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Pelvic node removal and disease-free survival in cervical cancer patients treated with radical hysterectomy and pelvic lymphadenectomy
International Journal of Gynecology and Obstetrics 116 (2012) 43–46
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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Pelvic node removal and disease-free survival in cervical cancer patients treated with radical hysterectomy and pelvic lymphadenectomy Prapaporn Suprasert a,⁎, Kittipat Charoenkwan a, Surapan Khunamornpong b a b
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chiang Mai University, Chang Mai, Thailand Division of Gynecologic Pathology, Department of Pathology, Chiang Mai University, Chang Mai, Thailand
a r t i c l e
i n f o
Article history: Received 18 April 2011 Received in revised form 31 July 2011 Accepted 1 August 2011 Keywords: Cervical cancer Disease-free survival Pelvic lymphadenectomy Pelvic node removal Radical hysterectomy
a b s t r a c t Objective: To examine the relationship between the number of pelvic nodes removed and 5-year disease-free survival in early-stage cervical cancer patients who underwent radical hysterectomy and pelvic lymphadenectomy (RHPL). Methods: The medical records of 826 cervical cancer patients who underwent RHPL and who had at least 11 pelvic nodes removed at Chiang Mai University Hospital between January 2002 and December 2008 were reviewed. The patients were divided into 4 groups according to the number of nodes removed: 11–20 nodes (n = 243); 21–30 nodes (n = 344); 31–40 nodes (n = 171); and ≥ 41 nodes (n = 68). The 5-year disease-free survival of patients in each group was compared. The clinicopathological factors were analyzed using Cox regression to identify independent prognostic factors. Result: Five-year disease-free survival was not significantly different among the 4 groups. When patients with and without nodal involvement were considered separately, the 5-year disease-free survival in all groups was not significantly different. At multivariate analysis, the number of pelvic nodes removed was not an independent prognostic factor. Conclusion: The number of pelvic nodes removed was not associated with 5-year disease-free survival or number of positive pelvic nodes. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Radical hysterectomy and pelvic lymphadenectomy (RHPL) are the standard treatment for early-stage cervical cancer [1, 2]. The goal of a systematic lymphadenectomy is to identify and remove tumor cells that have been transported to the lymphatic tissue around the uterine cervix and the upper vagina. The status of pelvic node metastasis is one of the most important prognostic factors and also an indicator of the need for postoperative radiation. Sakuragi [3] summarized that the median or mean number of pelvic lymph nodes removed at lymphadenectomy varied among studies, from 13 to 56. In the EORTCGCG study, removal of more than 11 pelvic nodes was suggested as one of the quality indicators for pelvic lymphadenectomy [4]. However, the relationship between the number of nodes removed and the number of positive nodes has not been discussed in previous reports. Moreover, the association between the number of nodes removed and disease-free survival is still debatable. Pieterse et al. [5] found that a higher number of nodes removed had a positive impact on survival only in patients with positive lymph nodes. This result was inconsistent with the recent study by Shah et al. [6], which revealed that more extensive lymphadenectomy was associated with improved ⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: + 66 1 9933909; fax: + 66 53 946112. E-mail address: [email protected] (P. Suprasert).
survival in patients without nodal metastasis. However, this was not the case in patients with positive lymph nodes. With these conflicting results, the present retrospective study was conducted to examine the association between the number of pelvic nodes removed and the disease-free survival and number of positive pelvic nodes in early-stage cervical cancer patients who underwent RHLP. 2. Materials and methods Following approval by the Research Ethics Committee, the medical records of cervical cancer patients who had undergone RHPL at Chiang Mai University Hospital between January 25, 2002, and December 26, 2008, were reviewed. All patients who had had at least 11 pelvic nodes removed were included in the study. The patients whose operative schedule was more than 1 month from the first visit received neoadjuvant chemotherapy with cisplatin. The systematic pelvic lymphadenectomy in the study was carried out by removing all fatty tissue along both sides of the common iliac, external iliac, and internal iliac vessels, and also the fatty tissue inside the obturator fossa. Paraaortic lymphadenectomy was performed only when gross metastasis to the common iliac nodes or para-aortic nodes was suspected. All surgical specimens were examined by gynecologic pathologists. All resected lymph nodes were carefully dissected off surrounding fatty tissue before being fixed in formalin. The number of lymph nodes obtained from each group was initially recorded. All lymph nodes were submitted in entirety for tissue processing and preparation of
0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2011.08.001
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P. Suprasert et al. / International Journal of Gynecology and Obstetrics 116 (2012) 43–46
