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Analysis of adjuvant chemotherapy in patients undergoing curative-intent resection of localized adrenocortical carcinoma
Ali Al Asadi, Daniel M. Hubbs, Patrick J. Sweigert, Marshall S. Baker, Adam S. Kabaker
PII:
S0002-9610(20)30679-6
DOI: https://doi.org/10.1016/j.amjsurg.2020.10.038
Reference:
AJS 14106
To appear in:
The American Journal of Surgery
Received Date: 1 May 2020
Revised Date: 12 October 2020
Accepted Date: 30 October 2020
Please cite this article as: Al Asadi A, Hubbs DM, Sweigert PJ, Baker MS, Kabaker AS, Analysis of adjuvant chemotherapy in patients undergoing curative-intent resection of localized adrenocortical carcinoma, The American Journal of Surgery (2020), doi: https://doi.org/10.1016/j.amjsurg.2020.10.038.
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.
@ 2020 Published by Elsevier Inc.
Abstract:
Background:
Studies evaluating the role of adjuvant chemotherapy (ACT) in Adrenocortical Carcinoma (ACC) are limited due to its rarity. The objective of this study was to evaluate if ACT provides a survival benefit in patients who underwent curative-intent resection of localized ACC and to determine factors associated with receipt of ACT.
Methods:
The National Cancer Data Base was queried to identify patients (2010-2016) with curative-intent resection of localized ACC (T1-T3, NO, MO).
Results:
Of 577 patients with adrenalectomy, 389 (67%) had adrenalectomy alone, and 188 (33%) received ACT. Private insurance, lymphovascular invasion, stage II, and radiotherapy were predictors of ACT (P < 0.05). Advanced (T3) stage lymphovascular invasion, and being uninsured were associated with decreased OS (P < 0.05). There was no association between ACT and OS.
Conclusions:
For patient who underwent curative-intent resection of localized ACC, there was no association between ACT and OS . Private insurance, lymphovascular invasion, stage II disease, and radiotherapy were associated with receipt of ACT.
Keywords: NCDB, Adrenocortical Carcinoma, Adjuvant Chemotherapy
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Table of Contents Summary:
The National Cancer Data Base was queried to identify patients who underwent curative-intent resection of localized adrenocortical carcinoma (T1-T3, N0, M0), between 2010 and 2016. In this analytic cohort, adjuvant chemotherapy had no associated increase in OS. Several high-risk subgroups including those with T3 disease, lymphovascular invasion, and positive margin status also failed to demonstrate a survival benefit associated with the use of adjuvant chemotherapy.
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Analysis of Adjuvant Chemotherapy in Patients Undergoing Curative-Intent Resection of Localized Adrenocortical Carcinoma
Ali Al Asadi1a, Daniel M. Hubbs1b, Patrick J. Sweigertb, Marshall S. Bakerb Adam S. Kabakerb
ALoyola University Chicago Stritch School of Medicine 2160 S 1st Ave, Maywood, IL 60153
Department of Surgery, Loyola University Medical Center Department of Surgery 2160 S 1st Ave, Maywood, IL 60153
“Shared co-first authorship
Corresponding author: Daniel M. Hubbs, Daniel.Hubbs@lumc.edu
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Introduction
Adrenocortical carcinoma (ACC) is an ultrarare malignancy with a prevalence of approximately 1 per million people making prospective randomized controlled trials and definitive treatment recommendations difficult1,2. ACC is also notable among endocrine malignancies for its poor prognosis even when identified prior to metastasizing. The primary treatment of localized ACC includes tumor resection via radical adrenalectomy to negative margins in an effort to avoid capsular violation. The operation should be performed by experienced surgeons to obtain optimal outcomes, however, overall 5-year survival for patients who undergo resection remains low at 35-40%3,4. The role of adjuvant chemotherapy in this surgically-treated population remains incompletely understood 5-7.
