- Email: [email protected]
Optimal Surgical Timing After Neoadjuvant Therapy for Stage IIIa Non-Small Cell Lung Cancer
Journal Pre-proof Optimal Surgical Timing after Neoadjuvant Therapy for Stage IIIa Non-Small Cell Lung Cancer Jonathan D. Rice, M.D., Ph.D., Justin Heidel, B.S., Jaimin R. Trivedi, M.D., M.P.H., Victor H. van Berkel, M.D., Ph.D PII:
S0003-4975(19)31705-9
DOI:
https://doi.org/10.1016/j.athoracsur.2019.09.076
Reference:
ATS 33220
To appear in:
The Annals of Thoracic Surgery
Received Date: 14 March 2019 Revised Date:
13 September 2019
Accepted Date: 27 September 2019
Please cite this article as: Rice JD, Heidel J, Trivedi JR, van Berkel VH, Optimal Surgical Timing after Neoadjuvant Therapy for Stage IIIa Non-Small Cell Lung Cancer, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.076. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 by The Society of Thoracic Surgeons
Optimal Surgical Timing after Neoadjuvant Therapy for Stage IIIa Non-Small Cell Lung Cancer Running Head: Optimal Surgical Timing for Stage IIIa NSCLC
Jonathan D. Rice, M.D., Ph.D.; Justin Heidel, B.S.; Jaimin R. Trivedi, M.D., M.P.H., Victor H. van Berkel, M.D., Ph.D.
Department of Cardiovascular and Thoracic Surgery, The University of Louisville School of Medicine, Louisville KY, 40202
Meeting Presentation: The Society of Thoracic Surgeons 55th Annual Meeting, San Diego CA, January 27-30th 2019
Classification: Lung Cancer, diagnosis (including staging, imaging, fiducials) Lung cancer surgery, Lung pathology
Word Count: 3260
Corresponding Author: Victor H. van Berkel, M.D., Ph.D., 201 Abraham Flexner Way, Suite 1200, Louisville, KY 40202, email: [email protected]
1
Abstract
Background: Patients with clinically/pathologically diagnosed stageIIIa non-small cell lung cancer(NSCLC) considered for surgery are recommended to undergo neoadjuvant chemotherapy with/without radiation. Timing of operation after therapy is not standardized. We investigate timing of intervention after neoadjuvant therapy and impact on outcomes in this demographic.
Methods: The National Cancer Database was queried for patients with clinical/pathological StageIIIa NSCLC between 2010-2015. Patients were then divided into short(<77days),mid(77-114days)and longdelay(>114days)groups based on interquartile values. These groups were then compared for age, race, gender, insurance type, Charlson-Deyo Score, length of stay, readmission rate and overall survival based on timing of operation.
Results: There were 31357 patients with clinical/pathological StageIIIs NSCLC. 5946 patients underwent surgical intervention. Preoperatively, 3593 patients underwent chemo-radiotherapy, 2185 underwent chemotherapy only and 168 patients received radiation alone. The short, mid and long delay groups were clinically and statistically similar in age, gender, insurance type, comorbidity index, treating facility type and distance from home. Long delay groups had larger tumor size compared to other groups. Postoperative length of stay, rates of 30-day readmission as well as 30-and 90-day mortality were similar across all groups. Cox modeling demonstrated a significant difference in survival when patients underwent earlier operative intervention compared to late and when patients received chemoradiation compared to chemotherapy alone. Short, mid and long delay groups 1-year survival was 82%, 83% and 80% and 3-year survival was 59%, 58% and 52% respectively(p=0.0003).
Conclusions: The delay in surgical resection of StageIIIa NSCLC is not associated increased early mortality, however it is associated with worse 3-year post-resection survival.
2
Lung cancer is the 2nd most common cancer diagnosis in both genders only behind prostate in men and breast in women.{Siegel, 2018 #75} Lung cancer encompasses an estimated 19% of all cancerrelated deaths and stage IIIa non-small cell lung cancer (NSCLC) constitutes an estimated 15% of new lung cancer diagnosis{Cheng, 2016 #68;Gillaspie, 2016 #69}. Stage IIIa NSCLC has an estimated fiveyear survival of 36%.{, #76} By comparison, the 5-year survival rates for stage I and stage II NSCLC ranged from 68–92% and 53-60%, respectively.{, #76} Given the poor overall prognosis, stage IIIa NSCLC is a critical stage for disease management, as it is considered one of the last stages amenable to surgical resection. Currently treatment plans include; surgery followed by adjuvant chemotherapy, neoadjuvant chemotherapy, radiation or chemoradiation followed by surgical intervention or non-surgical options alone such as chemotherapy, chemoradiation or radiation alone. There is no consensus on the exact management algorithm for patients who present with Stage III NSCLC.{Veeramachaneni, 2012 #58} When Stage IIIa NSCLC is considered operable, the combination of neoadjuvant therapy and surgery improved survival outcomes compared to surgery alone.{Rosell, 1994 #77;Roth, 1994 #78} Although this has been known for several decades now, the appropriate clinical management and timing of surgical intervention for patients diagnosed with stage IIIa NSCLC continues to remain a topic of controversy. For those with operable stage IIIa cancer, a number of management strategies have been investigated which combine resection with neoadjuvant chemotherapy, and/or radiotherapy, {Gillaspie, 2016 #69;Yang, 2016 #71;Hancock, 2014 #72;Rosell, 1994 #77;Roth, 1994 #78}. There are few reports evaluating time of surgery post neoadjuvant therapy, showing a significant reduction in survival with longer intervals until operative resection {Gao, 2017 #61;Pless, 2015 #73}. This suggests that the timing of resection after neoadjuvant therapy may affect patient survival, but still indicates the optimal treatment strategy and timing has yet to be identified. This study sought to investigate the effect of delay until surgical intervention (short, mid, and long) in patients diagnosed with stage IIIa NSCLC in respect to neoadjuvant modalities – chemotherapy only, radiation only, or chemoradiotherapy – on post-resection survival.