histologic slides. The final number of lymph nodes resected in each case was obtained after verification by microscopic examination of the histologic slides. The patients received adjuvant concurrent platinum-based chemoradiation when the pathological report revealed at least one of the high risk factors, consisting of positive lymph nodes, positive parametrium, or positive surgical margins. In addition, if two intermediate risk factors including deep cervical stromal invasion and positive lymphovascular space invasion (LVSI) were found, chemoradiation was offered. For the patients with positive LVSI as the only risk factor identified, adjuvant treatment with cisplatin was given. The high-risk patients with impaired renal function received radiation alone instead of concurrent chemoradiation. After completion of treatment, patients were followed up regularly. Treatment failure was defined either by pathological proof of recurrence or by imaging showing the regrowth of a tumor or an enlargement of lymph nodes. Disease-free survival was defined as a period of time between the month of operation and the month of tumor recurrence or last follow-up. To identify the effect of the extent of lymphadenectomy on the number of positive pelvic nodes and disease-free survival, the studied patients were categorized into 4 groups according to the total number of nodes removed: 11–20 nodes; 21–30 nodes; 31–40 nodes; and ≥ 41 nodes. The number of positive nodes and other factors in each group were compared using the χ2 test. ANOVA was used to compare the mean ages of the patients in the 4 groups. Descriptive data are presented as mean (range) and discrete data are reported as number and percentage. Five-year disease-free survival was calculated using the
Kaplan-Meier method and was compared between the groups using the log rank test. Moreover, separate analysis was performed for lymph node positive and node negative patients. Multivariate analysis was carried out using a Cox proportional hazards regression model to identify the independent prognostic factors. Statistical analysis was performed using SPSS for Windows (SPSS, Chicago, IL, USA). P b 0.05 was considered statistically significant. 3. Results During the study period, 843 patients with stage IA–IIA cervical cancer underwent RHPL. Seventeen patients were excluded because the number of pelvic nodes removed was less than 11, leaving 826 patients whose records were reviewed. The demographic data according to the number of pelvic nodes removed are shown in Table 1. Most patients had 21–30 nodes removed (n = 344) followed by 11–20 nodes (n = 243), 31–40 nodes (n = 171), and more than 40 nodes (n = 68). The mean number of nodes removed was 26 (range, 11–89). The mean age of the patients was 45 years (range, 19–75). The clinical and pathological data among the 4 groups were not significantly different for mean age, stage, histology, tumor grade, positive parametrium, positive vaginal margin, deep stromal invasion, positive pelvic nodes, and treatment. For those with pelvic node metastasis, the mean number of positive nodes was 2 (range, 1–21). Of the 126 patients with positive pelvic nodes, 59 (46.8%) had a single positive node and the distribution of patients with single node metastasis was not significantly different among the groups. The
Table 1 Demographic data stratified by the number of pelvic nodes removed a. Clinical data
No. of patients Mean age, y Stage IA IA1 IA2 IB1 IB2 IIA Histology Squamous Adeno Adenosquamous Neuroendocrine Other Tumor grade I II III Unknown Positive pelvic lymph nodes Percentage of positive pelvic lymph nodes in each group No. of patients with single node positive Positive parametrium Positive vaginal margin Invasive HSIL DSI Positive LVSI Neoadjuvant chemotherapy Treatment RHPL RHPL + RT RHPL + CCRT RHPL + chemotherapy Recurrence
No. of pelvic nodes removed
Total no. of patients
P value
11–20
21–30
31–40
N 40
243 45.6
344 45.1
171 44.8
68 43.6
826 45.1
6 (0.7) 5 (0.6) 9 (1.1) 168 (20.3) 29 (3.5) 26 (3.1)
16 (1.9) 9 (1.1) 8 (1.0) 223 (27.0) 50 (6.1) 38 (4.6)
9 (1.1) 0 (0) 3 (0.4) 119 (14.4) 20 (2.4) 20 (2.4)
1 (0.1) 1 (0.1) 1 (0.1) 47 (5.7) 10 (1.2) 8 (1.0)
32 15 21 557 109 92
(3.9) (1.8) (2.5) (67.4) (13.2) (11.1)
0.676
160 (19.4) 55 (6.7) 13 (1.6) 11 (1.3) 4 (0.5)
228 (27.6) 76 (9.2) 21 (2.5) 9 (1.1) 10 (1.2)
119 (14.4) 33 (4.0) 9 (1.1) 6 (0.7) 4 (0.5)
45 (5.4) 18 (2.2) 3 (0.4) 0 (0) 2 (0.2)
552 182 46 26 20
(66.8) (22.0) (5.6) (3.1) (2.4)
0.866
53 (6.4) 105 (12.7) 35 (4.2) 50 (6.1) 48 (5.8) 19.8 24 (50.0) 38 (4.6)
95 (11.5) 133 (16.1) 45 (5.5) 70 (8.5) 48 (5.8) 14.0 21 (44.7) 54 (6.5)
35 (4.2) 72 (8.7) 31 (3.8) 33 (4.0) 24 (2.9) 14.0 12 (50.0) 20 (2.4)
16 (1.9) 29 (3.5) 8 (1.0) 15 (1.8) 6 (0.7) 8.8 2 (33.3) 6 (0.7)
199 (24.1) 339 (41.1) 119 (14.4) 168 (20.4) 126 (15.3) 15.3 59 (46.8) 118 (14.3)
0.671
7 (0.8) 15 (1.8) 106 (12.9) 125 (15.2) 67 (8.1)
10 (1.2) 5 (0.6) 167 (20.3) 171 (20.8) 87 (10.5)
7 (0.8) 10 (1.2) 81 (9.8) 80 (9.7) 49 (5.9)
1 (0.1) 3 (0.4) 32 (3.9) 32 (3.9) 21 (2.5)
25 33 386 408 224
(3.0) (4.0) (46.8) (49.7) (27.1)
0.069
136 19 72 16 17
213 (25.8) 25 (3.0) 92 (11.1) 14 (1.7) 22 (2.7)
42 (5.1) 2 (0.2) 21 (2.5) 3 (0.4) 6 (0.7)
495 58 228 45 61
(59.9) (7.0) (27.6) (5.4) (7.4)
0.683
(16.5) (2.3) (8.7) (1.9) (2.1)
104 12 43 12 16
(12.6) (1.5) (5.2) (1.5) (1.9)
0.280
0.085 0.237 0.319
0.676 0.814 0.730
0.636
Abbreviations: HSIL, high-grade squamous intraepithelial lesion; DSI, deep stromal invasion; LVSI, lymphovascular space invasion; RHPL, radical hysterectomy and pelvic node lymphadenectomy; RT, radical therapy; CCRT, concurrent chemoradiation. a Values are given as number (percentage) unless otherwise given.
