Francesco Raspagliesi

Neoadjuvant Chemotherapy and Radical Surgery Versus Exclusive Radiotherapy in Locally Advanced Squamous Cell Cervical Cancer: Results From the Italian Multicenter Randomized Study

PURPOSE Neoadjuvant chemotherapy (NACT) and radical surgery (RS) have emerged as a possible alternative to conventional radiation therapy (RT) in locally advanced cervical carcinoma. In 1990, a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity. PATIENTS AND METHODS Patients with squamous cell, International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study. They received cisplatin-based NACT followed by RS (type III to V radical hysterectomy plus systematic pelvic lymphadenectomy) (arm A) or external-beam RT (45 to 50 Gy) followed by brachyradiotherapy (20 to 30 Gy) (arm B). RESULTS Of 441 patients randomly assigned to NACT+RS or RT, eligibility was confirmed in 210 and 199 patients, respectively. Treatment was administered according to protocol in 76% of arm A patients and 72% of arm B patients. Adjuvant treatment was delivered in 48 operated patients (29%). There was no evidence for any significant excess of severe morbidity in one of the two arms. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.9% and 55.4% for arm A and 44.5% and 41.3% for arm B (P =.007 and P =.02), respectively. Subgroup survival analysis shows OS and PFS rates of 64.7% and 59.7% (stage IB2-IIB, NACT+RS), 46.4% and 46.7% (stage IB2-IIB, RT) (P =.005 andP =.02), 41.6% and 41.9% (stage III, NCAT+RS), 36.7% and 36.4% (stage III, RT) (P =.36 and P =.29), respectively. Treatment had a significant impact on OS and PFS. CONCLUSION Although significant only for the stage IB2 to IIB group, a survival benefit seems to be associated with the NACT+RS compared with conventional RT.

Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial.

BACKGROUND Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. METHODS For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. FINDINGS 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). INTERPRETATION Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. FUNDING Amgen.

Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion in the treatment of recurrent epithelial ovarian cancer: a phase II clinical study.

Aims and Background The optimal salvage therapy for recurrent ovarian carcinoma has not been clearly established. Response to second-line chemotherapy is low, with a short median survival (8.8-15 months). We investigated the effect of an aggressive approach consisting of surgery followed by intraperitoneal drug delivery and local hyperthermia. Patients and Methods In a phase II clinical study, 27 patients with advanced/recurrent ovarian carcinoma were treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Median patient age was 53 years (range, 30-67) and mean follow-up was 17.4 months (range, 0.3-36.0). Patients had been surgically staged and heavily pretreated with cisplatin-based, taxol-based or taxol/platinum-containing regimens. Nineteen (70%) patients were cytoreduced to minimal residual disease <2.5 mm. The intraperitoneal hyperthermic perfusion was performed with the closed abdomen technique, using a preheated polysaline perfusate containing cisplatin (25 mg/m2/L) + mitomycin C (3.3 mg/m2/L) through a heart-lung pump (mean flow of 700 mL/min) for 60 min in the hyperthermic phase (42.5 °C). Results Two-year overall survival was 55%. Median times to overall progression and local progression were 16 months and 21.8 months, respectively. Variables that affected the overall survival or time to progression were as follows: residual disease (P = 0.00025), patient age (P = 0.04), and lag time between diagnosis and cytoreductive surgery + intraperitoneal hyperthermic perfusion (P = 0.04). Treatment-related morbidity, mortality and acute toxicity (grade II-III) rates were 11%, 4% and 11%, respectively. Eight (89%) of 9 patients had ascites resolution. Conclusion Our results suggest that cytoreductive surgery + intraperitoneal hyperthermic perfusion is a well-tolerated, feasible and promising alternative in the management of selected patients with recurrent ovarian cancer, but further randomized controlled studies are needed in order to confirm our findings.

