Abstract
Background:
As exemplified in patients with adenoid cystic carcinoma (ACC), metastatic salivary gland cancers display heterogenous behavior. Though anatomic site of metastasis has been suggested to be prognostic for survival in this population, this is not adequately characterized in the current literature.
Methods:
Using the National Cancer Database (NCDB), patients with newly diagnosed metastatic salivary gland cancers with distant metastasis to a single organ were identified.
Results:
858 patients (n=284 bone-only, n=322 lung-only, n=252 other-site-only) were identified. Anatomic site of distant metastasis was not associated with survival in the cohort as a whole; however, on pre-planned subgroup analysis, lung-only metastasis, relative to bone-only metastasis, was the only factor associated with improved survival in patients with ACC (HR:0.52; 95%-CI:0.30–0.93; P=.029).
Conclusions:
Anatomic site of metastasis is strongly associated with survival in patients with metastatic ACC and should be considered in future studies aiming to optimize therapy in this population.
Keywords: metastasis, head and neck neoplasms, salivary gland neoplasms, adenoid cystic carcinoma
INTRODUCTION
Malignant salivary neoplasms are a rare, heterogenous class of cancers, which account for only a small percentage of all head and neck cancers.1 The most recent World Health Organization classification recognizes greater than 20 different malignant salivary gland histologies, among which the propensity for distant metastasis vary considerably.1,2 Long-term prognosis following distant metastasis is also quite variable among patients afflicted by salivary gland neoplasms; while tumors of some histologies have been demonstrated to proceed along a relatively indolent course after distant metastasis, somewhat uniformly poor outcomes have been reported following distant metastasis in other histologies.3
Several series describe long-term survival despite distant metastasis in patients with salivary gland cancers; this is most prominently reported in patients with adenoid cystic carcinoma (ACC).3–7 Although most patients with ACC have localized disease at the time of presentation, long-term rates of distant metastasis approach 50% in some series.7–9 While survival in excess of 10 years following distant metastasis has been reported in some patients with ACC3,7 this is not the norm; rather, the median survival following distant metastasis has been estimated to be around 3 years.6,8 There are little data to explain the disparate long-term outcomes observed among patients with metastatic ACC. Though prognostic factors within this population are not well-characterized currently, it has been suggested that anatomic site of distant metastasis may be an indicator of long-term outcomes.4–6
Among patients with ACC, distant metastasis most commonly occurs to the lung followed by the bone and liver, respectively.1,9,10 It has been suggested that relative to metastasis to the bone, liver, and other distant sites, lung metastasis is associated with a less aggressive phenotype and improved long-term survival in patients with metastatic ACC.4–6 While several series have demonstrated improved outcomes among patients with distant metastasis to the lung compared to other anatomic sites, the conclusions of these series are largely restricted by their small sample size and inherent inability to adequately account for multiple potentially confounding variables that may also be associated with survival in this population.4–6 Moreover, given that the majority of ACCs initially metastasize to the lung,1,9,10 the involvement of other metastatic sites may reflect increasing disease burden rather than distinct biology and/or may introduce an immortal time bias where the improved survival with lung-only metastasis simply represents an earlier state of metastatic progression.7 Thus, it remains unclear how the survival of patients with metastatic ACC is influenced by the anatomic site of metastasis in the context of other distinct patient, tumor, and treatment variables.
Given that the currently reported literature does not adequately characterize the impact of site of metastasis on long-term survival among patients with metastatic ACC, we used the National Cancer Database (NCDB) to investigate this further. In an attempt to control for differing degrees of disease burden and potential immortal time bias, we limited our study to the subset of patients with de novo metastatic disease and metastasis limited to a single anatomic site at the time of initial presentation. We hypothesized that in patients with newly diagnosed metastatic ACC with metastases in one anatomic site, patients with metastases in only the lung would have improved survival compared to patients with metastasis limited to the bone or a different anatomic site. Given that few, if any, studies have examined the prognostic value of site of metastasis in salivary gland histologies besides ACC, we similarly examined the impact of metastatic site in patients with other major salivary gland histologies in whom metastatic disease was limited to a single organ at the time of their initial presentation with the hypothesis that metastatic site may also be prognostic in patients with other salivary gland histologies.
MATERIALS AND METHODS
Data sources
This study utilized the NCDB which is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC’s NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified 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. The NCDB has set criteria to ensure the data submission by each cancer center meets pre-specified quality benchmarks. Exemption from review was provided by The University of Illinois at Chicago Institutional Review Board.
Definition of the analyzed cohort
This analysis included patients age ≥ 18 years old who had de novo metastatic salivary gland cancers involving a single organ site at the time of initial diagnosis (e.g. one or more pulmonary metastases or alternatively one or more osseous metastases, but not both pulmonary and osseous metastases). Patients received at least part of the initial treatment at the reporting facility. Patients diagnosed prior to the year 2010 were excluded from this analysis, as the site of distant metastasis was not recorded in the NCDB prior to this year.
