Alessandro Buda

Randomized Trial of Neoadjuvant Chemotherapy Comparing Paclitaxel, Ifosfamide, and Cisplatin With Ifosfamide and Cisplatin Followed by Radical Surgery in Patients With Locally Advanced Squamous Cell Cervical Carcinoma: The SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study

PURPOSEnNeoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival.nnnPATIENTS AND METHODSnPatients (n = 219) were randomly assigned to ifosfamide 5 g/m(2) during 24 hours plus cisplatin 75 mg/m(2), or paclitaxel 175 mg/m(2) plus ifosfamide 5 g/m(2) during 24 hours and cisplatin 75 mg/m(2) every 3 weeks for three courses.nnnRESULTSnGrades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%; odds ratio, 3.22; 95% CI, 1.69 to 5.88; P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75; 95% CI, 0.48 to 1.17; P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66; 95% CI, 0.39 to 1.10; P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88; 95% CI, 2.50 to 13.84; P < .0001).nnnCONCLUSIONnThe TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for 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

PURPOSEnTo assess the activity, efficacy, and tolerability of single-agent paclitaxel and a platinum-containing regimen in previously treated patients with recurrent ovarian cancer.nnnPATIENTS AND METHODSnPatients 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.nnnRESULTSnBetween 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).nnnCONCLUSIONnRechallenge 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

BACKGROUNDnHigh 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.nnnMETHODSnEleven 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.nnnRESULTSnPelvic 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.nnnCONCLUSIONnThis 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.

A multicentric trial (Olympia–MITO 13) on the accuracy of laparoscopy to assess peritoneal spread in ovarian cancer

OBJECTIVEnThe objective of the study was to prospectively evaluate the accuracy of laparoscopy performed in satellite centers (SCs) to describe intraabdominal diffusion of advanced ovarian cancer (AOC).nnnSTUDY DESIGNnPatients with a clinical/radiological suspicion of AOC were included in the protocol. SCs were selected among those surgeons, spending a short intensive training period at the coordinator center (CC) to learn the application of staging laparoscopy (S-LPS) in AOC. All women underwent S-LPS at the SCs, and the surgical procedure was recorded and blindly reviewed at the CC. Calculating specificity, positive and negative predictive values, and the accuracy for each parameter with respect to the CC assessed the diagnostic performance of S-LPS. The Cohens kappa was used to test the interobserver agreement of each parameter.nnnRESULTSnOne hundred sixty-eight cases were considered eligible for the study. A per-protocol analysis was performed on 120 cases. The worst laparoscopic assessable feature was mesenteric retraction, whereas the remaining variables ranged from 99.2% (peritoneal carcinomatosis) to 90% (bowel infiltration). All but 1 SC (SC number 4) reached an accuracy rate of 80% or greater for both single parameters and overall score. The Cohens kappa and the P value for overall predicitive index value were 0.685 and .01, respectively, but improved to 0.773 and .388 after removing the SC number 4 from the analysis.nnnCONCLUSIONnS-LPS allows an accurate and reliable assessment of intraperitoneal diffusion of disease in AOC patients in trained gynecological oncology centers.

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

OBJECTIVEnNodal 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.nnnMETHODSnFrom 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.nnnRESULTSnOne 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.nnnCONCLUSIONSnThis 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.

Feasibility and morbidity of total laparoscopic radical hysterectomy with or without pelvic limphadenectomy in obese women with stage I endometrial cancer

ObjectiveThe aim of this study was to describe the feasibility and morbidity rates associated with total laparoscopic radical hysterectomy (TLRH) with or without pelvic lymphadenectomy for stage I endometrial cancer in obese women.Patients and methodsObese patients with stage I endometrial cancer who underwent total laparoscopic radical surgery at the Department of Obstetrics and Gynecology of San Gerardo Hospital were compared to nonobese patients. The same group of obese patients was compared with patients who underwent radical laparotomic surgery. Obesity was defined as a body mass index more than 30xa0kg/m2.ResultsBetween September 2003 and September 2007, 75 women underwent TLRH. Median age was 54xa0years and median body mass index was 28xa0kg/m2. Thirty-seven women were obese.There were no differences between nonobese and obese women in operative, time length of parametria and pelvic nodes removed and operative or late complications. Blood loss was significantly higher in obese patients.Comparing retrospectively laparoscopy and laparotomy in obese women treated in our center, laparotomy was associated with decreased operative time, but also with increased blood loss, transfusion rate, duration of hospitalization and frequency of post surgical complications.ConclusionsTotal laparoscopic radical hysterectomy (with pelvic lymphadenectomy) is a safe option in patients with endometrial cancer. Obesity is not a contraindication to perform a TRLH with no differences in surgical parameters between obese and nonobese population. TLRH show a significant decrease of complications compared to laparotomic radical surgery in obese women.

