1,26]. Historically, surgery evidence (www.evidence.nhs.uk), PubMed (www.ncbi.nlm.nih. alone has been considered to have a limited role in the primary gov/pmc/) and Embase (www.embase.com), from 1966 to 2019. treatment of early-stage SCLC as it had been associated with an Studies published in languages other than English were excluded. overall 5-year survival close to 0%. In 1969, the British Medical Search terms included: Early small cell lung cancer, Small cell Research Council Trial randomly allocated 144 operable patients lung cancer, Stereotactic body radiotherapy, Stereotactic ablative with a SCLC diagnosed on bronchial biopsy to either surgical radiotherapy, and Surgery. Prospective, retrospective, meta- resection or RT. The mean and 10-year overall survival results analysis, case–control, and case reports with more than 5 patients showed that radical RT was associated to a moderately better were included in the study. result than surgery (300 days for radical RT vs. 199 days for surgery – P=0.04 – and 1% for radical RT vs. 0% for surgery). 2. Treatment of ES-SCLC. Surgery versus SBRT The conclusion of this study was that radical RT is preferable to 2.1. Defining limited/early stage SCLC surgery in the treatment of patients with SCLC [27-29]. These results were broadly in line with those published by Mountain In 1957, the Veterans Administration Lung Cancer Study et al. in 1974 [30] and Martini et al. in 1975 [31]. Group (VALSG) established a dichotomous stage system for SCLC: Limited disease when the tumor was confined to one 2.2.2. Surgery within multimodality treatment for T1-2N0M0 hemithorax and extended disease in case of bilateral pulmonary SCLC or extrathoracic involvement. From a practical point of view, a 2.2.2.1. Rationale for surgery in early stage SCLC limited disease would be encompassed within an acceptable RT Systemic therapy plus concurrent RT is considered the gold field, while the RT field required for treating the extended disease standard for patients with T1-2N0SCLC and RT is a crucial would be too large and would be associated with inadmissible component for the local treatment. However, the local in-field toxicity. This simplified two-stage system, applied in clinical failure rate after CRT is high and ranges from 30 to 70% [17,32-35]. practice and trials during many years, has proven to be adequate In addition, despite having achieved complete radiologic response, for most clinical decisions and carries additional prognostic up to 70% of these patients will have detectable residual disease in information [13]. In 1989, the IASLC proposed a modification the resected specimen [32,36]. to the VALSG classification of the limited disease including The above-mentioned highlights a possible role of surgery in contralateral mediastinal or supraclavicular lymph node metastases the local treatment of T1-2N0SCLC. Many authors have addressed and ipsilateral pleural effusions independent of cytology. this matter [37-40]. The rationale for surgical resection in SCLC In 1993, Shepherd et al. points out the relevance of an accurate can be summarized as follows: clinical staging of limited SCLC as a helpful system to differentiate 1. Intraoperative diagnosis on frozen section of SCLC of a prognostic subgroups and proposed the term of “very limited solitary nodule not suspected to be a SCLC. Although this disease” for the SCLC with a negative cervical mediastinoscopy scenario is very unlikely due to the aggressiveness of the and/or no evidence of enlarged mediastinal lymph nodes on SCLC, there is a small subgroup of patients (3-5%) who radiologic examinations [14]. presents initially with disease strictly limited to the lung [8]. The prognostic value of the TNM staging system has been observed in small series of patients undergoing surgical resection In this subset of patients, aggressive treatment (anatomic for SCLC, mainly in the setting of a multimodal therapy [14-22]. resection, systematic lymphadenectomy, and adjuvant CT or Nonetheless, the TNM staging system for SCLC was not formally CRT) can achieve similar survival rates to that of non–small- recommended by the AJCC till 2009. In 2009 (7th edition) and cell lung cancer. 2015 (8th edition), based on the prognostic value of both clinical SCLC tend to be accurately diagnosed intraoperatively and pathological TNM staging, the International Union for Cancer on frozen section, in some cases it can represent a difficult Control (UICC) Classification of Malignant Tumors recommended diagnostic problem [41]. In a series of 125 unexpected the use of the TNM staging system for SCLC [23,24]. A recent study SCLC diagnosed after pulmonary resection, only 78 conducted by Abdel-Rahman validates both the prognostic value of cases were diagnosed as SCLC by intraoperative frozen TNM lung cancer staging system and the improvement over the section examinations. The other 47 cases were diagnosed prognostic value of the old veterans’ administration system [25]. intraoperatively as poorly differentiated, non-specific lung Despite the above-mentioned, a considerable variation exists cancer or carcinoid tumors. There was also inconsistencies concerning which definition should be used for classifying SCLC, between the clinical and pathological stage of these unexpected even in the context of multidisciplinary team meetings. SCLC mainly caused by nodal upstaging, highlighting the importance of an adequate systematic nodal dissection [42]. 