From the initially identified 37,168 patients in the NCDB with major salivary gland cancers, patients with no clinical or pathologic evidence of metastatic disease were excluded yielding 2,163 patients. Patients with unknown or more than one anatomic site of metastasis were subsequently excluded resulting in 1,049 patients. Although patients with squamous cell carcinoma (SCC) were initially included and analyzed as part of our cohort; given the exceedingly rare nature of primary salivary gland SCC and the concern that a significant proportion of these cases may represent patients with distant metastases to the salivary glands from non-salivary primaries,11,12 this subpopulation was subsequently excluded from the cohort yielding 858 patients for analysis. The criteria used to delineate the analyzed population are further detailed in Figure 1.
Figure 1. Schema to define the study cohort.
From the initially identified 37,168 patients in the NCDB with major salivary gland cancers, patients with no clinical or pathologic evidence of metastatic disease were excluded yielding 2,163 patients. Patients with unknown or more than one sites of metastasis were subsequently exlcluded resulting in 1,049 patients. Given the exceedingly rare nature of primary squamous cell carcinoma of the major salivary glands and concern that the majority of these cases likely represented metastases from distant primary sites, squamous cell carcinomas were excluded yielding the final cohort of 858 patients.
Variables
Demographic variables included age, sex, comorbidity, and year of diagnosis. Age was grouped into four categories: ≤ 50 years, 51–60 years, 61–70 years, and > 70 years. Comorbidity index was based on Charlson-Deyo comorbidity score of either 0–1 or ≥ 2.13 Year of diagnosis was grouped into 2 categories: 2010–2013 and 2014–2016. Clinical variables included the site of the primary malignancy, histology of the primary malignancy, AJCC 7th edition clinical T-classification, AJCC 7th edition clinical N-classification, and site of distant metastasis. Sites of the primary malignancy included: parotid gland, submandibular gland, sublingual gland, and salivary gland not otherwise specified (NOS). Histology of the primary malignancy was grouped into 8 categories: ACC, acinar, adenocarcinoma, ductal/lobular, epithelial, mucoepidermoid, sarcoma, and other/NOS. Clinical T-classification was grouped into cT0, cT1-T2, and cT3-T4. Clinical N-classification was grouped into cN0–1 and cN2–3. Site of distant metastasis was grouped into 3 categories: bone-only, lung-only, and other-site-only (i.e. a single anatomic site other than bone or lung); other sites of metastasis included brain, liver, distant lymph nodes, and other/NOS. Treatments received included surgery, radiotherapy, chemotherapy, and immunotherapy.
Statistical analysis
Data were analyzed using JMP version 14 (Cary, NC, USA). All tests of statistical significance were two-sided and significance was defined as a value of P < .05. The chi-square test was used to test for associations among categorical variables. Central tendency of continuous variables is represented by the median, which is presented in addition to the interquartile range (IQR) where relevant. Differences among medians of continuous variables were assessed using the Kruskal-Wallis test. Logistic regression was performed to obtain odds ratios (ORs) for patient/tumor variables and site of distant metastasis, which are reported with their respective 95% confidence intervals (CIs); likelihood ratios were used to test for associations between patient/tumor variables and site of distant metastasis. Survival curves were created using the Kaplan-Meier method and comparisons to determine the effect of site of metastasis on survival were made using the log-rank test. The Cox-model was used to determine hazard ratios (HRs) for overall survival for the examined variables. HRs and their respective 95% CIs were estimated on univariable analysis and subsequently multivariable analysis adjusting for relevant covariates (defined as a value of P < .10 on univariable analysis).
RESULTS
A total of 858 patients with a single anatomic site of distant metastatic disease were included in the analyzed cohort; 284 (33.1%) had bone-only metastases, 322 (37.5%) had lung-only metastases, and 252 (29.3%) had distant metastases in a different single anatomic site. Among patients with distant metastases to other sites, 68 (27.0%) had liver metastases, 22 (8.7%) had brain metastases, and 9 (3.6%) had distant lymph node metastases; site of distant metastasis was NOS for the remaining 153 (60.7%) patients with non-osseous, non-pulmonary sites of metastatic disease. 366 (42.7%) patients were indicated to have disease that was pathologically-classified as M1, while the remainder of the patients included were indicated to be clinically M1 with pathology obtained from a non-distant site.
Patient and treatment characteristics are shown, stratified by anatomic site of metastasis, in Table 1. Median follow-up for the entire cohort was 14.4 months (IQR 6.4–26.5 months) and did not vary significantly among those with bone-only metastases, lung-only metastases, and other solitary metastatic sites (P = .4195). The median age of patients in the cohort was 66 years (IQR 56–76 years) at the time of diagnosis. Age at the time of diagnosis did not differ by site of distant metastasis (P = .7683). Women (n = 277) accounted for 32.2% of the cohort and had different anatomic patterns of distant metastasis compared to men (P = .0002). Most notably, women were less likely to develop bone-only metastasis as opposed to lung-only metastasis, relative to men (Table 2; OR 0.49; 95% CI 0.34–0.69; P < .0001). The median Charlson-Deyo Comorbidity Index score was 0 (IQR 0–1) and comorbidity index did not vary significantly among groups (P = .3457).