Adjuvant treatment of ACC with mitotane has been studied retrospectively and is currently recommended for patients with a perceived high risk of recurrence in the European Society of Endocrinology- European Network for the Study of Adrenal Tumors (ESE-ENSAT) Clinical Practice Guidelines on the Management of ACC in Adults8,9. High risk features include ENSAT stage III disease, R1 resection, or Ki67 >10%. These guidelines however do not recommend for or against adjuvant treatment in patients with Stage I-II disease. The National Comprehensive Cancer Network (NCCN) guidelines include consideration of adjuvant mitotane in patients with high risk of recurrence but notes that this is Category C evidence “with major NCCN disagreement that the intervention is appropriate”10. A recent study showed the frequency of adjuvant chemotherapy use in ACC patients has been increasing since 2007, now with approximately 35% of surgically treated patients receiving adjuvant chemotherapy6. Controversy remains as some studies show a benefit to disease free survival, but a consistent
overall survival (OS) benefit has not been demonstrated8,1112. Most of the research guiding current adjuvant chemotherapy has come from European patient populations. To date, a survival benefit associated with use of adjuvant systemic chemotherapy following resection of ACC has not been demonstrated in a North American population. At this time no American professional organizations have weighed in with adjuvant treatment recommendations in ACC, and internationally there is still no consensus regarding adjuvant treatment of ACC patients with Stage I-II disease.
ACC staging is uniform between the AJCC 8th edition TNM staging and the ENSAT staging system. Stage I and stage II disease both have no regional lymph node metastasis or distant metastasis. Stage I disease is defined by T1 tumors that are ≤5cm in size. Stage II disease is defined by T2 tumors that are > 5cm but without extra-adrenal invasion. Stage III disease includes T1 and T2 tumors with regional lymph node involvement as well as more invasive T3 and T4 tumors with or without regional lymph node involvement. T3 tumors can be of any size but are defined by their local extra-adrenal invasion. T4 tumors have more extensive invasion and involves adjacent organs. When evaluating patients for surgery, patients with T1-3 tumors are often candidates for curative intent surgery via radical adrenalectomy.
The objective of the current study was to evaluate if adjuvant chemotherapy provides a survival benefit in patients who underwent curative-intent resection of localized ACC and to determine the factors associated with receipt of adjuvant chemotherapy. The secondary aim of this study was to investigate if adjuvant chemotherapy provides a survival benefit in subgroups of patients with lymphovascular invasion, positive margin status, or T3 (Stage III) disease.
Methods
Data Source and Study Population
The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society which offers participating accredited centers access to a nationwide, comprehensive user file containing de- identified patient data13. The NCDB is a prospectively maintained hospital-based registry that collects information on >70% of malignant diagnoses in the United States compiled from thousands of accredited institutions. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigators. A data use agreement was obtained and this study met criteria for exemption from the Loyola University Chicago Institutional Review Board.
In an effort to identify a population of localized ACC patients most likely to have undergone resection with curative intent, the dataset was queried to identify adults with histologically confirmed invasive ACC diagnosed between January 1, 2010 - December 31, 2016 who underwent surgical resection with evidence of non-metastatic and localized disease without lymph node metastasis or invasion into surrounding structures (T1-T3, N0, M0). The third edition of the International Classification of Diseases for Oncology (ICD-O-3) codes for adrenal glands (C74.0 -C74.9) and histology codes for carcinoma (8010), adenocarcinoma (8140), and adrenal cortical carcinoma (8370) were used. All patients with surgical resection except those with local tumor destruction, local tumor excision, and unknown surgical treatment data were included. Patients with neoadjuvant, sandwich, or missing chemotherapy data were
excluded from analysis (Figure 1). Patients were stratified into two comparison groups based on receipt of adjuvant systemic chemotherapy: surgery alone group vs surgery and adjuvant chemotherapy group. Those with other cancer diagnoses were excluded before survival analysis was performed.
Variables & Outcomes
Study variables included demographics (age, sex, and race), insurance status, Charlson- Deyo comorbidity score, tumor size, lymphovascular invasion, vascular invasion, grade, stage, surgical approach, margin status, treating facility type, and radiotherapy treatment. Race was categorized as white, black, and others. Insurance status subgroups included patients with public insurance (Medicare, Medicaid, and Other Government), privately insured, uninsured, and those with an unknown insurance status. Tumor size was sorted into 3 groups: less than 5 cm, greater than or equal to 5 cm, and unknown. Grade I and grade II tumors were grouped into a single category while grade III and grade IV were combined into one category. The surgical approach comprised three subgroups: open, laparoscopic, and robotic. Those with minimally invasive approaches converted to open were treated as open procedures. Margin status was classified as negative margin, positive margin (any microscopic or macroscopic residual tumor), and unknown. Treating facilities were classified based on the site of surgical resection using the American College of Surgeons Committee on Cancer definitions for academic/research facilities, and non-academic/research facilities. Receipt of radiotherapy was treated in a binary fashion regardless of administration modality and timing. The primary outcome was defined by overall survival.
