National Treatment Practice for Adrenocortical Carcinoma: Have They Changed and Have We Made Any Progress?
John F. Tierney,1 Sitaram V. Chivukula,1 Jennifer Poirier,1 Sam G. Pappas,1 Erik Schadde,1,2,3,4 Martin Hertl,2 Electron Kebebew,5 and Xavier Keutgen6
1 Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, Chicago, Illinois 60612;
2Division of Transplant, Department of Surgery, Rush University Medical Center, Chicago, Illinois 60612;
3Cantonal Hospital Winterthur, Department of Surgery, 8400 Winterthur, Switzerland; 4Institute of Physiology, University of Zurich, 8006 Zurich, Switzerland; 5Division of General Surgery, Department of Surgery, Stanford University, Stanford, California 94305; and 6Endocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, The University of Chicago, Chicago, Illinois 60637
ORCID numbers: 0000-0003-0993-5534 (J. F. Tierney).
Background: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials.
Methods: The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). x2 tests were performed, and Cox proportional hazards models were created.
Results: From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after re- section (hazard ratio range: 1.39 to 3.09; P < 0.03).
Conclusions: Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed. (J Clin Endocrinol Metab 104: 5948-5956, 2019)
A drenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 0.72 to 2 per million (1, 2). It is the second-most aggressive endocrine
malignancy behind anaplastic thyroid cancer, and its disease-specific 5-year survival rate, ranging from 12% to 60%, has not changed in the past six decades (1, 3, 4).
First Published Online 30 July 2019
Abbreviations: ACC, adrenocortical carcinoma; FIRM-ACT, First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment; mitotane plus EDP, mitotane and etoposide, doxorubicin, and cisplatin; NCDB, National Cancer Database.
A previous study by Bilimoria et al. (3), which used the National Cancer Database (NCDB) to evaluate national treatment practices and survival for patients with ACC diagnosed from 1985 to 2005, found that only 16% of patients underwent surgery and received adjuvant therapy.
Since then, two landmark trials from a multicenter European group have been published regarding the role of chemotherapy in ACC. The first, published in 2007 by Terzolo et al. (5), demonstrated improved recurrence-free and overall survival for patients with resected ACC with macroscopically negative margins who received adjuvant mitotane compared with those who did not receive ad- juvant therapy. The second, the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT), published in 2012 by Fassnacht et al. (6), demonstrated improved progression-free survival for patients with unresectable tumors who received mitotane and etopo- side, doxorubicin, and cisplatin (mitotane plus EDP) compared with patients who received mitotane and streptozocin.
The effect of these studies on treatment of ACC re- mains unclear. The study by Terzolo et al. (5) is par- ticularly controversial, as it used a retrospective cohort design with heterogeneous follow-up between centers, which may have resulted in lead-time bias, and dem- onstrated relatively high recurrence rates in the control groups who did not receive mitotane, which may indicate incomplete initial resection (5, 7, 8).
We therefore used the NCDB to determine whether the publication of these trials affected national treatment practice and ultimately survival in the largest available cohort of patients with ACC. We hypothesized that a considerably higher proportion of patients received ad- juvant chemotherapy after 2007 and that this was as- sociated with longer survival in patients who underwent resection.
Methods
The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The NCDB and the hospitals participating in the NCDB are the source of the deidentified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors. Although the NCDB is not a population database, it is useful for examining treatment patterns, as it contains 70% of patients diagnosed with cancer in the United States from a wide range of treatment centers (9, 10). This study was exempt from institutional review board review because the NCDB is a public database that does not contain personally identifiable patient information.
Patients diagnosed with ACC from 2006 to 2015 were identified from the NCDB by primary site of either adrenal
cortex (C74.0) or adrenal gland not otherwise specified (C74.9) and by histology of adrenal cortical carcinoma (8370). Patients younger than 18 years were excluded. Patients diagnosed from 2006 to 2015 comprised the contemporary cohort.
