Definitive chemoradiation in vulvar squamous cell carcinoma: outcome and toxicity from an observational multicenter Italian study on vulvar cancer (OLDLADY 1.1).

BACKGROUND: Vulvar carcinoma is a rather uncommon gynecological malignancy affecting elderly women and the treatment of loco-regional advanced carcinoma of the vulva (LAVC) is a challenge for both gynecologic and radiation oncologists. Definitive chemoradiation (CRT) is the treatment of choice, but with disappointing results. In this multicenter study (OLDLADY-1.1), several institutions have combined their retrospective data on LAVC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of CRT. METHODS: The primary study end-point was 2-year-local control (LC), secondary end-points were 2-year-metastasis free-survival (MFS), 2-year-overall survival (OS) and the rate and severity of acute and late toxicities. Participating centers were required to fill data sets including age, stage, histology, grading as well as technical/dosimetric details of CRT. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. The toxicity was a posteriori documented through the Common Terminology Criteria for Adverse Events version 5 scale. RESULTS: Retrospective analysis was performed on 65 patients with primary or recurrent LAVC treated at five different radiation oncology institutions covering 11-year time interval (February 2010-November 2021). Median age at diagnosis was 72 years (range 32-89). With a median follow-up of 19 months (range 1-114 months), 2-year actuarial LC, MFS and OS rate were 43.2%, 84.9% and 59.7%, respectively. In 29 patients (44%), CRT was temporarily stopped (median 5 days, range 1-53 days) due to toxicity. The treatment interruption was statistically significant at univariate analysis of factors predicting LC (p: 0.05) and OS rate (p: 0.011), and it was confirmed at the multivariate analysis for LC rate (p: 0.032). In terms of toxicity profile, no G4 event was recorded. Most adverse events were reported as grade 1 or 2. Only 14 acute G3 toxicities, all cutaneous, and 7 late G3 events (3 genitourinary, 3 cutaneous, and 1 vaginal stenosis) were recorded. CONCLUSION: In the context of CRT for LAVC, the present study reports encouraging results even if there is clearly room for further improvements, in terms of both treatment outcomes, toxicity and treatment interruption management.

Endometrial stromal tumors of the uterus: Epidemiology, pathological and biological features, treatment options and clinical outcomes.

Endometrial stromal tumors (EST) are uterine mesenchymal tumors, which histologically resemble endometrial stroma of the functioning endometrium. The majority of EST are malignant tumors classified as low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). Overall, ESTs are rare malignancies, with an annual incidence of approximately 0.30 per 100'000 women, mainly affecting peri- or postmenopausal women. The most common genetic alteration identified in LG-ESS is the JAZF1-SUZ12 rearrangement, while t(10;17)(q23,p13) translocation and BCOR gene abnormalities characterize two major subtypes of HG-ESS. The absence of specific genetic abnormalities is the actual hallmark of UUS. Unlike HG-ESSs, LG-ESSs usually express estrogen and progesterone receptors. Total hysterectomy without morcellation and bilateral salpingo-oophorectomy (BSO) is the first-line treatment of early-stage LG-ESS. Ovarian preservation, fertility-sparing treatment, and adjuvant hormonal therapy ± radiotherapy may be an option in selected cases. In advanced or recurrent LG-ESS, surgical cytoreduction followed by hormonal treatment, or vice versa, are acceptable treatments. The standard treatment for apparently early-stage HG-ESS and UUS is total hysterectomy without morcellation with BSO. Ovarian preservation and adjuvant chemotherapy ± radiotherapy may be an option. In advanced or recurrent HG-ESS, surgical cytoreduction and neoadjuvant or adjuvant chemotherapy can be considered. Alternative treatments, including biological agents and immunotherapy, are under investigation. LG-ESSs are indolent tumor with a 5-year overall survival (OS) of 80-100% and present as stage I-II at diagnosis in two third of patients. HG-ESSs carry a poor prognosis, with a median OS ranging from 11 to 24 months, and 70% of patients are in stage III-IV at presentation. UUS median OS ranges from 12 to 23 months and, at diagnosis, 70% of patients are in stage III-IV. The aim of this review is to assess the clinical, pathological, and biological features and the therapeutic options for malignant ESTs.

Consensus statements and treatment algorithm to guide clinicians in the selection of maintenance therapy for patients with newly diagnosed, advanced ovarian carcinoma: Results of a Delphi study.

