Next Article in Journal
A Cross-Sectional Study on the Acceptability of Implementing a Lung Cancer Screening Program in Belgium
Previous Article in Journal
Tumor Microenvironment before and after Chemoradiation in Locally Advanced Rectal Cancer: Beyond PD-L1
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 15
Issue 1
10.3390/cancers15010277
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data

by
Jingjing Zhao
1,
Linfang Wu
1,2,
Chen Hu
3,*,
Nan Bi
1,* and
Luhua Wang
4
1
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2
Cancer Research UK Cambridge Institute, University of Cambridge Li Ka Shing Center, Cambridge CB2 0RE, UK
3
Division of Quantitative Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
*
Authors to whom correspondence should be addressed.
Cancers 2023, 15(1), 277; https://doi.org/10.3390/cancers15010277
Submission received: 22 November 2022 / Revised: 25 December 2022 / Accepted: 25 December 2022 / Published: 31 December 2022
(This article belongs to the Topic Advances in Radiotherapy and Prognosis)
Browse Figures
Versions Notes

Abstract

:

Simple Summary

The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) remains debatable due to inconclusive evidence. With a comprehensive systematic review involving not only randomized controlled trials (RCTs) but real-world cohorts and single-arm trials, we conducted two principled yet distinctive meta-analyses of the efficacy and safety differences between hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT), and hyperfractionated TRT (HyperTRT) regimens, especially in the modern era. In the one-stage meta-analysis using 8006 reconstructed individual patient data (IPD) from 53 studies, the overall survival (OS) rates were similar between the three fractionation regimens. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules. Results of the aggregated data (AD)-based network meta-analysis were consistent with those of the IPD analysis. The three TRT fraction regimens are acceptable options for LS-SCLC in the modern radiation era.

Abstract

The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) using modern techniques remain unclear. We conducted systematic review and meta-analyses of the efficacy and safety differences between definitive hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT) and hyperfractionated TRT (HyperTRT), especially in the modern era. Eligible randomized controlled trials (RCTs), real-world cohorts, and single-arm trials published between 1990 and 2021 were identified. Two meta-analyses of overall survival (OS) were conducted: (i) a random-effects meta-analysis based on reconstructed individual-patient data (IPD) of all studies; and (ii) a Bayesian network meta-analysis based on study-level aggregated data (AD) of RCTs. The incidences of severe radiation-related toxicities were compared using the random-effects meta-regression model. Overall, 53 of the 30,031 publications met the inclusion criteria, and a total of 8006 IPD were reconstructed. After adjusting for key treatment variables and stratification by study type, there were no significant differences in the OS rates between the altered fractionation regimens (HypoTRT vs. HyperTRT, aHR [adjusted HR] = 1.05, 95% CI 0.93–1.19; ConvTRT vs. HyperTRT, aHR = 1.00, 95% CI 0·90–1.11; HypoTRT vs. ConvTRT, aHR = 1.05, 95% CI 0.91–1.20). In the modern era, the survival outcomes of all three schedules, while remaining comparable, have improved significantly. Results of the AD-based network meta-analysis were consistent with those of IPD analysis, and HypoTRT was ranked as the best regimen (SUCRA = 81%). There were no significant differences in toxicities between groups when using modern radiation techniques. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules in LS-SCLC. HypoTRT may be associated with moderate and non-significant OS improvements, which should be further confirmed in prospective randomized phase III trials.

1. Introduction

Thoracic radiotherapy (TRT), in combination with chemotherapy, is regarded as the standard treatment for inoperable limited-stage small cell lung cancer (LS-SCLC) [1,2,3]. Altered TRT dose and fractionation regimens may have meaningful impacts on survival and radiation-related adverse events due to the unique tumor biology characteristics of SCLC such as rapid doubling time and the accelerated proliferation of tumor cells [4,5,6].
The clinical benefits of a hyperfractionated twice-daily TRT (HyperTRT) regimen was first established by the landmark Intergroup 0096 phase III study in the 1990s [7]. Since then, significant progress in imaging and radiotherapy techniques have led to improved clinical outcomes and reduced toxicities in lung cancer as well as continued exploration of optimal TRT regimens [8,9]. Among these efforts, the CONVERT trial was a randomized phase III trial using modern and precise RT techniques, and demonstrated that comparable survival and toxicity outcomes did not differ between HyperTRT and conventional TRT (ConvTRT) [10]. Most recently, the randomized phase III trial CALGB 30610/RTOG 0538 showed that high-dose ConvTRT (70 Gy in 35 daily fractions) might be an acceptable dose and fractionation regimen, with comparable outcomes to HyperTRT [11]. Collectively, the optimal TRT dose and fractionation have not yet been well-established, especially in the modern radiotherapy era [12,13].
Simultaneously, the once-daily hypofractionated TRT (HypoTRT) regimen, which is delivered with a higher radiation dose per fraction within a shorter overall treatment time, has been proven feasible for LS-SCLC with the development of modern diagnostic and RT techniques [14,15,16,17,18,19,20]. Despite its radiobiological efficiency and convenience, currently, only a handful of randomized phase II trials focusing on HypoTRT have been completed, and there are no phase III trials to support its wide adoption.
To date, no randomized controlled trials (RCTs) have provided head-to-head comparisons between the three altered fractionation schedules. Several meta-analyses have been conducted to fill this evidence gap, however, their applicability and relevance to contemporary patients may be questionable [21,22]. One existing individual patient data (IPD) meta-analysis was conducted in the era of the outdated 2D radiotherapy technique and could not reflect its modern practice [21]. A more recent aggregated data (AD) meta-analysis, which compared once-daily and twice-daily schedules using five RCTs that ranged over three decades, inappropriately pooled time-to-event survival data as dichotomous outcomes [22].
Because high-quality and well-conducted systematic reviews and meta-analyses in this field are still warranted, we conducted a comprehensive systematic review involving not only RCTs but real-world cohorts and single-arm trials. Furthermore, we conducted two principled yet distinctive meta-analyses: (i) a one-stage meta-analysis using reconstructed IPD, and (ii) two-stage network meta-analysis of the study-level AD to compare the three altered fractionation regimens directly and indirectly. Considering the rapid development of radiotherapy delivery, we also explored whether the outcome discrepancies, if any, might vary with modern radiation techniques as a pre-planned subgroup analysis.

2. Methods and Materials

2.1. Search Strategy and Eligibility Criteria

The meta-analyses were conducted following the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary Table S1). A literature search was performed across the PubMed, EMBASE, and Web of Science databases from 1 January 1990 to 31 July 2021. Studies presented at major conferences were also searched. The Supplementary Materials show the detailed search strategy (Figure S1).
The eligibility criteria were as follows: (1) diagnosis of LS-SCLC; (2) TRT with chemotherapy administered as curative intent; (3) RCTs, observational studies, or single arm phase II trials; and (4) separate and high-resolution Kaplan–Meier curves of overall survival (OS) for different fraction modalities. Additional eligibility criteria are presented in the Supplementary Materials (Method S1).
The eligible studies were classified into three categories: (1) RCTs; (2) comparative observational studies that directly compared different dose and fractionated schedules; and (3) single-fractionation prospective trials (aka prospective non-RCT studies).

2.2. Assessment of Study Quality

Two reviewers assessed the quality of the included studies, and a third author resolved any disagreements in the assessments. The Cochrane Collaboration risk-of-bias-tool 2 (ROB 2), Newcastle–Ottawa scale (NOS), and methodological index for non-randomized studies (MINORS) criteria were used to evaluate the quality of the RCTs, observational studies, and single-arm trials, respectively. The quality assessment results of the included studies are summarized in the Supplementary Materials (Tables S2–S4).

2.3. Data Extraction and IPD Reconstruction

Data were reviewed and extracted by two independent authors including the study characteristics, patient demographics, treatment details, and survival outcomes. Radiation esophagitis (RE) and radiation pneumonitis (RP) were recorded as primary radiation-related adverse events.
The R package (IPD from KM) was used to preprocess the raw data and reconstruct the IPD [23]. Raw data coordinates (time and survival probability) were extracted from published K–M survival curves using the Engauge Digitizer. The number of patients at risk and the total number of events were required for an accurate estimation if available. The accuracy of the reconstruction was quantified using several summary statistics including the root mean square error, maximum absolute error, mean absolute error, and Kolmogorov–Smirnov test [23]. The visualized and quantitative comparisons between the reconstructed and original curves are shown in the Supplementary Materials (Figure S2).

