Thoracic radiotherapy for extensive-stage small-cell lung cancer: What is the optimal dose and timing

REVIEW

Thoracic radiotherapy for extensive-stage small-cell lung cancer:

what is the optimal dose and timing?

Guler Yavas1 &Cagdas Yavas1

Received: 20 June 2019 / Accepted: 10 October 2019

# Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract

Small-cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 12–20% of all lung cancers. Most of the SCLC patients present with extensive-stage (ES) disease. Primary therapy for ES-SCLC is 4–6 cycles of platinum-based chemotherapy (CT) followed by prophylactic cranial irradiation (PCI) in selected cases. Although the response rate to CT is approximately 60– 70%, median survival times are very limited. The main problem of ES-SCLC patients after CT is intra-thoracic tumor recurrence since 75% of the patients had persisting intra-thoracic disease after CT, and approximately 90% of the patients had intra-thoracic progressive disease within the first year after diagnosis. Such high rate of intra-thoracic disease progression explains the need of local treatment in selected patients. There are three randomized studies and two meta-analyses evaluating the role of thoracic radiotherapy (TRT) in patients with ES-SCLC who responded to CT. Two of the randomized trials and one of the meta-analyses showed survival benefit of TRT. According to the results of relevant studies, the patients who responded to CT and have intra-thoracic residual disease after CT, who had limited metastatic sites (≤ 2), and who have good performance status and limited weight loss have more benefit from TRT. We need novel studies evaluating the optimal dose fractionation schedules, optimal timing of RT, impact of time interval between RT and CT, immunotherapy and RT combinations, and number of CT cycles. Keywords Small-cell lung cancer . Extensive stage . Thoracic radiotherapy, Radiation dose . Survival

Introduction

Small-cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 12–20% of all lung cancers [1,2]. SCLC is characterized by its rapid growth, early development of me-tastases, and development of treatment resistance in patients with metastatic disease [3]. Approximately 60–70% of SCLC patients present with disseminated disease [4]. Although SCLC is highly responsive to both chemotherapy (CT) and radiotherapy (RT), it commonly relapses within months de-spite treatment, and survival of SCLC is very poor.

The Veterans’ Administration Lung Study Group (VALSG) two-stage classification scheme has been routinely used for the clinical staging of SCLC since 1957 [5]. The VALSG system defines limited-stage (LS) as follows: (1)

disease confined to one hemi-thorax, although local extension may be present; (2) no extra-thoracic metastases except for ipsilateral supraclavicular lymph nodes if they can be included in the same radiation port as the primary tumor; and (3) pri-mary tumor and regional nodes that can be adequately encompassed in a radiation port. ES disease is defined as disease that cannot be classified as limited, including malig-nant pleural or pericardial effusions, contralateral hilar or supraclavicular lymph nodes, and hematogenous metastases. In 1989, the International Association for the Study of Lung Cancer (IASLC) proposed a modification of the VALSG sys-tem in which limited-stage small-cell lung cancer (LS-SCLC) was expanded to include contralateral mediastinal or supraclavicular lymph node metastases and ipsilateral pleural effusions independent of cytology [6]. ES-SCLC remained any disease at sites beyond the definition of limited disease. In practice, most clinicians and clinical trials blend the VALSG and IASLC criteria by considering contralateral mediastinal and ipsilateral supraclavicular lymph node involvement to be LS. The classification of contralateral supraclavicular or hilar lymph node involvement remains con-troversial, with treatment usually determined individually * Guler Yavas

guler.aydinyavas@gmail.com

1 _{Department of Radiation Oncology, Faculty of Medicine, Selcuk} University, 42075 Konya, Turkey

based on the ability to include these regions in a safe RT port. The IASLC has proposed that the newly revised TNM staging classification for lung cancer (American Joint Committee on Cancer (AJCC)) [7] and the National Comprehensive Cancer Network (NCCN) adopted a combination approach for stag-ing and the older VA scheme for SCLC [8]. According to the NCCN guideline, LS-SCLC is defined as stages I–III (T any, N any, M0) that can be safely treated with definitive RT doses but excludes T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan; and ES-SCLC is defined as stage IV (T any, N any, M1a/b) or T3-4 due to multiple lung nodules that are too extensive or have tumor/ nodal volume that is too large to be encompassed in a tolerable radiation plan [8].

