Eric L. Eisenhauer

Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm☆

OBJECTIVE To determine the impact on progression-free survival (PFS) and overall survival (OS) of a programmatic change in surgical approach to advanced epithelial ovarian cancer. METHODS Two groups of patients with stage IIIC and IV ovarian, tubal, and peritoneal carcinoma were compared. Group 1, the control group, consisted of all 168 patients who underwent primary cytoreduction from 1/96 to 12/99. Group 2, the study group, consisted of all 210 patients who underwent primary surgery from 1/01 to 12/04, during which time a more comprehensive debulking of upper abdominal disease was utilized. RESULTS There were no differences between the groups in age, primary site of disease, surgical stage, tumor grade, American Society of Anesthesiologists class, preoperative serum CA-125 and platelet levels, percentage with or amount of ascites, size or location of largest tumor mass, or type of postoperative chemotherapy. Patients in Group 2 vs Group 1 more frequently had extensive upper abdominal procedure(s) (38% vs 0%, respectively; P<0.001) and cytoreduction to residual disease <1 cm (80% vs 46%, respectively; P<0.01). Five-year PFS and OS rates were significantly improved in Group 2. For Group 2 vs Group 1 patients, 5-year PFS rates were 31% vs 14%, respectively (hazard ratio, 0.757; 95% CI, 0.601-0.953; P=0.01]; and 5-year OS rates were 47% vs 35%, respectively (HR, 0.764; 95% CI, 0.592-0.987; P=0.03]. CONCLUSION The incorporation of extensive upper abdominal procedures resulted in increased optimal cytoreduction rates and significantly improved PFS and OS. A paradigm shift toward more complete primary cytoreduction can improve survival for patients with advanced ovarian, tubal, and peritoneal carcinomas.

Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment

OBJECTIVE Define subgroups of patients at highest risk for major morbidity and mortality after a traditional approach of maximal surgical efforts followed by chemotherapy for advanced ovarian cancer (AOC). METHODS Preoperative health, intra-operative findings and outcomes were assessed in consecutive patients with primary AOC from 4 centers. Initial tumor dissemination was stratified into 3 groups based on volume of disease. Surgery was categorized using a previously described surgical complexity score (SCS). Statistical analysis was directed toward validating a multivariable risk-adjusted model. RESULTS 576 patients with stage IIIC (N=447, 77.6%) or IV AOC (N=129, 22.4%) were analyzed. Age (HR (per year): 1.02; 95%CI: 1.01-1.03), high tumor dissemination (HTD) (HR: 1.73; 95%CI: 1.19-2.56), residual disease (RD) >1 cm (HR: 2.46; 95%CI: 1.74-3.53), and stage IV (HR: 1.93; 95% CI: 1.51-2.45), independently correlated with OS. We identified a small subgroup of patients who comprised a high-risk group (N=38, 6.6%) characterized by all of the following characteristics: high initial tumor dissemination (HTD) or stage IV plus poor performance or nutritional status plus age ≥ 75. In this group, high SCS to achieve low RD was associated with morbidity of 63.6% and limited survival benefit. CONCLUSIONS Optimal management of AOC requires accurate, risk-adjusted predictors of outcomes allowing a tailored approach starting with primary therapy. Complex surgical procedures to render low RD improve survival, and in the majority of cases, the benefits of such surgery appear to outweigh the morbidity. However careful analysis identifies a subgroup of patients in whom an alternative approach may be the better strategy.

A contemporary analysis of the ability of preoperative serum CA-125 to predict primary cytoreductive outcome in patients with advanced ovarian, tubal and peritoneal carcinoma