2.2. Surgery for ES-SCLC 2. Surgical resection for very limited-SCLC (defined as T1N0, T2N0) may improve local control compared to 2.2.1. Surgery alone for ES-SCLC CRT [8-10,16,18,21,34,43-88]. The first sites of recurrence Concurrent CRT is considered to be the standard of care for after complete remission are either the primary tumor patients with ES-SCLC, resulting in a median survival of 17 months region or the hilar and mediastinal lymph nodes. It has DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 36 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 been demonstrated that local control after multimodality Ahmed et al. identified 1902 patients with Stage I SCLC from treatment including complete surgical resection is 95- the SEER database. Of these, 28.5% underwent surgical resection, 100% [15,16,18,48,74,89,90]. a percentage that remained unchanged from 2007 to 2013 despite Accurate hilar and mediastinal staging are mandatory in this improved outcomes with surgical resection as part of a multimodal subgroup of patients with a potentially resectable SCLC. approach. The authors point out the significant disparities in the Ideally, the mediastinal staging should include invasive management of patients with Stage I SCLC and the need to educate techniques as endobronchial ultrasonographic needle physicians on the importance to consider surgical resection for aspiration, endoscopic ultrasonographic needle aspiration, this subgroup of patients [46]. conventional and extended cervical mediastinoscopy, Jones et al. conducted a best evidence topic published in 2013 anterior mediastinotomy, and video-assisted thoracic surgery. concluding that surgery would be indicated in clinical Stages I Thomas et al. studied 477 patients with clinical Stage I SCLC or II SCLC after an accurate pre-operative staging of mediastinal (cT1-2aN0M0) from the National Cancer Database treated lymph nodes including a mediastinoscopy. In this scenario, surgery with curative-intent resection, followed by adjuvant therapy. for T1-2N0SCLC improves the prognosis as part of a multimodal Initial clinical and final pathological stages were compared to treatment. However, patients with Stage III disease are unlikely to determine the upstaging rate; it was 25%, 30% due to a higher benefit from surgery [100,101]. pathologic T descriptor, and 81% due to the presence of nodal The effectiveness of surgery in patients with locally advanced disease. Overall 5-year survival was significantly worse for SCLC (Stages II and III) has been specifically addressed in upstaged patients compared with those who remained a both retrospective series of cases [10,18,48,74,87,89,100,102] pathologically Stage I (36% vs. 52%, P<0.001) [60]. and propensity score matching analyses [103]. Data from these 3. Combined histology tumors (a SCLC tumor with a NSCLC studies show that surgery is highly effective in local control and is component). The incidence of combined SCLC ranges from associated with a significant overall survival benefit after complete 2% to 28% [91-95]. It is thought that relapse or failure to resection in the context of a multimodal treatment including respond to CT may be due to the NSCLC component. neoadjuvant/adjuvant chemoradiation and prophylactic cranial 4. Salvage surgery for chemoresistant localized SCLC or local irradiation (PCI). Nevertheless, the favorable survival associated relapse after an initial response to C/CRT. In this scenario, to the surgery-based multi-modality treatment appears to be stage- selected patients may benefit from surgical resection more dependent, ranging from 20 to 57% (5-year overall probability of than a second-line CT [17,96,97]. survival), with a detrimental impact on hazard ratio for OS over the stages. 2.2.2.2. Does surgical resection of T1-2N0SCLC improve overall With the aim of assessing the potential role of surgery for survival? pathologically confirmed SCLC, Staged T1-4 N0-2 M0 (AJCC The role of surgery in small cell lung cancer (SCLC) is 8th edition), Wei et al. used propensity score-matching analysis controversial. Two old randomized controlled trials have shown to compare overall survival (OS) in a matched cohort of 1562 no significant benefit from surgery compared to conventional patients from the SEER database (2004-2014). In the matched treatment [36,98]. In the largest study conducted by Lad et al., cohort, surgery was associated with a significant 5-year OS a total of 146 patients with SCLC received induction CT. improvement (from 16.8% to 36.7%, P<0.001). After adjustment Patients achieving at least partial response after induction and for confounders using a Cox regression model, survival benefit of fit enough for thoracotomy were randomized to surgery or no surgery was significant in all subgroups, including N1-2 disease, intervention. Complete resection rate was 77%. All patients except for patients with a tumor size > 5.0 cm or T3 disease. The had chest and brain irradiation postoperatively. There was no authors concluded that selected patients (T size <5 cm/T1-2) with difference in