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The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system
Gynecologic Oncology xxx (xxxx) xxx
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The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system Kyra N. McComas a, Anna M. Torgeson b, Bryan J. Ager b, Christopher Hellekson b, Lindsay M. Burt b, Kathryn A. Maurer c, Teresa L. Werner d, David K. Gaffney b, * a
University of Utah School of Medicine, Salt Lake City, UT, USA University of Utah, Department of Radiation Oncology, Salt Lake City, UT, USA University of Utah, Department of Obstetrics & Gynecology, Salt Lake City, UT, USA d University of Utah, Department of Internal Medicine, Salt Lake City, UT, USA b c
h i g h l i g h t s Prognosis in cervical cancer is negatively affected by the presence of lymph node metastases (LNM). The effect of LNM is variable by T stage. Large cervix primaries are affected less by lymph node metastases. Para-aortic LNM can have a large survival decrement particularly in smaller tumors.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 July 2019 Received in revised form 15 October 2019 Accepted 21 October 2019 Available online xxx
Objective: The 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer changed from a clinical system to a clinical/pathologic/radiologic system with stages IIIC1 and IIIC2 indicating positive pelvic and para-aortic lymph nodes, respectively. We evaluated the National Cancer Database (NCDB) for the impact on survival of lymph node metastases (LNM). Methods: The NCDB from 2004 to 2015 was queried for patients with cervical cancer, yielding 115,819 patients. Patients with FIGO IVB (22,569), non-adeno/squamous cell histologies (5,909), unknown nodal status (60,695), or unknown survival time (9,473) were excluded. Survival was compared using Cox proportional hazard model based on nodal status. Univariate (UVA) and multivariate analyses (MVA) were done for the overall cohort, followed by UVA by individual stage. Results: In 17,173 eligible patients, LNM negatively affected survival (UVA IIIC1 Hazard Ratio [HR] 2.0, p < 0.001, IIIC2 HR 3.9, p < 0.001, MVA IIIC1 HR 1.36, p < 0.001, IIIC2 HR 2.14, p < 0.001). In T1B, the effect of IIIC2 was most pronounced (HR 5.38, p < 0.001 versus HR 1.5 p ¼ 0.001 for IIIC1 disease). In T3, the effect of LNM was markedly less: (HR 1.7, p < 0.001 for IIIC2 versus HR 1.2 p ¼ 0.02 for IIIC1). Within T1B, there was no difference in survival for IIIC1 for the smaller T stages (IB1-2). Conclusion: In this study, LNM negatively affects prognosis in cervical cancer. The impact on survival varies by T stage with the greatest effect seen in stage T1B with IIIC2 disease. © 2019 Elsevier Inc. All rights reserved.
Keywords: Cervical cancer Lymph nodes Prognosis varies T stage
1. Introduction In the United States (US) in 2018, cervical cancer affected approximately 15,000 women, with an incidence of 2.7% and a mortality of 1.9% [1]. The worldwide incidence of cervix cancer is high, with 90% of deaths from cervical cancer occurring in low- and
* Corresponding author. Huntsman Cancer Hospital, Radiation Oncology 1950 Circle of Hope Drive Room 1570, Salt Lake City, UT, 84112, USA. E-mail address: [email protected] (D.K. Gaffney).
middle-income countries [2e4]. Cervix cancer remains an enormous public health concern. One recent publication indicated that 9.4 million women from 2015 to 2035 in low- and middle-income countries would require treatment with radiotherapy [4]. Geographic variation is reflective of variable access to screening and subsequent prevention, as well as human papillomavirus (HPV) prevalence [3,5], which is detectable in 99.7% of cervical cancers [6]. Given geographic and socioeconomic disparities in incidence, staging, radiographic modalities and treatment options, radiological and surgical findings have not been included in previous
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Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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iterations of the International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging system [3]. Thus, nodal involvement has not previously been included despite extensive literature describing its effect on prognosis [7e11]. Nodal involvement has been found to negatively affect prognosis in the surgical setting, with patient survival decreasing with increasing numbers of lymph nodes involved [8,9], and with increasing ratios of distant lymph node positivity [10], given the contiguous nature of cervical cancer spread. Clinical nodal involvement by 18-Fluoro deoxyglucose positron emission tomography (FDG-PET) has been found to correlate with both more advanced T stage and decreased survival [11]. In 2018, FIGO consequently instigated changes to staging for better prognostic power, including removing horizontal spread as a stipulation for stage IA disease, further subcategorizing stage IB by tumor size, and adding stage IIIC disease based on the presence of nodal metastases by radiologic imaging or pathologic data, with stage IIIC1 and IIIC2 involving pelvic and para-aortic lymph nodes, respectively [3]. The FIGO IIIC designation associates nodal involvement with the worst prognoses, aside from tumors with alternate pelvic organ invasion (IVA) or distant spread (IVB) [3], but disregards local tumor stage. In light of these new additions to the staging system, we sought to examine the impact of nodal positivity and local tumor burden on prognosis in a cohort of patients from a nationwide hospital database. Our study aims to describe the impact of pelvic and paraaortic nodal metastasis on survival outcomes, stratified by 2018 FIGO T stage. 1.1. Methods and materials The National Cancer Database (NCDB) was queried for patients diagnosed with cervical cancer from 2004 to 2014. The NCDB is a joint program of the Commission on Cancer and the American Cancer Society, which includes data from approximately 1500 hospitals and clinics in the United States and its territories. This database captures nearly 70% of new cancer diagnoses made in the US [12]. All NCDB data are de-identified and thus are exempt from institutional review board review. The initial query yielded 115,819 patients. We excluded FIGO stage IVB (22,569), non-adenocarcinoma or squamous cell carcinoma histology (5,909), unknown nodal status (60,695), or unknown survival time or survival time less than three months (9,473) (see Fig. 1). Patients were not excluded if they did not receive treatment, though the great majority of these patients who did not receive treatment were excluded for other reasons. The primary outcome variable was overall survival, stratified by nodal status (node-negative [N0], positive pelvic nodes [IIIC1], or positive para-aortic nodes [IIIC2]). Nodal status included both clinical nodal assessment via imaging and pathologic nodal assessment. Chi-square analysis was used to compare demographic and tumor characteristics by nodal status (see Table 1). Demographic factors examined included age, race, Charlson comorbidity score, primary payer, facility type, census region, area income, percent of residents without a high school degree, distance from the treatment facility, and urban density. Tumor characteristics included tumor size, lymphovascular space invasion (LVSI), FIGO T stage, grade, and histology. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were then used to analyze the association between nodal status and risk of death, as well as other covariates that may be predictive of survival. Factors with P values of 0.1 or less on UVA were included in the multivariate model. A P value of 0.1 was chosen in order to maintain more stringent standards for inclusion in the MVA. Subgroup analyses were then undertaken to determine the effect of nodal status on survival by T stage. Five-year overall
survival times were also collected for the overall cohort by nodal status, and by individual stage. All analyses were performed using the STATA 14.0 statistical package (Stata Corporation, College Station, Texas). 2. Results After the appropriate exclusions were made, 17,173 patients with cervical cancer remained (Table 1). There were 11,853 N0 patients, 4451 IIIC1 patients, and 869 IIIC2 patients. Node-positive (IIIC1 and IIIC2) patients were more likely to be younger (87e88% versus 84%, p < 0.001), non-white (33e37% versus 25%, p < 0.001), uninsured or on Medicaid (36e38% versus 30%, p < 0.001), live in areas where 29% or more of the population did not have a high school diploma (52% versus 48%, p < 0.001), have squamous cell histology (79e80% versus 68%, p < 0.001), poorly-differentiated tumors (47e56% versus 35%), have tumors 4.0 cm (cm) or more in size (68e78% versus 42%, p < 0.001), and more locally advanced tumors (70e86% FIGO T2A-4A versus 47%, p < 0.001). Of patients with known LVSI status, node-positive patients were more likely to have LVSI (38e45% versus 28%, p < 0.001). On UVA, all demographic and tumor factors were significant save for distance from the facility (Table 2). Nodal status was particularly significant for survival on UVA. Hazard ratio (HR) for death with IIIC1 disease was double that of node-negative patients (HR 2.0, p < 0.001, 95% Confidence Interval [CI] I 1.86e2.14), and with IIIC2 almost quadruple that of node-negative patients (HR 3.8, p < 0.001, 95% CI 3.43e4.25). On MVA, nodal status remained significant for both IIIC1 (HR 1.4, p < 0.001, 95% CI 1.17e1.59) and IIIC2 disease (HR 2.1 p < 0.001, 95% CI 1.69e2.68). On subgroup analysis, there was no statistically significant increased risk for death for patients with IIIC1 disease in T stages 1A, 1B1, or 1B2 compared to N0 patients (Table 3). For patients with IIIC2 disease, there was a large increase in the risk of death for stage T1B patients, though this is difficult to interpret for the T1B1 patients due to only having six patients and two events. (Table 3, Fig. 2). Similarly, there were only 2 of 891 stage T1A patients with IIIC2 disease, so the effect of IIIC2 disease could not be evaluated. For T stages 1B3-3, both IIIC1 and IIIC2 diseases were detrimental to survival compared to N0 patients (Table 3, Fig. 2). Five-year overall survival (OS) for the overall cohort was 78.5% (95% CI 77.5e74.9%), 61.9% (95% CI 59.9e63.7%), and 39.4% (95% CI 35.0e43.9%) for N0, IIIC1, and IIIC2 respectively (Table 3). Stage T1A patients had a 5-year OS of 94e95.8% regardless of nodal status. For stage T1B patients overall, the effect of lymph node status was much greater than more advanced T stages (5-year OS 86.3% [95% CI 84.5e87.9%], 80.3% [95% CI 75.9e84.1%], and 36.8% (95% CI 19.0e54.0%] for N0, IIIC1, and IIIC2 disease, respectively) compared to more locally advanced patients. T2 patients had a 5-year OS of 66.9% (95% CI 63.8e69.8%), 57.2% (95% CI 51.9e62.3%), and 42.2% (95% CI 29.3e54.5%) for N0, IIIC1, and IIIC2 disease, respectively. T3 patients had 5-year OS of 47.7% (95% CI 43.4e51.9%), 39.7% (95% CI 34.5e44.8%), and 31.4% (95% CI 23.8e39.3%) for N0, IIIC1, and IIIC2 disease, respectively. There was no difference in survival for T4A disease based on nodal status. 3. Discussion This retrospective cohort study of 17,173 women with cervical cancer examined the impact on survival as a function of lymph node involvement both in the overall cohort and by T stage. Tumor characteristics, including larger tumor size, locally advanced disease, squamous cell histology, higher grade, and LVSI positivity were associated with nodal positivity. Demographic characteristics suggestive of lower socioeconomic status (lack of a high school diploma or private insurance) were also associated with an
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
K.N. McComas et al. / Gynecologic Oncology xxx (xxxx) xxx
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Fig. 1. CONSORT diagram. Legend: Abbreviations: NCDB¼National Cancer Data Base, LNM ¼ lymph node metastases.
