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Objective: To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival., Methods: In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated., Results: 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years., Conclusions: Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Most guidelines advise no adjuvant radiotherapy in vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis. However, several recent studies have questioned the validity of this recommendation. The aim of this study was to analyze the groin recurrence rate in patients with a single intracapsular positive lymph node treated without adjuvant radiotherapy., Methods: Patients with a single clinically occult intracapsular lymph node metastasis, treated without adjuvant radiotherapy, formed the basis for this study. Groin recurrences, and the risk of death, were analyzed in relation to the size of the metastasis in the lymph node and the lymph node ratio. Data were analyzed using SPSS, version 26.0 for Windows., Results: After a median follow-up of 64 months, one of 96 patients (1%) was diagnosed with an isolated groin recurrence and another two (2.1%) were diagnosed with a combination of a local and a groin recurrence. The only isolated groin recurrence occurred in a contralateral lymph node negative groin. Size of the metastasis and lymph node ratio had no impact on the groin recurrence risk, nor on survival. The 5-year actuarial disease-specific and overall survivals were 79% and 62.5% respectively. The 5-year actuarial groin recurrence-free survival was 97%., Conclusion: Because of the low risk of groin recurrence and the excellent groin recurrence-free survival, we recommend that adjuvant radiotherapy to the groin in patients with vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis can be safely omitted to prevent unnecessary toxicity and morbidity., Competing Interests: Declaration of Competing Interest Authors do not declare any conflict of interest related to this paper., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to describe the pattern of recurrence and survival related to prognostic variables, including type of surgery as a clinical variable, in patients surgically treated for early cervix cancer., Methods: Records of 2124 patients who underwent a radical hysterectomy for International Federation of Gynaecology and Obstetrics stage I/IIA cervical cancer between 1982 and 2011 were reviewed. Clinical-pathologic prognostic variables, also including extent of parametrectomy, were identified and used in a multivariable Cox proportional hazard model to explore associations between disease-free survival (DFS) and prognostic variables., Results: The 5-year DFS for the total group was 86%. Large tumor diameter, nonsquamous histology, lymph node metastases, parametrial involvement, lymph vascular space invasion, deep stromal invasion, and less radical surgery were independent poor prognostic variables for survival. Disease-free survival was independently associated with the type of radical hysterectomy with pelvic lymphadenectomy in favor of more radical parametrectomy (hazard ratio, 2.0; 95% confidence interval, 1.6-2.5). This difference was not found in tumors with a diameter of at least 20 mm., Conclusions: This study confirms that variables such as large tumor diameter, nonsquamous histology, lymph vascular space invasion, deep stromal invasion, positive lymph nodes, and parametrial infiltration are poor prognostic variables in early cervix cancer treated by surgery. The extent of parametrectomy had no influence on survival in tumors of 20 mm or less. For larger tumors, a more radical hysterectomy might be associated with better DFS. Taking into account the possible bias in this study as a result of its retrospective design, ideally a prospective cohort study with clear definition of radicality is necessary to answer this important clinical question.

Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n=156 and adenocarcinoma, n=49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n=96 and adenocarcinoma, n=31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P<0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival (P=0.022) and disease-specific survival (P=0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages (P=0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors (P=0.001 for squamous cell carcinoma and P=0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway.