P. Suprasert et al. / International Journal of Gynecology and Obstetrics 116 (2012) 43–46
Fig. 1. Disease-free survival (DFS) stratified by the number of pelvic nodes removed (mean, 43 months; median, 46 months; range, 1–105 months).
patient who demonstrated the highest number of positive pelvic nodes (n = 21) was 45 years old. She presented with stage IB2 cancer with an initial tumor size measuring approximately 5 cm. She received 1 cycle of cisplatin before undergoing RHPL and para-aortic node sampling. The final pathology revealed moderately differentiated squamous cell carcinoma. The tumor had invaded the outer third of cervical stroma and showed positive LVSI without para-aortic node involvement. The total number of nodes removed in this patient was 32. She received adjuvant concurrent chemoradiation. However, distant recurrence in her left supraclavicular lymph node, lungs, and brain was found at 12 months after completing treatment. The patient died from her disease 2 months after the diagnosis of recurrence. The mean follow-up time was 43 months and the recurrence rate for the entire cohort of 826 patients was 7.4%, with no significant difference among the 4 groups. The 5-year disease-free survival among the 4 groups ranged from 89.7%–96.6% (Fig. 1), and was not significantly different. According to subgroup analysis based on nodal status, the 5-year disease-free survival ranged from 80.9%–83.3% in patients with positive nodes (Fig. 2) and 90.2%–97.8% in those with negative nodes (Fig. 3). There was no significant association between the number of resected pelvic nodes and the 5-year disease-free survival, regardless of nodal status. Cox regression analysis for diseasefree survival was carried out by incorporating the possible prognostic factors, as given in Table 2. The number of pelvic nodes removed was not
45
Fig. 3. Disease-free survival (DFS) stratified by the number of pelvic nodes removed in patients with negative lymph nodes (mean, 43 months; median, 46 months; range, 1–105 months).
an independent prognostic factor (P = 0.402), while nonsquamous cell carcinoma (P = 0.001), stage IB2-IIA (P = 0.002), poorly differentiated tumor grade (P = 0.001), positive pelvic node (P = 0.001), vaginal margin involvement (P = 0.034), and LVSI (P = 0.009) were independent prognostic factors. 4. Discussion Systematic pelvic lymphadenectomy is an important part of surgical treatment for early-stage cervical cancer. The mean or median number of pelvic nodes removed varied from 13–65 in previous reports [3, 7]. The variation in number of nodes removed depended on several factors, including anatomy of the patient, status of local inflammation, extent of surgery, processing of the specimen, and its examination by the pathologist [3]. However, the EORTC-GCG study into quality indicators for RHPL found that more than 90% of patients who underwent pelvic lymphadenectomy had over 11 nodes removed [4]. In the present study, the mean number of nodes removed was 26 and 97.5% of patients had more than 11 nodes removed. The number of positive pelvic nodes was not significantly different among the 4 groups. This result did not corresponded to that of the study by Pieterse et al. [5], who reported the highest incidence of positive nodes in a group of patients with less than 10 nodes removed. This might be explained by the inclusion of patients who only
Table 2 Cox regression analysis of the effect of prognostic factors on disease-free survival.
Fig. 2. Disease-free survival (DFS) stratified by the number of pelvic nodes removed in patients with positive lymph nodes (mean, 43 months; median, 46 months; range, 1–105 months).
Factors
Hazard 95% confidence P value ratio interval
Neoadjuvant chemotherapy setting (none vs received) Adjuvant treatment setting (none vs received) Number of pelvic nodes removed (compared 4 groups) Histology (SCCA vs non-SCCA) Stage (IA-IB1-IB2-IIA) Grade (I and II vs III) Lymph node (negative vs positive) Parametrium (negative vs positive) Vaginal margin (negative vs positive) DSI (inner and middle vs outer) LVSI (negative vs positive)
1.356
0.719–2.557
0.348
0.809 1.135
0.383–1.706 0.844–1.525
0.577 0.402
2.827 2.620 2.672 3.117 0.757 1.773 1.280 2.742
1.556–5.138 1.430–4.801 1.482–4.816 1.555–6.247 0.3591.599 1.044–3.011 0.650–2.517 1.292–5.819
0.001 0.002 0.001 0.001 0.466 0.034 0.475 0.009
Abbreviations: SCCA, squamous cell carcinoma; DSI, deep stromal invasion; LVSI, lymphovascular space invasion.
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P. Suprasert et al. / International Journal of Gynecology and Obstetrics 116 (2012) 43–46
underwent node sampling in their series. The lowest number of nodes removed in that study was 1 in the negative node group and 4 in the positive node group, while the present study only included patients who had at least 11 nodes removed to ensure adequate pelvic node dissection. However, in the present study, the number of pelvic nodes removed was not associated with pelvic node involvement. Recent publications have demonstrated that higher numbers of resected lymph nodes were associated with better survival in patients with various types of cancer, including breast, lung, colon, and endometrial cancers. These findings suggest that extensive lymphadenectomy may have a therapeutic impact [8-16]. Conversely, the benefit of this is still debated in early-stage cervical cancer. Pieterse et al. [5] studied the number of pelvic lymph nodes removed in 467 earlystage cervical cancer patients who underwent radical hysterectomy. They concluded that there was no relationship between the larger numbers of nodes removed with either cancer-specific survival or disease-free survival in patients with negative nodes. However, in patients with positive pelvic nodes, they found a significant relationship between the number of lymph nodes removed and disease-free survival, but no such relationship for cancer-specific survival. This result is in contrast to the study by Shah et al. [6]. They analyzed the data for 5522 early-stage cervical cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database and reported that the higher number of pelvic nodes removed was associated with improved survival in patients with negative nodes, but not in those with positive nodes. In the present study, we did not find a significant improvement in disease-free survival associated with the number of resected nodes, regardless of nodal metastasis status. This result was confirmed using a Cox regression model to analyze potential prognostic variables. From the analysis, the number of pelvic nodes removed was not associated with disease-free survival. The strongest independent prognostic factor in the present study was status of lymph node involvement, followed by nonsquamous cell carcinoma, presence of LVSI, poorly differentiated tumor grade, more advanced stage, and vaginal margin. These data correspond with previous reports [17-19]. However, parametrial invasion was not found to be an independent prognostic factor in the present study. This result was confirmed by Yuan et al. [20] who analyzed over 1000 cervical cancer patients who underwent radical hysterectomy; multivariate analysis in that study revealed that parametrial invasion was not the important prognostic factor. For patients with positive pelvic nodes, the nonsignificant difference in disease-free survival among the study groups could be explained by the comparable distribution of single node metastasis in each group. Sakuraki et al. [21] suggested that survival among single node positive patients was similar to that among node negative patients. The strength of the present study is its large sample size. In addition, all participants were recruited from a single institution, which meant uniform treatment guidelines and surgical technique. Furthermore, all specimens were examined by gynecologic pathologists. Of note, the limitations of the study include its retrospective nature and lack of information on cancer-specific survival. In conclusion, the number of pelvic nodes removed was not associated with disease-free survival regardless of whether the patient had pelvic node metastasis. Furthermore, positive pelvic node involvement was not significantly associated with the number of nodes removed. In our opinion, for standard pelvic lymphadenectomy, a total of more than 10 nodes should be removed.