2.4. Treatment Characteristics

Eligible modalities of TRT were grouped into three types of fractionations: HypoTRT, ConvTRT, and HyperTRT (twice daily, with a minimum of 4–6 h between fractions). To account for the known prognostic impacts of overall treatment time, we calculated the biologically effective dose (BED) corrected for the time factor and adjusted in the analysis accordingly (Supplementary Method S2) [4,5].

2.5. Outcomes

The primary endpoint was OS, whose differences were quantified through hazard ratios (HRs) and the 95% confidence interval (CI). The secondary endpoint was the incidence of Grades 3–5 RE and RP. The Common Terminology Criteria for Adverse Events (CTCAE)/Radiation Therapy Oncology Group (RTOG) grading system was applied to assess the treatment related toxicities, as reported by each study.

2.6. Data Analysis

A one-stage meta-analysis was employed to analyze OS using the reconstructed IPD. A random-effect shared frailty Cox proportional hazard model was used to account for the heterogeneity within and across studies, with non-parametric penalized likelihood estimation and spline smoothing for the baseline hazard functions [24,25]. To further account for the heterogeneity across different study types, a frailty model stratified by study type was used. Key study-level treatment factors were also adjusted as fixed effects in the aforementioned shared frailty Cox model. To confirm the robustness of the IPD meta-analysis, a Bayesian network meta-analysis was also performed based on the study-level AD of RCTs, which permits indirect comparisons of altered fractionation groups using existing pairwise comparisons of HypoTRT vs. HyperTRT, ConvTRT vs. HyperTRT, and HypoTRT vs. ConvTRT. The resulting HR and associated 95% Bayesian credible intervals (CrI) were presented for statistical inference (Supplementary Method S3). The R package frailtypack was used for one-stage IPD analysis, and gemtc was used for Bayesian network AD meta-analysis.
The incidences of radiation-related toxicities between the TRT fraction modalities were compared using the random effects meta-regression model (Supplementary Method S3) [26,27]. The R package meta and metafor were used for the analysis of adverse events. A p-value < 0.05 was considered statistically significant. All analyses were performed using R Studio (version 4.0.5). The study protocol was prospectively registered in PROSPERO (CRD42022343063).

2.7. Subgroup Analysis

Subgroup analyses were conducted to assess if and how findings may differ across study types, especially focusing on analysis in the subset of patients who underwent modern and precise techniques including three-dimensional conformal radiotherapy or intensity-modulated radiotherapy (3D-CRT/IMRT).

3. Results

3.1. Study Selection and Characteristics

The systematic review retrieved 19,152 studies from a total of 30,031 after removing duplicates. A total of 138 full-text articles and one conference abstract were carefully reviewed and divided into three predefined subgroups depending on the study design and comparative information: RCTs, observational studies, and prospective non-RCT studies. Among them, 86 papers were excluded and the detailed reasons are displayed in Figure 1.
Ultimately, a total of 53 studies with 8006 patients were identified from 30,031 study records; the PRISMA flow diagram is shown in Figure 1. Among the enrolled studies, seven [7,10,11,18,20,28,29] were classified into the RCTs category, nine [14,15,16,17,30,31,32,33,34] into the comparative observational studies category, and 37 [35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71] into prospective non-RCT studies. A total of 1689 (21%) patients from 13 studies were treated with HypoTRT, 3118 (39%) patients from 27 studies were treated with ConvTRT, and 3199 (40%) patients from 29 studies were treated with HyperTRT. 3D-CRT or IMRT was used in 21 studies with 3493 (44%) patients. Table 1 summarizes the patient demographics and treatment details of the enrolled studies [7,10,11,14,15,16,17,18,20,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71]. Detailed descriptions of the main characteristics of each study are provided in Supplementary Table S5.
Based on the study-level AD, 5178 (65%) participants were male and 2828 (35%) were female. A total of 91% patients underwent concurrent chemoradiotherapy (CCRT) in the all included studies and 100% in the RCTs. A total of 52% patients received TRT within the first two cycles of induction chemotherapy, while the proportion varied widely across study types (81% in RCTs, 12% in comparative observational studies, and 47% in prospective non-RCT studies). The use of prophylactic cranial irradiation (PCI) ranged from 12% to 100% across studies. Most studies in the HypoTRT group were administered 2.5–3.0 Gy per fraction once daily, with a total dose ranging from 37.5 Gy to 65.0 Gy, which corresponded to 39.04–66.40 Gy corrected BED10. The total dose administered in the ConvTRT group was 45.0–70.0 Gy of 1.8–2.1 Gy per fraction, and the corrected BED10 ranged from 39.49 to 64.61 Gy. Studies in the HyperTRT group was delivered with 45.0–60.0 Gy twice daily (1.4–1.5 Gy per fraction) with a minimum of 4–6 h between fractions, and the corrected BED10 ranged from 39.53 Gy to 58.28 Gy.

3.2. IPD Meta-Analysis

For the entire cohort of 8006 patients from 53 studies, the median follow-up was 60.0 months (IQR 40.67–88.23), with a total of 5795 deaths occurring. Based on the shared frailty Cox model stratified by study types, the estimated survival curves of each fractionation regimen, along with those from each study, are shown in Figure 2A. The overall 2-, 3-, and 5-year survival rates were 49%, 35%, and 27% in the HypoTRT group, 48%, 33%, and 23% in the ConvTRT group, and 53%, 36%, and 25% in the HyperTRT group, respectively. The OS rates were comparable between HypoTRT and HyperTRT (HR = 1.04, 95% CI 0.92–1.18) or ConvTRT (HR = 0.93, 95% CI 0.83–1.06); meanwhile ConvTRT was inferior to HyperTRT (HR = 1.12, 95% CI 1.03–1.21, Figure 3A). However, after adjusting for the corrected BED10, CCRT, and TRT timing [5,10,67,72], the OS rates became similar between the three groups (HypoTRT vs. HyperTRT, adjusted HR = 1.05, 95% CI 0.93–1.19; ConvTRT vs. HyperTRT, adjusted HR = 1.00, 95% CI 0.90–1.11; HypoTRT vs. ConvTRT, adjusted HR = 1.05, 95% CI 0.91–1.20, Figure 3A).

3.3. AD Network Meta-Analysis

Similar results were found when using a Bayesian network meta-analysis based on RCTs (Supplementary Figure S3). Results from the direct comparisons are summarized in the Supplementary Materials (Table S6). The OS rates were similar between HypoTRT, ConvTRT, and HyperTRT, respectively (HypoTRT vs. HyperTRT, HR = 0.96, 95% CrI 0.77–1.20; ConvTRT vs. HyperTRT, HR = 1.10, 95% CrI 0.95–1.20; HypoTRT vs. ConvTRT, HR = 0.90, 95% CrI 0.71–1.10; Figure 4A). The results of the ranking plot with the surface under the cumulative ranking curve (SUCRA), HypoTRT (SUCRA = 71%), and HyperTRT (SUCRA = 62%) were found to be most likely the best among the three regimens (Figure 4B). Furthermore, no treatment factors were found to be significantly associated with OS (Supplementary Table S7).

