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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 884-889 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0566 Sentinel Node Dissection Is Safe in the Treatment of Early-Stage Vulvar Cancer
From the University Medical Center Groningen, University of Groningen, Groningen; Radboud University Nijmegen Medical Center, Nijmegen; Erasmus Medical Center, Rotterdam; VU University Medical Center; Academic Medical Center, Amsterdam; Leiden University Medical Center, Leiden; University Medical Center Utrecht, Utrecht; Maastricht University Medical Center, Maastricht; Catharina Hospital, Eindhoven, the Netherlands; University Hospitals Leuven, Leuven, Belgium; European Cancer Institute, Milan, Italy; Addenbrooke's Hospital, Cambridge, United Kingdom; Hôpital Notre Dame-Centre Hospitalier de l'Université de Montreal, Montreal, Quebec, Canada; and Charité-Universitätsmedizin Berlin, Berlin, Germany Corresponding author: Ate G.J. Van der Zee, MD, PhD, Department of Obstetrics and Gynecology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands; e-mail: a.g.j.van.der.zee{at}og.umcg.nl
Purpose To investigate the safety and clinical utility of the sentinel node procedure in early-stage vulvar cancer patients. Patients and Methods A multicenter observational study on sentinel node detection using radioactive tracer and blue dye was performed in patients with T1/2 (< 4 cm) squamous cell cancer of the vulva. When the sentinel node was found to be negative at pathologic ultrastaging, inguinofemoral lymphadenectomy was omitted, and the patient was observed with follow-up for 2 years at intervals of every 2 months. Stopping rules were defined for the occurrence of groin recurrences. Results From March 2000 until June 2006, a sentinel node procedure was performed in 623 groins of 403 assessable patients. In 259 patients with unifocal vulvar disease and a negative sentinel node (median follow-up time, 35 months), six groin recurrences were diagnosed (2.3%; 95% CI, 0.6% to 5%), and 3-year survival rate was 97% (95% CI, 91% to 99%). Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy (wound breakdown in groin: 11.7% v 34.0%, respectively; P < .0001; and cellulitis: 4.5% v 21.3%, respectively; P < .0001). Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy (recurrent erysipelas: 0.4% v 16.2%, respectively; P < .0001; and lymphedema of the legs: 1.9% v 25.2%, respectively; P < .0001). Conclusion In early-stage vulvar cancer patients with a negative sentinel node, the groin recurrence rate is low, survival is excellent, and treatment-related morbidity is minimal. We suggest that sentinel node dissection, performed by a quality-controlled multidisciplinary team, should be part of the standard treatment in selected patients with early-stage vulvar cancer.
Squamous cell cancer of the vulva is a rare disease with an annual incidence of two to three per 100,000 women.1-3 Current standard treatment for early-stage disease consists of radical excision of the tumor with elective inguinofemoral lymphadenectomy. The efficacy of this treatment is good, with reported groin recurrence rates varying between 1% and 10%.4-11 However, only 25% to 35% of patients with early-stage disease will have lymph node metastases,5-9 and the remaining 65% to 75% of patients are unlikely to benefit from elective inguinofemoral lymphadenectomy but will be at risk for its significant morbidity. In the short term, wound healing in the groin is compromised by infection and breakdown in 20% to 40% of patients. In the long term, lymphedema of the legs with increased risk for erysipelas occurs in 30% to 70% of patients.10,12-14 Despite significant surgical morbidity and a low frequency of lymph node metastases, an elective lymphadenectomy is regarded as standard of care because unrecognized disease in the inguinofemoral lymph nodes is nearly always fatal. A noninvasive or minimally invasive technique that allows the detection of inguinofemoral metastases with a low false-negative rate is desirable. To date, noninvasive imaging techniques are neither sensitive nor specific enough for the detection of (micro)metastases in inguinofemoral lymph nodes.15,16 In a variety of malignancies, such as breast cancer and cutaneous melanoma, the false-negative rate of the sentinel node procedure seems to be low (range, 0% to 29%; average, 7.3%).17,18 In breast cancer, not only was the nodal recurrence rate in the axilla exceptionally low (0.1% to 0.3%), but the sentinel node procedure was also associated with lower morbidity and improved quality of life when compared with complete lymphadenectomy.19-23 Studies in vulvar cancer in which sentinel node detection was followed