Demographic characteristics (age, sex, race, ethnicity, in- come, education), tumor characteristics (laterality, size, dis- tant metastases), and hospital type were examined, and descriptive statistics were calculated. Surgical procedures were classified as either adrenal resection, adrenal resection in combination with a contiguous organ, debulking, and surgery not otherwise specified. Margin data were combined into three categories: involved resection margins, did not involve re- section margins, and unknown. Patients were classified as being treated with surgery plus adjuvant therapy if they un- derwent primary site surgery (RX_SUMM_SURG_PRIM_ SITE) and either chemotherapy (RX_SUMM_CHEMO), radiation therapy (RX_SUMM_RADIATION), or both. Pa- tients treated with mitotane were classified as receiving che- motherapy in the NCDB. Median survival time was calculated for the contemporary cohort.
X- tests were used to examine treatment modalities over time. Specific patient populations of interest were patients who underwent surgery and had adjuvant therapy before and after 2007 [the publication of the Terzolo et al. (5) study] and those who did not have surgery and were diagnosed before and after 2011 (after publication of the Fassnacht et al. (6) study). Patients with any stage of disease who underwent surgery and were diagnosed from 2006 to 2007 were com- pared with those diagnosed from 2008 to 2015 [before and after the publication of the Terzolo et al. (5) study], and patients with any stage disease who were diagnosed from 2006 to 2011 and did not have an operation were compared with those diagnosed from 2012 to 2015 (before and after the publication of the Fassnacht et al. (6) study). Treatment modalities were also compared between the current cohort of patients diagnosed from 2006 to 2015 and a historical cohort of patients diagnosed from 1985 to 2005 that was identified from a previously published NCDB study using the same inclusion criteria (3).
Kaplan-Meier curves were created for patients who un- derwent surgery with and without adjuvant therapy from 2006 to 2007 and from 2008 to 2010 and for patients who received chemotherapy alone from 2006 to 2012 and 2012 to 2015. Differences in survival were compared using Mantel-Haenszel tests. Demographic, surgical, and tumor characteristics were also compared between these groups using x tests (for cate- gorical variables) and Wilcoxon rank-sum tests (for age and tumor size).
Five-year survival and median survival rates were calculated for patients who had undergone resection. Cox proportional hazards models were created and compared to examine whether the following factors were associated with survival after an operation: age, margins, distant metastases, surgery type, sex, race, Hispanic ethnicity, income level, educational level, lat- erality, tumor size, adjuvant treatment, and hospital type. Grade and regional lymph node status were not evaluated because of missing data.
Finally, to assess whether ACC is being detected at an earlier stage than it was historically detected, x2 tests were used to compare the proportion of patients with distant metastases at the time of diagnosis as well as the rate at which patients with
distant metastases underwent surgery between the historical cohort and the current cohort.
All analyses were conducted in R 3.3.2 (11). P values for post hoc comparisons were adjusted using the Benjamini-Hochberg procedure. P values ≤0.05 were considered significant.
Results
A total of 2752 patients diagnosed with ACC from 2006 to 2015 (contemporary cohort) were included and were compared with 3982 patients diagnosed from 1985 to 2005 (historical cohort). Overall median survival for all stages in patients in the contemporary cohort was 24.0 months (95% CI: 21.9 to 26.6 months). Median age at the time of diagnosis was 56 years (interquartile range: 45 to 67 years), and 59% of patients (1632) were female. Median tumor size at diagnosis was 10.2 cm (interquartile range: 7 to 14 cm). Thirty-five percent of patients (951) presented with distant metastases at the time of diagnosis. Additional demographic and clinical characteristics for the contemporary cohort are presented in Table 1.
