Laparoscopic pelvic and paraaortic lymphadenectomy in gynecologic oncology

In the early 1990s, different authors independently developed techniques for pelvic and paraaortic lymph node sampling. Since then, laparoscopic lymphadenectomy has been demonstrated to yield the same number of nodes when compared with the laparotomic approach. Only one microscopically involved lymph node was lost at laparoscopic lymphadenectomy when a laparotomic control followed immediately after. It seems bleeding, which is the most serious perioperative complication, is more common during laparoscopic lymphadenectomy than during laparotomy; however, the incidence will decrease with experience of the surgeon. The laparoscopic procedure does not seem to influence negatively the survival of patients with early stage endometrial and cervical cancer. There does not seem to be a significant reduction in overall hospital charges for laparoscopic surgery in oncology, but patients who undergo laparoscopic surgery recover significantly sooner than those who undergo laparotomy.     

Laparoscopic radical hysterectomy with pelvic lymphadenectomy in early invasive cervical cancer

Laparoscopic radical hysterectomy is one surgical procedure currently performed to treat gynecologic cancer. The objective of this review was to update the current knowledge of laparoscopic radical hysterectomy in early invasive cervical cancer. Articles indexed in the MEDLINE database using the key words "Laparoscopic radical hysterectomy" and "Cancer of the cervix" were reviewed. Studies of laparoscopic radical hysterectomy for treatment of early cervical cancer with a minimum study population of 10 patients were selected. The laparoscopic approach was associated with less surgical morbidity (surgical bleeding) and with shorter length of hospital stay, although the duration of the operation may be longer. Laparoscopic radical hysterectomy with endoscopic pelvic lymphadenectomy, and paraaortic lymphadenectomy if needed, is a safe surgical option for treatment and staging of early invasive cervical cancer considering surgical risk, intraoperative bleeding, intraoperative and postoperative complications, and patient recovery. It is important to respect the learning curve. Surgical advances including new laparoscopic instrumentation and, in particular, use of robotics will contribute to reducing the duration of the operation and to facilitating learning and teaching of the procedure.     

A phase I study of concurrent weekly topotecan and cisplatin chemotherapy with whole pelvic radiation therapy in locally advanced cervical cancer: a gynecologic oncology group study

Purpose

To determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLT) of intravenous topotecan administered with weekly cisplatin during pelvic radiation therapy in patients with locally advanced cervical cancer.

Methods

Patients were treated at one of two dose levels receiving intravenous topotecan at 0.5 mg/m² and cisplatin at either 30 or 40 mg/m² given weekly for 6 weeks concurrently with pelvic radiation and intracavitary brachytherapy. The primary endpoint for the escalation study was acute dose-limiting toxicities occurring within 30 days of completing radiation therapy.

Results

Eleven patients were enrolled. Dose-limiting toxicity consisting of Grade 3 nausea and vomiting lasting > 24 h in one patient and grade 3 febrile neutropenia in another patient occurred at the first dose level of weekly topotecan 0.5 mg/m² and cisplatin 40 mg/m². This necessitated de-escalation to weekly cisplatin 30 mg/m² in combination with topotecan 0.5 mg/m² and pelvic radiation. This dose level was tolerable in 6 evaluable patients with only one DLT consisting of grade 4 thrombocytopenia, grade 3 abdominal pain and grade 3 elevated gamma glutamyl transpeptidase (GGT).

Conclusions

In women with locally advanced cervical cancer, intravenous topotecan 0.5 mg/m² and cisplatin 30 mg/m² given weekly for 6 weeks with concurrent pelvic radiation and intracavitary brachytherapy were tolerable. Further expansion of the feasibility cohort of this study was suspended based on the results of a phase 3 trial comparing the efficacy of platinum combinations in advanced and recurrent cervical cancer.     

Pilot evaluation of high-dose carboplatin and paclitaxel followed by high-dose melphalan supported by peripheral blood stem cells in previously untreated advanced ovarian cancer: a gynecologic oncology group study