The European Society for Medical Oncology (ESMO) [3], the NCCN [8], and the American College of Chest Physicians (ACCP) guidelines [9] recommend that patients with extensive-stage disease receive 4–6 cycles (but not > 6 cycles) of cisplatin- or carboplatin-based combination chemotherapy (e.g., cisplatin plus etoposide or irinotecan). In March 2019, the FDA approved atezolizumab in combination with carboplatin and etoposide for first-line treatment of adult pa-tients with ES-SCLC based on the results of the IMpower133 study, which demonstrated that the addition of atezolizumab to chemotherapy in the first-line treatment of ES-SCLC resulted in significantly longer overall survival (OS) and progression-free survival (PFS) than chemotherapy alone [10].

Historically, the role of RT in ES-SCLC was only for pal-liative purpose. However, the importance of thoracic RT (TRT) in ES-SCLC was demonstrated in two phase III ran-domized trials [11,12]. Both of these studies suggested that consolidation chest RT, after chemotherapy for ES-SCLC, im-proved local control (LC) which may influence OS. Moreover, the systemic revew of these phase III randomized trials revealed that TRT, improves OS and PFS, with a small incremental risk of esophageal toxicity. Therefore TRT should be considered in patients with ES-SCLC, who have had a favoorable response to CT [13]. However, there are limited evidence with respect to the patient selection, the optimal dose, and the optimal timing of TRT in ES-SCLC patients who had a favorable response to CT. The aim of the current review is to discuss the patient selection for TRT and optimal timing and dose of consolidative TRT in ES-SCLC patients.

The rationale of consolidative thoracic

radiotherapy

Although ES-SCLC is highly sensitive to CT and RT, nearly all patients eventually experience relapse of disease. Standard treatment options including immunotherapies, cytotoxic

chemotherapies, and modern RT techniques have been evolv-ing durevolv-ing the past decades. Despite the various efforts to optimize treatment outcome of ES-SCLC patients, median survival times and OS times are still very limited. With CT, the median survival times are 9–12 months, while 5-year survivals of only 1–2% [11, 14–16].

In a phase III trial, it was shown that prophylactic cranial irradiation (PCI) following response to induction CT improves survival in ES-SCLC patients [17]. The cranial RT doses were varied according to the treatment centers, and the following schedules for cranial irradiation were used: 20 Gy in 5 or 8 fractions, 24 Gy in 12 fractions, 25 Gy in 10 fractions, or 30 Gy in 10 or 12 fractions. The biologically equivalent doses for these schedules range from 25 to 39 Gy. In this study, incidence of symptomatic brain metastases decreased signifi-cantly in the PCI group, and 1-year survival rates were im-proved with PCI. However, intra-thoracic tumor progression was the main problem since 75% of the patients had persisting intra-thoracic disease after CT, and approximately 90% of the patients had intra-thoracic progressive disease within the first year after diagnosis. Such high rate of intra-thoracic disease progression explains the need of local treatment in selected patients with ES-SCLC. During the past years, there have been enormous developments in the field of oncology. Introduction of modern RT techniques including 3-dimesional conformal RT and intensity-modulated radiother-apy (IMRT) allowed radiation oncologist to apply RT more frequently with higher doses and lower side effects.

The first prospective randomized phase III study evaluating the role of TRT in ES-SCLC patients was published in 1999 by Jeremic et al. [11]. According to the results of the past studies, the authors postulated that (1) significant proportion of patients with ES-SCLC experience intra-thoracic (loco-regional) treatment failure, which cannot be successfully treat-ed with second-line CT, (2) these failures may also become the source of subsequent metastatic disease (in patients with pre-vious non-metastatic ES-SCLC) and lead to death, (3) TRT could control intra-thoracic tumor burden, and (4) if success-ful, this may lead to improved and prolonged intra-thoracic tumor control and, if significant, may lead to an improvement in overall survival. The ultimate question overshadowing all these considerations was: which subgroup of patients may have been suitable for testing the place and role of TRT in ES-SCLC [18].