Overall, the percentage of patients who underwent an operation in the contemporary cohort diagnosed from 2006 to 2015 was smaller than the percentage in the historical cohort of patients diagnosed from 1985 to 2005 (69% vs 73%; P < 0.001). A higher proportion of patients were also treated with both surgery and adjuvant therapy in the contemporary cohort (31% vs 16%; P < 0.001) (Fig. 1). The proportion of patients in the current cohort who had distant metastases at the time of di- agnosis was higher than the proportion in the historical cohort (35.6% vs 21.6%; P < 0.001). There was no difference between the current and historic cohorts in the rate at which patients with metastases at diagnosis un- derwent surgery (34.1% vs 38.4%; P = 0.06).
Compared with patients diagnosed from 2006 to 2007, patients diagnosed from 2008 to 2015 who underwent surgery were more likely to receive adjuvant therapy (35.1% vs 20.4%; P < 0.001) (Fig. 2; Table 2). Five-year survival rates for patients who underwent an operation and received adjuvant chemotherapy improved from 25% in 2006 to 2007 to 41% from 2008 to 2010 (P = 0.02) (Fig. 3). There were no differences in the presence of distant metastases at diagnosis, type of surgery, resection margins, patient age, tumor size, or tumor laterality be- tween patients in these two groups (P = 0.12 to 0.86) (Table 3). Patients who had surgery with adjuvant che- motherapy from 2008 to 2010 were more likely to receive radiation therapy than those diagnosed in 2006 to 2007 (OR: 3.13; P = 0.005). A multivariable Cox proportional hazards model that included these variables as well as chemotherapy and date of diagnosis was created but failed proportionality assumptions because the relationship
between chemotherapy and survival was not consistent across time (P = 0.008).
There was no significant difference in survival among patients who underwent surgery without adjuvant therapy between 2006 to 2007 and 2008 to 2010 (5-year survival was 51.4% vs 44.4%; P = 0.11).
Among patients with unresected tumors, there was no difference in the proportion of patients who re- ceived chemotherapy from 2006 to 2011 compared with those who received chemotherapy from 2012 to 2015 (10.7% vs 11.2%; P = 0.75). Among pa- tients who did not undergo surgery, there was also no
| Characteristics | n | % |
|---|---|---|
| Patients | 2752 | |
| Women | 1632 | 59.3 |
| Median age (interquartile range), y | 56 (45-67) | |
| Race | ||
| White | 2459 | 85.7 |
| Black | 258 | 9.4 |
| Asian/Pacific Islander | 74 | 2.7 |
| Other/unknown | 61 | 2.2 |
| Hispanic | 185 | 6.7 |
| Median income (2012)ª | ||
| <$38,000 | 434 | 16.0 |
| $38,000-$47,999 | 633 | 23.4 |
| $48,000-$62,999 | 748 | 27.6 |
| $63,000+ | 893 | 33.0 |
| Education (2012) (% w/o high school degree)b | ||
| 21% + | 467 | 17.2 |
| 13%-20% | 700 | 25.8 |
| 7%-12.9% | 860 | 31.7 |
| <7% | 683 | 25.2 |
| Laterality | ||
| Right | 1195 | 43.4 |
| Left | 1430 | 52.0 |
| Unilateral NOS | 9 | 0.3 |
| Bilateral | 14 | 0.5 |
| Unknown | 104 | 3.8 |
| Median tumor size in cm (interquartile range)" 10.2 (7-14) | ||
| Distant metastasesª | 951 | 34.6 |
| Hospital type | ||
| Academic/research program (including | 1155 | 42.0 |
| NCI) | ||
| Comprehensive community cancer | 763 | 27.7 |
| program | ||
| Integrated network cancer program | 237 | 8.6 |
| Community cancer program | 137 | 5.0 |
| Unknown | 460 | 16.7 |
Abbreviations: NCI, National Cancer Institute; NOS, not otherwise specified.
ªForty-four patients (1.6%) were missing data on income.
bForty-two patients (1.5%) were missing data on education.
“Two hundred eighty-eight patients (10.5%) were missing data on tumor size.
Eighty-four patients (3.1%) were missing data on distant metastases.