OBJECTIVE We previously reported that preoperative CA-125 may predict primary cytoreductive outcome in patients with stage III ovarian carcinoma (OC). The objective of this study was to perform a contemporary analysis of the ability of CA-125 to predict cytoreductive outcome in advanced OC since our programmatic change in surgical approach that currently incorporates the utilization of extensive upper abdominal procedures, as needed, to achieve maximal cytoreduction. METHODS We reviewed the records of all patients with advanced ovarian, tubal or peritoneal carcinoma who underwent primary cytoreduction at our institution between 1/01 and 4/05. RESULTS The study cohort included 277 patients. Primary disease sites were: ovary, 232 (84%); tubal, 9 (3%); and peritoneum, 36 (13%). Stages were: IIIA, 6 (2%); IIIB, 12 (4%); IIIC, 215 (78%); and IV, 44 (16%). Tumor grades were: grade 1, 6 (2%); grade 2, 30 (11%); grade 3, 233 (84%), and undifferentiated, 8 (3%). Cytoreductive outcomes were: no gross residual disease (RD), 68 (25%); <or=1 cm RD, 153 (55%); and >cm RD, 56 (20%). There was no threshold CA-125 level that accurately predicted cytoreductive outcome. However, with CA-125 values >500 U/mL, 50% (57/113) of patients required extensive upper abdominal surgery to achieve RD <or=1 cm, compared to 27% (25/93) for those with CA-125 <500 U/mL (P=0.001). CONCLUSION Following our change in surgical paradigm that the incorporated extensive upper abdominal procedures to attain optimal debulking, preoperative CA-125 did not predict the primary cytoreductive outcome of patients with advanced ovarian, tubal, or peritoneal carcinoma. However, with a preoperative CA-125 >500 U/mL, extensive upper abdominal procedures were necessary in 50% of cases to achieve residual disease <or=1 cm. These data may be useful as part of preoperative surgical counseling and planning.

Comparing Surgical Outcomes in Obese Women Undergoing Laparotomy, Laparoscopy, or Laparotomy With Panniculectomy for the Staging of Uterine Malignancy

BackgroundLimiting surgical morbidity while maintaining staging adequacy is a primary concern in obese patients with uterine malignancy. The goal of this study was to compare the surgical adequacy and postoperative morbidity of three surgical approaches to staging the disease of obese women with uterine cancer.MethodsThe records of all patients with a body mass index (BMI) of ≥35 undergoing primary surgery for uterine corpus cancer at our institution from January 1993 to May 2006 were reviewed. Patients were assigned to three groups on the basis of planned surgical approach—standard laparotomy, laparoscopy, or laparotomy with panniculectomy. Standard statistical tests appropriate to group size were used to compare the three groups.ResultsIn all, 206 patients with a BMI of ≥35 were grouped as follows: laparotomy, 154 patients; laparoscopy, 25 patients; and laparotomy with panniculectomy, 27 patients. Median BMI was 41 (range, 35–84). Regional lymph nodes were removed in 45% of the laparotomy patients, 40% of the laparoscopy patients, and 70% of the panniculectomy patients (P = .04). Compared with laparotomy, both laparoscopy and panniculectomy yielded higher median pelvic and total lymph node counts (P = .001). Operative time was shortest after standard laparotomy, and blood loss was greatest after panniculectomy. The incidence of all incisional complications was lower for panniculectomy (11%) and laparoscopy (8%) compared with standard laparotomy (35%) (P = .002). On multivariate analysis, a significantly lower risk of total incisional complications was seen for patients undergoing panniculectomy (risk ratio, .25; 95% confidence interval, .071–.88) and laparoscopy (risk ratio, .19; 95% confidence interval, .04–.94).ConclusionsBoth laparoscopic staging and panniculectomy in a standardized fashion were associated with an improved lymph node count and a lower rate of incisional complications than laparotomy alone. Although definitive conclusions are limited by low patient numbers, the substantial decrease in wound complications suggests that these two approaches should be considered for obese patients undergoing uterine cancer staging.

Surveillance for the detection of recurrent ovarian cancer: Survival impact or lead-time bias?

