Tiziana Dell'Anna

Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis

No randomised trials have addressed the value of systematic aortic and pelvic lymphadenectomy (SL) in ovarian cancer macroscopically confined to the pelvis. This study was conducted to investigate the role of SL compared with lymph nodes sampling (CONTROL) in the management of early stage ovarian cancer. A total of 268 eligible patients with macroscopically intrapelvic ovarian carcinoma were randomised to SL (N=138) or CONTROL (N=130). The primary objective was to compare the proportion of patients with retroperitoneal nodal involvement between the two groups. Median operating time was longer and more patients required blood transfusions in the SL arm than the CONTROL arm (240 vs 150 min, P<0.001, and 36 vs 22%, P=0.012, respectively). More patients in the SL group had positive nodes at histologic examination than patients on CONTROL (9 vs 22%, P=0.007). Postoperative chemotherapy was delivered in 66% and 51% of patients with negative nodes on CONTROL and SL, respectively (P=0.03). At a median follow-up of 87.8 months, the adjusted risks for progression (hazard ratio [HR]=0.72, 95%CI=0.46–1.21, P=0.16) and death (HR=0.85, 95%CI=0.49–1.47, P=0.56) were lower, but not statistically significant, in the SL than the CONTROL arm. Five-year progression-free survival was 71.3 and 78.3% (difference=7.0%, 95% CI=–3.4–14.3%) and 5-year overall survival was 81.3 and 84.2% (difference=2.9%, 95% CI=−7.0–9.2%) respectively for CONTROL and SL. SL detects a higher proportion of patients with metastatic lymph nodes. This trial may have lacked power to exclude clinically important effects of SL on progression free and overall survival.

Randomized Controlled Trial of Single-Agent Paclitaxel Versus Cyclophosphamide, Doxorubicin, and Cisplatin in Patients With Recurrent Ovarian Cancer Who Responded to First-Line Platinum-Based Regimens

PURPOSE To assess the activity, efficacy, and tolerability of single-agent paclitaxel and a platinum-containing regimen in previously treated patients with recurrent ovarian cancer. PATIENTS AND METHODS Patients who achieved complete remission with platinum-based regimens and whose disease recurred after a progression-free interval of more than 12 months were included in the study. Every 21 days, patients received paclitaxel 175 mg/m(2) intravenously (IV) over 3 hours or cyclophosphamide 500 mg/m(2), doxorubicin 50 mg/m(2), and cisplatin 50 mg/m(2) (CAP) IV. RESULTS Between June 1992 and May 1995, 97 consecutive patients with assessable or measurable disease were randomized to paclitaxel (n = 50) or CAP (n = 47). The median number of cycles on each arm was six. Toxicities included grade 3/4 leukopenia (4% for paclitaxel v 34% for CAP), grade 3/4 neutropenia (13% v 36%), grade 1/2 myalgia (19% v 4%), allergic reactions (15% v 2%), and grade 2/3 nausea and vomiting (17% v 51%). Complete responses were achieved in 17% and 30% of patients receiving paclitaxel and CAP, respectively, and partial responses were achieved in 28% and 25%, respectively (P =.062). At a median follow-up time of 49 months, median progression-free intervals were 9 months for paclitaxel and 15.7 months for CAP (Cox analysis: hazards ratio [HR], 0.60; 95% confidence interval [CI], 0.37 to 0.97; P =.038); median overall survival times were 25.8 months for paclitaxel and 34.7 months for CAP (Cox analysis: HR, 0.58; 95% CI, 0.34 to 0.98; P =.043). CONCLUSION Rechallenge with either single-agent paclitaxel or platinum-based chemotherapy is effective in this patient population. Preliminary results suggest that single-agent paclitaxel may not be as active as platinum-based chemotherapy in recurrent ovarian cancer. Larger randomized trials are needed.