OBJECTIVES: To evaluate the efficacy and safety of multiple cycles of high-dose carboplatin and paclitaxel and one consolidation cycle of high-dose melphalan with all cycles supported by hematopoietic stem cells and cytokine, in previously untreated patients with optimally debulked stage III epithelial ovarian cancer. PATIENTS AND METHOD: Patients had histologically documented epithelial ovarian cancer and optimal initial cytoreductive surgery. No prior chemotherapy was permitted. Adequate performance status, bone marrow, hepatic, and renal function was required. After being mobilized with cyclophosphamide 3 g/m(2), paclitaxel 300 mg/m(2), and filgrastim 5 microg/kg/day, peripheral blood stem cells (PBSC) were collected by leukapheresis. Patients received three cycles of carboplatin AUC 15 mg. min/ml iv, paclitaxel 250 mg/m(2), and PBSC with filgrastim every 28 days, followed by one cycle of melphalan 140 mg/m(2) and hematopoietic support. RESULTS: Nine patients entered the trial and received all planned cycles of chemotherapy. Of the eight patients who consented to surgical reassessment upon completing therapy, four had residual small-volume macroscopic disease, three had microscopic residual disease, and one had pathologic complete response. The estimated probability of a pathologic complete response was 12.5% (95% confidence interval: 0.3-52.7%). Hematologic toxicity was severe but manageable. Eleven of 45 cycles (24.4%) resulted in hospital admission for neutropenic fever, dehydration +/- diarrhea, syncope, or shortness of breath and pain secondary to tense ascites. CONCLUSIONS: The low pathological complete response rate did not justify toxicity; thus, the study was closed. High-dose chemotherapy as first-line treatment for epithelial ovarian cancer remains experimental and should be restricted to clinical trials.     

CA125 regression in ovarian cancer patients treated with intravenous versus intraperitoneal platinum-based chemotherapy: a gynecologic oncology group study

Objective

CA125 is a non-specific marker of peritoneal irritation which has the potential for false elevation during intraperitoneal treatment. The purpose of this study is to identify the rate of CA125 regression during intraperitoneal (IP) versus intravenous (IV) chemotherapy for ovarian cancer.

Methods

GOG 114, a randomized control trial evaluating IP and IV treatment, includes an intensive CA125 measurement schema with weekly CA125 levels until ≤ 35 units/ml for both IP- and IV-treated patients. Rate of CA125 normalization, median CA125 values for each treatment cycle, as well as clinical and pathologic features were compared between the treatment groups. Baseline CA125 levels and rate of CA125 decline were evaluated with respect to overall survival.

Results

CA125 data were available for 223 patients who received IV cisplatin/paclitaxel and for 231 patients who received IV carboplatin followed by IP cisplatin/paclitaxel. Standard prognostic criteria and baseline CA125 values were similar between the treatment groups. For treatment cycles in which IP-treatment was administered, there was no statistically significant difference in CA125 levels between IV- and IP-treated patients. The rate of CA125 normalization was similar between IV- and IP-treated patients (p = 0.55). Patients with low pre-chemotherapy CA125 levels which rapidly declined during treatment demonstrated a survival advantage (p < 0.0001).

Conclusions

No difference in CA125 decline was identified between IP- and IV-treated patients undergoing a weekly CA125 monitoring schedule. This data supports the utilization of standard CA125 response criteria in the therapeutic monitoring for patients receiving IP treatment.     

Contribution of BRCA1 and BRCA2 to familial ovarian cancer: a gynecologic oncology group study

OBJECTIVES: The aim of the study was to determine the prevalence of BRCA1 and BRCA2 germline mutations among ovarian cancer patients ascertained to have a family history of ovarian cancer. METHODS: Ovarian cancer patients were eligible if they had a family history of cancer that met any one of the following criteria: (1) a first-degree relative with ovarian cancer; (2) a second-degree relative with ovarian cancer plus a first-degree relative with breast cancer (diagnosed younger than 50 years of age); or (3) a first- and a second-degree relative with breast cancer (diagnosed younger than 50 years of age). The entire coding sequence of BRCA1 and exon 11 of BRCA2 were screened for germline alterations by single-strand conformation polymorphism analysis. RESULTS: Of 26 eligible patients screened for mutations, 12 had deleterious alterations, 8 in BRCA1 and 4 in BRCA2. A correlation was noted between the presence of a BRCA1 mutation and the strength of family history of breast ovarian cancer, with the likelihood of a mutation increasing with the number of affected relatives (P = 0.0002). No association was detected between the location of mutations in BRCA1 and the ratio of ovarian cancer cases relative to breast cancer (P = 0.28). CONCLUSIONS: Mutations in BRCA1 or BRCA2 are present in about 50% of ovarian cancer patients with at least one first-degree relative with disease, and in 70% of patients with two or more relatives with ovarian cancer.     

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: A gynecologic oncology group study

Objectives

To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.

Background

Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.

Methods

We performed a randomized phase II trial of intravenous temsirolimus 25 mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20 mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.

Results

There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.

Conclusions

Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.     