3
Patients and Methods Data and Study Population This retrospective study was approved by the University of Louisville Institutional Review Board prior to initiation. The National Cancer Database (NCDB) was queried for patients (>/= 18 years) diagnosed with clinical stage IIIa non-small cell lung cancer between years 2004 and 2015 who received a neo-adjuvant therapy (chemotherapy and/or radiation therapy) prior to undergoing cancer resection. Incorporating both pTNM and cTMN diagnoses of stage IIIa NSCLC in accordance with the 7th edition of the AJCC TMN staging system.{Goldstraw, 2016 #74} Only patients who ultimately received an operation were included. Patients receiving non-surgical treatment only or receiving surgery as first line of treatment were excluded from the analysis. After applying inclusion and exclusion criteria there were 5946 patients in the final study dataset. The available data set was then divided in 3 groups based on timing of surgery after neo-adjuvant therapy: The short delay, mid delay and long delay groups. The cut-off or threshold values for the study groups were based on interquartile range of the duration between neo-adjuvant therapy and surgery. Patients receiving surgery within 77 days of neo-adjuvant therapy were in short delay group, between 77-114 days were in mid delay group and after 114 days were in long delay group. Data Analysis The 3 study groups were initially compared by their demographics and pre-operative risk factors as well as clinical and surgical parameters. The primary study outcome was all-cause post-surgical morality. The secondary outcomes were length of initial hospital stay and 30 day post-op readmission. The primary outcome of post-surgical mortality was initially evaluated at 30-and 90-days. A KaplanMeier curve was computed to evaluate mid-term and long-term survival outcomes. Non-parametric tests were used to evaluate differences between the study groups. Kruskal-Wallis test was used for numerical variable and chi-square estimates were used for categorical variables. Logrank test was used to evaluate survival outcomes. A multi-variate Cox Proportional Hazard model was
4
generated to identify factors associated with survival outcomes. All the analyses were performed using SAS 9.4 (SAS Inc., NC) at 95% confidence level.
Results There were 31,357 patients identified with clinical or pathological Stage III NSCLC between 2010-2015. 5,946 (18.9%) patients underwent surgical intervention. 3,593 patients underwent neoadjuvant chemo-radiotherapy, 2,185 neoadjuvant chemotherapy and 168 neoadjuvant radiation alone. There were 1,558, 2,950 and 1,438 patients undergoing surgical resection in short (<77 days), mid (77114 days) and long (>114 days) delay groups respectively (Figure 1). The median age of all patients who underwent surgical intervention was 63 (56-69) years. Study groups were clinically and statistically similar in age, gender, insurance type, comorbidity index, treatment facility type and distance to travel to obtain treatment (Table 1). African Americans had a higher percentage of patients in the long delay group (11% vs. 9% and 8%, p=0.002) Tumor size, neoadjuvant treatment arms, histology, nodal status, type of operation (open vs minimally invasive), and R0 resection status based on timing of surgery are described in Table 2. Tumor size was larger in the long delay group compared to the other two delay groups, (45mm vs. 42mm and 42mm p=0.0003). More patients in the long delay group had chemotherapy only compared to short and mid delay groups (43% compared to 30%, 37% respectively p<0.0001), whereas more patients in short delay group had chemoradiotherapy (64%, 61% and 55%, p<0.001) compared to other groups. The majority of patients in all groupings received an R0 resection (88%, 93% and 92% respectively for short, mid and long delay, p < 0.0001). Outcomes by delay in surgery including length of stay, 30-day readmission, 30- and 90-day mortality, 1- and 3-year survival are listed in Table 3. Postoperative length of stay was similar across all groups with a median length of stay of 5 days. Readmission rate was similar in all delay groups with no readmission at 30 days in 93%, 92% and 94% in short, mid and long delay groups respectively (p=0.2).