increased likelihood of nodal positivity. Increasingly advanced nodal involvement negatively affected survival, with IIIC2 disease demonstrating a more dramatic decrease in survival versus IIIC1 disease. The survival detriment was found to be dependent on local tumor burden, which seemed to progress in a step-wise fashion. Surprisingly, patients with local T stage 1A, 1B1, 1B2, and 4A disease did not experience a statistically significant survival detriment with pelvic nodal involvement (IIIC1). In comparison, the effect of paraaortic nodal involvement (IIIC2) was more pronounced in patients with T1B disease (HR 5.4, p < 0.01, 95% CI 3.64e7.94), but was similar to the effect of involved pelvic nodes with increasing local tumor burden (T2 IIIC1 HR 1.45, [95% CI 1.24e1.71], p < 0.01 IIIC2 HR 2.01, p < 0.01, [95% CI 1.52e2.65] T3 IIIC1 HR 1.19, p ¼ 0.02, [95% CI 1.03e1.38] IIIC2 HR 1.70, p < 0.01, [95% CI 1.39e2.07]). The likelihood of positive nodes based on local tumor factors is expected and lends to the validity of this dataset [11]. Specifically, a large retrospective study of 560 patients found that the frequency of lymph node metastasis (LNM) detected by PET-CT increased with local tumor burden, and was associated with poorer survival [11]. The effect of LNM on survival in the overall cohort is expected, given the concordant findings of previous studies of smaller numbers of patients in patients who were diagnosed either radiographically or surgically [8e11]. The effect of nodal status concerning variable local tumor burden is intriguing; however, the “IIIC” designation in the new FIGO staging system would suggest that LNM are associated with the poorest prognosis aside from pelvic organ invasion or distant
metastases, regardless of local tumor burden. In this dataset, patients with tumors 4 cm or less confined to the cervix did not experience an increased risk for death with pelvic LNM. In line with the FIGO staging system, T4A (FIGO IVA) patients did not experience a survival detriment with either pelvic or para-aortic LNM, despite reasonable sample size (201 N0, 174 IIIC1, and 51 IIIC2). Thus, this dataset suggests that the impact of pelvic LNM varies with local tumor burden. These data run concordant to the findings of Matsuo et al. who used the US Surveillance, Epidemiology and End Results (SEER) Database to validate the new staging system. Interestingly, they found that in all patients with pelvic LNM, survival varied greatly between T1, T2, and T3 disease, with higher T stages correlating with significantly worse survival [13]. These results, taken together, suggest that local tumor burden may still be equal to, if not more important than, nodal status in prognosis. Another interesting finding from this study is the variability of the effect of para-aortic (PA) LNM in FIGO T1B compared to T2 and T3. In T1B, PA LNM was associated with drastically decreased survival from the baseline (HR 5.4, p < 0.001 95% CI 3.64e7.94), though was, fortunately, an uncommon finding in T1B1 (0.6%), T1B2 (1.1%), and T1B3 disease (3.5%). By T2 (4.8% of patients, HR 2.0 p < 0.001, 95% CI 1.52e2.65) and T3 (11.9% of patients, HR 1.7, p < 0.001, 95% CI 1.39e2.07), however, the effect of PA LNM was reduced, though PA LNM were a more common finding. These results cannot be compared to SEER since PA LNM are not coded in SEER [13]. However, these findings are in concordance with previous retrospective results where the HR for death increased incrementally
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Table 1 Patient characteristics by nodal status. Variable Age 18e45 46e65 Older than 65 Race White Black Hispanic Other Insurance Status Uninsured Private Medicaid Medicare Gov NOS Unknown Charlson Score 0 1 2 3 Census Region Northeast South Midwest West Area Income 0-29,999$ 30-34,999$ 35-45,999$ 46,000$þ % w/o HS Diploma 29%þ 20e28.9% 14e19% <14% Facility Type Community CC Academic Integrated Urban Density Metropolitan Urban Rural Histology Squamous Cell Adenocarcinoma Grade 1 2 3 LVSI Negative Positive Unknown Tumor Size 0e0.49 0.5-0.9 1.0e1.9 2.0e3.9 4.0 or more FIGO T stage T1A1 T1A2 T1B1 T1B2 T1B3 T2A1 T2A2 T2B T3A T3B T4A
N0
%
IIIC1
%
IIIC2
%
4785 5251 1817
40% 44% 15%
1813 2091 547
41% 47% 12%
274 479 116
32% 55% 15%
8000 1586 1491
68% 13% 6%
2835 690 645
64% 16% 15%
569 149 91
67% 17% 11%
932 5815 2616 2175 172 143
8% 49% 22% 18% 1% 1%
437 2019 1167 673 72 83
10% 45% 26% 15% 2% 2%
103 371 230 141 10 14
12% 43% 26% 16% 1% 2%
10006 1394 262 131
85% 12% 2% 1%
3785 545 76 45
85% 12% 2% 1%
740 109 17 3
85% 13% 2% <1%
1777 3373 2047 1519
20% 39% 23% 17%
630 1299 746 592
19% 40% 23% 18%
136 278 177 111
19% 40% 25% 16%
1912 2337 3329 3912
17% 20% 29% 34%
802 906 1234 1365
19% 21% 29% 32%
139 191 260 259
16% 22% 31% 31%
2481 3002 2648 3356
22% 26% 23% 29%
1076 1157 941 1131
25% 27% 22% 26%
212 232 193 212
25% 27% 23% 25%
575 3300 3692 1149
7% 38% 42% 13%
196 1229 1408 434
6% 38% 43% 13%
49 246 312 95
7% 35% 44% 14%
9613 1336 631
83% 12% 5%
3591 511 241
83% 12% 6%
693 113 46
81% 13% 5%
8044 3809
68% 32%
3547 904
80% 20%
686 183
79% 21%
1629 4319 3157
18% 47% 35%
200 1622 1624
6% 47% 47%
32 257 373
5% 39% 56%
5125 1964 4764
43% 17% 40%
791 1310 2350
18% 29% 53%
138 169 562
16% 19% 65%
964 802 1243 2231 3765
11% 9% 14% 25% 42%
10 58 224 795 2338
1% 2% 6% 23% 68%
6 11 21 96 480
1% 2% 3% 16% 78%
656 208 834 1019 848 98 252 1596 128 847 201
10% 3% 12% 15% 13% 1% 4% 24% 2% 13% 3%
13 12 85 226 294 15 86 555 80 556 147
1% 1% 4% 11% 14% 1% 4% 27% 4% 27% 7%
2 0 6 14 41 9 14 107 16 202 51
<1% 0% 1% 3% 9% 2% 3% 23% 3% 44% 11%
P value <0.01
<0.01
<0.01
0.15
0.46
<0.01
<0.01
0.70
0.66
<0.01
<0.01
<0.01
<0.01
<0.01
Abbreviations: LVSI, lymphovascular space invasion; Gov NOS, government not otherwise specified; % w/o HS diploma, % of constituents without a high school diploma; CC, comprehensive community; cm, centimeters; FIGO T Stage, International Federation of Gynecologic Oncology Tumor Stage..