Acknowledgment The National Research University Project under Thailand's Office of Higher Education Commission and Chiang Mai University provided financial support. Conflict of interest The authors declare that there are no conflicts of interest References [1] Ketcham AS, Hoye RC, Taylor PT, Deckers PJ, Thomas LB, Chretien PB. Radical hysterectomy and pelvic lymphadenectomy for carcinoma of the uterine cervix. Cancer 1971;28(5):1272–7. [2] Kjorstad KE, Kolbenstvedt A, Strickert T. The value of complete lymphadenectomy in radical treatment of cancer of the cervix, Stage IB. Cancer 1984;54(10):2215–9. [3] Sakuragi N. Up-to-date management of lymph node metastasis and the role of tailored lymphadenectomy in cervical cancer. Int J Clin Oncol 2007;12(3):165–75. [4] Verleye L, Vergote I, Reed N, Ottevanger PB. Quality assurance for radical hysterectomy for cervical cancer: the view of the European Organization for Research and Treatment of Cancer–Gynecological Cancer Group (EORTC-GCG). Ann Oncol 2009;20(10):1631–8. [5] Pieterse QD, Kenter GG, Gaarenstroom KN, Peters AA, Willems SM, Fleuren GJ, et al. The number of pelvic lymph nodes in the quality control and prognosis of radical hysterectomy for the treatment of cervical cancer. Eur J Surg Oncol 2007;33(2):216–21. [6] Shah M, Lewin SN, Deutsch I, Burke WM, Sun X, Herzog TJ, et al. Therapeutic role of lymphadenectomy for cervical cancer. Cancer 2011;117(2):310–7. [7] Hosaka M, Watari H, Mitamura T, Konno Y, Odagiri T, Kato T, et al. Survival and prognosticators of node-positive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. Int J Clin Oncol 2011;16(1):33–8. [8] Chan AD, Essner R, Wanek LA, Morton DL. Judging the therapeutic value of lymph node dissections for melanoma. J Am Coll Surg 2000;191(1):16–22. [9] Chang GJ, Rodriguez-Bigas MA, Skibber JM, Moyer VA. Lymph node evaluation and survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst 2007;99(6):433–41. [10] Cragun JM, Havrilesky LJ, Calingaert B, Synan I, Secord AA, Soper JT, et al. Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol 2005;23(16):3668–75. [11] Gajra A, Newman N, Gamble GP, Kohman LJ, Graziano SL. Effect of number of lymph nodes sampled on outcome in patients with stage I non-small-cell lung cancer. J Clin Oncol 2003;21(6):1029–34. [12] Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin III F, et al. Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 1995;56(1):29–33. [13] Krag DN, Single RM. Breast cancer survival according to number of nodes removed. Ann Surg Oncol 2003;10(10):1152–9. [14] Sosa JA, Diener-West M, Gusev Y, Choti MA, Lange JR, Dooley WC, et al. Association between extent of axillary lymph node dissection and survival in patients with stage I breast cancer. Ann Surg Oncol 1998;5(2):140–9. [15] Tepper JE, O'Connell MJ, Niedzwiecki D, Hollis D, Compton C, Benson III AB, et al. Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 2001;19(1):157–63. [16] Weir L, Speers C, D'yachkova Y, Olivotto IA. Prognostic significance of the number of axillary lymph nodes removed in patients with node-negative breast cancer. J Clin Oncol 2002;20(7):1793–9. [17] Takeda N, Sakuragi N, Takeda M, Okamoto K, Kuwabara M, Negishi H, et al. Multivariate analysis of histopathologic prognostic factors for invasive cervical cancer treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy. Acta Obstet Gynecol Scand 2002;81(12):1144–51. [18] Trattner M, Graf AH, Lax S, Forstner R, Dandachi N, Haas J, et al. Prognostic factors in surgically treated stage ib-iib cervical carcinomas with special emphasis on the importance of tumor volume. Gynecol Oncol 2001;82(1):11–6. [19] Chen SW, Liang JA, Yang SN, Lin FJ. Early stage cervical cancer with negative pelvic lymph nodes: pattern of failure and complication following radical hysterectomy and adjuvant radiotherapy. Eur J Gynaecol Oncol 2004;25(1):81–6. [20] Yuan C, Wang P, Lai C, Tsu E, Yen M, Ng H. Recurrence and survival analyses of 1,115 cervical cancer patients treated with radical hysterectomy. Gynecol Obstet Invest 1999;47(2):127–32. [21] Sakuragi N, Satoh C, Takeda N, Hareyama H, Takeda M, Yamamoto R, et al. Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with Stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy. Cancer 1999;85(7):1547–54.