The study by Jeremic et al. was the first study show-ing that TRT plays an indispensable role in the treat-ment of ES-SCLC patients. In this study, a total of 210 patients with ES-SCLC were initially treated with three cycles of standard dose of cisplatin/etoposide (PE). After three cycles of PE, patients were reevaluated and restaged. A hundred and nine patients who had com-plete response (CR) at both local and distant levels and those with partial response (PR) within the thorax

accompanied with CR elsewhere were considered en-rolled. Patients were randomized to receive accelerated hyperfractionated TRT with 54 Gy in 36 fractions over 18 treatment days and concurrent low-dose daily CT consisting of carboplatin and etoposide (CE), 50 mg each, given on each RT day, followed by PCI (25 Gy in 10 fractions) and then by two additional cycles of PE (group 1) or four additional cycles of PE and PCI (group 2). Patients who achieved their worst response, i.e., those who achieved CR or PR within the thorax but only a PR elsewhere (CR/PR, group 3; PR/PR, group 4), were treated with two additional PE cycles followed by the same TRT and CE treatment and, in the case of CR at distant level, PCI as well. Those with stable disease or disease progression (group 5) were either observed until death (treated with supportive care only) or treated with orally administered etoposide, 50 mg/m2, on days 1 through 21 every 28 days for a total of six cycles or until further progression (on oral etoposide). Patients achieving worse re-sponse were not randomized. Their results showed that the patients in group 1 had significantly better survival rates than those in group 2 (the median survival time, 17 vs 11 months; 5-year survival rate, 9.1% vs 3.7%, respectively;p = 0.041). There was no difference in distant metastasis-free survival between groups 1 and 2. Acute high-grade toxicity was higher in group 2 than in group 1. According to the study by Jeremic et al., the addition of accelerated hyperfractionated TRT to the treatment of the most favorable subset of patients improved the overall survival times over that ob-tained with CT alone.

The second prospective randomized phase III study (CREST study) evaluating the role of TRT in ES-SCLC was performed by Slotman et al. [12]. In this study, patients with World Health Organization PS of 0 to 2 and confirmed ES-SCLC without clinical evidence of brain, leptomeningeal, or pleural metastases, who achieved any response to 4–6 cycles of PE, were treated with either TRT or no TRT, while all patients receive PCI. PCI was given as 20 Gy in five fractions, 25 Gy in ten fractions, or 30 Gy in ten, 12, or 15 fractions. TRT was delivered to a dose of 30 Gy in ten fractions. The planning target volume included the post-chemotherapy vol-ume with a 15-mm margin to account for microscopic disease and setup errors. Hilar and mediastinal nodal stations that were considered involved prechemotherapy and were always included, even in case of response. PCI and TRT preferably had to start within 6 weeks, but not later than 7 weeks after chemotherapy. If there was acute grade 2 or higher toxic ef-fects of CT, RT did not start within 2 weeks after CT. Their results showed that the addition of TRT to PCI for patients with ES-SCLC did not improve survival at 1 year. However, 2-year overall survival was 13% for the patients who received TRT and 3% for the patients who did not (p = 0.004). Moreover, PFS was significantly longer in the TRT arm. Intra-thoracic progression was seen less frequently in the

TRT arm. Almost a 50% reduction in intra-thoracic recur-rences (80 vs 44%, respectively;p = 0.001) was observed.

Radiation Therapy Oncology Group (RTOG) 0937 phase II randomized study evaluated the role of TRT in addition to PCI for patients with ES-SCLC [19]. In the RTOG 0937 study, ES-SCLC patients with 1–4 extra-cranial metastases were deemed eligible after achieving CR to PR after initial CT. Patients received either PCI alone or PCI + TRT + consolidative RT to metastases. All patients were to receive 25 Gy PCI at 2.5 Gy/fraction. The recommended radiation dose to all extra-cranial sites was 45 Gy delivered in 15 daily fractions of 3 Gy. Thirty to 40 Gy was acceptable if dose reduction was necessary to meet normal tissue dose constraints. Radiation was delivered to post-chemotherapy volumes, including to the site of the primary and involved nodal regions at diagnosis. Metastases were treated if they did not have a CR to CT. In this study, PCI was recommended to start concurrently with TRT, although sequential therapy was allowed at the discretion of the treating physician. At planned interim analysis, the study crossed the futility boundary for OS and was closed prior to meeting the accrual target. Median follow-up was 9 months. One-year OS was not different between the groups. Three-and 12-month rates of progression were 53.3% Three-and 79.6% for PCI and 14.5% and 75% for PCI + TRT + consolidative RT to metastases. Time to progression favored the PCI + TRT +consolidative RT group. The authors concluded that OS exceeded predictions for both arms with the consolidative RT delaying progression but not improving the 1-year OS.

