YGYNO-976204; No. of pages: 8; 4C: Gynecologic Oncology xxx (2016) xxx–xxx
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Natural history and outcome of neuroendocrine carcinoma of the cervix Benjamin Margolis a,f, Ana I. Tergas a,c,d,f, Ling Chen a, June Y. Hou a,d,f, William M. Burke a,d,f, Jim C. Hu e,f, Cande V. Ananth a,c, Alfred I. Neugut b,c,d,f, Dawn L. Hershman b,c,d,f, Jason D. Wright a,d,f,⁎ a
Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, United States Department of Medicine, Columbia University College of Physicians and Surgeons, United States Department of Epidemiology, Mailman School of Public Health, Columbia University, United States d Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, United States e Department of Urology, Weill Cornell Medical College, United States f New York Presbyterian Hospital, United States b c
H I G H L I G H T S • NECC are aggressive tumors associated with an increased risk of death. • Survival is inferior for NECC compared to squamous cell tumors for women with both early and advanced stage disease. • Further studies are needed to improve therapeutic options for NECC.
a r t i c l e
i n f o
Article history: Received 5 January 2016 Received in revised form 30 January 2016 Accepted 8 February 2016 Available online xxxx Keywords: Cervical cancer Neuroendocrine carcinoma Squamous cell carcinoma Cervical carcinoma Cervix
a b s t r a c t Objective. Neuroendocrine carcinomas of the cervix (NECC) are rare and thought to be aggressive. We performed a population-based analysis to examine the natural history, treatment patterns and outcomes of women with NECC compared to squamous cell carcinoma (SCCC) and adenocarcinoma (AC) of the cervix. Methods. The National Cancer Database (NCDB) was utilized to identify women with NECC, SCCC, and AC treated from 1998 to 2011. Clinical, demographic, and treatment characteristics were compared between the groups. The association between tumor histology and survival was examined using Kaplan-Meier analyses and multivariable Cox proportional hazards regression models. Results. We identified 127,332 patients, including 1,896 (1.5%) with NECC and 101,240 (79.5%) with SCCC and 24,196 (19.0%) with AC. Patients with NECC were younger, more often white, commercially insured, and diagnosed with metastatic disease at presentation compared to women with SCCC. Patients with early-stage NECC were more likely to receive adjuvant chemotherapy and radiation after surgery (P b 0.05 for both). In multivariable models stratified by stage and adjusted for clinical and demographic characteristics, the risk of death was higher for patients with NECC compared to SCCC for all stages of disease: stages IB–IIA (HR = 2.96; 95% CI, 2.48–3.52), stages IIB–IVA (HR = 1.70; 95% CI, 1.45–1.99) and stage IVB (HR = 1.14; 95% CI, 0.91–1.43). Conclusion. NECC are aggressive tumors associated with an increased risk of death. Survival is inferior for NECC compared to squamous cell tumors for women with both early and advanced stage disease. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Neuroendocrine carcinomas of the cervix (NECC) are rare tumors that comprise 2–5% of cervical malignancies [1–4]. This category of tumors is comprised of small cell, large cell, carcinoid and atypical carcinoid histologic types. Small cell and large cell tumors are poorly differentiated and are characterized by a high mitotic rate, necrosis, ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Ave, 8th Floor, New York, NY 10032, United States. E-mail address: [email protected] (J.D. Wright).
frequent lymphovascular space involvement and a more aggressive clinical course. Carcinoid and atypical carcinoid tumors are welldifferentiated, are thought to be derived from neural crest cells, and are extremely rare [1]. Atypical carcinoid tumors display significant nuclear atypia and are poorly studied. In general, NECCs are characterized by early spread beyond the cervix and a poor prognosis. Five-year survival rates for NECC are reported at 0–30% [5]. Given that NECC is uncommon, data to guide clinical decision-making is limited and treatment regimens are often extrapolated from neuroendocrine tumors from other sites. Therapy for early stage disease involves radical surgery for tumors b4 cm, often in combination with adjuvant chemotherapy. Advanced
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Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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B. Margolis et al. / Gynecologic Oncology xxx (2016) xxx–xxx
stage disease is treated with combination chemotherapy and radiation. The chemotherapy regimens most commonly utilized include cisplatin and etoposide (EP) or vincristine, doxorubicin, and cyclophosphamide
(VAC). Prior work has shown that among women with NECC chemotherapy improves survival, particularly for locally advanced stage disease [6].
Table 1 Descriptive characteristics of the cohort stratified by histology. Squamous cell
All Year of diagnosis 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Age b30 30–39 40–49 50–59 60–69 ≥70 Race White Black Hispanic Other Unknown Insurance status Commercial Medicare Medicaid Uninsured Other Unknown Region Northeast Midwest South West Location Metropolitan Urban Rural Unknown Hospital type Community cancer program Comprehensive community cancer program Academic Other Stage IA (IA, IA1, IA2) IB (IB, IB1, IB2, INOS) IIA (IIA, IIA1, IIA2) IIB (IIB, IINOS) IIIA IIIB IVA IVB IVNOS Unknown Primary treatment Surgery Radiation No surgery or radiation Unknown
Adenocarcinoma
Neuroendocrine
P-value
N
(%)
N
(%)
N
(%)
101,240
(79.5)
24,196
(19.0)
1896
(1.5) b0.001
8567 8211 8138 7744 7440 6982 6848 6894 6864 6884 6869 6898 6513 6388
(8.5) (8.1) (8.0) (7.7) (7.4) (6.9) (6.8) (6.8) (6.8) (6.8) (6.8) (6.8) (6.4) (6.3)
1752 1653 1695 1623 1626 1529 1585 1633 1732 1746 1820 1985 1922 1895
(7.2) (6.8) (7.0) (6.7) (6.7) (6.3) (6.6) (6.8) (7.2) (7.2) (7.5) (8.2) (7.9) (7.8)
130 112 126 118 138 141 118 133 135 129 162 142 144 168
(6.9) (5.9) (6.7) (6.2) (7.3) (7.4) (6.2) (7.0) (7.1) (6.8) (8.5) (7.5) (7.6) (8.9)
5410 20,677 27,069 20,850 13,961 13,273
(5.3) (20.4) (26.7) (20.6) (13.8) (13.1)
1291 6055 6926 4343 2754 2827
(5.3) (25.0) (28.6) (18.0) (11.4) (11.7)
213 377 409 377 259 261
(11.2) (19.9) (21.6) (19.9) (13.7) (13.8)
63,615 18,444 13,237 4642 1302
(62.8) (18.2) (13.1) (4.6) (1.3)
17,992 2124 2601 1.141 338
(74.4) (8.8) (10.8) (4.7) (1.4)
1296 293 195 102 10
(68.4) (15.5) (10.3) (5.4) (0.5)
45,845 18,452 19,791 10,978 1001 5173
(45.3) (18.2) (19.6) (10.8) (1.0) (5.1)
15,057 3746 2598 1542 241 1012
(62.2) (15.5) (10.7) (6.4) (1.0) (4.2)
1006 366 270 152 11 91
(53.1) (19.3) (14.2) (8.0) (0.6) (4.8)
18,606 22,946 42,071 17,617
(18.4) (22.7) (41.6) (17.4)
4624 5644 9105 4823
(19.1) (23.3) (37.6) (19.9)
361 391 758 386
(19.0) (20.6) (40.0) (20.4)
77,896 15,965 1924 5455
(76.9) (15.8) (1.9) (5.4)
18,882 3439 384 1491
(78.0) (14.2) (1.6) (6.2)
1512 265 35 84
(79.8) (14.0) (1.9) (4.4)
8222 46,489 43,997 2532
(8.1) (45.9) (43.5) (2.5)
1582 11,890 10,170 554
(6.5) (49.1) (42.0) (2.3)
108 901 856 31
(5.7) (47.5) (45.2) (1.6)
15,408 29,461 929 18,146 1531 18,938 2924 6017 1042 6844
(15.2) (29.1) (0.9) (17.9) (1.5) (18.7) (2.9) (5.9) (1.0) (6.8)
4185 10,592 245 2500 236 2248 337 1424 274 2155
(17.3) (43.8) (1.0) (10.3) (1.0) (9.3) (1.4) (5.9) (1.1) (8.9)
49 519 14 187 24 380 55 447 64 157
(2.6) (27.4) (0.7) (9.9) (1.3) (20.0) (2.9) (23.6) (3.4) (8.3)
48,855 36,404 6528 9453
(48.3) (36.0) (6.5) (9.3)
16,462 4949 1493 1292
(68.0) (20.5) (6.2) (5.3)
716 710 347 123
(37.8) (37.5) (18.3) (6.5)
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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Table 2 Patterns of treatment stratified by stage and histology. Squamous cell
Stages IA2–IIA Primary treatment Surgery Radiation No surgery or radiation Unknown Adjuvant therapya Radiation Combination External beam Brachytherapy None/unknown Chemotherapya Yes No Unknown Stages IIB–IVA Primary treatment Surgery Radiation No treatment Unknown Concurrent chemotherapyb Yes No Unknown
b
Neuroendocrine
P-value
(%)
N
(%)
N
(%)
23,131 5624 738 2410
(72.5) (17.6) (2.3) (7.6)
9494 1217 224 512
(82.9) (10.6) (2.0) (4.5)
373 121 18 28
(69.1) (22.4) (3.3) (5.2)
2390 3879 1051 15,811
(10.3) (16.8) (4.5) (68.4)
726 1110 347 7311
(7.7) (11.7) (3.7) (77.0)
36 117 18 202
(9.7) (31.4) (4.8) (54.2)
4194 18,363 574
(18.1) (79.4) (2.5)
1222 8056 216
(12.9) (84.9) (2.3)
272 87 14
(72.9) (23.3) (3.8)
8300 25,227 2326 5686
(20.0) (60.7) (5.6) (13.7)
1753 2738 319 511
(32.9) (51.5) (6.0) (9.6)
188 337 73 48
(29.1) (52.2) (11.3) (7.4)
19,909 5036 282
(78.9) (20.0) (1.1)
2077 634 27
(75.9) (23.2) (1.0)
301 33 3
(89.3) (9.8) (0.9)
3933 1924 160
(65.4) (32.0) (2.7)
871 504 49
(61.2) (35.4) (3.4)
320 116 11
(71.6) (26.0) (2.5)
b0.001
b0.001
b0.001
b0.001
b0.001
Stage IVB Chemotherapy Yes No Unknown a
Adenocarcinoma
N
0.001
Among patients treated with primary surgery. Among patients treated with primary radiotherapy.