Contents lists available at SciVerse ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Pelvic node removal and disease-free survival in cervical cancer patients treated with radical hysterectomy and pelvic lymphadenectomy Prapaporn Suprasert a,⁎, Kittipat Charoenkwan a, Surapan Khunamornpong b a b
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chiang Mai University, Chang Mai, Thailand Division of Gynecologic Pathology, Department of Pathology, Chiang Mai University, Chang Mai, Thailand
a r t i c l e
i n f o
Article history: Received 18 April 2011 Received in revised form 31 July 2011 Accepted 1 August 2011 Keywords: Cervical cancer Disease-free survival Pelvic lymphadenectomy Pelvic node removal Radical hysterectomy
a b s t r a c t Objective: To examine the relationship between the number of pelvic nodes removed and 5-year disease-free survival in early-stage cervical cancer patients who underwent radical hysterectomy and pelvic lymphadenectomy (RHPL). Methods: The medical records of 826 cervical cancer patients who underwent RHPL and who had at least 11 pelvic nodes removed at Chiang Mai University Hospital between January 2002 and December 2008 were reviewed. The patients were divided into 4 groups according to the number of nodes removed: 11–20 nodes (n = 243); 21–30 nodes (n = 344); 31–40 nodes (n = 171); and ≥ 41 nodes (n = 68). The 5-year disease-free survival of patients in each group was compared. The clinicopathological factors were analyzed using Cox regression to identify independent prognostic factors. Result: Five-year disease-free survival was not significantly different among the 4 groups. When patients with and without nodal involvement were considered separately, the 5-year disease-free survival in all groups was not significantly different. At multivariate analysis, the number of pelvic nodes removed was not an independent prognostic factor. Conclusion: The number of pelvic nodes removed was not associated with 5-year disease-free survival or number of positive pelvic nodes. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Radical hysterectomy and pelvic lymphadenectomy (RHPL) are the standard treatment for early-stage cervical cancer [1, 2]. The goal of a systematic lymphadenectomy is to identify and remove tumor cells that have been transported to the lymphatic tissue around the uterine cervix and the upper vagina. The status of pelvic node metastasis is one of the most important prognostic factors and also an indicator of the need for postoperative radiation. Sakuragi [3] summarized that the median or mean number of pelvic lymph nodes removed at lymphadenectomy varied among studies, from 13 to 56. In the EORTCGCG study, removal of more than 11 pelvic nodes was suggested as one of the quality indicators for pelvic lymphadenectomy [4]. However, the relationship between the number of nodes removed and the number of positive nodes has not been discussed in previous reports. Moreover, the association between the number of nodes removed and disease-free survival is still debatable. Pieterse et al. [5] found that a higher number of nodes removed had a positive impact on survival only in patients with positive lymph nodes. This result was inconsistent with the recent study by Shah et al. [6], which revealed that more extensive lymphadenectomy was associated with improved ⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: + 66 1 9933909; fax: + 66 53 946112. E-mail address: [email protected] (P. Suprasert).
survival in patients without nodal metastasis. However, this was not the case in patients with positive lymph nodes. With these conflicting results, the present retrospective study was conducted to examine the association between the number of pelvic nodes removed and the disease-free survival and number of positive pelvic nodes in early-stage cervical cancer patients who underwent RHLP. 2. Materials and methods Following approval by the Research Ethics Committee, the medical records of cervical cancer patients who had undergone RHPL at Chiang Mai University Hospital between January 25, 2002, and December 26, 2008, were reviewed. All patients who had had at least 11 pelvic nodes removed were included in the study. The patients whose operative schedule was more than 1 month from the first visit received neoadjuvant chemotherapy with cisplatin. The systematic pelvic lymphadenectomy in the study was carried out by removing all fatty tissue along both sides of the common iliac, external iliac, and internal iliac vessels, and also the fatty tissue inside the obturator fossa. Paraaortic lymphadenectomy was performed only when gross metastasis to the common iliac nodes or para-aortic nodes was suspected. All surgical specimens were examined by gynecologic pathologists. All resected lymph nodes were carefully dissected off surrounding fatty tissue before being fixed in formalin. The number of lymph nodes obtained from each group was initially recorded. All lymph nodes were submitted in entirety for tissue processing and preparation of
0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2011.08.001
44
