Effect of Thoracic Radiotherapy Timing and Fractionation on Survival in Nonmetastatic Small Cell Lung Carcinoma

Accepted Manuscript The impact of thoracic radiotherapy timing and fractionation on survival in nonmetastatic small cell lung carcinoma Andrew T. Wong, M.D., Justin Rineer, M.D., David Schwartz, M.D., Daniel Becker, M.D., Joseph Safdieh, M.D., Virginia Osborn, M.D., David Schreiber, M.D. PII:

S1525-7304(16)30189-9

DOI:

10.1016/j.cllc.2016.07.009

Reference:

CLLC 523

To appear in:

Clinical Lung Cancer

Received Date: 2 May 2016 Revised Date:

12 July 2016

Accepted Date: 29 July 2016

Please cite this article as: Wong AT, Rineer J, Schwartz D, Becker D, Safdieh J, Osborn V, Schreiber D, The impact of thoracic radiotherapy timing and fractionation on survival in non-metastatic small cell lung carcinoma, Clinical Lung Cancer (2016), doi: 10.1016/j.cllc.2016.07.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The impact of thoracic radiotherapy timing and fractionation on survival in non-metastatic small cell lung carcinoma

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Andrew T. Wong, M.D.1,2, Justin Rineer, M.D.3, David Schwartz, M.D.1,2, Daniel Becker, M.D.2,4, Joseph Safdieh, M.D.1,2, Virginia Osborn, M.D.1,2, David Schreiber, M.D.1,2

2 SUNY Downstate Medical Center, Brooklyn, NY

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3 UF Health Cancer Center – Orlando Health, Orlando, FL

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1 Department of Veterans Affairs, New York Harbor Healthcare, Brooklyn, NY

4 New York University Langone Medical Center, New York, NY

Corresponding Author: Andrew T. Wong, M.D., SUNY Downstate Medical Center, Department of Radiation Oncology, 450 Clarkson Ave, Box 1211, Brooklyn, NY 11203

Fax: (718) 270-1535

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Phone: (631) 833-9993

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Email Address: [email protected]

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Conflicts of Interest: none

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Funding support: none

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MicroAbstract: This study examined the National Cancer Data Base to assess practice patterns and survival for thoracic radiation therapy timing in relation to chemotherapy for non-metastatic small cell lung carcinoma. Early initiation of thoracic radiation therapy was associated with

was utilized. Clinical Practice Points: •

The standard of care for limited stage small cell lung carcinoma is combined modality

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therapy with chemotherapy and radiation therapy. •

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improved survival compared with late initiation, particularly when hyperfractionated radiation

The optimal timing of the initiation of radiation therapy in relation to chemotherapy is unclear. Multiple randomized trials addressing this issue have reached discrepant conclusions.

We analyzed the National Cancer Data Base to assess the impact on survival of radiation therapy timing.

•

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We discovered that early initiation of radiation therapy (within 0-20 days of initiation of

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chemotherapy) was associated with improved survival, particularly for patients treated with hyperfractionated radiation therapy. This is the largest study examining the survival impact of radiation therapy timing for

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•

nonmetastatic small cell lung cancer. The results of this study strengthen the argument for early initiation of radiation therapy.

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Abstract: Background:

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The optimal timing of thoracic radiation therapy (RT) in relation to chemotherapy is unknown in the treatment of non-metastatic small cell lung cancer (SCLC). We analyzed the National Cancer Data Base (NCDB) to assess the impact on overall survival (OS) of RT timing

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with chemotherapy for patients with SCLC.

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Materials and Methods:

The NCDB was queried for patients diagnosed with non-metastatic SCLC between 19982011 who underwent definitive chemoradiation. Patients were stratified into quartiles based on the interval between the start of chemotherapy and RT. The 1st and 2nd quartiles (RT started 0-20 days after chemotherapy) were classified as “early” RT and the 3rd and 4th quartiles (between 21-

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126 days) as “late” RT. Patients were included if they received hyperfractionated 45Gy in 30 fractions (HFX) or standard fractionation of ≥60Gy in 1.8-2Gy fractions (SFX). Kaplan-Meier analyses of OS were performed and multivariable cox regression analysis (MVA) was conducted

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Results:

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to assess the impact of covariates on OS.