In 2016, the systematic review of two phase III randomized studies by Jeremic et al. and Slotman et al. was published [13]. In this systemic review, Palma et al. evaluated 604 patients with ES-SCLC (302 received TRT, and 302 did not receive TRT). They demonstrated that overall delivery of TRT was associated with improved OS and PFS. Although esophageal toxicity was increased with the use of TRT, grade 3 or higher esophageal toxicity in the TRT arm remained uncommon and was infrequent in patients receiving a TRT dose of 30 Gy in 10 fractions. Bronchopulmonary toxicity (grade 3 or higher) was similar in both TRT and non-TRT groups.

In 2019, the systemic review and meta-analysis of 3 ran-domized controlled trials (two phase III and one phase II) including the studies by Jeremic et al., Slotman et al., and Gore et al. (RTOG 0937 study) was published by Rathod et al. [20]. In this updated meta-analysis, a total of 690 patients evaluated and showed that TRT significantly reduced thoracic progression as the first site of failure and improved PFS ben-efit but did not offer significant OS benben-efit. The present meta-analysis is the first one reporting that there is no OS benefit of TRT in ES-SCLC patients.

Based on the results of the above studies, it seems to be reasonable to use TRT for the ES-SCLC patients who have responded to CT. However, the use of consolidative TRT in ES-SCLC patients should be considered on a case-by-case

basis. It seems to be a selected group of patients has survival benefit from TRT. Therefore, we think that the most important issue with respect to the role of TRT in ES-SCLC patients is to define the patients who might have benefit more. Probably the dose fractionation schedules, the treatment duration, the tech-nical details of RT, and the systemic therapy options have a significant contribution to this benefit. Therefore, we need novel studies evaluating the optimal dose fractionation sched-ules, optimal timing of RT, impact of time interval between RT and CT, immunotherapy and RT combinations, and number of CT cycles.

Which patients are most likely to benefit

from thoracic radiotherapy?

The Dutch CREST phase III study by Slotman et al. showed that a relatively low dose of TRT (30 Gy in 10 fractions) was able to reduce the risk of intra-thoracic progression from near-ly 44–80% [12]. Furthermore, TRT was associated with a significant OS benefit at 2 years. A stratification factor in the CREST study was the presence or absence of residual disease after CT, which was assessed in 97% of all randomized pa-tients using a computed tomography (CT) scan of the thorax [12]. Intra-thoracic progression, either with or without pro-gression elsewhere, was reported in 43.7% of the TRT group and in 81.3% in the control group (p < 0·0001). Additional analyses of the CREST study confirmed that patients with persistent intra-thoracic disease demonstrated significant im-provements in OS and PFS in addition to risk of intra-thoracic progression [21–23]. No survival benefit of TRT was seen in patients without intra-thoracic persistent disease, suggesting that the patients who have intra-thoracic residual disease after CT should be considered for TRT since it seems that this patient population benefit from TRT.

The extent and location of metastatic disease could have a significant prognostic impact. In a secondary analysis, Slotman et al. also evaluated prognostic importance of number and sites of metastases in patients included in the CREST study [21]. In this analysis of 260 patients from 9 centers, the authors demonstrated that both the OS and PFS were sig-nificantly higher in patients with≤ 2 metastases. Survival of patients with 0 compared with 1 or 2 distant metastases did not differ significantly. Furthermore, patients with liver and bone metastases had significantly worse OS. In the study by Jeremic et al., more than 90% of patients who undergone TRT had less than 2 metastases and did show OS benefit with TRT [11]. The RTOG 0937 study included the patients with 1–4 metastases who had CR or PR to CT; therefore, this study focuses on the oligometastatic patients [19]. In the RTOG 0937 study, the authors excluded the patients with brain me-tastasis. The original stratification included PR vs CR after CT and 1 vs 2–4 metastases; age < 65 vs ≥ 65 was added after an

observed imbalance. In the RTOG 0937 trial, 36% patients had only one metastasis, and 64% had 2–4 metastases. From the patients who received both PCI and TRT, 31.8% had only one metastasis, and 68.2% had 2–4 metastases. Therefore, the RTOG 0937 study also focused on favorable subpopulation of patients with oligometastatic disease.