Institutional reviews of NECC typically include small numbers of women treated over the course of many years or decades [7–11]. To date, large studies examining the patterns of care and outcomes of women with NECC are limited [12]. We performed a population-based analysis of NECC to examine the natural history, treatment patterns and outcomes of women with these tumors.
2. Methods 2.1. Data source and patient selection The National Cancer Data Base (NCDB) was analyzed. The NCDB is a registry developed and sponsored by the American College of Surgeons and American Cancer Society that includes hospitals from across the United States [13, 14]. The NCDB captures all patients with newly diagnosed invasive cancers from over 1500 Commission on Cancer (CoC) affiliated hospitals from across the nation. NCDB collects data on patient demographics, tumor characteristics, including stage, primary and adjuvant therapy, and survival [13, 14]. Incident tumor cases are abstracted by trained registrars and the data is audited regularly to ensure accuracy. It is estimated that nearly 80% of women with invasive cervical cancer in the U.S. are recorded in NCDB [15]. The Columbia University Institutional Review Board deemed the study exempt. We identified all women with stages I–IV neuroendocrine carcinomas of the cervix, squamous cell carcinoma of the cervix (SCCC), and adenocarcinomas (AC) diagnosed from 1998 to 2011. As NCDB only reports survival for patients with five or more years of follow-up, survival was analyzed in the subset of patients diagnosed from 1998 to 2006.
2.2. Clinical and demographic characteristics Demographic data analyzed included age at diagnosis (b30, 30–39, 40–49, 50–59, 60–69, ≥ 70 years), race (white, black, Hispanic, other or unknown), and insurance status (commercial, Medicare, Medicaid, uninsured and unknown). Tumor stage (stages IA–IVB or unknown) was recorded for each patient. Hospital characteristics included region (Northeast, Midwest, South, or West) and location (metropolitan, urban, rural or unknown). Based on the ACS CoC criteria, hospitals were also classified as academic centers, community centers or comprehensive community cancer centers [14]. Primary treatment was classified as surgery, radiation (including chemoradiation), chemotherapy, or none. Patients were stratified by stage (IA2–IIA, IIB–IVA, IVB) for analysis, and primary and adjuvant therapies were recorded for each stage group.
2.3. Statistical analysis Frequency distributions between categorical variables were compared using χ2 tests. Overall survival was estimated as the number of months from diagnosis until death from any cause. Cox proportional hazards regression models were developed to evaluate the association between type of histology and survival while adjusting for other clinical and demographic characteristics. Separate models stratified by stage were developed for early-stage (stages IB–IIA), locally advanced (stages IIB–IVA), and metastatic (stage IVB) tumors. Given that NECC is uncommon and potentially subject to pathologic misclassification, we performed a sensitivity analysis limited to academic centers and comprehensive community cancer centers to mitigate any histologic misclassification at hospitals that treat NECC infrequently. Kaplan-
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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Table 3 Multivariable models of risk of death stratified by stage.
Histology Squamous cell Adenocarcinoma Neuroendocrine Year of diagnosis 1998 1999 2000 2001 2002 2003 2004 2005 2006 Age b30 30–39 40–49 50–59 60–69 ≥70 Race White Black Hispanic Other Unknown Insurance status Commercial Medicare Medicaid Uninsured Other Unknown Region Northeast Midwest South West Location Metropolitan Urban Rural Unknown Hospital type Academic Community cancer program Comprehensive community cancer program Other Stage IB1 IB2 IB NOS (IB, IB NOS) IIA IIB IIIA IIIB IVA Treatment Surgery Radiation No therapy Unknown Chemotherapy Yes No Unknown
Stages IB–IIAa
Stages IIB–IVAb
Stage IVBc
Referent 0.86 (0.80–0.92)⁎ 2.96 (2.48–3.52)⁎
Referent 1.19 (1.11–1.27)⁎ 1.70 (1.45–1.99)⁎
Referent 1.05 (0.89–1.25) 1.14 (0.91–1.43)
Referent 0.99 (0.88–1.10) 1.12 (1.00–1.24)⁎ 1.09 (0.97–1.22) 1.30 (1.16–1.45)⁎ 0.85 (0.76–0.95)⁎ 1.03 (0.92–1.15) 0.95 (0.85–1.06) 0.98 (0.87–1.10)
Referent 1.29 (1.19–1.41)⁎ 1.39 (1.27–1.51)⁎ 1.47 (1.35–1.60)⁎ 1.49 (1.37–1.62)⁎ 0.81 (0.74–0.87)⁎ 0.83 (0.77–0.90)⁎ 0.81 (0.75–0.88)⁎ 0.79 (0.73–0.86)⁎
Referent 1.06 (0.78–1.43) 1.10 (0.81–1.48) 1.13 (0.84–1.51) 1.03 (0.76–1.39) 1.01 (0.76–1.35) 0.95 (0.72–1.26) 0.96 (0.72–1.27) 0.87 (0.66–1.15)
Referent 0.87 (0.75–1.01) 1.00 (0.87–1.15) 1.30 (1.12–1.50)⁎ 1.73 (1.49–2.01)⁎ 2.83 (2.41–3.32)⁎
Referent 1.01 (0.87–1.18) 1.02 (0.88–1.18) 1.02 (0.88–1.19) 1.07 (0.92–1.25) 1.43 (1.22–1.67)⁎
Referent 1.17 (0.64–2.14) 1.00 (0.56–1.79) 1.25 (0.70–2.22) 1.44 (0.81–2.58) 1.50 (0.83–2.73)
Referent 1.16 (1.08–1.25)⁎ 0.73 (0.66–0.81)⁎ 0.74 (0.64–0.86)⁎ 0.80 (0.61–1.05)
Referent 0.99 (0.94–1.04) 0.71 (0.66–0.76)⁎ 0.72 (0.65–0.80)⁎ 0.91 (0.72–1.14)
Referent 0.82 (0.69–0.97)⁎ 0.76 (0.58–0.99)⁎ 0.63 (0.42–0.94)⁎ 0.93 (0.57–1.51)
Referent 1.61 (1.46–1.77)⁎ 1.61 (1.48–1.76)⁎ 1.40 (1.25–1.57)⁎ 1.38 (1.01–1.88)⁎ 1.19 (1.05–1.35)⁎
Referent 1.27 (1.19–1.36)⁎ 1.17 (1.10–1.24)⁎ 1.01 (0.94–1.08) 1.24 (1.01–1.52)⁎ 1.19 (1.09–1.31)⁎
Referent 1.14 (0.93–1.40) 1.09 (0.89–1.33) 1.21 (0.98–1.49) 1.29 (0.65–2.56) 1.02 (0.75–1.40)
Referent 0.98 (0.90–1.07) 1.03 (0.95–1.12) 0.90 (0.82–0.99)⁎
Referent 1.02 (0.96–1.08) 1.02 (0.97–1.08) 1.09 (1.02–1.16)⁎
Referent 0.98 (0.80–1.19) 0.87 (0.73–1.03) 1.03 (0.81–1.30)
Referent 1.12 (1.04–1.21)⁎ 0.99 (0.81–1.20) 1.00 (0.89–1.14)
Referent 1.01 (0.96–1.07) 0.93 (0.81–1.08) 1.02 (0.94–1.12)
Referent 1.00 (0.83–1.20) 1.38 (0.93–2.03) 1.18 (0.90–1.54)
Referent 0.98 (0.88–1.10) 1.07 (1.01–1.14)⁎ 1.18 (0.94–1.49)
Referent 1.04 (0.96–1.11) 1.06 (1.01–1.10)⁎ 1.01 (0.88–1.16)
Referent 1.11 (0.89–1.39) 1.24 (1.07–1.43)⁎ 0.95 (0.65–1.40)
Referent 1.41 (1.24–1.61)⁎ 1.95 (1.80–2.11)⁎ 2.36 (2.02–2.75)⁎ – – – –
– – – – Referent 1.61 (1.47–1.77)⁎ 1.83 (1.75–1.91)⁎ 2.73 (2.55–2.94)⁎
– – – – – – – –
Referent 2.54 (2.38–2.71)⁎ – –
– – – –
– – – –
– – –
Referent 1.47 (1.41–1.55)⁎ 1.17 (0.98–1.40)
Referent 1.86 (1.61–2.15)⁎ 0.88 (0.61–1.27)
Adjusted hazard ratio (95% confidence interval). a Limited to patients who received primary treatment with either radiation or surgery (n = 23,758). b Limited to patients who received radiation (n = 16,535). c Patients in no treatment group (n = 1069). ⁎ Indicates P value b0.05.