OBJECTIVE To compare the survival impact of diagnosing recurrent disease by routine surveillance testing versus clinical symptomatology in patients with recurrent epithelial ovarian cancer (EOC) who have achieved a complete response following primary therapy. METHODS We identified all patients who underwent primary surgery for EOC at two institutions between 1/1997 and 12/2004 and were diagnosed with recurrent disease following a complete clinical response to primary chemotherapy. Survival and post-recurrence management were compared between asymptomatic patients in which recurrent disease was diagnosed at a scheduled visit by routine surveillance testing and symptomatic patients in which recurrent disease was diagnosed based on clinical symptomatology at an unscheduled office visit or hospitalization. RESULTS Of the 121 patients that met inclusion criteria, 22 (18.2%) were diagnosed with a symptomatic recurrence. Median primary PFS was similar for asymptomatic and symptomatic patients (24.8 versus 22.6 months, P = 0.36); however, post-recurrence survival was significantly greater in asymptomatic patients (45.0 versus 29.4 months, P = 0.006). Secondary cytoreductive surgery (SCRS) was attempted equally in both groups (41% versus 32%, P = NS); however, optimal residual disease (<or=5mm) was more often achieved in asymptomatic patients (90% versus 57%, P = 0.053). On multivariate analysis, detection of asymptomatic recurrence was a significant and independent predictor of improved overall survival (P = 0.001). Median OS was significantly greater for asymptomatic patients (71.9 versus 50.7 months, P = 0.004). CONCLUSIONS In patients with platinum-sensitive EOC, detection of asymptomatic recurrences by routine surveillance testing was associated with a high likelihood of optimal SCRS in operative candidates and extended overall survival.

Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer

OBJECTIVE We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with recurrent or persistent carcinoma of the cervix. METHODS Eligible patients had persistent or recurrent cervical cancer not amenable to curative intent treatment. No prior chemotherapy for recurrence was allowed. Treatment consisted of cisplatin 50 mg/m(2) day 1, topotecan 0.75 mg/m(2) days 1, 2 and 3 and bevacizumab 15 mg/kgday 1 every 21 days until disease progression or limiting toxicity. The primary endpoint was progression free survival at 6 months. We explored PET/CT as a potential early indicator of response to therapy. RESULTS Twenty-seven eligible patients received a median of 3 treatment cycles (range, 1-19). Median follow-up was 10 months (range, 1.7-33.4). The 6-month PFS was 59% (80% CI: 46-70%). In 26 evaluable patients, we observed 1 CR (4%; 80% CI: 0.4-14%) and 8 PR (31%; 80% CI: 19-45%) lasting a median of 4.4 months. Ten patients had SD (39%; 80% CI: 25-53%) with median duration of 2.2 months. Median PFS was 7.1 months (80% CI: 4.7-10.1) and median OS was 13.2 months (80% CI: 8.0-15.4). All patients were evaluated for toxicity. Grade 3-4 hematologic toxicity was common (thrombocytopenia 82% leukopenia 74%, anemia 63%, neutropenia 56%). Most patients (78%) required unanticipated hospital admissions for supportive care and/or management of toxicities. CONCLUSION The addition of bevacizumab to topotecan and cisplatin results in an active but highly toxic regimen. Future efforts should focus on identification of predictive biomarkers of prolonged response and regimen modifications to minimize toxicity.

Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer

OBJECTIVE Weekly paclitaxel has been shown to be an effective cytotoxic regimen for recurrent epithelial ovarian cancer (EOC), and may act through inhibition of angiogenesis. Bevacizumab, a potent angiogenesis inhibitor, has also been shown to have activity in patients with EOC. Therefore, we sought to determine if the addition of bevacizumab to weekly paclitaxel led to an increased survival compared to weekly paclitaxel alone. METHODS A single institutional review was conducted for patients with recurrent EOC treated with weekly paclitaxel (60-70mg/m(2)) on days 1, 8, 15, and 22 of a 28day cycle and those treated with weekly paclitaxel and bevacizumab (10-15mg/kg on day 1 and 15). Response rates (RR) were calculated, and progression-free survival (PFS), and overall survival (OS) were compared using Kaplan-Meier survival analysis. RESULTS Twenty-nine patients treated with weekly paclitaxel and 41 patients treated with paclitaxel/bevacizumab were identified. The groups were similar in demographics, initial optimal cytoreduction, stage, histology, grade, platinum sensitivity, and median number of previous regimens (4 vs. 4, p=0.69).The overall response rate (ORR) was 63% (complete response (CR) 34% and partial response (PR) 29%) for paclitaxel/bevacizumab and 48% (CR 17% and PR 31%) for weekly paclitaxel (p=0.23). Improvement in PFS was seen in those treated with paclitaxel/bevacizumab in comparison to weekly paclitaxel alone (median PFS 13.2 vs. 6.2months, p<.01). There was a trend towards improved OS for paclitaxel/bevacizumab (median OS 20.6 vs. 9.1months; p=0.12). Toxicities were similar between the two regimens although more bowel perforations (2 vs. 0) were seen in the paclitaxel/bevacizumab group. CONCLUSION A significant increase in PFS with a trend towards improved OS was demonstrated in this heavily pretreated population treated with paclitaxel/bevacizumab as compared to weekly paclitaxel alone. This data should be helpful in guiding future trials to determine the optimal care for women with recurrent EOC.