Table 1.
Patient and treatment characteristics (Number of patients = 858)
| Site of Metastasis |
||||
|---|---|---|---|---|
| Bone-only No. of pts (%) |
Lung-only No. of pts (%) |
Other-site-only No. of pts (%) |
P value | |
| Median follow-up (mo.) (IQR) | 14.4 (6.7–25.7) |
15.3 (6.7–28.8) |
13.3 (5.8–26.4) |
.4195 |
| Age (years) | .7683 | |||
| ≤ 50 | 47 (16.6) | 43 (13.4) | 33 (13.1) | |
| 51–60 | 60 (21.1) | 69 (21.4) | 50 (19.8) | |
| 61–70 | 70 (24.7) | 79 (24.5) | 73 (29.0) | |
| > 70 | 107 (37.7) | 131 (40.7) | 96 (38.1) | |
| Sex | .0002 | |||
| Male | 214 (75.4) | 193 (59.9) | 174 (69.1) | |
| Female | 70 (24.7) | 129 (40.1) | 78 (31.0) | |
| Year of diagnosis | .0509 | |||
| 2010–2013 | 144 (50.7) | 164 (50.9) | 151 (59.9) | |
| 2014–2016 | 140 (49.3) | 158 (49.1) | 101 (40.1) | |
| Charlson-Deyo | .3457 | |||
| 0–1 | 269 (94.7) | 298 (92.6) | 240 (95.2) | |
| ≥ 2 | 15 (5.3) | 24 (7.5) | 12 (4.8) | |
| Site | < .0001 | |||
| Parotid gland | 198 (69.8) | 177 (55.0) | 172 (68.3) | |
| Submandibular gland | 28 (9.9) | 61 (18.9) | 36 (14.3) | |
| Sublingual gland | 1 (0.4) | 12 (3.7) | 2 (0.8) | |
| NOS* | 57 (20.1) | 72 (22.4) | 42 (16.7) | |
| Histology | < .0001 | |||
| Adenoid cystic | 25 (8.8) | 99 (30.8) | 34 (13.5) | |
| Acinar | 7 (2.5) | 12 (3.7) | 7 (2.8) | |
| Adenocarcinoma | 98 (34.5) | 74 (23.0) | 75 (29.8) | |
| Ductal carcinoma | 24 (8.5) | 12 (3.7) | 10 (4.0) | |
| Epithelial | 17 (6.0) | 12 (3.7) | 16 (6.4) | |
| Mucoepidermoid | 18 (6.3) | 37 (11.5) | 23 (9.1) | |
| Other/NOS* | 78 (27.5) | 51 (15.8) | 69 (27.4) | |
| Sarcoma | 17 (6.0) | 25 (7.8) | 18 (7.1) | |
| T-classification | .5584 | |||
| cT0 | 72 (25.4) | 78 (24.2) | 70 (27.8) | |
| cT1-T2 | 75 (26.4) | 91 (28.3) | 59 (23.4) | |
| cT3–4 | 126 (44.4) | 144 (44.8) | 119 (47.2) | |
| Unknown | 11 (3.9) | 9 (2.8) | 4 (1.6) | |
| N-classification | .0086 | |||
| cN0–1 | 117 (41.2) | 175 (54.4) | 107 (42.5) | |
| cN2–3 | 126 (44.4) | 108 (33.5) | 113 (44.8) | |
| Unknown | 41 (14.4) | 39 (12.1) | 32 (12.7) | |
| Surgery | .2912 | |||
| No | 182 (64.1) | 191 (59.3) | 145 (57.5) | |
| Yes | 102 (35.9) | 131 (40.7) | 106 (42.1) | |
| Unknown | 0 (0.0) | 0.0 (0.0) | 1 (0.4) | |
| Radiotherapy | .2270 | |||
| No | 116 (40.9) | 159 (49.4) | 120 (47.6) | |
| Yes | 163 (57.4) | 160 (49.7) | 130 (51.6) | |
| Unknown | 5 (1.8) | 3 (0.9) | 2 (0.8) | |
| Chemotherapy | .1003 | |||
| No | 129 (45.4) | 182 (56.5) | 125 (49.6) | |
| Yes | 142 (50.0) | 128 (39.8) | 115 (45.6) | |
| Unknown | 13 (4.6) | 12 (3.7) | 12 (4.8) | |
| Immunotherapy | .1342 | |||
| No | 265 (93.3) | 310 (96.3) | 246 (97.6) | |
| Yes | 18 (6.3) | 11 (3.4) | 5 (2.0) | |
| Unknown | 1 (0.4) | 1 (0.3) | 1 (0.4) | |
NOS = Not otherwise specified
Table 2.