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

Epithelial ovarian cancer (EOC) is the gynecological disease with the highest death rate. We applied an automatic class discovery procedure based on gene expression profiling to stages III–IV tumors to search for molecular signatures associated with the biological properties and progression of EOC. Using a complementary DNA microarray containing 4451 cancer-related, sequence-verified features, we identified a subset of EOC characterized by the expression of numerous genes related to the extracellular matrix (ECM) and its remodeling, along with elements of the fibroblast growth factor 2 (FGF2) signaling pathway. A total of 10 genes were validated by quantitative real-time polymerase chain reaction, and coexpression of FGF2 and fibroblast growth factor receptor 4 in tumor cells was revealed by immunohistochemistry, confirming the reliability of gene expression by cDNA microarray. Since the functional relationships among these genes clearly suggested involvement of the identified molecular signature in processes related to epithelial–stromal interactions and/or epithelial–mesenchymal cellular plasticity, we applied supervised learning analysis on ovarian-derived cell lines showing distinct cellular phenotypes in culture. This procedure enabled construction of a gene classifier able to discriminate mesenchymal-like from epithelial-like cells. Genes overexpressed in mesenchymal-like cells proved to match the FGF2 signaling and ECM molecular signature, as identified by unsupervised class discovery on advanced tumor samples. In vitro functional analysis of the cell plasticity classifier was carried out using two isogenic and immortalized cell lines derived from ovarian surface epithelium and displaying mesenchymal and epithelial morphology, respectively. The results indicated the autocrine, but not intracrine stimulation of mesenchymal conversion and cohort/scatter migration of cells by FGF2, suggesting a central role for FGF2 signaling in the maintenance of cellular plasticity of ovary-derived cells throughout the carcinogenesis process. These findings raise mechanistic hypotheses on EOC pathogenesis and progression that might provide a rational underpinning for new therapeutic modalities.

Combined preoperative chemoradiotherapy followed by radical surgery in locally advanced vulvar carcinoma: A pilot study

Although for decades exenterative surgery has represented the standard treatment for patients with locally advanced vulvar cancer, combined approaches, including preoperative radiation with or without chemotherapy, are now considered the treatment of choice. We report the results of a pilot study on concurrent chemoradiotherapy followed by radical surgery for patients with locally advanced squamous cell carcinoma of the vulva.

A systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer.

INTRODUCTION The prognosis of advanced/recurrent cervical cancer patients is generally poor with 1-year survival ranging between 15 and 20%. Cisplatin (CDDP) based treatments are considered the most effective regimens; unfortunately toxicity is an issue in a population in which the treatment remains palliative in the finality. Carboplatin (CBDCA), with its more favorable non toxicity profile and the convenience of outpatient administration, may be a suitable alternative to CDDP in combination regimens. MATERIALS AND METHODS We performed a systematic review of the literature comparing CDDP and CBDCA based chemotherapy for advanced cervical cancer (recurrent, persistent or metastatic disease). Only studies that met the following criteria were considered for the present review: 1) patients treated with CDDP/paclitaxel or CBDCA/paclitaxel combinations as first line chemotherapy for metastatic disease; 2) one or more of the following data available: overall response rate (RR), progression free survival (PFS) or time to progression (TTP), overall survival (OS); 3) single-arm retrospective or prospective study; and 4) at least 20 patients enrolled. RESULTS 17 eligible studies comprehensive of 1181 patients were included in the final analysis. The objective RR was 48.5% for CBDCA and 49.3% for CDDP-based chemotherapy. Median PFS for CDDP and CBDCA-based treatments was 6.9months and 5months respectively (p=0.03); the corresponding figures for median OS were 12.87 and 10months respectively (p=0.17). DISCUSSION Our study indicates that CBDCA may represent an attractive and valid alternative to the more toxic and equally effective CDDP in the treatment of advanced or recurrent cervical cancer.

Trabectedin in advanced uterine leiomyosarcomas: A retrospective case series analysis from two reference centers

BACKGROUND Treatment options for patients with metastatic uterine leiomyosarcoma are limited. Over the last few years, trabectedin has emerged as an effective agent for patients with advanced soft tissue sarcomas resistant to anthracyclines and ifosfamide. The aim of this retrospective analysis was to look at the efficacy of trabectedin in the subgroup of uterine leiomyosarcoma. PATIENTS AND METHODS A retrospective analysis was carried out on patients with uterine leiomyosarcoma treated with trabectedin at two reference sarcoma centers between 2000 and 2010. Radiological response, progression-free and overall survival, as well as serious and unexpected adverse events, were assessed. RESULTS Sixty-six patients with metastatic uterine leiomyosarcoma were identified. The median number of previous chemotherapy regimens was 3 (range 1-5). Eleven patients (16%) achieved a partial response and 23 (35%) had a stable disease. The progression-free survival of the entire cohort was 3.3 months (CI 95% 2-5), and the progression-free rate at 3 and 6 months was 53% and 33%, respectively. CONCLUSIONS Trabectedin is a therapeutic option in the palliative approach to the metastatic uterine leiomyosarcoma patient.