by inguinofemoral lymphadenectomy suggest that the sentinel node procedure is highly accurate in identifying lymph node metastases with a negative predictive value approaching 100%.24-34 However, safety and clinical utility still need to be proven in large clinical trials. The optimal design would be an equivalence randomized trial in which patients with a negative sentinel node are randomly assigned to either observation alone or inguinofemoral lymphadenectomy. However, because of the low incidence of the disease and the high number of patients needed, several collaborative groups in gynecologic cancer deemed such a design as highly unrealistic. The aims of this observational study were to investigate the safety of omitting inguinofemoral lymphadenectomy in patients with a negative sentinel node and to compare short- and long-term morbidity between sentinel node removal only and inguinofemoral lymphadenectomy performed in patients with a positive sentinel node. Groin recurrences were regarded as the most serious short-term threat for participating patients with a negative sentinel node. Therefore, for safety reasons, stopping rules were formulated, using continuous sequential analysis of the occurrence of groin recurrences in the first 2 years of follow-up for each patient.
Patients Eligible patients had T1 or T2, less than 4 cm, squamous cell cancer of the vulva with a depth of invasion more than 1 mm and clinically nonsuspicious inguinofemoral lymph nodes. To ensure the quality of the sentinel node procedure in the participating centers, it was determined that each gynecologic oncology center needed to have documented successful experience of the sentinel node procedure with subsequent inguinofemoral lymphadenectomy in at least 10 vulvar cancer patients (see Appendix, online only). Permission from all local ethics committees was obtained. All patients gave written informed consent. Patients were only included when registered at the University Medical Center Groningen (Groningen, the Netherlands) before the start of treatment of the patient. Central data management was performed at the University Medical Center Groningen.
Sentinel Node Detection and Treatment Protocol
Morbidity and Follow-Up
Histopathology
Sample Size
Stopping Rules
Statistics All analyses were performed using SPSS software, version 11 (SPSS Inc, Chicago, IL). Differences in the distributions of patient characteristics were analyzed with the  2 test. Differences between characteristics such as tumor diameter were tested with the t test. We performed analyses of survival using the Kaplan-Meier method. Differences associated with a P < .05 were considered significant. Follow-up and survival rates were calculated from the date of primary surgery to the date of last examination or death.
Patients From March 2000 until June 2006, 457 patients from 15 centers were registered (see Appendix). All centers had fulfilled the quality criteria. The median number of registered patients per center was 21 (range, three to 113 patients). In 403 patients, a sentinel node procedure according to the protocol was performed. The clinical characteristics of these patients are listed in Table 1. In 127 (31.5%) of 403 patients, pathology showed  one metastatic sentinel node, and therefore, a total of 276 (68.5%) of 403 patients were eligible for the observational study.
Sentinel Node Characteristics In 623 groins of 403 patients, a sentinel node procedure was performed (183 patients only unilateral). In 163 groins (26.2%), metastatic sentinel node(s) were found. Routine pathologic examination detected 95 (58.3%) of 163 groins with metastatic sentinel nodes, and ultrastaging detected 68 (41.7%) of 163 groins with metastatic sentinel nodes.
Short-Term and Long-Term Complications
Stopping Rules In October 2003, of 139 patients with a negative sentinel node on study, two patients with multifocal disease (two separate vulvar lesions that were injected separately) and a negative sentinel node suffered from a groin recurrence within a short period of time. Despite the fact that the stopping rules had not yet been activated, it was decided to amend the protocol and to further exclude patients with multifocal disease. This amendment was approved by the ethics committees in all participating centers. Figure 1 shows the performance of the stopping rule for the observational study in unifocal patients at the time of activation because of passing the safety border. At that time, the groin recurrence rate for patients who had completed 2 years of follow-up (n = 126) was 4.0% (95% CI, 1.6% to 8.0%). After reaching the number of 259 patients with unifocal disease and a negative sentinel node, the study was closed in June 2006.