Treatment Modalities over Time
100%
3,10%
3.90%
12.40%
10.50%
80%
60%
37.90%
57.40%
40%
31.20%
20%
16%
0%
11.20%
16.30%
1985-2005 (n =3982)
2006-2015 (n =2752)
Radiation and /or Chemotherapy Surgery and Adjuvant Therapy
Surgery Only
No treatment
Unknown
difference in 2-year survival rates before and after the publication of the FIRM-ACT trial. Among patients with unresected tumors, the 2-year survival rate was 15.9% for patients diagnosed from 2006 to 2011 and 11.5% for patients diagnosed from 2012 to 2015 (P = 0.79).
On univariable analysis, older patient age, tumor size >10 cm, presence of distant metastases, debulking sur- gery, or resection with contiguous organ removal (compared with adrenal resection), positive margins, and unknown laterality (compared with right-sided) tumors were associated with decreased survival in patients who underwent an operation (Table 4). On multivariable analysis, when controlling for other significant variables, older age, tumor size >10 cm, distant metastases, and positive margins were associated with decreased survival after an operation (hazard ratio: 1.39 to 3.09; P < 0.03) (Table 5).
Treatment Modalities Before and After 2007
100.00%
11.50%
10.80%
80.00%
36.50%
60.00%
52.60%
40.00%
35.10%
20.00%
20.40%
15.50%
17.60%
0.00%
2006-2007 (n =470)
2008-2015 (n =2176)
Radiation and /or Chemotherapy Surgery and Adjuvant Therapy
Surgery Only
No treatment
Discussion
This study demonstrated that overall survival among patients with ACC remains low, particularly among pa- tients with unresectable disease.
The Terzolo et al. (5) study pub- lished in 2007 found that patients who received adjuvant mitotane follow- ing resection of ACC had prolonged recurrence-free and overall survival rates compared with those who un- derwent resection alone. It was criti- cized following its publication because it was not a randomized controlled trial and because it showed relatively high recurrence rates of 91% and 73% in the groups of patients who did not receive mitotane (7, 8). Subsequent publications sought to refute its finding and instead emphasized the completeness of resection as the most important prognostic factor (7). Despite these valid critiques of Terzolo et al. (5), we found that the use of adjuvant therapy in the United States did in fact increase after 2007. Although the NCDB does not provide information on the type of chemotherapy each patient receives, it is likely that this increase reflects greater use of mitotane in ACC, as the systemic options for ACC treatment are few and, to our knowledge, no published trials have used other che- motherapies in the adjuvant setting. The increased use of adjuvant therapy reflects the current guidelines from the European Society of Endocrinology, which recom- mend that adjuvant mitotane be given to patients with grossly negative surgical margins but a high risk of recurrence, which is defined as European Society of Endocrinology stage III, or R1 re- section, or Ki67 > 10% (12).
Of note, similar to the findings of Terzolo et al. (5), in our study survival among patients who underwent an operation with adjuvant chemother- apy significantly improved after 2007, despite the fact that there were no differences in patient age, stage at di- agnosis, type of surgery, or resection margins between the two groups. Pa- tients who underwent surgery with adjuvant chemotherapy were more likely to receive radiation therapy after 2007, which may confound any con- clusions regarding survival. However, on univariable or multivariable anal- ysis in this study, radiation therapy
| Treatment Modality | 2006-2007 | 2008-2015 | P Value | ||
|---|---|---|---|---|---|
| N | % | N | % | ||
| Radiation and/or chemotherapy | 73 | 15.5% | 384 | 17.6% | 0.30 |
| Surgery and adjuvant therapy | 96 | 20.4% | 763 | 35.1% | <0.001 |
| Surgery only | 247 | 52.6% | 795 | 36.5% | <0.001 |
| No or other treatment modality | 54 | 11.5% | 234 | 10.8% | 0.70 |
was not associated with prolonged survival after resection and was not shown to prolong disease-free or overall survival rates in previous studies, despite possibly de- creasing local recurrence (13). We attempted to perform a multivariable survival analysis that included chemother- apy and the other factors that were significantly associated with survival, but the model failed because the relationship between chemotherapy use and survival changed over time. We therefore hypothesize that patients who received chemotherapy after 2007 had improved survival because they received chemotherapy, as no other differences be- tween the two groups explained the longer survival.