Detection of nodal metastases by 18F-FDG PET/CT in apparent early stage ovarian cancer: a prospective study

BACKGROUNDnThe rate of nodal metastases in ovarian cancer macroscopically confined to the pelvis is about 15%-20%. Systematic pelvic and aortic lymphadenectomy improves staging but it is associated with increased morbidity and costs. The purpose of this study was to evaluate the role of 18F-FDG PET/CT in the pre-operative nodal metastases detection in ovarian cancer grossly confined to the pelvis.nnnMETHODSnFrom 2006 to 2012, 68 consecutive women with epithelial ovarian cancer confined to the pelvis underwent 18F-FDG PET/CT followed by surgery inclusive of systematic pelvic and aortic lymphadenectomy (SAPL). 18F-FDG PET/CT images were analyzed and correlated to histological examination.nnnRESULTSnTwenty-six women underwent bilateral and 42 unilateral SAPL with 3165 nodes removed and analyzed. Median number of dissected nodes was 42 (range 16-91). Twelve women (17.6%) had nodal metastases. 18F-FDG PET/CT correctly identified 10 patients with nodal involvement. Sensitivity, specificity, accuracy, positive and negative-predictive value of 18F-FDG PET/CT in detecting nodal metastases were 83.3%, 98.2%, 95.6%, 90.9% and 96.5%, respectively, on overall patient-based, and 75.5%, 99.4%, 98.1%, 87.5% and 98.6%, respectively, on nodal lesion site-based analysis.nnnCONCLUSIONn18F-FDG PET/CT is an accurate tool for the detection of nodal metastases. Metabolic imaging could be used to select women who could benefit from systematic lymphadenectomy. The high negative predictive value allows avoidance of SAPL in the vast majority of women, minimizing operative and post surgical complications. Further larger prospective investigation is required to confirm our data.

Systematic lymphadenectomy in ovarian cancer at second-look surgery: A randomised clinical trial

Background:The role of systematic aortic and pelvic lymphadenectomy (SAPL) at second-look surgery in early stage or optimally debulked advanced ovarian cancer is unclear and never addressed by randomised studies.Methods:From January 1991 through May 2001, 308 patients with the International Federation of Gynaecology and Obstetrics stage IA–IV epithelial ovarian carcinoma were randomly assigned to undergo SAPL (n=158) or resection of bulky nodes only (n=150). Primary end point was overall survival (OS).Results:The median operating time, blood loss, percentage of patients requiring blood transfusions and hospital stay were higher in the SAPL than in the control arm (P<0.001). The median number of resected nodes and the percentage of women with nodal metastases were higher in the SAPL arm as well (44% vs 8%, P<0.001 and 24.2% vs 13.3%, P:0.02). After a median follow-up of 111 months, 171 events (i.e., recurrences or deaths) were observed, and 124 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for progression and death were not statistically different (hazard ratio (HR) for progression=1.18, 95% confidence interval (CI)=0.87–1.59; P=0.29; 5-year progression-free survival (PFS)=40.9% and 53.8%; HR for death=1.04, 95% CI=0.733–1.49; P=0.81; 5-year OS=63.5% and 67.4%, in the SAPL and in the control arm, respectively).Conclusion:SAPL in second-look surgery for advanced ovarian cancer did not improve PFS and OS.

Better anatomical and cosmetic results using tunneled lotus petal flap for plastic reconstruction after demolitive surgery for vulvar malignancy.

Objective To evaluate the efficacy of tunneled lotus petal flap in terms of anatomical and cosmetic results in patients who underwent vulvoperineal reconstruction for vulvar malignancy. Methods Between March 2010 and July 2011, 22 women underwent vulvoperineal reconstruction using tunneled lotus petal flap for primary or recurrent disease at San Gerardo Hospital, Monza. In 16 cases, lotus flaps were bilateral, whereas in 6 cases, they were monolateral. Results The median age was 72 years (range, 53–87 years). The mean operating time was 85 minutes. The mean length of follow-up was 10 months (range, 2–16 months). Postoperative complications occurred in 2 patients, including one case of partial flap necrosis and one case of donor site breakdown. Conclusions Tunneled lotus petal flap is safe, easy and fast to perform, has a low rate of complications, and good functional and cosmetic results. This technique represents an optimal solution for plastic reconstruction in case of primary or recurrent vulvar disease, or in case of introital stenosis after primary inadequate closure.

Regarding: "pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging".