3.4. Subgroup Analysis of 3D-CRT or IMRT

Among 3493 patients treated with modern radiotherapy, 2281 deaths occurred over a follow-up period of 55.10 months (IQR 36.10–71.90). In total, 557 patients across eight studies were allocated to the HypoTRT group, 1255 patients across 10 studies to the ConvTRT group, and 1681 patients across 14 studies to the HyperTRT group.
Using a one-stage random-effect meta-analysis model based on reconstructed IPD, we found that the 2-, 3-, and 5-year OS rates were 59%, 44%, and 35% in the HypoTRT group, 55%, 40%, and 29% in the ConvTRT group, and 59%, 41%, and 30% in the HyperTRT group, respectively (Figure 2B). The OS results with the HypoTRT (HR = 0.51, 95% CI 0.36–0.73), ConvTRT (HR = 0.84, 95% CI 0.70–0.99), and HyperTRT regimens (HR = 0.95, 95% CI 0.79–1.15) (HR = 0.95, 95% CI 0.79–1.15) were significantly higher than those in the 2D era.
HyperTRT was comparable with either HypoTRT or ConvTRT in the OS rates (HypoTRT vs. HyperTRT, HR = 0.95, 95% CI 0.81–1.10; ConvTRT vs. HyperTRT, HR = 1.09, 95% CI 0.98–1.21). HypoTRT was associated with a marginally higher OS than ConvTRT (HR = 0.87, 95%CI 0.74–1.02) (Figure 3B). After adjusting the aforementioned treatment characteristics, these conclusions did not change (HypoTRT vs. HyperTRT, adjusted HR = 0.95, 95% CI 0.81–1.10; ConvTRT vs. HyperTRT, adjusted HR = 1.05, 95% CI 0.92–1.21; HypoTRT vs. ConvTRT, adjusted HR = 0.90, 95%CI 0.75–1.08) (Figure 3B).
Similar findings of pairwise comparisons in the two-stage Bayesian network meta-analysis were observed (Figure 4C). In terms of the results from the ranking plot with SUCRA, the beneficial orders for OS from the greatest to the least were HypoTRT (SUCRA = 81%), HyperTRT (SUCRA = 51%), and ConvTRT (SUCRA = 18%) (Figure 4D).

3.5. Incidences of RE and RP

A total of 44 studies that reported severe RE (10, 20, and 26 in HypoTRT, ConvTRT, and HyperTRT, respectively) were included. The rates of pooled grades 3–5 RE incidence were 9% (95% CI 4–16), 11% (95% CI 7–16), and 18% (95% CI 13–23) for the HypoTRT, ConvTRT, and HyperTRT group, respectively. Meta-regression analysis showed that severe (grades 3–5) RE incidence were similar between HypoTRT and ConvTRT (p = 0.62) while there was a higher incidence with HyperTRT (vs HypoTRT, p = 0.03; vs. ConvTRT, p = 0.04). A total of 38 studies reported severe grade 3–5 RP (9, 18, and 23 in HypoTRT, ConvTRT, and HyperTRT, respectively). The rates of severe RP were 3% (95% CI 1–6), 4% (95% CI 2–6), and 3% (95% CI 2–5), respectively, which were similar across the different groups (Supplementary Figure S4). There was no publication bias for the enrolled studies (RE, p = 0.49; RP, p = 0.08) (Supplementary Figure S5).
In the modern era, there is no pronounced difference in either severe RE (HypoTRT vs. HyperTRT, 14% vs. 17%, p = 0.49; ConvTRT vs. HyperTRT, 12% vs. 17%, p = 0.21; HypoTRT vs. ConvTRT, 14% vs. 12%, p = 0.77) or RP (HypoTRT vs. HyperTRT, 5% vs. 3%, p = 0.24; ConvTRT vs. HyperTRT, 5% vs. 3%, p = 0.30; HypoTRT vs. ConvTRT, 5% vs. 5%, p = 0.95) (Supplementary Figure S4).
Additionally, a total of ten studies have reported the incidence of late grade 3–5 RE and RP (supplementary Table S8). The incidence of the most frequently recorded event for the overall cohort was no more than 5%. Only one earlier study utilizing the 2D technique and HypoTRT regimen reported an extremely high risk of severe late lung toxicity (38%) [41].

4. Discussion

To our best knowledge, this is the first and largest meta-analysis (8006 patients) of reconstructed time-to-event analysis of TRT fractionation for LS-SCLC. In this systematic review and meta-analyses, HyperTRT yielded similar survival outcomes as ConvTRT with advanced radiotherapy techniques, which confirms the generalizability of the existing landmark phase III RCTs by synthesizing evidence across all study types [10,11]. Our findings further support that HypoTRT should be considered as an acceptable regimen, which provide powerful evidence for the updated recommendations in the latest NCCN guidelines, especially in the absence of phase III RCTs [13]. It is worth noting that in the network meta-analysis, HypoTRT was ranked the best regimen, far beyond the two other modalities within the 3D-CRT/IMRT subgroup (SUCRA = 81%). Therefore, HypoTRT is an attractive alternative because of its favorable treatment effects, toxicity tolerance, decreased resource utilization, and patient convenience.
Several unique features make our work distinct from the existing meta-analysis in this field. The Meta-Analysis of Radiotherapy in Lung Cancer (MAR-LC) collaborative group conducted an IPD meta-analysis based on two trials published in the 1990s. The results showed a non-significant difference in OS between HyperTRT and ConvTRT (3- and 5- year OS rates, 31% vs. 30% and 24% vs. 22%, HR= 0.87, 95% CI 0.74–1.02) and an increased incidence of acute severe RE in the HyperTRT regimen (HyperTRT vs. ConvTRT, 25% vs. 12%, p < 0.01) when non-contemporary radiotherapy techniques were used [21]. In contrast, our work showed more recent and relevant results with significantly improved OS (ConvTRT vs. HyperTRT, 3- and 5- year OS rates, 40% vs. 41% and 29% vs. 30%, adjusted HR = 1.05, 95% CI 0.92–1.21) and a decreased incidence of severe RE in the HyperTRT group (vs ConvTRT, 17% vs. 12%, p = 0.21) in the modern era. More recently, Viani et al. reported a meta-regression analysis based on the study-level information of five RCTs with limited sample size, where the HypoTRT group consisted of only 172 patients from two phase II trials. They concluded that the OS rates were similar between ConvTRT and HyperTRT, while HypoTRT yielded more survival benefits (HyperTRT vs. HypoTRT, HR = 1.45, or equivalently, HypoTRT vs. HyperTRT, HR = 0.69, p = 0.03) in the subgroup analysis [22]. In contrast, our two-stage analysis based on study-level information yielded a consistent, although somewhat attenuated effect of HypoTRT when compared with HyperTRT in the modern era (HR = 0.90, 95% CrI 0.68–1.20). When including more studies and expanding the study types to observational cohorts and non-randomized trials, our findings may represent less optimistic but probably more realistic benefits of HypoTRT in the real-world after accounting for other treatment characteristics including corrected BED10. Nevertheless, a moderate survival benefit of HypoTRT, coupled with the favorable safety profile and treatment convenience, could still be a preferred option that warrants prospective randomized phase III trials to confirm its true benefit/risk profile.
Apart from its inclusivity and large sample size, a key strength of the present work was our use of a reconstructed time-to-event IPD to granularly assess the survival differences between altered fractionations. An IPD meta-analysis is highly desirable in evidence synthesis, and plays a critical role in defining practice in the absence of large, randomized trials [73,74]. When carefully conducted, reconstructed IPD provides an alternative approach to access individual time-to-event survival data from an unrestricted pool of studies. To robustly evaluate the comparative effectiveness of the three fractionation regimens, we included not only RCTs but real-world cohorts and single-fractionation prospective trials in one-stage IPD analysis. This approach not only mitigated the challenges due to the limited number of RCTs, but also enhanced the generalizability and relevance of our findings in the modern era. Admittedly, the heterogeneity caused by the reported and unreported covariates cannot be ignored. Several measures were taken to mitigate such a risk. First, the shared frailty model stratified by study type was used for one-stage IPD analysis that accounted for the heterogeneity within and across studies. Second, correction for study-level key factors reduced the bias caused by various treatment characteristics, especially important for prospective trials without related head-to-head comparisons in TRT fractionation. Third, given the value of the time factor in rapidly growing SCLC, we calculated and adjusted for the time corrected BED10, which allowed for the comparisons between the altered fractionation schedules [5]. In addition, a two-stage approach was used for a validation analysis, and the results confirmed our conclusions from the study-level analysis. Furthermore, considering the long time-span of the enrolled studies, we performed a subgroup analysis in the modern era for both the survival and toxicity files. Notably, regarding severe RE, increased rates were observed in HypoTRT (9% change to 14%) and ConvTRT (11% change to 12%) in the 3D-CRT/IMRT subgroup, and the differences narrowed between the three regimens (HypoTRT vs. HyperTRT, 9% vs. 18%, p = 0.03 change to 14% vs. 17%, p = 0.49; ConvTRT vs. HyperTRT, 11% vs. 18%, p = 0.04 change to12% vs. 17%, p = 0.21). This might be explained in part by the decrease in the incidence of severe RE in the HyperTRT group in the modern radiation era, and on the other hand, the application of advanced RT techniques allowing for a higher TRT dose delivery in the HypoTRT and ConvTRT groups, which could cause a higher toxicity incidence.
There were some limitations in this work. First, although the reconstructed IPD provides an accurate estimation of individual patient time-to-event, this algorithm is limited in its ability to obtain additional patient-level characteristics. To correct for treatment-related confounding factors and accommodate for the heterogeneity across studies, we extracted some important study-level covariates including the corrected BED10, CCRT, TRT timing, and radiation technique. However, these statistical adjustments may or may not adequately isolate their impacts when estimating the possibly incremental but clinically meaningful improvements due to HypoTRT. Second, because the toxicities were reported inconsistently across all studies, we chose to focus on grade 3–5 RE and RP and thus exclude studies reporting symptomatic or any grade of toxicities. Third, acute and late radiation-related toxicities, which potentially reflect different tissue responses to modified fractionation, have not been listed separately and clearly in some studies, which may cause bias in event statistics. Fourth, considering that there are so many factors associated with the occurrence of hematologic toxicities, especially the chemotherapy regimens, which had the greatest impact in pancytopenia, we did not summarize the incidence of hematologic toxicities in this research. Finally, the various study types in the enrolled literature potentially increased the heterogeneity. Although a number of measures have been taken, the inherent biases of enrollment such as population selection bias, attrition, and data quality cannot be completely eliminated by study design or statistical methods.
To our knowledge, a phase III multicenter RCT is currently underway to compare the effects between HypoTRT (45 Gy in 15 fractions over three weeks) and ConvTRT (60 Gy in 30 fractions over six weeks) concomitant with chemotherapy for inoperable LS-SCLC (NCT02688036), which will provide robust evidence for the effect of HypoTRT using advanced techniques. Similarly, the final results of the CALGB 30610/RTOG 0538 trial, which compares high-dose ConvTRT and standard HyperTRT, are expected to be reported soon.