13 Pelvic and para-aortic lymphadenectomy in cancer of the ovary

The role of the lymphadenectomy in ovarian carcinoma is widely discussed. The natural history of disease, its tendency to spread to peritoneal cavity and the lack of any reported series of careful node dissections undertaken during surgical exploration has made it difficult to establish the real significance of nodal metastatization and the optimal therapeutic approach for patients with positive nodes. At the Istituto Nazionale Tumori, Milan, 341 patients with ovarian carcinoma have been subjected to lymph node dissection. In 253 cases in which lymphadenectomy has been carried out during first surgery, the lymphonodal diffusion has been evaluated by stage, grading and histology. The incidence of lymphonodal metastases increased with the diffusion of the primitive tumour and this is particularly evident for the serous adenocarcinoma. From our data (as shown in our series of 173 cases Stage III with peritoneal and retroperitoneal diffusion) the lymphonodal involvement has to be considered as a negative prognostic factor, influencing survival in a statistically significant way. In the 88 patients subjected to radical lymphadenectomy during second-look surgery, after chemotherapy, a smaller percentage of positive nodes was observed as compared to untreated cases but, on the other hand, we documented a portion of positive nodes not sterilized by sistemic therapy. All this data confirm the necessity to perform radical lymphadenectomy not only as a staging procedure (because of low sensitivity of lymphangiography) but also as a therapeutic one for some patients.

Diagnostic accuracy of sentinel node in endometrial cancer by using hysteroscopic injection of radiolabeled tracer

OBJECTIVE Retrospective and perspective series have shown the feasibility of sentinel lymph-node (SLN) identification of pelvic nodes in endometrial cancer using a cervical injection of tracers. We designed a perspective study to assess the detection rate and diagnostic accuracy of the SLN procedure by means of hysteroscopic injection of a radiolabeled tracer in endometrial cancer patients. METHODS Patients with endometrial cancer underwent hysteroscopic technetium injection. SLN assessment was performed intraoperatively. A systematic pelvic and paraaortic dissection was carried out thereafter. SLNs were examined by standard and immunochemistry methods. The primary endpoint was estimation of sensitivity and negative predictive value (NPV) of sentinel-node biopsy. RESULTS From 2005 to 2010, 80 consecutive patients entered the study. No severe complications occurred during or after the injection or during surgical SLN biopsy. At least one SLN was detected in 76 of the 80 eligible patients. Fifty nine patients were evaluable according to the study protocol. Ten of these patients (17%) had node metastases. Thirty-three patients (56%) had SLN in the para-aortic area. NPV was 98% (95% CI 89.4-100) and sensitivity 90% (55.5-99.8). CONCLUSIONS SLN detection for endometrial cancer patients has a high sensitivity and NPV when injection is carried out by hysteroscopy. The occurrence of a 56% of sentinel node in paraaortic area may suggest a better sensitivity in this area using hysteroscopic injection compared to cervical injection.

New classification system of radical hysterectomy: Emphasis on a three-dimensional anatomic template for parametrial resection

OBJECTIVE The international acceptance of a universal classification system for radical hysterectomy is one of the important challenges in gynecologic oncology. The recently published classification system by Querleu and Morrow is a relevant proposal that has been well received by the professional community. However, it does not include a description of parametrial resection in three dimensions, which mostly determines post-operative morbidity. METHODS The intention of this follow-up paper was to further develop the classification system based on the four proposed types of radical hysterectomy (A-D) into a three-dimensional model using standard anatomical landmarks for definition of resection margins in longitudinal and transverse dimensions and demonstrate it on pictures. RESULTS Resection margins were defined in longitudinal and transverse dimensions for each suggested type of radical hysterectomy on all three parts of the parametria. Besides precise description using stable anatomical landmarks, all resection lines have been shown on intra-operative photographs. CONCLUSION Four types of radical hysteretomy can be precisely defined on a three-dimensional anatomical template, including nerve sparing procedure. Our paper should contribute to better standardization (including nomenclature) of the radical hysterectomy, enhancing harmonization of clinical practice in gynecological oncology.