Role of the integrated FDG PET/CT in the surgical management of patients with high risk clinical early stage endometrial cancer: Detection of pelvic nodal metastases

BACKGROUND High risk clinical stage I endometrial cancer (grade 2 and deep myometrial invasion, grade 3 and serous and clear-cell carcinoma) had 10-35% of nodal involvement. Surgical staging is considered reasonable in this setting of women, although unnecessary in 70-90%. The purpose of this study was to determine prospectively the diagnostic accuracy of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography 18F-FDG PET/CT in the detection of nodal metastases in patients with high risk endometrial cancer. METHODS Eleven women with grade 2 and deep myometrial invasion and 26 with grade 3 endometrial cancer underwent 18F-FDG PET/CT, followed by total hysterectomy, bilateral salpingo-oophorectomy and systematic pelvic lymphadenectomy. Histopathological findings served as the reference standard. Diagnostic performance of 18F-FDG PET/CT in nodal disease detection was reported in terms of accuracy value both in a patient-based and a lesion site-based analysis. RESULTS Pelvic nodes metastases were found at histopathological analysis in 9 of the 37 patients (24.3%). Patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG PET/CT for detection of nodal disease were 77.8%, 100.0%, 100.0%, 93.1% and 94.4%, respectively. Nodal lesion site-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG PET/CT were 66.7%, 99.4%, 90.9%, 97.2% and 96.8%, respectively. CONCLUSION This study shows that 18F-FDG PET/CT is an accurate method for the presurgical evaluation of pelvic nodes metastases. The high negative predictive value may be useful in selecting patients who only may benefit from lymphadenectomy, minimizing operative and surgical complications.

Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in patients with Ib1 stage cervical cancer: Analysis of surgical and oncological outcome

AIM To evaluate safety, feasibility and oncological outcome of total laparoscopic radical hysterectomy (TLRH) in patients with early invasive cervical cancer. METHODS Data of patients with Ib1 cervical cancer who underwent TLRH were prospectively collected. Inclusion criteria were: good general condition, tumor size <3 cm, and no evidence of lymph node metastases in imaging study (MRI and/or CT and/or PET). Radical hysterectomy was performed with a PlasmaKinetic tissue management system. Adjuvant therapy was administered according to surgical risk factors. RESULTS Between September 2001 and October 2007 107 patients underwent laparoscopic radical hysterectomy and pelvic lymphadenectomy. Conversion to laparotomy was necessary in 6 patients. Median number of resected pelvic lymph nodes was 26. Median blood loss was 200 ml and median duration of surgery was 305 min. Minor intraoperative complications were registered in two patients, while five patients needed a second surgery for postoperative complications. Thirteen patients had microscopic nodal metastasis. A total of 24 patients received adjuvant therapy. After a median follow-up of 30 months 11 patients had a recurrence; survival rate is 95%. CONCLUSION Total laparoscopic radical hysterectomy, in experienced hands, has to be considerate an adequate and feasible surgical technique. Considering historical data the oncological outcome can be considered comparable to patients treated with laparotomy, as the relapse rate in our population was 11% and the overall survival good.

Simple conization and lymphadenectomy for the conservative treatment of stage IB1 cervical cancer. An Italian experience.

OBJECTIVES Simple conization represents a plausible treatment scheme for managing stage IA1-2 tumors conservatively. However its curative potential has not been widely exploited as regards stage IB1 lesions. Recent studies suggest that, in selected circumstances, patients with stage IB1 disease undergoing radical hysterectomy could have been safely cured by simple hysterectomy and even by cervical conization. METHODS Patients with stage IB1 cervical cancer desiring conservative management underwent simple conization and pelvic lymphadenectomy in three Italian institutes. RESULTS Thirty-six women received the conservative treatment since 1995 to 2010. Median age was 31 (range 24-40) years and median tumor size was 11.7 mm (range 8-25 mm). Adenocarcinoma was present in 12 cases (33%) and grade 3 neoplasia in 5 (14%). Lymph-vascular space involvement was detected in five patients (14%). Eleven had already a child while two had experienced an early abortion and a fetal loss at second trimester. After a median follow-up of 66 months (range 6-168) only one pelvic lymphnodal relapse was observed. Twenty-one pregnancies occurred in 17 patients and 14 live babies have been born (two preterm at 27 and 32 weeks) while one is ongoing. Three first-trimester miscarriages, one second-trimester fetal loss, an ectopic pregnancy and a termination of pregnancy have been recorded. Five patients decided to undergo hysterectomy after 3-12 years after conservative therapy: in one residual microinvasive adenocarcinoma was found. CONCLUSIONS Cervical conization represents a feasible conservative management of stage IB1 cervical cancer and shows a low risk of relapse, provided that patients are selected carefully. Conization would be suitable to treat stage IB lesions smaller than 15-20mm. with pathologic negative lymphnodes.