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Table 2 Univariate and multivariate analysis of survival in cervical cancer. Variable Age 18e45 46e65 Older than 65 Race White Black Hispanic Other Insurance Status Uninsured Private Medicaid Medicare Gov NOS Unknown Charlson Score 0 1 2 3 Census Region Northeast South Midwest West Area Income 0-29,999$ 30-34,999$ 35-45,999$ 46,000$þ % w/o HS Diploma 29%þ 20e28.9% 14e19% <14% Facility Type Community CC Academic Integrated Urban Density Metropolitan Urban Rural Histology Squamous Cell Adenocarcinoma Grade 1 2 3 LVSI Negative Positive Unknown Tumor Size 0e0.49 0.5-0.9 1.0e1.9 2.0e3.9 4.0 or more FIGO T stage T1A1 T1A2 T1B1 T1B2 T1B3 T2A1 T2A2 T2B T3A T3B T4A Nodal Status
UVA
95% CI
P value
MVA
P value
Standard 1.48 2.76
Standard 1.37-1.60 2.53-3.02
Standard <0.01 <0.01
Standard 1.07 1.44
Standard 0.87-1.31 1.10-1.88
Standard 0.51 <0.01
Standard 1.38 0.68 0.88
Standard 1.22-1.45 0.60-0.76 0.76-1.03
Standard <0.01 <0.01 0.12
Standard 1.03 0.73 0.99
Standard 0.85-1.25 0.57-0.93 0.73-1.34
Standard 0.76 0.01 0.94
Standard 0.60 1.00 1.62 0.62 1.11
Standard 0.53-0.68 0.88-1.13 1.43-1.83 0.44-0.87 0.85-1.46
Standard <0.01 0.97 <0.01 <0.01 0.43
Standard 0.78 1.08 1.31 0.45 0.93
Standard 0.61-1.00 0.84-1.40 0.99-1.73 0.17-1.25 0.51-1.68
Standard 0.05 0.54 0.06 0.13 0.80
Standard 1.36 1.94 2.13
Standard 1.24-1.50 1.62-2.34 1.65-2.74
Standard <0.01 <0.01 <0.01
Standard 1.46 1.55 1.85
Standard 1.22-1.74 1.10-2.16 1.17-2.94
Standard <0.01 0.01 <0.01
Standard 1.08 1.17 0.95
Standard 0.98-1.19 1.05-1.31 0.84-1.07
Standard 0.17 <0.01 0.39
Standard 1.08 1.16 1.03
Standard 0.89-1.30 0.92-1.36 0.83-1.29
Standard 0.46 0.27 0.77
Standard 0.94 0.83 0.70
Standard 0.84-1.04 0.76-0.92 0.63-0.77
Standard 0.20 <0.01 <0.01
Standard 0.97 0.90 0.78
Standard 0.78-1.20 0.72-1.12 0.60-1.02
Standard 0.76 0.35 0.07
Standard 1.03 0.89 0.79
Standard 0.94-1.13 0.81-0.99 0.71-0.86
Standard 0.52 0.03 <0.01
Standard 1.17 1.16 1.20
Standard 0.96-1.43 0.92-1.46 0.93-1.54
Standard 0.12 0.20 0.16
Standard 0.95 0.81 0.88
Standard 0.82-1.10 0.70-0.94 0.75-1.05
Standard 0.48 <0.01 0.15
Standard 1.23 0.88 1.06
Standard 0.92-1.65 0.66-1.18 0.77-1.48
Standard 0.17 0.40 0.77
Standard 1.09 1.16
Standard 0.98-1.20 1.01e1.33
Standard 0.11 0.04
Standard 0.84 0.76
Standard 0.68-1.04 0.56-1.03
Standard 0.11 0.08
Standard 0.62
Standard 0.57-0.67
Standard <0.01
Standard 1.22
Standard 1.02-1.45
Standard 0.03
Standard 2.08 3.24
Standard 1.76-2.44 2.76-3.80
Standard <0.01 <0.01
Standard 1.04 1.40
Standard 0.99-1.80 1.04-1.88
Standard 0.71 0.03
Standard 1.56 2.73
Standard 1.40-1.74 2.51-2.97
Standard <0.01 <0.01
Standard 1.04 0.98
Standard 0.83-1.32 0.82-1.17
Standard 0.71 0.79
Standard 1.60 1.76 4.02 9.85
Standard 1.03-2.48 1.14-2.52 2.84-5.71 7.02e13.83
Standard 0.04 0.01 <0.01 <0.01
Standard 0.99 1.00 1.56 2.62
Standard 0.37-2.67 0.35-2.91 0.58-4.18 0.99-6.90
Standard 0.98 1.00 0.37 0.05
Standard 1.26 1.12 2.49 5.72 5.42 8.68 8.50 16.62 17.5 23.15
Standard 0.60-2.65 0.67-1.87 1.59-3.90 3.72-8.78 3.02e9.72 5.51-13.70 5.60-12.89 10.57-26.15 11.58-26.56 15.07e35.58
Standard 0.54 0.67 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01
Standard 1.06 0.55 0.80 0.98 1.52 1.43 1.61 2.60 2.86 3.60
Standard 0.35-3.22 0.20-1.51 0.31-2.08 0.39-2.47 0.54-4.28 0.55-3.70 0.65-4.00 0.99-6.78 1.14-7.14 1.4e9.15
Standard 0.92 0.24 0.65 0.96 0.43 0.46 0.31 0.05 0.02 <0.01 (continued on next page)
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Table 2 (continued ) Variable
UVA
95% CI
P value
MVA
N0 IIIC1 IIIC2
Standard 2.00 3.82
Standard 1.86-2.14 3.43-4.25
Standard <0.01 <0.01
Standard 1.36 2.12
P value Standard 1.17-1.59 1.69-2.68
Standard <0.01 <0.01
Abbreviations: 95% CI, 95% Confidence Interval LVSI, lymphovascular space invasion; Gov NOS- government not otherwise specified; % w/o HS diploma, % of constituents without a high school diploma; CC, comprehensive community; cm, centimeters; FIGO T Stage, International Federation of Gynecologic Oncology Tumor Stage; IIIC1, positive pelvic lymph nodes; IIIC2- positive para-aortic lymph nodes. Bold ¼ statistically significant on multivariate.
Table 3 Overall Survival by Nodal Status and Tumor (T) stage. T stage
Patient Number
Hazard Ratio (HR) for Death, 95% Confidence Interval
P value
5 year Overall Survival %
95% Confidence Interval
All, N0 All, Pelvis þ All, PA þ IA, N0 IA, Pelvis þ IA, PAþ IB, N0 IB, Pelvis þ IB, PA þ IB1, N0 IB1, Pelvis þ IB1, PA þ IB2, N0 IB2, Pelvis þ IB2, PA þ IB3, N0 IB3, Pelvis þ IB3, PA þ II, N0 II, Pelvis þ II, PA þ III, N0 III, Pelvis þ III, PA þ IVA, N0 IVA, Pelvis þ IVA, PA þ
11853 4451 869 864 25 2 2701 601 65 834 85 6 1019 226 14 848 294 41 1946 656 130 975 636 218 201 174 51
Standard 2.00, 1.86e2.14 3.85, 3.43e4.25 Standard 0.82, 0.11e6.03 N/A Standard 1.50, 1.18-1.91 5.38, 3.64e7.94 Standard 1.18, 0.42e3.43 9.70, 2.32e40.4 Standard 0.94, 0.58e1.53 5.40, 2.36e12.3 Standard 1.34, 1.00e1.80 3.19, 2.00e5.10 Standard 1.45, 1.24-1.71 2.01, 1.52e2.65 Standard 1.19, 1.03-1.38 1.70, 1.39e2.07 Standard 1.00, 0.75e1.33 1.02, 0.67e1.55
Standard <0.01 <0.01 Standard 0.84 N/A Standard <0.01 <0.01 Standard 0.75 <0.01 Standard 0.81 <0.01 Standard <0.05 <0.01 Standard <0.01 <0.01 Standard 0.02 <0.01 Standard 0.98 0.92
78.5% 61.9% 39.4% 94% 95.8% N/A 86.3% 80.3% 36.8% 94.6% 93.2% 66.7% 86.2% 86.8% 38.5% 78.1% 71.4% 32.2% 66.9% 57.2% 42.2% 47.7% 39.7% 31.4% 28.1% 46.9% 40.8%
77.5e79.4% 59.9e63.7% 35.0e43.9% 90.8e96.1% 73.9e99.4% N/A 84.5e87.9% 75.9e84.1% 19.0e54.0% 92.2e96.2% 82.4e97.4% 19.4e90.4% 82.7e89% 79.4e91.7% 7.0e70.0% 74.4e81.4% 64.6e77.5% 13.5e52.7% 63.8e69.8% 51.9e62.3% 29.3e54.5% 43.4e51.9% 34.5e44.8% 23.8e39.3% 19.5e37.2% 22.6e46.2% 26.0e55.0%
Abbreviations: N0, no lymph node metastases; Pelvisþ, pelvic lymph node metastases; PAþ, para-aortic lymph node metastases. Bold, statistically significant.