Follow-Up in Sentinel Node–Negative Patients
Local recurrences and disease-specific and overall survival. During follow-up, 16 (5.8%) of 276 patients died of intercurrent disease, and 10 patients (3.6%) died of vulvar cancer. In 34 patients (12.3%), a local recurrence occurred (median time to recurrence, 16 months; range, 2 to 67 months). Treatment in these patients was at the discretion of the individual center. Five patients with local recurrence eventually died of distant metastases (15, 18, 22, 41, and 41 months after primary treatment). Figure 2B shows the disease-specific survival curve for patients with negative sentinel nodes. The 3-year disease-specific survival rate for patients with unifocal vulvar disease and negative sentinel nodes was 97.0%.
This prospective study is the largest study on surgical techniques ever performed in vulvar cancer. The low groin recurrence rate (3% including multifocal disease; 2.3% in unifocal vulvar disease) and excellent disease-specific survival rate of 97% at 3 years in sentinel node–negative patients suggest that the sentinel node procedure is a safe alternative to elective inguinofemoral lymphadenectomy for selected vulvar cancer patients. Apart from two small, single-institution series from which no conclusions with respect to efficacy and safety could be drawn, comparable data in vulvar cancer do not exist.32,33 The primary end point in our study was groin recurrence rate because groin recurrences are often fatal9 and of major concern when considering a less radical approach of the groin in vulvar cancer. Groin recurrence rates in often small, retrospective studies vary from 0% to 5.8% for lymph node–negative patients8,10,11 (see Appendix). The groin recurrence rate in sentinel node–negative patients in the current study seems to be at least comparable to that reported for patients with early-stage vulvar cancer treated with formal lymphadenectomy of any type. The nodal recurrence risk may seem less favorable when compared with that seen after the sentinel node procedure in the treatment of breast cancer (0.1% to 0.3%).35 This might be partly explained by the fact that the majority of breast cancer patients will receive adjuvant treatment after surgery, whereas vulvar cancer patients with a negative sentinel node do not receive any adjuvant treatment. However, from studies where the sentinel node procedure was followed by formal lymphadenectomy, the variation in false-negative rates (range, 0% to 27%; average, 6.7%)17 seems to be higher in breast cancer than the variation found for the sentinel node procedure in vulvar cancer (typically 0% to 2%). The excellent performance of the sentinel node technique in vulvar cancer is perhaps surprising given that the accuracy of the sentinel node procedure is strongly associated with the experience of the surgeon. In the Axillary Lymphatic Mapping Against Nodal Axillary Clearance trial in breast cancer, centers were only allowed to participate after at least 40 successful sentinel node procedures followed by full axillary lymphadenectomy.21 Even in countries where treatment of vulvar cancer is centralized, such figures are not realistic because of the rarity of the disease. It may be that the more superficial location of the inguinofemoral region compared with the axillary region facilitates easier and thus more accurate detection, even by less experienced surgeons such as in our multicenter study. However, in depth analysis of our eight patients with false-negative results revealed surgeon- and procedure-related factors in four of eight patients, stressing the necessity of strict adherence to the sentinel node protocol by the entire multidisciplinary team to prevent false-negative results. Therefore, implementation of the sentinel node procedure in routine treatment of early-stage vulvar cancer requires quality control at each step of this multidisciplinary procedure, including injection of radioactive tracer by either the surgeon or a nuclear medicine physician familiar with vulvar anatomy, careful interpretation of lymphoscintigram, a surgeon with successful experience (sentinel node procedure followed by full lymphadenectomy) in at least 10 patients, and a pathology department experienced in ultrastaging of the sentinel nodes. All sentinel nodes that are negative at routine HE examination need to be further analyzed by ultrastaging. Finally, to keep the experience at a high level, an exposure of at least five to 10 patients per year per surgeon should be regarded