The World Health Organization (WHO)/The Eastern Cooperative Oncology Group (ECOG) performance status al-so could have an impact of TRT. The secondary analysis of the CREST study demonstrated that patients with better perfor-mance had improved OS and PFS with TRT [19]. Moreover, the CREST study had more unfavorable patients (ECOG per-formance statuses 0–2, 10% vs 0%) than the Jeremic et al. study [11]. In the study by Jeremic et al., analyses of pretreat-ment factors also revealed that performance status was a strong prognostic factor [11,18]. Furthermore, in the RTOG 0937 study, there were some imbalances with respect to the performance status of the study groups that could have been potentially contributing the lack of survival benefit [19]. Lastly, the analyses of pretreatment prognostic fac-tors of the study by Jeremic et al. revealed that various pretreatment prognostic factors including no significant weight loss were strong prognosticators of improved outcome [18].

There is limited evidence with respect to the effect of age and gender on the impact of TRT in ES-SCLC patients. In the Dutch CREST study, the authors did not record any significant differences in OS in subgroups divided by age and sex [12]. In the RTOG 0937 trial, the median age of the patients was 63 years (range between 35 and 86 years). This study closed early, since at planned interim analysis, the study crossed the futility boundary for OS. The lack of survival benefit of the RTOG 0937 study was attributed to several factors including ineffective RT dose and schedule, advanced age, and an im-balance in disease burden. In a retrospective study by Xu et al., it was found that there was no relationship between the age, sex, and OS [24]. Moreover, Li-Ming et al. showed that≥ 65 years of age was associated with poor survival [25]. In this study, although in univariate analysis male gender was a significant unfavorable prognostic factor, multivariate anal-ysis did not confirm this. According to the NCCN guideline, while the advanced chronologic age does adversely affect the tolerance to treatment, the functional status of an individual patient is much more useful than age guiding clinical decision-making [8]. It seems that we need more evidence to define the effect of gender and age on the consolidative TRT in ES-SCLC patients.

It is reasonable to use consolidative TRT for ES-SCLC patients with response to CT and who have good performance status, residual intra-thoracic disease, and limited extra-thoracic disease. However, further prospective well-designed studies are warranted in order to define the patient population who might have benefited more.

What is the optimal dose of thoracic

radiotherapy?

As mentioned above, there are three randomized trials inves-tigating the role of TRT in ES-SCLC patients. Interestingly, the radiation dose used in those studies were different from each other; therefore, we have limited data regarding the op-timal dose fractionation schedule that may be the most appro-priate one (Table1). However, it has been suggested that there may be a subset of patients who benefit from higher dose of consolidative TRT as seen in the Jeremic et al. trial; consider-ing 30 Gy in 10 fractions is a palliative dose fractionation schedule [26]. Jeremic et al. used 54 Gy in 35 fractions in 18 days, and the biologically effective dose (BED) of this study was higher than the CREST study. Additionally, the treatment fields were different between these two studies since the RT fields were larger in Jeremic et al.’s study than the CREST study (Table1). Jeremic et al. reported a 65% 1-year OS rate, much higher than the 33% in the CREST study. Furthermore, the 1-year OS rates in non-TRT groups were higher in Jeremic et al.’s study (46% vs 28%). One more important point for the CREST study is that the authors did not include patients with brain, leptomeningeal, or pleural metastases; however, only 13% of asymptomatic patients underwent brain imaging following CT [12,27]. It is therefore possible that the patients with brain metastasis might have been included in the randomization.

The last randomized trial investigating the consolidative TRT in ES-SCLC patients is the RTOG 0937 study, which could not demonstrate OS benefit of TRT [19]. In this study, the recommended radiation dose to all extra-cranial sites in-cluding the thoracic disease was 45 Gy in 15 daily fractions. However, 30 to 45 Gy was acceptable if dose reduction was necessary to meet normal tissue dose constraints. In the RTOG

0937 study, a higher BED was employed than the CREST study; however, at planned interim analysis of the primary endpoint, the 1-year OS in the experimental arm of the study was not higher than the control arm (1-year OS 60.1% for control arm and 50.8% for experimental arm,p = 0.21); the study closed early due to futility. Although the authors could not demonstrate an OS benefit, they found that consolidative TRT improved thoracic disease control. Similar with the CREST study in the RTOG study, the authors used palliative dose fractionation schedules. Furthermore, there were some imbalances in the two study groups in RTOG 0937 that could potentially contribute to the lack of OS benefit from consolidative TRT.