with increasing LN echelon, with pelvic LNM at 2.40, and paraaortic LNM at 5.88 [11]. Beyond prognostic ramifications, these findings may also have implications for the workup and/or treatment of patients presenting with cervical cancer. Certainly, the variability of the impact of pelvic and PA LNM by the local stage would suggest the importance of adequate treatment to the primary site, whether the patient undergoes surgery or radiotherapy as primary treatment. Intensifying and improving local treatment (e.g., image-guided brachytherapy) was found to impact both tumor control and survival in the RetroEMBRACE study compared to historical controls [14] and has previously been reported elsewhere [15e18], though brachytherapy, in general, continues to be underutilized [19e21]. The importance of adequate surgery in cervical cancer is exemplified by a recent randomized trial demonstrating reduced survival for minimally invasive surgery in early-stage cervical cancer [22]. In terms of lymph node work-up and management, the role of these findings is less clear. Questions raised by these data have been extensively debated in cervical cancer, including: the role for extended field radiotherapy to include the PAs in patients at highrisk for PA LNM, the role of surgical debulking of pathologically enlarged lymph nodes [23,24], appropriate radiotherapy boost doses to known positive LN [25e31], and the role of adjuvant chemotherapy for advanced disease [32]. Ultimately, a greater appreciation of disease extent may permit more precise treatment
delivery. It is also plausible that advanced nodal disease may also indicate a greater likelihood of treatment resistance and systemic progression regardless of delivery. While this study has significant power and inclusion of a large percentage of patients nationwide, it is limited by the use of a large, nationwide database with missing variables. There were 115,819 patients in the original dataset, and almost 90% of those patients were excluded due to unknown or missing information, with the majority of patients being excluded for unknown nodal status. Some node-positive subsets included few patients. Most importantly, one possible explanation for the impact of local T stage on the prognostic value of LNM may be the way in which the nodes were evaluated. In earlier stages, patients are increasingly likely to be surgically staged as a part of their definitive surgery, and thus risk factors can be addressed appropriately in the adjuvant setting as needed. In more advanced stages, patients are not surgically staged-only radiographically. Even with more advanced imaging techniques, the false-negative rate for lymph nodes remains significant, especially for small-volume disease. Therefore, a proportion of patients with N0 disease by radiology only may have had small-volume metastases, which would make the impact of positive nodes decrease at higher stages. Delivery of treatment may also have been a source of confounding (e.g. omitting brachytherapy or chemotherapy or inadequate surgery).
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Fig. 2. Kaplan Meier Survival Curves By T stage. Legend: Solid black line, N0 or node-negative; Dashed Line, IIIC1 or pelvic lymph node metastases; Grey Line, IIIC2 or para-aortic lymph node metastases.
Further, while known factors were included in the MVA to limit the effect of confounding, it is possible that unknown factors (e.g., performance status, smoking history, anemia) were also present and a possible source of bias. This study did not evaluate the extent of nodal positivity per lymph node station, which is a known prognostic factor since the goal of this report is to relate findings to the new FIGO staging system [8]. Finally, these data were obtained from the US and represent a region that has access to advanced surgery and radiotherapy, which may not be the case in other regions of the world. A major strength of this research is its’ position as the first large hospital-based study to examine the revised 2018 FIGO staging system for stage IIIC cervical cancer, with attention to specific lymph node metastases as a function of T stage.In conclusion, the large hospital database cohort studied here reinforces the evidence that nodal status influences survival, with the risk of death at nearly 1.5 times greater for pelvic node involvement (HR 1.36, p < 0.0001, 95% CI 1.17e1.59) and 2 times greater for para-
aortic node involvement (HR 2.12, p < 0.001, 95% CI 1.69e2.68). The impact of lymph node positivity on survival varies greatly by local T stage with the greatest effect seen in stage T1B. This study also highlights the importance of the local or cervical disease burden in advanced stages. The dramatically decreased survival in para-aortic lymph node positive disease (IIIC2) for lower FIGO T stage suggests a robust application for the new FIGO staging system.
Author contributions McComas-study design, data curation, writing-original draft, writing-review and editing; Torgeson-study design, data analysis, writing-original draft, writing-review and editing; Ager and Hellekson-study design, writing-original draft, writing-review and editing, statistics analysis; Burt, Maurer, and Werner-study design,
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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writing-review and editing; Gaffney-conceptualization, writingreview and editing, supervision, project administration. Funding statement No funds were required for the production of this work. Declaration of competing interest The authors have no conflicts of interest to declare. Acknowledgements Michelle Denney, for editing and manuscript preparation. References [1] Organization WH, Cervix Uteri. Globocan 2018, International Agency for Research on Cancer, 2019. [2] Organization WH, Cervical Cancer, 2018. [3] N. Bhatla, D. Aoki, D.N. Sharma, R. Sankaranarayanan, Cancer of the cervix uteri, Int. J. Gynaecol. Obstet. 143 (Suppl 2) (2018) 22e36. [4] D.B.E. Rodin, R. Atun, et al., Scale-up of radiotherapy in the era of cervical cancer vaccination in low-income and middle-income countries: a modelbased analysis of need and economic impact, Lancet Oncol. 20 (7) (2019) 915e923. [5] C. Marth, F. Landoni, S. Mahner, M. McCormack, A. Gonzalez-Martin, N. Colombo, et al., Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann. Oncol. 29 (2018) iv262. [6] J.M. Walboomers, M.V. Jacobs, M.M. Manos, F.X. Bosch, J.A. Kummer, K.V. Shah, et al., Human papillomavirus is a necessary cause of invasive cervical cancer worldwide, J. Pathol. 189 (1999) 12e19. [7] N. Singh, S. Arif, Histopathologic parameters of prognosis in cervical cancer–a review, Int. J. Gynecol. Cancer 14 (2004) 741e750. [8] O.K. Macdonald, J. Chen, M. Dodson, C.M. Lee, D.K. Gaffney, Prognostic significance of histology and positive lymph node involvement following radical hysterectomy in carcinoma of the cervix, Am. J. Clin. Oncol. 32 (2009) 411e416. [9] H. Lu, R. Guo, H. Yang, H. Wang, X. Liang, Z. Hu, et al., The prognostic value of negative lymph node count for patients with cervical cancer after radical surgery, Oncotarget 9 (2018) 2810e2818. [10] J.H. Joo, Y.S. Kim, J.H. Nam, Prognostic significance of lymph node ratio in node-positive cervical cancer patients, Medicine (Baltim.) 97 (2018), e11711. [11] E.A. Kidd, B.A. Siegel, F. Dehdashti, J.S. Rader, D.G. Mutch, M.A. Powell, et al., Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis, J. Clin. Oncol. : Off. J. Am. Soc. Clin. Oncol. 28 (2010) 2108e2113. [12] K.Y. Bilimoria, A.K. Stewart, D.P. Winchester, C.Y. Ko, The National Cancer Data Base: a powerful initiative to improve cancer care in the United States, Ann. Surg. Oncol. 15 (2008) 683e690. [13] K. Matsuo, H. Machida, R.S. Mandelbaum, I. Konishi, M. Mikami, Validation of the 2018 FIGO cervical cancer staging system, Gynecol. Oncol. 152 (2019) 87e93. [14] A. Sturdza, R. Potter, L.U. Fokdal, C. Haie-Meder, L.T. Tan, R. Mazeron, et al., Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study, Radiother. Oncol. 120 (2016) 428e433.
