Donata Grimm

Management of patients with vulvar cancer: a perspective review according to tumour stage

Treatment of patients with vulvar cancer is challenging for gynaecologic oncologists. Owing to the localization in a sensitive area, surgical radicality and the indication for adjuvant treatment have to be balanced with psychosocial aspects to treat patients adequately. Clinical management is therefore highly dependent on the tumour stage. For patients with early-stage disease (FIGO I–II) therapy mainly concentrates on surgery with resection of the primary tumour and staging of the groin lymph nodes. In intermediate-stage vulvar cancer (FIGO III), advanced disease is expressed by affected inguinofemoral lymph nodes bringing radical lymphadenectomy and adjuvant therapy as well as radiation or chemoradiation into the focus of treatment. For locally advanced or metastatic vulvar cancer (FIGO IV) neoadjuvant or definitive chemoradiation has to be considered besides surgery. Owing to the low incidence of the disease, the level of evidence for different treatment modalities is poor. This review therefore puts different recommendations of clinical management in context and highlights the need for future trials.

Systemic treatment of vulvar cancer

Squamous cell carcinoma of the vulva is a rare disease, accounting for approximately 5% of cancers of the female genital tract. Standard therapy for early-stage vulvar cancer mainly comprises of surgery of the vulva and groins. In locally advanced or metastatic vulvar cancer, neoadjuvant or definitive chemoradiation is often considered as an alternative treatment option. Given its rarity, the level of evidence for different treatment modalities is poor and few clinical trials have been performed on this disease. Therefore indication criteria for systemic treatment in advanced stage vulvar cancer vary widely among countries and institutions. This review focuses on the different systemic treatment options for patients with locally advanced, recurrent or metastatic vulvar cancer, and highlights the need for an international multicenter approach to identify the most effective therapeutic options.

Clinical management of epithelial ovarian cancer during pregnancy.

UNLABELLED Epithelial ovarian cancer (EOC) in pregnancy is a rare situation. Due to its low incidence with a consecutive lack of clinical trials many questions regarding indication of different treatment approaches are unanswered. This article discusses the current literature to elaborate recommendations for the management of EOC during pregnancy. A literature search of diagnostic approaches and treatment strategies for EOC complicated by pregnancy was performed. We reviewed the available information with emphasis on surgery as well as chemotherapeutical treatment options. EOC in pregnancy is often diagnosed at early stage and no data support that concurrent pregnancy influences the growth rate or propensity for spread of EOC. Radical cytoreduction of all visible tumour followed by subsequent systemic chemotherapy is the standard treatment of EOC in most non-pregnant women. In pregnant women, however, chemotherapy as well as radical surgery should be avoided in the first trimester because of teratogenesis and high abortion rates. Besides induced abortion followed by classic management of EOC, pregnancy preserving surgery, followed by chemotherapy in the second or third trimester, timely delivery as well as neo-adjuvant chemotherapy with subsequent completing surgery appear to be viable treatment options. CONCLUSIONS Since there is only very limited information regarding the optimal therapeutic approach to EOC during pregnancy, each case needs to be addressed individually. Treatment in specialised centres should be intended especially in this rare and challenging situation.

Surgical management and perioperative morbidity of patients with primary borderline ovarian tumor (BOT)

BackgroundSurgery is the cornerstone for clinical management of patients with borderline ovarian tumors (BOT). As these patients have an excellent overall prognosis, perioperative morbidity is the critical point for decision making when the treatment strategy is developed and the primary surgical approach is defined.MethodsClinical and surgical parameters of patients undergoing surgery for primary BOT at our institutions between 1993 and 2008 were analyzed with regard to perioperative morbidity depending on the surgical approach (laparotomy vs. laparoscopy).ResultsA total of 105 patients were analyzed (44 with primary laparoscopy [42%], 61 with primary laparotomy [58%]). Complete surgical staging was achieved in 33 patients at primary surgical approach (31.4%) frequently leading to formal indication of re-staging procedures. Tumor rupture was significantly more frequent during laparoscopy compared to laparotomy (29.5% vs. 13.1%, p = 0.038) but no other intraoperative complications were seen in laparoscopic surgery in contrast to 7 of 61 laparotomies (0% vs. 11.5%, p = 0.020). Postoperative complication rates were similar in both groups (19.7% vs. 18.2%, p = 0.848).ConclusionsIrrespective of the surgical approach, surgical management of BOT has acceptable rates of perioperative complications and morbidity. Choice of initial surgical approach can therefore be made independent of complication-concerns. As the recently published large retrospective AGO ROBOT study observed similar oncologic outcome for both approaches, laparoscopy can be considered for staging of patients with BOT if this appears feasible. An algorithm for the surgical management of BOT patients has been developed.