A total of 8,391 patients were included (50.5% received early RT). Early RT was

associated with a significant improvement in survival (5-year OS 21.9% vs. 19.1%, p=0.01). On subgroup analysis, this survival advantage for early RT was significant for patients receiving HFX (28.2% vs. 21.2%, p=0.004) but not for those receiving SFX (19.8% vs. 18.4%, p=0.29).

Abbreviations: RT=radiation therapy; TRT=thoracic radiation therapy; SCLC=small cell lung carcinoma; HFX=hyperfractionated radiation therapy; SFX=standard fractionation radiation therapy; OS=overall survival; MVA=multivariable analysis

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On MVA, HFX was associated with reduced mortality (HR 0.90, 95%CI 0.85-0.96, p=0.001) whereas early RT was not (HR 0.98, 95%CI 0.94-1.04, p=0.53).

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Conclusion: These data support the early initiation of hyperfractionated thoracic radiation.

Keywords: small cell lung cancer; radiation therapy; combined modality therapy; limited stage;

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timing

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Introduction: Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer representing

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approximately 15% of the 220,000 cases of lung cancer reported annually (1). Roughly 30% of patients will present with non-metastatic disease. For patients with disease in excess of clinical stage T1-2N0, national guidelines (2) currently recommend concurrent chemotherapy with

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thoracic radiation therapy (TRT).

The addition of TRT to chemotherapy has been demonstrated to improve survival (3), but

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the optimal timing of TRT in relation to chemotherapy has been the subject of numerous studies. Multiple randomized trials have addressed this issue, but they have varied in their design, chemotherapy regimens, and RT fractionation. Consequently, these trials have reached differing conclusions, with some favoring early TRT and others finding no difference in outcomes.

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Several meta-analyses have also been performed but have failed to definitively answer this question as they have also reported discordant results. Fried et al. included 7 studies and over 1500 patients (4) and reported a 17% relative increase in overall survival at 2 years with early

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TRT (defined as beginning before 9 weeks after chemotherapy initiation) compared to late RT (defined as beginning 9 weeks or later after chemotherapy initiation). Pijls-Johannesma et al. (5)

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also included 7 studies in their meta-analysis. Utilizing a different definition of early TRT (within 30 days of chemotherapy initiation), they reported improved 2-year and 5-year overall survival with early TRT when only trials using platinum-based chemotherapy were included. In this study, we utilized the National Cancer Data Base (NCDB) in order to analyze a large cohort of patients receiving chemoradiation. We sought to determine if early or late

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initiation of thoracic radiation had any impact on survival and whether differences in radiation fractionation played a role in this relationship.

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Materials and Methods: The NCDB is a joint project of the American Cancer Society and the Commission on Cancer of the American College of Surgeons. It is estimated that 70% of all diagnosed

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malignancies in the United States are captured by facilities participating in this registry and

reported to the NCDB. The Commission on Cancer’s NCDB and the hospitals participating in

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the NCDB are the source of the de-identified data used in this study. However, they have not verified and are not responsible for the statistical validity or conclusions derived by the authors of this study.

Adult patients with non-metastatic small cell lung cancer who were treated with

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definitive chemoradiation between 1998-2011 were included. Patients had to have complete information regarding the total radiation dose as well as the number of radiation fractions. The NCDB does not specifically report whether radiation treatments were delivered once or twice-

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daily. However, we classified those who received 45Gy in 30 fractions as having undergone accelerated hyperfractionation rather than 1.5Gy per day. Patients who received ≥60Gy in 1.8 or