5. Conclusions

In conclusion, HypoTRT, ConvTRT, and HyperTRT had comparable survival outcomes in LS-SCLC, while HyperTRT was associated with higher rates of severe RE. In the modern radiation therapy era, no significant differences in OS rates and severe radiation-related adverse events were observed between the altered schedules. HypoTRT may be associated with a moderate and non-significant survival benefit while prospective randomized phase III trials are warranted.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers15010277/s1, Method S1: Eligibility criteria; Method S2: Data extraction; Method S3: Statistical analysis; Table S1: PRISMA checklist; Table S2: Risk of bias assessment according to ROB-2; Table S3: Risk of bias assessment according to NOS; Table S4: Risk of bias assessment according to the MINORS criteria; Table S5: Characteristics of each enrolled study; Table S6: Summary of the results from direct comparisons for overall survival; Table S7: Network meta-regression results; Table S8: Late severe radiation-related adverse events; Figure S1: Search strategy; Figure S2: Comparisons of the reconstructed and original curves; Figure S3: Network plots; Figure S4: Forest plots of severe radiation related events for altered fractionation modalities; Figure S5: Funnel plot according to the double arcsine transformed proportion for publication bias.

Author Contributions

Conceptualization, N.B., C.H. and L.W. (Luhua Wang); Methodology, C.H.; Software, J.Z.; Validation, N.B., C.H. and L.W. (Luhua Wang); Formal analysis, C.H. and J.Z.; Resources, J.Z. and L.W. (Linfang Wu); Data curation, J.Z. and L.W. (Linfang Wu); Writing—original draft preparation, J.Z.; Writing—review and editing, N.B. and C.H.; Visualization, C.H. and J.Z.; Supervision, N.B., C.H. and L.W. (Luhua Wang); Project administration, N.B. and C.H.; Funding acquisition, N.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Capital’s Funds for Health Improvement and Research of China (2020-2-4022).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Pignon, J.P.; Arriagada, R.; Ihde, D.C.; Johnson, D.H.; Perry, M.C.; Souhami, R.L.; Brodin, O.; Joss, R.A.; Kies, M.S.; Lebeau, B.; et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N. Engl. J. Med. 1992, 327, 1618–1624. [Google Scholar] [CrossRef] [PubMed]
  2. Warde, P.; Payne, D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J. Clin. Oncol. 1992, 10, 890–895. [Google Scholar] [CrossRef]
  3. Zeng, H.; De Ruysscher, D.K.M.; Hu, X.; Zheng, D.; Yang, L.; Ricardi, U.; Kong, F.-M.S.; Hendriks, L.E.L. Radiotherapy for small cell lung cancer in current clinical practice guidelines. J. Natl. Cancer Cent. 2022, 2, 113–125. [Google Scholar] [CrossRef]
  4. De Ruysscher, D.; Lueza, B.; Le Péchoux, C.; Johnson, D.H.; O’Brien, M.; Murray, N.; Spiro, S.; Wang, X.; Takada, M.; Lebeau, B.; et al. Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: Usefulness of the individual patient data meta-analysis. Ann. Oncol. 2016, 27, 1818–1828. [Google Scholar] [CrossRef] [PubMed]
  5. De Ruysscher, D.; Pijls-Johannesma, M.; Bentzen, S.M.; Minken, A.; Wanders, R.; Lutgens, L.; Hochstenbag, M.; Boersma, L.; Wouters, B.; Lammering, G.; et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J. Clin. Oncol. 2006, 24, 1057–1063. [Google Scholar] [CrossRef] [PubMed]
  6. Kim, J.J.; Tannock, I.F. Repopulation of cancer cells during therapy: An important cause of treatment failure. Nat. Rev. Cancer 2005, 5, 516–525. [Google Scholar] [CrossRef]
  7. Turrisi, A.T.; Kim, K.; Blum, R.; Sause, W.T.; Livingston, R.B.; Komaki, R.; Wagner, H.; Aisner, S.; Johnson, D.H. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N. Engl. J. Med. 1999, 340, 265–271. [Google Scholar] [CrossRef]
  8. Chun, S.G.; Hu, C.; Choy, H.; Komaki, R.U.; Timmerman, R.D.; Schild, S.E.; Bogart, J.A.; Dobelbower, M.C.; Bosch, W.; Galvin, J.M.; et al. Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial. J. Clin. Oncol. 2017, 35, 56–62. [Google Scholar] [CrossRef]
  9. Wang, J.; Zhou, Z.; Liang, J.; Feng, Q.; Xiao, Z.; Hui, Z.; Wang, X.; Lv, J.; Chen, D.; Zhang, H.; et al. Intensity-Modulated Radiation Therapy May Improve Local-Regional Tumor Control for Locally Advanced Non-Small Cell Lung Cancer Compared With Three-Dimensional Conformal Radiation Therapy. Oncologist 2016, 21, 1530–1537. [Google Scholar] [CrossRef] [Green Version]
  10. Faivre-Finn, C.; Snee, M.; Ashcroft, L.; Appel, W.; Barlesi, F.; Bhatnagar, A.; Bezjak, A.; Cardenal, F.; Fournel, P.; Harden, S.; et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): An open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017, 18, 1116–1125. [Google Scholar] [CrossRef]
  11. Bogart, J.A.; Wang, X.F.; Masters, G.A.; Gao, J.; Komaki, R.; Kuzma, C.S.; Heymach, J.; Petty, W.J.; Gaspar, L.E.; Waqar, S.N.; et al. Phase 3 comparison of high-dose once-daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC): CALGB 30610 (Alliance)/RTOG 0538. J. Clin. Oncol. 2021, 39, 8505. [Google Scholar] [CrossRef]
  12. Daly, M.E.; Ismaila, N.; Decker, R.H.; Higgins, K.; Owen, D.; Saxena, A.; Franklin, G.E.; Donaldson, D.; Schneider, B.J. Radiation Therapy for Small-Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline. J. Clin. Oncol. 2021, 39, 931–939. [Google Scholar] [CrossRef] [PubMed]
  13. Ganti, A.K.P.; Loo, B.W.; Bassetti, M.; Blakely, C.; Chiang, A.; D’Amico, T.A.; D’Avella, C.; Dowlati, A.; Downey, R.J.; Edelman, M.; et al. Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2021, 19, 1441–1464. [Google Scholar] [CrossRef]
  14. Zhang, J.; Fan, M.; Liu, D.; Zhao, K.-L.; Wu, K.-L.; Zhao, W.-X.; Zhu, Z.-F.; Fu, X.-L. Hypo- or conventionally fractionated radiotherapy combined with chemotherapy in patients with limited stage small cell lung cancer. Radiat. Oncol. 2017, 12, 51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Zayed, S.; Chen, H.; Ali, E.; Rodrigues, G.B.; Warner, A.; Palma, D.A.; Louie, A.V. Is There a Role for Hypofractionated Thoracic Radiation Therapy in Limited-Stage Small Cell Lung Cancer? A Propensity Score Matched Analysis. Int. J. Radiat. Oncol. Biol. Phys. 2020, 108, 575–586. [Google Scholar] [CrossRef]
  16. Yan, M.; Sigurdson, S.; Greifer, N.; Kennedy, T.A.C.; Toh, T.S.; Lindsay, P.E.; Weiss, J.; Hueniken, K.; Yeung, C.; Sugumar, V.; et al. A Comparison of Hypofractionated and Twice-Daily Thoracic Irradiation in Limited-Stage Small-Cell Lung Cancer: An Overlap-Weighted Analysis. Cancers 2021, 13, 2895. [Google Scholar] [CrossRef]