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Overall Survival The 30-day mortality post resection was 2% in all delay groups (p=0.8) and 90-day mortality was 5%, 4% and 5% for short, mid and long delay groups respectively (p=0.3) (Table 3). Kaplan-Meier curves showed that 1-year survival was 82%, 83% and 80% (p=0.003) and 3-year survival was 59%, 58% and 52% (p=0.003) for short, mid and long delay groups respectively (Wilcoxon p-value = 0.0033 (Figure 2)). Cox proportion hazard model was performed on several factors including age, sex, race, insurance type, distance to treatment center, neoadjuvant therapy and delay until surgical intervention (Table 4). As age increases, patients have a higher likelihood of mortality (HR=1.008, p=0.0107). Female patients have a lower likelihood of mortality compared to male counterparts (HR 0.779, p<0.0001). Mortality increased with increasing Charlson-Deyo Score (HR=1.116, p=0.0005) and when patients received neoadjuvant chemotherapy only compared to chemoradiation (HR 1.595, p=0.0002). Long delay compared to short delay until surgical intervention increased mortality (HR 1.25, p=0.0005), while mid delay group compared to short delay had mixed results (HR 1.073, p=0.1984). More patients received an R0 resection compared to not (HR 0.564 p<0.0001). Additionally, more patients received adjuvant chemotherapy compared to not (HR 0.862 p=0.0077).
Comment The timing of operative intervention prior to surgical resection has been investigated previously for patients who underwent neoadjuvant chemoradiation.{Gao, 2017 #61} Gao et al. found that delaying surgery greater than 6 and less than 9 weeks had a decrease in overall survival.{Gao, 2017 #61} Although they address the timing of surgery after a patient undergoes chemoradiation, they do not address patients who received neoadjuvant chemotherapy alone or radiation therapy alone, these groups were added to our analysis. Furthermore, our study includes the addition of a more recent time interval (2010 to 2015). Finally, we investigated a larger delay interval, with our longest delay being up to and >114 days from ending neoadjuvant therapy until the timing of surgical intervention.
6
Comparing demographics by delay, the median age was 63 years in all delay groups. Female gender was slightly less affected by NSCLC in all 3 groups compared to males. Although slim, the majority of all operations occurred at academic institutions in all 3 delay groups. As expected, the tumor size was on average larger in the long delay group when compared to the short and mid delay group. When comparing neoadjuvant treatments, neoadjuvant chemotherapy alone had a worse overall survival compared to neoadjuvant chemoradiation prior to surgical resection. This result differs from multiple reports that state the addition of radiation does not improve the overall survival.{Guo, 2016 #65;Xu, 2015 #66;Chen, 2018 #67} Our cox regression for survival analysis showed a significant difference in survival when patients underwent earlier operative intervention compared to late intervention at 1- and 3-year survival marks. Of note, it appears that the delay until surgery does not influence 30- or 90-day mortality as all delay groups had similar reported outcomes at these time points. This suggest that the timing after neoadjuvant treatment does not have a significant mortality impact from the operation itself. Yet, both the 1- and 3year survival analysis showed a significant drop in survival when comparing the short delay to the long delay groups. Suggesting that the overall oncologic outcome is influenced by the timing of surgical intervention after neoadjuvant treatment. Although overall survival was down when comparing the mid delay to the long delay group, it was not statically significant. These findings are consistent with previously reported outcomes with longer delay from neoadjuvant treatment to the start of surgical intervention.{Gao, 2017 #61} Some limitations of this paper should be noted. First, this is a retrospective review of a national database, which is unlikely to capture the complete clinical picture of all patients with Stage IIIa NSCLC. Important confounders that could delay surgical therapy in the late group compared to the earlier surgical groups are not captured inside of the database. Second, the individual nature of why certain delays occur for certain patients are not captured. We are unable to capture the overall clinical picture of an individual and if that clinical picture has influenced the operative surgeon to delay the procedure or even move the planned procedure up. Unfortunately, there is no documentation of clinical progress between therapy and
7
surgery to evaluate the reasons behind the delay hence we did not consider surgeries performed beyond 6 months as salvage. Third, not all tumor characteristics are captured by the database. The database does not allow us to capture if the tumor was responding or not to the neoadjuvant treatment, which could significantly impact the timing of operative intervention. Fourth, the 10-year time period we used is extremely wide in terms of oncologic advancement. Chemotherapy protocols and treatment regimens drastically change over a 10-year period and unfortunately this is not captured in the database. We chose to use this wide time period to increase sample size and address the question of timing of surgical intervention after neo-adjuvant therapy. In conclusion, this study supports that delay in surgical resection after neoadjuvant treatment did not significantly impact early mortality at 30- and 90-day time points, suggesting that from a surgical standpoint, there is no maximally beneficial window for operating after adjuvant therapy. Despite this, at 1- and 3- years, mortality was worse for patients that were in the long delay group compared to both the mid and short delay groups.
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by Stage]. Available from: https://www.cancer.org/cancer/non-small-cell-lung-cancer/detectiondiagnosis-staging/survival-rates.html. 5.
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comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994;330(3):153-8. 6.
Roth JA, Fossella F, Komaki R, Ryan MB, Putnam JB, Jr., Lee JS, et al. A randomized trial
comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA nonsmall-cell lung cancer. J Natl Cancer Inst. 1994;86(9):673-80. 7.
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Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in
stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-56.