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2.0Gy fractions were classified as receiving standard once-daily treatments. We excluded patients who were identified as American Joint Committee on Cancer M1 disease, or patients who were identified as having received their radiation treatments to a site other than the lung. We also excluded those who had unknown Charlson/Deyo scores as well as those who were noted to have a tumor size >10cm, in order to avoid skewing of results in favor of those with better prognostic features who may have been more likely to receive earlier thoracic radiation, as

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it was noted that both of these groups of patients were much more likely to receive late thoracic radiation than early. In an effort to reduce the impact of unmeasured bias, these patients were

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excluded from this study. The NCDB does not include specific details regarding chemotherapy agents used nor the number of cycles delivered. However, it does identify whether or not chemotherapy was used

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and when it was started in relation to the diagnosis. It also identifies when external beam

radiation was started in relation to the initial diagnosis. Therefore, we were able to derive the

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sequence of chemotherapy and radiation usage relative to each other. We included patients who were identified as having started their chemotherapy between 0 and 126 days prior to starting radiation therapy. Per National Comprehensive Cancer Network guidelines, chemotherapy recommended for limited stage small cell lung cancer is cisplatin/carboplatin and etoposide delivered for 4 to 6 cycles every 21 days. Our selection of 0 to 126 days was meant to identify

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those whose radiation treatments started within the first 6 cycles of chemotherapy delivery. Those undergoing radiation therapy more than 126 days after initiating chemotherapy are presumed to have received sequential chemotherapy and radiation therapy. Patients were then

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divided into quartiles in order to analyze outcomes of those receiving “early” (first or second

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quartile) or “late” (third or fourth quartile) thoracic radiation. The quartiles consisted of the following: quartile 1= radiation started 0-1 days after chemotherapy, quartile 2= radiation started 2-20 days after chemotherapy, quartile 3= radiation started 21-41 days after chemotherapy, quartile 4= radiation started 42-126 days after chemotherapy. Of note, while chemotherapy cycles are typically described as starting on day 1 of a cycle, the first day of chemotherapy and radiation was described as day 0 in the current study. Therefore, treatment started on day 20 in the current study represents day 21 in the typical description of chemotherapy cycles.

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There were 10,431 patients who were identified as having undergone definitive radiation therapy for small cell lung cancer with doses of 4500cGy BID or doses between 6000-7200cGy via standard fractionation and had data regarding chemotherapy and radiation therapy timing. An

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additional 1,461 patients were excluded because they started their chemotherapy longer than 126 days before their radiation treatments or started their chemotherapy after their radiation

treatments, 253 were excluded for having tumor sizes larger than 10cm in size and 326 were

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excluded for having an unknown Charlson/Deyo score. Therefore, the final cohort consisted of

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8,391 patients.

Demographic details were compared between patients who received early or late thoracic radiation via Chi Square and Fisher’s Exact test where appropriate. Kaplan Meier analyses of overall survival (OS) were performed comparing patients who received early or late thoracic radiation and compared via the log-rank test. Multivariate Cox Regression was performed to

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assess for the impact of covariables on overall survival. The covariables measured included age (), Charlson/Deyo score (0,1,≥2, unknown), race (White, Black, Other), T-stage (Tx, T1, T2, T3,T4), N-stage (Nx, N0-1, N2, N3), radiation fractionation (twice daily or once daily radiation

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therapy), and radiation timing (early or late). Significant values were defined as those with a p-

NY).

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value <0.05. Statistical analysis was performed using SPSS, Version 23 (IBM Inc, Armonk,

Results:

Patient Characteristics There were a total of 8,391 patients included in this study, of which 4,240 (50.5%) received early thoracic radiation and 4,151 (49.5%) received late radiation. Those receiving

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hyperfractionated radiation were more likely to receive early thoracic radiation, with 1,039 (54.4%) receiving their radiation within the first two quartiles compared to 3,201 (49.4%) in the once daily group (p<0.001). Those with smaller tumors, lower nodal stage and lower T-stage

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were also more likely to receive early thoracic radiation. Further details regarding patient characteristics as it pertains to early or late thoracic radiation can be found in Table 1.