[15] R. Potter, P. Georg, J.C. Dimopoulos, M. Grimm, D. Berger, N. Nesvacil, et al., Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer, Radiother. Oncol. : J. Eur. Soc. Ther. Radiol. Oncol. 100 (2011) 116e123. [16] J.C. Lindegaard, L.U. Fokdal, S.K. Nielsen, J. Juul-Christensen, K. Tanderup, MRIguided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective, Acta Oncol. 52 (2013) 1510e1519. [17] I. Ribeiro, H. Janssen, M. De Brabandere, A. Nulens, D. De Bal, I. Vergote, et al., Long term experience with 3D image guided brachytherapy and clinical outcome in cervical cancer patients, Radiother. Oncol. 120 (2016) 447e454. [18] P. Castelnau-Marchand, C. Chargari, P. Maroun, I. Dumas, E.R. Del Campo, K. Cao, et al., Clinical outcomes of definitive chemoradiation followed by intracavitary pulsed-dose rate image-guided adaptive brachytherapy in locally advanced cervical cancer, Gynecol. Oncol. 139 (2015) 288e294. [19] K. Han, M. Milosevic, A. Fyles, M. Pintilie, A.N. Viswanathan, Trends in the utilization of brachytherapy in cervical cancer in the United States, Int. J. Radiat. Oncol. Biol. Phys. 87 (2013) 111e119. [20] T.M. Ma, M.M. Harkenrider, C.M. Yashar, A.N. Viswanathan, J.S. Mayadev, Understanding the underutilization of cervical brachytherapy for locally advanced cervical cancer, Brachytherapy 18 (2019) 361e369. [21] Alimena Sea, Disparities in Utilization and Timing of Brachytherapy for Patients with Locally Advanced Cervical Cancer, A National Cancer Database study, 2019. [22] P.T. Ramirez, M. Frumovitz, R. Pareja, A. Lopez, M. Vieira, R. Ribeiro, et al., Minimally invasive versus abdominal radical hysterectomy for cervical cancer, N. Engl. J. Med. 379 (2018) 1895e1904. [23] R. Kupets, G.M. Thomas, A. Covens, Is there a role for pelvic lymph node debulking in advanced cervical cancer? Gynecol. Oncol. 87 (2002) 163e170. [24] J. Tammela, B. Bundy, K. Odunsi, Reassessment of pelvic lymph node debulking in advanced cervical cancer, Gynecol. Oncol. 92 (2004) 1014e1015. [25] A. Ramlov, P.S. Kroon, I.M. Jurgenliemk-Schulz, A.A. De Leeuw, L.C. Gormsen, L.U. Fokdal, et al., Impact of radiation dose and standardized uptake value of (18)FDG PET on nodal control in locally advanced cervical cancer, Acta Oncol. 54 (2015) 1567e1573. [26] J.A. Vargo, H. Kim, S. Choi, P. Sukumvanich, A.B. Olawaiye, J.L. Kelley, et al., Extended field intensity modulated radiation therapy with concomitant boost for lymph node-positive cervical cancer: analysis of regional control and recurrence patterns in the positron emission tomography/computed tomography era, Int. J. Radiat. Oncol. Biol. Phys. 90 (2014) 1091e1098. [27] J. Lee, J.B. Lin, C.L. Chang, Y.T. Jan, F.J. Sun, M.H. Wu, et al., Prophylactic lower para-aortic irradiation using intensity-modulated radiotherapy mitigates the risk of para-aortic recurrence in locally advanced cervical cancer: a 10-year institutional experience, Gynecol. Oncol. 146 (2017) 20e26. [28] J.C. Lindegaard, M. Assenholt, A. Ramlov, L.U. Fokdal, M. Alber, K. Tanderup, Early clinical outcome of coverage probability based treatment planning for simultaneous integrated boost of nodes in locally advanced cervical cancer, Acta Oncol. 56 (2017) 1479e1486. [29] I.M. Jurgenliemk-Schulz, S. Beriwal, A.A.C. de Leeuw, J.C. Lindegaard, C.N. Nomden, R. Potter, et al., Management of nodal disease in advanced cervical cancer, Semin. Radiat. Oncol. 29 (2019) 158e165. [30] M. Wakatsuki, T. Ohno, S. Kato, K. Ando, S.E. Noda, H. Kiyohara, et al., Impact of boost irradiation on pelvic lymph node control in patients with cervical cancer, J. Radiat. Res. 55 (2014) 139e145. [31] K. Gerszten, K. Colonello, D.E. Heron, R.J. Lalonde, I.D. Fitian, J.T. Comerci, et al., Feasibility of concurrent cisplatin and extended field radiation therapy (EFRT) using intensity-modulated radiotherapy (IMRT) for carcinoma of the cervix, Gynecol. Oncol. 102 (2006) 182e188. [32] A. Duenas-Gonzalez, J.J. Zarba, F. Patel, J.C. Alcedo, S. Beslija, L. Casanova, et al., Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix, J. Clin. Oncol. 29 (2011) 1678e1685.
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system Kyra N. McComas a, Anna M. Torgeson b, Bryan J. Ager b, Christopher Hellekson b, Lindsay M. Burt b, Kathryn A. Maurer c, Teresa L. Werner d, David K. Gaffney b, * a
University of Utah School of Medicine, Salt Lake City, UT, USA University of Utah, Department of Radiation Oncology, Salt Lake City, UT, USA University of Utah, Department of Obstetrics & Gynecology, Salt Lake City, UT, USA d University of Utah, Department of Internal Medicine, Salt Lake City, UT, USA b c
h i g h l i g h t s Prognosis in cervical cancer is negatively affected by the presence of lymph node metastases (LNM). The effect of LNM is variable by T stage. Large cervix primaries are affected less by lymph node metastases. Para-aortic LNM can have a large survival decrement particularly in smaller tumors.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 July 2019 Received in revised form 15 October 2019 Accepted 21 October 2019 Available online xxx
Objective: The 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer changed from a clinical system to a clinical/pathologic/radiologic system with stages IIIC1 and IIIC2 indicating positive pelvic and para-aortic lymph nodes, respectively. We evaluated the National Cancer Database (NCDB) for the impact on survival of lymph node metastases (LNM). Methods: The NCDB from 2004 to 2015 was queried for patients with cervical cancer, yielding 115,819 patients. Patients with FIGO IVB (22,569), non-adeno/squamous cell histologies (5,909), unknown nodal status (60,695), or unknown survival time (9,473) were excluded. Survival was compared using Cox proportional hazard model based on nodal status. Univariate (UVA) and multivariate analyses (MVA) were done for the overall cohort, followed by UVA by individual stage. Results: In 17,173 eligible patients, LNM negatively affected survival (UVA IIIC1 Hazard Ratio [HR] 2.0, p < 0.001, IIIC2 HR 3.9, p < 0.001, MVA IIIC1 HR 1.36, p < 0.001, IIIC2 HR 2.14, p < 0.001). In T1B, the effect of IIIC2 was most pronounced (HR 5.38, p < 0.001 versus HR 1.5 p ¼ 0.001 for IIIC1 disease). In T3, the effect of LNM was markedly less: (HR 1.7, p < 0.001 for IIIC2 versus HR 1.2 p ¼ 0.02 for IIIC1). Within T1B, there was no difference in survival for IIIC1 for the smaller T stages (IB1-2). Conclusion: In this study, LNM negatively affects prognosis in cervical cancer. The impact on survival varies by T stage with the greatest effect seen in stage T1B with IIIC2 disease. © 2019 Elsevier Inc. All rights reserved.
Keywords: Cervical cancer Lymph nodes Prognosis varies T stage
1. Introduction In the United States (US) in 2018, cervical cancer affected approximately 15,000 women, with an incidence of 2.7% and a mortality of 1.9% [1]. The worldwide incidence of cervix cancer is high, with 90% of deaths from cervical cancer occurring in low- and
* Corresponding author. Huntsman Cancer Hospital, Radiation Oncology 1950 Circle of Hope Drive Room 1570, Salt Lake City, UT, 84112, USA. E-mail address: [email protected] (D.K. Gaffney).
middle-income countries [2e4]. Cervix cancer remains an enormous public health concern. One recent publication indicated that 9.4 million women from 2015 to 2035 in low- and middle-income countries would require treatment with radiotherapy [4]. Geographic variation is reflective of variable access to screening and subsequent prevention, as well as human papillomavirus (HPV) prevalence [3,5], which is detectable in 99.7% of cervical cancers [6]. Given geographic and socioeconomic disparities in incidence, staging, radiographic modalities and treatment options, radiological and surgical findings have not been included in previous
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Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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iterations of the International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging system [3]. Thus, nodal involvement has not previously been included despite extensive literature describing its effect on prognosis [7e11]. Nodal involvement has been found to negatively affect prognosis in the surgical setting, with patient survival decreasing with increasing numbers of lymph nodes involved [8,9], and with increasing ratios of distant lymph node positivity [10], given the contiguous nature of cervical cancer spread. Clinical nodal involvement by 18-Fluoro deoxyglucose positron emission tomography (FDG-PET) has been found to correlate with both more advanced T stage and decreased survival [11]. In 2018, FIGO consequently instigated changes to staging for better prognostic power, including removing horizontal spread as a stipulation for stage IA disease, further subcategorizing stage IB by tumor size, and adding stage IIIC disease based on the presence of nodal metastases by radiologic imaging or pathologic data, with stage IIIC1 and IIIC2 involving pelvic and para-aortic lymph nodes, respectively [3]. The FIGO IIIC designation associates nodal involvement with the worst prognoses, aside from tumors with alternate pelvic organ invasion (IVA) or distant spread (IVB) [3], but disregards local tumor stage. In light of these new additions to the staging system, we sought to examine the impact of nodal positivity and local tumor burden on prognosis in a cohort of patients from a nationwide hospital database. Our study aims to describe the impact of pelvic and paraaortic nodal metastasis on survival outcomes, stratified by 2018 FIGO T stage. 1.1. Methods and materials The National Cancer Database (NCDB) was queried for patients diagnosed with cervical cancer from 2004 to 2014. The NCDB is a joint program of the Commission on Cancer and the American Cancer Society, which includes data from approximately 1500 hospitals and clinics in the United States and its territories. This database captures nearly 70% of new cancer diagnoses made in the US [12]. All NCDB data are de-identified and thus are exempt from institutional review board review. The initial query yielded 115,819 patients. We excluded FIGO stage IVB (22,569), non-adenocarcinoma or squamous cell carcinoma histology (5,909), unknown nodal status (60,695), or unknown survival time or survival time less than three months (9,473) (see Fig. 1). Patients were not excluded if they did not receive treatment, though the great majority of these patients who did not receive treatment were excluded for other reasons. The primary outcome variable was overall survival, stratified by nodal status (node-negative [N0], positive pelvic nodes [IIIC1], or positive para-aortic nodes [IIIC2]). Nodal status included both clinical nodal assessment via imaging and pathologic nodal assessment. Chi-square analysis was used to compare demographic and tumor characteristics by nodal status (see Table 1). Demographic factors examined included age, race, Charlson comorbidity score, primary payer, facility type, census region, area income, percent of residents without a high school degree, distance from the treatment facility, and urban density. Tumor characteristics included tumor size, lymphovascular space invasion (LVSI), FIGO T stage, grade, and histology. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were then used to analyze the association between nodal status and risk of death, as well as other covariates that may be predictive of survival. Factors with P values of 0.1 or less on UVA were included in the multivariate model. A P value of 0.1 was chosen in order to maintain more stringent standards for inclusion in the MVA. Subgroup analyses were then undertaken to determine the effect of nodal status on survival by T stage. Five-year overall