Patient characteristics and odds of developing bone-only, lung-only, and other-site-only metastases (Number of patients = 858)
| Bone-only vs. Lung-only |
Bone-only vs. Other-site-only |
Lung-only vs. Other-site-only |
||||
|---|---|---|---|---|---|---|
|
|
||||||
| OR (95% CI) | P value | OR (95% CI) | P value | OR (95% CI) | P value | |
| Age (years) | ||||||
| ≤ 50 | Reference | Reference | Reference | |||
| 51–60 | 0.80 (0.46–1.36) | .4058 | 0.84 (0.47–1.51) | .5641 | 1.06 (0.59–1.89) | .8466 |
| 61–70 | 0.81 (0.48–1.37) | .4324 | 0.67 (0.39–1.17) | .1608 | 0.83 (0.48–1.45) | .5112 |
| > 70 | 0.75 (0.46–1.22) | .2402 | 0.78 (0.46–1.32) | .3587 | 1.05 (0.62–1.77) | .8631 |
| Sex | ||||||
| Male | Reference | Reference | Reference | |||
| Female | 0.49 (0.34–0.69) | < .0001 | 0.73 (0.50–1.07) | .1038 | 1.49 (1.05–2.11) | .0244 |
| Year of diagnosis | ||||||
| 2010–2013 | Reference | Reference | Reference | |||
| 2014–2016 | 1.01 (0.73–1.39) | .9554 | 1.45 (1.03–2.05) | .0326 | 1.44 (1.03–2.01) | .0320 |
| Charlson-Deyo | ||||||
| 0–1 | Reference | Reference | Reference | |||
| ≥ 2 | 0.69 (0.36–1.35) | .2792 | 1.12 (.52–2.43) | .7837 | 1.61 (0.79–3.29) | .1904 |
| Site | ||||||
| Parotid gland | Reference | Reference | Reference | |||
| Submandibular gland | 0.41 (0.25–0.67) | .0004 | 0.68 (0.40–1.15) | .1505 | 1.65 (1.04–2.61) | .0345 |
| Sublingual gland | 0.07 (0.01–0.58) | .0130 | 0.43 (0.04–4.83) | .4975 | 5.83 (1.29–26.34) | .0222 |
| NOS* | 0.71 (0.47–1.06) | .0921 | 1.18 (0.75–1.85) | .4713 | 1.67 (1.08–2.57) | .0214 |
| Histology | ||||||
| Adenoid cystic | Reference | Reference | Reference | |||
| Acinar | 2.31 (0.82–6.47) | .1112 | 1.36 (0.42–4.37) | .6059 | 0.59 (0.21–1.62) | .3041 |
| Adenocarcinoma | 5.24 (3.08–8.93) | < .0001 | 1.78 (0.98–3.23) | .0593 | 0.34 (0.20–0.56) | < .0001 |
| Ductal carcinoma | 7.92 (3.49–17.99) | < .0001 | 3.26 (1.33–8.03) | .0100 | 0.41 (0.16–1.04) | .0604 |
| Epithelial | 5.61 (2.38–13.25) | < .0001 | 1.45 (0.61–3.40) | .3993 | 0.26 (0.11–0.60) | .0016 |
| Mucoepidermoid | 1.93 (0.94–3.93) | .0718 | 1.06 (0.48–2.38) | .8792 | 0.55 (0.29–1.06) | .0736 |
| Other/NOS* | 6.06 (3.45–10.64) | < .0001 | 1.54 (0.84 −2.83) | .1667 | 0.25 (0.15 −0.43) | < .0001 |
| Sarcoma | 2.69 (1.26–5.74) | .0103 | 1.28 (0.55–2.98) | .5593 | 0.48 (0.23–0.98) | .0440 |
| T-classification | ||||||
| cT0 | Reference | Reference | Reference | |||
| cT1-T2 | 0.89 (0.57–1.39) | .6159 | 1.24 (0.77–1.99) | .3811 | 1.38 (0.87–2.19) | .1658 |
| cT3–4 | 0.95 (0.64–1.41) | .7931 | 1.03 (0.68–1.57) | .8907 | 1.09 (0.73–1.63) | .6889 |
| Unknown | 1.32 (0.52–3.38) | .5572 | 2.67 (0.81–8.79) | .1055 | 2.02 (0.60–6.85) | .2594 |
| N-classification | ||||||
| cN0–1 | Reference | Reference | Reference | |||
| cN2–3 | 1.75 (1.23–2.47) | .0017 | 1.02 (0.71–1.47) | .9164 | 0.58 (0.41–0.84) | .0032 |
| Unknown | 1.57 (0.96–2.58) | .0742 | 1.17 (0.69–1.99) | .5589 | 0.75 (0.44–1.26) | .2728 |
NOS = Not otherwise specified
Salivary gland primary site varied significantly among groups (P < .0001); bone-only metastases occurred less commonly than lung-only metastases in patients with submandibular gland primaries (OR 0.41; 95% CI 0.25–0.67; P = .0004) and sublingual gland primaries (OR 0.07; 95% CI 0.01–0.58; P = .0130) compared to patients with parotid gland primaries. Histology also varied significantly among groups (P < .0001); ACC was the most common histology in patients with lung-only metastases (n = 99, 30.8%), while adenocarcinomas comprised the largest component of patients with bone-only metastases (n = 98, 34.5%) and other solitary sites of metastatic disease (n = 75, 29.8%). The ORs for bone-only metastasis, relative to lung-only metastasis, were significantly higher in patients with adenocarcinoma (OR 5.24; 95% CI 3.08–8.93; P < .0001), ductal carcinoma (OR 7.92; 95% CI 3.49–17.99; P < .0001), epithelial (OR 5.61; 95% CI 2.38–13.25; P < .0001), sarcoma (OR 2.69; 95% CI 1.26–5.74; P = .0103), and other/NOS (OR 6.06; 95% CI 3.45–10.64; P < .0001) histologies, relative to ACC. Site of distant metastasis did not vary by clinical T-classification (P = .5584); however, among patients with clinical N2–3 disease, relative to clinical N0–1 disease, lung-only metastases were less frequent compared to bone-only metastases (OR 0.57; 95% CI 0.40–0.81; P = .0017) and other isolated sites of metastatic disease (OR 0.58; 95% CI 0.41–0.84; P = .0032). Treatment did not vary significantly among patients with different anatomic sites of distant metastasis with respect to receipt of surgery (P = .2912), radiotherapy (P = .2270), chemotherapy (P = .1003), or immunotherapy (P = .1342).