Human immunodeficiency virus testing in patients with invasive cervical carcinoma: a prospective trial of the gynecologic oncology group

To determine the frequency of positive human immunodeficiency virus (HIV) serostatus among North American women 50 years of age or younger with invasive cervical cancer and to define their tolerance to treatment. Consenting patients with newly diagnosed invasive cervical cancer, age 50 or younger were tested by enzyme-linked immunosorbent assay. The study design anticipated that approximately 3% of patients would be HIV positive. After the accrual of 913 eligible and evaluable patients, interim analysis revealed that only 9/913 ( approximately 1%) patients were HIV seropositive, indicating that it would not be feasible to achieve the study objective. The study was closed to further accrual. Between 1994 and 1997, the frequency of positive HIV serostatus among North American women with newly diagnosed cervical cancer was quite low. As a consequence, no evaluation of response to treatment or treatment tolerance can be made.     

Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a gynecologic oncology group study.

Objective. The goal of this study was to estimate the antitumor activity and toxicity of recombinant human interleukin-12 (rhIL-12) in patients with recurrent or refractory epithelial ovarian cancer. Methods. From December 1997 to March 1999, patients with recurrent or refractory epithelial ovarian cancer were entered on a Gynecologic Oncology Group phase II study of intravenous rhIL-12. All patients had measurable disease, had a performance status of 0-2, and had failed first-line platinum-based chemotherapy regimen. Eligible patients received rhIL-12, 250 ng/kg IV bolus, as a single dose on Day 1 followed by a 2-week rest period, with subsequent cycles administered daily for 5 days followed by a 16-day rest period per cycle, until disease progression or adverse effects prohibited further therapy. Results. Twenty-eight patients were entered and evaluable for toxicity, while 26 were evaluable for response. The median age was 59.5 years (range: 45-77). The median number of cycles was 2 (range: 1-9). There were no complete responders; however, one patient (3.8%) was a partial responder and 13 patients (50%) had stable disease. Grade 4 myelotoxicity occurred in 21% of patients. Two patients experienced capillary leak syndrome: one grade 2 and one grade 4. Conclusion. As a single agent, rhIL-12 is tolerable and shows a low response rate in recurrent epithelial cancer with measurable disease.     

Laparoscopic para-aortic lymphadenectomy in advanced cervical cancer: morbidity and impact on therapy

BackgroundLaparoscopic para-aortic lymphadenectomy (PAL) is being used increasingly to stage patients with locally advanced cervical cancer (LACC) and to define radiation field limits before chemoradiation therapy (CRT). This study aimed to define clinical implications, review complications, and determine whether surgical complications delayed the start of CRT.Patients and methodsWe retrospectively reviewed a continuous series of patients with LACC, with no positive para-aortic (PA) nodes on positron emission tomography-computed tomography (PET-CT) and who had undergone a primary laparoscopic PAL.ResultsFrom November 2007 to June 2010, 98 patients with LACC underwent pretherapeutic PAL. Two patients did not undergo PAL: extensive carcinomatosis was discovered in one case and a technical problem arose in the other. No perioperative complications occurred. Seven patients had a lymphocyst requiring an imaging-guided (or laparoscopic) puncture. Eight patients (8.4%, which corresponds to the false-negative PET-CT rate) had metastatic disease within PA lymph nodes. In cases of suspicious pelvic nodes on PET-CT, the risk for PA nodal disease was greater (24.0% versus 2.9%). When patients with and without surgical morbidity were compared, the median delay to the start of treatment was not significantly different (15 days; range, 3–49 days versus 18 days; range, 3–42 days).Discussion and conclusionsThe morbidity of laparoscopic PAL was limited and the completion of treatment was not delayed when complications occurred. Nevertheless, if PET-CT of the pelvic area is negative, the interest in staging PAL could be discussed because the risk for PA nodal disease is very low.     

Intraperitoneal interferon-alpha in residual ovarian carcinoma: a phase II gynecologic oncology group study.