survival times were also collected for the overall cohort by nodal status, and by individual stage. All analyses were performed using the STATA 14.0 statistical package (Stata Corporation, College Station, Texas). 2. Results After the appropriate exclusions were made, 17,173 patients with cervical cancer remained (Table 1). There were 11,853 N0 patients, 4451 IIIC1 patients, and 869 IIIC2 patients. Node-positive (IIIC1 and IIIC2) patients were more likely to be younger (87e88% versus 84%, p < 0.001), non-white (33e37% versus 25%, p < 0.001), uninsured or on Medicaid (36e38% versus 30%, p < 0.001), live in areas where 29% or more of the population did not have a high school diploma (52% versus 48%, p < 0.001), have squamous cell histology (79e80% versus 68%, p < 0.001), poorly-differentiated tumors (47e56% versus 35%), have tumors 4.0 cm (cm) or more in size (68e78% versus 42%, p < 0.001), and more locally advanced tumors (70e86% FIGO T2A-4A versus 47%, p < 0.001). Of patients with known LVSI status, node-positive patients were more likely to have LVSI (38e45% versus 28%, p < 0.001). On UVA, all demographic and tumor factors were significant save for distance from the facility (Table 2). Nodal status was particularly significant for survival on UVA. Hazard ratio (HR) for death with IIIC1 disease was double that of node-negative patients (HR 2.0, p < 0.001, 95% Confidence Interval [CI] I 1.86e2.14), and with IIIC2 almost quadruple that of node-negative patients (HR 3.8, p < 0.001, 95% CI 3.43e4.25). On MVA, nodal status remained significant for both IIIC1 (HR 1.4, p < 0.001, 95% CI 1.17e1.59) and IIIC2 disease (HR 2.1 p < 0.001, 95% CI 1.69e2.68). On subgroup analysis, there was no statistically significant increased risk for death for patients with IIIC1 disease in T stages 1A, 1B1, or 1B2 compared to N0 patients (Table 3). For patients with IIIC2 disease, there was a large increase in the risk of death for stage T1B patients, though this is difficult to interpret for the T1B1 patients due to only having six patients and two events. (Table 3, Fig. 2). Similarly, there were only 2 of 891 stage T1A patients with IIIC2 disease, so the effect of IIIC2 disease could not be evaluated. For T stages 1B3-3, both IIIC1 and IIIC2 diseases were detrimental to survival compared to N0 patients (Table 3, Fig. 2). Five-year overall survival (OS) for the overall cohort was 78.5% (95% CI 77.5e74.9%), 61.9% (95% CI 59.9e63.7%), and 39.4% (95% CI 35.0e43.9%) for N0, IIIC1, and IIIC2 respectively (Table 3). Stage T1A patients had a 5-year OS of 94e95.8% regardless of nodal status. For stage T1B patients overall, the effect of lymph node status was much greater than more advanced T stages (5-year OS 86.3% [95% CI 84.5e87.9%], 80.3% [95% CI 75.9e84.1%], and 36.8% (95% CI 19.0e54.0%] for N0, IIIC1, and IIIC2 disease, respectively) compared to more locally advanced patients. T2 patients had a 5-year OS of 66.9% (95% CI 63.8e69.8%), 57.2% (95% CI 51.9e62.3%), and 42.2% (95% CI 29.3e54.5%) for N0, IIIC1, and IIIC2 disease, respectively. T3 patients had 5-year OS of 47.7% (95% CI 43.4e51.9%), 39.7% (95% CI 34.5e44.8%), and 31.4% (95% CI 23.8e39.3%) for N0, IIIC1, and IIIC2 disease, respectively. There was no difference in survival for T4A disease based on nodal status. 3. Discussion This retrospective cohort study of 17,173 women with cervical cancer examined the impact on survival as a function of lymph node involvement both in the overall cohort and by T stage. Tumor characteristics, including larger tumor size, locally advanced disease, squamous cell histology, higher grade, and LVSI positivity were associated with nodal positivity. Demographic characteristics suggestive of lower socioeconomic status (lack of a high school diploma or private insurance) were also associated with an
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Fig. 1. CONSORT diagram. Legend: Abbreviations: NCDB¼National Cancer Data Base, LNM ¼ lymph node metastases.
increased likelihood of nodal positivity. Increasingly advanced nodal involvement negatively affected survival, with IIIC2 disease demonstrating a more dramatic decrease in survival versus IIIC1 disease. The survival detriment was found to be dependent on local tumor burden, which seemed to progress in a step-wise fashion. Surprisingly, patients with local T stage 1A, 1B1, 1B2, and 4A disease did not experience a statistically significant survival detriment with pelvic nodal involvement (IIIC1). In comparison, the effect of paraaortic nodal involvement (IIIC2) was more pronounced in patients with T1B disease (HR 5.4, p < 0.01, 95% CI 3.64e7.94), but was similar to the effect of involved pelvic nodes with increasing local tumor burden (T2 IIIC1 HR 1.45, [95% CI 1.24e1.71], p < 0.01 IIIC2 HR 2.01, p < 0.01, [95% CI 1.52e2.65] T3 IIIC1 HR 1.19, p ¼ 0.02, [95% CI 1.03e1.38] IIIC2 HR 1.70, p < 0.01, [95% CI 1.39e2.07]). The likelihood of positive nodes based on local tumor factors is expected and lends to the validity of this dataset [11]. Specifically, a large retrospective study of 560 patients found that the frequency of lymph node metastasis (LNM) detected by PET-CT increased with local tumor burden, and was associated with poorer survival [11]. The effect of LNM on survival in the overall cohort is expected, given the concordant findings of previous studies of smaller numbers of patients in patients who were diagnosed either radiographically or surgically [8e11]. The effect of nodal status concerning variable local tumor burden is intriguing; however, the “IIIC” designation in the new FIGO staging system would suggest that LNM are associated with the poorest prognosis aside from pelvic organ invasion or distant
metastases, regardless of local tumor burden. In this dataset, patients with tumors 4 cm or less confined to the cervix did not experience an increased risk for death with pelvic LNM. In line with the FIGO staging system, T4A (FIGO IVA) patients did not experience a survival detriment with either pelvic or para-aortic LNM, despite reasonable sample size (201 N0, 174 IIIC1, and 51 IIIC2). Thus, this dataset suggests that the impact of pelvic LNM varies with local tumor burden. These data run concordant to the findings of Matsuo et al. who used the US Surveillance, Epidemiology and End Results (SEER) Database to validate the new staging system. Interestingly, they found that in all patients with pelvic LNM, survival varied greatly between T1, T2, and T3 disease, with higher T stages correlating with significantly worse survival [13]. These results, taken together, suggest that local tumor burden may still be equal to, if not more important than, nodal status in prognosis. Another interesting finding from this study is the variability of the effect of para-aortic (PA) LNM in FIGO T1B compared to T2 and T3. In T1B, PA LNM was associated with drastically decreased survival from the baseline (HR 5.4, p < 0.001 95% CI 3.64e7.94), though was, fortunately, an uncommon finding in T1B1 (0.6%), T1B2 (1.1%), and T1B3 disease (3.5%). By T2 (4.8% of patients, HR 2.0 p < 0.001, 95% CI 1.52e2.65) and T3 (11.9% of patients, HR 1.7, p < 0.001, 95% CI 1.39e2.07), however, the effect of PA LNM was reduced, though PA LNM were a more common finding. These results cannot be compared to SEER since PA LNM are not coded in SEER [13]. However, these findings are in concordance with previous retrospective results where the HR for death increased incrementally
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Table 1 Patient characteristics by nodal status. Variable Age 18e45 46e65 Older than 65 Race White Black Hispanic Other Insurance Status Uninsured Private Medicaid Medicare Gov NOS Unknown Charlson Score 0 1 2 3 Census Region Northeast South Midwest West Area Income 0-29,999$ 30-34,999$ 35-45,999$ 46,000$þ % w/o HS Diploma 29%þ 20e28.9% 14e19% <14% Facility Type Community CC Academic Integrated Urban Density Metropolitan Urban Rural Histology Squamous Cell Adenocarcinoma Grade 1 2 3 LVSI Negative Positive Unknown Tumor Size 0e0.49 0.5-0.9 1.0e1.9 2.0e3.9 4.0 or more FIGO T stage T1A1 T1A2 T1B1 T1B2 T1B3 T2A1 T2A2 T2B T3A T3B T4A
N0
%
IIIC1
%
IIIC2
%
4785 5251 1817
40% 44% 15%
1813 2091 547
41% 47% 12%
274 479 116
32% 55% 15%
8000 1586 1491
68% 13% 6%
2835 690 645
64% 16% 15%
569 149 91
67% 17% 11%
932 5815 2616 2175 172 143
8% 49% 22% 18% 1% 1%
437 2019 1167 673 72 83
10% 45% 26% 15% 2% 2%
103 371 230 141 10 14
12% 43% 26% 16% 1% 2%
10006 1394 262 131
85% 12% 2% 1%
3785 545 76 45
85% 12% 2% 1%
740 109 17 3
85% 13% 2% <1%
1777 3373 2047 1519
20% 39% 23% 17%
630 1299 746 592
19% 40% 23% 18%
136 278 177 111
19% 40% 25% 16%
1912 2337 3329 3912
17% 20% 29% 34%
802 906 1234 1365
19% 21% 29% 32%
139 191 260 259
16% 22% 31% 31%
2481 3002 2648 3356
22% 26% 23% 29%
1076 1157 941 1131
25% 27% 22% 26%
212 232 193 212
25% 27% 23% 25%
575 3300 3692 1149
7% 38% 42% 13%
196 1229 1408 434
6% 38% 43% 13%
49 246 312 95
7% 35% 44% 14%
9613 1336 631
83% 12% 5%
3591 511 241
83% 12% 6%
693 113 46
81% 13% 5%
8044 3809
68% 32%
3547 904
80% 20%
686 183
79% 21%
1629 4319 3157
18% 47% 35%
200 1622 1624
6% 47% 47%
32 257 373
5% 39% 56%
5125 1964 4764
43% 17% 40%
791 1310 2350
18% 29% 53%
138 169 562
16% 19% 65%
964 802 1243 2231 3765
11% 9% 14% 25% 42%
10 58 224 795 2338
1% 2% 6% 23% 68%
6 11 21 96 480
1% 2% 3% 16% 78%
656 208 834 1019 848 98 252 1596 128 847 201
10% 3% 12% 15% 13% 1% 4% 24% 2% 13% 3%
13 12 85 226 294 15 86 555 80 556 147
1% 1% 4% 11% 14% 1% 4% 27% 4% 27% 7%
2 0 6 14 41 9 14 107 16 202 51
<1% 0% 1% 3% 9% 2% 3% 23% 3% 44% 11%
P value <0.01
<0.01
<0.01
0.15
0.46
<0.01
<0.01
0.70
0.66
<0.01
<0.01
<0.01
<0.01
<0.01
Abbreviations: LVSI, lymphovascular space invasion; Gov NOS, government not otherwise specified; % w/o HS diploma, % of constituents without a high school diploma; CC, comprehensive community; cm, centimeters; FIGO T Stage, International Federation of Gynecologic Oncology Tumor Stage..