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Overall Survival:

There was a small improvement in overall survival associated with early thoracic

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radiation. The median overall survival was 21.0 months and the 5 year overall survival was 21.9% in those receiving early thoracic radiation compared to a median of 20.0 months and 3 year overall survival of 19.1% in the late thoracic radiation group (p=0.01) (Figure 1). On subgroup analysis, those who received twice daily radiation were noted to have a significant

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improvement in overall survival with early thoracic radiation. The median overall survival was 24.2 months and the 5 year overall survival was 28.2% in those receiving early thoracic radiation compared to a median of 20.5 months and a 5 year overall survival of 21.2% in those receiving

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late thoracic radiation (p=0.004) (Figure 2).

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However, when the subgroups were limited to those receiving standard fractionation radiation treatments, there were no longer any differences associated with early thoracic radiation. The median overall survival was 20.2 months and the 5 year overall survival was 19.8% in those receiving early thoracic radiation compared to a median of 19.8 months and a 5 year overall survival of 18.4% in those receiving late thoracic radiation (p=0.29) (Figure 3). Univariate and Multivariate Analysis:

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On multivariate analysis, treatment with BID radiation was associated with reduced mortality (HR 0.90, 95% CI 0.85-0.96, p=0.001). Although treatment with early thoracic radiation was associated with an improvement in overall survival on univariate analysis (HR

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0.94, 95% CI 0.89-0.99, p=0.01), there was no longer any benefit noted on multivariate analysis (HR 0.98, 95% CI 0.94-1.04, p=0.53). Increasing age was noted to be associated with worse survival. Black race was associated with improved survival on multivariate analysis, as well

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earlier T and N stage. Further details are available in Table 2.

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Discussion:

In this retrospective analysis of a large, hospital-based dataset, we detected a small but statistically significant improvement in overall survival with early TRT compared to late TRT. Early TRT was associated with a 1 month improvement in median survival and an absolute

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improvement of 2.8% in 5-year OS compared to late TRT. Upon further subgroup analysis, this survival advantage was limited to patients receiving hyperfractionated TRT. Patients that received standard once daily fractionation derived no benefit from early compared to late TRT.

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Multiple randomized trials have been conducted to address the issue of TRT timing with chemotherapy, but these have differed in their design and subsequently their findings. The Japan

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Clinical Oncology Group (JCOG) randomized 231 patients with limited-stage SCLC to either concurrent (TRT starting with 1st cycle of chemotherapy) or sequential (TRT starting after 4th cycle of chemotherapy) chemoradiation (6). These patients received 4 cycles of cisplatin and etoposide administered every 4 weeks (concurrent) or every 3 weeks (sequential). The TRT dose was 45 Gy in 30 fractions delivered twice daily. Overall survival was non-significantly favored the concurrent arm (median survival 27 months vs. 20 months, p=0.097). The National Cancer

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Institute of Canada (NCIC) randomized 308 patients with limited-stage SCLC to either early TRT (week 3) or late TRT (week 15) (7). Patients were treated with cyclophosphamide, doxorubicin, and vincristine chemotherapy alternating with etoposide and cisplatin, administered

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for 3 cycles each every 3 weeks. The TRT dose was 40 Gy in 15 once daily fractions. The

authors reported significant improvements in 3-year progression-free survival (26% vs. 19%, p=0.036), 3-year overall survival (29.7% vs. 21.5%, p=0.006), and median survival (21 months

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vs. 16 months, p=0.008) in favor of early TRT. The London Lung Cancer Group replicated the NCIC trial but failed to detect any significant advantages in survival for early TRT (median

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survival 13.7 months with early TRT vs. 15.1 months with late TRT, p=0.23) (8). Multiple meta-analyses have also been performed to attempt to reconcile the contradictory findings of these randomized trials. Huncharek et al. included 8 randomized trials in their analysis and reported a 60% relative benefit in 2-year overall survival for early TRT (OR

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1.60, 95%CI 1.29-1.99) which increased to an 81% relative benefit (OR 1.81, 95%CI 1.38-2.37) when including only the trials utilizing cisplatin/etoposide-based chemotherapy (9). An analysis by Fried et al. included 7 randomized trials and reported a more modest 17% relative

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improvement in 2-year overall survival for early TRT (RR 1.17, 95%CI 1.02-1.35, p=0.03) (4).