It is also possible that the improved survival with surgery and adjuvant chemotherapy after 2007 is not necessarily attributable to the adjuvant use of mitotane, but could reflect a selection bias, whereby chemotherapy was offered to patients who had a naturally better prognosis; this explanation is less likely, however, because patients receiving adjuvant chemotherapy were similar in characteristics to patients who did not receive it. Other
Strata
Group=2006-2007 + Group=2008-2010
1.00
0.75
Survival probability
0.50
0.25
0.00
0
25
50
75
100
125
Months
retrospective studies have shown that the use of adjuvant mitotane is associated with improved disease-free survival and improved overall survival, which supports its effect on survival in this study (5, 7). It remains to be determined whether all patients with resected ACC require adjuvant mitotane or if only certain high-risk features should be considered for this therapy. An ongoing randomized controlled trial of adjuvant mitotane after initial resection of ACC should help explain some of this uncertainty (14).
It is also worth noting that median survival after re- section of 41 months in our study was longer than the 32 months found in a previous NCDB analysis by Bilimoria et al. (3). Similar to that study, we found that older age, larger tumor size, presence of distant metastases, and positive margins were independently associated with decreased survival after resection (1, 3, 11). The persis- tence of margin status as a predictor of mortality un- derscores the effect of obtaining an adequate resection on overall survival. The study by Bilimoria et al. (3) found that nearly 20% of patients who underwent resection had positive margins and therefore empha- sized the importance of adequate sur- gical resection.
The most important prognostic factor for survival remains the presence of distant metastases, which is associ- ated with a 5-year survival rate of just 9.5% and a threefold increased risk of death after an operation. In this study, we found that patients were more likely to have distant metastases at diagnosis than patients in the Bilimoria et al. (3) study (35.6% vs 21.6%, re- spectively). We presume that this finding is explained by more aggressive staging strategies and improved resolution of modern imaging, allowing for detection of smaller metastases, rather than a more aggressive tumor biology.
We also found that the publication of the FIRM-ACT trial in 2012 did not influence the percentage of patients who did not receive systemic treatment
| 2006-2007 | 2008-2010 | P Value | |||
|---|---|---|---|---|---|
| n | % | n | % | ||
| Stage | 0.80 | ||||
| No metastases at diagnosis | 293 | 65.3% | 517 | 66.0% | |
| metastases at diagnosis | 156 | 34.7% | 266 | 34.0% | |
| Type of surgery | 0.86 | ||||
| Resection | 279 | 78.8% | 460 | 76.7% | |
| Resection with contiguous organ | 58 | 16.4% | 107 | 17.8% | |
| Debulking | 3 | 0.8% | 8 | 1.3% | |
| Surgery NOS | 14 | 4.0% | 25 | 4.2% | |
| Resection margins | 0.37 | ||||
| Uninvolved | 231 | 86.2% | 389 | 84.9% | |
| Microscopic | 29 | 10.8% | 61 | 13.3% | |
| Macroscopic | 8 | 3.0% | 8 | 1.7% | |
| Laterality | 0.76 | ||||
| Right | 47 | 49.0% | 127 | 46.9% | |
| Left | 47 | 49.0% | 140 | 51.7% | |
| Unilateral NOS | 0 | 0% | 0 | 0% | |
| Bilateral | 0 | 0% | 0 | 0% | |
| Unknown | 2 | 2.1% | 4 | 1.5% | |
| Median | SD | Median | SD | ||
| Age, y | 49.2 | 15.9 | 49.6 | 15.0 | 0.85 |
| Tumor size, cm | 126.5 | 55.8 | 115.4 | 61.7 | 0.12 |
Abbreviation: NOS, not otherwise specified.