Statistical Analysis
Descriptive statistics were presented as mean (standard deviation) and frequency (%) for continuous and categorical variables, respectively. Two-sample student’s t-tests (for continuous variables) and chi-squared tests (for categorical variables) were employed on bivariate analysis to test association of characteristics with receipt of adjuvant chemotherapy. To assess factors associated with receipt of adjuvant chemotherapy on adjusted analysis, multivariable logistic regression was utilized using independent covariates determined a priori as clinically and epidemiologically relevant. Univariate and multivariate Cox proportional hazards models were used to detect variables that influenced risk of death. Unadjusted survival functions were developed using the Kaplan-Meier method and equality of survival functions were assessed with the log-rank test. Odds (OR) and hazard ratios (HR) were reported with 95% confidence intervals (95% CI). STATA software (v 14.2; StataCorp LLC; College Station, TX) was used to perform all statistical analysis and statistical significance was set at a = 0.05.
Results
Over the 2010-2016 study period, a total of 577 ACC patients met the inclusion criteria for analysis; 188 (33%) received adjuvant chemotherapy. The majority of patients were female (60%), white (86%), and privately insured (54.8%). Additionally, most patients had tumors >= 5cm (73%), stage II disease (58.8%), open adrenalectomy (68.5%), and negative margin (77.6%). Patients treated with surgery alone or surgery and adjuvant chemotherapy were similar in terms of sex, race, comorbidity score, tumor size, grade, surgical approach, and margin status (Table 1). However, patients in the adjuvant chemotherapy group were more likely to be younger (mean age 51.6 vs 57; p < 0.0001), privately insured (65.4% vs 49.6%; p = 0.002), have lymphovascular invasion (45.7% vs 30.8%; p = 0.001), and have vascular invasion (31.4% vs
20.1%; p = 0.01). Adjuvant chemotherapy patients were more likely to have T3 (stage III) disease (31.4% vs 24.9%; p = 0.02) and to have had radiotherapy (36.2 % vs 11.1%; p < 0.001), but less likely to be treated at a community center (28.7% vs 39.6%; p = 0.001).
A multivariable logistic regression model adjusting for age, insurance status, lymphovascular invasion, vascular invasion, stage, treating facility type, and radiotherapy treatment was employed to assess for variables that predicted the receipt of adjuvant chemotherapy. ACC patients with private insurance (OR 1.71; 95% CI 1.06 - 2.76; P = 0.03), lymphovascular invasion (OR 1.82; 95% CI 1.12 - 2.97; P = 0.02), stage II disease (OR 1.95; 95% CI 1.03 - 3.70; P = 0.04), and radiotherapy treatment (OR 4.69; 95% CI 2.95 - 7.46; P < 0.001) were more likely to receive adjuvant chemotherapy (Table 2).
Median overall survival for the surgery alone group trended higher but did not reach statistical significance (74.2 months vs 56 months; log-rank P = 0.17) (Fig. 2). On univariate Cox analysis, older age (HR 1.01; 95% CI 1.00 - 1.03; P = 0.01), advanced (II-III) stage (HR 4.66; 95% CI 2.23 - 9.76; P <0.001), lymphovascular invasion (HR 1.77; 95% CI 1.23 - 2.53; P = 0.002), and positive margin status (HR 2.57; 95% CI 1.74 - 3.78; P < 0.001) were associated with worsened overall survival (Table 3). On multivariate Cox analysis, uninsured (HR 2.91; 95% CI 1.33 - 6.40; P 0.01), older age (HR 1.04; 95% CI 1.02 - 1.07; P < 0.001), advanced (II- III) stage (HR 4.28; 95% CI 1.69 - 10.82; P = 0.002), worsened (III/IV) grade (HR 3,36; 95% CI 1.36 - 8.31; P = 0.01), and positive margin status (HR 1.96; 95% CI 1.19 - 3.22; P = 0.01) were associated with decreased survival. Notably, there was no associated survival benefit to adjuvant chemotherapy in either univariate (HR 1.25; 95% CI 0.91 - 1.73; P = 0.17) nor multivariate analysis (HR 1.21; 95% CI 0.84 - 1.74; P = 0.30) (Figure 2).