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Gao SJ, Corso CD, Wang EH, Blasberg JD, Detterbeck FC, Boffa DJ, et al. Timing of Surgery after
Neoadjuvant Chemoradiation in Locally Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2017;12(2):314-22. 11.
Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, et al. The IASLC
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Bilfinger T, Keresztes R, Albano D, Nemesure B. Five-Year Survival Among Stage IIIA Lung Cancer
Patients Receiving Two Different Treatment Modalities. Med Sci Monit. 2016;22:2589-94. 13.
Veeramachaneni NK, Feins RH, Stephenson BJ, Edwards LJ, Fernandez FG. Management of stage
IIIA non-small cell lung cancer by thoracic surgeons in North America. Ann Thorac Surg. 2012;94(3):9226; discussion 6-8. 14.
Guo SX, Jian Y, Chen YL, Cai Y, Zhang QY, Tou FF. Neoadjuvant Chemoradiotherapy vesus
Chemotherapy alone Followed by Surgery for Resectable Stage III Non-Small-Cell Lung Cancer: a MetaAnalysis. Sci Rep. 2016;6:34388. 15.
Xu YP, Li B, Xu XL, Mao WM. Is There a Survival Benefit in Patients With Stage IIIA (N2) Non-small
Cell Lung Cancer Receiving Neoadjuvant Chemotherapy and/or Radiotherapy Prior to Surgical Resection: A Systematic Review and Meta-analysis. Medicine (Baltimore). 2015;94(23):e879. 16.
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chemotherapy for resectable stage III A/N2 non-small cell lung cancer: a meta-analysis. World J Surg Oncol. 2018;16(1):8.
10
Table 1: Demographics by delay in surgery Short Delay
Mid Delay
Long Delay
n = 1558
n = 2950
n = 1438
Median Age (Years)
63 (55-69)
63 (56-69)
0.7
Gender (Female)
742 (48%)
63 (56-69) 1411 (48%)
704 (49%)
0.7
237 (8%)
162 (11%)
0.002
Characteristics
Race (African American) Insurance Type Private
147 (9%)
736 (47%)
Medicare
618 (40%)
Medicaid
95 (6%)
Academic Institution
856 (55%)
Distance to Treatment Center (Miles)
11 (5-28)
1401 (48%) 1210 (41%) 187 (6%) 1687 (57%) 12 (5-29)
pvalue
647 (45%) 0.08 598 (42%) 118 (8%) 792 (55%)
0.2
13 (5-32)
0.1
Charlson-Deyo Score 0
1011 (65%) >0
547 (35%)
1926 (65%) 1024 (35%)
922 (64%) 0.7 516 (36%)
11
Table 2: Clinical characteristics by delay in surgery Short Delay
Mid Delay
Long Delay
n = 1558
n = 2950
n = 1438
Tumor Size (mm)
42 (27-64)
45 (28-72)
Chemotherapy only
30% (465)
Radiotherapy only
6% (93)
42 (27-64) 37% (1098) 2% (53) 61% (1799)
Characteristic
Chemotherapy + Radiotherapy 64% (1000)
43% (622)
p-value 0.0003 <0.0001
1% (22) 55% (794)
Histology Adenocarcinoma
48% (742)
Squamous Cell Carcinoma
34% (528)
Lymph Node Surgery (Yes)
94% (1468)
Open Surgical Resection
66% (1025)
R0 Resection
88% (1297)
52% (1545) 32% (952) 98% (2885) 63% (1866) 93% (2677)
50% (740) 34% (485) 96% (1382) 65% (941) 92% (1287)
0.01
<0.0001 0.1 <0.0001
12
Table 3: Outcomes by delay in surgery Short Delay Characteristic n = 1558 Length of Stay (days) 30-day Mortality 90-day Mortality 1-year Survival 3-year Survival No Readmission at 30 Days
5 (4-8) 34 (2%) 80 (5%) 82% 59% 1441 (93%)
Mid Delay n = 2950
Long Delay n = 1438
5 (4-7) 67 (2%) 130 (4%) 83% 58% 2724 (92%)
5 (4-8) 34 (2%) 74 (5%) 80% 52% 1349 (94%)
pvalue 0.07 0.8 0.3 0.0003 0.0003 0.2
13
Table 4: Cox regression model for post-surgical mortality Parameter
Reference
Age
Hazard Ratio
pvalue
95% Lower Limit
95% Upper Limit
1.008
0.0107
1.002
1.014
Sex (Female)
Male
0.779
<.0001
0.711
0.853
Race (AA)
Other
0.928
0.3661
0.788
1.092
Insurance Type (None)
Private
1.133
0.3674
0.864
1.486
Insurance Type (Medicaid)
Private
0.975
0.7993
0.804
1.184
Insurance Type (Medicare)
Private
1.232
0.0004
1.098
1.382
Insurance Type (Other)
Private
1.39
0.072
0.971
1.99
Non-academic
0.958
0.3413
0.877
1.047
1.116
0.0005
1.049
1.188
1
0.624
1
1
Academic Charlson-Deyo Score Distance to Treatment Center Neoadjuvant Treatment (Chemo Only)
Chemoradiation
1.595
0.0002
1.243
2.049
Neoadjuvant Treatment (Radiation Only)
Chemoradiation
0.985
0.751
0.897
1.081
Delay to Surgical Intervention (Long)
Short
1.25
0.0005
1.103
1.416
Delay to Surgical Intervention (Mid)
Short
1.073
0.1984
0.964
1.195
Surgical Approach (Minimally Invasive vs. Open)