  17. Socha, J.; Guzowska, A.; Tyc-Szczepaniak, D.; Wierzchowski, M.; Sprawka, A.; Szczesna, A.; Kepka, L. Accelerated hypofractionated thoracic radiotherapy in limited disease small cell lung cancer: Comparison with the results of conventionally fractionated radiotherapy. J. BUON 2015, 20, 146–157. [Google Scholar] [PubMed]
  18. Grønberg, B.H.; Halvorsen, T.O.; Fløtten, Ø.; Brustugun, O.T.; Brunsvig, P.F.; Aasebø, U.; Bremnes, R.M.; Tollåli, T.; Hornslien, K.; Aksnessæther, B.Y.; et al. Randomized phase II trial comparing twice daily hyperfractionated with once daily hypofractionated thoracic radiotherapy in limited disease small cell lung cancer. Acta Oncol. 2016, 55, 591–597. [Google Scholar] [CrossRef] [Green Version]
  19. Turgeon, G.A.; Souhami, L.; Kopek, N.; Hirsh, V.; Ofiara, L.; Faria, S.L. Thoracic irradiation in 3 weeks for limited-stage small cell lung cancer: Is twice a day fractionation really needed? Cancer Radiothér. 2017, 21, 89–98. [Google Scholar] [CrossRef]
  20. Qiu, B.; Li, Q.; Liu, J.; Huang, Y.; Pang, Q.; Zhu, Z.; Yang, X.; Wang, B.; Chen, L.; Fang, J.; et al. Moderately Hypofractionated Once-Daily Compared With Twice-Daily Thoracic Radiation Therapy Concurrently With Etoposide and Cisplatin in Limited-Stage Small Cell Lung Cancer: A Multicenter, Phase II, Randomized Trial. Int. J. Radiat. Oncol. Biol. Phys. 2021, 111, 424–435. [Google Scholar] [CrossRef]
  21. Mauguen, A.; Le Péchoux, C.; Saunders, M.I.; Schild, S.E.; Turrisi, A.T.; Baumann, M.; Sause, W.T.; Ball, D.; Belani, C.P.; Bonner, J.A.; et al. Hyperfractionated or accelerated radiotherapy in lung cancer: An individual patient data meta-analysis. J. Clin. Oncol. 2012, 30, 2788–2797. [Google Scholar] [CrossRef] [Green Version]
  22. Viani, G.A.; Gouveia, A.G.; Matsuura, F.K.; Jacinto, A.A.; Moraes, F.Y. Once daily (OD) versus twice-daily (BID) chemoradiation for limited stage small cell lung cancer (LS-SCLC): A meta-analysis of randomized clinical trials. Radiother. Oncol. 2022. [Google Scholar] [CrossRef] [PubMed]
  23. Liu, N.; Zhou, Y.; Lee, J.J. IPDfromKM: Reconstruct individual patient data from published Kaplan-Meier survival curves. BMC Med. Res. Methodol. 2021, 21, 111. [Google Scholar] [CrossRef]
  24. de Jong, V.M.T.; Moons, K.G.M.; Riley, R.D.; Tudur Smith, C.; Marson, A.G.; Eijkemans, M.J.C.; Debray, T.P.A. Individual participant data meta-analysis of intervention studies with time-to-event outcomes: A review of the methodology and an applied example. Res. Synth. Methods 2020, 11, 148–168. [Google Scholar] [CrossRef] [PubMed]
  25. Smith, C.T.; Williamson, P.R.; Marson, A.G. Investigating heterogeneity in an individual patient data meta-analysis of time to event outcomes. Stat. Med. 2005, 24, 1307–1319. [Google Scholar] [CrossRef] [PubMed]
  26. Rücker, G.; Schwarzer, G.; Carpenter, J.; Olkin, I. Why add anything to nothing? The arcsine difference as a measure of treatment effect in meta-analysis with zero cells. Stat. Med. 2009, 28, 721–738. [Google Scholar] [CrossRef] [PubMed]
  27. DerSimonian, R.; Laird, N. Meta-analysis in clinical trials. Control. Clin. Trials 1986, 7, 177–188. [Google Scholar] [CrossRef]
  28. Blackstock, A.W.; Bogart, J.A.; Matthews, C.; Lovato, J.F.; McCoy, T.; Livengood, K.; Ho, C.; White, D.; Atkins, J.N.; Miller, A.A. Split-course versus continuous thoracic radiation therapy for limited-stage small-cell lung cancer: Final report of a randomized phase III trial. Clin. Lung Cancer 2005, 6, 287–292. [Google Scholar] [CrossRef]
  29. Bonner, J.A.; Sloan, J.A.; Shanahan, T.G.; Brooks, B.J.; Marks, R.S.; Krook, J.E.; Gerstner, J.B.; Maksymiuk, A.; Levitt, R.; Mailliard, J.A.; et al. Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J. Clin. Oncol. 1999, 17, 2681–2691. [Google Scholar] [CrossRef]
  30. Bettington, C.S.; Tripcony, L.; Bryant, G.; Hickey, B.; Pratt, G.; Fay, M. A retrospective analysis of survival outcomes for two different radiotherapy fractionation schedules given in the same overall time for limited stage small cell lung cancer. J. Med. Imaging Radiat. Oncol. 2013, 57, 105–112. [Google Scholar] [CrossRef]
  31. Gazula, A.; Baldini, E.H.; Chen, A.; Kozono, D. Comparison of once and twice daily radiotherapy for limited stage small-cell lung cancer. Lung 2014, 192, 151–158. [Google Scholar] [CrossRef] [PubMed]
  32. Han, D.; Hao, S.; Tao, C.; Zhao, Q.; Wei, Y.; Song, Z.; Li, B. Comparison of once daily radiotherapy to 60 Gy and twice daily radiotherapy to 45 Gy for limited stage small-cell lung cancer. Thorac. Cancer 2015, 6, 643–648. [Google Scholar] [CrossRef] [PubMed]
  33. Tan, Y.; Zhu, Q. Curative effect of hyperfractionated accelerated radiotherapy combined with EP chemotherapy regimen on limited-stage small cell lung cancer. J. BUON 2021, 26, 837–843. [Google Scholar] [PubMed]
  34. Tomita, N.; Kodaira, T.; Hida, T.; Tachibana, H.; Nakamura, T.; Nakahara, R.; Inokuchi, H. The impact of radiation dose and fractionation on outcomes for limited-stage small-cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 2010, 76, 1121–1126. [Google Scholar] [CrossRef] [PubMed]
  35. Baas, P.; Belderbos, J.S.; Senan, S.; Kwa, H.B.; van Bochove, A.; van Tinteren, H.; Burgers, J.A.; van Meerbeeck, J.P. Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: A Dutch multicenter phase II study. Br. J. Cancer 2006, 94, 625–630. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Bogart, J.A.; Herndon, J.E., 2nd; Lyss, A.P.; Watson, D.; Miller, A.A.; Lee, M.E.; Turrisi, A.T.; Green, M.R. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: Analysis of Cancer and Leukemia Group B study 39808. Int. J. Radiat. Oncol. Biol. Phys. 2004, 59, 460–468. [Google Scholar] [CrossRef]
  37. Bunn, P.A., Jr.; Crowley, J.; Kelly, K.; Hazuka, M.B.; Beasley, K.; Upchurch, C.; Livingston, R.; Weiss, G.R.; Hicks, W.J.; Gandara, D.R.; et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: A prospective phase III randomized study of the Southwest Oncology Group. J. Clin. Oncol. 1995, 13, 1632–1641. [Google Scholar] [CrossRef]
  38. Chen, G.Y.; Jiang, G.L.; Wang, L.J.; Qian, H.; Fu, X.L.; Yang, H.; Wu, K.L.; Zhao, S. Cisplatin/etoposide chemotherapy combined with twice daily thoracic radiotherapy for limited small-cell lung cancer: A clinical phase II trial. Int. J. Radiat. Oncol. Biol. Phys. 2005, 61, 70–75. [Google Scholar] [CrossRef]