Table 3 depicts the variables associated with overall survival for the entire cohort. On univariable analysis, age > 70 years (HR 1.84; 95% CI 1.41–2.43; P < .0001) and adenocarcinoma (HR 1.38; 95% CI 1.07–1.90; P = .0134), epithelial (HR 1.99; 95% CI 1.34–2.95; P = .0012), mucoepidermoid (HR 2.01; 95% CI 1.44–2.81; P < .0001), and other/NOS (HR 1.77; 95% CI 1.35–2.32; P < .0001) histologies, relative to ACC, were associated with worse overall survival. Patients treated with surgery (HR 0.61; 95% CI 0.52–0.73; P < .0001), radiotherapy (HR 0.84; 95% CI 0.71–1.00; P = .0465), chemotherapy (HR 0.80; 95% CI 0.67–0.95; P = .0100), and immunotherapy (HR 0.46; 95% CI 0.24–0.80; P = .0042) had superior overall survival on univariable analysis. Relative to bone-only metastasis, lung-only metastasis was associated with a trend towards improved overall survival (HR 0.84; 95% CI 0.69–1.03; P = .0905). 3-year overall survival was estimated to be 23.9%, 30.9%, and 22.6% using the Kaplan-Meier method, for patients with single organ distant metastases to the bone, lung, and other anatomic sites, respectively, (Figure 2A; P = .2278). On multivariable analysis, age > 70 years (HR 1.68; 95% CI 1.28–2.24; P = .0002) remained associated with worse overall survival as did epithelial (HR 1.71; 95% CI 1.12–2.61; P = .0127), mucoepidermoid (HR 1.89; 95% CI 1.32–2.70; P = .0005), and other/NOS (HR 1.71; 95% CI 1.27–2.31; P = .0004) histologies, relative to ACC. Treatment with surgery (HR 0.64; 95% CI 0.53–0.78; P < .0001), radiotherapy (HR 0.82; 95% CI 0.69–0.98; P = .0266), chemotherapy (HR 0.75; 95% CI 0.62–0.91; P = .0029), and immunotherapy (HR 0.48; 95% CI 0.26–0.89; P = .0192) remained associated with improved overall survival.
Table 3.
Univariable and multivariable analysis of survival (Number of patients = 858)
| Univariable Analysis |
Multivariable Analysis |
|||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Age (years) | ||||
| ≤ 50 | Reference | Reference | ||
| 51–60 | 1.06 (0.78–1.44) | .7128 | 1.04 (0.77–1.43) | .7892 |
| 61–70 | 1.13 (0.85–1.52) | .3932 | 1.06 (0.79–1.43) | .7046 |
| > 70 | 1.84 (1.41–2.43) | < .0001 | 1.68 (1.28–2.24) | .0002 |
| Sex | ||||
| Male | Reference | Reference | ||
| Female | 0.85 (0.71–1.02) | .0876 | 0.99 (0.81–1.20) | .8983 |
| Year of diagnosis | ||||
| 2010–2013 | ||||
| 2014–2016 | 0.90 (0.75–1.09) | .2830 | ||
| Charlson-Deyo | ||||
| 0–1 | Reference | |||
| ≥ 2 | 1.37 (0.93–1.94) | .1121 | ||
| Site | ||||
| Parotid gland | Reference | Reference | ||
| Submandibular gland | 0.89 (0.70–1.13) | .3537 | 1.10 (0.85–1.41) | .4653 |
| Sublingual gland | 0.47 (0.17–1.01) | .0539 | 0.55 (0.19–1.21) | .1517 |
| NOS* | 1.01 (0.81–1.26) | .8973 | 0.93 (0.73–1.18) | .5619 |
| Histology | ||||
| Adenoid cystic | Reference | Reference | ||
| Acinar | 1.16 (0.66–2.04) | .6162 | 1.21 (0.67–2.16) | .5211 |
| Adenocarcinoma | 1.38 (1.07–1.90) | .0134 | 1.26 (0.94–1.69) | .1247 |
| Ductal carcinoma | 0.99 (0.64–1.55) | .9686 | 1.29 (0.80–2.08) | .2913 |
| Epithelial | 1.99 (1.34–2.95) | .0012 | 1.71 (1.12–2.61) | .0127 |
| Mucoepidermoid | 2.01 (1.44–2.81) | < .0001 | 1.89 (1.32–2.70) | .0005 |