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Contrastingly, the meta-analysis by Pijls-Johannesma et al.(5) included 7 randomized trials but failed to demonstrate any significant differences in 2-year overall survival between early and late TRT (HR 0.86, 95%CI0.68-1.08, p=0.18). However, when the one trial employing nonplatinum-based chemotherapy was excluded, there was a significant survival advantage in favor of early TRT (HR 0.73, 95%CI 0.57-0.94, p=0.01). Considered together with our findings, the preponderance of evidence supports early TRT over late TRT.

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Interestingly, we found that the survival advantage in favor of early TRT was limited to those patients receiving hyperfractionated TRT. The efficacy of hyperfractionated BID TRT for SCLC has been previously demonstrated in the landmark Intergroup trial by Turrisi et al (10). In

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the meta-analysis by Fried et al. (4), it was reported that the benefit for early TRT was most pronounced in those patients receiving hyperfractionated TRT (RR 1.44, 95%CI 1.17-1.83,

p=0.001). Other studies have suggested that overall treatment time is an important predictor for

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survival. A meta-analysis by DeRuysscher et al. (11) found that 5-year overall survival was significantly improved when the time between the first day of chemotherapy and the completion

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of TRT was less than 30 days (RR 0.62, 95%CI 0.49-0.80, p=0.0003). Treatment-related accelerated tumor repopulation has long been recognized as a factor in treatment failure for various malignancies (12-14). These data therefore suggest that reducing the impact of accelerated repopulation may contribute to the survival advantage we observed with early,

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hyperfractionated TRT.

Our results are suggestive that the TRT fractionation schedule may be of greater importance than the timing of TRT. On multivariate analysis, hyperfractionation remained a

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significant predictor of overall survival whereas TRT timing did not.

Although the

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aforementioned trial by Turrisi et al. has established twice daily TRT as an accepted standard of care, adoption of hyperfractionated TRT remains low (15). One of the criticisms levied against the trial by Turrisi et al. is the low biological effective dose of the once daily TRT arm. Preliminary results of the Concurrent Once Daily Versus Twice-Daily Radiotherapy (CONVERT) trial were recently reported (16). In this phase III trial of 547 patients with limited stage SCLC, no significant differences in overall survival were detected between patients who received twice daily TRT (to a total dose of 45 Gy in 30 fractions) or those who received once

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daily TRT (to a total dose of 66 Gy in 33 fractions). Another similarly designed trial conducted by the Radiation Therapy Oncology Group (RTOG) is ongoing. The mature results of these two

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trials should help to clarify the optimal TRT fractionation. Our multivariate analysis confirms previous reports of the significance of age (17) and nodal status (18) as predictors of overall survival. Interestingly, we found that Black race was

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associated with improved survival compared to White race. This finding contradicts previous reports of worse or similar outcomes among Black cancer patients compared to their White

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counterparts (19, 20). It is unclear from our analysis whether this finding is the consequence of inherent differences in disease biology or imbalances with regards to stage at presentation or socioeconomic factors. Either way, this apparent racial disparity warrants further study. We acknowledge that there are several important limitations to our analysis. Firstly, the NCDB does not encode data on cause of death or treatment failure patterns. Given the aggressiveness of

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SCLC, the majority of patients likely died as a result of their disease but we cannot rule out competing causes of death. Secondly, we are unable to account for unmeasured confounding factors that may have contributed to the selection of the timing or the fractionation schedule of

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TRT. For example, those receiving BID radiation may have had better prognostic features or

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have been more physically able to withstand the more intense treatment, in ways we are unable to measure within the database. Thirdly, detailed data regarding chemotherapy including the agents, dosing, or the number of cycles administered are not encoded in the NCDB. The most commonly utilized agents are cisplatin and etoposide, but other regimens have been previously utilized. Fourth, we are unable to differentiate whether patients received sequential chemotherapy followed by radiation or chemoradiation alone, which may skew our findings in favor of the early thoracic group. Lastly, we are unable to analyze differences in toxicity in

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relation to TRT timing. Treatment-induced toxicity following the first cycle of chemotherapy may potentially have delayed the initiation of TRT in some patients, or delayed some patients beyond our definition of 6 cycles (126 days, leading to their exclusion from this study. A

and severe esophagitis with early TRT compared to late TRT (21).