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Table 2 Univariate and multivariate analysis of survival in cervical cancer. Variable Age 18e45 46e65 Older than 65 Race White Black Hispanic Other Insurance Status Uninsured Private Medicaid Medicare Gov NOS Unknown Charlson Score 0 1 2 3 Census Region Northeast South Midwest West Area Income 0-29,999$ 30-34,999$ 35-45,999$ 46,000$þ % w/o HS Diploma 29%þ 20e28.9% 14e19% <14% Facility Type Community CC Academic Integrated Urban Density Metropolitan Urban Rural Histology Squamous Cell Adenocarcinoma Grade 1 2 3 LVSI Negative Positive Unknown Tumor Size 0e0.49 0.5-0.9 1.0e1.9 2.0e3.9 4.0 or more FIGO T stage T1A1 T1A2 T1B1 T1B2 T1B3 T2A1 T2A2 T2B T3A T3B T4A Nodal Status
UVA
95% CI
P value
MVA
P value
Standard 1.48 2.76
Standard 1.37-1.60 2.53-3.02
Standard <0.01 <0.01
Standard 1.07 1.44
Standard 0.87-1.31 1.10-1.88
Standard 0.51 <0.01
Standard 1.38 0.68 0.88
Standard 1.22-1.45 0.60-0.76 0.76-1.03
Standard <0.01 <0.01 0.12
Standard 1.03 0.73 0.99
Standard 0.85-1.25 0.57-0.93 0.73-1.34
Standard 0.76 0.01 0.94
Standard 0.60 1.00 1.62 0.62 1.11
Standard 0.53-0.68 0.88-1.13 1.43-1.83 0.44-0.87 0.85-1.46
Standard <0.01 0.97 <0.01 <0.01 0.43
Standard 0.78 1.08 1.31 0.45 0.93
Standard 0.61-1.00 0.84-1.40 0.99-1.73 0.17-1.25 0.51-1.68
Standard 0.05 0.54 0.06 0.13 0.80
Standard 1.36 1.94 2.13
Standard 1.24-1.50 1.62-2.34 1.65-2.74
Standard <0.01 <0.01 <0.01
Standard 1.46 1.55 1.85
Standard 1.22-1.74 1.10-2.16 1.17-2.94
Standard <0.01 0.01 <0.01
Standard 1.08 1.17 0.95
Standard 0.98-1.19 1.05-1.31 0.84-1.07
Standard 0.17 <0.01 0.39
Standard 1.08 1.16 1.03
Standard 0.89-1.30 0.92-1.36 0.83-1.29
Standard 0.46 0.27 0.77
Standard 0.94 0.83 0.70
Standard 0.84-1.04 0.76-0.92 0.63-0.77
Standard 0.20 <0.01 <0.01
Standard 0.97 0.90 0.78
Standard 0.78-1.20 0.72-1.12 0.60-1.02
Standard 0.76 0.35 0.07
Standard 1.03 0.89 0.79
Standard 0.94-1.13 0.81-0.99 0.71-0.86
Standard 0.52 0.03 <0.01
Standard 1.17 1.16 1.20
Standard 0.96-1.43 0.92-1.46 0.93-1.54
Standard 0.12 0.20 0.16
Standard 0.95 0.81 0.88
Standard 0.82-1.10 0.70-0.94 0.75-1.05
Standard 0.48 <0.01 0.15
Standard 1.23 0.88 1.06
Standard 0.92-1.65 0.66-1.18 0.77-1.48
Standard 0.17 0.40 0.77
Standard 1.09 1.16
Standard 0.98-1.20 1.01e1.33
Standard 0.11 0.04
Standard 0.84 0.76
Standard 0.68-1.04 0.56-1.03
Standard 0.11 0.08
Standard 0.62
Standard 0.57-0.67
Standard <0.01
Standard 1.22
Standard 1.02-1.45
Standard 0.03
Standard 2.08 3.24
Standard 1.76-2.44 2.76-3.80
Standard <0.01 <0.01
Standard 1.04 1.40
Standard 0.99-1.80 1.04-1.88
Standard 0.71 0.03
Standard 1.56 2.73
Standard 1.40-1.74 2.51-2.97
Standard <0.01 <0.01
Standard 1.04 0.98
Standard 0.83-1.32 0.82-1.17
Standard 0.71 0.79
Standard 1.60 1.76 4.02 9.85
Standard 1.03-2.48 1.14-2.52 2.84-5.71 7.02e13.83
Standard 0.04 0.01 <0.01 <0.01
Standard 0.99 1.00 1.56 2.62
Standard 0.37-2.67 0.35-2.91 0.58-4.18 0.99-6.90
Standard 0.98 1.00 0.37 0.05
Standard 1.26 1.12 2.49 5.72 5.42 8.68 8.50 16.62 17.5 23.15
Standard 0.60-2.65 0.67-1.87 1.59-3.90 3.72-8.78 3.02e9.72 5.51-13.70 5.60-12.89 10.57-26.15 11.58-26.56 15.07e35.58
Standard 0.54 0.67 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01
Standard 1.06 0.55 0.80 0.98 1.52 1.43 1.61 2.60 2.86 3.60
Standard 0.35-3.22 0.20-1.51 0.31-2.08 0.39-2.47 0.54-4.28 0.55-3.70 0.65-4.00 0.99-6.78 1.14-7.14 1.4e9.15
Standard 0.92 0.24 0.65 0.96 0.43 0.46 0.31 0.05 0.02 <0.01 (continued on next page)
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Table 2 (continued ) Variable
UVA
95% CI
P value
MVA
N0 IIIC1 IIIC2
Standard 2.00 3.82
Standard 1.86-2.14 3.43-4.25
Standard <0.01 <0.01
Standard 1.36 2.12
P value Standard 1.17-1.59 1.69-2.68
Standard <0.01 <0.01
Abbreviations: 95% CI, 95% Confidence Interval LVSI, lymphovascular space invasion; Gov NOS- government not otherwise specified; % w/o HS diploma, % of constituents without a high school diploma; CC, comprehensive community; cm, centimeters; FIGO T Stage, International Federation of Gynecologic Oncology Tumor Stage; IIIC1, positive pelvic lymph nodes; IIIC2- positive para-aortic lymph nodes. Bold ¼ statistically significant on multivariate.