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
B. Margolis et al. / Gynecologic Oncology xxx (2016) xxx–xxx
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Table 4 Multivariable models of risk of death stratified by stage among neuroendocrine patients.
Year of diagnosis 1998 1999 2000 2001 2002 2003 2004 2005 2006 Age b30 30–39 40–49 50–59 60–69 ≥70 Race White Black Hispanic Other Unknown Insurance status Commercial Medicare Medicaid Uninsured Other Unknown Region Northeast Midwest South West Location Metropolitan Urban Rural Unknown Hospital type Academic Community cancer program Comprehensive community cancer program Other Stage IB1 IB2 IB NOS (IB, IB NOS) IIA IIB IIIA IIIB IVA Treatment Surgery Radiation No therapy Unknown Chemotherapy Yes No Unknown
Stages IB–IIAa
Stages IIB–IVAb
Stage IVBc
Referent 0.84 (0.36–1.98) 0.54 (0.25–1.20) 0.48 (0.20–1.14) 1.04 (0.49–2.24) 1.08 (0.56–2.08) 1.48 (0.61–3.59) 0.57 (0.26–1.24) 0.82 (0.40–1.68)
Referent 0.25 (0.10–0.62)⁎ 0.23 (0.09–0.58)⁎ 0.28 (0.13–0.61)⁎ 0.37 (0.16–0.84)⁎ 0.24 (0.10–0.56)⁎ 0.27 (0.12–0.59)⁎ 0.15 (0.07–0.34)⁎ 0.25 (0.10–0.58)⁎
Referent 1.68 (0.55–5.19) 1.85 (0.58–5.86) 0.82 (0.24–2.82) 0.81 (0.27–2.42) 1.87 (0.65–5.42) 0.81 (0.32–2.01) 0.34 (0.12–0.97)⁎ 1.53 (0.47–5.00)
Referent 0.41 (0.23–0.72)⁎ 0.76 (0.42–1.38) 0.72 (0.39–1.34) 0.50 (0.20–1.27) 0.59 (0.22–1.60)
Referent 1.41 (0.56–3.54) 1.47 (0.66–3.29) 1.76 (0.81–3.81) 1.85 (0.71–4.81) 1.43 (0.40–5.13)
Referent 1.47 (0.28–7.80) 1.14 (0.25–5.12) 1.87 (0.41–8.59) 1.08 (0.20–5.75) 1.16 (0.15–8.64)
Referent 1.30 (0.65–2.60) 0.61 (0.29–1.29) 0.90 (0.39–2.10) 1.37 (0.16–11.50)
Referent 0.77 (0.45–1.33) 0.33 (0.16–0.65)⁎ 0.42 (0.20–0.91)⁎ 0.69 (0.08–5.66)
Referent 0.79 (0.36–1.75) 0.43 (0.14–1.34) 0.91 (0.13–6.26) 0.86 (0.16–4.60)
Referent 1.62 (0.72–3.61) 1.43 (0.74–2.78) 1.07 (0.48–2.40) – 1.12 (0.52–2.42)
Referent 1.72 (0.77–3.81) 1.62 (0.94–2.79) 0.93 (0.46–1.89) 1.30 (0.12–13.70) 1.79 (0.62–5.16)
Referent 1.00 (0.41–2.44) 1.49 (0.56–3.93) 0.98 (0.39–2.43) 0.46 (0.04–4.95) 0.93 (0.33–2.61)
Referent 1.69 (0.90–3.20) 1.45 (0.83–2.53) 1.06 (0.54–2.08)
Referent 0.97 (0.49–1.89) 1.21 (0.65–2.26) 1.21 (0.62–2.36)
Referent 1.83 (0.80–4.17) 0.65 (0.30–1.39) 0.51 (0.17–1.53)
Referent 1.02 (0.62–1.69) 0.36 (0.08–1.54) 1.34 (0.60–2.99)
Referent 1.60 (0.93–2.76) 0.29 (0.04–2.42) 2.02 (0.80–5.10)
Referent 0.72 (0.30–1.74) 1.71 (0.51–5.70) 0.74 (0.09–5.79)
Referent 1.66 (0.77–3.61) 1.38 (0.90–2.13) 1.95 (0.21–17.91)
Referent 1.01 (0.47–2.17) 0.80 (0.54–1.18) 0.64 (0.07–5.74)
Referent 0.69 (0.25–1.92) 1.34 (0.67–2.68) 0.42 (0.04–4.17)
Referent 1.21 (0.53–2.74) 3.01 (1.69–5.37)⁎ 15.76 (4.97–50.01)⁎ – – – –
– – – – Referent 2.72 (1.22–6.07)⁎ 1.35 (0.90–2.01) 2.91 (1.11–7.63)⁎
– – – – – – – –
Referent 1.59 (0.97–2.60) – –
– – – –
– – – –
– – –
Referent 1.58 (0.81–3.08) 0.39 (0.05–3.09)
Referent 3.36 (1.69–6.67)⁎ 1.76 (0.40–7.67)
Adjusted hazard ratio (95% confidence interval). a Limited to patients who received primary treatment with either radiation or surgery (n = 276). b Limited to patients who received radiation (n = 202). c Patients in no treatment group (n = 103). ⁎ Indicates P value b0.05.
Meier survival curves were developed to contrast survival between women with NECC and SCCC. The log-rank test was used to compare the curves. All hypothesis tests were two-sided. A P-value of b 0.05 was considered statistically significant. All analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).
3. Results We identified a total of 127,332 patients including 1,896 (1.5%) with NECC, 101,240 (79.5%) with SCCC, and 24,196 (19.0%) with AC (Table 1). Patients with NECC were more likely to be diagnosed before age 30
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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histologic subtypes (72.5% for SCCC, 82.9% for AC, and 69.1% for NECC), however, more patients with NECC were treated primarily with radiation (22.4% versus 17.6% SCCC and 10.6% AC, P b 0.001). Adjuvant chemotherapy was used in 72.9% of those with NECC compared to 18.1% of women with SCC and 12.9% with AC (P b 0.001). Similarly, use of external beam radiotherapy was more common for NECC (31.4% versus 16.8% for SCC and 11.7% for AC). For patients with advanced stage (IIB–IVA) disease, radiation was the most common treatment modality. Concurrent chemotherapy was administered to 78.9% of women with SCCC, 75.9% of those with AC and 89.3% of those with NECC (P b 0.001). Among those with metastatic disease (stage IVB neoplasms), chemotherapy was utilized in 65.4% of women with SCCC, 61.2% of those with AC and 71.6% of those with NECC (P = 0.001). The risk of death was higher for patients with NECC compared to SCCC for all stages (Table 3). Among women with early-stage disease, the hazard ratio for death for patients with NECC was 2.96 (95% CI, 2.48–3.52) times higher than for SCCC. Compared to women with SCCC, the hazard ratio for death for women with stages IIB–IVA NECC was 1.70 (95% CI, 1.45–1.99) and 1.14 (95% CI, 0.91–1.43) for those with stage IVB neoplasms. In models that only included women with NECC, year of diagnosis and race were independent predictors of death for women with locally advanced tumors (Table 4). In a sensitivity analysis limited to women treated at comprehensive community cancer centers and academic hospitals, the findings were similar (Supplemental Table 1). Similar survival findings were noted in the Kaplan-Meier analyses (Fig. 1A–C). Survival was worse for NECC compared to SCCC for stages IB–IIA (P b 0.001) and stages IIB–IVA (P b 0.001), while the findings for stage IVB tumors was not significant (P = 0.37). Among women with stage IB tumors, five-year survival was 80.4% (95% CI, 79.7– 81.0%) for squamous cell tumors, 85.7% (95% CI, 84.7–86.6%) for AC and 55.4% (95% CI, 49.3–61.2%) for NECC. Similarly, for stage IIIB tumors, five-year survival was 43.3% (95% CI, 42.3–44.2%) for SCCC, 39.4% (95% CI, 36.6–42.1%) for AC and 24.4% (95% CI, 18.8–30.4%) for those with NECC (Table 5). 4. Discussion
Fig. 1. A. Kaplan-Meier curve of survival stratified by histology: stages IB–IIA (P b 0.001). B. Kaplan-Meier curve of survival stratified by histology: stages IIB–IVA (P b 0.001). C. Kaplan-Meier curve of survival stratified by histology: stage IVB (P = 0.37).