Sexual Activity and Function in Patients With Gynecological Malignancies After Completed Treatment

Objective Sexual activity (SA) and sexual function (SF) after completion of treatment are central for quality of life (QoL) in women affected by gynecological cancer (GC). The aim of this study was to analyze the sexual outcome and overall QoL of women after treatment for primary GC compared with a healthy control group (CG). Methods In a multicenter cross-sectional study, 77 women aged 28 to 67 years were surveyed at least 12 months after completion of primary therapy for cervical, endometrial, or vulvar cancer [gynecological cancer group (GCG)]. Data were collected through validated questionnaires (Female Sexual Function Index-d, EORTC Quality of Life Questionnaire-C30, and Sexual Activity Questionnaire) and compared to a control of 60 healthy women (CG). Results In the GCG, 41.3% were sexually active compared to 78.0% in the CG. Twelve women of the CG and 42 women of the GCG indicated the reasons for their sexual inactivity. The most common reason for sexual inactivity in the GCG was “the-presence-of-a-physical-problem” [18/42 (42.9%) vs 2/12 (16.7%) in the CG], whereas in the CG, “because-I-do-not-have-a-partner” was most common [6/12 (50.0%) vs 11/42 (26.2%) in the GCG]. Sexually active patients in the GCG had an SF comparable to the CG. In multivariate analysis of the total cohort (n = 137), relationship status [solid partnership vs living alone; odds ratio (OR), 33.82; 95% confidence interval (CI), 4.83–236.70], smoking (OR, 0.25; 95% CI, 0.06–1.03), and age (OR, 0.87; 95% CI, 0.79–0.94) influenced SA significantly. The probability of SA thereby decreased with increasing age. Quality of life and subjective general health status were not significantly different between the GCG and the CG (EORTC Quality of Life Questionnaire-C30 score 68.25 vs 69.67). Conclusions A high number of patients with GC remain sexually inactive after treatment, indicating that women experience persistent functional problems. However, women who regain SA after completed treatment have a good overall SF and vice versa.

Beyond Bevacizumab: An Outlook to New Anti-Angiogenics for the Treatment of Ovarian Cancer

In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. Nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease, two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication. Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated.

Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer

Background Approximately 20-25% of ovarian cancers are attributable to germline or somatic BRCA1/2 mutations, resulting in defects in the homologous recombination pathway. Inactivation of these genes can also be mediated by epigenetic changes, e.g., hypermethylation of CpG islands in the promoter regions. In such homologous recombination deficient tumors, platinum based chemotherapy is in general effective, however, loss of hypermethylation might lead to refractory disease. The aim of this study was to evaluate the stability of BRCA1 promoter hypermethylation in recurrent disease after platinum based chemotherapy. Methods Tumor tissue from 76 patients with primary and 48 patients with platinum-sensitive recurrent high-grade ovarian cancer was collected. In a subgroup of 12 patients, ‘paired’ tumor tissue from primary and recurrent surgery was available. BRCA1 promoter methylation status was assessed using methylation specific polymerase chain reaction and was verified by Sanger Sequencing. Results 73.7% (56/76) of primary and 20.8% (10/48) of recurrent tumors displayed BRCA1 promoter hypermethylation. BRCA1 promoter methylation status was not associated with progression-free- or overall survival. In the paired subgroup 83.3% (10/12) of the primary vs. 16.7% (2/12) of the recurrent tumors showed hypermethylation. In eight patients loss of BRCA1 hypermethylation was observed, whereas two patients had stable methylation status. Conclusions Loss of BRCA1 promoter methylation may be a mechanism to restore BRCA1 function in recurrent disease. However, currently the clinical significance is still unclear and should be evaluated in prospective clinical trials.