INTRODUCTION: Standard treatment of newly diagnosed, advanced ovarian carcinoma (OC) consists of cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab. Maintenance therapy with PARP inhibitors and olaparib-bevacizumab has recently shown to significantly improve progression-free survival in the first-line setting. Some practical aspects of maintenance therapy, however, are still poorly defined. AIM OF THE STUDY: To provide guidance to clinicians in the selection of maintenance therapy for newly diagnosed, advanced ovarian carcinoma. METHODS: A board of six gynecologic oncologists with expertise in the treatment of OC in Italy convened to address issues related to the new options for maintenance treatment. Based on scientific evidences, the board produced practice-oriented statements. Consensus was reached via a modified Delphi study that involved a panel of 22 experts from across Italy. RESULTS: Twenty-seven evidence- and consensus-based statements are presented, covering the following areas of interest: use of biomarkers (BRCA mutations and presence of homologous recombination deficiency); timing and outcomes of surgery; selection of patients eligible for bevacizumab; definition of response to treatment; toxicity and contraindications; evidence of synergy of bevacizumab plus PARP inhibitor. Two treatment algorithms are also included, for selecting maintenance therapy based on timing and outcomes of surgery, response to platinum-based chemotherapy and biomarker status. A score for the assessment of response to chemotherapy is proposed, but its validation is ongoing. CONCLUSIONS: We provide here consensus statements and treatment algorithms to guide clinicians in the selection of appropriate and personalized maintenance therapy in the first-line setting of advanced OC management.

Molecular Characterization of Peritoneal Involvement in Primary Colon and Ovary Neoplasm: The Possible Clinical Meaning of the P2X7 Receptor-Inflammasome Complex.

INTRODUCTION: Colon cancer (CC) and epithelial ovarian cancer (EOC) are common and severe neoplasms frequently sharing a massive inflammatory involvement of peritoneum. A detailed molecular characterization of such carcinomatosis has not been performed, so far. METHODS: Omental adipocytes were isolated from thirty-three adult women who underwent primary surgery for CC or EOC. Expression of several pro-inflammatory genes was determined by real-time PCR and immunofluorescence. Data were related to the clinical phenotype of the patients. RESULTS: CD68, FGFR1, and IL-6 were significantly more expressed in adipocytes from CC patients and VEGF in adipocytes from EOC. TNFα, TGFß, or MCP-1, as well as the pro-inflammatory platform P2X7R-NLRP3, did not differ between the 2 cancers. White blood cell count, mirroring systemic inflammation, was related to adipocyte P2X7R (R = 0.508, p = 0.003), NLRP3 (R = 0.405; p = 0.02), and MCP-1 (R = 0.448; p = 0.009). P2X7R and NLRP3 were the only inflammatory factors significantly more expressed in patients carrying both omental and peritoneal carcinosis, who were also characterized by a higher leukocytosis. None of the tested inflammatory markers was associated with tumor grading for both neoplasms; however, the presence of metastases was associated with a higher adipocyte expression of FGFR1 and TGFß. CONCLUSION: We show here that rarely measured molecules seem to specifically characterize omental carcinomatosis of CC or EOC, while more common inflammatory agents like TNFα, TGFß, or MCP-1 do not; the P2X7R-NLRP3 complex marks omental and peritoneal carcinosis and is related to circulating white blood cells and MCP-1, involved in monocyte-macrophage tissue infiltration; increased TGFß and FGFR1 characterize the tumoral dissemination.

Observational multicenter Italian study on vulvar cancer adjuvant radiotherapy (OLDLADY 1.2): a cooperation among AIRO Gyn, MITO and MaNGO groups.