  39. Elias, A.; Ibrahim, J.; Skarin, A.T.; Wheeler, C.; McCauley, M.; Ayash, L.; Richardson, P.; Schnipper, L.; Antman, K.H.; Frei, E., 3rd. Dose-intensive therapy for limited-stage small-cell lung cancer: Long-term outcome. J. Clin. Oncol. 1999, 17, 1175. [Google Scholar] [CrossRef]
  40. Ettinger, D.S.; Berkey, B.A.; Abrams, R.A.; Fontanesi, J.; Machtay, M.; Duncan, P.J.; Curran, W.J., Jr.; Movsas, B.; Byhardt, R.W. Study of paclitaxel, etoposide, and cisplatin chemotherapy combined with twice-daily thoracic radiotherapy for patients with limited-stage small-cell lung cancer: A Radiation Therapy Oncology Group 9609 phase II study. J. Clin. Oncol. 2005, 23, 4991–4998. [Google Scholar] [CrossRef]
  41. Gregor, A.; Drings, P.; Burghouts, J.; Postmus, P.E.; Morgan, D.; Sahmoud, T.; Kirkpatrick, A.; Dalesio, O.; Giaccone, G. Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: A European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J. Clin. Oncol. 1997, 15, 2840–2849. [Google Scholar] [CrossRef] [PubMed]
  42. Grønberg, B.H.; Killingberg, K.T.; Fløtten, Ø.; Brustugun, O.T.; Hornslien, K.; Madebo, T.; Langer, S.W.; Schytte, T.; Nyman, J.; Risum, S.; et al. High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: An open-label, randomised, phase 2 trial. Lancet Oncol. 2021, 22, 321–331. [Google Scholar] [CrossRef] [PubMed]
  43. Han, J.Y.; Cho, K.H.; Lee, D.H.; Kim, H.Y.; Kim, E.A.; Lee, S.Y.; Lee, J.S. Phase II study of irinotecan plus cisplatin induction followed by concurrent twice-daily thoracic irradiation with etoposide plus cisplatin chemotherapy for limited-disease small-cell lung cancer. J. Clin. Oncol. 2005, 23, 3488–3494. [Google Scholar] [CrossRef]
  44. Han, J.Y.; Lee, D.H.; Song, J.E.; Lee, S.Y.; Kim, H.Y.; Kim, H.T.; Lee, J.S. Randomized phase 2 study of irinotecan plus cisplatin versus gemcitabine plus vinorelbine as first-line chemotherapy with second-line crossover in patients with advanced nonsmall cell lung cancer. Cancer 2008, 113, 388–395. [Google Scholar] [CrossRef] [PubMed]
  45. Hanna, N.; Ansari, R.; Fisher, W.; Shen, J.; Jung, S.H.; Sandler, A. Etoposide, ifosfamide and cisplatin (VIP) plus concurrent radiation therapy for previously untreated limited small cell lung cancer (SCLC): A Hoosier Oncology Group (HOG) phase II study. Lung Cancer 2002, 35, 293–297. [Google Scholar] [CrossRef]
  46. Hu, X.; Bao, Y.; Xu, Y.J.; Zhu, H.N.; Liu, J.S.; Zhang, L.; Guo, Y.; Jin, Y.; Wang, J.; Ma, H.L.; et al. Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses. Cancer 2020, 126, 840–849. [Google Scholar] [CrossRef] [PubMed]
  47. Hügli, A.; Moro, D.; Mermillod, B.; Bolla, M.; Alberto, P.; Bonnefoi, H.; Miralbell, R. Phase II trial of up-front accelerated thoracic radiotherapy combined with chemotherapy and optional up-front prophylactic cranial irradiation in limited small-cell lung cancer. Groupe d’Oncologie Thoracique des Régions Alpines. J. Clin. Oncol. 2000, 18, 1662–1667. [Google Scholar] [CrossRef] [PubMed]
  48. Jeremic, B.; Shibamoto, Y.; Acimovic, L.; Milisavljevic, S. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: A randomized study. J. Clin. Oncol. 1997, 15, 893–900. [Google Scholar] [CrossRef]
  49. Jett, J.R.; Everson, L.; Therneau, T.M.; Krook, J.E.; Dalton, R.J.; Marschke, R.F., Jr.; Veeder, M.H.; Brunk, S.F.; Mailliard, J.A.; Twito, D.I.; et al. Treatment of limited-stage small-cell lung cancer with cyclophosphamide, doxorubicin, and vincristine with or without etoposide: A randomized trial of the North Central Cancer Treatment Group. J. Clin. Oncol. 1990, 8, 33–38. [Google Scholar] [CrossRef]
  50. Johnson, B.E.; Bridges, J.D.; Sobczeck, M.; Gray, J.; Linnoila, R.I.; Gazdar, A.F.; Hankins, L.; Steinberg, S.M.; Edison, M.; Frame, J.N.; et al. Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J. Clin. Oncol. 1996, 14, 806–813. [Google Scholar] [CrossRef]
  51. Kakolyris, S.; Agelidou, A.; Androulakis, N.; Tsaroucha, E.; Kouroussis, C.; Agelidou, M.; Karvounis, N.; Veslemes, M.; Christophylakis, C.; Argyraki, A.; et al. Cisplatin plus etoposide chemotherapy followed by thoracic irradiation and paclitaxel plus cisplatin consolidation therapy for patients with limited stage small cell lung carcinoma. Lung Cancer 2006, 53, 59–65. [Google Scholar] [CrossRef] [PubMed]
  52. Kelley, M.J.; Bogart, J.A.; Hodgson, L.D.; Ansari, R.H.; Atkins, J.N.; Pang, H.; Green, M.R.; Vokes, E.E. Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206. J. Thorac. Oncol. 2013, 8, 102–108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Kubota, K.; Hida, T.; Ishikura, S.; Mizusawa, J.; Nishio, M.; Kawahara, M.; Yokoyama, A.; Imamura, F.; Takeda, K.; Negoro, S.; et al. Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): A randomised phase 3 study. Lancet Oncol. 2014, 15, 106–113. [Google Scholar] [CrossRef] [PubMed]
  54. Le, Q.T.; Moon, J.; Redman, M.; Williamson, S.K.; Lara, P.N., Jr.; Goldberg, Z.; Gaspar, L.E.; Crowley, J.J.; Moore, D.F., Jr.; Gandara, D.R. Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limited-stage small-cell lung cancer: SWOG 0222. J. Clin. Oncol. 2009, 27, 3014–3019. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Maurer, L.H.; Herndon, J.E., 2nd; Hollis, D.R.; Aisner, J.; Carey, R.W.; Skarin, A.T.; Perry, M.C.; Eaton, W.L.; Zacharski, L.L.; Hammond, S.; et al. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: A Cancer and Leukemia Group B study. J. Clin. Oncol. 1997, 15, 3378–3387. [Google Scholar] [CrossRef] [PubMed]
  56. McClay, E.F.; Bogart, J.; Herndon, J.E., 2nd; Watson, D.; Evans, L.; Seagren, S.L.; Green, M.R. A phase III trial evaluating the combination of cisplatin, etoposide, and radiation therapy with or without tamoxifen in patients with limited-stage small cell lung cancer: Cancer and Leukemia Group B Study (9235). Am. J. Clin. Oncol. 2005, 28, 81–90. [Google Scholar] [CrossRef]
  57. Mennecier, B.; Jacoulet, P.; Dubiez, A.; Westeel, V.; Bosset, J.F.; Magnin, V.; Depierre, A. Concurrent cisplatin/etoposide chemotherapy plus twice daily thoracic radiotherapy in limited stage small cell lung cancer: A phase II study. Lung Cancer 2000, 27, 137–143. [Google Scholar] [CrossRef]