Decreased hypersensitivity reactions with carboplatin-pegylated liposomal doxorubicin compared to carboplatin-paclitaxel combination: Analysis from the GCIG CALYPSO relapsing ovarian cancer trial

OBJECTIVE To describe and analyze observed hypersensitivity reactions (HSR) from the randomized, multicenter phase III CALYPSO trial that evaluated the efficacy and safety of the combination of carboplatin and pegylated liposomal doxorubicin (CD) compared with standard carboplatin-paclitaxel (CP) in patients with platinum-sensitive relapsed ovarian cancer (ROC). METHODS HSR documented within case report forms and SAE reports were specifically analyzed. Analyses were based on the population with allergy of any grade and for grade >2 allergy. RESULTS Overall 976 patients were recruited to this phase III trial, with toxicity data available for 466 and 502 on the CD and CP arms, respectively. There was a 15.5% HSR rate associated with CD (2.4% grade >2) versus 33.1% with CP (8.8% grade >2), p<0.001. HSRs occurred more often during first cycle in the CD (46%) arm than in the CP arm (16%). Multivariate predictors of allergy were chemotherapy regimen and age; patients randomized to CD and patients ≥ 70 years old on CP had less allergy. Few patients (<6%) stopped treatment due to allergy. Allergy rates were higher in patients who did not receive prior supportive treatment; however there was no relationship between allergy and the type of carboplatin product received, or response rate. CONCLUSIONS Use of PLD with carboplatin instead of paclitaxel and older age were the only 2 factors predicting a low rate of HSRs in patients with ROC. CD has previously demonstrated superior progression-free survival and therapeutic index than CP. Taken together these data support the use of CD as a safe and effective therapeutic option for platinum-sensitive ROC.

Preoperative staging of cervical cancer: Is 18-FDG-PET/CT really effective in patients with early stage disease?

OBJECTIVE Nodal status is one of the most important findings in patients with early-stage cervical cancer that requires post-surgical adjuvant therapies and influences prognosis of patients. The purpose of this study was to determine the diagnostic accuracy of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) in the detection of nodal metastases. METHODS From 2004 to 2010 women with Ib1-IIa <4cm cervical cancer underwent 18F-FDG-PET/CT followed by radical hysterectomy and pelvic lymphadenectomy in our institution. 18F-FDG-PET/CT images were analyzed and histopathological findings served as the reference standard. Diagnostic performance of 18F-FDG-PET/CT in nodal disease detection was reported in terms of accuracy value. A sub analysis of women with tumor diameter <2cm (group 1) or 2-4cm (group 2) was performed in order to verify the efficacy of 18F-FDG-PET/CT in each group. RESULTS One hundred fifty-nine women were enrolled. 65% had squamous histotype and 51% had grade 3 disease. Median number of nodes dissected was 29 (range 11-61). 28/159 women (18%) showed nodal metastases. Overall patient-based sensitivity, specificity, positive and negative predictive value of 18F-FDG-PET/CT for detection of nodal disease were 32.1%, 96.9%, 69.2%and 87.0% respectively. Among the 97 (61%) women included in group 1, 8 had nodal metastases (8.2%) and 2 was discovered through 18F-FDG-PET/CT (25%), while 20/62 women of the group 2 (32.3%) had nodal involvement, of which 7 (35%) was detected by 18F-FDG-PET/CT. CONCLUSIONS This study showed that 18F-FDG-PET/CT had low sensitivity and had a minimal clinical impact in the pretreatment planning of stage Ib1-IIa <4cm cervical cancer.