(11.2% NECC vs 5.3% SCCC vs. 5.3% AC, P b 0.001), present with stage IVB disease (23.6% NECC vs 5.9% SCCC vs. 5.9% AC, P b 0.001) and not receive either surgery or radiation therapy (18.3% NECC vs 6.5% SCCC vs. 6.2% AC, P b 0.001). Patients with NECC, patients were less likely to be black (15.5% NECC vs.18.2% SCCC vs 8.8% AC, P b 0.001), Hispanic (10.3% NECC vs 13.1% SCCC vs. 10.8% AC, P b 0.001) and have Medicaid insurance coverage (14.2% NECC vs 19.6% SCCC vs. 10.7% AC, P b 0.001). Treatment patterns are displayed in Table 2. For women with earlystage disease, surgery was the most common primary treatment for all
Our data suggest that neuroendocrine tumors of the cervix have a distinct natural history and follow an aggressive course. Survival for both early and late stage tumors is inferior to that of squamous cell carcinomas. The differential in survival is greatest for women with earlystage tumors. Compared to women with squamous cell tumors, those with NECC are more likely to receive adjuvant chemotherapy and radiotherapy. Given that NECC are relatively uncommon, few large scale studies of these tumors have been reported [12]. Like other cervical cancers, NECC appear to be associated with human papillomavirus (HPV) [16]. One report from a cohort in Thailand found HPV 16 and/or 18 in 89% of NECCs, however the prevalence varies widely in the literature [16]. Despite the association, it is unknown whether HPV vaccination is protective against the development of NECC. Our data confirm that survival for women with NECC tumors is poor overall. For women with stage IB tumors, we found that five-year survival was only 55% compared to 80% for patients with squamous cell tumors and 86% for adenocarcinomas. For those with stage IIIB tumors, five-year survival rates were 24% and 43%, respectively. A prior institutional series reported median survival rates for women with NECC of 31 months for those with stages IA–IB2 and 6 months for patients with stages IIB–IV neoplasms [9]. Women with NECC are at particularly high risk for distant failure [17]. Unlike prior studies, we found that early-stage AC was associated with a more favorable prognosis than SCCC [18]. These findings warrant further investigation. Most commonly, patients with NECC are diagnosed with early-stage disease. In our cohort, we noted that over 60% of women with NECC
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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Table 5 Five-year survival. Squamous cell
Stage IA (1A1, 1A2) Stage IB (1B1, IB2, IB) IIB IIIB IVA IVB a
Adenocarcinoma
P-valuea
Neuroendocrine
5-year survival
(95% CI)
5-year survival
(95% CI)
5-year survival
(95% CI)
96.4% 80.4% 57.2% 43.3% 20.0% 13.3%
(95.8%–97.0%) (79.7%–81.0%) (56.2%–58.2%) (42.3%–44.2%) (18.1%–22.0%) (12.1%–14.5%)
98.2% 85.7% 51.2% 39.4% 13.3% 12.3%
(97.2%–98.9%) (84.7%–86.6%) (48.3%–54.1%) (36.6%–42.1%) (9.0%–18.5%) (10.1%–14.8%)
81.8% 55.4% 22.2% 24.4% 4.1% 7.1%
(44.7%–95.1%) (49.3%–61.2%) (14.1%–31.4%) (18.8%–30.4%) (0.3%–17.5%) (4.3%–10.9%)
0.02 b0.001 b0.001 b0.001 0.12 b0.001
P-value was from log-rank test.
were diagnosed with stages I or II tumors. Despite the early-stage at diagnosis, these patients are at higher risk for the development of systemic disease. Recent consensus guidelines by the Society of Gynecologic Oncology (SGO) recommend multimodal therapy for early stage tumors [19]. Initial treatment usually consists of surgery with radical hysterectomy and regional lymphadenectomy followed by adjuvant chemotherapy along with consideration for adjuvant radiation [10, 11, 17, 19]. The chemotherapy regimens that have been the most widely studied include etoposide/cisplatin (EP), vincristine/doxorubicin/cyclophosphamide (VAC), and alternating VAC/EP regimens [5]. Although the addition of radiation is often recommended, the survival benefit of adjuvant radiotherapy is poorly defined [20]. For women with early-stage tumors N 4 cm in diameter, treatment with either primary chemoradiation or neoadjuvant chemotherapy prior to surgical resection may be considered [21, 22]. For women with advanced stage NECC, treatment typically consists of a combination of chemotherapy and radiation. While these recommendations are extrapolated from treatment regimens for other histologic subtypes of cervical cancer, the British Columbia Cancer Agency reported results from patients treated from 1998 to 2002 with a regimen of etoposide and cisplatin in combination with external beam radiation and intracavitary brachytherapy. Of note, there were only 8 patients in this study with stage III/IV disease, highlighting the need for more data to guide treatment [17]. Survival estimates for advanced stage disease range from 38 to 40% at 3 years [12, 17]. Given the fact that many of the current treatment recommendations for NECC are extrapolated from data in patients with small cell lung cancer, it is reasonable to look towards emerging SCLC therapies including targeted therapy [23]. Multiple targeted therapies are under study including angiogenesis inhibitors, mTOR inhibitors, and PARP inhibitors. Improvements in 3 month PFS have been shown in small cell lung cancer with the addition of aflibercept, a VEGF inhibitor in combination with topotecan for recurrent disease [24]. When bevacizumab is incorporated into first line therapy it has been shown to increase PFS and is also under study for recurrent disease [25]. While not studied specifically for NECC, bevacizumab is now approved for the treatment of recurrent cervical cancer and likely represents a reasonable option for women with NECC [26]. The tyrosine kinase inhibitor sunitinib has also been shown to increase PFS in small cell lung cancer in a phase II randomized trial [27]. Given that small cell lung cancers have high expression of PARP1, PARP inhibition is another attractive strategy. PARP inhibitors are currently being explored in clinical trials [28]. Given the rarity of NECC, trials of targeted therapy specifically designed for women with neuroendocrine cervical tumors are unlikely. While our study benefits from the inclusion of a large sample of women with NECC, we recognize a number of important limitations. The NCDB captures approximately 70% of newly diagnosed cancer patients in the US. As such, these findings may not be generalizable to the entire population. Given that neuroendocrine tumors are relatively rare, we cannot exclude the possibility that a small number of women were misclassified, as central pathologic review was not performed. Within the NCDB, data on some important tumor characteristics,
including tumor size, are limited. Additionally, while we can identify use of adjuvant chemotherapy, we cannot discern the particular agents utilized and lack data on the treatment of recurrences. Finally, as with any study using administrative data, we cannot capture individual patient and physician preferences that influenced treatment. We found that NECC is a rare and aggressive type of cervical cancer that is generally associated with poor survival. Survival is inferior for NECC compared to squamous cell tumors for women with both early and advanced stage disease. Although treatment guidelines exist for NECC, they are derived from small cohort studies and from experience with neuroendocrine tumors from other sites. Further studies to prospectively document the natural history, treatment and outcomes of women with NECC are clearly needed. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2016.02.008. Conflicts of interests The authors have no conflicts of interests. Acknowledgements The authors have no conflicts of interest or disclosures. Dr. Wright (NCI R01CA169121-01A1) and Dr. Hershman (NCI R01CA134964) are recipients of grants from the National Cancer Institute. References [1] J. Albores-Saavedra, O. Larraza, S. Poucell, H.A. Rodriguez Martinez, Carcinoid of the uterine cervix: additional observations on a new tumor entity, Cancer 38 (1976) 2328–2342. [2] R.E. Scully, P. Aguirre, R.A. DeLellis, Argyrophilia, serotonin, and peptide hormones in the female genital tract and its tumors, Int. J. Gynecol. Pathol. 3 (1984) 51–70. [3] B. Miller, M. Dockter, M. el Torky, G. Photopulos, Small cell carcinoma of the cervix: a clinical and flow-cytometric study, Gynecol. Oncol. 42 (1991) 27–33. [4] J.R. van Nagell Jr., E.S. Donaldson, J.C. Parker, A.H. van Dyke, E.G. Wood, The prognostic significance of pelvic lymph node morphology in carcinoma of the uterine cervix, Cancer 39 (1977) 2624–2632. [5] J.K. Chan, V. Loizzi, R.A. Burger, J. Rutgers, B.J. Monk, Prognostic factors in neuroendocrine small cell cervical carcinoma: a multivariate analysis, Cancer 97 (2003) 568–574. [6] J.G. Cohen, D.S. Kapp, J.Y. Shin, et al., Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients, Am. J. Obstet. Gynecol. 203 (2010) 347 (e1–6). [7] T. Kasamatsu, Y. Sasajima, T. Onda, M. Sawada, T. Kato, M. Tanikawa, Surgical treatment for neuroendocrine carcinoma of the uterine cervix, Int. J. Gynaecol. Obstet. 99 (2007) 225–228. [8] A.N. Viswanathan, M.T. Deavers, A. Jhingran, P.T. Ramirez, C. Levenback, P.J. Eifel, Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence, Gynecol. Oncol. 93 (2004) 27–33. [9] O. Zivanovic, M.M. Leitao Jr., K.J. Park, et al., Small cell neuroendocrine carcinoma of the cervix: analysis of outcome, recurrence pattern and the impact of platinumbased combination chemotherapy, Gynecol. Oncol. 112 (2009) 590–593. [10] D.M. Boruta 2nd, J.O. Schorge, L.A. Duska, C.P. Crum, D.H. Castrillon, E.E. Sheets, Multimodality therapy in early-stage neuroendocrine carcinoma of the uterine cervix, Gynecol. Oncol. 81 (2001) 82–87.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Natural history and outcome of neuroendocrine carcinoma of the cervix Benjamin Margolis a,f, Ana I. Tergas a,c,d,f, Ling Chen a, June Y. Hou a,d,f, William M. Burke a,d,f, Jim C. Hu e,f, Cande V. Ananth a,c, Alfred I. Neugut b,c,d,f, Dawn L. Hershman b,c,d,f, Jason D. Wright a,d,f,⁎ a
Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, United States Department of Medicine, Columbia University College of Physicians and Surgeons, United States Department of Epidemiology, Mailman School of Public Health, Columbia University, United States d Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, United States e Department of Urology, Weill Cornell Medical College, United States f New York Presbyterian Hospital, United States b c
H I G H L I G H T S • NECC are aggressive tumors associated with an increased risk of death. • Survival is inferior for NECC compared to squamous cell tumors for women with both early and advanced stage disease. • Further studies are needed to improve therapeutic options for NECC.