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histologic slides. The final number of lymph nodes resected in each case was obtained after verification by microscopic examination of the histologic slides. The patients received adjuvant concurrent platinum-based chemoradiation when the pathological report revealed at least one of the high risk factors, consisting of positive lymph nodes, positive parametrium, or positive surgical margins. In addition, if two intermediate risk factors including deep cervical stromal invasion and positive lymphovascular space invasion (LVSI) were found, chemoradiation was offered. For the patients with positive LVSI as the only risk factor identified, adjuvant treatment with cisplatin was given. The high-risk patients with impaired renal function received radiation alone instead of concurrent chemoradiation. After completion of treatment, patients were followed up regularly. Treatment failure was defined either by pathological proof of recurrence or by imaging showing the regrowth of a tumor or an enlargement of lymph nodes. Disease-free survival was defined as a period of time between the month of operation and the month of tumor recurrence or last follow-up. To identify the effect of the extent of lymphadenectomy on the number of positive pelvic nodes and disease-free survival, the studied patients were categorized into 4 groups according to the total number of nodes removed: 11–20 nodes; 21–30 nodes; 31–40 nodes; and ≥ 41 nodes. The number of positive nodes and other factors in each group were compared using the χ2 test. ANOVA was used to compare the mean ages of the patients in the 4 groups. Descriptive data are presented as mean (range) and discrete data are reported as number and percentage. Five-year disease-free survival was calculated using the
Kaplan-Meier method and was compared between the groups using the log rank test. Moreover, separate analysis was performed for lymph node positive and node negative patients. Multivariate analysis was carried out using a Cox proportional hazards regression model to identify the independent prognostic factors. Statistical analysis was performed using SPSS for Windows (SPSS, Chicago, IL, USA). P b 0.05 was considered statistically significant. 3. Results During the study period, 843 patients with stage IA–IIA cervical cancer underwent RHPL. Seventeen patients were excluded because the number of pelvic nodes removed was less than 11, leaving 826 patients whose records were reviewed. The demographic data according to the number of pelvic nodes removed are shown in Table 1. Most patients had 21–30 nodes removed (n = 344) followed by 11–20 nodes (n = 243), 31–40 nodes (n = 171), and more than 40 nodes (n = 68). The mean number of nodes removed was 26 (range, 11–89). The mean age of the patients was 45 years (range, 19–75). The clinical and pathological data among the 4 groups were not significantly different for mean age, stage, histology, tumor grade, positive parametrium, positive vaginal margin, deep stromal invasion, positive pelvic nodes, and treatment. For those with pelvic node metastasis, the mean number of positive nodes was 2 (range, 1–21). Of the 126 patients with positive pelvic nodes, 59 (46.8%) had a single positive node and the distribution of patients with single node metastasis was not significantly different among the groups. The
Table 1 Demographic data stratified by the number of pelvic nodes removed a. Clinical data
No. of patients Mean age, y Stage IA IA1 IA2 IB1 IB2 IIA Histology Squamous Adeno Adenosquamous Neuroendocrine Other Tumor grade I II III Unknown Positive pelvic lymph nodes Percentage of positive pelvic lymph nodes in each group No. of patients with single node positive Positive parametrium Positive vaginal margin Invasive HSIL DSI Positive LVSI Neoadjuvant chemotherapy Treatment RHPL RHPL + RT RHPL + CCRT RHPL + chemotherapy Recurrence
No. of pelvic nodes removed
Total no. of patients
P value
11–20
21–30
31–40
N 40
243 45.6
344 45.1
171 44.8
68 43.6
826 45.1
6 (0.7) 5 (0.6) 9 (1.1) 168 (20.3) 29 (3.5) 26 (3.1)
16 (1.9) 9 (1.1) 8 (1.0) 223 (27.0) 50 (6.1) 38 (4.6)
9 (1.1) 0 (0) 3 (0.4) 119 (14.4) 20 (2.4) 20 (2.4)
1 (0.1) 1 (0.1) 1 (0.1) 47 (5.7) 10 (1.2) 8 (1.0)
32 15 21 557 109 92
(3.9) (1.8) (2.5) (67.4) (13.2) (11.1)
0.676
160 (19.4) 55 (6.7) 13 (1.6) 11 (1.3) 4 (0.5)
228 (27.6) 76 (9.2) 21 (2.5) 9 (1.1) 10 (1.2)
119 (14.4) 33 (4.0) 9 (1.1) 6 (0.7) 4 (0.5)
45 (5.4) 18 (2.2) 3 (0.4) 0 (0) 2 (0.2)
552 182 46 26 20
(66.8) (22.0) (5.6) (3.1) (2.4)
0.866
53 (6.4) 105 (12.7) 35 (4.2) 50 (6.1) 48 (5.8) 19.8 24 (50.0) 38 (4.6)
95 (11.5) 133 (16.1) 45 (5.5) 70 (8.5) 48 (5.8) 14.0 21 (44.7) 54 (6.5)
35 (4.2) 72 (8.7) 31 (3.8) 33 (4.0) 24 (2.9) 14.0 12 (50.0) 20 (2.4)
16 (1.9) 29 (3.5) 8 (1.0) 15 (1.8) 6 (0.7) 8.8 2 (33.3) 6 (0.7)
199 (24.1) 339 (41.1) 119 (14.4) 168 (20.4) 126 (15.3) 15.3 59 (46.8) 118 (14.3)
0.671
7 (0.8) 15 (1.8) 106 (12.9) 125 (15.2) 67 (8.1)
10 (1.2) 5 (0.6) 167 (20.3) 171 (20.8) 87 (10.5)
7 (0.8) 10 (1.2) 81 (9.8) 80 (9.7) 49 (5.9)
1 (0.1) 3 (0.4) 32 (3.9) 32 (3.9) 21 (2.5)
25 33 386 408 224
(3.0) (4.0) (46.8) (49.7) (27.1)
0.069
136 19 72 16 17
213 (25.8) 25 (3.0) 92 (11.1) 14 (1.7) 22 (2.7)
42 (5.1) 2 (0.2) 21 (2.5) 3 (0.4) 6 (0.7)
495 58 228 45 61
(59.9) (7.0) (27.6) (5.4) (7.4)
0.683
(16.5) (2.3) (8.7) (1.9) (2.1)
104 12 43 12 16
(12.6) (1.5) (5.2) (1.5) (1.9)
0.280
0.085 0.237 0.319
0.676 0.814 0.730
0.636
Abbreviations: HSIL, high-grade squamous intraepithelial lesion; DSI, deep stromal invasion; LVSI, lymphovascular space invasion; RHPL, radical hysterectomy and pelvic node lymphadenectomy; RT, radical therapy; CCRT, concurrent chemoradiation. a Values are given as number (percentage) unless otherwise given.