survival between the two groups. The conclusion SCLC would benefit from surgery, including N1-2 disease [104]. of the authors was that surgery does not add any benefit in Du et al. conducted another propensity score matching analysis terms of survival or local disease control to multimodality of patients with SCLC from the SEER database (2010-2015) to treatment of SCLC. Nevertheless, quality of the evidence from investigate the impact of surgery on survival. A total of 1,707 these randomized trials is very low [99] and the results should patients were included in the matched cohort. The authors found be taken with caution as the staging pre-operative methods; that patients who did not receive surgery had an increased risk of pre-operative neoadjuvant therapy and surgical procedures death when compared with patients who did. The results support used in these studies do not reflect current knowledge and that patients with SCLC with Stage I-IIA (T1-2N0M0) and clinical practice. selected IIB (N1) may benefit from surgery [105]. Similar results Ever since, many small series (largely retrospective, but also were found by Peng et al. in regard to the impact of surgery on Phase II trials, meta-analysis, systematic reviews, and propensity lung cancer specific survival in a cohort of 2453 patients with early matched score analysis) have shown excellent survival for patients stage SCLC from the SEER database [106]. Yu et al. analyzed a with T1-2N0SCLC treated surgically, mainly in the setting of a series of 1560 patients with stage I SCLC from the SEER database, multimodal approach [8-10,16,18,21,34,43-88]. of which 399 treated surgically (242 underwent lobectomy, 121 Table 1 summarizes surgical and survival data for patients with had local tumor excision/ablation, ten had a pneumonectomy, and SCLC published in the past 25 years. unknown type of surgery in 21). Most of the surgical group of DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 37 Table 1. Surgical and survival dates for patients with SCLC (period time revised 1995‑2020) Study Study type and Inclusion Number patients Neoadjuvant/adjuvant PCI Survival (Sv) data time period LOE criteria treatments Jin, 2018 RS, SEER 2004‑2013 cI‑II N=2129 ‑ 5‑year OS T1N0 46.0% versus [131] 3A S 387, RT 1032 23.8% S versus RT S+RT 154 5‑year OS T2N0: 42.6% versus No S nor RT 556 24.7% S versus RT T3N0 or T1‑2N1 (stage IIB) SCLC patients who underwent S did not have higher 5‑year OS and LCSS rates than patients who received RT Ahmed, RS, SEER 2007‑2013 Stage I SCLC N=1902 ‑ ‑ MST 50 mos. (S) 2017 [46] 3A S 427, S+RT 115 MST 60+mos. (S+RT) Wakeam, RS, NCDB cT1‑2N0M0 N=5079 MST 25.3 mos. 2017 [134] 2004‑13 3A Wakeam RS, NCDB cI‑III N=2619 No adjuvant treatment _ MST Stage I 38.6 versus 22.9 mos. 2017 [53] 2004‑2013 24% S versus NST Stage‑specific NC or NR 4% MST Stage II 23.4 versus 20.7 mos. Propensity score AC 27%; AR 1% S versus NST match S versus NST ACR 32%; NC or NR MST stage IIIA21.7 versus 16.0 3A and AC or AR 2% mos. S versus NST, Other 10% Combs, RS, NCDB1998‑2011 cT1‑3N0‑2 N=2,476 All ‑ 5‑year OS: 54% (cIA); 36% (cIB 2015 [102] 3A SCLC S 841 cIA, 168 S: 68% cIB Ogawa, RS, 1995‑2008 cI‑III N=28 (23 SCLC NC 8 ‑ 5‑year OS 47% 2012 [45] Institutional pI‑III SCLC before S) AC 19, ACR 2 4 S 21cI,5 cII,7 cIII2 Ju, RS,1990‑2009 pI‑III N=34 NC 3 ‑ 5‑year OS 66% 2012 [79] Institutional AC 1, AR 19, 10 CRT 4 Vallières, RS, IASLC Resected N=349 (68 pIA, ‑ ‑  5‑year OS: 53% (pIA); 44% (pIB) 2009 [136] 1990‑2000 SCLC 91 pIB) 3A Wang, RS, Institutional pI‑III N=122 CT and CRT (not ‑ MST 50 mos. 2007 [47] 4 specified) 5‑year OS 66% Veronesi, RS, Institutional cI‑IIIA N=23 AC all ‑ MST 24 mos. 2007 [44] 4 Tsuchiya, Prospective Phase II cI‑IIIA N=62 AC 42 (69%) ‑ MST not reached in pI stage 2005 [83] trial 1991‑1996 MST 449 days in pII stage 2B MST 712 days in pIIIA disease. 3‑year OS 61% 3‑year Sv rate cI, cII, cIIIA stage 68%, 56%, and 13%, respectively Brock, RS, Institutional Resected N=82 (24 Stage AC 55% 23% 5‑year OS: 86% (platinum); 2005 [72] 1976‑2002 SCLC I→S + AC) 42% (non‑platinum) 4 Nakamura, RS, Institutional cI‑III SCLC N=69 S 37, NC 32, ‑ 5‑year Sv 48.9% cI 33.3% cII 2004 [43] 4 AC 41, ACR 7 20.2% cIIIA 0% cIIIB. Badzio, Comparative cI‑III N=134 S 67 (all AC) 34% only MST 22 mos. (S) 2004 [70] RS, Institutional balanced in Non‑S 67 (all CT) S group MST 11 mos. (non‑S) 1984‑1996 both, S and 5‑year OS S 27%, non‑S 4% 4 non‑S groups (Contd...) DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 38 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 Table 1. (Continued) Study Study type and Inclusion Number patients Neoadjuvant/adjuvant PCI Survival (Sv) data time period LOE criteria treatments Lewinski, RS, Institutional cI‑IIIA SCLC N=75 NC all If CR to MST N0+1 25 mos. 2001 [20] 1976‑2002 46 underwent NC MST N2 14 mos. 4 thoracotomy and MST resected 18 mos. 35 lung resection 5‑year OS resected 29% Cataldo, RS, Institutional cI‑III SCLC N=60 AC 88% 41% 5‑year Sv rate 40% pI, 36% pII, and 2000 [137] 1982‑1992 pII AR (11%) 15% pIII. 4 pIII AR (21%) Inoue, RS, Institutional Resected N=91 (32 cIA, 30 All 78% 5.5% MST 53 mos. 5‑year OS 49% (cIA) 2000 [18] 1975‑1994 SCLC cIB) MST 25 mos. 5‑year OS 47% (cIB) 4 Kobayashi, RS, Institutional cI‑III SCLC N=59 NC 