Subgroup analysis examined patients with lymphovascular invasion, positive margin status, or T3 (Stage III) disease. In patients with lymphovascular invasion there was no statistical difference in the median overall survival between patients receiving surgery alone and patients receiving surgery and adjuvant chemotherapy (47.1 months (surgery alone), n=82 vs 40.3 months (surgery and adjuvant chemotherapy), n=62; P = 0.82). The positive margin subgroup demonstrated longer overall survival in those treated with adjuvant chemotherapy in comparison to surgery alone [22.0 months (surgery alone), n=30 vs 46.7 months (surgery and adjuvant chemotherapy), n=23; P =0.59]. Similarly, the T3 tumor subgroup showed longer overall survival in those treated with adjuvant chemotherapy [36.5 months (surgery alone), n=65 vs 40.3 months (surgery and adjuvant chemotherapy), n=45; P = 0.40]. However, both trends were not statistically significant.
Discussion
The aim of this study was to evaluate if adjuvant chemotherapy provided a survival benefit in patients who underwent curative-intent resection of localized ACC and to determine the factors associated with receipt of adjuvant therapy. Surgical resection of the primary tumor remains the mainstay of treatment but recently there has been a significant increase in use of adjuvant chemotherapy despite conflicting evidence7. A previous study looking at 3,185 patients with ACC in the NCDB concluded that there was not an increased OS with adjuvant therapy in patients with stage I-III disease who received curative-intent surgery14. Our study further explores this subgroup of surgically treated patients with localized ACC and found no difference in OS between patients who received surgery alone vs surgery and adjuvant chemotherapy. This
study also contributes to the debate regarding treatment in tumors with a high risk of recurrence. In our cohort of surgically treated patients with localized ACC, adjuvant chemotherapy also showed no statistical difference in OS for subgroups of patients with lymphovascular invasion, positive margin status, or T3 (Stage III) disease.
Optimal post-operative treatment regimens have been difficult to study in ACC due to the ultrarare nature of the disease. Utilizing institutional databases and national datasets, progress has been made identifying subsets of ACC patients who may benefit from adjuvant chemotherapy. Though the NCDB does not specify the type of adjuvant therapy, the most commonly discussed is Mitotane. This is the primary antineoplastic agent used in the treatment of ACC due to its cytotoxic properties in adrenal tissue5. Adverse effects from mitotane therapy are most commonly GI complaints such as nausea and emesis but neuromuscular symptoms and adrenal insufficiency are also described5,12,15 .
The current study identified patients with private insurance, lymphovascular invasion, stage II disease, and radiotherapy treatment to be associated with the receipt of adjuvant chemotherapy. Of these factors only stage II disease and uninsured insurance status was found to have an increased risk of death on multivariate analysis. The association between private insurance and increased receipt of adjuvant chemotherapy in ACC patients is not unique. Studies examining treatment with adjuvant chemotherapy in pancreatic cancer and adjuvant radioactive iodine therapy in papillary thyroid cancer have both shown increased adjuvant therapy in patients with private insurance16,17. The associations with insurance status and adjuvant treatment are likely multifactoral with insured patients having more favorable socioeconomic status and easier access to advanced oncology care.