BACKGROUND: Adjuvant radiotherapy (aRT) has been shown to reduce the risk of local relapse in vulvar cancer (VC). In this multicentre study (OLDLADY-1.2), several Institutions have combined their retrospective data on VC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of aRT. METHODS: The primary study end-point was the 2-year-local control, secondary end-points were the 2-year-metastasis free-survival, the 2-year-overall survival and the rate and severity of acute and late toxicities. Participating centres were required to fill data sets including age, stage, tumor diameter, type of surgery, margin status, depth of invasion, histology, grading as well technical/dosimetric details of radiotherapy. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. RESULTS: One hundred eighty-one patients with invasive VC from 9 Institutions were retrospectively identified. The majority of patients were stage III (63%), grade 2 (62.4%) squamous carcinoma (97.2%). Positive nodes were observed in 117 patients (64.6%), moreover tumor diameter > 4 cm, positive/close margins and depth of invasion deeper than 5 mm were found in 59.1%, 38.6%, 58% of patients, respectively. Sixty-one patients (33.7%) received adjuvant chemoradiation, and 120 (66.3%) received radiotherapy alone. aRT was started 3 months after surgery in 50.8% of patients. Prescribed volumes and doses heterogeneity was recorded according to margin status and nodal disease. Overall, 42.5% locoregional recurrences were recorded. With a median follow-up of 27 months (range 1-179), the 2-year actuarial local control rate, metastasis free and overall survival were 68.7%, 84.5%, and 67.5%, respectively. In term of safety, aRT leads to a prevalence of acute skin toxicity with a low incidence of severe toxicities. CONCLUSIONS: In the context of aRT for VC the present study reports a broad spectrum of approaches which would deserve greater standardization in terms of doses, volumes and drugs used.

Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial.

BACKGROUND: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.

Endometrial Cancer: When Upfront Surgery Is Not an Option.

Background and Summary: The management of endometrial cancer, in an ever-older population with considerable comorbidity, remains a challenge for gynecological and radiation oncologists. Key Message: The present paper reviews literature data on treatment options for endometrial cancer patients unfit for surgery.

Clear cell carcinoma of the ovary: Epidemiology, pathological and biological features, treatment options and clinical outcomes.

Clear cell carcinoma of the ovary is a rare and distinct histotype of epithelial ovarian carcinomas. Women diagnosed with clear cell carcinomas are usually younger and diagnosed at earlier stages than those with the most common high-grade serous histology. Endometriosis is considered a main risk factor for the development of clear cell carcinoma of the ovary, and it can be considered a precursor of of this tumor, as it is identified in more than 50% of patients with clear cell carcinoma. Different molecular pathways and alterations heve been identified in ovarian clear cell carcinoma, including the most common mutations of AT-rich interaction domain 1A [ARID1A] and phosphatidylinositol-4,5-bisphosphate 3-kinase [PIK3] catalytic subunit alpha [PIK3CA]. The prognosis of patients at early stage is favorable, while patients with advanced or recurrent disease experience a poor oncologic outcomes. Despite a lower rate of responses due to an intrinsic chemoresistance, the treatment strategy for advanced disease resembles the treatment of high-grade serous carcinoma, which includes aggressive cytoreductive surgery and platinum-based chemotherapy. For this reason, the role of adjuvant chemotherapy in patients with stage I disease undergoing complete surgical staging is still under debate. Alternative treatments, including biological agents that target different pathways constitute the most promising treatment strategies, and well-designed, collaborative international trials should be designed in order to improve the oncologic outcomes and the quality of life of patients with this aggressive disease.

Adjuvant chemotherapy in early-stage endometrioid endometrial cancer with >50% myometrial invasion and negative lymph nodes.

OBJECTIVE: The role of adjuvant chemotherapy as an addition or alternative to radiotherapy for early-stage high-risk endometrioid endometrial cancer is controversial. This study aimed to investigate the role of adjuvant chemotherapy in early-stage high-risk endometrioid endometrial cancer. METHODS: We identified patients with stage I or II endometrioid grade 2 or 3 endometrial cancer with myometrial invasion >50% and negative lymph nodes after pelvic with or without para-aortic lymphadenectomy at four institutions (USA and Italy). Associations between chemotherapy and cause-specific and recurrence-free survival were assessed with Cox proportional hazards models. Hematogenous, peritoneal, and lymphatic recurrences were defined as 'non-vaginal'. RESULTS: We identified 329 patients of mean (SD) age 66.4 (9.8) years. The median follow-up among those alive was 84 (IQR 44-133) months. The 5-year cause-specific survival was 86.1% (95% CI 82.0% to 90.4%) and the 5-year recurrence-free survival was 82.2% (95% CI 77.9% to 86.8%). Stage II (vs stage IB) was associated with poorer cause-specific and recurrence-free survival. A total of 58 (90.6%) of 64 patients who had chemotherapy had 4-6 cycles of platinum-based regimen. In adjusted analysis, we did not observe a statistically significant improvement in cause-specific survival (HR 0.34; 95% CI 0.11 to 1.03; p=0.06) or non-vaginal recurrence-free survival (HR 0.36; 95% CI 0.12 to 1.08; p=0.07) with adjuvant chemotherapy. Sixteen of 18 lymphatic recurrences (88.9%; 3/5 pelvic, all 13 para-aortic) were observed in the 265 patients who did not receive adjuvant chemotherapy. Among stage II patients, no deaths (100% 5-year recurrence-free survival) were observed in the eight patients who received adjuvant chemotherapy compared with 66% 5-year recurrence-free survival in the 34 patients who did not. CONCLUSION: Although we observed that adjuvant chemotherapy was associated with improved oncologic outcomes in early-stage high-risk endometrioid endometrial cancer, the associations did not meet conventional levels of statistical significance. Further research is warranted in this relatively uncommon subgroup of patients.