Li-Ming et al. retrospectively evaluated 306 ES-SCLC pa-tients, of which 170 received TRT [25]. All the patients re-ceived EP (30 mg/m2cisplatin from days 1 to 3; 100 mg etoposide from days 1 to 5), CE (500 mg carboplatin for day 1; 100 mg etoposide from days 1 to 5), or EP-like regimens (platinum-based CT) as the first-line treatment. Patients re-ceived a median of six CT cycles. The median radiation dose was 60 Gy. Because of different radiation fractionations employed clinically, the authors used BED in RT for conver-sion between different fractionation schemes to estimate the malignant and normal biological effects in tissues. The gross target volume (GTV) encompassed the primary tumor and any positive lymph nodes, whereas the clinical target volume (CTV) was expanded from the GTV by a 0.5–0.8-cm uniform margin and included the draining area of any positive lymph nodes. In addition, the planning target volume (PTV) included the CTV plus a margin of 0.5–1.0 cm. PCI was applied to 13.5% patients in TRT and 3% patients in CT-only groups, respectively. The authors demonstrated the addition of consolidative TRT to CT improved OS. Moreover, this study revealed that higher TRT doses (BED > 50 Gy) improved OS.

Table 1 Randomized trials investigating the role of consolidative thoracic radiotherapy in extensive-stage small-cell lung cancer patients First author Year RCT design Patients CT RT sequence PCI dose TRT details Results Jeremic [10] 1999 Phase III N = 109 3 cycles of PE Post-CT 25 Gy/10 fr 54 Gy/36 fr/18 days to

gross chest disease, ipsilateral hilum, mediastinum, bilateral supraclavicular fossae Improved median OS (17 vs 11 months) Increased esophageal toxicity Slotman (CREST study) [11]

2015 Phase III N = 495 4–6 cycles of PE

Post-CT 30 Gy/12 fr 25 Gy/10 fr 20 Gy/5 fr

30 Gy/10 fr to residual gross disease and prechemotherapy involved hilar and mediastinal lymph nodes Improved 2-year OS (15% vs 3%,p = 0.004); no difference in 1-year OS Gore (RTOG 0937) [18] 2017 Phase II N = 97 4–6 cycles of platinum--based CT

Concomitant 25 Gy/10 fr 45 Gy/15 fr to disease within the chest and 1–4 oligometastatic lesions

No difference in 1-year OS (60.1% vs 50.8%,p = 0.21)

CTchemotherapy, OS overall survival, PCI prophylactic cranial radiotherapy, PE platinum etoposide, RCT randomized controlled trial, RT radiotherapy, TRT thoracic radiotherapy

Hasan et al. retrospectively analyzed 3280 stage IV SCLC patients treated with double-agent CT and TRT within the National Cancer Data Base (NCDB) [26]. In this study, the authors evaluated the survival outcomes for patients who re-ceived at least 45 Gy of TRT and those who rere-ceived > 45 Gy. The 1- and 2-year survival for patients receiving at least 45 Gy was 58.1% and 25.2% compared with 43.8% and 15.1% among patients less than 45 Gy (HR = 0.70, 95% CI 0.65– 0.76,p < 0.001). The current study was the largest retrospec-tive study evaluating the consolidaretrospec-tive TRT in ES-SCLC pa-tients and demonstrated that dose escalation of at least 45 Gy was an independent predictor for increased survival.

The current National Comprehensive Cancer Network (NCCN) guidelines recommend consolidation TRT for pa-tients with ES-SCLC with response to systemic CT, based on the positive results of two randomized clinical trials, which varied in patient selection in addition to the radiation therapy doses used [28]. Mitin et al. designed an online survey to learn how radiation oncologists in the United States (US) counsel patients with ES-SCLC with respect to consolidative TRT, what doses they prescribe in various clinical situations, and what factors influence the doctors’ clinical approaches [29]. Their analyses revealed that most of the physicians recom-mend TRT to ES-SCLC patients who responded to systemic CT in accordance with NCCN guideline. They prefer the shorter and less toxic regimen of 30 Gy in 10 fractions.