of ACC, which remained ~11%. The NCDB does not distinguish between different types of chemotherapy, which limited our ability to evaluate the effect of the FIRM-ACT trial. It is possible that patients with unre- sectable tumors are now receiving mitotane plus EDP instead of streptozocin, which was an established treat- ment of ACC before 2012 (15, 16). Regardless of this uncertainty, however, we found that survival in unre- sected patients who received chemotherapy did not change after 2012. This is altogether not unexpected, as FIRM-ACT demonstrated a response rate for mitotane plus EDP of merely 23%, without an overall survival benefit (6).
Over the past decade, numerous small-scale phase 2 trials of targeted chemotherapy and immunotherapies for ACC, including sorafenib, erlotinib, sunitinib, axitinib, and bevacizumab, have been published with disap- pointing results (17-21). A study of 135 ACC samples found that more than half of the tumors expressed biomarkers that mediate resistance to either mitotane, etoposide, doxorubicin, or cisplatin, but the authors suggested that molecular profiling could detect specific mutations that could serve as targets of therapy (22). The persistent poor survival rates for patients with unresectable tumors demonstrated here-a 2-year survival rate of 11.5% from 2012 to 2015-reinforces the urgency of continuing to investigate novel therapies for ACC.
This study has several limitations, in addition to the inherent data entry errors common to all large database studies. First, the NCDB is a retrospective database, so any findings regarding differences in survival are ob- servational and subject to selection bias. Second, the NCDB does not provide information regarding the specific type of chemotherapy used. We are therefore able to say that the use of adjuvant chemotherapy increased after 2008 and that survival among patients who received adjuvant therapy improved, but we are unable to directly attribute that improved survival to mitotane. We are also unable to determine whether patients received thera- peutic levels of mitotane or complete courses of EDP. Third, the NCDB only provides information regarding treatment in the first 6 months after diagnosis, so we were unable to investigate time to recurrence or the treatment of recurrences. Fourth, the NCDB does not provide in- formation about hormones secreted by tumors, which may affect survival and treatment decisions (7, 15, 23). Finally, tumor grade, which can influence whether pa- tients receive adjuvant chemotherapy, was missing in a majority of patients, preventing inclusion of this variable in the analysis.
This study demonstrated that adjuvant therapy has been used more frequently in patients with resected ACC since 2007 and that survival for these patients has improved but remains low. Complete resection with negative margins remains an essential component of
| Factors | 5-Year Observed Survival | Median Survival (Month) | P Value |
|---|---|---|---|
| Sex | 0.47 | ||
| Male (n = 389) | 44.6% | 44.8 | |
| Female (n = 565) | 42.5% | 40.1 | |
| Age | <0.001 | ||
| 18-35 y (n = 129) | 42.1% | 40.1 | |
| 36-55 y (n = 411) | 50.0% | 57.6 | |
| 56-75 y (n = 347) | 39.3% | 32.1 | |
| 76 y or more (n = 67) | 25.9% | 19.9 | |
| Race | 0.66 | ||
| White (n = 837) | 42.9% | 40.1 | |
| Black (n = 75) | 46.4% | 46.5 | |