Thromboembolic events and antithrombotic prophylaxis in advanced ovarian cancer patients treated with bevacizumab: secondary analysis of the phase IV MITO-16A/MaNGO-OV2A trial.

INTRODUCTION: The use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial. METHODS: In this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated. RESULTS: From October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61). CONCLUSIONS: In our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis. TRIAL REGISTRATION NUMBER: NCT01706120.

Bevacizumab, carboplatin, and paclitaxel in the first line treatment of advanced ovarian cancer patients: the phase IV MITO-16A/MaNGO-OV2A study.

OBJECTIVE: To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab. METHODS: A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m2) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints. RESULTS: From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported. CONCLUSIONS: Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors. TRIAL REGISTRATION NUMBER: EudraCT 2012-003043-29; NCT01706120.

Adenoid Cystic Carcinoma of Bartholin's Gland: What Is the Best Approach?

Background and summary: Among all vulvar cancers, primary adenoid cystic carcinoma (ACC) of Bartholin's gland is a very rare tumor characterized by a slow growth, a high local aggressiveness, and a remarkable recurrence rate. Due to its rarity, treatment remains a challenge for oncologists and gynecological surgeons. Key message: The present paper reports clinical, radiological, and histological features of ACC of Bartholin's gland and reviews the literature data on the treatment options with a particular focus on the potential role of particle radiation therapy.

Locally advanced squamous cell carcinoma of the vulva: A challenging question for gynecologic oncologists.

Squamous cell carcinoma of the vulva is a rare female malignancy, with an incidence increasing with age. Unfortunately, one third of the patients are diagnosed with locally advanced disease, which constitutes a clinical challenge for the clinicians who treat these patients. The main challenges are represented by: 1. The primary site of the disease, which can be proximal to anatomical structures like the anal canal posteriorly, or the urethra and the bladder anteriorly, that in some circumstances cannot be spared without a bowel and/or urinary stoma; 2. The locoregional nodes that can be involved by the tumor, and they can be bulky, fixed or ulcerated; 3. The clinical condition of the patient, who may carry several comorbidities. Treatment modalities include radiation with or without chemotherapy, and surgery. In order to preserve the bowel and the urinary function without a permanent stoma, a personalized management with a multimodality approach is warranted. In this systematic review, we first clarify the different definitions of "locally advanced vulvar carcinoma". Secondly, we evaluated the different treatment modalities described in the literature, and the impact of the different treatment strategies on prognosis and on preservation of bowel/urinary function. Finally, we offer a possible algorithm that may help the clinicians in treating patients with these uncommon and challenging situations with a multidisciplinary approach.

Pregnancy-associated cancers: frequency and temporal trends in Italy.

OBJECTIVE: Limited data are available on the frequency and time trends of pregnancy-associated cancers, particularly from Southern European countries. The aim of this study was to analyze the frequency and time trends of pregnancy-associated cancer in Italy. METHODS: This was a population-based linkage study using the regional hospital discharge forms database of four Italian regions with more than 17 million inhabitants. All resident women with a hospital discharge form reporting a birth or abortion in the time period under consideration were identified. The time period of the study was 2003-2015 for the Piemonte and Puglia region, 2006-2015 for the Tuscany region, and 2005-2015 for the Veneto region. Risk of developing a pregnancy-associated cancer was calculated as the ratio of the number of pregnancy-related cancers to the total number of pregnancies. RESULTS: A total of 2 297 648 pregnancies were identified. Overall, the pregnancy-associated cancer frequency was 134.8 per 100 000 pregnancies: the frequency ranged from 127.1 in Puglia to 157.3 in Tuscany. The frequency for 100 000 pregnancies was 66.4 in women aged <30 years; the risk increased with age, with a frequency of 275.6 among women aged 40+ years. Approximately two-thirds of cancers were associated with pregnancies resulting in a delivery and one-third with pregnancies resulting in a termination of pregnancy or spontaneous pregnancy loss. No clear trend emerged in the risk of pregnancy-associated cancer per 100 000 pregnancies and calendar year. CONCLUSION: No clear time trend was observed in the frequency of pregnancy-associated cancers in Italy during the last 10 years, the rates being 104, 164, and 130 per 100 000 pregnancies, respectively, in 2003, 2010, and 2015.