71% ‑ 5‑year survival rate 55% pI, 33% 2000 [138] 1982‑19922 pII, 23% pIII. 4 Eberhardt, Prospective phase cIB‑cIIIB N=46 IB/IIA had NC+S ‑ MST all patients 36 mos. 1999 [48] II trial. Institutional IIB/IIIA had NCR+S MST R0 patients 68 mos. 1991‑1995 5‑year Sv rate all patients 46% 2B 5‑year Sv rate R0 patients 63% Rea, RS, Institutional cI ‑III SCLC N=104 51 cI‑II received 35% MST 28 mos. 1998 [21] 1981‑1995 S+ACR 5‑year OS rate 32% 4 53 cIII received 5‑year OS pI 52.2%, pII 30% pIII NC+S + AR 15.3% Lucchi, RS, Institutional Resected N=1272001 15 S 10% MST 18 mos. 1997 [69] 1975‑1995 SCLC 92 S+AC+AR if 5‑year actuarial Sv rate 22.6% 4 N1‑2 (34 patients) 15 NC Fujimori, RS, Institutional cI‑IIIA SCLC N=22 NC all – MST 62 mos. 1997 [49] 1987‑1993 3‑year OS rate67% 4 3‑y OS ratecI‑II 73% 3‑year OS rate cIII 43% Wada, RS, Institutional cI ‑III SCLC N=46 NC+AC 37.0% AC _ 5‑year Sv rate cI‑II who received 1995 [139] 1976‑1991 50.5% the S 12,5% NC 80.0% 4 5‑year Sv rate cI‑II who received AC 37.7% 5‑year Sv rate cIII‑IIIb who received NC 10.0% 5‑year Sv rate cIIIa or IIIb who received AC 0.0% Karrer and Prospective RCT T12N0M0 N=183 AC 100% 2.5‑year Sv rate 63% for 68 patients Ulsperger, ISC‑LCSG SCLC after R0‑pTN0M0 1995 [75] 2B 2.5‑year Sv rate 37% for 27 patients after R0‑pTN2M0 SCLC: Small cell lung cancer; PCI: Prophylactic cranial irradiation; RS: Retrospective study; SEER: Surveillance, epidemiology, and end results database; ISC‑LCSG: The Lung Cancer Study Group of the International Society of Chemotherapy; S: Surgery; CT: Chemotherapy; RT: Radiotherapy; NCDB, National Cancer Data Base; cIA, clinical stage IA; cIB, clinical stage IB IASLC: International Association for the study of Lung Cancer; pI (A): Pathologic stage IA; pI (B), pathologic stage I (B); pII: pathologic stage II; pIII (A): Pathologic stage IIIA; pIII (B): pathologic stage IIIB; R0: Complete resection; AC: adjuvant chemotherapy; MST, median survival time; NC: neoadjuvant chemotherapy; ACR: adjuvant chemoradiotherapy. CR: complete response; NST: non‑surgical treatment; A dash represents lack of information or details; LOE, Level of evidence (From the Centre for Evidence‑Based Medicine, http://www.cebm.net.) patients did not receive radiation therapy. The authors found that total of 2089 patients with a SCLC clinically Staged I-IIIA were surgery, even without RT, seems to offer acceptable OS outcomes matched. The study aimed to evaluate outcomes of curative surgery for Stage I patients who undergo lobectomy (5-year OS 50.3%, in comparison to CT-based non-surgical treatment. Surgery was 95% CI 43.1-57.1%, for the group of lobectomies without RT and associated with longer survival across all the stages. In a sub- 57.1%, 95% CI 37.4-72.7%, for the group of lobectomies with analyses by T and N descriptors, significant differences in OS was RT) [65]. observed in favor of patients who underwent surgical resection Wakeam et al. performed a propensity score matching analysis ofT3/T4 N0 tumors (median OS 33.0 vs. 16.8 months, P=0.008), of patients with SCLC from the National Cancer Database. A N1 (24.4 vs. 18.3 months P=0.03), and N2 tumors (20.1 vs. 14.6 DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 39 months, P=0.007). The authors conclude that surgical resection is 2.3. SBRT for early ES-SCLC associated with significantly longer survival for early SCLC [53]. The standard treatment for patients with intrathoracic Regarding the type of resection, there is evidence suggesting SCLC disease is concurrent CRT, while surgical resection is that patients who underwent a lobectomy had significant better recommended for patients with early stage SCLC (T1-2N0). OS over sublobar resection [8,53,65,67,86,87,90,102,105]. In For medically inoperable patients or those who refuse surgery, the retrospective study of SCLC patients in the National Cancer definitive radiation therapy concurrently with systemic therapy is Data Base published by Combs et al., lobectomy was associated the standard approach. There is an increasing interest in evaluating with a 5-year overall survival of 40% compared with 21% the role of SBRT for inoperable early stage SCLC. for sublobar and 22% for pneumonectomy (HR for death after SBRT, otherwise known as stereotactic ablative radiotherapy sublobar resections vs. lobectomy 1.38,95% CI 1.12-1.71) [102]. (SABR), is an advanced technique that delivers a highly Similar results were found in the propensity-matched analysis conformed ablative radiation dose with great precision into a of survival of patients from the same database published by small tumor volume, usually <5 cm. It is given over a limited Wakeam et al. [53] comparing resection of Stage I-IIIA SCLC number of fractions, typically from 3 to 8. This technique allows with CT-based non-surgical treatment, as well as in the systematic minimizing the dose to surrounding normal tissues due to a review and meta-analysis of the role of surgery in Stage I to III very steep dose gradient, being the reason for the low toxicity SCLC published by Liu et al. [66] and in the study of Schreiber (Figure 1). et al. [87] using the SEER database to analyze survival outcomes of patients who underwent surgery with both localized disease and SBRT has been demonstrated to be an