P. Suprasert et al. / International Journal of Gynecology and Obstetrics 116 (2012) 43–46
Fig. 1. Disease-free survival (DFS) stratified by the number of pelvic nodes removed (mean, 43 months; median, 46 months; range, 1–105 months).
patient who demonstrated the highest number of positive pelvic nodes (n = 21) was 45 years old. She presented with stage IB2 cancer with an initial tumor size measuring approximately 5 cm. She received 1 cycle of cisplatin before undergoing RHPL and para-aortic node sampling. The final pathology revealed moderately differentiated squamous cell carcinoma. The tumor had invaded the outer third of cervical stroma and showed positive LVSI without para-aortic node involvement. The total number of nodes removed in this patient was 32. She received adjuvant concurrent chemoradiation. However, distant recurrence in her left supraclavicular lymph node, lungs, and brain was found at 12 months after completing treatment. The patient died from her disease 2 months after the diagnosis of recurrence. The mean follow-up time was 43 months and the recurrence rate for the entire cohort of 826 patients was 7.4%, with no significant difference among the 4 groups. The 5-year disease-free survival among the 4 groups ranged from 89.7%–96.6% (Fig. 1), and was not significantly different. According to subgroup analysis based on nodal status, the 5-year disease-free survival ranged from 80.9%–83.3% in patients with positive nodes (Fig. 2) and 90.2%–97.8% in those with negative nodes (Fig. 3). There was no significant association between the number of resected pelvic nodes and the 5-year disease-free survival, regardless of nodal status. Cox regression analysis for diseasefree survival was carried out by incorporating the possible prognostic factors, as given in Table 2. The number of pelvic nodes removed was not
45
Fig. 3. Disease-free survival (DFS) stratified by the number of pelvic nodes removed in patients with negative lymph nodes (mean, 43 months; median, 46 months; range, 1–105 months).
an independent prognostic factor (P = 0.402), while nonsquamous cell carcinoma (P = 0.001), stage IB2-IIA (P = 0.002), poorly differentiated tumor grade (P = 0.001), positive pelvic node (P = 0.001), vaginal margin involvement (P = 0.034), and LVSI (P = 0.009) were independent prognostic factors. 4. Discussion Systematic pelvic lymphadenectomy is an important part of surgical treatment for early-stage cervical cancer. The mean or median number of pelvic nodes removed varied from 13–65 in previous reports [3, 7]. The variation in number of nodes removed depended on several factors, including anatomy of the patient, status of local inflammation, extent of surgery, processing of the specimen, and its examination by the pathologist [3]. However, the EORTC-GCG study into quality indicators for RHPL found that more than 90% of patients who underwent pelvic lymphadenectomy had over 11 nodes removed [4]. In the present study, the mean number of nodes removed was 26 and 97.5% of patients had more than 11 nodes removed. The number of positive pelvic nodes was not significantly different among the 4 groups. This result did not corresponded to that of the study by Pieterse et al. [5], who reported the highest incidence of positive nodes in a group of patients with less than 10 nodes removed. This might be explained by the inclusion of patients who only
Table 2 Cox regression analysis of the effect of prognostic factors on disease-free survival.
Fig. 2. Disease-free survival (DFS) stratified by the number of pelvic nodes removed in patients with positive lymph nodes (mean, 43 months; median, 46 months; range, 1–105 months).
Factors
Hazard 95% confidence P value ratio interval
Neoadjuvant chemotherapy setting (none vs received) Adjuvant treatment setting (none vs received) Number of pelvic nodes removed (compared 4 groups) Histology (SCCA vs non-SCCA) Stage (IA-IB1-IB2-IIA) Grade (I and II vs III) Lymph node (negative vs positive) Parametrium (negative vs positive) Vaginal margin (negative vs positive) DSI (inner and middle vs outer) LVSI (negative vs positive)
1.356
0.719–2.557
0.348
0.809 1.135
0.383–1.706 0.844–1.525
0.577 0.402
2.827 2.620 2.672 3.117 0.757 1.773 1.280 2.742
1.556–5.138 1.430–4.801 1.482–4.816 1.555–6.247 0.3591.599 1.044–3.011 0.650–2.517 1.292–5.819
0.001 0.002 0.001 0.001 0.466 0.034 0.475 0.009
Abbreviations: SCCA, squamous cell carcinoma; DSI, deep stromal invasion; LVSI, lymphovascular space invasion.
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underwent node sampling in their series. The lowest number of nodes removed in that study was 1 in the negative node group and 4 in the positive node group, while the present study only included patients who had at least 11 nodes removed to ensure adequate pelvic node dissection. However, in the present study, the number of pelvic nodes removed was not associated with pelvic node involvement. Recent publications have demonstrated that higher numbers of resected lymph nodes were associated with better survival in patients with various types of cancer, including breast, lung, colon, and endometrial cancers. These findings suggest that extensive lymphadenectomy may have a therapeutic impact [8-16]. Conversely, the benefit of this is still debated in early-stage cervical cancer. Pieterse et al. [5] studied the number of pelvic lymph nodes removed in 467 earlystage cervical cancer patients who underwent radical hysterectomy. They concluded that there was no relationship between the larger numbers of nodes removed with either cancer-specific survival or disease-free survival in patients with negative nodes. However, in patients with positive pelvic nodes, they found a significant relationship between the number of lymph nodes removed and disease-free survival, but no such relationship for cancer-specific survival. This result is in contrast to the study by Shah et al. [6]. They analyzed the data for 5522 early-stage cervical cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database and reported that the higher number of pelvic nodes removed was associated with improved survival in patients with negative nodes, but not in those with positive nodes. In the present study, we did not find a significant improvement in disease-free survival associated with the number of resected nodes, regardless of nodal metastasis status. This result was confirmed using a Cox regression model to analyze potential prognostic variables. From the analysis, the number of pelvic nodes removed was not associated with disease-free survival. The strongest independent prognostic factor in the present study was status of lymph node involvement, followed by nonsquamous cell carcinoma, presence of LVSI, poorly differentiated tumor grade, more advanced stage, and vaginal margin. These data correspond with previous reports [17-19]. However, parametrial invasion was not found to be an independent prognostic factor in the present study. This result was confirmed by Yuan et al. [20] who analyzed over 1000 cervical cancer patients who underwent radical hysterectomy; multivariate analysis in that study revealed that parametrial invasion was not the important prognostic factor. For patients with positive pelvic nodes, the nonsignificant difference in disease-free survival among the study groups could be explained by the comparable distribution of single node metastasis in each group. Sakuraki et al. [21] suggested that survival among single node positive patients was similar to that among node negative patients. The strength of the present study is its large sample size. In addition, all participants were recruited from a single institution, which meant uniform treatment guidelines and surgical technique. Furthermore, all specimens were examined by gynecologic pathologists. Of note, the limitations of the study include its retrospective nature and lack of information on cancer-specific survival. In conclusion, the number of pelvic nodes removed was not associated with disease-free survival regardless of whether the patient had pelvic node metastasis. Furthermore, positive pelvic node involvement was not significantly associated with the number of nodes removed. In our opinion, for standard pelvic lymphadenectomy, a total of more than 10 nodes should be removed.