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Conclusion:

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previous meta-analysis also noted increased rates of acute toxicity including severe pneumonitis

We conclude that early TRT, particularly when given via hyperfractionation, is

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associated with improved survival compared to late TRT for patients with non-metastatic SCLC. These findings add to the growing body of literature supporting early, hyperfractionated TRT.

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Acknowledgements: none

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References: 1) National Cancer Institute website. Available at

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http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessional/page1. Accessed 2/5/16.

2) National Comprehensive Cancer Network Guidelines for Small Cell Lung Cancer. Available

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at http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed 2/5/16.

3) Pignon JP, Arriagada R, Ihde DC et al. A meta-analysis of thoracic radiotherapy for small-cell

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lung cancer. N Engl J Med 1992;327:1618-1624.

4) Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin

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Oncol 2004;22:4837-45.

5) Pijls-Johannesma M, De Ruysscher D, Vansteenkiste J, Kester A, Rutten I, Lambin P. Cancer Treat Rev 2007;33:461-73.

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6) Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell

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lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002;20:3054-60.

7) Murray N, Coy P, Pater JL, 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;11:336-44.

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8) Spiro SG, James LE, Rudd RM, et al. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group

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multicenter randomized clinical trial and meta-analysis. J Clin Oncol 2006;24:3823-30. 9) Huncharek M, McGarry R. A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer. Oncologist 2004;9:665-72.

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10) Turrisi AT 3rd, Kim K, Blum R et al. Twice-daily compared with once-daily thoracic

radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.

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N Engl J Med 1999;340:265-271.

11) De Ruysscher D, Pijls-Johannesma M, Bentzen SM, 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;24:1057-63.

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12) Withers HR, Taylor JM, Maczejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988;27:131-146.

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13) Davis AJ, Tannock IF. Repopulation of tumor cells between cycles of chemotherapy: A neglected factor. Lancet Oncol 2000;1:86-93.

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14) Yom SS. Accelerated repopulation as a cause of radiation treatment failure in non-small cell lung cancer: review of current data and future clinical strategies. Semin Radiat Oncol 2015;25:93-9.

15) Komaki R, Khalid N, Langer CJ, et al. Penetration of recommended procedures for lung cancer staging and management in the United States over 10 years: a quality research in radiation oncology survey. Int J Radiat Oncol Biol Phys 2013;85:1082-9.

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16) Faivre-Finn C, Snee M, Ashcroft L, et al. CONVERT: An international randomised trial of concurrent chemo-radiotherapy (cCTRT) comparing twice-daily (BD) and once-daily (OD) radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good

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performance status (PS). J Clin Oncol 2016; 34(suppl). Abstract 8504.

17) Salama JK, Hodgson L, Pang H, et al. A pooled analysis of limited stage small cell lung

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cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904. J Thorac Oncol 2013;8:1043-9.

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18) Shepherd FA, Crowley J, Van Houtte P, et al. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2007;2:1067-77.

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19) Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group. J Natl Cancer Inst 2009;101:984-92. 20) Blackstock AE, Herndon JE 2nd, Paskett ED, et al. Similar outcomes between African

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American and non-African American patients with extensive-stage small-cell lung carcinoma:

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report from the Cancer and Leukemia Group B. J Clin Oncol 2006;24:407-12. 21) De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, Kester A, Rutten I, Lambin P. Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol 2006;17:543-52. Figure Legends:

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Figure 1: Kaplan-Meier curves for overall survival for the overall cohort by thoracic radiotherapy (TRT) timing.

radiation by thoracic radiotherapy (TRT) timing.