Objective: Standard treatment of primary T1 squamous cell carcinoma (SCC) of the vulva <4cm consists of wide local excision (WLE) and sentinel lymph node (SLN) procedure of the groin(s). In case of a local recurrence WLE and inguino femoral lymphadenectomy (IFL) is generally recommended. In this study we assessed the feasibility of repeat SLN procedure in patients with recurrent vulvar SCC who were not able or willing to undergo IFL., Methods: A retrospective study was performed in consecutive patients with recurrent vulvar SCC who underwent a repeat SLN procedure between 2006 and 2014. We present the clinical and pathological outcomes. The study conforms to the STROBE guidelines., Results: A total number of 27 patients aged 35-87years at first diagnosis of SCC of the vulva were identified. Median follow-up after 2nd surgery was 27.4 (range 2-96) months. In 78% of patients and in 84% of the groins the repeat SLN procedure was successful. No structured questionnaires were used to describe details on the repeat SLN procedures but in general the gynecologic oncologists experienced repeat SLN procedures more challenging compared to primary procedures. There were no groin recurrences documented., Conclusions: Our findings suggest that it is feasible to perform a repeat SLN procedure in recurrent vulvar SCC, but the procedure appears technically more challenging compared to primary setting, resulting in a lower SLN identification rate., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Despite changes in technique, morbidity after surgery for vulvar cancer is high and mainly related to the groin dissection. Primary radiotherapy to the groin is expected to result in lower morbidity. However, studies on the efficacy of primary radiotherapy to the groin in terms of groin recurrences and survival show conflicting results., Objectives: To determine whether the effectiveness and safety of primary radiotherapy to the inguinofemoral lymph nodes in early vulvar cancer is comparable with surgery., Search Strategy: We searched The Cochrane Gynaecological Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE from 1966 to July 2010., Selection Criteria: We selected randomised clinical trials (RCTs) comparing inguinofemoral lymph node dissection and primary radiotherapy of the inguinofemoral lymph nodes for patients with early squamous cell cancer of the vulva., Data Collection and Analysis: Two reviewers independently assessed study quality and extracted results. Primary outcome measures were the incidence of groin recurrences, patient survival and morbidity., Main Results: No new RCTs were identified by the updated search. Out of twelve identified papers only one met the selection criteria. From this one small RCT of 52 women, there was a trend towards increased groin recurrence rates (relative risk (RR) 10.21, 95% confidence interval (CI) 0.59 to 175.78), lower disease-specific survival rates (RR 3.70, 95% CI 0.87 to 15.80), less lymphoedema (RR 0.06, 95% CI 0.00 to 1.03) and fewer life-threatening cardiovascular complications (RR 0.08, 95% CI 0.00 to 1.45) in the radiotherapy group. Primary surgery was associated with a longer hospital stay than primary groin irradiation (RR 0.28, 95% CI 0.13 to 0.58)., Authors' Conclusions: Primary radiotherapy to the groin results in less morbidity but may be associated with a higher risk of groin recurrence and decreased survival when compared with surgery. Due to the small numbers in this trial and criticisms regarding the depth of radiotherapy applied, corroboration of these findings by larger RCTs using a standardised radiotherapy method, is desirable. However, until better evidence is available, surgery should be considered the first choice treatment for the groin nodes in women with vulvar cancer. Individual patients not physically able to withstand surgery may be treated with primary radiotherapy.

Introduction: Patients with cervical carcinoma that invade the bladder or rectum (International Federation of Obstetrics and Gynecology stage IVA) have a high risk to develop vesicovaginal and/or rectovaginal fistulae. If we could identify pretreatment factors that predict fistula formation, these patients could be offered less debilitating treatment., Materials and Methods: Data were retrieved from the database of consecutive patients diagnosed with stage IVA cervical cancer from 1992 to 2008. Overall survival and fistula-free survival were calculated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were used to study the association between pretreatment prognostic variables and fistula formation., Results: Thirty patients with stage IVA cervical cancer were diagnosed. Extension to the bladder was present in 27 patients; three patients had only rectal involvement. Twenty-three patients (77%) had curative radiotherapy with or without chemotherapy and/or hyperthermia. Seven patients (23%) received only palliative therapy or no treatment at all. The 5-year overall survival in the curatively treated group was 42%. Five (22%) of these 23 patients developed one or more fistulae: 3 vesicovaginal, 1 rectovaginal, and 1 vesicovaginal and rectovaginal fistulae. The 5-year fistula-free survival of this group was 64%. No significant association was found between the prognostic variables and fistula formation., Conclusions: The risk to develop vesicovaginal and/or rectovaginal fistulae is high after curative radiotherapy with or without chemotherapy and/or hyperthermia in patients with stage IVA cervical cancer. We could not identify further pretreatment factors that might have predicted fistula formation.

Objectives: The aim of the current study was, first, to determine whether laterality of lymph node metastases has prognostic significance, independent of the number of lymph node metastases. Second was to determine the prognostic significance of extracapsular spread irrespective of the number of lymph node metastases., Methods: Data on 134 patients with stage III/IVA vulva cancer from 1982 till 2004 and treated with curative intent in either the Academic Medical Centre in Amsterdam or the Mercy Hospital for Women in Melbourne were reviewed. The impact of the number of lymph node metastases, extracapsular spread, and bilateral existence of lymph node metastases on survival was determined., Results: The bilateral presence of lymph node metastases is not a significant predictor for survival if a correction is made for the number of lymph node metastases (hazards ratio, 1.31; 95% confidence interval, 0.68-2.51; P = 0.420). If extracapsular spread is put into the model as well, this is the only parameter of prognostic significance in multivariate analysis (hazards ratio, 5.27; 95% confidence interval, 2.60-10.67; P < 0.001). The five-year survival of patients with extracapsular spread is only 31%, which is considerably lower than the 80% survival of patients with only intracapsular metastases., Conclusions: In conclusion, there is growing evidence that bilateral existence of lymph node metastases is not a sufficient variable to qualify stage. Extracapsular spread, however, seems to be the most valuable lymph node-associated prognostic factor for survival.