Participation of elderly gynecological cancer patients in clinical trials

BackgroundElderly patients are underrepresented in clinical trials in gynecological cancer, even though they are disproportionally often affected. This study aimed to evaluate the disposition and apprehension of elderly patients toward study participation.Methods112 elderly gynecological cancer patients (median age 70) were surveyed in a multicenter cross-sectional study. Besides fitness, state of disease, education and domestic situation, questions aimed at the general willingness to participate in a clinical trial. Personal reasons for refusal and anticipated advantages/disadvantages that might evolve from participation were inquired.ResultsWillingness to participate in a clinical study was generally high (72%, 74/102). Reasons for potential study participation were: ‘better monitoring of the disease’ (67.1%), ‘better medical care’ (46.1%), ‘to help medical research’ (44.7%), ‘better medication’ (35.5%) and ‘because of my doctor’s recommendation’ (22.4%). Reasons for potential refusal were: ‘too time consuming’ (24.4%), ‘fear of side effects’ (21.8%), ‘misuse as experimental animal’ (18%), ‘long distance to clinic’ (14.1%) and ‘too little or unclear information’ (10.3%). 37.2% (29/78) of the patients stated that they had ‘no objection’ at all against study participation. The question if patients anticipated having a longer life due to study participation was answered with ‘yes’ or ‘rather yes’ in 42% (38/90); 28.9% answered ‘no’ or ‘rather no’ (29% undecided). No statistical significant relation between willingness to participate in a study and general fitness (p = 0.133), education (p = 0.122), age (p = 0.474) or domestic situation (p = 0.123) could be observed in a multivariate logistic regression model.ConclusionsElderly patients are generally willing to participate in clinical studies, in our cohort regardless of their fitness. Benefits of participation seem to be unclear among a majority of potential study participants. Therefore, it might be decisive to provide more general information regarding benefits and safety for elderly patients in a clinical trial.

Prognose und Verlauf beim mikroinvasiven Vulvakarzinom

Zielsetzung: Vulvakarzinome mit einer Stromainvasion ≤1 mm und Durchmesser ≤20 mm werden als mikroinvasiv bezeichnet. Diese Karzinome gelten als prognostisch gunstig. Daten liegen kaum vor. Diese Arbeit untersucht Verlauf und Prognose beim mikroinvasiven Vulvakarzinom. Methoden: Es handelt sich um eine retrospektive Analyse von 46 Patientinnen im Alter von 36 – 87 Jahren (median 58) mit mikroinvasivem Plattenepithelkarzinom der Vulva, die zwischen 1996 – 2015 im Universitatsklinikum-Hamburg Eppendorf mittels weiter Exzision primar operativ behandelt wurden. Ergebnisse: Bei 38/46 (84,7%) Patientinnen lagen begleitende Dysplasien und/oder chronische Dermatosen der Vulva vor (32 (69,6%) high-grade VIN, 5 (10,7%) Lichen sclerosus und high-grade VIN, 1 (2,3%) alleiniger Lichen sclerosus). Eine R0-Resektion lag bei 35 (76,1%) Patientinnen vor; in 2 (4,4%) Fallen waren Tumorzellen randstandig und in 2 (4,4%) eine VIN, bei 7 (15,2%) war der R-Status unbekannt. Das mittlere Follow-up betrug 56 Monate (10 – 185 Monate). Vier Patientinnen (8,7%) erlitten ein invasives Rezidiv nach 4-, 17-, 40- und 60 Monaten, davon drei vulvar und eine inguinal. Alle Lokalrezidive traten bei Frauen mit Lichen sclerosus auf. Zwei Lokalrezidive wurden erneut operativ behandelt, beide zeigten eine Makroinvasion und erhielten eine inguino-femorale-Lymphonodektomie (pN0). Die dritte Patientin lehnte jede weitere Therapie ab. Das Leistenrezidiv wurde mit einer inguino-femorale-Lymphonodektomie beidseits pN (1/15) gefolgt von einer adjuvanten Radiatio von Leisten und Becken behandelt. Alle Patientinnen mit Rezidiv waren bis zum letzten Follow-up rezidivfrei (10-, 29-, 51- und 65 Monaten). Zusammenfassung: Mikroinvasive Vulvakarzinome zeichnen sich durch eine sehr gute Prognose aus. Die alleinige operative Therapie weist eine hohe Effektivitat auf. Bei Patientinnen mit Lichen sclerosus scheint ein erhohtes Rezidivrisiko vorzuliegen.