as a minimum figure. In a rare tumor such as vulvar cancer, this will require centralization of early-stage vulvar cancer treatment in oncology centers. Two years after the activation of the study, a protocol amendment was made when two groin recurrences occurred in 19 patients with multifocal disease. Analysis revealed that peritumoral injection of the tracer in multifocal disease seemed likely to not be representative of the extent of the tumors. Fortunately, no further recurrences were observed in the additional 19 patients with negative sentinel nodes already registered on the study. If all patients with multifocal disease are excluded, only six groin recurrences occurred, pointing to an even lower groin recurrence rate (six of 259 patients; 2.3%; 95% CI, 1% to 5%). Apart from multifocal disease, we also excluded patients with tumors greater than 4 cm from our study. Although this figure was arbitrarily chosen, representative injection of tracer around larger tumors is less likely. Furthermore, nodal involvement increases with lesion size, and alterations in lymphatic flow that may occur with large involved nodes could further increase the likelihood of false-negative results.35 The main purpose of the introduction of the sentinel node technique in early-stage vulvar cancer is reduction of treatment-related morbidity in patients without metastatic nodes. We have shown that sentinel node removal alone resulted in less short- and long-term morbidity compared with inguinofemoral lymphadenectomy. The rates of short- and long-term morbidity after inguinofemoral lymphadenectomy in this study were comparable to those reported in the literature.10,12-14 Long-term morbidity was especially high in patients who underwent inguinofemoral lymphadenectomy followed by radiotherapy. In the ongoing Groningen International Study on Sentinel Nodes in Vulvar Cancer-II study, patients with a metastatic sentinel node will receive radiotherapy instead of inguinofemoral lymphadenectomy to reduce morbidity caused by double-modality treatment. In conclusion, our study demonstrates that the introduction of the sentinel node procedure in the management of early-stage vulvar cancer performed by a quality-controlled multidisciplinary team results in decreased morbidity without compromising groin recurrence or survival rates. Sentinel node detection should be discussed as a safe treatment option when counseling a patient with unifocal, early-stage vulvar cancer.
The author(s) indicated no potential conflicts of interest.
Conception and design: Ate G.J. Van der Zee, Joanne A. De Hullu, Anca C. Ansink, Ignace Vergote, René H. Verheijen, Jacobus Van der Velden, Administrative support: Ate G.J. Van der Zee Provision of study materials or patients: Ate G.J. Van der Zee, Maaike H. Oonk, Joanne A. De Hullu, Anca C. Ansink, Ignace Vergote, René H. Verheijen, Angelo Maggioni, Katja N. Gaarenstroom, Peter J. Baldwin, Eleonora B. Van Dorst, Jacobus Van der Velden, Ralph H. Hermans, Hans van der Putten, Pierre Drouin, Achim Schneider Collection and assembly of data: Ate G.J. Van der Zee, Maaike H. Oonk, Joanne A. De Hullu, Anca C. Ansink, Ignace Vergote, René H. Verheijen, Angelo Maggioni, Katja N. Gaarenstroom, Peter J. Baldwin, Eleonora B. Van Dorst, Jacobus Van der Velden, Ralph H. Hermans, Hans van der Putten, Pierre Drouin, Achim Schneider Data analysis and interpretation: Ate G.J. Van der Zee, Maaike H. Oonk, Wim J. Sluiter Manuscript writing: Ate G.J. Van der Zee, Maaike H. Oonk, Joanne A. De Hullu, Anca C. Ansink, Ignace Vergote, Peter J. Baldwin, Jacobus Van der Velden, Wim J. Sluiter Final approval of manuscript: Ate G.J. Van der Zee, Maaike H. Oonk, Joanne A. De Hullu, Anca C. Ansink, Ignace Vergote, René H. Verheijen, Angelo Maggioni, Katja N. Gaarenstroom, Peter J. Baldwin, Eleonora B. Van Dorst, Jacobus Van der Velden, Ralph H. Hermans, Hans van der Putten, Pierre Drouin, Achim Schneider, Wim J. Sluiter
Quality Control of the Sentinel Node Procedure Before Start of Participation in the Study Successful experience with the sentinel node procedure and subsequent inguinofemoral lymphadenectomy needed to be documented in at least 10 patients. Successful was defined as identification of the sentinel node(s) and no false-negative results. When false-negative results occurred, another five patients needed to have procedure performed with subsequent inguinofemoral lymphadenectomy before patients could be included in the Groningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS-V).