Objectives: To validate the results of a previous study with the tissue microarray technology showing that cyclooxygenase 2 (COX-2) overexpression and absent caspase 3 expression are associated with poor disease-specific survival in univariate analysis., Methods: The study group comprised 80 consecutive patients with vulva cancer treated in the period from 1999 to 2003 in a university hospital. A tissue microarray with 3 tumor tissue cores per patient was constructed and stained with antibodies against COX-2, caspase 3, epidermal growth factor receptor, p16 INK4, cyclin D1, and Ki-67. The impact of the expression of these protein markers and selected clinicopathologic variables on disease-specific as well as disease-free survival was measured. Cox proportional hazard model was used for both univariate and multivariate analyses., Results: In multivariate analysis, lymph node metastases and strong COX-2 expression were related to disease-free (hazard ratio [HR], 8.33, 95% confidence interval [CI], 2.97-23.36; P < 0.001; and HR, 6.42; 95% CI, 2.33-17.72; P < 0.001) and disease-specific survival (HR, 6.04; 95% CI, 2.12-17.19; P = 0.001; and HR, 5.11; 95% CI, 1.82-14.36; P = 0.002). In the present series, no association was found between caspase 3 expression and survival., Conclusion: The prognostic significance of COX-2 overexpression was confirmed. In contrast, in the present series, no relation was found between caspase 3 expression and survival.

The aim of the study was to validate tissue microarray (TMA) for vulvar cancer by comparing immunohistochemical staining results of triplicate core biopsies on TMA with the results of full section analysis. The study material consisted of slides and selected tissue blocks from 40 patients with vulvar cancer. A TMA was constructed with 3 cores/case. Both the TMA and the slides were stained with the same antibodies against COX-2, Caspase-3, epidermal growth factor receptor, p16INK4, Cyclin D1, and Ki67. For COX-2, 2 different scoring systems were applied. Agreement in the readings between TMA and slides was expressed in total agreement and kappa. Expression patterns of antibodies can be reproduced on TMA with good reliability (kappa 0.68 to 0.75) for Ki-67, p16INK4, COX-2, Cyclin D1, and epidermal growth factor receptor in comparison with whole slides. For Caspase-3 agreement is only slight with a kappa of 0.40. The majority of discordant cases for COX-2 and Ki67 were negative on slide and positive on TMA. For epidermal growth factor receptor and Caspase-3 an opposite pattern was found. For COX-2, the use of an alternative scoring system resulted in a decrease of kappa from 0.68 to 0.21. Agreement between results on TMA and slides depends on the distribution of the protein in the cancer tissue and on the scoring system used.

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.

Purpose: To prevent morbidity associated with double modality treatment, early-stage cervical cancer patients should only be offered surgery when there is a low likelihood for adjuvant radiotherapy. We analyzed whether serum squamous cell carcinoma antigen (SCC-ag) analysis allows better preoperative identification of patients with a low likelihood for adjuvant radiotherapy than currently used clinical parameters., Patients and Methods: In a cohort study, International Federation of Gynecology and Obstetrics (FIGO) stage, tumor size, and preoperative serum SCC-ag levels, as determined by enzyme immunoassay, were related to the frequency of postoperative indications for adjuvant radiotherapy in 337 surgically treated, FIGO stage IB/IIA, squamous cell cervical cancer patients., Results: In patients with normal preoperative SCC-ag, 16% of IB1 and 29% of IB2/IIA had postoperative indications for adjuvant radiotherapy, in contrast to 57% of IB1 and 74% of IB2/IIA patients with elevated (> 1.9 ng/mL) serum SCC-ag (P < .001). Serum SCC-ag was the only independent predictor for a postoperative indication for radiotherapy (odds ratio, 7.1; P < .001). Furthermore, in IB1 patients that did not have indications for adjuvant radiotherapy, 15% of patients with elevated preoperative serum SCC-ag levels recurred within 2 years, compared with 1.6% of patients with normal serum SCC-ag levels (P = .02)., Conclusion: In early-stage cervical cancer, determination of serum SCC-ag levels allows more refined preoperative estimation of the likelihood for adjuvant radiotherapy than current clinical parameters, and simultaneously identifies patients at high risk for recurrence when treated with surgery only. The role of preoperative serum SCC-ag in the management of patients with early-stage cervical cancer deserves further investigation.