a r t i c l e
i n f o
Article history: Received 5 January 2016 Received in revised form 30 January 2016 Accepted 8 February 2016 Available online xxxx Keywords: Cervical cancer Neuroendocrine carcinoma Squamous cell carcinoma Cervical carcinoma Cervix
a b s t r a c t Objective. Neuroendocrine carcinomas of the cervix (NECC) are rare and thought to be aggressive. We performed a population-based analysis to examine the natural history, treatment patterns and outcomes of women with NECC compared to squamous cell carcinoma (SCCC) and adenocarcinoma (AC) of the cervix. Methods. The National Cancer Database (NCDB) was utilized to identify women with NECC, SCCC, and AC treated from 1998 to 2011. Clinical, demographic, and treatment characteristics were compared between the groups. The association between tumor histology and survival was examined using Kaplan-Meier analyses and multivariable Cox proportional hazards regression models. Results. We identified 127,332 patients, including 1,896 (1.5%) with NECC and 101,240 (79.5%) with SCCC and 24,196 (19.0%) with AC. Patients with NECC were younger, more often white, commercially insured, and diagnosed with metastatic disease at presentation compared to women with SCCC. Patients with early-stage NECC were more likely to receive adjuvant chemotherapy and radiation after surgery (P b 0.05 for both). In multivariable models stratified by stage and adjusted for clinical and demographic characteristics, the risk of death was higher for patients with NECC compared to SCCC for all stages of disease: stages IB–IIA (HR = 2.96; 95% CI, 2.48–3.52), stages IIB–IVA (HR = 1.70; 95% CI, 1.45–1.99) and stage IVB (HR = 1.14; 95% CI, 0.91–1.43). Conclusion. NECC are aggressive tumors associated with an increased risk of death. Survival is inferior for NECC compared to squamous cell tumors for women with both early and advanced stage disease. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Neuroendocrine carcinomas of the cervix (NECC) are rare tumors that comprise 2–5% of cervical malignancies [1–4]. This category of tumors is comprised of small cell, large cell, carcinoid and atypical carcinoid histologic types. Small cell and large cell tumors are poorly differentiated and are characterized by a high mitotic rate, necrosis, ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Ave, 8th Floor, New York, NY 10032, United States. E-mail address: [email protected] (J.D. Wright).
frequent lymphovascular space involvement and a more aggressive clinical course. Carcinoid and atypical carcinoid tumors are welldifferentiated, are thought to be derived from neural crest cells, and are extremely rare [1]. Atypical carcinoid tumors display significant nuclear atypia and are poorly studied. In general, NECCs are characterized by early spread beyond the cervix and a poor prognosis. Five-year survival rates for NECC are reported at 0–30% [5]. Given that NECC is uncommon, data to guide clinical decision-making is limited and treatment regimens are often extrapolated from neuroendocrine tumors from other sites. Therapy for early stage disease involves radical surgery for tumors b4 cm, often in combination with adjuvant chemotherapy. Advanced
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Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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B. Margolis et al. / Gynecologic Oncology xxx (2016) xxx–xxx
stage disease is treated with combination chemotherapy and radiation. The chemotherapy regimens most commonly utilized include cisplatin and etoposide (EP) or vincristine, doxorubicin, and cyclophosphamide
(VAC). Prior work has shown that among women with NECC chemotherapy improves survival, particularly for locally advanced stage disease [6].
Table 1 Descriptive characteristics of the cohort stratified by histology. Squamous cell
All Year of diagnosis 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Age b30 30–39 40–49 50–59 60–69 ≥70 Race White Black Hispanic Other Unknown Insurance status Commercial Medicare Medicaid Uninsured Other Unknown Region Northeast Midwest South West Location Metropolitan Urban Rural Unknown Hospital type Community cancer program Comprehensive community cancer program Academic Other Stage IA (IA, IA1, IA2) IB (IB, IB1, IB2, INOS) IIA (IIA, IIA1, IIA2) IIB (IIB, IINOS) IIIA IIIB IVA IVB IVNOS Unknown Primary treatment Surgery Radiation No surgery or radiation Unknown
Adenocarcinoma
Neuroendocrine
P-value
N
(%)
N
(%)
N
(%)
101,240
(79.5)
24,196
(19.0)
1896
(1.5) b0.001
8567 8211 8138 7744 7440 6982 6848 6894 6864 6884 6869 6898 6513 6388
(8.5) (8.1) (8.0) (7.7) (7.4) (6.9) (6.8) (6.8) (6.8) (6.8) (6.8) (6.8) (6.4) (6.3)
1752 1653 1695 1623 1626 1529 1585 1633 1732 1746 1820 1985 1922 1895
(7.2) (6.8) (7.0) (6.7) (6.7) (6.3) (6.6) (6.8) (7.2) (7.2) (7.5) (8.2) (7.9) (7.8)
130 112 126 118 138 141 118 133 135 129 162 142 144 168
(6.9) (5.9) (6.7) (6.2) (7.3) (7.4) (6.2) (7.0) (7.1) (6.8) (8.5) (7.5) (7.6) (8.9)
5410 20,677 27,069 20,850 13,961 13,273
(5.3) (20.4) (26.7) (20.6) (13.8) (13.1)
1291 6055 6926 4343 2754 2827
(5.3) (25.0) (28.6) (18.0) (11.4) (11.7)
213 377 409 377 259 261
(11.2) (19.9) (21.6) (19.9) (13.7) (13.8)
63,615 18,444 13,237 4642 1302
(62.8) (18.2) (13.1) (4.6) (1.3)
17,992 2124 2601 1.141 338
(74.4) (8.8) (10.8) (4.7) (1.4)
1296 293 195 102 10
(68.4) (15.5) (10.3) (5.4) (0.5)
45,845 18,452 19,791 10,978 1001 5173
(45.3) (18.2) (19.6) (10.8) (1.0) (5.1)
15,057 3746 2598 1542 241 1012
(62.2) (15.5) (10.7) (6.4) (1.0) (4.2)
1006 366 270 152 11 91
(53.1) (19.3) (14.2) (8.0) (0.6) (4.8)
18,606 22,946 42,071 17,617
(18.4) (22.7) (41.6) (17.4)
4624 5644 9105 4823
(19.1) (23.3) (37.6) (19.9)
361 391 758 386
(19.0) (20.6) (40.0) (20.4)
77,896 15,965 1924 5455
(76.9) (15.8) (1.9) (5.4)
18,882 3439 384 1491
(78.0) (14.2) (1.6) (6.2)
1512 265 35 84
(79.8) (14.0) (1.9) (4.4)
8222 46,489 43,997 2532
(8.1) (45.9) (43.5) (2.5)
1582 11,890 10,170 554
(6.5) (49.1) (42.0) (2.3)
108 901 856 31
(5.7) (47.5) (45.2) (1.6)
15,408 29,461 929 18,146 1531 18,938 2924 6017 1042 6844
(15.2) (29.1) (0.9) (17.9) (1.5) (18.7) (2.9) (5.9) (1.0) (6.8)
4185 10,592 245 2500 236 2248 337 1424 274 2155
(17.3) (43.8) (1.0) (10.3) (1.0) (9.3) (1.4) (5.9) (1.1) (8.9)
49 519 14 187 24 380 55 447 64 157
(2.6) (27.4) (0.7) (9.9) (1.3) (20.0) (2.9) (23.6) (3.4) (8.3)
48,855 36,404 6528 9453
(48.3) (36.0) (6.5) (9.3)
16,462 4949 1493 1292
(68.0) (20.5) (6.2) (5.3)
716 710 347 123
(37.8) (37.5) (18.3) (6.5)
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
B. Margolis et al. / Gynecologic Oncology xxx (2016) xxx–xxx
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Table 2 Patterns of treatment stratified by stage and histology. Squamous cell
Stages IA2–IIA Primary treatment Surgery Radiation No surgery or radiation Unknown Adjuvant therapya Radiation Combination External beam Brachytherapy None/unknown Chemotherapya Yes No Unknown Stages IIB–IVA Primary treatment Surgery Radiation No treatment Unknown Concurrent chemotherapyb Yes No Unknown
b
Neuroendocrine
P-value
(%)
N
(%)
N
(%)
23,131 5624 738 2410
(72.5) (17.6) (2.3) (7.6)
9494 1217 224 512
(82.9) (10.6) (2.0) (4.5)
373 121 18 28
(69.1) (22.4) (3.3) (5.2)
2390 3879 1051 15,811
(10.3) (16.8) (4.5) (68.4)
726 1110 347 7311
(7.7) (11.7) (3.7) (77.0)
36 117 18 202
(9.7) (31.4) (4.8) (54.2)
4194 18,363 574
(18.1) (79.4) (2.5)
1222 8056 216
(12.9) (84.9) (2.3)
272 87 14
(72.9) (23.3) (3.8)
8300 25,227 2326 5686
(20.0) (60.7) (5.6) (13.7)
1753 2738 319 511
(32.9) (51.5) (6.0) (9.6)
188 337 73 48
(29.1) (52.2) (11.3) (7.4)
19,909 5036 282
(78.9) (20.0) (1.1)
2077 634 27
(75.9) (23.2) (1.0)
301 33 3
(89.3) (9.8) (0.9)
3933 1924 160
(65.4) (32.0) (2.7)
871 504 49
(61.2) (35.4) (3.4)
320 116 11
(71.6) (26.0) (2.5)
b0.001
b0.001
b0.001
b0.001
b0.001
Stage IVB Chemotherapy Yes No Unknown a
Adenocarcinoma
N
0.001
Among patients treated with primary surgery. Among patients treated with primary radiotherapy.
Institutional reviews of NECC typically include small numbers of women treated over the course of many years or decades [7–11]. To date, large studies examining the patterns of care and outcomes of women with NECC are limited [12]. We performed a population-based analysis of NECC to examine the natural history, treatment patterns and outcomes of women with these tumors.
2. Methods 2.1. Data source and patient selection The National Cancer Data Base (NCDB) was analyzed. The NCDB is a registry developed and sponsored by the American College of Surgeons and American Cancer Society that includes hospitals from across the United States [13, 14]. The NCDB captures all patients with newly diagnosed invasive cancers from over 1500 Commission on Cancer (CoC) affiliated hospitals from across the nation. NCDB collects data on patient demographics, tumor characteristics, including stage, primary and adjuvant therapy, and survival [13, 14]. Incident tumor cases are abstracted by trained registrars and the data is audited regularly to ensure accuracy. It is estimated that nearly 80% of women with invasive cervical cancer in the U.S. are recorded in NCDB [15]. The Columbia University Institutional Review Board deemed the study exempt. We identified all women with stages I–IV neuroendocrine carcinomas of the cervix, squamous cell carcinoma of the cervix (SCCC), and adenocarcinomas (AC) diagnosed from 1998 to 2011. As NCDB only reports survival for patients with five or more years of follow-up, survival was analyzed in the subset of patients diagnosed from 1998 to 2006.
2.2. Clinical and demographic characteristics Demographic data analyzed included age at diagnosis (b30, 30–39, 40–49, 50–59, 60–69, ≥ 70 years), race (white, black, Hispanic, other or unknown), and insurance status (commercial, Medicare, Medicaid, uninsured and unknown). Tumor stage (stages IA–IVB or unknown) was recorded for each patient. Hospital characteristics included region (Northeast, Midwest, South, or West) and location (metropolitan, urban, rural or unknown). Based on the ACS CoC criteria, hospitals were also classified as academic centers, community centers or comprehensive community cancer centers [14]. Primary treatment was classified as surgery, radiation (including chemoradiation), chemotherapy, or none. Patients were stratified by stage (IA2–IIA, IIB–IVA, IVB) for analysis, and primary and adjuvant therapies were recorded for each stage group.
2.3. Statistical analysis Frequency distributions between categorical variables were compared using χ2 tests. Overall survival was estimated as the number of months from diagnosis until death from any cause. Cox proportional hazards regression models were developed to evaluate the association between type of histology and survival while adjusting for other clinical and demographic characteristics. Separate models stratified by stage were developed for early-stage (stages IB–IIA), locally advanced (stages IIB–IVA), and metastatic (stage IVB) tumors. Given that NECC is uncommon and potentially subject to pathologic misclassification, we performed a sensitivity analysis limited to academic centers and comprehensive community cancer centers to mitigate any histologic misclassification at hospitals that treat NECC infrequently. Kaplan-
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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Table 3 Multivariable models of risk of death stratified by stage.
Histology Squamous cell Adenocarcinoma Neuroendocrine Year of diagnosis 1998 1999 2000 2001 2002 2003 2004 2005 2006 Age b30 30–39 40–49 50–59 60–69 ≥70 Race White Black Hispanic Other Unknown Insurance status Commercial Medicare Medicaid Uninsured Other Unknown Region Northeast Midwest South West Location Metropolitan Urban Rural Unknown Hospital type Academic Community cancer program Comprehensive community cancer program Other Stage IB1 IB2 IB NOS (IB, IB NOS) IIA IIB IIIA IIIB IVA Treatment Surgery Radiation No therapy Unknown Chemotherapy Yes No Unknown
Stages IB–IIAa
Stages IIB–IVAb
Stage IVBc
Referent 0.86 (0.80–0.92)⁎ 2.96 (2.48–3.52)⁎
Referent 1.19 (1.11–1.27)⁎ 1.70 (1.45–1.99)⁎
Referent 1.05 (0.89–1.25) 1.14 (0.91–1.43)
Referent 0.99 (0.88–1.10) 1.12 (1.00–1.24)⁎ 1.09 (0.97–1.22) 1.30 (1.16–1.45)⁎ 0.85 (0.76–0.95)⁎ 1.03 (0.92–1.15) 0.95 (0.85–1.06) 0.98 (0.87–1.10)
Referent 1.29 (1.19–1.41)⁎ 1.39 (1.27–1.51)⁎ 1.47 (1.35–1.60)⁎ 1.49 (1.37–1.62)⁎ 0.81 (0.74–0.87)⁎ 0.83 (0.77–0.90)⁎ 0.81 (0.75–0.88)⁎ 0.79 (0.73–0.86)⁎
Referent 1.06 (0.78–1.43) 1.10 (0.81–1.48) 1.13 (0.84–1.51) 1.03 (0.76–1.39) 1.01 (0.76–1.35) 0.95 (0.72–1.26) 0.96 (0.72–1.27) 0.87 (0.66–1.15)
Referent 0.87 (0.75–1.01) 1.00 (0.87–1.15) 1.30 (1.12–1.50)⁎ 1.73 (1.49–2.01)⁎ 2.83 (2.41–3.32)⁎
Referent 1.01 (0.87–1.18) 1.02 (0.88–1.18) 1.02 (0.88–1.19) 1.07 (0.92–1.25) 1.43 (1.22–1.67)⁎
Referent 1.17 (0.64–2.14) 1.00 (0.56–1.79) 1.25 (0.70–2.22) 1.44 (0.81–2.58) 1.50 (0.83–2.73)
Referent 1.16 (1.08–1.25)⁎ 0.73 (0.66–0.81)⁎ 0.74 (0.64–0.86)⁎ 0.80 (0.61–1.05)
Referent 0.99 (0.94–1.04) 0.71 (0.66–0.76)⁎ 0.72 (0.65–0.80)⁎ 0.91 (0.72–1.14)
Referent 0.82 (0.69–0.97)⁎ 0.76 (0.58–0.99)⁎ 0.63 (0.42–0.94)⁎ 0.93 (0.57–1.51)
Referent 1.61 (1.46–1.77)⁎ 1.61 (1.48–1.76)⁎ 1.40 (1.25–1.57)⁎ 1.38 (1.01–1.88)⁎ 1.19 (1.05–1.35)⁎
Referent 1.27 (1.19–1.36)⁎ 1.17 (1.10–1.24)⁎ 1.01 (0.94–1.08) 1.24 (1.01–1.52)⁎ 1.19 (1.09–1.31)⁎
Referent 1.14 (0.93–1.40) 1.09 (0.89–1.33) 1.21 (0.98–1.49) 1.29 (0.65–2.56) 1.02 (0.75–1.40)
Referent 0.98 (0.90–1.07) 1.03 (0.95–1.12) 0.90 (0.82–0.99)⁎
Referent 1.02 (0.96–1.08) 1.02 (0.97–1.08) 1.09 (1.02–1.16)⁎
Referent 0.98 (0.80–1.19) 0.87 (0.73–1.03) 1.03 (0.81–1.30)
Referent 1.12 (1.04–1.21)⁎ 0.99 (0.81–1.20) 1.00 (0.89–1.14)
Referent 1.01 (0.96–1.07) 0.93 (0.81–1.08) 1.02 (0.94–1.12)
Referent 1.00 (0.83–1.20) 1.38 (0.93–2.03) 1.18 (0.90–1.54)
Referent 0.98 (0.88–1.10) 1.07 (1.01–1.14)⁎ 1.18 (0.94–1.49)
Referent 1.04 (0.96–1.11) 1.06 (1.01–1.10)⁎ 1.01 (0.88–1.16)
Referent 1.11 (0.89–1.39) 1.24 (1.07–1.43)⁎ 0.95 (0.65–1.40)
Referent 1.41 (1.24–1.61)⁎ 1.95 (1.80–2.11)⁎ 2.36 (2.02–2.75)⁎ – – – –
– – – – Referent 1.61 (1.47–1.77)⁎ 1.83 (1.75–1.91)⁎ 2.73 (2.55–2.94)⁎
– – – – – – – –
Referent 2.54 (2.38–2.71)⁎ – –
– – – –
– – – –
– – –
Referent 1.47 (1.41–1.55)⁎ 1.17 (0.98–1.40)
Referent 1.86 (1.61–2.15)⁎ 0.88 (0.61–1.27)
Adjusted hazard ratio (95% confidence interval). a Limited to patients who received primary treatment with either radiation or surgery (n = 23,758). b Limited to patients who received radiation (n = 16,535). c Patients in no treatment group (n = 1069). ⁎ Indicates P value b0.05.
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
B. Margolis et al. / Gynecologic Oncology xxx (2016) xxx–xxx
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Table 4 Multivariable models of risk of death stratified by stage among neuroendocrine patients.
Year of diagnosis 1998 1999 2000 2001 2002 2003 2004 2005 2006 Age b30 30–39 40–49 50–59 60–69 ≥70 Race White Black Hispanic Other Unknown Insurance status Commercial Medicare Medicaid Uninsured Other Unknown Region Northeast Midwest South West Location Metropolitan Urban Rural Unknown Hospital type Academic Community cancer program Comprehensive community cancer program Other Stage IB1 IB2 IB NOS (IB, IB NOS) IIA IIB IIIA IIIB IVA Treatment Surgery Radiation No therapy Unknown Chemotherapy Yes No Unknown
Stages IB–IIAa
Stages IIB–IVAb
Stage IVBc
Referent 0.84 (0.36–1.98) 0.54 (0.25–1.20) 0.48 (0.20–1.14) 1.04 (0.49–2.24) 1.08 (0.56–2.08) 1.48 (0.61–3.59) 0.57 (0.26–1.24) 0.82 (0.40–1.68)
Referent 0.25 (0.10–0.62)⁎ 0.23 (0.09–0.58)⁎ 0.28 (0.13–0.61)⁎ 0.37 (0.16–0.84)⁎ 0.24 (0.10–0.56)⁎ 0.27 (0.12–0.59)⁎ 0.15 (0.07–0.34)⁎ 0.25 (0.10–0.58)⁎
Referent 1.68 (0.55–5.19) 1.85 (0.58–5.86) 0.82 (0.24–2.82) 0.81 (0.27–2.42) 1.87 (0.65–5.42) 0.81 (0.32–2.01) 0.34 (0.12–0.97)⁎ 1.53 (0.47–5.00)
Referent 0.41 (0.23–0.72)⁎ 0.76 (0.42–1.38) 0.72 (0.39–1.34) 0.50 (0.20–1.27) 0.59 (0.22–1.60)
Referent 1.41 (0.56–3.54) 1.47 (0.66–3.29) 1.76 (0.81–3.81) 1.85 (0.71–4.81) 1.43 (0.40–5.13)
Referent 1.47 (0.28–7.80) 1.14 (0.25–5.12) 1.87 (0.41–8.59) 1.08 (0.20–5.75) 1.16 (0.15–8.64)
Referent 1.30 (0.65–2.60) 0.61 (0.29–1.29) 0.90 (0.39–2.10) 1.37 (0.16–11.50)
Referent 0.77 (0.45–1.33) 0.33 (0.16–0.65)⁎ 0.42 (0.20–0.91)⁎ 0.69 (0.08–5.66)
Referent 0.79 (0.36–1.75) 0.43 (0.14–1.34) 0.91 (0.13–6.26) 0.86 (0.16–4.60)
Referent 1.62 (0.72–3.61) 1.43 (0.74–2.78) 1.07 (0.48–2.40) – 1.12 (0.52–2.42)
Referent 1.72 (0.77–3.81) 1.62 (0.94–2.79) 0.93 (0.46–1.89) 1.30 (0.12–13.70) 1.79 (0.62–5.16)
Referent 1.00 (0.41–2.44) 1.49 (0.56–3.93) 0.98 (0.39–2.43) 0.46 (0.04–4.95) 0.93 (0.33–2.61)
Referent 1.69 (0.90–3.20) 1.45 (0.83–2.53) 1.06 (0.54–2.08)
Referent 0.97 (0.49–1.89) 1.21 (0.65–2.26) 1.21 (0.62–2.36)
Referent 1.83 (0.80–4.17) 0.65 (0.30–1.39) 0.51 (0.17–1.53)
Referent 1.02 (0.62–1.69) 0.36 (0.08–1.54) 1.34 (0.60–2.99)
Referent 1.60 (0.93–2.76) 0.29 (0.04–2.42) 2.02 (0.80–5.10)
Referent 0.72 (0.30–1.74) 1.71 (0.51–5.70) 0.74 (0.09–5.79)
Referent 1.66 (0.77–3.61) 1.38 (0.90–2.13) 1.95 (0.21–17.91)
Referent 1.01 (0.47–2.17) 0.80 (0.54–1.18) 0.64 (0.07–5.74)
Referent 0.69 (0.25–1.92) 1.34 (0.67–2.68) 0.42 (0.04–4.17)
Referent 1.21 (0.53–2.74) 3.01 (1.69–5.37)⁎ 15.76 (4.97–50.01)⁎ – – – –
– – – – Referent 2.72 (1.22–6.07)⁎ 1.35 (0.90–2.01) 2.91 (1.11–7.63)⁎
– – – – – – – –
Referent 1.59 (0.97–2.60) – –
– – – –
– – – –
– – –
Referent 1.58 (0.81–3.08) 0.39 (0.05–3.09)
Referent 3.36 (1.69–6.67)⁎ 1.76 (0.40–7.67)
Adjusted hazard ratio (95% confidence interval). a Limited to patients who received primary treatment with either radiation or surgery (n = 276). b Limited to patients who received radiation (n = 202). c Patients in no treatment group (n = 103). ⁎ Indicates P value b0.05.
Meier survival curves were developed to contrast survival between women with NECC and SCCC. The log-rank test was used to compare the curves. All hypothesis tests were two-sided. A P-value of b 0.05 was considered statistically significant. All analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).
3. Results We identified a total of 127,332 patients including 1,896 (1.5%) with NECC, 101,240 (79.5%) with SCCC, and 24,196 (19.0%) with AC (Table 1). Patients with NECC were more likely to be diagnosed before age 30
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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histologic subtypes (72.5% for SCCC, 82.9% for AC, and 69.1% for NECC), however, more patients with NECC were treated primarily with radiation (22.4% versus 17.6% SCCC and 10.6% AC, P b 0.001). Adjuvant chemotherapy was used in 72.9% of those with NECC compared to 18.1% of women with SCC and 12.9% with AC (P b 0.001). Similarly, use of external beam radiotherapy was more common for NECC (31.4% versus 16.8% for SCC and 11.7% for AC). For patients with advanced stage (IIB–IVA) disease, radiation was the most common treatment modality. Concurrent chemotherapy was administered to 78.9% of women with SCCC, 75.9% of those with AC and 89.3% of those with NECC (P b 0.001). Among those with metastatic disease (stage IVB neoplasms), chemotherapy was utilized in 65.4% of women with SCCC, 61.2% of those with AC and 71.6% of those with NECC (P = 0.001). The risk of death was higher for patients with NECC compared to SCCC for all stages (Table 3). Among women with early-stage disease, the hazard ratio for death for patients with NECC was 2.96 (95% CI, 2.48–3.52) times higher than for SCCC. Compared to women with SCCC, the hazard ratio for death for women with stages IIB–IVA NECC was 1.70 (95% CI, 1.45–1.99) and 1.14 (95% CI, 0.91–1.43) for those with stage IVB neoplasms. In models that only included women with NECC, year of diagnosis and race were independent predictors of death for women with locally advanced tumors (Table 4). In a sensitivity analysis limited to women treated at comprehensive community cancer centers and academic hospitals, the findings were similar (Supplemental Table 1). Similar survival findings were noted in the Kaplan-Meier analyses (Fig. 1A–C). Survival was worse for NECC compared to SCCC for stages IB–IIA (P b 0.001) and stages IIB–IVA (P b 0.001), while the findings for stage IVB tumors was not significant (P = 0.37). Among women with stage IB tumors, five-year survival was 80.4% (95% CI, 79.7– 81.0%) for squamous cell tumors, 85.7% (95% CI, 84.7–86.6%) for AC and 55.4% (95% CI, 49.3–61.2%) for NECC. Similarly, for stage IIIB tumors, five-year survival was 43.3% (95% CI, 42.3–44.2%) for SCCC, 39.4% (95% CI, 36.6–42.1%) for AC and 24.4% (95% CI, 18.8–30.4%) for those with NECC (Table 5). 4. Discussion
Fig. 1. A. Kaplan-Meier curve of survival stratified by histology: stages IB–IIA (P b 0.001). B. Kaplan-Meier curve of survival stratified by histology: stages IIB–IVA (P b 0.001). C. Kaplan-Meier curve of survival stratified by histology: stage IVB (P = 0.37).
(11.2% NECC vs 5.3% SCCC vs. 5.3% AC, P b 0.001), present with stage IVB disease (23.6% NECC vs 5.9% SCCC vs. 5.9% AC, P b 0.001) and not receive either surgery or radiation therapy (18.3% NECC vs 6.5% SCCC vs. 6.2% AC, P b 0.001). Patients with NECC, patients were less likely to be black (15.5% NECC vs.18.2% SCCC vs 8.8% AC, P b 0.001), Hispanic (10.3% NECC vs 13.1% SCCC vs. 10.8% AC, P b 0.001) and have Medicaid insurance coverage (14.2% NECC vs 19.6% SCCC vs. 10.7% AC, P b 0.001). Treatment patterns are displayed in Table 2. For women with earlystage disease, surgery was the most common primary treatment for all
Our data suggest that neuroendocrine tumors of the cervix have a distinct natural history and follow an aggressive course. Survival for both early and late stage tumors is inferior to that of squamous cell carcinomas. The differential in survival is greatest for women with earlystage tumors. Compared to women with squamous cell tumors, those with NECC are more likely to receive adjuvant chemotherapy and radiotherapy. Given that NECC are relatively uncommon, few large scale studies of these tumors have been reported [12]. Like other cervical cancers, NECC appear to be associated with human papillomavirus (HPV) [16]. One report from a cohort in Thailand found HPV 16 and/or 18 in 89% of NECCs, however the prevalence varies widely in the literature [16]. Despite the association, it is unknown whether HPV vaccination is protective against the development of NECC. Our data confirm that survival for women with NECC tumors is poor overall. For women with stage IB tumors, we found that five-year survival was only 55% compared to 80% for patients with squamous cell tumors and 86% for adenocarcinomas. For those with stage IIIB tumors, five-year survival rates were 24% and 43%, respectively. A prior institutional series reported median survival rates for women with NECC of 31 months for those with stages IA–IB2 and 6 months for patients with stages IIB–IV neoplasms [9]. Women with NECC are at particularly high risk for distant failure [17]. Unlike prior studies, we found that early-stage AC was associated with a more favorable prognosis than SCCC [18]. These findings warrant further investigation. Most commonly, patients with NECC are diagnosed with early-stage disease. In our cohort, we noted that over 60% of women with NECC
Please cite this article as: B. Margolis, et al., Natural history and outcome of neuroendocrine carcinoma of the cervix, Gynecol Oncol (2016), http:// dx.doi.org/10.1016/j.ygyno.2016.02.008
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Table 5 Five-year survival. Squamous cell
Stage IA (1A1, 1A2) Stage IB (1B1, IB2, IB) IIB IIIB IVA IVB a
Adenocarcinoma
P-valuea
Neuroendocrine
5-year survival
(95% CI)
5-year survival
(95% CI)
5-year survival
(95% CI)
96.4% 80.4% 57.2% 43.3% 20.0% 13.3%
(95.8%–97.0%) (79.7%–81.0%) (56.2%–58.2%) (42.3%–44.2%) (18.1%–22.0%) (12.1%–14.5%)
98.2% 85.7% 51.2% 39.4% 13.3% 12.3%
(97.2%–98.9%) (84.7%–86.6%) (48.3%–54.1%) (36.6%–42.1%) (9.0%–18.5%) (10.1%–14.8%)
81.8% 55.4% 22.2% 24.4% 4.1% 7.1%
(44.7%–95.1%) (49.3%–61.2%) (14.1%–31.4%) (18.8%–30.4%) (0.3%–17.5%) (4.3%–10.9%)
0.02 b0.001 b0.001 b0.001 0.12 b0.001
P-value was from log-rank test.
were diagnosed with stages I or II tumors. Despite the early-stage at diagnosis, these patients are at higher risk for the development of systemic disease. Recent consensus guidelines by the Society of Gynecologic Oncology (SGO) recommend multimodal therapy for early stage tumors [19]. Initial treatment usually consists of surgery with radical hysterectomy and regional lymphadenectomy followed by adjuvant chemotherapy along with consideration for adjuvant radiation [10, 11, 17, 19]. The chemotherapy regimens that have been the most widely studied include etoposide/cisplatin (EP), vincristine/doxorubicin/cyclophosphamide (VAC), and alternating VAC/EP regimens [5]. Although the addition of radiation is often recommended, the survival benefit of adjuvant radiotherapy is poorly defined [20]. For women with early-stage tumors N 4 cm in diameter, treatment with either primary chemoradiation or neoadjuvant chemotherapy prior to surgical resection may be considered [21, 22]. For women with advanced stage NECC, treatment typically consists of a combination of chemotherapy and radiation. While these recommendations are extrapolated from treatment regimens for other histologic subtypes of cervical cancer, the British Columbia Cancer Agency reported results from patients treated from 1998 to 2002 with a regimen of etoposide and cisplatin in combination with external beam radiation and intracavitary brachytherapy. Of note, there were only 8 patients in this study with stage III/IV disease, highlighting the need for more data to guide treatment [17]. Survival estimates for advanced stage disease range from 38 to 40% at 3 years [12, 17]. Given the fact that many of the current treatment recommendations for NECC are extrapolated from data in patients with small cell lung cancer, it is reasonable to look towards emerging SCLC therapies including targeted therapy [23]. Multiple targeted therapies are under study including angiogenesis inhibitors, mTOR inhibitors, and PARP inhibitors. Improvements in 3 month PFS have been shown in small cell lung cancer with the addition of aflibercept, a VEGF inhibitor in combination with topotecan for recurrent disease [24]. When bevacizumab is incorporated into first line therapy it has been shown to increase PFS and is also under study for recurrent disease [25]. While not studied specifically for NECC, bevacizumab is now approved for the treatment of recurrent cervical cancer and likely represents a reasonable option for women with NECC [26]. The tyrosine kinase inhibitor sunitinib has also been shown to increase PFS in small cell lung cancer in a phase II randomized trial [27]. Given that small cell lung cancers have high expression of PARP1, PARP inhibition is another attractive strategy. PARP inhibitors are currently being explored in clinical trials [28]. Given the rarity of NECC, trials of targeted therapy specifically designed for women with neuroendocrine cervical tumors are unlikely. While our study benefits from the inclusion of a large sample of women with NECC, we recognize a number of important limitations. The NCDB captures approximately 70% of newly diagnosed cancer patients in the US. As such, these findings may not be generalizable to the entire population. Given that neuroendocrine tumors are relatively rare, we cannot exclude the possibility that a small number of women were misclassified, as central pathologic review was not performed. Within the NCDB, data on some important tumor characteristics,
including tumor size, are limited. Additionally, while we can identify use of adjuvant chemotherapy, we cannot discern the particular agents utilized and lack data on the treatment of recurrences. Finally, as with any study using administrative data, we cannot capture individual patient and physician preferences that influenced treatment. We found that NECC is a rare and aggressive type of cervical cancer that is generally associated with poor survival. Survival is inferior for NECC compared to squamous cell tumors for women with both early and advanced stage disease. Although treatment guidelines exist for NECC, they are derived from small cohort studies and from experience with neuroendocrine tumors from other sites. Further studies to prospectively document the natural history, treatment and outcomes of women with NECC are clearly needed. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2016.02.008. Conflicts of interests The authors have no conflicts of interests. Acknowledgements The authors have no conflicts of interest or disclosures. Dr. Wright (NCI R01CA169121-01A1) and Dr. Hershman (NCI R01CA134964) are recipients of grants from the National Cancer Institute. References [1] J. Albores-Saavedra, O. Larraza, S. Poucell, H.A. Rodriguez Martinez, Carcinoid of the uterine cervix: additional observations on a new tumor entity, Cancer 38 (1976) 2328–2342. [2] R.E. Scully, P. Aguirre, R.A. DeLellis, Argyrophilia, serotonin, and peptide hormones in the female genital tract and its tumors, Int. J. Gynecol. Pathol. 3 (1984) 51–70. [3] B. Miller, M. Dockter, M. el Torky, G. Photopulos, Small cell carcinoma of the cervix: a clinical and flow-cytometric study, Gynecol. Oncol. 42 (1991) 27–33. [4] J.R. van Nagell Jr., E.S. Donaldson, J.C. Parker, A.H. van Dyke, E.G. Wood, The prognostic significance of pelvic lymph node morphology in carcinoma of the uterine cervix, Cancer 39 (1977) 2624–2632. [5] J.K. Chan, V. Loizzi, R.A. Burger, J. Rutgers, B.J. Monk, Prognostic factors in neuroendocrine small cell cervical carcinoma: a multivariate analysis, Cancer 97 (2003) 568–574. [6] J.G. Cohen, D.S. Kapp, J.Y. Shin, et al., Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients, Am. J. Obstet. Gynecol. 203 (2010) 347 (e1–6). [7] T. Kasamatsu, Y. Sasajima, T. Onda, M. Sawada, T. Kato, M. Tanikawa, Surgical treatment for neuroendocrine carcinoma of the uterine cervix, Int. J. Gynaecol. Obstet. 99 (2007) 225–228. [8] A.N. Viswanathan, M.T. Deavers, A. Jhingran, P.T. Ramirez, C. Levenback, P.J. Eifel, Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence, Gynecol. Oncol. 93 (2004) 27–33. [9] O. Zivanovic, M.M. Leitao Jr., K.J. Park, et al., Small cell neuroendocrine carcinoma of the cervix: analysis of outcome, recurrence pattern and the impact of platinumbased combination chemotherapy, Gynecol. Oncol. 112 (2009) 590–593. [10] D.M. Boruta 2nd, J.O. Schorge, L.A. Duska, C.P. Crum, D.H. Castrillon, E.E. Sheets, Multimodality therapy in early-stage neuroendocrine carcinoma of the uterine cervix, Gynecol. Oncol. 81 (2001) 82–87.
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