Acknowledgment The National Research University Project under Thailand's Office of Higher Education Commission and Chiang Mai University provided financial support. Conflict of interest The authors declare that there are no conflicts of interest References [1] Ketcham AS, Hoye RC, Taylor PT, Deckers PJ, Thomas LB, Chretien PB. Radical hysterectomy and pelvic lymphadenectomy for carcinoma of the uterine cervix. Cancer 1971;28(5):1272–7. [2] Kjorstad KE, Kolbenstvedt A, Strickert T. The value of complete lymphadenectomy in radical treatment of cancer of the cervix, Stage IB. Cancer 1984;54(10):2215–9. [3] Sakuragi N. Up-to-date management of lymph node metastasis and the role of tailored lymphadenectomy in cervical cancer. Int J Clin Oncol 2007;12(3):165–75. [4] Verleye L, Vergote I, Reed N, Ottevanger PB. Quality assurance for radical hysterectomy for cervical cancer: the view of the European Organization for Research and Treatment of Cancer–Gynecological Cancer Group (EORTC-GCG). Ann Oncol 2009;20(10):1631–8. [5] Pieterse QD, Kenter GG, Gaarenstroom KN, Peters AA, Willems SM, Fleuren GJ, et al. The number of pelvic lymph nodes in the quality control and prognosis of radical hysterectomy for the treatment of cervical cancer. Eur J Surg Oncol 2007;33(2):216–21. [6] Shah M, Lewin SN, Deutsch I, Burke WM, Sun X, Herzog TJ, et al. Therapeutic role of lymphadenectomy for cervical cancer. Cancer 2011;117(2):310–7. [7] Hosaka M, Watari H, Mitamura T, Konno Y, Odagiri T, Kato T, et al. Survival and prognosticators of node-positive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. Int J Clin Oncol 2011;16(1):33–8. [8] Chan AD, Essner R, Wanek LA, Morton DL. Judging the therapeutic value of lymph node dissections for melanoma. J Am Coll Surg 2000;191(1):16–22. [9] Chang GJ, Rodriguez-Bigas MA, Skibber JM, Moyer VA. Lymph node evaluation and survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst 2007;99(6):433–41. [10] Cragun JM, Havrilesky LJ, Calingaert B, Synan I, Secord AA, Soper JT, et al. Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol 2005;23(16):3668–75. [11] Gajra A, Newman N, Gamble GP, Kohman LJ, Graziano SL. Effect of number of lymph nodes sampled on outcome in patients with stage I non-small-cell lung cancer. J Clin Oncol 2003;21(6):1029–34. [12] Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin III F, et al. Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 1995;56(1):29–33. [13] Krag DN, Single RM. Breast cancer survival according to number of nodes removed. Ann Surg Oncol 2003;10(10):1152–9. [14] Sosa JA, Diener-West M, Gusev Y, Choti MA, Lange JR, Dooley WC, et al. Association between extent of axillary lymph node dissection and survival in patients with stage I breast cancer. Ann Surg Oncol 1998;5(2):140–9. [15] Tepper JE, O'Connell MJ, Niedzwiecki D, Hollis D, Compton C, Benson III AB, et al. Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 2001;19(1):157–63. [16] Weir L, Speers C, D'yachkova Y, Olivotto IA. Prognostic significance of the number of axillary lymph nodes removed in patients with node-negative breast cancer. J Clin Oncol 2002;20(7):1793–9. [17] Takeda N, Sakuragi N, Takeda M, Okamoto K, Kuwabara M, Negishi H, et al. Multivariate analysis of histopathologic prognostic factors for invasive cervical cancer treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy. Acta Obstet Gynecol Scand 2002;81(12):1144–51. [18] Trattner M, Graf AH, Lax S, Forstner R, Dandachi N, Haas J, et al. Prognostic factors in surgically treated stage ib-iib cervical carcinomas with special emphasis on the importance of tumor volume. Gynecol Oncol 2001;82(1):11–6. [19] Chen SW, Liang JA, Yang SN, Lin FJ. Early stage cervical cancer with negative pelvic lymph nodes: pattern of failure and complication following radical hysterectomy and adjuvant radiotherapy. Eur J Gynaecol Oncol 2004;25(1):81–6. [20] Yuan C, Wang P, Lai C, Tsu E, Yen M, Ng H. Recurrence and survival analyses of 1,115 cervical cancer patients treated with radical hysterectomy. Gynecol Obstet Invest 1999;47(2):127–32. [21] Sakuragi N, Satoh C, Takeda N, Hareyama H, Takeda M, Yamamoto R, et al. Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with Stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy. Cancer 1999;85(7):1547–54.