To the Editor: W e read with great interest the article of Kim et al,1 which highlights some important challenges of sentinel node (SN) mapping in early-stage endometrial cancer. Taking a cue from the interesting article, wewould like to add some aspects not covered in this valuable article, in particular the role of preoperative imaging using PET/CT and its possible integration in algorithm of SN mapping in women with high-risk early-stage endometrial cancer. Data analysis from 508 women with endometrial cancer demonstrated that SN mapping with pathologic ultrastaging detects additional 4.5% of low-volume metastases that would otherwise go undetected with routine evaluations. The authors’ conclusion recommended the incorporation of pathologic ultrastaging SN in endometrial carcinoma with any degree of myoinvasion. Regardless of those observations, some further questions arise as follows: First question, ‘‘Is there really a commitment to offer lymphadenectomy to all women with preoperative earlystage high-risk endometrial cancer?’’ If we take a look at what happens in breast cancer, it is reasonable to presume that the debate on whether or not performing lymphadenectomy in apparent early-stage endometrial cancer seems at least strange because data from 2 randomized trials and a meta-analysis, even if largely criticized for their flaws in design and conduction reducing the strength of their results, failed to demonstrate apparent therapeutic effects of systematic lymphadenectomy. After the publication of the results of the Z0011, it showed no outcome difference in patients with positive SN between axillary dissection versus no further axillary surgery, raising doubts on the role of SN biopsy (SNB) itself. Based on these observations, a new prospective randomized trial comparing SNB versus observation when axillary ultrasound is negative in patients with small breast cancer, which are candidates for breast-conserving surgery, is ongoing at the European Institute of Oncology of Milan.2 In endometrial cancer, most recent clinical researches were focused on innovative imaging techniques for an accurate preoperative staging, as SN mapping and 18F-FDG PET/CT. Looking to the subgroup of high-risk patients, 80% to 90% of women who undergo pelvic and/or aortic lymphadenectomy received a surgical overtreatment. These data should be considered in terms of morbidity and costs. In intermediate and high-risk groups of the SEPAL study,3 results showed that the combination of pelvic and para-aortic lymphadenectomy can significantly improve survival in patients at intermediate and high-risk recurrence. However, the incidence of pelvic and para-aortic lymph node involvement was 14% and 18%, respectively, confirming that most women have little advantages from systematic aortic lymphadenectomy. Furthermore, the issue regarding the risk of isolated aortic metastasis with negative pelvic node occurs in less than 1%of lowrisk and 2% to 4% of high-risk endometrial cancer. Second question, ‘‘Is there a workup algorithm or nomogram to assess the nodal risk involvement of high-risk cases with the aim to better select the percentage of women that can really benefit from retroperitoneal surgical staging or conversely are suitable only for SNB?’’ Some argue that the rate of lymph node metastasis of randomized trial was most likely underestimated and that 15% of pelvic recurrence in nodenegative patients seems to be related to the presence of occult micrometastases not detected by conventional hematoxylin and eosin pathologic assessment. Considering that the risk of occult metastasis is independent of the baseline risk of nodal metastasis, the prognostic significance of micrometastases remains debatable. Notwithstanding, in the article of Bendifallah et al,4 the authors suggested that primary tumor characteristics between patients with lymph node micrometastases andwithmacrometastases are significantly different. By applying a probability nomogram, they argue that the frequency of micrometastases seems to occur earlier and in tumors with lower oncological aggressiveness, suggesting that micrometastasis could represent an ‘‘intermediate state’’ between disease-free lymph node and macrometastasis. The same group in a recent study found that the prediction of lymph node macrometastasis detected by conventional histopathology seems to be feasible using a nomogram based on pathological characteristics of the hysterectomy specimen, whereas prediction of lymph node micrometastasis detected by ultrastaging on SN is not correlated with LN involvement probability. They finally suggest performing SN mapping in low and intermediate-risk endometrial cancers. Looking at results published from Memorial Sloan-Kettering, the use of SN algorithms in preoperative stage I endometrial cancer reduces the need for standard lymphadenectomy without adversely affecting the rate of stage IIIC detection with an acceptable 5% falsenegative rate. Some Authors consider that the spatial resolution limit equal to or lower than 5 mm in the detection of micrometastases of F-FDG PET/CT cannot substitute a whole surgical staging. Recently, Crivellaro et al5 presented a valuable assessment of the role of PET/CT in high-risk early-stage endometrial cancer, confirming our previous data on the use of PET/CT scan in preoperative risk assessment of pelvic nodal involvement of patients with endometrial cancer. In this group of patients, FDG PET/CT sensitivity, specificity, accuracy, and negative predictive value in detecting lymph node metastases were 78.6%, 98.4%, 94.7%, and 95.3%, respectively. Moreover, the maximal standardized uptake value, metabolic tumor volume, and total lesion glycolysis of the primary tumor are LETTERS TO THE EDITOR