effective treatment for medically inoperable early-stage NSCLC, with local control regional SCLC. Du et al. conducted a propensity score matching rates of 80-90% [111-115]. On the basis of these findings analysis of patients with SCLC included in the SEER database and knowing the high radiosensitivity of SCLC, SBRT has from 2010 to 2015 and concluded as well that patients who recently emerged as a potential therapeutic option in medically received a sublobar resection had a significant increased risk of inoperable T1-2N0 SCLC. Principles of SBRT for early mortality when compared with patients who received a lobectomy SCLC, in the absence of other data, are similar to those used (P=0.03) [105]. for early NSCLC: Small volume (<5 cm), non-involvement of 2.2.2.3. What do guidelines say on surgical treatment of mediastinal structures, and DBE (dose biological equivalent) T1-2N0SCLC? >100 Gy. Despite not having randomized studies, the use of this There is not a complete agreement on the indication of surgery technique is increasing, while awaiting new results that validate in T1-2N0 SCLC between the different guidelines. The National this treatment approach. Comprehensive Cancer Network (NCCN) [107], ASTRO [108], 2.3.1. Review of literature’s data and ASCO [109] guidelines recommend surgery as the initial treatment option in operable patients having a Stage T1-2N0M0 Table 2 summarizes several retrospective SBRT series for (I-IIA) SCLC. The ESMO Clinical Practice Guidelines (108) patients with early stage SCLC published in recent years: Multi- recommend surgical treatment for patients with a SCLC stage institutional retrospective series, database reviews, and cases T1-2N0-1M0. All the guidelines state that indication of surgical series reports. treatment and RT should be based on the American Joint Videtic et al. published in 2013 the first results of patients Committee on Cancer/Union for International Cancer Control with ES-SCLC (T1-T2aN0) treated with SBRT with a dose of TNM Staging System. An accurate pre-operative mediastinal staging is universally recommended before indicating surgical treatment. Nevertheless, recommendations to rule out mediastinal lymph node involvement differ substantially between guidelines. After a standard staging, the NCCN recommends an endoscopic (endobronchial and/or endoscopic ultrasound biopsy) or surgical staging (mediastinoscopy, mediastinotomy, and videothoracoscopy) of the lymph nodes to all patients candidates for definitive surgical resection [107]. The ESMO guidelines, however, recommend a direct surgical approach in patients without mediastinal lymph node involvement on CT scan and PET-CT scan (in these patients, mediastinal lymph node biopsy would not be required before surgery) and to perform an EBUS and/or mediastinoscopy only if there are enlarged or positive lymph nodes on CT scan and/or PET-CT scan [110]. With regard to the type of resection, lobectomy with mediastinal lymph node dissection is the recommended type of resection. Figure 1. SBRT planning treatment. DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 40 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 Table 2. SBRT data for early stage SCLC Study Study type Inclusion Cohort size Dose CT PCI Results criteria LC OS PFS Videtic, RS‑single center Stage I N=6 60 Gy (3 fx) 66,6% 66,6% 100% (1y) 63% (1y) 75% (1y) 2013 [116] (2004‑2010) SCLC 50 Gy (5 fx) (4/6) (4/6) 30 Gy (1 fx) Ly, 2014 RS‑single center Stage I N=8 50 Gy (4 fx) 62.5% 0% 100% (3y) 37% (3y) ‑ [115] (2007‑2011) SCLC (3/8) 60% (3y‑CT) Recurrent N=3 0% 33.3% 100% (1y) 33% (1y) ‑ Stage I (1/3) SCLC Shioyama, RS‑multicenter Stage I N=64 48 Gy (4 fx) 56.2% 15.6% 89.3% (2y) 76.3% (2y) ‑ 2015 [117] SCLC (36/64) (10/64) Stahl, 2017 RS‑database NCDB Stage I N=285 48‑60Gy 45.6% ‑ 35.2% (3y) ‑ ‑ [120] (2004‑2013) SCLC (3‑5 fx) (130/285) 21.5% (5y) Verma, RS‑Multicenter Stage I N=74 50 Gy (5fx) 59.2 23% 96% (3y) 31.4m (CT) 61.3m (CT) 2017 [12] (2005‑2015) SCLC (45/74) (17/74) 14.3m (no CT) 9m (no CT) Shioyama, RS‑ database Stage I N=43 36‑60 Gy 18.6% 18.6% 80.2%(2y) 72.3% (2y) 44.6% (2y) 2018 [118] JRS‑SBRTSG SCLC (3‑10fx) (8/43) (8/43) 47.2% (2y) (2004‑2012) (Dm1PFS) Verma, RS‑database NCDB Stage I SBRT/CT=149 45‑60 Gy 100% ‑ 83.8% (1y) ‑ ‑ 2019 [11] (2004‑2014) SCLC CFRT/CT=1958 (3‑8 fx) 29.2m (SBRT) 45‑70Gy 31.2m (CFRT) (25‑35fx) Newman, RS‑database NCDB Stage I N (total)= 1378 BED10≥100 SBRT: ‑ 27% (5y) SBRT ‑ ‑ 2019 [121] (2004‑2015) SCLC N (SBRT)= 239 Gy 35.1% 26% (5y) CFRT N (CFRT)= 1139 (≤8 fx) (84/239) 36% (5y) SBRT+CT CFRT: 27.5% (5y) 88.8% CFRT+CT (1012/1139) Singh, 2019 RS‑RSSPR Stage I N=21 mBED10105.6 19% (4/21) ‑ 100% (1y) 73.1% (1y) 85.7% (1y) [122] (2008‑2018) SCLC Gy 100% (2y) 36.6% (2y) 42.9% (2y) (3‑5 fx) 100% (3y) 100% (1y‑CT) 63% (1y‑no CT) SCLC: Small cell lung cancer; CT: Chemotherapy; PCI: Prophylactic cranial irradiation; SBRT: Stereotactic radiation therapy; CFRT: Conventionally fractionated radiation therapy; fx: Fractions; OS: Overall survival; LC: Local control; DFS: Disease free survival; Dm1 PFS: Distant metastases free survival; m: Months; y: Years; RS: Retrospective study; NCDB: National Cancer Data Base; JRSSBRTSG: Japanese Radiological Society MultiInstitutional SBRT Study Group: RSSPS: RSSearch Patient