The controversy regarding efficacy of adjuvant treatment of ACC is largely driven by retrospective studies. Mitotane use in ACC patients was first studied in the 1960s18,19. Several small studies examining its efficacy were conducted in the following decades, but the landmark study that promoted its uses was published in 20078. In this study a cohort of 47 Italian patients who received neoadjuvant mitotane was compared against two control groups: one group of 55 Italian patients and a group of 75 German patients who did not receive adjuvant mitotane. Recurrence free survival (RFS) was significantly prolonged in the mitotane group (42 months vs 10 months). This study was the subject of much debate with concerns raised over possible lead- time bias and high recurrence rates suggestive of incomplete initial resection. There was a subsequent study from The University of Texas M.D. Anderson Cancer Center (MDACC) examining adjuvant mitotane11. Their study demonstrated that recurrence rates after ACC resection at MDACC (50%) were similar to the Italian patients treated with adjuvant mitotane (49%) despite the fact that the overwhelming majority of patients at MDACC did not receive mitotane. Within their study population they did note an increased RFS but no increased OS in patients receiving adjuvant therapy. Even with both studies utilizing institutional data from high volume centers the sample sizes were relatively small and heterogeneous. By utilizing the NCDB our study was able to perform analysis on a larger cohort of localized ACC patient at the cost of some more detailed outcomes such as RFS.
The first meta-analysis of adjuvant mitotane use in ACC patients was published in 2018. Tang et al. utilized 5 retrospective studies with 1,249 patients and included patients with nodal disease and stage IV disease. Studies with distant metastasis were excluded from the meta- analysis. This study showed that, as a whole, adjuvant mitotane increased both RFS and OS15. Utilization of meta-analysis helps to increase the sample size significantly but results in a loss of
some detail. In this meta-analysis it was not possible to focus exclusively on the T1-3, N0. The current study would suggest within the entire cohort of ACC patients the non-metastatic subgroup see the least benefit from adjuvant therapy with no difference in OS.
The NCDB was previously used by Tella et al. to examine predictors of survival in ACC patients14. This was a retrospective study examining all 3,185 patients with pathologically confirmed ACC from 2004 to 2015. The NCDB did not include variables regarding surgical approach until 2010. The surgical approach was a relevant variable as we were focused on a surgical cohort; thus our study only included ACC patients who underwent surgical resection with known surgical approach data (2010 to 2016). The study by Tella et al. reported that 72% of their patient population received surgical intervention and 23% received adjuvant chemotherapy. It was difficult to determine exactly which patients received adjuvant chemotherapy as the stage of ACC was unknown in 49% of patients included. Subgroup analysis of their patients with Stage I-III disease reveled that 96% of patients underwent surgery and 35% received adjuvant chemotherapy. Our study excluded Stage III patients with nodal Vozilaértelmetlen man involvement and noted a slightly lower rate of adjuvant chemotherapy use at 31%. The study by Tella et al. also highlights the importance of surgery when possible. Their multivariate Cox model noted that a worse survival outcome was associated with patients that had no surgical therapy.
A recent study from Italy examined adjuvant mitotane therapy in non-metastatic ACC patients and focused on high risk subgroups12. Their study included patients with ENSAT Stage I-III disease, 52 who received surgery alone and 100 who received surgery and adjuvant mitotane. They found patients receiving adjuvant mitotane treatment had increased RFS but the
OS was not significantly different. They also highlighted the importance of identifying subgroups that are most likely to benefit from adjuvant treatment and demonstrated that subgroups with ENSAT Stage III disease (n=37) and elevated Ki-67 (n=90) had improved OS when treated with adjuvant mitotane. In the present study we noted adjuvant chemotherapy had no statistical difference in OS for subgroups of patients with lymphovascular invasion, positive margin status, or T3 (Stage III) disease. Both studies are worth considering in the context of ESE-ENSAT guidelines that suggest adjuvant mitotane treatment for patients with a perceived high risk of recurrence. High risk features include ENSAT stage III disease, R1 resection, or Ki- 67>10%9. The NCCN guidelines also discuss consideration of adjuvant therapy with mitotane in patients with high risk of local recurrence as defined by Ki-67>10%, Non-RO resection, rupture of capsule, large size, or high grade10. Though we noted positive margin status and T3 (Stage III) disease had no statistical difference in OS with adjuvant chemotherapy it is significant that our study was unstable to asses RFS which may be relevant for clinical decision making. Another consideration for subgroup analysis of this ultrarare malignancy is the sample size. Despite using the NCDB, subgroup samples sizes were relatively small for patients who underwent curative-intent resection of localized ACC. We identified 144 patient with lymphovascular invasion, 110 patients with T3 (Stage III) disease, and 53 patients with positive margins. The subgroup with positive margins treated with adjuvant chemotherapy had over twice the median survival (46.7 months vs 22.0 months) in comparison to the surgery alone group, however, this was not statistically significant likely due to the sample size. 12
There are several limitations to consider when evaluating this study. Chiefly, the investigators note the retrospective design of our analysis introduces selection bias. Additionally, while the NCDB gathers data using trained clinical abstractors using validated techniques, there
are notably missing data with respect to details of chemotherapy regimens utilized and decision- making regarding their use20,21. Additionally, the absence of reported anatomic or operative variables limit our ability to stratify patients based on resectability of the primary tumor. To account for these shortcomings, we attempted to isolate a surgical population of patients without evidence of significant extra-adrenal disease. Finally, the authors recognize that the findings herein represent treatment patterns within Commission on Cancer centers and may not be externally generalizable to populations outside of this national hospital-based registry.