Taken together with the results of these three randomized trials and retrospective studies, it can be concluded that OS can be improved with the addition of consolidative TRT in selected patients. However, the optimal BED for chest irradi-ation in ES-SCLC is still unknown. The available data sug-gests using dose escalation of 45 Gy or higher since it seems to be that higher doses were associated with an improvement in survival. However, the current NCCN guideline recommends dose ranges between 30 Gy in 10 fractions and 60 Gy in 30 fractions [28]. More research is needed to determine the opti-mal field and the dose fractionation schedule for TRT and to clarify the role of consolidative RT to asymptomatic metastatic sites.

What is the optimal timing of thoracic

radiotherapy?

Repopulation of clonogenic tumor cells during fractionated RT is recognized as an important factor affecting local control. Accelerated proliferation of tumor clonogens during RT has been shown to affect the outcome in squamous cell carcinoma of the head and neck [30–32]. Although there is limited evi-dence with respect to the other solid tumors, accelerated pro-liferation probably is a universal response to fractionated RT [33]. On the other hand, the cytotoxic CT may also induce accelerated repopulation; however, there is limited data about

this affect. Given the longer intervals between cycles and lon-ger total duration of treatment, the impact of repopulation is likely to be greater following CT [34].

SCLC is characterized by rapid doubling time, high growth fraction, and early development of metastases [35]. Although there is limited knowledge with respect to the accelerated repopulation of tumor clonogens during RT or CT in SCLC, the available data suggests that the overall duration of the RT and CT package is the most relevant predictor for outcome, and this has specifically been proposed for limited-stage small-cell lung cancer (LS-SCLC) as a result of the natural history of the disease [30,36]. Three important meta-analyses demonstrated that a low time between the first day of the CT and the last day of TRT is associated with improved survival in LS-SCLC patients [30,37,38]. The highly significant re-lationship between the time interval of CT and RT and the survival supports the occurrence of accelerated proliferation of tumor clonogens during CT and RT. Accordingly, the best survival of patients with a tumor of rapid doubling time and high growth fraction may be achieved when two or three full-dose cycles of CT and TRT are delivered before accelerated tumor cell proliferation starts, whether triggered by CT or by TRT. On the other hand, the toxicity profile of these regimens should be considered as well, since in Jeremic et al.’s study, the authors used concomitant CT with accelerated hyperfractionated RT and observed severe esophageal toxicity [11]. However, in Jeremic et al.’s study, RT was applied using 2-dimesional technique to relatively larger treatment fields. Nowadays, novel modern RT techniques allow radiation on-cologists to apply higher doses with lower toxicity profile.

There is limited evidence with respect to sequence of CT and RT in ES-SCLC patients. Although there are some meta-analyses demonstrating the importance of treatment duration in LS-SCLC patients, we have no idea about the impact of treatment duration on survival in ES-SCLC patients. We be-lieve that it is an important point since the patients with ES-SCLC have a limited survival and ES-SCLC is a rapidly growing tumor. Future studies evaluating the optimal treatment combi-nation, number of CT before RT, dose fractiocombi-nation, concur-rent vs sequential TRT, and timing of PCI may help to address unanswered questions.

Conclusion

In conclusion, available data shows that consolidative TRT offers survival advantage in selected ES-SCLC patients par-ticularly who responded to CT, who have limited metastatic sites, and who have a good performance status. The patients who have a complete response in thoracic disease seem to have no survival benefit from TRT. Before PCI, the brain imaging should be repeated in order to eliminate the patients with brain metastases since the patients with brain, bone, and

liver metastases may not benefit from TRT. Use of TRT in ES-SCLC should be considered on a case-by-case basis. Further research studies to identify the following questions are needed:

& To identify the subset of ES-SCLC patients who are likely to have more OS benefit

& The optimal dose fractionation schedule of TRT & The number of CT cycles

& The optimal timing of TRT and the optimal CT-TRT sequence

& The timing of PCI and TRT

& The role of consolidative RT to asymptomatic metastatic sites

& Immunotherapy and RT combinations in ES-SCLC

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

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