Table 3 Overall Survival by Nodal Status and Tumor (T) stage. T stage
Patient Number
Hazard Ratio (HR) for Death, 95% Confidence Interval
P value
5 year Overall Survival %
95% Confidence Interval
All, N0 All, Pelvis þ All, PA þ IA, N0 IA, Pelvis þ IA, PAþ IB, N0 IB, Pelvis þ IB, PA þ IB1, N0 IB1, Pelvis þ IB1, PA þ IB2, N0 IB2, Pelvis þ IB2, PA þ IB3, N0 IB3, Pelvis þ IB3, PA þ II, N0 II, Pelvis þ II, PA þ III, N0 III, Pelvis þ III, PA þ IVA, N0 IVA, Pelvis þ IVA, PA þ
11853 4451 869 864 25 2 2701 601 65 834 85 6 1019 226 14 848 294 41 1946 656 130 975 636 218 201 174 51
Standard 2.00, 1.86e2.14 3.85, 3.43e4.25 Standard 0.82, 0.11e6.03 N/A Standard 1.50, 1.18-1.91 5.38, 3.64e7.94 Standard 1.18, 0.42e3.43 9.70, 2.32e40.4 Standard 0.94, 0.58e1.53 5.40, 2.36e12.3 Standard 1.34, 1.00e1.80 3.19, 2.00e5.10 Standard 1.45, 1.24-1.71 2.01, 1.52e2.65 Standard 1.19, 1.03-1.38 1.70, 1.39e2.07 Standard 1.00, 0.75e1.33 1.02, 0.67e1.55
Standard <0.01 <0.01 Standard 0.84 N/A Standard <0.01 <0.01 Standard 0.75 <0.01 Standard 0.81 <0.01 Standard <0.05 <0.01 Standard <0.01 <0.01 Standard 0.02 <0.01 Standard 0.98 0.92
78.5% 61.9% 39.4% 94% 95.8% N/A 86.3% 80.3% 36.8% 94.6% 93.2% 66.7% 86.2% 86.8% 38.5% 78.1% 71.4% 32.2% 66.9% 57.2% 42.2% 47.7% 39.7% 31.4% 28.1% 46.9% 40.8%
77.5e79.4% 59.9e63.7% 35.0e43.9% 90.8e96.1% 73.9e99.4% N/A 84.5e87.9% 75.9e84.1% 19.0e54.0% 92.2e96.2% 82.4e97.4% 19.4e90.4% 82.7e89% 79.4e91.7% 7.0e70.0% 74.4e81.4% 64.6e77.5% 13.5e52.7% 63.8e69.8% 51.9e62.3% 29.3e54.5% 43.4e51.9% 34.5e44.8% 23.8e39.3% 19.5e37.2% 22.6e46.2% 26.0e55.0%
Abbreviations: N0, no lymph node metastases; Pelvisþ, pelvic lymph node metastases; PAþ, para-aortic lymph node metastases. Bold, statistically significant.
with increasing LN echelon, with pelvic LNM at 2.40, and paraaortic LNM at 5.88 [11]. Beyond prognostic ramifications, these findings may also have implications for the workup and/or treatment of patients presenting with cervical cancer. Certainly, the variability of the impact of pelvic and PA LNM by the local stage would suggest the importance of adequate treatment to the primary site, whether the patient undergoes surgery or radiotherapy as primary treatment. Intensifying and improving local treatment (e.g., image-guided brachytherapy) was found to impact both tumor control and survival in the RetroEMBRACE study compared to historical controls [14] and has previously been reported elsewhere [15e18], though brachytherapy, in general, continues to be underutilized [19e21]. The importance of adequate surgery in cervical cancer is exemplified by a recent randomized trial demonstrating reduced survival for minimally invasive surgery in early-stage cervical cancer [22]. In terms of lymph node work-up and management, the role of these findings is less clear. Questions raised by these data have been extensively debated in cervical cancer, including: the role for extended field radiotherapy to include the PAs in patients at highrisk for PA LNM, the role of surgical debulking of pathologically enlarged lymph nodes [23,24], appropriate radiotherapy boost doses to known positive LN [25e31], and the role of adjuvant chemotherapy for advanced disease [32]. Ultimately, a greater appreciation of disease extent may permit more precise treatment
delivery. It is also plausible that advanced nodal disease may also indicate a greater likelihood of treatment resistance and systemic progression regardless of delivery. While this study has significant power and inclusion of a large percentage of patients nationwide, it is limited by the use of a large, nationwide database with missing variables. There were 115,819 patients in the original dataset, and almost 90% of those patients were excluded due to unknown or missing information, with the majority of patients being excluded for unknown nodal status. Some node-positive subsets included few patients. Most importantly, one possible explanation for the impact of local T stage on the prognostic value of LNM may be the way in which the nodes were evaluated. In earlier stages, patients are increasingly likely to be surgically staged as a part of their definitive surgery, and thus risk factors can be addressed appropriately in the adjuvant setting as needed. In more advanced stages, patients are not surgically staged-only radiographically. Even with more advanced imaging techniques, the false-negative rate for lymph nodes remains significant, especially for small-volume disease. Therefore, a proportion of patients with N0 disease by radiology only may have had small-volume metastases, which would make the impact of positive nodes decrease at higher stages. Delivery of treatment may also have been a source of confounding (e.g. omitting brachytherapy or chemotherapy or inadequate surgery).
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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Fig. 2. Kaplan Meier Survival Curves By T stage. Legend: Solid black line, N0 or node-negative; Dashed Line, IIIC1 or pelvic lymph node metastases; Grey Line, IIIC2 or para-aortic lymph node metastases.
Further, while known factors were included in the MVA to limit the effect of confounding, it is possible that unknown factors (e.g., performance status, smoking history, anemia) were also present and a possible source of bias. This study did not evaluate the extent of nodal positivity per lymph node station, which is a known prognostic factor since the goal of this report is to relate findings to the new FIGO staging system [8]. Finally, these data were obtained from the US and represent a region that has access to advanced surgery and radiotherapy, which may not be the case in other regions of the world. A major strength of this research is its’ position as the first large hospital-based study to examine the revised 2018 FIGO staging system for stage IIIC cervical cancer, with attention to specific lymph node metastases as a function of T stage.In conclusion, the large hospital database cohort studied here reinforces the evidence that nodal status influences survival, with the risk of death at nearly 1.5 times greater for pelvic node involvement (HR 1.36, p < 0.0001, 95% CI 1.17e1.59) and 2 times greater for para-
aortic node involvement (HR 2.12, p < 0.001, 95% CI 1.69e2.68). The impact of lymph node positivity on survival varies greatly by local T stage with the greatest effect seen in stage T1B. This study also highlights the importance of the local or cervical disease burden in advanced stages. The dramatically decreased survival in para-aortic lymph node positive disease (IIIC2) for lower FIGO T stage suggests a robust application for the new FIGO staging system.
Author contributions McComas-study design, data curation, writing-original draft, writing-review and editing; Torgeson-study design, data analysis, writing-original draft, writing-review and editing; Ager and Hellekson-study design, writing-original draft, writing-review and editing, statistics analysis; Burt, Maurer, and Werner-study design,
Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025
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writing-review and editing; Gaffney-conceptualization, writingreview and editing, supervision, project administration. Funding statement No funds were required for the production of this work. Declaration of competing interest The authors have no conflicts of interest to declare. Acknowledgements Michelle Denney, for editing and manuscript preparation. References [1] Organization WH, Cervix Uteri. Globocan 2018, International Agency for Research on Cancer, 2019. [2] Organization WH, Cervical Cancer, 2018. [3] N. Bhatla, D. Aoki, D.N. Sharma, R. Sankaranarayanan, Cancer of the cervix uteri, Int. J. Gynaecol. Obstet. 143 (Suppl 2) (2018) 22e36. [4] D.B.E. Rodin, R. Atun, et al., Scale-up of radiotherapy in the era of cervical cancer vaccination in low-income and middle-income countries: a modelbased analysis of need and economic impact, Lancet Oncol. 20 (7) (2019) 915e923. [5] C. Marth, F. Landoni, S. Mahner, M. McCormack, A. Gonzalez-Martin, N. Colombo, et al., Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann. Oncol. 29 (2018) iv262. [6] J.M. Walboomers, M.V. Jacobs, M.M. Manos, F.X. Bosch, J.A. Kummer, K.V. Shah, et al., Human papillomavirus is a necessary cause of invasive cervical cancer worldwide, J. Pathol. 189 (1999) 12e19. [7] N. Singh, S. Arif, Histopathologic parameters of prognosis in cervical cancer–a review, Int. J. Gynecol. Cancer 14 (2004) 741e750. [8] O.K. Macdonald, J. Chen, M. Dodson, C.M. Lee, D.K. Gaffney, Prognostic significance of histology and positive lymph node involvement following radical hysterectomy in carcinoma of the cervix, Am. J. Clin. Oncol. 32 (2009) 411e416. [9] H. Lu, R. Guo, H. Yang, H. Wang, X. Liang, Z. Hu, et al., The prognostic value of negative lymph node count for patients with cervical cancer after radical surgery, Oncotarget 9 (2018) 2810e2818. [10] J.H. Joo, Y.S. Kim, J.H. Nam, Prognostic significance of lymph node ratio in node-positive cervical cancer patients, Medicine (Baltim.) 97 (2018), e11711. [11] E.A. Kidd, B.A. Siegel, F. Dehdashti, J.S. Rader, D.G. Mutch, M.A. Powell, et al., Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis, J. Clin. Oncol. : Off. J. Am. Soc. Clin. Oncol. 28 (2010) 2108e2113. [12] K.Y. Bilimoria, A.K. Stewart, D.P. Winchester, C.Y. Ko, The National Cancer Data Base: a powerful initiative to improve cancer care in the United States, Ann. Surg. Oncol. 15 (2008) 683e690. [13] K. Matsuo, H. Machida, R.S. Mandelbaum, I. Konishi, M. Mikami, Validation of the 2018 FIGO cervical cancer staging system, Gynecol. Oncol. 152 (2019) 87e93. [14] A. Sturdza, R. Potter, L.U. Fokdal, C. Haie-Meder, L.T. Tan, R. Mazeron, et al., Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study, Radiother. Oncol. 120 (2016) 428e433.
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Please cite this article as: K.N. McComas et al., The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.10.025