Conclusion
When compared to resection alone for localized non-metastatic (T1-3, NO) ACC, no OS benefit was observed with the addition of adjuvant systemic chemotherapy. Several patient and tumor factors including lymphovascular invasion, Stage II disease, and radiotherapy utilization demonstrated association with adjuvant chemotherapy use following adrenalectomy. In our analytic cohort, several high-risk subgroups including those with T3 disease, lymphovascular invasion, and positive margin status failed to demonstrate a survival benefit associated with the use of adjuvant chemotherapy. Use of adjuvant chemotherapy following adrenalectomy for localized non-metastatic ACC should be reserved for select populations after informed discussion with the patient and provider understanding there is a lack of clear and reproducible survival benefit observed in this complex patient population.
Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Adrenal PUF n=5,577
ACC Only n=3,918
cT1-T3, NO, MO ACC n=731
Only Patients With Adjuvant Chemotherapy Or No Chemotherapy n=712
Only Patients With Adrenalectomy n=577
389 Surgery Alone
188 Surgery and Adjuvant Chemotherapy
| Surgery Alone n=389 | Surgery and Adjuvant n=188 | Chemotherapy p | |
|---|---|---|---|
| Age (years), mean (SD) | 57 (15.1) | 51.6 (14.2) | <0.0001 |
| Sex | |||
| Male | 161 (41.4%) | 68 (36.2%) | 0.23 |
| Female | 228 (58.6%) | 120 (63.8%) | |
| Race | 0.24 | ||
| White | 330 (84.8%) | 168 (89.3%) | |
| Black | 39 (10%) | 11 (5.9%) | |
| Other | 20 (5.2%) | 9 (4.8%) | |
| Insurance | |||
| Public | 172 (44.2%) | 54 (28.7%) | 0.002 |
| Private | 193 (49.6%) | 123 (65.4%) | |
| Uninsured | 21 (5.4%) | 8 (4.3%) | |
| Unknown | 3 (0.8%) | 3 (1.6%) | |
| Charlson-Deyo | |||
| 0 | 279 (71.7%) | 144 (76.6%) | 0.34 |
| 1 | 86 (22.1%) | 37 (19.7%) | |
| >=2 | 24 (6.2%) | 7 (3.7%) | |
| Tumor size | |||
| <5cm | 51 (13.1%) | 21 (11.2%) | 0.79 |
| >=5cm | 281 (72.2%) | 140 (74.5%) | |
| Unknown | 57 (14.7%) | 27 (14.3%) | |
| Lymphovascular invasion | |||
| No | 184 (47.3%) | 63 (33.5%) | 0.001 |
| Yes | 120 (30.8%) | 86 (45.7%) | |
| Unknown | 85 (21.9%) | 39 (20.8%) | |
| Vascular Invasion | |||
| No | 237 (60.9%) | 99 (52.7%) | 0.01 |
| Yes | 78 (20.1%) | 59 (31.4%) | |
| Unknown/NA | 74 (19.0%) | 30 (15.9%) | |
| Grade | |||
| I/II | 34 (8.7%) | 13 (6.9%) | 0.59 |
| III/IV | 45 (11.6%) | 26 (13.8%) | |
| Unknown | 310 (79.7%) | 149 (79.3%) | |
| NCDB Analytic Stage | |||
| Stage I | 65 (16.7%) | 16 (8.5%) | 0.02 |
| Stage II | 227 (58.4%) | 112 (59.6%) |
| Stage III Unknown/NA | 97 (24.9%) 0 (0%) | 59 (31.4%) 1 (0.5%) | |