| Asian/Pacific Islander (n = 22) | 57.1% | 78.2 | |
| Other/unknown (n = 20) | 33.2% | 41.5 | |
| Hispanic ethnicity | 0.86 | ||
| Hispanic (n = 56) | 48.2% | 56.9 | |
| Not Hispanic (n = 821) | 42.8% | 40.5 | |
| Unknown (n = 77) | 45.1% | 43.0 | |
| Income 2012 | 0.56 | ||
| <$38,000 (n = 131) | 40.5% | 37.4 | |
| $38,000-$47,999 (n = 232) | 44.9% | 49.0 | |
| $48,000-$62,999 (n = 263) | 43.5% | 44.1 | |
| $63,000+ (n = 301) | 44.8% | 40.2 | |
| Education 2012 (% with no high school degree) | 0.97 | ||
| 21%+ (n = 145) | 45.6% | 44.9 | |
| 13%-20% (n = 243) | 42.9% | 46.6 | |
| 7%-12.9% (n = 307) | 43.5% | 40.5 | |
| <7% (n = 233) | 44.5% | 40.1 | |
| Laterality | 0.02 | ||
| Primary right (n= 417) | 44.0% | 46.0 | |
| Primary left (n = 521) | 43.6% | 37.9 | |
| Unilateral unspecified (n = 2) | 50% | 6.2 | |
| Unknown (n = 14) | 14% | 13.9 | |
| Tumor size | <0.001 | ||
| <10 cm (n = 402) | 49.7% | 56.3 | |
| ≥10 cm (n = 477) | 36.4% | 32.3 | |
| Distant metastases | <0.001 | ||
| Absent (n = 760) | 50.2% | 60.2 | |
| Present (n = 151) | 9.5% | 12.4 | |
| Hospital Type | 0.08 | ||
| Academic/research (includes NCI) (n = 391) | 42.5% | 35.0 | |
| Comprehensive community cancer program (n = 261) | 38.9% | 36.5 | |
| Integrated network cancer program (n = 85) | 44.3% | 41.0 | |
| Community cancer program (n = 36) | 75.8% | 96.8 | |
| Type of surgery | <0.001 | ||
| Resection (n = 739) | 45.9% | 47.1 | |
| Resection with contiguous organ (n = 165) | 34.1% | 28.2 | |
| Debulking (n = 11) | 0% | 7.5 | |
| Surgery NOS (n = 39) | 46.4% | 49.4 | |
| Margin status | <0.001 | ||
| Uninvolved (n = 620) | 51.8% | 66.5 | |
| Microscopic (n = 90) | 31.7% | 22.4 | |
| Macroscopic (n = 16) | 34.7% | 12.6 | |
| Chemotherapy | 0.07 | ||
| No (n = 608) | 46.4% | 47.2 | |
| Yes (n = 316) | 36.1% | 30.8 | |
| Radiation therapy | 0.96 | ||
| No (n = 831) | 43.5% | 42.1 | |
| Yes (n = 115) | 40.8% | 36.3 |
Abbreviations: NCI, National Cancer Institute; NOS, not otherwise specified.
| Variable | HR | 95% CI | P Value |
|---|---|---|---|
| Age: 56-75 y | 1.49 | 1.07-2.07 | 0.02 |
| Age: 76 y or more | 2.29 | 1.48-3.54 | <0.001 |
| Tumor size 10 cm or greater | 1.39 | 1.12-1.72 | 0.002 |
| Distant metastases present | 3.09 | 2.39-3.99 | <0.001 |
| Microscopic or macroscopic margins present | 1.76 | 1.35-2.30 | <0.001 |
Reference groups (HR = 1): age: 55 y of age or younger; tumor size <10 cm; distant metastases absent; margins uninvolved. Abbreviation: HR, hazard ratio.
treatment of localized disease. Further research should focus on novel therapies for patients with advanced, recurrent, unresectable, and margin-positive disease.
Acknowledgments
Presented in part at the 2018 Clinical Congress of the American College of Surgeons, Boston, Massachusetts, October 2018.
Author Contributions: All authors approved the final manuscript.
Additional Information
Correspondence and Reprint Requests: Xavier Keutgen, MD, Department of Surgery, Division of General Surgery and Surgical Oncology, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 4052, Chicago, Illinois 60637. E-mail: xkeutgen@surgery.bsd.uchicago.edu.
Disclosure Summary: The authors have nothing to disclose.
Data Availability: Restrictions apply to the availability of data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
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