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Figure 2: Kaplan-Meier curves for overall survival for patients receiving hyperfractionated

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Figure 3: Kaplan-Meier curves for overall survival for patients receiving standard fractionation

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Tables: Table 1: Patient characteristics and comparison between groups. Late TRT

(days 0-20)

(days 21-126)

64 years

65 years

Age (median)

0.02 0.21

2,739 (50.1%)

2,730 (49.9%)

1

1,120 (52.1%)

1,029 (47.9%)

2

381 (49.3%)

Race

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0

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Charlson/Deyo score

p-value

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Early TRT

392 (50.7%)

0.37

3,845 (50.5%)

Black

292 (49.2%)

Tumor size Unknown

978 (47.7%)

2,292 (53.5%)

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≤5cm

103 (55.1%)

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Other

5-10cm

3,765 (49.5%) 302 (50.8%)

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White

84 (44.9%) <0.001

1,072

(52.3%) 1,994 (46.5%)

970 (47.2%)

1,085 (52.8%)

T-stage

<0.001 Tx

609 (47.5%)

672 (52.5%)

1

T1

1,000 (54.9%)

821 (45.1%)

T2

1,315 (51.1%)

1,258(48.9%)

T3

470 (51.5%)

443 (48.5%)

T4

846 (46.9%)

957 (53.1%) <0.001

Nx

447 (47.8%)

488 (52.2%)

1,252 (55.1%)

1,019

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N0-1

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N-stage

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(44.9%)

N2

2,076 (50.3%)

2,050

(49.7%)

465 (43.9%)

594

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N3

(56.1%)

BID

870 (45.6%)

3,201 (49.4%)

3,281 (50.6%)

<0.001

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QD

1,039 (54.4%)

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Radiation Fractionation

BID = twice daily QD = once daily

Table 2: Univariate and multivariate analysis for survival:

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Univariate Analysis p-value

Age

1.02 (1.01-1.02)

(95% CI) <0.001

Charlson/Deyo 1

1

1.12 (1.06-1.19)

<0.001

≥2

1.26 (1.16-1.37)

<0.001

White

1

Black

0.82 (0.83-1.02)

Other

0.98 (0.82-1.17)

Tx

0.93 (0.86-1.01)

T1 T2

T4

1

1.11 (1.04-1.17)

0.001

1.22 (1.12-1.33)

<0.001

1 0.04

0.83

0.98 (0.82-1.17)

0.82

0.10

0.85 (0.77-0.94)

0.002

0.80 (0.74-0.86)

<0.001

0.79 (0.73-0.86)

<0.001

0.95 (0.89-1.02)

0.18

0.95 (0.89-1.02)

0.20

0.97 (0.88-1.06)

0.50

0.99 (0.91-1.09)

0.91

TE D

0.90 (0.81-0.99)

AC C

T3

<0.001

0.10

EP

T-stage

1.02 (1.01-1.02)

M AN U

0

Race

p-value

RI PT

(95% CI)

Hazard Ratio

SC

Hazard Ratio

Multivariate Analysis

1

1

N-stage

Nx

0.87 (0.79-0.96)

0.007

0.92 (0.82-1.03)

0.15

N0-1

0.66 (0.60-0.72)

<0.001

0.63 (0.58-0.69)

<0.001

N2

0.88 (0.82-0.95)

0.001

0.87 (0.80-0.94)

<0.001

N3

1

1 3

ACCEPTED MANUSCRIPT

Radiation Fractionation 0.87 (0.81-0.92)

QD

1

<0.001

Late

1

0.01

0.53

1

CI = confidence interval

M AN U

BID = twice daily

0.98 (0.94-1.04)

SC

0.94 (0.89-0.99)

0.001

1

Radiation Timing Early

0.90 (0.85-0.96)

RI PT

BID

AC C

EP

TE D

QD = once daily

4

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT