Original Article Gynecol Obstet Invest 2015;79:172–178 DOI: 10.1159/000367920
Received: November 28, 2012 Accepted after revision: August 27, 2014 Published online: December 11, 2014
A Multicenter Study of the Importance of Systemic Chemotherapy for Patients with Small-Cell Neuroendocrine Carcinoma of the Uterine Cervix Shin-Wha Lee a Kyung-Taek Lim c Duk Soo Bae d Sang Yoon Park f Young Tae Kim e Kyu-Rae Kim b Joo-Hyun Nam a Departments of a Obstetrics and Gynecology and b Pathology, Asan Medical Center, University of Ulsan, c Department of Obstetrics and Gynecology, Cheil General Hospital & Women’s Healthcare Center, d Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, and e Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University, Seoul, and f Department of Obstetrics and Gynecology, Research Institute and Hospital, National Cancer Center, Goyang-si, Korea
Abstract Aims: We investigated the prognosis of patients with smallcell neuroendocrine carcinoma of the uterine cervix (SCNEC) in relation to treatment modalities. Methods: We retrospectively reviewed the medical records and pathological reports of 102 patients who were histologically diagnosed with SCNEC at 5 different institutes. Time to progression (TTP) and overall survival (OS) were analyzed for each treatment modality. Results: Of the patients with early-stage [International Federation of Obstetrics and Gynecology (FIGO) stage IB2 or below] SCNEC, 57.8 and 79.3% underwent radical hysterectomy followed by adjuvant therapy. In advanced-stage SCNEC, concurrent chemoradiation therapy was given to 51.4% of the patients. The overall recurrence rate was 51.6%. In early- and advanced-stage SCNEC, the TTP was not different (22.3 vs. 13.3 months, p = 0.104), but the OS was different (40.7 vs. 21.4 months, p = 0.029). Parametrial involvement and lymph vascular space invasion were found to be associated with an unfavorable prognosis. Inter-
© 2014 S. Karger AG, Basel 0378–7346/14/0793–0172$39.50/0 E-Mail [email protected] www.karger.com/goi
estingly, survival was the most unfavorable in patients with early-stage SCNEC who had never received chemotherapy. FIGO stage and use of chemotherapy were identified as independent prognostic factors in SCNEC patients. Conclusions: SCNEC requires systemic chemotherapy as part of the initial treatment, along with surgery or radiation, even in patients with early-stage disease. © 2014 S. Karger AG, Basel
Introduction
Small-cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare disease that accounts for less than 5% of all uterine cervical carcinomas [1–3]. However, SCNEC is an aggressive type of cancer that develops distant metastases even in its early stages [4, 5]. Lymph node involvement and lymph vascular space invasion are thus present relatively early on in the progression of SCNEC and are related to early relapse due to hematogenous dissemination [6, 7]. Relapsed SCNEC often occurs in the liver, lung, bone, brain, or lymph node within 2 years of the diagnosis. Five-year survival rates vary from 0 to 30% [6, 7], and long-term survival can be achieved Joo-Hyun Nam Department of Obstetrics and Gynecology Asan Medical Center, College of Medicine, University of Ulsan 388-1 Pungnap-2-dong, Songpa-gu, Seoul 138-736 (Korea) E-Mail jhnam @ amc.seoul.kr
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Key Words Small-cell carcinoma · Neuroendocrine carcinoma · Cervical cancer · Chemotherapy
Patients and Methods We retrospectively reviewed the medical records and pathological reports of 102 patients who were histologically diagnosed with SCNEC and who received treatment at the following 5 institutes between January 1991 and December 2010: Asan Medical Center, Severance Hospital, Samsung Medical Center, National Cancer Center, and Cheil Hospital. All histopathologic reviews were carried out by pathologists at the Department of Pathology of each institute. The International Federation of Obstetrics and Gynecology (FIGO) staging classification was used to determine the stage for each patient. Patients with stage IB2 or lower disease were classified as early stage and those with IIA or higher were classified as having advanced cervical carcinoma. This retrospective study was performed with ethics committee approval from each institute to protect patient confidentiality. RECIST (Response Evaluation Criteria in Solid Tumors) criteria were used to determine the treatment responses [13]. Time to progression (TTP) was defined as the time from when the disease was initially diagnosed to when progressive disease was again identified after treatment, or to the last day of follow-up observations in patients who showed no progressive disease. Clinical characteristics and pathological prognostic factors, such as parametrial involvement and positive resection margin, lymph node metastasis and mass size, and depth of stromal invasion and
Systemic Chemotherapy for SCNEC
Table 1. Clinical characteristics of the current study patients with
SCNEC Median age (range), years FIGO stage (n = 102) IA IB IIA IIB III IV Treatment modalities (n = 95)a RH only RH and adjuvant therapy No OP Recurrence (n = 95)a Early stage (IA to IB) Advanced stage (II–IV) Site of recurrence, n Liver Lymph node Lung Bone Pelvis Brain
50.0 (27–84) 5 (4.9) 54 (52.9) 6 (5.9) 18 (17.6) 10 (9.8) 9 (8.8) 6 (6.3) 56 (58.9) 33 (34.7) 28 (48.3) 21 (56.8) 17 15b 14c 13 9d 8
Values are presented as numbers (%) unless otherwise stated. RH = Radical hysterectomy; OP = operation. a The number of analyzed patients was 95 because 2 patients (stage III) died due to other causes and 5 patients (2 stage IV, 2 stage III, and 1 stage II) refused treatment. RH includes abdominal radical hysterectomy and laparoscopy-assisted radical hysterectomy. b Para-aortic lymph node metastasis in 8 cases, supraclavicular lymph node metastasis in 2 cases, neck lymph node metastasis in 2 cases, and iliac lymph node metastasis in 3 cases. c Lung parenchyma in 11 cases and pleura in 3 cases. d Pelvic wall in 3 cases, vagina in 3 cases, rectum in 2 cases, and bladder in 1 case.
lymph vascular space invasion, were analyzed using the Cox proportional hazards model to define negative prognostic indicators. TTP and overall survival (OS) were analyzed using the KaplanMeier method and log rank test, and the Cox proportional hazards model was used to identify the prognostic factors affecting OS among several treatment modalities. p < 0.05 was considered statistically significant.
Results
Among the 102 patients diagnosed with SCNEC at the 5 different institutes, the median age was 50.0 years (range 27–84) and the percentage of patients with early-stage disease (FIGO stage IB2 or below) was 57.8% (table 1). Gynecol Obstet Invest 2015;79:172–178 DOI: 10.1159/000367920
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only in patients with limited-stage disease [7, 8]. Factors affecting the prognosis of SCNEC include lesion size, lymph vascular space invasion, depth of stromal invasion, and lymph node metastasis [4, 6, 9–11]. Aggressive therapeutic strategies are thus required for local disease control and to reduce distant relapses in SCNEC cases. However, because this cancer is rare, it has been difficult to derive clear treatment recommendations from prospective trials. Furthermore, few large-scale retrospective studies of SCNEC have been conducted to date. We previously completed a matched case-control study to analyze the clinical and pathological characteristics, and prognoses, of 32 SCNEC cases [12]. We found in that study that the survival outcomes of the early-stage SCNEC group were remarkably poorer than those of the corresponding squamous cell carcinoma (SCC) group and almost identical to those of advanced-stage SCNEC patients. In addition, we found that negative prognostic factors for SCNEC included parametrial involvement and lymph vascular space invasion but not clinical stage. Our present study series included 102 patients with a histologically confirmed SCNEC from 5 different institutes. We analyzed the clinical and pathological characteristics of these subjects to explore the relationship between prognosis and treatment modality. Our ultimate aim was to define appropriate treatment regimens for this disease.
1.0
1.0
0.8 Probability of survival
0.8 Probability of survival
Early stage Advanced stage
0.6
0.4
0.6
0.4
0.2
0.2
p < 0.05
p = 0.104 0
a
0 0
10
20
30
40
50
60
TTP (months)
b
0
20
80 40 60 OS (months)
100
120
Fig. 1. TTP (a) and OS (b) outcomes according to SCNEC stage. The TTP was not different (22.3 vs. 13.3 months, p = 0.104) but the OS
was different (40.7 vs. 21.4 months, p = 0.029) between early-stage and advanced-stage SCNEC patients, respectively.
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Gynecol Obstet Invest 2015;79:172–178 DOI: 10.1159/000367920
Table 2. Treatment modalities in early-stage SCNEC and advanced-stage SCNEC patients (n = 95)
Early-stage SCNEC (n = 58) Radical hysterectomy 7 (12.1) Radical hysterectomy with adjuvant therapy Preop CT 2 (3.4) Preop CT + Postop CT 8 (13.8) Preop CT + Postop RT 1 (1.7) Preop CT + Postop CCRT 3 (5.2) Postop CT 8 (13.8) Postop RT 10 (17.2) Postop CCRT 14 (24.1) CT 0 RT 0 CCRT 5 (8.6)
Advanced-stage SCNEC (n = 37) 0 0 0 0 4 (10.8) 0 1 (2.7) 4 (10.8) 7 (18.9) 2 (5.4) 19 (51.4)
Values are presented as numbers (%). CT = Chemotherapy; RT = radiotherapy; Preop = preoperative; Postop = postoperative.
lapse site was the liver, and other common relapse sites included the lung, bone, brain, and para-aortic lymph node (table 1). The median TTP was 22.3 months (range 5.0–218.7) for early-stage SCNEC and 13.3 months (range 0.8–169.2) for advanced-stage SCNEC. There were no statistical differences according to stage (p = 0.104; fig. 1). The median OS was 40.7 months (range 5.0–218.7) for Lee/Lim/Bae/Park/Kim/Kim/Nam
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The level of SCC antigen (SCC-Ag), the most important tumor marker used, was normal in 94.5% of the patients. A radical hysterectomy was performed in 65.2% of the patients. Six patients underwent a radical surgery without any adjuvant treatment following the initial diagnosis, and 56 patients underwent a radical hysterectomy with preoperative or postoperative adjuvant therapy. The other patients (34.7%) did not undergo a radical hysterectomy and were treated with chemotherapy, radiotherapy, or concurrent chemoradiation therapy (CCRT) (table 1). For early-stage SCNEC, radical hysterectomy with adjuvant therapy was performed in 79.3% of patients and adjuvant therapies were administered using diverse methods. Radical hysterectomy followed by CCRT was the most common intervention in early-stage SCNEC. In advanced-stage SCNEC cases, CCRT was given to 51.4% of patients and chemotherapy to 18.9% (table 2). After radical hysterectomy, 74.2% of patients showed pathological risk factors. Of the high-risk factors, parametrial involvement was detected in 24.2% of patients, a positive resection margin was found in 9.7%, and lymph node metastasis was found in 37.1%. Among the intermediate-risk factors, a large mass (≥4 cm) was evident in 22.6%, a more than 50% depth of stromal invasion was seen in 51.6%, and lymph vascular space invasion was found in 51.6% of patients. The recurrence rate was 51.6%, and there were no significant differences between early and advanced cervical SCNEC cases (p = 0.390) (table 1). The most common re-
1.0
0.8
0.8 Probability of survival
Probability of survival
1.0
0.6
0.4 p < 0.05
0.2
0.4 p < 0.05 0.2
0
a
0.6
No chemotherapy in the early stage Chemotherapy in the advanced stage Chemotherapy in the early stage
0 0
10
20 30 40 TTP (months)
50
60
b
0
10
20 30 40 OS (months)
50
60
Fig. 2. TTP (a) and OS (b) outcomes according to SCNEC stage and chemotherapy. The outcomes differed according to treatment modality. TTP and OS were the most unfavorable in patients with early-stage SCNEC who had never been treated with chemotherapy (p = 0.025 and p = 0.020).
Table 3. Univariate and multivariate analysis of OS based on pathological factors in early-stage SCNEC
PM(+) RM(+) LN(+) Size >4 cm DOI >1/2 LVSI(+)
Univariate analysis
Multivariate analysis
HR
p
HR
p
95% CI
6.640 7.000 1.406 1.141 6.423 17.993
0.010a 0.008a 0.524 0.286 0.011a 0.000a, b
2.119 2.940 1.012 1.866 2.426 6.549
0.045a 0.086 0.914 0.172 0.514 0.000a, c
1.124–6.356
2.455–17.468
PM(+) = Parametrial involvement; RM(+) = positive resection margin; LN(+) = lymph node metastasis; DOI = depth of invasion; LVSI(+) = lymph vascular space invasion. a Statistically significant. b 0.00002. c 0.00017.
early-stage SCNEC and 21.4 months (range 0.8–169.2) for advanced-stage SCNEC patients (p = 0.029; fig. 1). Parametrial involvement and lymph vascular space invasion were unfavorable prognostic factors for OS (table 3). The subgroup of our patients with early-stage SCNEC who had never been treated with chemotherapy showed a significantly poorer TTP and OS than our early- and advanced-stage SCNEC patients who had received chemotherapy (p = 0.025 and p = 0.020; fig. 2). Multivariate analysis, which included FIGO stage and treatment modality (radical surgery, radiotherapy, and chemotherapy), was performed (table 4) and revealed that the FIGO stage (early
vs. advanced) was a significant survival factor. Interestingly, the use of chemotherapy was found to be significantly associated with a long OS (HR 0.294, 95% CI 0.140–0.618, p = 0.001), even though radical surgery and radiotherapy did not improve the survival outcomes of our SCNEC patients.
Systemic Chemotherapy for SCNEC
Gynecol Obstet Invest 2015;79:172–178 DOI: 10.1159/000367920
Discussion
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Cervical SCNEC is a high-grade malignancy [14, 15] and most patients experience treatment failure due to early recurrences and distant metastases to the lung, liver,
Stageb Radical surgeryc Radiotherapyc Chemotherapyc, d
HR
p
95% CI
2.438 0.229 1.006 0.294
0.011a 0.632 0.316 0.001a
1.227–4.843 0.140–0.618
a Statistically significant. b Early-stage (IA to IB2) vs. advancedstage (IIA to IV). c Not done vs. done. d Includes chemotherapy alone or concurrent chemoradiation therapy.
brain, or bone. Five-year survival rates after radical hysterectomy are as low as 14% and most patients die within 3 years [16, 17]. That is why postoperative adjuvant therapy is strongly emphasized in the treatment of early-stage SCNEC. In most previous reports on adjuvant chemotherapy for the treatment of SCNEC, the reported median survival is approximately 28–51 months [9, 11, 18]. These reports have also indicated that the addition of adjuvant chemotherapy tends to be more effective than a single treatment for increasing the survival rate in SCNEC cases. Hoskins et al. [19] reported on 31 SCNEC patients treated with their protocol, which was a combination chemotherapy that included paclitaxel, cisplatin, and etoposide followed by brachytherapy and external-beam radiation to the pelvis and para-aortic fields. The 3-year failure-free survival of their patients with early-stage disease (I and II) was 80%. In another report by Sevin et al. [6], in which surgery and radiation were used without chemotherapy for early-stage disease, the 5-year disease-free survival was reported to be 36.4%. However, Sheets et al. [11] reported on 14 patients with early-stage SCNEC, all of whom were treated with surgery and adjuvant radiation for positive nodes or other high-risk features. All of these patients showed disease recurrence and 2 had died by the time of that reporting. Abulafia et al. [20] conducted combination chemotherapy with radiation therapy and reported that 70% of their SCNEC patients who received 4 cycles of cisplatin and etoposide along with radiation therapy had serious adverse events, such as leucopenia, and that the 3-year survival rate was as low as 28%. Chang et al. [21] reviewed the data of patients with early-stage SCNEC treated with radical hysterectomy and adjuvant chemotherapy and compared their earlier cases treated with cisplatin, vinblastine, and bleomycin (PVB) with later cases treated with vincristine, doxorubicin, and cyclophosphamide alternating with cisplatin and etoposide 176
Gynecol Obstet Invest 2015;79:172–178 DOI: 10.1159/000367920
(VAC/PE). Of the 23 patients in that study treated with radical hysterectomy and chemotherapy, 10 out of 14 cases receiving VAC/PE showed no evidence of disease, compared to 3 out of 9 patients who received the other regimen. The authors suggested that chemotherapy, which is proven to be effective in treating small-cell carcinoma of the lung, could provide a treatment benefit to patients with SCNEC. Although many studies have been conducted on this cancer, it would still be premature to conclude that adjuvant chemotherapy or CCRT can improve the prognosis of SCNEC patients because most studies of these treatments have been conducted on a small number of cases. In an earlier multicenter retrospective Korean study, Lee et al. [22] reported that the 2-year and 5-year survival rates of all SCNEC patients were 64.6 and 46.6%, respectively, from a review of a total of 68 patients with FIGO stage IB to IIA disease who were surgically treated. However, we obtained quite remarkable results from our previous matched case-control study that analyzed the clinical and pathological characteristics and prognosis of 32 patients with SCNEC [12]. In this latter study from our laboratory, 59.4% of patients with SCNEC experienced recurrence in the bone, liver, and brain, and the 5-year OS rate was 25.3%. Notably, the survival of our patients with early-stage SCNEC was remarkably lower than that of patients with SCC and it was not better than in cases with advanced-stage SCNEC. This lower survival outcome in early-stage SCNEC suggests that radical hysterectomy followed by adjuvant therapy, which is the usual treatment for other types of cervical carcinoma, is not sufficiently effective for the treatment of this particular type of cervical carcinoma. This opinion runs counter to the findings of the aforementioned multicenter retrospective Korean study that showed that primary radical surgery followed by adjuvant chemotherapy is the preferred treatment modality for patients with early-stage SCNEC [22]. Our current study was planned as a multicenter retrospective analysis of SCNEC patients treated at 5 different institutes in Korea to clarify the prognosis and optimal treatment modalities for this cancer. We found no significant differences in TTP between our earlyand advanced-staged cases, but the OS was better for the early-stage SCNEC patients in our current series. Interestingly, both the TTP and the OS were significantly poorer in our early-stage patients who had never received chemotherapy compared to other patients, including advanced-stage cases, who had received chemotherapy. The outcomes of the early-stage patients withLee/Lim/Bae/Park/Kim/Kim/Nam
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Table 4. Multivariate analysis of OS based on the available treatment modalities for SCNEC
out chemotherapy were therefore similar to those of patients with advanced-stage SCNEC. In our present study, parametrial involvement was evident in 24.2% of patients and lymph vascular space invasion was seen in 51.6% of cases after radical hysterectomy. Our present findings could explain why most patients with earlystage SCNEC experience treatment failure due to hematogenous metastasis and why their survival rate is not better than that of patients with advanced-stage SCNEC [21]. Zivanovic et al. [23] claimed previously that systemic therapy should be used as an addition to radiation therapy in patients with early-stage SCNEC because the propensity of these tumors is similar to that of small-cell lung cancer (SCLC). In actual fact, surgery was once the treatment of choice for all types of lung cancer, but it was abandoned for subtypes of SCLC that were characterized by rapid growth and early metastatic dissemination. The current treatment standard for limited-stage SCLC is systemic chemotherapy plus concurrent thoracic radiotherapy [24]. Recently, Cohen et al. [25] reported 5-year disease-specific survival rates among 188 patients with stage I-IIA and IIB-IVA SCNEC of 36.8 and 9.8%, respectively. These authors suggested that early-stage disease and the use of chemotherapy or chemoradiation were independent prognostic factors for improved survival. These survival rates are poorer than those we here report, i.e. 52.0 and 48.3% for early- and advanced-stage cases, respectively. This discrepancy seems to be related to a lower frequency of chemotherapy use, i.e. in less than 50% of the patients in Cohen’s study but in about 80% of the patients in our present study series. In our study, the use of che-
motherapy was also found to be an independent prognostic factor for improved survival among different treatment modalities. Our present study had some limitations including its retrospective design and the fact that the effect of each adjuvant treatment was not analyzed. However, strengths of our current analysis are that we evaluated a relatively large number of SCNEC patients from 5 institutions in Korea and used a multidisciplinary approach to assess the prognosis of these cases. In conclusion, our present study findings indicate that the unfavorable prognosis associated with SCNEC is related to hematogenous metastases to distant organs via parametrial involvement and lymph vascular space invasion. Thus, even though the worldwide accepted treatment for patients with early cervical cancer is radical hysterectomy with pelvic lymphadenectomy [26, 27], earlystage SCNEC requires systemic chemotherapy as part of the initial treatment along with surgery or radiation. Clinical trials are warranted to confirm the appropriate regimen and schedule of chemotherapy to improve the survival of patients with SCNEC.
Acknowledgements We thank all of our colleagues at the following institutions from the Korean Gynecologic Cancer Surgery Study Group who participated in this retrospective multicenter study: University of Ulsan Asan Medical Center, Cheil General Hospital & Women’s Healthcare Center, Samsung Medical Center Sungkyunkwan University School of Medicine, National Cancer Center, and Yonsei University Severance Hospital.
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Received: November 28, 2012 Accepted after revision: August 27, 2014 Published online: December 11, 2014
A Multicenter Study of the Importance of Systemic Chemotherapy for Patients with Small-Cell Neuroendocrine Carcinoma of the Uterine Cervix Shin-Wha Lee a Kyung-Taek Lim c Duk Soo Bae d Sang Yoon Park f Young Tae Kim e Kyu-Rae Kim b Joo-Hyun Nam a Departments of a Obstetrics and Gynecology and b Pathology, Asan Medical Center, University of Ulsan, c Department of Obstetrics and Gynecology, Cheil General Hospital & Women’s Healthcare Center, d Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, and e Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University, Seoul, and f Department of Obstetrics and Gynecology, Research Institute and Hospital, National Cancer Center, Goyang-si, Korea
Abstract Aims: We investigated the prognosis of patients with smallcell neuroendocrine carcinoma of the uterine cervix (SCNEC) in relation to treatment modalities. Methods: We retrospectively reviewed the medical records and pathological reports of 102 patients who were histologically diagnosed with SCNEC at 5 different institutes. Time to progression (TTP) and overall survival (OS) were analyzed for each treatment modality. Results: Of the patients with early-stage [International Federation of Obstetrics and Gynecology (FIGO) stage IB2 or below] SCNEC, 57.8 and 79.3% underwent radical hysterectomy followed by adjuvant therapy. In advanced-stage SCNEC, concurrent chemoradiation therapy was given to 51.4% of the patients. The overall recurrence rate was 51.6%. In early- and advanced-stage SCNEC, the TTP was not different (22.3 vs. 13.3 months, p = 0.104), but the OS was different (40.7 vs. 21.4 months, p = 0.029). Parametrial involvement and lymph vascular space invasion were found to be associated with an unfavorable prognosis. Inter-
© 2014 S. Karger AG, Basel 0378–7346/14/0793–0172$39.50/0 E-Mail [email protected] www.karger.com/goi
estingly, survival was the most unfavorable in patients with early-stage SCNEC who had never received chemotherapy. FIGO stage and use of chemotherapy were identified as independent prognostic factors in SCNEC patients. Conclusions: SCNEC requires systemic chemotherapy as part of the initial treatment, along with surgery or radiation, even in patients with early-stage disease. © 2014 S. Karger AG, Basel
Introduction
Small-cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare disease that accounts for less than 5% of all uterine cervical carcinomas [1–3]. However, SCNEC is an aggressive type of cancer that develops distant metastases even in its early stages [4, 5]. Lymph node involvement and lymph vascular space invasion are thus present relatively early on in the progression of SCNEC and are related to early relapse due to hematogenous dissemination [6, 7]. Relapsed SCNEC often occurs in the liver, lung, bone, brain, or lymph node within 2 years of the diagnosis. Five-year survival rates vary from 0 to 30% [6, 7], and long-term survival can be achieved Joo-Hyun Nam Department of Obstetrics and Gynecology Asan Medical Center, College of Medicine, University of Ulsan 388-1 Pungnap-2-dong, Songpa-gu, Seoul 138-736 (Korea) E-Mail jhnam @ amc.seoul.kr
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Key Words Small-cell carcinoma · Neuroendocrine carcinoma · Cervical cancer · Chemotherapy
Patients and Methods We retrospectively reviewed the medical records and pathological reports of 102 patients who were histologically diagnosed with SCNEC and who received treatment at the following 5 institutes between January 1991 and December 2010: Asan Medical Center, Severance Hospital, Samsung Medical Center, National Cancer Center, and Cheil Hospital. All histopathologic reviews were carried out by pathologists at the Department of Pathology of each institute. The International Federation of Obstetrics and Gynecology (FIGO) staging classification was used to determine the stage for each patient. Patients with stage IB2 or lower disease were classified as early stage and those with IIA or higher were classified as having advanced cervical carcinoma. This retrospective study was performed with ethics committee approval from each institute to protect patient confidentiality. RECIST (Response Evaluation Criteria in Solid Tumors) criteria were used to determine the treatment responses [13]. Time to progression (TTP) was defined as the time from when the disease was initially diagnosed to when progressive disease was again identified after treatment, or to the last day of follow-up observations in patients who showed no progressive disease. Clinical characteristics and pathological prognostic factors, such as parametrial involvement and positive resection margin, lymph node metastasis and mass size, and depth of stromal invasion and
Systemic Chemotherapy for SCNEC
Table 1. Clinical characteristics of the current study patients with
SCNEC Median age (range), years FIGO stage (n = 102) IA IB IIA IIB III IV Treatment modalities (n = 95)a RH only RH and adjuvant therapy No OP Recurrence (n = 95)a Early stage (IA to IB) Advanced stage (II–IV) Site of recurrence, n Liver Lymph node Lung Bone Pelvis Brain
50.0 (27–84) 5 (4.9) 54 (52.9) 6 (5.9) 18 (17.6) 10 (9.8) 9 (8.8) 6 (6.3) 56 (58.9) 33 (34.7) 28 (48.3) 21 (56.8) 17 15b 14c 13 9d 8
Values are presented as numbers (%) unless otherwise stated. RH = Radical hysterectomy; OP = operation. a The number of analyzed patients was 95 because 2 patients (stage III) died due to other causes and 5 patients (2 stage IV, 2 stage III, and 1 stage II) refused treatment. RH includes abdominal radical hysterectomy and laparoscopy-assisted radical hysterectomy. b Para-aortic lymph node metastasis in 8 cases, supraclavicular lymph node metastasis in 2 cases, neck lymph node metastasis in 2 cases, and iliac lymph node metastasis in 3 cases. c Lung parenchyma in 11 cases and pleura in 3 cases. d Pelvic wall in 3 cases, vagina in 3 cases, rectum in 2 cases, and bladder in 1 case.
lymph vascular space invasion, were analyzed using the Cox proportional hazards model to define negative prognostic indicators. TTP and overall survival (OS) were analyzed using the KaplanMeier method and log rank test, and the Cox proportional hazards model was used to identify the prognostic factors affecting OS among several treatment modalities. p < 0.05 was considered statistically significant.
Results
Among the 102 patients diagnosed with SCNEC at the 5 different institutes, the median age was 50.0 years (range 27–84) and the percentage of patients with early-stage disease (FIGO stage IB2 or below) was 57.8% (table 1). Gynecol Obstet Invest 2015;79:172–178 DOI: 10.1159/000367920
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only in patients with limited-stage disease [7, 8]. Factors affecting the prognosis of SCNEC include lesion size, lymph vascular space invasion, depth of stromal invasion, and lymph node metastasis [4, 6, 9–11]. Aggressive therapeutic strategies are thus required for local disease control and to reduce distant relapses in SCNEC cases. However, because this cancer is rare, it has been difficult to derive clear treatment recommendations from prospective trials. Furthermore, few large-scale retrospective studies of SCNEC have been conducted to date. We previously completed a matched case-control study to analyze the clinical and pathological characteristics, and prognoses, of 32 SCNEC cases [12]. We found in that study that the survival outcomes of the early-stage SCNEC group were remarkably poorer than those of the corresponding squamous cell carcinoma (SCC) group and almost identical to those of advanced-stage SCNEC patients. In addition, we found that negative prognostic factors for SCNEC included parametrial involvement and lymph vascular space invasion but not clinical stage. Our present study series included 102 patients with a histologically confirmed SCNEC from 5 different institutes. We analyzed the clinical and pathological characteristics of these subjects to explore the relationship between prognosis and treatment modality. Our ultimate aim was to define appropriate treatment regimens for this disease.
1.0
1.0
0.8 Probability of survival
0.8 Probability of survival
Early stage Advanced stage
0.6
0.4
0.6
0.4
0.2
0.2
p < 0.05
p = 0.104 0
a
0 0
10
20
30
40
50
60
TTP (months)
b
0
20
80 40 60 OS (months)
100
120
Fig. 1. TTP (a) and OS (b) outcomes according to SCNEC stage. The TTP was not different (22.3 vs. 13.3 months, p = 0.104) but the OS
was different (40.7 vs. 21.4 months, p = 0.029) between early-stage and advanced-stage SCNEC patients, respectively.
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Table 2. Treatment modalities in early-stage SCNEC and advanced-stage SCNEC patients (n = 95)
Early-stage SCNEC (n = 58) Radical hysterectomy 7 (12.1) Radical hysterectomy with adjuvant therapy Preop CT 2 (3.4) Preop CT + Postop CT 8 (13.8) Preop CT + Postop RT 1 (1.7) Preop CT + Postop CCRT 3 (5.2) Postop CT 8 (13.8) Postop RT 10 (17.2) Postop CCRT 14 (24.1) CT 0 RT 0 CCRT 5 (8.6)
Advanced-stage SCNEC (n = 37) 0 0 0 0 4 (10.8) 0 1 (2.7) 4 (10.8) 7 (18.9) 2 (5.4) 19 (51.4)
Values are presented as numbers (%). CT = Chemotherapy; RT = radiotherapy; Preop = preoperative; Postop = postoperative.
lapse site was the liver, and other common relapse sites included the lung, bone, brain, and para-aortic lymph node (table 1). The median TTP was 22.3 months (range 5.0–218.7) for early-stage SCNEC and 13.3 months (range 0.8–169.2) for advanced-stage SCNEC. There were no statistical differences according to stage (p = 0.104; fig. 1). The median OS was 40.7 months (range 5.0–218.7) for Lee/Lim/Bae/Park/Kim/Kim/Nam
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The level of SCC antigen (SCC-Ag), the most important tumor marker used, was normal in 94.5% of the patients. A radical hysterectomy was performed in 65.2% of the patients. Six patients underwent a radical surgery without any adjuvant treatment following the initial diagnosis, and 56 patients underwent a radical hysterectomy with preoperative or postoperative adjuvant therapy. The other patients (34.7%) did not undergo a radical hysterectomy and were treated with chemotherapy, radiotherapy, or concurrent chemoradiation therapy (CCRT) (table 1). For early-stage SCNEC, radical hysterectomy with adjuvant therapy was performed in 79.3% of patients and adjuvant therapies were administered using diverse methods. Radical hysterectomy followed by CCRT was the most common intervention in early-stage SCNEC. In advanced-stage SCNEC cases, CCRT was given to 51.4% of patients and chemotherapy to 18.9% (table 2). After radical hysterectomy, 74.2% of patients showed pathological risk factors. Of the high-risk factors, parametrial involvement was detected in 24.2% of patients, a positive resection margin was found in 9.7%, and lymph node metastasis was found in 37.1%. Among the intermediate-risk factors, a large mass (≥4 cm) was evident in 22.6%, a more than 50% depth of stromal invasion was seen in 51.6%, and lymph vascular space invasion was found in 51.6% of patients. The recurrence rate was 51.6%, and there were no significant differences between early and advanced cervical SCNEC cases (p = 0.390) (table 1). The most common re-
1.0
0.8
0.8 Probability of survival
Probability of survival
1.0
0.6
0.4 p < 0.05
0.2
0.4 p < 0.05 0.2
0
a
0.6
No chemotherapy in the early stage Chemotherapy in the advanced stage Chemotherapy in the early stage
0 0
10
20 30 40 TTP (months)
50
60
b
0
10
20 30 40 OS (months)
50
60
Fig. 2. TTP (a) and OS (b) outcomes according to SCNEC stage and chemotherapy. The outcomes differed according to treatment modality. TTP and OS were the most unfavorable in patients with early-stage SCNEC who had never been treated with chemotherapy (p = 0.025 and p = 0.020).
Table 3. Univariate and multivariate analysis of OS based on pathological factors in early-stage SCNEC
PM(+) RM(+) LN(+) Size >4 cm DOI >1/2 LVSI(+)
Univariate analysis
Multivariate analysis
HR
p
HR
p
95% CI
6.640 7.000 1.406 1.141 6.423 17.993
0.010a 0.008a 0.524 0.286 0.011a 0.000a, b
2.119 2.940 1.012 1.866 2.426 6.549
0.045a 0.086 0.914 0.172 0.514 0.000a, c
1.124–6.356
2.455–17.468
PM(+) = Parametrial involvement; RM(+) = positive resection margin; LN(+) = lymph node metastasis; DOI = depth of invasion; LVSI(+) = lymph vascular space invasion. a Statistically significant. b 0.00002. c 0.00017.
early-stage SCNEC and 21.4 months (range 0.8–169.2) for advanced-stage SCNEC patients (p = 0.029; fig. 1). Parametrial involvement and lymph vascular space invasion were unfavorable prognostic factors for OS (table 3). The subgroup of our patients with early-stage SCNEC who had never been treated with chemotherapy showed a significantly poorer TTP and OS than our early- and advanced-stage SCNEC patients who had received chemotherapy (p = 0.025 and p = 0.020; fig. 2). Multivariate analysis, which included FIGO stage and treatment modality (radical surgery, radiotherapy, and chemotherapy), was performed (table 4) and revealed that the FIGO stage (early
vs. advanced) was a significant survival factor. Interestingly, the use of chemotherapy was found to be significantly associated with a long OS (HR 0.294, 95% CI 0.140–0.618, p = 0.001), even though radical surgery and radiotherapy did not improve the survival outcomes of our SCNEC patients.
Systemic Chemotherapy for SCNEC
Gynecol Obstet Invest 2015;79:172–178 DOI: 10.1159/000367920
Discussion
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Cervical SCNEC is a high-grade malignancy [14, 15] and most patients experience treatment failure due to early recurrences and distant metastases to the lung, liver,
Stageb Radical surgeryc Radiotherapyc Chemotherapyc, d
HR
p
95% CI
2.438 0.229 1.006 0.294
0.011a 0.632 0.316 0.001a
1.227–4.843 0.140–0.618
a Statistically significant. b Early-stage (IA to IB2) vs. advancedstage (IIA to IV). c Not done vs. done. d Includes chemotherapy alone or concurrent chemoradiation therapy.
brain, or bone. Five-year survival rates after radical hysterectomy are as low as 14% and most patients die within 3 years [16, 17]. That is why postoperative adjuvant therapy is strongly emphasized in the treatment of early-stage SCNEC. In most previous reports on adjuvant chemotherapy for the treatment of SCNEC, the reported median survival is approximately 28–51 months [9, 11, 18]. These reports have also indicated that the addition of adjuvant chemotherapy tends to be more effective than a single treatment for increasing the survival rate in SCNEC cases. Hoskins et al. [19] reported on 31 SCNEC patients treated with their protocol, which was a combination chemotherapy that included paclitaxel, cisplatin, and etoposide followed by brachytherapy and external-beam radiation to the pelvis and para-aortic fields. The 3-year failure-free survival of their patients with early-stage disease (I and II) was 80%. In another report by Sevin et al. [6], in which surgery and radiation were used without chemotherapy for early-stage disease, the 5-year disease-free survival was reported to be 36.4%. However, Sheets et al. [11] reported on 14 patients with early-stage SCNEC, all of whom were treated with surgery and adjuvant radiation for positive nodes or other high-risk features. All of these patients showed disease recurrence and 2 had died by the time of that reporting. Abulafia et al. [20] conducted combination chemotherapy with radiation therapy and reported that 70% of their SCNEC patients who received 4 cycles of cisplatin and etoposide along with radiation therapy had serious adverse events, such as leucopenia, and that the 3-year survival rate was as low as 28%. Chang et al. [21] reviewed the data of patients with early-stage SCNEC treated with radical hysterectomy and adjuvant chemotherapy and compared their earlier cases treated with cisplatin, vinblastine, and bleomycin (PVB) with later cases treated with vincristine, doxorubicin, and cyclophosphamide alternating with cisplatin and etoposide 176
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(VAC/PE). Of the 23 patients in that study treated with radical hysterectomy and chemotherapy, 10 out of 14 cases receiving VAC/PE showed no evidence of disease, compared to 3 out of 9 patients who received the other regimen. The authors suggested that chemotherapy, which is proven to be effective in treating small-cell carcinoma of the lung, could provide a treatment benefit to patients with SCNEC. Although many studies have been conducted on this cancer, it would still be premature to conclude that adjuvant chemotherapy or CCRT can improve the prognosis of SCNEC patients because most studies of these treatments have been conducted on a small number of cases. In an earlier multicenter retrospective Korean study, Lee et al. [22] reported that the 2-year and 5-year survival rates of all SCNEC patients were 64.6 and 46.6%, respectively, from a review of a total of 68 patients with FIGO stage IB to IIA disease who were surgically treated. However, we obtained quite remarkable results from our previous matched case-control study that analyzed the clinical and pathological characteristics and prognosis of 32 patients with SCNEC [12]. In this latter study from our laboratory, 59.4% of patients with SCNEC experienced recurrence in the bone, liver, and brain, and the 5-year OS rate was 25.3%. Notably, the survival of our patients with early-stage SCNEC was remarkably lower than that of patients with SCC and it was not better than in cases with advanced-stage SCNEC. This lower survival outcome in early-stage SCNEC suggests that radical hysterectomy followed by adjuvant therapy, which is the usual treatment for other types of cervical carcinoma, is not sufficiently effective for the treatment of this particular type of cervical carcinoma. This opinion runs counter to the findings of the aforementioned multicenter retrospective Korean study that showed that primary radical surgery followed by adjuvant chemotherapy is the preferred treatment modality for patients with early-stage SCNEC [22]. Our current study was planned as a multicenter retrospective analysis of SCNEC patients treated at 5 different institutes in Korea to clarify the prognosis and optimal treatment modalities for this cancer. We found no significant differences in TTP between our earlyand advanced-staged cases, but the OS was better for the early-stage SCNEC patients in our current series. Interestingly, both the TTP and the OS were significantly poorer in our early-stage patients who had never received chemotherapy compared to other patients, including advanced-stage cases, who had received chemotherapy. The outcomes of the early-stage patients withLee/Lim/Bae/Park/Kim/Kim/Nam
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Table 4. Multivariate analysis of OS based on the available treatment modalities for SCNEC
out chemotherapy were therefore similar to those of patients with advanced-stage SCNEC. In our present study, parametrial involvement was evident in 24.2% of patients and lymph vascular space invasion was seen in 51.6% of cases after radical hysterectomy. Our present findings could explain why most patients with earlystage SCNEC experience treatment failure due to hematogenous metastasis and why their survival rate is not better than that of patients with advanced-stage SCNEC [21]. Zivanovic et al. [23] claimed previously that systemic therapy should be used as an addition to radiation therapy in patients with early-stage SCNEC because the propensity of these tumors is similar to that of small-cell lung cancer (SCLC). In actual fact, surgery was once the treatment of choice for all types of lung cancer, but it was abandoned for subtypes of SCLC that were characterized by rapid growth and early metastatic dissemination. The current treatment standard for limited-stage SCLC is systemic chemotherapy plus concurrent thoracic radiotherapy [24]. Recently, Cohen et al. [25] reported 5-year disease-specific survival rates among 188 patients with stage I-IIA and IIB-IVA SCNEC of 36.8 and 9.8%, respectively. These authors suggested that early-stage disease and the use of chemotherapy or chemoradiation were independent prognostic factors for improved survival. These survival rates are poorer than those we here report, i.e. 52.0 and 48.3% for early- and advanced-stage cases, respectively. This discrepancy seems to be related to a lower frequency of chemotherapy use, i.e. in less than 50% of the patients in Cohen’s study but in about 80% of the patients in our present study series. In our study, the use of che-
motherapy was also found to be an independent prognostic factor for improved survival among different treatment modalities. Our present study had some limitations including its retrospective design and the fact that the effect of each adjuvant treatment was not analyzed. However, strengths of our current analysis are that we evaluated a relatively large number of SCNEC patients from 5 institutions in Korea and used a multidisciplinary approach to assess the prognosis of these cases. In conclusion, our present study findings indicate that the unfavorable prognosis associated with SCNEC is related to hematogenous metastases to distant organs via parametrial involvement and lymph vascular space invasion. Thus, even though the worldwide accepted treatment for patients with early cervical cancer is radical hysterectomy with pelvic lymphadenectomy [26, 27], earlystage SCNEC requires systemic chemotherapy as part of the initial treatment along with surgery or radiation. Clinical trials are warranted to confirm the appropriate regimen and schedule of chemotherapy to improve the survival of patients with SCNEC.
Acknowledgements We thank all of our colleagues at the following institutions from the Korean Gynecologic Cancer Surgery Study Group who participated in this retrospective multicenter study: University of Ulsan Asan Medical Center, Cheil General Hospital & Women’s Healthcare Center, Samsung Medical Center Sungkyunkwan University School of Medicine, National Cancer Center, and Yonsei University Severance Hospital.
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