|---|---|---|---|
| Surgical Approach | 0.16 | ||
| Open | 257 (66.1%) | 138 (73.4%) | |
| Laparoscopic | 93 (23.9%) | 38 (20.2%) | |
| Robotic | 39 (10%) | 12 (6.4%) | |
| Margin Status | 0.18 | ||
| Negative | 310 (79.7%) | 138 (73.4%) | |
| Positive | 47 (12.1%) | 33 (17.6%) | |
| Unknown | 32 (8.2%) | 17 (9.0%) | |
| Treating Facility | 0.001 | ||
| Non- Academic/Research | 154 (39.6%) | 54 (28.7%) | |
| Academic Research | 185 (47.6%) | 89 (47.3%) | |
| Unknown | 50 (12.9%) | 45 (23.9%) | |
| Radiotherapy | <0.001 | ||
| No | 346 (88.9%) | 119 (63.3%) | |
| Yes | 43 (11.1%) | 68 (36.2%) | |
| Unknown | 0 (0%) | 1 (0.5%) |
| Predictor | OR 95% CI | P value | ||
|---|---|---|---|---|
| Age | 0.99 | 0.97 | 1.01 | 0.25 |
| Insurance | ||||
| Public | Reference | - | ||
| Private | 1.71 | 1.06 | 2.76 | 0.03 |
| Uninsured | 1.01 | 0.38 | 2.69 | 0.98 |
| Unknown | 3.77 | 0.65 | 21.72 | 0.14 |
| Lymph vascular invasion | ||||
| No | Reference | - | ||
| Yes | 1.82 | 1.12 | 2.97 | 0.02 |
| Unknown | 1.89 | 1.10 | 3.24 | 0.02 Proof |
| Vascular Invasion | ||||
| No | Reference | - | ||
| Yes | 1.18 | 0.71 | 1.97 | 0.53 |
| Unknown/NA | 0.72 | 0.42 | 1.25 | 0.24 |
| NCDB Analytic Stage | ||||
| Stage I | Reference | - | ||
| Stage II | 1.95 | 1.03 | 3.70 | 0.04 |
| Stage III | 1.86 | 0.93 | 3.75 | 0.08 |
| Unknown/NA | 1.00 | - | - | - |
| Treating Facility | ||||
| Non-Academic/Research | Reference | - | ||
| Academic Research | 1.42 0.92 | 2.21 | 0.12 | |
| Unknown | 1.62 | 0.72 | 3.65 | 0.25 |
| Radiotherapy | ||||
| No | Reference | - | ||
| Yes | 4.69 | 2.95 | 7.46 | <0.001 |
| Unknown | 1.00 | - | - | - |
| Univariate | Multivariate | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% | CI | p | HR | 95% | CI | p | ||
| Treatment Modality | |||||||||
| Surgery Alone Surgery and Adjuvant Chemotherapy | Ref | Ref | |||||||
| 1.25 | 0.91 | 1.73 | 0.17 | 1.21 | 0.84 | 1.74 | 0.30 | ||
| Age (year) | 1.01 | 1 | 1.03 | 0.01 | 1.04 | 1.02 | 1.07 | <0.001 | |
| Sex | |||||||||
| Male | Ref | Ref | |||||||
| Female | 0.97 | 0.7 | 1.34 | 0.86 | 0.94 | 0.66 | 1.34 | 0.74 | |
| Race | |||||||||
| White | Ref | Ref | |||||||
| Black | 1.07 | 0.6 | 1.88 | 0.83 | 1.30 | 0.71 | 2.38 | 0.40 | |
| Other | 0.61 | 0.25 | 1.5 | 0.28 | 0.73 | 0.29 | 1.84 | 0.51 | |
| Insurance | |||||||||
| Public | Ref | Ref | |||||||
| Private | 0.77 | 0.55 | 1.08 | 0.14 | 1.33 | 0.84 | 2.12 | 0.23 | |
| Uninsured | 1.36 | 0.73 | 2.53 | 0.33 | 2.91 | 1.33 | 6.40 | 0.01 | |
| Unknown | 2.09 | 0.76 | 5.77 | 0.16 | 1.64 | 0.51 | 5.25 | 0.41 | |
| Charlson-Deyo | |||||||||
| 0 | Ref | Ref | |||||||