Detailed Treatment Protocol of GROINSS-V Surgical treatment protocol. Treatment consisted of excision of the primary tumor in combination with the sentinel node procedure. Only when sentinel nodes were positive was unilateral or bilateral inguinofemoral lymphadenectomy by separate incisions performed. The lymphadenectomy was performed immediately after the sentinel node procedure when frozen section showed lymph node metastases. When the frozen section was negative but definitive histopathologic examination (including multiple sectioning and immunohistochemistry) showed metastatic disease, lymphadenectomy was performed in a second operation. In case of a positive sentinel node on one side and negative sentinel node on the other side, full lymphadenectomy was only performed on the side with the positive sentinel node. However, in case of a real midline tumor, unilateral flow was considered as a technical failure, and complete inguinofemoral lymphadenectomy was performed in the side without sentinel node identification. When the tumor did not cross the midline but the medial margin of the tumor was within 1 cm from the midline, in the majority of the patients, bilateral lymph drainage was visualized on the lymphoscintigram. However, in case of unilateral lymph flow, a unilateral sentinel lymph node procedure was sufficient if the sentinel node procedure was performed according to the protocol. Separate incisions for the lymphadenectomy were made parallel to the inguinal ligament, and then the node-bearing fat pad was removed. The extent of the dissection was the inguinal ligament cephalad, the adductor longus muscle medially, and the sartorius muscle inferolaterally. After opening of the cribiform fascia, all node-bearing fatty tissue medially from the femoral vein was removed as well. The vulvar excision varied with the location of the lesion. The standard local treatment was radical local excision with tumor-free margins of at least 1 cm. Histopathology. The pathologist received the sentinel node(s) and, if applicable, the lymphadenectomy specimens separately. Initially, the sentinel nodes were cut in the middle for frozen section and cytologic specimen. Later on, from every half, four sections were cut for hematoxylin and eosin staining (routine histopathologic examination). Of all sentinel nodes that were negative on routine histopathologic examination, additional pairs of sections were subsequently cut, with three sections per millimeter. One section of each pair was stained with hematoxylin and eosin, and the other section was immunostained with cytokeratin 1% AE1:AE3 antikeratin solution (Boehringer Mannheim, Mannheim, Germany). From the lymphadenectomy specimens, all lymph nodes were studied individually. One section per 0.5-cm diameter of the nodes was cut for hematoxylin and eosin staining.
Detailed Statistical Design
Participating Centers
Historical Groin Recurrence Rate Appendix Table A2 (online only) provides an overview of groin recurrences in vulvar cancer patients with negative lymph nodes at primary treatment, with different surgical techniques for groin treatment. Studies were included only if the groin recurrence rate in lymph node–negative patients was separately discussed. The groin recurrence rate after more conservative surgical techniques for groin treatment is low, ranging from 0% to 4.7% for lymph node–negative patients. For superficial inguinal lymphadenectomy, the groin recurrence rate seems higher (0% to 8.7% for lymph node–negative patients).