Analysis of Gene Expression in Early-Stage Ovarian Cancer

Purpose: Gene expression profile was analyzed in 68 stage I and 15 borderline ovarian cancers to determine if different clinical features of stage I ovarian cancer such as histotype, grade, and survival are related to differential gene expression. Experimental Design: Tumors were obtained directly at surgery and immediately frozen in liquid nitrogen until analysis. Glass arrays containing 16,000 genes were used in a dual-color assay labeling protocol. Results: Unsupervised analysis identified eight major patient partitions, one of which was statistically associated to overall survival, grading, and histotype and another with grading and histotype. Supervised analysis allowed detection of gene profiles clearly associated to histotype or to degree of differentiation. No difference was found between borderline and grade 1 tumors. As to recurrence, a subset of genes able to differentiate relapsers from nonrelapsers was identified. Among these, cyclin E and minichromosome maintenance protein 5 were found particularly relevant, as their expression was inversely correlated to progression-free survival (P = 0.00033 and 0.017, respectively). Conclusions: Specific molecular signatures define different histotypes and prognosis of stage I ovarian cancer. Mucinous and clear cells histotypes can be distinguished from the others regardless of tumor grade. Cyclin E and minichromosome maintenance protein 5, whose expression was found previously to be related to a bad prognosis of advanced ovarian cancer, appear to be potential prognostic markers in stage I ovarian cancer too, independent of other pathologic and clinical variables.

Delivery delay with neoadjuvant chemotherapy for cervical cancer patients during pregnancy: A series of nine cases and literature review

OBJECTIVE Treatment of locally invasive cervical cancer diagnosed during pregnancy in women who desire to retain their pregnancy is a major challenge to physicians. Neoadjuvant chemotherapy followed by radical hysterectomy has been reported to be an attractive option to delay delivery until fetal viability has been reached. METHODS Between 1994 and 2009 9 patients were treated at San Gerardo Hospital (Monza, Italy) for cervical cancer during pregnancy. RESULTS FIGO stage was IB1 in four patients and IB2 in five. Tumor diameter ranged between 20 and 70 mm. After neoadjuvant platinum-based chemotherapy partial response was achieved in 5 patients, while 4 had a stable disease. One patient received a second-line chemotherapy during pregnancy due to progressive disease, achieving a partial response. Median duration of therapy delay until cesarean section was 16 weeks. Between 30 and 36 weeks of gestation all patients underwent cesarean section. Piver II radical hysterectomy with pelvic lymphadenectomy was performed. Two children had mild perinatal morbidities and were discharged in good conditions after 14 and 40 days. Three patients received adjuvant therapy for pathological risk factors. Four patients relapsed (44%) and two of them (23%) died because of tumor progression. CONCLUSION During pregnancy, the oncological outcome of cervical cancer patients is similar to non-pregnant ones. Chemotherapy does not seem to affect fetal health and development, even if longer follow-up is required. Therefore, neoadjuvant chemotherapy for the treatment of locally invasive cervical cancer during pregnancy seems to be a reasonable option for delay definitive treatment until fetal viability is obtained.

Preoperative 18F-FDG PET/CT in the management of advanced epithelial ovarian cancer

OBJECTIVE The introduction of 18-FDG-PET/CT during preoperative evaluation of patients with epithelial ovarian cancer (EOC) has led to an increase of the detection of extra-abdominal metastases. However, the clinical impact of this upstage remains unclear. METHODS Patients with suspected advanced EOC underwent 18-FDG-PET/CT within two weeks prior to debulking surgery. RESULTS Between 2006 and 2011 95 patients met the inclusion criteria. Based on the concordance or the discrepancy of clinical and PET/CT stage, patients were divided into 3 groups (A: clinical and PET III; B: clinical III and PET IV; C: clinical and PET IV). Twenty-five patients were upstaged from FIGO stage III to stage IV by PET/CT. The proportion of patients who achieved a residual tumor <1cm in group B and C was similar, whereas it was significantly lower compared to group A. Similarly, complete response to adjuvant chemotherapy was achieved more frequently in patients in group A. PFS was similar in the three groups (17, 17 and 12 months in group A, B and C), as well as OS (51, 41 and 35 months). CONCLUSIONS PET/CT is able to detect distant metastases in EOC patients. The presence of extra-abdominal disease probably indicates a more aggressive disease which also shows a lower response to standard chemotherapy. However, upstaged patients have a similar prognosis compared to stage III patients, probably because intra-abdominal disease is more likely to lead patients to death. This might also explain why residual tumor is the most important prognostic factor for advanced EOC patients.