Patterns of Failures and Clinical Outcome of Patients with Early-Stage, High-Risk, Node-Negative Endometrial Cancer Treated with Surgery Followed by Adjuvant Platinum-Based Chemotherapy and Vaginal Brachytherapy.

OBJECTIVE: To assess the clinical outcome of patients with high-risk early-stage endometrial cancer and negative pelvic nodes who received adjuvant platinum-based chemotherapy plus vaginal brachytherapy (VBT). METHODS: This investigation assessed 80 patients who underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy for stage Ib-II, grade 2-3 endometrioid (n = 43) or stage Ia-II nonendometrioid (n = 37) endometrial cancer. RESULTS: Five-year local control rate, 5-year disease-free survival, and 5-year overall survival were 97, 87, and 97%, respectively, for endometrioid carcinoma, and 66, 50, and 72%, respectively, for nonendometrioid carcinoma. CONCLUSIONS: This retrospective study appears to show that adjuvant platinum-based chemotherapy plus VBT achieve very good results in endometrioid carcinoma. This combined treatment seems to be less effective in nonendometrioid carcinoma.

Uterine smooth muscle tumors of unknown malignant potential: A challenging question.

Uterine smooth muscle tumors of unknown malignant potential [STUMP]s are neoplasms with pathological features that preclude an equivocal diagnosis of leiomyosarcoma, but that do not fulfill the criteria for leiomyoma or its variants, and raise concerns that the tumors may behave in a malign fashion. Total hysterectomy with or without bilateral salpingo-oophorectomy is the standard treatment if fertility is completed, whereas myomectomy alone can be taken into consideration in young patients who desire to preserve childbearing potential. A careful surveillance every 6 months for 5 years and then yearly is strongly warranted. Patients with STUMP can relapse as either STUMP or leiomyosarcoma in approximately 11-13% of the cases, and their 5-year overall survival ranges from 92 to 100%. The present paper reviews the clinicopathological features of uterine STUMPs with a particular focus on most commonly accepted histopathological criteria for the diagnosis and on biological behaviour of these controversial neoplasms.

Placental site trophoblastic tumor and epithelioid trophoblastic tumor: Clinical and pathological features, prognostic variables and treatment strategy.

Placental site trophoblastic tumor [PSTT] and epithelioid trophoblastic tumor [ETT] are the rarest gestational trophoblastic neoplasias, developing from intermediate trophoblast of the implantation site and chorion leave, respectively. PSTT and ETT share some clinical-pathological features, such as slow growth rates, early stage at presentation, relatively low ßhCG levels and poor response to chemotherapy. The mortality rate ranges from 6.5% to 27% for PSTT and from 10% to 24.2% for ETT. Advanced stage, long interval between antecedent pregnancy and diagnosis, and presence of clear cells are the independent prognostic variables for PSTT, and they may be similar for ETT. Hysterectomy can represent the only therapy for early disease, whereas adjuvant chemotherapy should be reserved to patients with poor risk factors, such as an interval from the antecedent pregnancy >4 years, deep myometrial invasion or serosal involvement. Few cases of fertility-sparing treatment in young women have been reported. An individualized multidisciplinary approach, including chemotherapy and debulking surgery with abdominal and/or extra-abdominal procedures, is warranted for advanced disease. EP/EMA and TP/TE are the preferred regimens in this setting. Immunohistochemistry has sometimes shown expression of EGFR, VEGF, MAPK, PDGF-R and PD-L1, and therefore investigational studies on biological agents targeting these molecules are strongly warranted for chemotherapy resistant-disease.

Secondary cytoreductive surgery in recurrent uterine leiomyosarcoma: a multi-institutional study.