Open
0.915
0.066
0.832
1.006
1.063
0.3289
0.94
1.202
1.015
0.776
0.918
1.122
0.564 0.862
<.0001 0.0077
0.492 0.773
0.647 0.962
Histology (Other v Adenocarcinoma) Histology (Squamous cell carcinoma v Adenocarcinoma)) R0 resection (Yes vs No) Adjuvant Chemo Treatment (Yes vs No)
14
Figures Legends Figure 1: Study profile. 5,946 patients that received surgical intervention following neoadjuvant therapy were subdivided into groups based on delay until operative intervention Figure 2: Kaplain-Meier survival curve stratified by delay in surgery
15
31,357 patients identified with Stage IIIa NSCLC (NCDB 20102015)
5,946 received surgical intervention
Short delay (< 77 d) 1,558 patients (26%)
Mid delay (77 - 114 d) 2,950 patients (50%)
Long delay (> 114 d) 1,438 patients (24%)
S0003-4975(19)31705-9
DOI:
https://doi.org/10.1016/j.athoracsur.2019.09.076
Reference:
ATS 33220
To appear in:
The Annals of Thoracic Surgery
Received Date: 14 March 2019 Revised Date:
13 September 2019
Accepted Date: 27 September 2019
Please cite this article as: Rice JD, Heidel J, Trivedi JR, van Berkel VH, Optimal Surgical Timing after Neoadjuvant Therapy for Stage IIIa Non-Small Cell Lung Cancer, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.076. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 by The Society of Thoracic Surgeons
Optimal Surgical Timing after Neoadjuvant Therapy for Stage IIIa Non-Small Cell Lung Cancer Running Head: Optimal Surgical Timing for Stage IIIa NSCLC
Jonathan D. Rice, M.D., Ph.D.; Justin Heidel, B.S.; Jaimin R. Trivedi, M.D., M.P.H., Victor H. van Berkel, M.D., Ph.D.
Department of Cardiovascular and Thoracic Surgery, The University of Louisville School of Medicine, Louisville KY, 40202
Meeting Presentation: The Society of Thoracic Surgeons 55th Annual Meeting, San Diego CA, January 27-30th 2019
Classification: Lung Cancer, diagnosis (including staging, imaging, fiducials) Lung cancer surgery, Lung pathology
Word Count: 3260
Corresponding Author: Victor H. van Berkel, M.D., Ph.D., 201 Abraham Flexner Way, Suite 1200, Louisville, KY 40202, email: [email protected]
1
Abstract
Background: Patients with clinically/pathologically diagnosed stageIIIa non-small cell lung cancer(NSCLC) considered for surgery are recommended to undergo neoadjuvant chemotherapy with/without radiation. Timing of operation after therapy is not standardized. We investigate timing of intervention after neoadjuvant therapy and impact on outcomes in this demographic.
Methods: The National Cancer Database was queried for patients with clinical/pathological StageIIIa NSCLC between 2010-2015. Patients were then divided into short(<77days),mid(77-114days)and longdelay(>114days)groups based on interquartile values. These groups were then compared for age, race, gender, insurance type, Charlson-Deyo Score, length of stay, readmission rate and overall survival based on timing of operation.
Results: There were 31357 patients with clinical/pathological StageIIIs NSCLC. 5946 patients underwent surgical intervention. Preoperatively, 3593 patients underwent chemo-radiotherapy, 2185 underwent chemotherapy only and 168 patients received radiation alone. The short, mid and long delay groups were clinically and statistically similar in age, gender, insurance type, comorbidity index, treating facility type and distance from home. Long delay groups had larger tumor size compared to other groups. Postoperative length of stay, rates of 30-day readmission as well as 30-and 90-day mortality were similar across all groups. Cox modeling demonstrated a significant difference in survival when patients underwent earlier operative intervention compared to late and when patients received chemoradiation compared to chemotherapy alone. Short, mid and long delay groups 1-year survival was 82%, 83% and 80% and 3-year survival was 59%, 58% and 52% respectively(p=0.0003).
Conclusions: The delay in surgical resection of StageIIIa NSCLC is not associated increased early mortality, however it is associated with worse 3-year post-resection survival.