| Other/NOS* | 1.77 (1.35–2.32) | < .0001 | 1.71 (1.27–2.31) | .0004 |
| Sarcoma | 1.21 (0.83–1.77) | .3260 | 1.30 (0.88–1.92) | .1990 |
| T-classification | ||||
| cT0 | Reference | |||
| cT1-T2 | 0.94 (0.75–1.20) | .6384 | ||
| cT3–4 | 1.14 (0.93–1.41) | .1996 | ||
| Unknown | 0.69 (0.34–1.24) | .2283 | ||
| N-classification | ||||
| cN0–1 | Reference | Reference | ||
| cN2–3 | 1.20 (1.00–1.43) | .0513 | 1.21 (0.99–1.47) | .0572 |
| Unknown | 1.13 (0.86–1.45) | .3792 | 1.10 (0.83–1.44) | .5104 |
| Surgery | ||||
| No | Reference | Reference | ||
| Yes | 0.61 (0.52–0.73) | < .0001 | 0.64 (0.53–0.78) | < .0001 |
| Unknown | -† | -† | ||
| Radiotherapy | ||||
| No | Reference | Reference | ||
| Yes | 0.84 (0.71–1.00) | .0465 | 0.82 (0.69–0.98) | .0266 |
| Unknown | 2.09 (0.89–4.11) | .0860 | 1.77 (0.79–3.93) | .1623 |
| Chemotherapy | ||||
| No | Reference | Reference | ||
| Yes | 0.80 (0.67–0.95) | .0100 | 0.75 (0.62–0.91) | .0029 |
| Unknown | 0.99 (0.63–1.48) | .9757 | 1.04 (0.66–1.65) | .8533 |
| Immunotherapy | ||||
| No | Reference | Reference | ||
| Yes | 0.46 (0.24–0.80) | .0042 | 0.48 (0.26–0.89) | .0192 |
| Unknown | 1.53 (0.38–3.98) | .2942 | 2.21 (0.79–1.16) | .1854 |
| Site of Metastasis | ||||
| Bone-only | Reference | Reference | ||
| Lung-only | 0.84 (0.69–1.03) | .0905 | 0.88 (0.71–1.09) | .2366 |
| Other-site-only | 0.94 (0.77–1.16) | .5730 | 0.92 (0.74–1.14) | .4328 |
NOS = Not otherwise specified,
Insufficient events
Figure 2. Survival outcomes.
(A) Kaplan-Meier curves for overall survival of the entire examined cohort of patients stratified by site of distant metastasis. 3-year overall survival was 23.9%, 30.9%, and 22.6% for patients with single organ distant metastases to the bone, lung, and other anatomic sites, respectively, (P = .2278). (B) Kaplan-Meier curves for overall survival in the subgroup of patients with adenoid cystic carcinoma histology stratified by site of distant metastasis. 3-year overall survival was 12.5%, 51.8%, and 26.4% for patients with single-organ distant metastases to the bone, lung, and other anatomic sites, respectively, (P = .0138).
Table 4 depicts the variables associated with overall survival on subgroup analysis in patients with ACC histology. On univariable analysis, lung-only metastasis, relative to bone-only metastasis, was strongly associated with improved survival in the subset of patients with ACC (HR 0.46; 95% CI 0.27–0.80; P = .0070). Treatment with surgery was also associated with improved survival (HR 0.63; 95% CI 0.41–0.97; P = .0347), while patients who received chemotherapy had a slight survival detriment (HR 1.64; 95% CI 1.02–2.59; P = .0421) on univariable analysis of patients with ACC. Notably, among patients with ACC, lung-only metastasis, relative to bone-only metastasis, remained the only variable associated with improved survival (HR 0.52; 95% CI 0.30–0.93; P = .0293) on multivariable analysis accounting for relevant covariates. In this subgroup, the 3-year survival of patients with lung-only metastases was 51.8% compared to 12.5% for patients with bone-only metastases and 26.4% for patients with other solitary sites of metastatic disease (P = .0138; Figure 2B).
Table 4.