Sustained progression-free survival with weekly paclitaxel and bevacizumab in recurrent ovarian cancer

OBJECTIVE To determine efficacy, toxicity, and survival in patients with recurrent epithelial ovarian cancer (EOC) receiving combination of weekly paclitaxel and biweekly bevacizumab (PB). METHODS We reviewed chemotherapy logs identifying all patients receiving combination PB. Toxicities were graded using CTCAEv3.0 criteria. Response rates (RR) were measured using RECIST criteria or by CA-125 levels per modified Rustin criteria. RR and progression-free survival (PFS) were determined and plotted using Kaplan-Meier survival analysis. RESULTS Fifty-one patients receiving at least two cycles of chemotherapy were evaluable for survival and 55 patients receiving one cycle of PB were evaluable in toxicity analysis. The mean number of previous regimens was four. The overall median PFS was 7 months and median OS was 12 months. The overall response rate (ORR) was 60% (CR 25% and PR 35%). Median PFS for complete and partial responders were 14 and 5 months respectively. Stable disease was seen in 26% with median PFS of 6 months. Thirteen experienced treatment delays for a variety of factors. The most G3/4 toxicities were fatigue (16%), hematologic (9%) and neurotoxicity (7%). Three patients (5%) experienced bowel perforations. CONCLUSIONS Combination of paclitaxel and bevacizumab is feasible and demonstrates an acceptable toxicity profile and a high response rate. These observations should be useful in planning future clinical trials with this combination therapy.

Upper abdominal surgical procedures: Liver mobilization and diaphragm peritonectomy/resection, splenectomy, and distal pancreatectomy

Patients with advanced-stage ovarian cancer often have metastatic disease in the upper abdominal region. In particular, metastases to the diaphragm are exceedingly common in these patients. A comprehensive approach to surgical cytoreduction, which has been associated with improved survival in patients with advanced ovarian cancer, should incorporate upper abdominal resection.

Incidence and management of pancreatic leaks after splenectomy with distal pancreatectomy performed during primary cytoreductive surgery for advanced ovarian, peritoneal and fallopian tube cancer☆

OBJECTIVE To determine the incidence, management, and outcome of patients diagnosed with a pancreatic leak after a distal pancreatectomy during primary surgical cytoreduction for ovarian, peritoneal, or tubal cancer. METHODS We performed a retrospective chart review of all patients who had a distal pancreatectomy at the time of primary surgery. Charts were reviewed to identify those patients who developed a persistent left upper quadrant abdominal fluid collection with elevated amylase levels. RESULTS A total of 17 patients had a distal pancreatectomy; of these, 4 patients (24%) developed a postoperative pancreatic leak. In these patients, persistent leukocytosis prompted evaluation with a computed tomography scan, which subsequently revealed a fluid collection. The median time from surgery to drainage of this collection was 9 days (range, 8-66). The drain remained in situ for a median of 29 days (range, 22-82). The median amylase level of the fluid was 22,945 U/L (range, 763-47,250). The median length of hospital stay for those patients with a leak was 33 days (range, 25-44), which was longer than those without a leak. However, the median time from surgery to treatment with systemic chemotherapy was 31 days (range, 16-43), which was equivalent to those without a pancreatic leak. CONCLUSION Twenty-four percent of patients who had undergone a distal pancreatectomy developed a pancreatic leak. This complication, which usually presents early in the postoperative period, can be managed conservatively with percutaneous drainage. Oral intake may be resumed, and total parenteral nutrition is not needed in the majority of cases. Systemic chemotherapy can be administered without significant delay.