  58. Miller, A.A.; Wang, X.F.; Bogart, J.A.; Hodgson, L.D.; Rocha Lima, C.M.; Radford, J.E.; Vokes, E.E.; Green, M.R. Phase II trial of paclitaxel-topotecan-etoposide followed by consolidation chemoradiotherapy for limited-stage small cell lung cancer: CALGB 30002. J. Thorac. Oncol. 2007, 2, 645–651. [Google Scholar] [CrossRef] [Green Version]
  59. Murray, N.; Coy, P.; Pater, J.L.; Hodson, I.; Arnold, A.; Zee, B.C.; Payne, D.; Kostashuk, E.C.; Evans, W.K.; Dixon, P.; et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 1993, 11, 336–344. [Google Scholar] [CrossRef]
  60. Saito, H.; Takada, Y.; Ichinose, Y.; Eguchi, K.; Kudoh, S.; Matsui, K.; Nakagawa, K.; Takada, M.; Negoro, S.; Tamura, K.; et al. Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group 9902. J. Clin. Oncol. 2006, 24, 5247–5252. [Google Scholar] [CrossRef]
  61. Schild, S.E.; Bonner, J.A.; Hillman, S.; Kozelsky, T.F.; Vigliotti, A.P.; Marks, R.S.; Graham, D.L.; Soori, G.S.; Kugler, J.W.; Tenglin, R.C.; et al. Results of a phase II study of high-dose thoracic radiation therapy with concurrent cisplatin and etoposide in limited-stage small-cell lung cancer (NCCTG 95-20-53). J. Clin. Oncol. 2007, 25, 3124–3129. [Google Scholar] [CrossRef] [PubMed]
  62. Sculier, J.P.; Lafitte, J.J.; Efremidis, A.; Florin, M.C.; Lecomte, J.; Berchier, M.C.; Richez, M.; Berghmans, T.; Scherpereel, A.; Meert, A.P.; et al. A phase III randomised study of concomitant induction radiochemotherapy testing two modalities of radiosensitisation by cisplatin (standard versus daily) for limited small-cell lung cancer. Ann. Oncol. 2008, 19, 1691–1697. [Google Scholar] [CrossRef] [PubMed]
  63. Skarlos, D.V.; Samantas, E.; Briassoulis, E.; Panoussaki, E.; Pavlidis, N.; Kalofonos, H.P.; Kardamakis, D.; Tsiakopoulos, E.; Kosmidis, P.; Tsavdaridis, D.; et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: A randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann. Oncol. 2001, 12, 1231–1238. [Google Scholar] [CrossRef]
  64. Sohn, J.H.; Moon, Y.W.; Lee, C.G.; Kim, G.E.; Chung, K.Y.; Chang, J.; Kim, S.K.; Kim, Y.S.; Choi, B.W.; Choi, H.J.; et al. Phase II trial of irinotecan and cisplatin with early concurrent radiotherapy in limited-disease small-cell lung cancer. Cancer 2007, 109, 1845–1950. [Google Scholar] [CrossRef]
  65. Sorensen, M.; Lassen, U.; Palshof, T.; Jensen, B.B.; Johansen, J.; Jensen, P.B.; Langer, S.W. Topotecan and cisplatin in combination with concurrent twice-daily chemoradiation in limited disease small cell lung cancer-a Danish Oncological Lung Cancer Group (DOLG) phase II trial. Lung Cancer 2008, 60, 252–258. [Google Scholar] [CrossRef]
  66. Sun, J.M.; Ahn, Y.C.; Choi, E.K.; Ahn, M.J.; Ahn, J.S.; Lee, S.H.; Lee, D.H.; Pyo, H.; Song, S.Y.; Jung, S.H.; et al. Phase III trial of concurrent thoracic radiotherapy with either first- or third-cycle chemotherapy for limited-disease small-cell lung cancer. Ann. Oncol. 2013, 24, 2088–2092. [Google Scholar] [CrossRef] [PubMed]
  67. Takada, M.; Fukuoka, M.; Kawahara, M.; Sugiura, T.; Yokoyama, A.; Yokota, S.; Nishiwaki, Y.; Watanabe, K.; Noda, K.; Tamura, T.; et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: Results of the Japan Clinical Oncology Group Study 9104. J. Clin. Oncol. 2002, 20, 3054–3060. [Google Scholar] [CrossRef]
  68. van Loon, J.; De Ruysscher, D.; Wanders, R.; Boersma, L.; Simons, J.; Oellers, M.; Dingemans, A.M.; Hochstenbag, M.; Bootsma, G.; Geraedts, W.; et al. Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: A prospective study. Int. J. Radiat. Oncol. Biol. Phys. 2010, 77, 329–336. [Google Scholar] [CrossRef]
  69. Wahba, H.A.; Halim, A.A.; El-Hadaad, H.A. Irinotecan plus cisplatin chemotherapy followed by concurrent thoracic irradiation with low-dose weekly cisplatin for limited-disease small-cell lung cancer. Med. Oncol. 2012, 29, 199–204. [Google Scholar] [CrossRef]
  70. Xenidis, N.; Kotsakis, A.; Kalykaki, A.; Christophyllakis, C.; Giassas, S.; Kentepozidis, N.; Polyzos, A.; Chelis, L.; Vardakis, N.; Vamvakas, L.; et al. Etoposide plus cisplatin followed by concurrent chemo-radiotherapy and irinotecan plus cisplatin for patients with limited-stage small cell lung cancer: A multicenter phase II study. Lung Cancer 2010, 68, 450–454. [Google Scholar] [CrossRef]
  71. Xia, B.; Hong, L.Z.; Cai, X.W.; Zhu, Z.F.; Liu, Q.; Zhao, K.L.; Fan, M.; Mao, J.F.; Yang, H.J.; Wu, K.L.; et al. Phase 2 study of accelerated hypofractionated thoracic radiation therapy and concurrent chemotherapy in patients with limited-stage small-cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 2015, 91, 517–523. [Google Scholar] [CrossRef]
  72. Fried, D.B.; Morris, D.E.; Poole, C.; Rosenman, J.G.; Halle, J.S.; Detterbeck, F.C.; Hensing, T.A.; Socinski, M.A. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J. Clin. Oncol. 2004, 22, 4837–4845. [Google Scholar] [CrossRef] [PubMed]
  73. Bourhis, J.; Overgaard, J.; Audry, H.; Ang, K.K.; Saunders, M.; Bernier, J.; Horiot, J.C.; Le Maître, A.; Pajak, T.F.; Poulsen, M.G.; et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: A meta-analysis. Lancet 2006, 368, 843–854. [Google Scholar] [CrossRef] [PubMed]
  74. Petit, C.; Lacas, B.; Pignon, J.P.; Le, Q.T.; Grégoire, V.; Grau, C.; Hackshaw, A.; Zackrisson, B.; Parmar, M.K.B.; Lee, J.W.; et al. Chemotherapy and radiotherapy in locally advanced head and neck cancer: An individual patient data network meta-analysis. Lancet Oncol. 2021, 22, 727–736. [Google Scholar] [CrossRef] [PubMed]
Cancers 15 00277 g001 550
Figure 1. Study selection. Abbreviations: RCT, randomized controlled trials; OS, overall survival; NCDB, National Cancer Database; IPD, individual patient data.
Figure 1. Study selection. Abbreviations: RCT, randomized controlled trials; OS, overall survival; NCDB, National Cancer Database; IPD, individual patient data.
Cancers 15 00277 g001
Cancers 15 00277 g002 550
Figure 2. Individual patient data frailty model survival curves of the different fractionated radiotherapy, along with those from each study. (A), Overall survival for all enrolled studies; (B), Overall survival for the subgroup of 3D-CRT/IMRT. Abbreviations: 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; HypoTRT, hypofractionated thoracic radiotherapy; ConvTRT, conventional fractionated thoracic radiotherapy; HyperTRT, hyperfractionated thoracic radiotherapy.