Univariable and multivariable analysis of survival for adenoid cystic histology (Number of patients = 858)
| Univariable Analysis |
Multivariable Analysis |
|||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Age (years) | ||||
| ≤ 50 | Reference | |||
| 51–60 | 0.85 (0.41–1.76) | .6582 | ||
| 61–70 | 0.95 (0.50–1.87) | .8823 | ||
| > 70 | 1.57 (0.87–3.00) | .1395 | ||
| Sex | ||||
| Male | Reference | |||
| Female | 0.80 (0.52–1.23) | .3097 | ||
| Year of diagnosis | ||||
| 2010–2013 | Reference | |||
| 2014–2016 | 0.85 (0.49–1.41) | .5375 | ||
| Charlson-Deyo | ||||
| 0–1 | Reference | |||
| ≥ 2 | 1.39 (0.49–3.11) | .4942 | ||
| Site | ||||
| Parotid gland | Reference | |||
| Submandibular gland | 1.14 (0.69–1.87) | .5998 | ||
| Sublingual gland | 0.44 (0.07–1.44) | .1984 | ||
| NOS* | 1.21 (0.69–2.08) | .4908 | ||
| T-classification | ||||
| cT0 | Reference | |||
| cT1-T2 | 1.23 (0.67–2.27) | .4995 | ||
| cT3–4 | 1.11 (0.66–1.93) | .7061 | ||
| Unknown | 3.16 (0.50–10.99) | .1841 | ||
| N-classification | ||||
| cN0–1 | Reference | |||
| cN2–3 | 1.40 (0.84–2.24) | .1903 | ||
| Unknown | 1.07 (0.47–2.12) | .8665 | ||
| Surgery | ||||
| No | Reference | Reference | ||
| Yes | 0.63 (0.41–0.97) | .0347 | 0.66 (0.42–1.02) | .0609 |
| Unknown | -† | -† | ||
| Radiotherapy | ||||
| No | Reference | |||
| Yes | 0.98 (0.64–1.53) | .9392 | ||
| Unknown | -† | |||
| Chemotherapy | ||||
| No | Reference | Reference | ||
| Yes | 1.64 (1.02–2.59) | .0421 | 1.34 (0.81–2.16) | .2491 |
| Unknown | -† | -† | ||
| Immunotherapy | ||||
| No | -† | -† | ||
| Yes | -† | -† | ||
| Unknown | -† | -† | ||
| Site of Metastasis | ||||
| Bone-only | Reference | Reference | ||
| Lung-only | 0.46 (0.27–0.80) | .0070 | 0.52 (0.30–0.93) | .0293 |
| Other-site-only | 0.58 (0.31–1.09) | .0891 | 0.65 (0.34–1.27) | .2057 |
NOS = Not otherwise specified,
Insufficient events
It should be noted that prior to the decision to exclude patients with SCC from the cohort, this subgroup was examined and lung-only metastasis was found to be a significant predictor of improved overall survival (HR 0.43; 95% CI 0.25–0.73; P = .0015) on multivariable analysis. In this subgroup, the 3-year survival of patients with lung-only metastases was 20.6% compared to 7.7% for patients with bone-only metastases and 22.1% for patients with other solitary metastatic sites (P = .0084). However, given the aforementioned concern that the vast majority of these cases likely represented metastases to the major salivary glands from non-salivary primaries, this subpopulation was subsequently excluded from the cohort and is not further discussed in our findings. Anatomic site of distant metastasis was not a significant predictor of survival in any of the remaining histologies upon subgroup analyses.
DISCUSSION
Here, we analyzed 858 patients in the NCDB with newly diagnosed de novo metastatic salivary gland cancers in whom distant metastasis was confined to a single organ at the time of presentation. Although a trend towards improved survival was noted among patients with lung-only metastasis, relative to bone-only metastasis, anatomic site of distant metastasis was not prognostic for survival in the cohort as a whole after accounting for other relevant covariates. However, as initially hypothesized, in the subgroup of patients with ACC histology, patients with lung-only metastasis had improved overall survival relative to patients with bone-only metastasis. Moreover, on multivariable analysis controlling for other covariates, lung-only metastasis was the only significant predictor of improved survival among patients with metastatic salivary ACC.
Despite a high propensity for distant metastasis, long-term outcomes have been demonstrated to vary significantly among patients with metastatic ACC, with some patients experiencing survival in excess of a decade following distant metastasis.3,7 Similar to previously published single-institution series,4–6 our findings reported herein support lung metastasis as a positive prognostic factor relative to other sites of distant metastasis in patients with salivary ACC. Notably, unlike previously published series, which have largely been limited by small sample sizes, our subset analysis included 158 patients and represents the largest reported cohort examining the prognostic effect of anatomic site of distant metastasis in patients with metastatic ACC of which we are aware. Moreover, unlike previous studies examining the prognostic role of site of distant metastasis in patients with ACC, which have included patients with metachronous metastatic disease, our cohort is composed of patients with de novo metastatic disease. This distinction is important given that the lung represents the most common and typically the earliest organ involved by distant metastasis in patients with ACC.1,9,10 Thus, involvement of other metastatic sites, besides the lung, may reflect increasing disease burden and/or may introduce an immortal time bias where the improved survival seen with lung-only metastasis may simply represent an earlier state during metastatic disease progression; as a result, our currently reported series uniquely accounts for these potentially confounding factors.
Although site of distant metastasis was not associated with survival in the cohort as a whole, it is of note that treatment modalities including chemotherapy, immunotherapy, surgery, and radiotherapy were individually associated with improved survival after accounting for patient age, comorbidities, and disease characteristics. Limited details regarding the therapy received are available from the data in the NCDB, though among patients receiving systemic therapy the overwhelming majority appear to have received either single or multiagent cytotoxic chemotherapy with a very small minority of patients receiving immunotherapy as the first line of systemic therapy. Among patients whose treatment included local therapy, it appears as though the vast majority underwent surgery and/or radiotherapy to the primary site, though in some instances patients received local therapy to one or more metastatic sites. Unfortunately, it is difficult to accurately characterize or quantify treatment in this cohort further based upon the limitations of the data in the NCDB.
Despite the limited nature of the data regarding the treatment received by the patients in our cohort, the reported benefits of local therapy are of particular interest given that the optimal management of patients with metastatic ACC14 and metastatic salivary gland cancer as a whole14 is not well-established. While receipt of local therapy could certainly serve as a harbinger of better performance status, fewer comorbidities, and/or lower burden of disease, beyond what can be ascertained from the data available in the NCDB, it is conceivable that local therapy may improve survival for some patients in this population. Local therapy has been demonstrated to improve the survival of select patients with low-burden metastatic disease in several disease sites including colorectal,15 prostate,16,17 and nasopharyngeal cancer.18,19 A growing body of evidence across multiple histologies also supports that metastasis-directed therapy may benefit a subset of patients presenting in an oligometastatic state, in which a limited volume of metastatic disease that is unlikely to progress rapidly is present.20–25 Notably, series report favorable outcomes among patients with metastatic salivary gland cancers following metastasis-directed thearpy.26–32 For instance, Girelli et al. reported a 66.8% 5-year survival rate for metastatic ACC patients following pulmonary metastasectomy and a 76.5% 5-year survival rate among patients with disease-free intervals greater than 3 years.26 While favorable outcomes in this and similar series may reflect selection for relatively indolent disease rather than an actual benefit of metastasis-directed therapy, taken with randomized data demonstrating the benefit of metastasis-directed therapy they support the feasibility and potential utility of including patients with metastatic salivary gland neoplasms in future studies of metastasis-directed therapy in the oligometastatic population. However, no conclusions regarding the benefit of local therapy to either the primary or metastatic sites in patients with metastatic salivary gland cancer can be made from our results given the nature of the study. Notably, our finding that site of metastatic disease is strongly associated with long-term overall survival in patients with metastatic ACC suggests that anatomic site of metastasis may be an important consideration and potentially a sensible stratification factor in future studies investigating the role of local therapy in this population.
Despite our conclusions, several important limitations must be considered in the interpretation of our study. As previously discussed, salivary gland cancers represent a heterogeneous disease.1,2 Our analysis was specifically limited to 858 patients with de novo metastatic disease confined to a single organ at the time of initial presentation, which represents a small fraction of salivary gland cancer patients in the NDCB, thus it is possible that our findings are not fully representative of the biology of metastatic salivary gland cancers as a whole. Moreover, while our study was intentionally focused on patients with de novo metastatic disease in whom metastases were limited to a single anatomic site in order to control for potentially confounding factors, such as differences in disease burden and/or potential immortal time bias, it is important to note that patients much more frequently develop metachronous metastatic disease, especially in the case of ACC.7–9 Thus, the implications of our findings are not completely clear for the larger population of patients with metachronous metastatic disease. Moreover, although our cohort was composed entirely of patients with metastasis to a single anatomic site, we were unable to control for number of metastases or volume of metastatic disease based upon the data available in the NCDB. It is also of note that the median follow-up of patients in our cohort was short at 14.4 months. This caveat is especially of note in the subset of patients with ACC given the prolonged survival seen in a subset of these patients.3,7 While the median survival of around 30 months in the ACC subgroup of our cohort approximates what has been reported in other series with longer follow-up,6,8 the short median follow-up in our study is certainly of note in this subset given the natural history of metastatic ACC. Additionally, although anatomic site of metastasis was not associated with survival in any of the examined histology subgroups besides ACC, it is important to note that our series may have been underpowered to detect differences in survival within many histologies given small sample sizes in these subgroups. Finally, as previously noted, it is possible that differences in patient performance status, comorbidities, disease characteristics, and/or treatment received exist beyond what could be ascertained from the data available in the NCDB and as a result, unaddressed confounding factors may be present.
In conclusion, our findings suggest that site of distant metastasis is strongly associated with survival in patients presenting with de novo metastatic ACC with metastases limited to one organ. After controlling for relevant covariates, metastasis to the lung was the only prognostic factor associated with improved survival among patients with ACC. Currently, the optimal management of patients with metastatic ACC,14 and metastatic salivary gland cancer as a whole,14 is not well-established; the results of ongoing and future studies will be important to further delineate this. In addition to improving prognostication for patients with metastatic disease, site of distant metastasis may be considered in the design of future trials aimed at widening the therapeutic ratio in this population.
Acknowledgments
Financial support: Burroughs Wellcome Career Award for Medical Scientists 1010964 (MTS); NIH/NIDCR R01DE027445–01 (MTS)
Footnotes
Meeting Presentation: Abstract accepted for presentation at the ASTRO 2020 Multidisciplinary Head and Neck Cancers Symposium
Conflict of Interest Statement: No relevant conflicts of interest.
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