Registry; LOE: Level of evidence (From the Centre for EvidenceBased Medicine: http://www.cebm.net.) 30 to 60 Gy in 1 to 3 fractions in a small series of six patients. results of a multi-institutional retrospective series of 43 patients Four of them underwent CT and adjuvant prophylactic cranial with Stage I SCLC treated with SBRT [118]. All patients had irradiation (PCI). Local control (LC), OS and DFS obtained at brain MRI/CT-scan and in 12 of them a staging 18-FDGPET-CT 1 year were 100%, 63% and 75%, respectively. There were no was performed. The administered dose was 30-60Gy (3-10 regional relapses and no toxicity ≥ G3. Despite a short follow- fractions). Eight patients received CT and PCI was performed up, the author concludes that SBRT in early stage SCLC offers in other eight. The 2-year OS, PFS, DmPFS (Distant metastatic excellent local control with low toxicity, being these results Progression Free Survival), and LC were 72.3%, 44.6%, 47.2%, similar to those obtained in early non-surgical stages of NSCLC and 80.2%, respectively. In the univariate analysis, female sex treated with SBRT [116]. and Stage IA were favorable prognostic factors for OS and The Japan Radiation Oncology Study Group (JROSG) reported PFS. Regional and distant metastases were 28% and 47%. This in 2015 an abstract with the results of 64 patients with Stage I low OS percentage corresponds to a tumor with a propensity SCLC treated with SBRT, with a dose range of 35-60 Gy in 3 to 19 for early development of metastatic disease, but probably also fractions. At 2 years, the LC, OS, and Progression-free survival related to insufficient staging and a low proportion of patients (PFS) were 89.3%, 76.3%, and 49.3%, respectively. Eighteen treated with CT. patients had regional relapse and 26 had distant metastases. In 2017, Verma et al. published a multi-institutional analysis Female gender and the use of CT were significantly correlated of 74 patients treated with SBRT for inoperable Stage I SCLC with favorable survival outcome in univariate and multivariate with a median dose of 50 Gy in5 fractions, demonstrating high analysis [117]. Later, the same group (JROSG) published the local control (96% at 3 years with low toxicity, 1% Grade >3). DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 41 On multivariate analysis, the addition of CT was associated when compared to NSCLC series treated with SBRT. However, with improved OS and DFS. PCI was not associated with OS rates are worse than those obtained in NSCLC. According survival improvement. The relapses were most commonly to the analyzed series, the OS were 63-83%, 35-76%, and distant (45.8%) and nodal (25%). After the publication of 21-26% at 1, 3, and 5 years, respectively, due to the high these results, clinical practice guidelines incorporated SBRT tendency of early spreading of SCLC; it can also be secondary into the therapeutic strategy of Stage I SCLC for inoperable to insufficient mediastinal and distant staging in many of the patients [119]. analyzed series, which often leads to understaging and therefore The National Cancer Database (NCDB) has published several to worse results. Hence, it seems highly recommendable to analyses of patients with early-stage SCLC treated with radiation systematically perform a correct regional and distant staging therapy: SBRT or Conventional Fraction Radiation Therapy with an18-FDG PET-CT-scan and mediastinoscopy or EBUS for all (CFRT) with or without CT. The first of them, published the patients to correctly assess the impact of SBRT on the survival results of 285 patients with Stage T1-T2 SCLC treated with of early-stage SCLC. SBRT between 2000 and 2013 [120], most of them (83%) in the 2.3.2.1. Adjuvant CT past 5 years. The most common dose received was 48-60 Gy in Another determining factor is the use of CT. The fact that up to 3-5 fractions. Almost half of the patients received CT, being as 50% of recurrences are distant must be considered. In the series neoadjuvant in 42.7% of them. Younger age and diagnosis in the in which CT is analyzed, a significant increase in survival can be initial years of the study were the only significant predictors of observed in the subgroup that receives CT, regardless of when it CT administration. After a 45.6 months follow-up, 3 and 5 years is given, and especially for tumors >2 cm [117,119,121]. The use OS were 35.2% and 21.5%. OS was not affected by the time that of CT and its sequence (neoadjuvant/adjuvant) is heterogeneous CT was administered: Neoadjuvant or adjuvant. No data about the in the analyzed series; since SBRT only requires few sessions it impact of systemic therapy in OS was analyzed in this study. In would not delay the beginning of CT, whereas CT would interfere this large group of patients, we can observe the increasing use of with volume delimitation of SBRT. It is, therefore, preferred to SBRT technique despite the lack of randomized evidence. perform SBRT before CT. In 2019, the NCDB analyzed 2107 T1-T2N0M0 SCLC, Tumor size at this very early stage of SCLC seems to be an all of them treated with CT and RT (SBRT or CFRT). CFRT important factor in all the analyzed series, as in some of them it represented 92.9% and the majority was followed by CT (85%). is observed that tumors >2 cm have worse prognosis than smaller On multivariate analyses SBRT technique was not related with ones [119,121,122]. This should be taken into account when an improvement of OS (31.2 m vs. 29.2 m, P=0.95). Predicting assessing the need for systemic therapy. factors of poorer OS were advanced age, male gender, and treatment in earlier years [11]. 2.3.2.2. RT technique The NCDB recently published, the results for a group of 1378 Regarding the RT technique used, in the series in which patients T1-T2N0M0 SCLC treated with radiation therapy (SBRT CFRT is compared to SBRT there is a non-significant trend of or CFRT). SBRT group received significantly less CT than CFRT a better OS in patients treated with SBRT, especially in elderly group, 35% compared to 88%. SBRT was significantly associated patients [11,121]. Principles of SBRT for SCLC are similar to with improved survival when CT was given (P<0.001).On those for NSCLC. The dose of SBRT that is used for SCLC is multivariate analysis in the CT group, adjusting for sex, age, and similar to that for NSCLC with a BED >100 Gy. There are no tumor size, the use of SBRT trended to improve survival (P=0.06). studies that have evaluated a different dose. Even though the SBRT was strongly associated with a survival benefit in elderly series include only a low number of patients, they have reported patients [121]. a low toxicity (<5% G≥3) which represents a clear advantage Singh, in 2019 identified 21 patients in the RSSearch Patient over conventional RT, as almost all patients are elderly and have Registry (RSSPR) with medically inoperable Stage I SCLC cardiorespiratory comorbidities. treated with SBRT. Only four patients received CT. The 1 and 2.3.2.3. PCI 3-year local control rates were both 100%. 1 and 2-year OS Up to 50% of patients with SCLC will develop brain were 73.1% and 36.6%, respectively. The study concluded that metastasis. Auperin’s meta-analysis [123] showed that PCI patient with T1N0 had better OS than T2N0, 85.7% and 33.3%, increases the rate of DFS and reduces the cumulative risk of brain respectively. Adjuvant CT improved OS, also for Stage I SCLC metastasis by up to 25%. PCI has a Category I recommendation over SBRT alone [122]. for localized stage SLCL. It cannot be ignored its potential 2.3.2. Conclusions about SBRT neurotoxicity, therefore different approaches to reduce it has been utilized, such as the hippocampus’s protection [124,125] or In light of the results obtained in these limited series (small the use Memantine [126]. number of patients, heterogeneous treatments, and low level The use of PCI in Stage I SCLC subgroup is controversial of evidence), we can conclude that: As expected, SBRT offers since the data that we have in retrospective surgical series show excellent local control, more than 85%, and low toxicity, <5% a lower risk of brain metastasis; it is estimated that between 10 Grade ≥ 3, for inoperable SCLC Stage I, with similar results and 15% will develop them [62,127,128]. Thus, expected benefit DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 42 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 in survival could be lower. An approach that seems reasonable in SCLC is a tumor with a high trend to early spreading and it the era of advanced imaging in this favorable group of patients is unknown why a high percentage of patients did not receive is active brain MRI surveillance, as an alternative to PCI. The chemotherapy. The data from surgical, CRT, and SBRT series salvage whole-brain RT for treatment of brain metastases does not support multimodal treatment with neoadjuvant or adjuvant appear to have a detrimental effect on OS [129-131]. More studies chemotherapy and PCI even in early-SCLC. Systemic treatment are needed to confirm these data. showed significant increase in OS in both surgical and SBRT series. According to the analyzed data, the range of benefit in OS 3. Discussion at 5 years goes from 10% to 30%, with a significant advantage The National Comprehensive Cancer Network (NCCN), in the chemotherapy group. The sequence of systemic treatment ASTRO, ASCO, and ESMO guidelines recommend surgery as – neoadjuvant/adjuvant – showed no significant impact in OS. the initial treatment option in operable patients having a well- However, in the context of a local primary treatment, surgery or staged cT1-2N0M0 (I-IIA) of the American Joint Committee on SBRT, it seems more reasonable that it be adjuvant. Cancer and the International Union for Cancer Control update PCI is associated with a significant reduction of brain tumor-node-metastasis (TNM) cancer staging system. Pathologic metastases in SCLC. The selected group of early SCLC has a mediastinal staging would be mandatory before surgical lower risk of brain metastasis; which is estimated between 10 indication to identifying patients with a very limited disease. and 15%. The impact on survival is lower than in other stages. These recommendations are based on many small series, largely The most appropriate approach is unclear. Active brain MRI retrospective, Phase II trials, meta-analysis, systematic reviews, surveillance may be an alternative option to PCI, especially in and propensity matched score analysis that has shown excellent very early stage (T1N0M0) SCLC. More studies are needed to survival for patients with T1-2N0SCLC who underwent surgical confirm these data. treatment, mainly in the setting of a multimodal approach [132]. According to the current data, it is difficult to compare Lobectomy with systematic lymph node dissection is the surgery and SBRT treatments. The patients in each group of recommended type of resection. treatment have different characteristics in terms of age and Notwithstanding, there is a clear underuse of surgery in the comorbidities. Surgery started earlier than SBRT as a local treatment of ES-SCLC. Wakeam et al. identified 9740 patients with treatment of early SCLC. Surgical series are extensive, with cT1 or cT2N0M0 SCLC cases from the National Cancer Database many patients analyzed, long-term follow-up, and robust (2004-2013), of which only 2210 (22.7%) underwent surgery in conclusions; on the other hands, SBRT is a new emergent spite of having no recognizable contraindication. Remarkably, treatment for early stage SCLC; therefore, current available between 2004 and 2013, the resection rates raised from 9.1% to studies are retrospective, heterogeneous, and with a small 21.7%. The authors suggest studies addressed to found the reason number of patients. Despite this, preliminary results of SBRT for this mismatch between guidelines and practice [133]. The same are promising and warrant future research. The advantage of group also showed that there is a large variability in the surgical SBRT over surgery is that it can be performed in elderly patients indication and type of resection for ES-SCLC, but also in survival with altered respiratory function or other comorbidities, without and mortality in the current clinical practice in the United States, increasing toxicity. Local control is similar for both treatments, which may represent a substantial opportunity for improvement in although regional relapse was superior in SBRT series, probably patients with ES-SCLC [134]. due to a mediastinal understaging in SBRT series. Therefore, it Almost 10 years have passed since Shepherd published in is difficult to compare both treatments and should be further the Journal of Thoracic Oncology the editorial entitled “Surgery investigated in randomized clinical trials. for Limited Stage Small Cell Lung Cancer. Time to Fish or Cut Taking into account the data analyzed, the limitations of the Bait” urging the international community to join forces to plan a series reviewed, and the recommendations of the international prospective trial to answer the question of the role of surgery in guidelines, we propose our approach in the management of the treatment of ES-SCLC [135]. T1-2N0 SCLC considering: Staging, operability, criteria for While surgery is considered the preferred local therapy in T1- SBRT, ability to systemic therapy and benefit of PCI (Figure 2). 2N0 SCLC, increasing data support the role of SBRT for inoperable 4. Conclusion Stage I SCLC, transferring the favorable experience obtained on inoperable early NSCLC. SBRT shows comparable local control T1-2N0M0SCLC represents a highly selected group of outcomes to surgical and CRT series, even though there are no patients who, despite having a very localized disease, requires a randomized studies comparing both treatments. Use of SBRT in multimodal approach due to the aggressive nature of the disease. early-SCLC as in NSCLC seems safe and does not increase the In spite of the absence of randomized studies, the current data risk of toxicity. The pattern of failure in SBRT series is regional in and guidelines recommend surgical treatment of well-staged early 25% of cases and distant in 50%. To correctly assess the impact of SCLC (cT1-2N0M0) in patients fit enough for surgery. Lobectomy SBRT on the survival of stage I SCLC is highly recommendable plus systematic nodal dissection is the preferred type of resection. to systematically perform a correct regional and distant staging: Nowadays, RT is the therapeutic option in those with surgical 18-FDG PET-CT scan, mediastinoscopy, and/or EBUS. contraindication, despite the lack of high quality clinical evidence; DOI: http://dx.doi.org/10.18053/jctres.07.202101.011 Farré et al. | Journal of Clinical and Translational Research 2021; 7(1): 34-48 43 Figure 2. Proposed algorithm for treatment of ES-SCLC. SBRT: Stereotactic body radiotherapy; CT: Chemotherapy; RT: Conventional radiotherapy (concomitant or sequential); PCI: Prophylactic cranial irradiation; MRI, Magnetic resonance imaging. SBRT is an emerging technique that is safe and effective for and Disparities between Different Sexes, Socioeconomic inoperable early stage SCLC. All patients should receive systemic Statuses and ages. Sci Rep 2017;7:1339. therapy due to the tendency of SCLC to metastasize early, with [6] Greene FL, Compton CC, Fritz AG, Shah JP, Winchester DP, the aim of increasing OS. PCI must be evaluated individually by editors. Thorax: Lung. In: American Joint Committee on a multidisciplinary team. Cancer Staging Atlas. Part III. Chicago: Springer; 2006. p. 167-76. Conflict of Interest [7] American Joint Committee on Cancer. Lung. AJCC The authors declare that they have no conflict of interest. Cancer Staging Manual. 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