INTRODUCTION: Uterine leiomyosarcoma (uLMS) represents a rare gynecological malignancy with high incidence of recurrence. Evidence in literature about the management of recurrent uLMS is limited, and the role of secondary cytoreduction has been evaluated in small and heterogeneous populations. The objective of this study is to assess the prognostic role of secondary cytoreductive surgery and its related complications in a large and homogeneous group of patients. METHODS: All consecutive patients who underwent surgery for recurrent uLMS between 01/2010-01/2018 at four Italian tertiary referral centers, were included. Relevant demographic and clinico-pathologic data were retrieved. Survival curves were estimated by Kaplan-Meier method and compared by log-rank test. Cox-proportional hazard model was used to assess the effect of the most predictive prognostic variables. RESULTS: 38 patients with recurrent uLMS were treated with secondary cytoreductive surgery in the study period. Recurrence presented as isolated disease in 17 (44.7%) cases. Bowel, bladder and upper abdominal surgery was performed in 50.0%, 18.4% and 28.9% of the cases, respectively. No residual tumor was the final surgical result in 35 (92.1%) patients. Median hospital stay was 7 days (range, 1-24). No women had major intra-operative and 4 (33.3%) had major post-operative complications. No patient died within 30-days from the secondary cytoreduction. Median time to the first cycle of adjuvant chemotherapy was 41-days (range, 29-78). Median recurrence-free survival was 16.0months (95%CI,11.6 to 26.1). 5-year overall survival (OS) was 76% (95%CI,53 to 89%). Time to first recurrence >12months significantly affected OS (p=0.04). DISCUSSION: Secondary cytoreduction in recurrent uLMS often requires complex and extensive surgical procedures. Referral to tertiary centers guarantees low peri-operative morbidity, short length of hospitalization and median time to chemotherapy within the standard of care. Therefore, secondary cytoreduction to no residual disease is an option that may be considered in recurrent uLMS, especially in patients with time to first recurrence >12months.

A case report of endorectal displacement of a right ureteral stent following radiochemotherapy and Bevacizumab.

BACKGROUND: The angiogenesis inhibitor monoclonal antibody Bevacizumab is presently the standard treatment for numerous neoplasms but particular toxicities are emerging, such as hypertension, haemorrhage, thromboembolism, gastrointestinal perforation, fistulae, and delayed wound healing. The addition of Bevacizumab to radio and chemotherapy has improved the overall survival rate in patients with metastatic, persistent or recurrent cervical carcinoma. However an increased risk of enteric or urinary fistula formation has been documented, related to hypoxia which is induced by the inhibition of angiogenesis. Moreover, previous pelvic surgery, repeated ureteral stenting and radiation are additional risk factors. CASE PRESENTATION: We describe the remarkable case of a right ureteral stent displacement inside the rectum lumen in a patient treated with Bevacizumab for pelvic recurrence of cervical cancer. The patient was referred to our Urology Department with urinary sepsis and bilateral hydronephrosis. Right ureteral stent substitution was planned; at cystoscopy the distal loop of the stent was not visualized inside the bladder. The presence of the distal loop of the right ureteral inside the rectum was clearly demonstrated with a CT scan. CONCLUSIONS: Since Bevacizumab is increasingly used in the treatment of gynaecological neoplasms and indwelling ureteral stents are often required to treat or prevent ureteral compressions, similar cases are likely to be diagnosed and this complication should be considered in the management of advanced pelvic cancers.

Angiosarcomaafteradjuvantradiotherapy in high-risksquamouscell carcinoma of the vulva: a case report.

Squamous cell carcinoma of the vulva represents 3-5% of gynecological cancers. The incidence is higher in postmenopausal patients; the mean age of women with vulvar cancer is between 64 and 70 years. Radiotherapy plays an increasing role in the treatment of high-risk squamous cell carcinoma of the vulva; associated with surgery it significantly improves prognosis but is also associated with serious late side-effects, such as secondary malignancies. We describe a case of a 75-year-old woman who underwent deep total vulvectomy with inguinal-femoral lymphadenectomy for high-risk, keratinizing variant HPV-negative, squamous cell carcinoma of the vulva, followed by adjuvant concomitant chemo-radiotherapy, at the University Hospital of Pisa in February 2013. Five years later she developed a very large angiosarcoma in the right abdominal wall, at the edge of the previous radiotherapy field, and underwent radical surgery. After four months, she developed bone metastasis of angiosarcoma, also treated with surgery. This experience shows that the use of new technologies allows the delivery of high doses of radiotherapy, significantly correlated with a better prognosis, but also associated with fortunately rare morbidity, such as radiation-induced angiosarcoma. Due to the presence of long, mostly post-menopausal survivors among irradiated patients, screening for second malignancies must be developed for selected high-risk survivor groups.