2
Lung cancer is the 2nd most common cancer diagnosis in both genders only behind prostate in men and breast in women.{Siegel, 2018 #75} Lung cancer encompasses an estimated 19% of all cancerrelated deaths and stage IIIa non-small cell lung cancer (NSCLC) constitutes an estimated 15% of new lung cancer diagnosis{Cheng, 2016 #68;Gillaspie, 2016 #69}. Stage IIIa NSCLC has an estimated fiveyear survival of 36%.{, #76} By comparison, the 5-year survival rates for stage I and stage II NSCLC ranged from 68–92% and 53-60%, respectively.{, #76} Given the poor overall prognosis, stage IIIa NSCLC is a critical stage for disease management, as it is considered one of the last stages amenable to surgical resection. Currently treatment plans include; surgery followed by adjuvant chemotherapy, neoadjuvant chemotherapy, radiation or chemoradiation followed by surgical intervention or non-surgical options alone such as chemotherapy, chemoradiation or radiation alone. There is no consensus on the exact management algorithm for patients who present with Stage III NSCLC.{Veeramachaneni, 2012 #58} When Stage IIIa NSCLC is considered operable, the combination of neoadjuvant therapy and surgery improved survival outcomes compared to surgery alone.{Rosell, 1994 #77;Roth, 1994 #78} Although this has been known for several decades now, the appropriate clinical management and timing of surgical intervention for patients diagnosed with stage IIIa NSCLC continues to remain a topic of controversy. For those with operable stage IIIa cancer, a number of management strategies have been investigated which combine resection with neoadjuvant chemotherapy, and/or radiotherapy, {Gillaspie, 2016 #69;Yang, 2016 #71;Hancock, 2014 #72;Rosell, 1994 #77;Roth, 1994 #78}. There are few reports evaluating time of surgery post neoadjuvant therapy, showing a significant reduction in survival with longer intervals until operative resection {Gao, 2017 #61;Pless, 2015 #73}. This suggests that the timing of resection after neoadjuvant therapy may affect patient survival, but still indicates the optimal treatment strategy and timing has yet to be identified. This study sought to investigate the effect of delay until surgical intervention (short, mid, and long) in patients diagnosed with stage IIIa NSCLC in respect to neoadjuvant modalities – chemotherapy only, radiation only, or chemoradiotherapy – on post-resection survival.
3
Patients and Methods Data and Study Population This retrospective study was approved by the University of Louisville Institutional Review Board prior to initiation. The National Cancer Database (NCDB) was queried for patients (>/= 18 years) diagnosed with clinical stage IIIa non-small cell lung cancer between years 2004 and 2015 who received a neo-adjuvant therapy (chemotherapy and/or radiation therapy) prior to undergoing cancer resection. Incorporating both pTNM and cTMN diagnoses of stage IIIa NSCLC in accordance with the 7th edition of the AJCC TMN staging system.{Goldstraw, 2016 #74} Only patients who ultimately received an operation were included. Patients receiving non-surgical treatment only or receiving surgery as first line of treatment were excluded from the analysis. After applying inclusion and exclusion criteria there were 5946 patients in the final study dataset. The available data set was then divided in 3 groups based on timing of surgery after neo-adjuvant therapy: The short delay, mid delay and long delay groups. The cut-off or threshold values for the study groups were based on interquartile range of the duration between neo-adjuvant therapy and surgery. Patients receiving surgery within 77 days of neo-adjuvant therapy were in short delay group, between 77-114 days were in mid delay group and after 114 days were in long delay group. Data Analysis The 3 study groups were initially compared by their demographics and pre-operative risk factors as well as clinical and surgical parameters. The primary study outcome was all-cause post-surgical morality. The secondary outcomes were length of initial hospital stay and 30 day post-op readmission. The primary outcome of post-surgical mortality was initially evaluated at 30-and 90-days. A KaplanMeier curve was computed to evaluate mid-term and long-term survival outcomes. Non-parametric tests were used to evaluate differences between the study groups. Kruskal-Wallis test was used for numerical variable and chi-square estimates were used for categorical variables. Logrank test was used to evaluate survival outcomes. A multi-variate Cox Proportional Hazard model was
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generated to identify factors associated with survival outcomes. All the analyses were performed using SAS 9.4 (SAS Inc., NC) at 95% confidence level.
Results There were 31,357 patients identified with clinical or pathological Stage III NSCLC between 2010-2015. 5,946 (18.9%) patients underwent surgical intervention. 3,593 patients underwent neoadjuvant chemo-radiotherapy, 2,185 neoadjuvant chemotherapy and 168 neoadjuvant radiation alone. There were 1,558, 2,950 and 1,438 patients undergoing surgical resection in short (<77 days), mid (77114 days) and long (>114 days) delay groups respectively (Figure 1). The median age of all patients who underwent surgical intervention was 63 (56-69) years. Study groups were clinically and statistically similar in age, gender, insurance type, comorbidity index, treatment facility type and distance to travel to obtain treatment (Table 1). African Americans had a higher percentage of patients in the long delay group (11% vs. 9% and 8%, p=0.002) Tumor size, neoadjuvant treatment arms, histology, nodal status, type of operation (open vs minimally invasive), and R0 resection status based on timing of surgery are described in Table 2. Tumor size was larger in the long delay group compared to the other two delay groups, (45mm vs. 42mm and 42mm p=0.0003). More patients in the long delay group had chemotherapy only compared to short and mid delay groups (43% compared to 30%, 37% respectively p<0.0001), whereas more patients in short delay group had chemoradiotherapy (64%, 61% and 55%, p<0.001) compared to other groups. The majority of patients in all groupings received an R0 resection (88%, 93% and 92% respectively for short, mid and long delay, p < 0.0001). Outcomes by delay in surgery including length of stay, 30-day readmission, 30- and 90-day mortality, 1- and 3-year survival are listed in Table 3. Postoperative length of stay was similar across all groups with a median length of stay of 5 days. Readmission rate was similar in all delay groups with no readmission at 30 days in 93%, 92% and 94% in short, mid and long delay groups respectively (p=0.2).