Presented at the 11th Biennial Meeting of the International Gynecologic Cancer Society, October 14-18, 2006, Santa Monica, CA, and the Society of Gynecologic Oncologists 37th Annual Meeting on Women's Cancer, March 22-26, 2006, Palm Springs, CA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Booth H, Cooper N, Quinn M (eds): Cancer statistics registration: Registration of cancer diagnosed in 2000, England. http://www.statistics.gov.uk/downloads/theme_health/Mb1_31/Mb1_31.pdf 2. US Cancer Statistics Working Group.United States Cancer Statistics: 2003 Incidence and Mortality. Atlanta, GA, US Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute, 2006 3. Hemminki K, Li X, Vaittinen P: Time trends in the incidence of cervical and other genital squamous cell carcinomas and adenocarcinomas in Sweden, 1958-1996. Eur J Obstet Gynecol Reprod Biol 101:64-69, 2002[CrossRef][Medline] 4. Homesley HD, Bundy BN, Sedlis A, et al: Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival: A Gynecologic Oncology Group study. Am J Obstet Gynecol 164:997-1004, 1991[Medline] 5. Burger MP, Hollema H, Emanuels AG, et al: The importance of the groin node status for the survival of T1 and T2 vulval carcinoma patients. Gynecol Oncol 57:327-334, 1995[CrossRef][Medline] 6. Hacker NF, Leuchter RS, Berek JS, et al: Radical vulvectomy and bilateral inguinal lymphadenectomy through separate groin incisions. Obstet Gynecol 58:574-579, 1981[Medline] 7. De Hullu JA, Hollema H, Lolkema S, et al: Vulvar carcinoma: The price of less radical surgery. Cancer 95:2331-2338, 2002[CrossRef][Medline] 8. Bell JG, Lea JS, Reid GC: Complete groin lymphadenectomy with preservation of the fascia lata in the treatment of vulvar carcinoma. Gynecol Oncol 77:314-318, 2000[CrossRef][Medline] 9. Katz A, Eifel PJ, Jhingran A, et al: The role of radiation therapy in preventing regional recurrences of invasive squamous cell carcinoma of the vulva. Int J Radiat Oncol Biol Phys 57:409-418, 2003[CrossRef][Medline] 10. Stehman FB, Bundy BN, Dvoretsky PM, et al: Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: A prospective study of the Gynecologic Oncology Group. Obstet Gynecol 79:490-497, 1992[Medline] 11. Kirby TO, Rocconi RP, Numnum TM, et al: Outcomes of stage I/II vulvar cancer patients after negative superficial inguinal lymphadenectomy. Gynecol Oncol 98:309-312, 2005[CrossRef][Medline] 12. De Hullu JA, Ansink AC, Tymstra T, et al: What doctors and patients think about false-negative sentinel lymph nodes in vulvar cancer. J Psychosom Obstet Gynaecol 22:199-203, 2001[Medline] 13. Rouzier R, Haddad B, Dubernard G, et al: Inguinofemoral dissection for carcinoma of the vulva: Effect of modifications of extent and technique on morbidity and survival. J Am Coll Surg 196:442-450, 2003[CrossRef][Medline] 14. Gaarenstroom KN, Kenter GG, Trimbos JB, et al: Postoperative complications after vulvectomy and inguinofemoral lymphadenectomy using separate groin incisions. Int J Gynecol Cancer 13:522-527, 2003[CrossRef][Medline] 15. Oonk MH, Hollema H, de Hullu JA, et al: Prediction of lymph node metastases in vulvar cancer: A review. Int J Gynecol Cancer 16:963-971, 2006[CrossRef][Medline] 16. Selman TJ, Luesley DM, Acheson N, et al: A systematic review of the accuracy of diagnostic tests for inguinal lymph node status in vulvar cancer. Gynecol Oncol 99:206-214, 2005[CrossRef][Medline] 17. Kim T, Giuliano AE, Lyman GH: Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: A metaanalysis. Cancer 106:4-16, 2006[Medline] 18. Thompson JF, Shaw HM: Sentinel node mapping for melanoma: Results of trials and current applications. Surg Oncol Clin N Am 16:35-54, 2007[CrossRef][Medline] 19. Purushotham AD, Upponi S, Klevesath