OBJECTIVE: The purpose of this study was to confirm the activity of interferon-alpha intraperitoneally in minimal residual epithelial ovarian cancer in a Phase II multi-institutional trial and to investigate the activity of the agent based on prior response to first-line platinum compounds. METHODS: Ninety-two patients with minimal residual (<0.5 cm) epithelial ovarian cancer at reassessment laparotomy were entered into a multicenter trial of intraperitoneal interferon-alpha given for 12 cycles unless disease progression or unacceptable toxicity occurred first. Patients were considered favorable if they were platinum sensitive and/or relapsed 6 months or longer after completing treatment and unfavorable if they were platinum insensitive and/or relapsed shorter than 6 months after completing treatment and/or had stable or progressive disease during initial therapy. A third-look laparotomy was performed within 12 weeks of completion of treatment in those patients who were in clinical remission. RESULTS: Eighty patients were clinically evaluable for toxicity only (48 favorable, 32 unfavorable) and 46 of them were evaluable for response, of whom 25 were favorable (platinum sensitive) and 21 unfavorable (platinum resistant). In the favorable group, there was a 28% surgically documented response rate (7/25 patients): 16% (4/25) had complete responses (negative reassessment operation), 12% (3/25) had partial responses, 32% (8/25) were nonresponders, and 40% (10 patients) developed progressive disease before planned reassessment operation. In the unfavorable group, there were no responding patients: 6 were nonresponders at reassessment operation and 15 developed progressive disease before planned reassessment operation. Of the 80 patients evaluable for toxicity, the most common adverse effects that were more than grade 2 were gastrointestinal (12; 15%), fever (8; 10%), neutropenia (7;9%), and leukopenia (6; 8%). Grade 4 toxicity was seen in 5 patients; each had fever and gastrointestinal toxicity, and 1 each had neutropenia and thrombocytopenia. CONCLUSIONS: Interferon-alpha is an active and generally well-tolerated agent in favorable patients with minimal residual epithelial ovarian cancer at second-look surgery. These results are comparable to those achieved with cytotoxic chemotherapy. If Phase III trials are considered in the patients with minimal residual ovarian cancer, they should be limited to the platinum-sensitive patient population.     

Paclitaxel in the treatment of carcinosarcoma of the uterus: a gynecologic oncology group study

OBJECTIVE: The goal of this study was to estimate the clinical activity of paclitaxel in patients with persistent or recurrent carcinosarcoma of the uterus who have failed other treatments. METHODS: The Gynecologic Oncology Group (GOG) conducted a phase II study of paclitaxel 170 mg/m(2) (135 mg/m(2) in those with prior irradiation) intravenously every 3 weeks in patients with histologic confirmation of carcinoma and measurable disease who had failed appropriate local therapy. RESULTS: A total of 53 patients were entered into the study between September 1994 and January 1997; 44 patients were evaluable for response. The median age of the patients treated was 65 years (range: 38-79). Twenty-six patients had heterologous mixed mesodermal tumors (MMTs) and 18 patients had homologous tumors. A median of three courses were administered (range: 1-18). Fifteen patients had previous radiation therapy and 33 patients had failed prior chemotherapy. Eight patients (18.2%) had a response to paclitaxel: four patients had a complete response and four had a partial response. Neutropenia was the most common toxic effect. CONCLUSIONS: Paclitaxel had moderate activity in patients with carcinosarcoma of the uterus. The GOG is currently studying the combination of paclitaxel and ifosfamide versus ifosfamide alone for patients with advanced or recurrent carcinosarcoma of the uterus.     

Sentinel lymph node identification and radical hysterectomy with lymphadenectomy in early stage cervical cancer: laparoscopy versus laparotomy

STUDY OBJECTIVE: To estimate the feasibility and results of sentinel lymph node identification and radical hysterectomy with pelvic lymphadenectomy entirely completed by laparoscopy versus laparotomy in early stage cervical cancer. DESIGN: Retrospective, nonrandomized clinical study (Canadian Task Force classification II-2). SETTING: Acute care, teaching hospital. PATIENTS: From September 2000 through January 2005, 50 consecutive patients with International Federation of Gynecology and Obstetrics stage IA(2), IB(1), and IIA disease less than 4 cm underwent radical hysterectomy and lymphadenectomy with intraoperative sentinel lymph node biopsy. INTERVENTIONS: The operation was performed entirely by laparoscopy in 20 patients and using the conventional abdominal approach in 30. Feasibility of sentinel lymph node identification, surgical morbidity, overall survival, and recurrence rate-free survival in both groups were compared. MEASUREMENTS AND MAIN RESULTS: The overall detection rate of the sentinel lymph node was 100% (false negative 0%). A mean of 2.50 sentinel nodes/patient was detected in the laparotomy group compared with a mean of 2.55 nodes in the laparoscopic group (p = .874). Bifurcation of the right common iliac artery was the most frequent nodal location. Blood loss and length of stay were significantly lower in the laparoscopic group, but surgical time was significantly longer. The median follow-up was 35 months (range 5-57) in the laparotomy group and 22.5 (range 2-52) in the laparoscopic group. Differences in overall survival and disease-free survival were not observed. CONCLUSION: Sentinel lymph node identification and radical hysterectomy in the initial treatment of early stage cervical cancer can be performed safely by laparoscopy with lower morbidity and overall survival and recurrence-free survival similar to standard laparotomy.     

Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer: a gynecologic oncology group study

OBJECTIVE: To evaluate toxicity, survival, and recurrence-free interval in women with loco-regionally advanced endometrial carcinoma treated with postoperative whole abdominal radiation therapy. METHODS: Whole abdominal irradiation with pelvic plus or minus para-aortic boost was initiated within 8 weeks of total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic washings, and selective pelvic and para-aortic node sampling in eligible, consenting patients. RESULTS: Of 180 evaluable patients entered on the study with surgically staged III and IV endometrial carcinoma maximally debulked to less than 2 cm, 77 had typical endometrial adenocarcinoma and 103 had high-risk histology, either papillary serous or clear cell carcinoma. Patients with typical endometrial adenocarcinoma were significantly younger and had significantly fewer poorly differentiated cancers. Proportionally, there were twice as many non-Whites with high-risk histologies as non-Whites with typical endometrial adenocarcinoma. Forty-five percent of patients with typical endometrial adenocarcinomas had positive pelvic nodes compared to 51% of those with high-risk histologies. Both histologic groups had similar distribution for performance status, para-aortic node positivity, site and extent of disease, and International Federation of Gynecology and Obstetrics (FIGO) stage. The frequency of severe or life-threatening adverse effects among 174 patients evaluable for radiation toxicity included 12.6% with bone marrow depression, 15% GI, and 2.2% hepatic toxicity. The recurrence-free survival rates were 29% and 27% (at 3 years) for the typical endometrial adenocarcinoma and high-risk histologies, respectively. The survival rates were 31% and 35%, respectively. No patient with gross residual disease survived. CONCLUSION: Whole abdominal irradiation in maximally resected advanced endometrial carcinoma has tolerable toxicity, and it is suggested that the outcome may be improved by this adjunctive treatment in patients with completely resected disease.     

Laparoscopic sentinel lymph nodes identification followed by trachelectomy in early stage cervical cancer

The status of regional lymph nodes is the main prognostic factor in diagnosis and treatment of early stage of the cervical cancer. If the first node that drains a tumor site (sentinel node) is not metastatic, other lymph nodes should also be free of the disease. Detection using blue dye and laparoscopic removal of the sentinel lymph nodes let to avoid radical hysterectomy with pelvic limphadenectomy and it is especially useful in young women who want to preserve fertility. We describe a case of a 33- year old woman with invasive cervical cancer who underwent laparoscopic sentinel lymph nodes detection followed by trachelectomy. Thus histopatological examination confirmed no metastasis in removed sentinel lymph nodes, trachelectomy as a minimally invasive procedure was performed.     

Fibrin application for preventing lymphocysts after retroperitoneal lymphadenectomy in patients with gynecologic malignancies.

OBJECTIVE: We performed a randomized, prospective trial to assess the impact of fibrin glue on the incidence of lymphocysts after systematic pelvic or pelvic and paraaortic lymphadenectomy in patients with gynecologic malignancies. METHODS: Ninety-three consecutive patients with gynecologic pelvic malignancies who underwent surgery including pelvic or pelvic and paraaortic lymphadenectomy were randomized during surgery to be treated with fibrin glue or not. Serial computed tomography (CT) scans were performed during follow-up. CT findings of a smooth and thin-walled cavity filled with a water-equivalent fluid, sharply demarcated from its surroundings and without signs of infiltration were interpreted as lymphocysts. RESULTS: Forty-seven patients (51%) were treated with fibrin glue and 46 (49%) were not. All 93 patients underwent pelvic lymphadenectomy; 15 patients (32%) of the fibrin group and 12 (26%) of the controls also underwent paraaortic lymphadenectomy. We found no significant differences between patients who received fibrin glue and those who did not. CONCLUSION: Intraoperative application of fibrin glue did not reduce the rate of postoperative lymphocysts after lymphadenectomy and had no impact on any follow-up parameter. Its use seems not to be indicated in systematic gynecologic pelvic or pelvic and paraaortic lymphadenectomy.     

Evaluation of paclitaxel in previously treated leiomyosarcoma of the uterus: a gynecologic oncology group study

OBJECTIVE: The purpose of this phase II trial was to evaluate the efficacy of intravenous paclitaxel in patients with recurrent or advanced leiomyosarcoma of the uterus. METHODS: To be eligible, patients with recurrent or persistent leiomyosarcoma of the uterus were to have measurable disease not previously treated with paclitaxel and adequate hematologic (WBC >or=3000/microl, platelet count >or=100000/microl), renal (serum creatinine 相似文献