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Overall Survival The 30-day mortality post resection was 2% in all delay groups (p=0.8) and 90-day mortality was 5%, 4% and 5% for short, mid and long delay groups respectively (p=0.3) (Table 3). Kaplan-Meier curves showed that 1-year survival was 82%, 83% and 80% (p=0.003) and 3-year survival was 59%, 58% and 52% (p=0.003) for short, mid and long delay groups respectively (Wilcoxon p-value = 0.0033 (Figure 2)). Cox proportion hazard model was performed on several factors including age, sex, race, insurance type, distance to treatment center, neoadjuvant therapy and delay until surgical intervention (Table 4). As age increases, patients have a higher likelihood of mortality (HR=1.008, p=0.0107). Female patients have a lower likelihood of mortality compared to male counterparts (HR 0.779, p<0.0001). Mortality increased with increasing Charlson-Deyo Score (HR=1.116, p=0.0005) and when patients received neoadjuvant chemotherapy only compared to chemoradiation (HR 1.595, p=0.0002). Long delay compared to short delay until surgical intervention increased mortality (HR 1.25, p=0.0005), while mid delay group compared to short delay had mixed results (HR 1.073, p=0.1984). More patients received an R0 resection compared to not (HR 0.564 p<0.0001). Additionally, more patients received adjuvant chemotherapy compared to not (HR 0.862 p=0.0077).
Comment The timing of operative intervention prior to surgical resection has been investigated previously for patients who underwent neoadjuvant chemoradiation.{Gao, 2017 #61} Gao et al. found that delaying surgery greater than 6 and less than 9 weeks had a decrease in overall survival.{Gao, 2017 #61} Although they address the timing of surgery after a patient undergoes chemoradiation, they do not address patients who received neoadjuvant chemotherapy alone or radiation therapy alone, these groups were added to our analysis. Furthermore, our study includes the addition of a more recent time interval (2010 to 2015). Finally, we investigated a larger delay interval, with our longest delay being up to and >114 days from ending neoadjuvant therapy until the timing of surgical intervention.
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Comparing demographics by delay, the median age was 63 years in all delay groups. Female gender was slightly less affected by NSCLC in all 3 groups compared to males. Although slim, the majority of all operations occurred at academic institutions in all 3 delay groups. As expected, the tumor size was on average larger in the long delay group when compared to the short and mid delay group. When comparing neoadjuvant treatments, neoadjuvant chemotherapy alone had a worse overall survival compared to neoadjuvant chemoradiation prior to surgical resection. This result differs from multiple reports that state the addition of radiation does not improve the overall survival.{Guo, 2016 #65;Xu, 2015 #66;Chen, 2018 #67} Our cox regression for survival analysis showed a significant difference in survival when patients underwent earlier operative intervention compared to late intervention at 1- and 3-year survival marks. Of note, it appears that the delay until surgery does not influence 30- or 90-day mortality as all delay groups had similar reported outcomes at these time points. This suggest that the timing after neoadjuvant treatment does not have a significant mortality impact from the operation itself. Yet, both the 1- and 3year survival analysis showed a significant drop in survival when comparing the short delay to the long delay groups. Suggesting that the overall oncologic outcome is influenced by the timing of surgical intervention after neoadjuvant treatment. Although overall survival was down when comparing the mid delay to the long delay group, it was not statically significant. These findings are consistent with previously reported outcomes with longer delay from neoadjuvant treatment to the start of surgical intervention.{Gao, 2017 #61} Some limitations of this paper should be noted. First, this is a retrospective review of a national database, which is unlikely to capture the complete clinical picture of all patients with Stage IIIa NSCLC. Important confounders that could delay surgical therapy in the late group compared to the earlier surgical groups are not captured inside of the database. Second, the individual nature of why certain delays occur for certain patients are not captured. We are unable to capture the overall clinical picture of an individual and if that clinical picture has influenced the operative surgeon to delay the procedure or even move the planned procedure up. Unfortunately, there is no documentation of clinical progress between therapy and
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surgery to evaluate the reasons behind the delay hence we did not consider surgeries performed beyond 6 months as salvage. Third, not all tumor characteristics are captured by the database. The database does not allow us to capture if the tumor was responding or not to the neoadjuvant treatment, which could significantly impact the timing of operative intervention. Fourth, the 10-year time period we used is extremely wide in terms of oncologic advancement. Chemotherapy protocols and treatment regimens drastically change over a 10-year period and unfortunately this is not captured in the database. We chose to use this wide time period to increase sample size and address the question of timing of surgical intervention after neo-adjuvant therapy. In conclusion, this study supports that delay in surgical resection after neoadjuvant treatment did not significantly impact early mortality at 30- and 90-day time points, suggesting that from a surgical standpoint, there is no maximally beneficial window for operating after adjuvant therapy. Despite this, at 1- and 3- years, mortality was worse for patients that were in the long delay group compared to both the mid and short delay groups.