| 1 | 1.23 | 0.83 | 1.82 | 0.29 | 1.39 | 0.91 | 2.11 | 0.13 | |
| >=2 | 1.8 | 0.94 | 3.44 | 0.08 | 0.78 | 0.37 | 1.63 | 0.51 | |
| Tumor Size | |||||||||
| <5cm | Ref | Ref | |||||||
| >=5cm | 1.53 | 0.91 | 2.57 | 0.11 | 0.98 | 0.50 | 1.90 | 0.94 | |
| Unknown | 1.16 | 0.15 | 8.77 | 0.88 | 0.95 | 0.11 | 7.86 | 0.96 | |
| NCDB Analytic Stage | |||||||||
| Stage I | Ref | Ref | |||||||
| Stage II | 2.74 | 1.33 | 5.66 | 0.01 | 3.20 | 1.31 | 7.82 | 0.01 | |
| Stage III | 4.66 | 2.23 | 9.76 | <0.001 | 4.28 | 1.69 | 10.82 | 0.002 | |
| Grade | |||||||||
| I/II | Ref | Ref | |||||||
| III/IV | 3.67 | 1.52 | 8.84 | 0.004 | 3.36 | 1.36 | 8.31 | 0.01 | |
| Unknown | 2.29 | 1.01 | 5.21 | 0.05 | 1.84 | 0.79 | 4.27 | 0.16 | |
| Lymphovascular Invasion | |||||||||
| No | Ref | Ref | |||||||
| Yes | 1.77 | 1.23 | 2.53 | 0.002 | 1.43 | 0.92 | 2.22 | 0.11 | |
| Unknown | 1.26 | 0.81 | 1.95 | 0.3 | 1.21 | 0.74 | 1.97 | 0.44 | |
| Vascular Invasion | |||||||||
| No | Ref | Ref | ||||||
|---|---|---|---|---|---|---|---|---|
| Yes | 1.22 0.84 | 1.76 | 0.3 | 1.06 | 0.68 | 1.64 | 0.81 | |
| Unknown | 1.46 0.95 | 2.25 | 0.09 | 1.44 | 0.89 | 2.33 | 0.14 | |
| Surgical Approach | ||||||||
| Open | Ref | Ref | ||||||
| Laparoscopic | 1.25 0.88 | 1.79 | 0.21 | 1.4 | 0.95 | 2.08 | 0.09 | |
| Robotic | 0.79 0.38 | 1.62 | 0.52 | 1.00 | 0.47 | 2.15 | 0.99 | |
| Margin Status | ||||||||
| Negative | Ref | Ref | ||||||
| Positive | 2.57 1.74 | 3.78 | <0.001 | 1.96 | 1.19 | 3.22 | 0.01 | |
| Unknown | 1.61 0.95 | 2.73 | 0.08 | 1.79 | 0.99 | 3.22 | 0.05 | |
| Facility Type | ||||||||
| Non-Academic/Research | Ref | Ref | ||||||
| Academic/Research | 1.2 0.84 | 1.72 | 0.32 | 1.40 0.94 | 2.08 | 0.10 | ||
| Unknown | 1.09 0.68 | 1.75 | 0.72 | 3.31 | 1.54 | 7.12 | 0.002 | |
| Radiotherapy | ||||||||
| No | Ref | Ref | ||||||
| Yes | 1.33 0.91 1 | 1.96 | 0.14 | 0.91 | 0.58 | 1.43 | 0.70 | |
Journa®
1.00
0.75
Survival
0.50
Pre-pro
0.25
0.00
0
20
40
60
80
Time to Death (Months)
100
Surgery Alone
Surgery and Adjuvant Chemotherapy
Reference:
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XE a.
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VIA A ČOTO NEBOLHERE.
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Journ 1804
Research Highlights
· NCDB study of neoadjuvant therapy in surgically treated population of localized ACC
· Lymphovascular invasion and radiotherapy associated with adjuvant chemotherapy
· Adjuvant chemotherapy in non-metastatic T3 ACC not associated with increased survival
· Adjuvant chemotherapy for localized ACC not associated with increased survival
Journal Pre-proof