MB, et al: Morbidity after sentinel lymph node biopsy in primary breast cancer: Results from a randomized controlled trial. J Clin Oncol 23:4312-4321, 2005 20. Veronesi U, Paganelli G, Viale G, et al: Sentinel-lymph-node biopsy as a staging procedure in breast cancer: Update of a randomised controlled study. Lancet Oncol 7:883-890, 2006[CrossRef][Medline] 21. Mansel RE, Fallowfield L, Kissin M, et al: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC trial. J Natl Cancer Inst 98:599-609, 2006 22. Wilke LG, McCall LM, Posther KE, et al: Surgical complications associated with sentinel lymph node biopsy: Results from a prospective international cooperative group trial. Ann Surg Oncol 13:491-500, 2006[CrossRef][Medline] 23. Lucci A, McCall LM, Beitsch PD, et al: Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol 25:3657-3663, 2007 24. Ansink AC, Sie-Go DMDS, van der Velden J, et al: Identification of sentinel lymph nodes in vulvar carcinoma patients with the aid of a patent blue V injection. Cancer 86:652-656, 1999[CrossRef][Medline] 25. De Cicco C, Sideri M, Bartolomei M, et al: Sentinel node biopsy in early vulvar cancer. Br J Cancer 82:295-299, 2000[CrossRef][Medline] 26. De Hullu JA, Hollema H, Piers DA, et al: Sentinel lymph node procedure is highly accurate in squamous cell carcinoma of the vulva. J Clin Oncol 18:2811-2816, 2000 27. Levenback C, Coleman RL, Burke TW, et al: Intraoperative lymphatic mapping and sentinel node identification with blue dye in patients with vulvar cancer. Gynecol Oncol 83:276-281, 2001[CrossRef][Medline] 28. Sliutz G, Reinthaller A, Lantzsch T, et al: Lymphatic mapping of sentinel nodes in early vulvar cancer. Gynecol Oncol 84:449-452, 2002[CrossRef][Medline] 29. Moore RG, DePasquale SE, Steinhoff MM, et al: Sentinel node identification and the ability to detect metastatic tumor to inguinal lymph nodes in squamous cell cancer of the vulva. Gynecol Oncol 89:475-479, 2003[CrossRef][Medline] 30. Puig-Tintoré LM, Ordi J, Vidal-Sicart S, et al: Further data on the usefulness of sentinel lymph node identification and ultrastaging in vulvar squamous cell carcinoma. Gynecol Oncol 88:29-34, 2003[CrossRef][Medline] 31. De Hullu JA, Doting E, Piers DA, et al: Sentinel lymph node identification with technetium-99m-labeled nanocolloid in squamous cell cancer of the vulva. J Nucl Med 39:1381-1385, 1998 32. Vidal-Sicart S, Puig-Tintoré LM, Lejárcegui JA, et al: Validation and application of the sentinel lymph node concept in malignant vulvar tumours. Eur J Nucl Med Mol Imaging 34:384-391, 2007[CrossRef][Medline] 33. Nyberg RH, Iivonen M, Parkkinen J, et al: Sentinel node and vulvar cancer: A series of 47 patients. Acta Obstet Gynecol Scand 86:615-619, 2007[CrossRef][Medline] 34. Terada KY, Shimizu DM, Jiang CS, et al: Outcomes for patients with T1 squamous cell cancer of the vulva undergoing sentinel node biopsy. Gynecol Oncol 102:200-203, 2006[CrossRef][Medline] 35. de Hullu JA, Oonk MH, Ansink AC, et al: Pitfalls in the sentinel lymph node procedure in vulvar cancer. Gynecol Oncol 94:10-15, 2004[CrossRef][Medline] Submitted August 20, 2007; accepted October 4, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, cumulating to .05 with 90% power. The ethical committee of each participating hospital would be informed of the activation of the stopping rule, and after the analysis of the data, the ethical committees would be requested to judge the proposal of the investigators, based on the results of this analysis, regarding the following: the closure of the study; or the progression of the study with an amended protocol; or the progression of the study with an unchanged protocol (stopping rule design detailed in Appendix). 