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Table 1: Demographics by delay in surgery Short Delay
Mid Delay
Long Delay
n = 1558
n = 2950
n = 1438
Median Age (Years)
63 (55-69)
63 (56-69)
0.7
Gender (Female)
742 (48%)
63 (56-69) 1411 (48%)
704 (49%)
0.7
237 (8%)
162 (11%)
0.002
Characteristics
Race (African American) Insurance Type Private
147 (9%)
736 (47%)
Medicare
618 (40%)
Medicaid
95 (6%)
Academic Institution
856 (55%)
Distance to Treatment Center (Miles)
11 (5-28)
1401 (48%) 1210 (41%) 187 (6%) 1687 (57%) 12 (5-29)
pvalue
647 (45%) 0.08 598 (42%) 118 (8%) 792 (55%)
0.2
13 (5-32)
0.1
Charlson-Deyo Score 0
1011 (65%) >0
547 (35%)
1926 (65%) 1024 (35%)
922 (64%) 0.7 516 (36%)
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Table 2: Clinical characteristics by delay in surgery Short Delay
Mid Delay
Long Delay
n = 1558
n = 2950
n = 1438
Tumor Size (mm)
42 (27-64)
45 (28-72)
Chemotherapy only
30% (465)
Radiotherapy only
6% (93)
42 (27-64) 37% (1098) 2% (53) 61% (1799)
Characteristic
Chemotherapy + Radiotherapy 64% (1000)
43% (622)
p-value 0.0003 <0.0001
1% (22) 55% (794)
Histology Adenocarcinoma
48% (742)
Squamous Cell Carcinoma
34% (528)
Lymph Node Surgery (Yes)
94% (1468)
Open Surgical Resection
66% (1025)
R0 Resection
88% (1297)
52% (1545) 32% (952) 98% (2885) 63% (1866) 93% (2677)
50% (740) 34% (485) 96% (1382) 65% (941) 92% (1287)
0.01
<0.0001 0.1 <0.0001
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Table 3: Outcomes by delay in surgery Short Delay Characteristic n = 1558 Length of Stay (days) 30-day Mortality 90-day Mortality 1-year Survival 3-year Survival No Readmission at 30 Days
5 (4-8) 34 (2%) 80 (5%) 82% 59% 1441 (93%)
Mid Delay n = 2950
Long Delay n = 1438
5 (4-7) 67 (2%) 130 (4%) 83% 58% 2724 (92%)
5 (4-8) 34 (2%) 74 (5%) 80% 52% 1349 (94%)
pvalue 0.07 0.8 0.3 0.0003 0.0003 0.2
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Table 4: Cox regression model for post-surgical mortality Parameter
Reference
Age
Hazard Ratio
pvalue
95% Lower Limit
95% Upper Limit
1.008
0.0107
1.002
1.014
Sex (Female)
Male
0.779
<.0001
0.711
0.853
Race (AA)
Other
0.928
0.3661
0.788
1.092
Insurance Type (None)
Private
1.133
0.3674
0.864
1.486
Insurance Type (Medicaid)
Private
0.975
0.7993
0.804
1.184
Insurance Type (Medicare)
Private
1.232
0.0004
1.098
1.382
Insurance Type (Other)
Private
1.39
0.072
0.971
1.99
Non-academic
0.958
0.3413
0.877
1.047
1.116
0.0005
1.049
1.188
1
0.624
1
1
Academic Charlson-Deyo Score Distance to Treatment Center Neoadjuvant Treatment (Chemo Only)
Chemoradiation
1.595
0.0002
1.243
2.049
Neoadjuvant Treatment (Radiation Only)
Chemoradiation
0.985
0.751
0.897
1.081
Delay to Surgical Intervention (Long)
Short
1.25
0.0005
1.103
1.416
Delay to Surgical Intervention (Mid)
Short
1.073
0.1984
0.964
1.195
Surgical Approach (Minimally Invasive vs. Open)
Open
0.915
0.066
0.832
1.006
1.063
0.3289
0.94
1.202
1.015
0.776
0.918
1.122
0.564 0.862
<.0001 0.0077
0.492 0.773
0.647 0.962
Histology (Other v Adenocarcinoma) Histology (Squamous cell carcinoma v Adenocarcinoma)) R0 resection (Yes vs No) Adjuvant Chemo Treatment (Yes vs No)
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Figures Legends Figure 1: Study profile. 5,946 patients that received surgical intervention following neoadjuvant therapy were subdivided into groups based on delay until operative intervention Figure 2: Kaplain-Meier survival curve stratified by delay in surgery
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31,357 patients identified with Stage IIIa NSCLC (NCDB 20102015)
5,946 received surgical intervention
Short delay (< 77 d) 1,558 patients (26%)
Mid delay (77 - 114 d) 2,950 patients (50%)
Long delay (> 114 d) 1,438 patients (24%)