Figure 2. Individual patient data frailty model survival curves of the different fractionated radiotherapy, along with those from each study. (A), Overall survival for all enrolled studies; (B), Overall survival for the subgroup of 3D-CRT/IMRT. Abbreviations: 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; HypoTRT, hypofractionated thoracic radiotherapy; ConvTRT, conventional fractionated thoracic radiotherapy; HyperTRT, hyperfractionated thoracic radiotherapy.
Cancers 15 00277 g002
Cancers 15 00277 g003 550
Figure 3. Forest plots showing the hazard ratio estimates based on the shared-frailty model. (A), Forest plot for all enrolled studies; (B), Forest plot for subgroup of 3D-CRT/IMRT. Abbreviations: HR, hazard ratio; CI, confidence interval; HypoTRT, hypofractionated thoracic radiotherapy; ConvTRT, conventional fractionated thoracic radiotherapy; HyperTRT, hyperfractionated thoracic radiotherapy; RCTs, randomized controlled studies; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy. a,b Adjusted for concurrent chemoradiotherapy, thoracic radiotherapy timing, and corrected biologically effective dose (all characteristics were regarded as binary variables).
Figure 3. Forest plots showing the hazard ratio estimates based on the shared-frailty model. (A), Forest plot for all enrolled studies; (B), Forest plot for subgroup of 3D-CRT/IMRT. Abbreviations: HR, hazard ratio; CI, confidence interval; HypoTRT, hypofractionated thoracic radiotherapy; ConvTRT, conventional fractionated thoracic radiotherapy; HyperTRT, hyperfractionated thoracic radiotherapy; RCTs, randomized controlled studies; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy. a,b Adjusted for concurrent chemoradiotherapy, thoracic radiotherapy timing, and corrected biologically effective dose (all characteristics were regarded as binary variables).
Cancers 15 00277 g003
Cancers 15 00277 g004 550
Figure 4. Forest plots for the hazard ratio and ranking plots with the surface under the cumulative ranking curve (SUCRA) in the network meta-analysis. (A), Forest plot for RCTs; (B), Forest plot for subgroup of 3D/CRT-IMRT; (C), SUCRA for RCTs; (D), SUCRA for subgroup of 3D-CRT/IMRT. Abbreviations: RCT, randomized controlled studies; HR, hazard ratio; CrI, credible interval; HypoTRT, hypofractionated thoracic radiotherapy; ConvTRT, conventional fractionated thoracic radiotherapy; HyperTRT, hyperfractionated thoracic radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; SURA, surface under the cumulative ranking curve.
Figure 4. Forest plots for the hazard ratio and ranking plots with the surface under the cumulative ranking curve (SUCRA) in the network meta-analysis. (A), Forest plot for RCTs; (B), Forest plot for subgroup of 3D/CRT-IMRT; (C), SUCRA for RCTs; (D), SUCRA for subgroup of 3D-CRT/IMRT. Abbreviations: RCT, randomized controlled studies; HR, hazard ratio; CrI, credible interval; HypoTRT, hypofractionated thoracic radiotherapy; ConvTRT, conventional fractionated thoracic radiotherapy; HyperTRT, hyperfractionated thoracic radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; SURA, surface under the cumulative ranking curve.
Cancers 15 00277 g004
Table
Table 1. Characteristics of the studies and participants.
Table 1. Characteristics of the studies and participants.
HypoTRTConvTRTHyperTRTTotal
Study TypesRCTsObsP non-RCTRCTsObsP non-RCTRCTsObsP non-RCTRCTsObsP non-RCTAll Types
Studies35557156617793753
Participants22632611379895081621109435117542309118545128006
Sex, No. (%)
 Male159 (70)193 (59)767 (67)531 (54)357 (70)1044 (64)615 (56)216 (62)1296 (74)1305 (57)766 (65)3107 (69)5178 (65)
 Female67 (30)133 (41)370 (33)458 (46)151 (30)577 (36)479 (44)135 (38)458 (26)1004 (43)419 (35)1405 (31)2828 (35)
Median age, years58–6359–6958–626355–7149–6658–6454–6654–6658–6454–7149–6649–71
TRT technique, No. (%)
 2DRT54 (24)0874 (77)394 (40)172 (34)651 (40)341 (31)37 (11)493 (28)789 (34)209 (18)2018 (45)3016 (38)
 3D-CRT/IMRT172 (76)326 (100)59 (5)595 (60)336 (66)324 (20)753 (69)314 (89)614 (35)1520 (66)976 (82)997 (22)3493 (44)
 Unreported00204 (18)00646 (40)00647 (37)001497 (33)1497 (19)
Corrected BED10, No. (%)
 High-dose group226 (100)270 (83)736 (65)651 (66)0201 (12)964 (88)351 (100)1754 (100)1841 (80)621 (52)2691 (60)5153 (64)
 Low-dose group056 (17)401 (35)338 (34)508 (100)1420 (88)130 (12)00468 (20)564 (48)1821 (40)2853 (36)
CCRT, No. (%)
 Yes226 (100)226 (69)972 (85)989 (100)325 (64)1546 (95)1094 (100)351 (100)1583 (90)2309 (100)902 (76)4101 (91)7312 (91)
 No/unreported0100 (31)165 (15)0183 (36)75 (5)00171 (10)0283 (24)411 (9)694 (9)
TRT timing, No. (%)
 Yes138 (61)111 (34)588 (52)857 (87)0550 (34)870 (80)26 (7)997 (57)1865 (81)137 (12)2135 (47)4137 (52)
 No/unreported88 (39)215 (66)549 (48)132 (13)508 (100)1071 (66)224 (20)325 (93)757 (43)444 (19)1048 (88)2377 (53)3869 (48)
PCI completion rates (%)5152–6764–10060–8521–6712–818154–6532–9051–8521–6712–10012–100
Median follow-up (months)14.7–5920.4–16219.5–6014.7–9622–6715–6924.3–9620.4–3416.3–75.614.7–9620.4–16215–75.614.7–162
Abbreviations: HypoTRT, hypofractionated thoracic; ConvTRT, conventional fractionated thoracic radiotherapy; HyperTRT, hyperfractionated thoracic radiotherapy; RCTs, randomized controlled trials; Obs, observational studies; P non-RCT, prospective non-RCT studies; TRT, thoracic radiotherapy; 2DRT, two-dimensional radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; BED10, biologically effective dose; CCRT, concurrent chemoradiotherapy; PCI, prophylactic cranial irradiation.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Zhao, J.; Wu, L.; Hu, C.; Bi, N.; Wang, L. Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data. Cancers 2023, 15, 277. https://doi.org/10.3390/cancers15010277

AMA Style

Zhao J, Wu L, Hu C, Bi N, Wang L. Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data. Cancers. 2023; 15(1):277. https://doi.org/10.3390/cancers15010277

Chicago/Turabian Style

Zhao, Jingjing, Linfang Wu, Chen Hu, Nan Bi, and Luhua Wang. 2023. "Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data" Cancers 15, no. 1: 277. https://doi.org/10.3390/cancers15010277

APA Style

Zhao, J., Wu, L., Hu, C., Bi, N., & Wang, L. (2023). Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data. Cancers, 15(1), 277. https://doi.org/10.3390/cancers15010277

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop