Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: multi-institutional phase-II trial

Objective.

The primary end-point of this multi-institutional phase-II trial was to assess results in terms of overall survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment-naive epithelial ovarian cancer (EOC) with advanced peritoneal involvement. Secondary end-points were treatment morbi-mortality and outcome effects of time to subsequent adjuvant systemic chemotherapy (TTC).

Methods.

Twenty-six women with stage III-IV EOC were prospectively enrolled in 4 Italian centers to undergo CRS and closed-abdomen HIPEC with cisplatin and doxorubicin. Then they received systemic chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m²) for 6 cycles.

Results.

Macroscopically complete cytoreduction was achieved in 15 patients; only minimal residual disease (≤ 2.5 mm) remained in 11. Major complications occurred in four patients and postoperative death in one. After a median follow-up of 25 months, 5-year overall survival was 60.7% and 5-year progression-free survival 15.2% (median 30 months). Excluding operative death, all the patients underwent systemic chemotherapy at a median of 46 days from combined treatment (range: 29-75). The median number of cycles per patient was 6 (range: 1-8). The time to chemotherapy did not affect the OS or PFS.

Conclusions.

In selected patients with advanced stage EOC, upfront CRS and HIPEC provided promising results in terms of outcome. Morbidity was comparable to aggressive cytoreduction without HIPEC. Postoperative recovery delayed the initiation of adjuvant systemic chemotherapy but not sufficiently to impact negatively on survival. These data warrant further evaluation in a randomized clinical trial.     

Risk factors for lymph node metastasis in apparent early-stage epithelial ovarian cancer: implications for surgical staging

Objectives

The extent of lymphadenectomy to be performed in apparent early-stage epithelial ovarian cancer (EOC) is not well defined. We evaluated the patterns of lymphatic spread in apparent early-stage EOC and risk factors for lymph node metastasis, as these have potential implications for clinical decision making.

Methods

All cases of apparent early-stage EOC diagnosed at our institution between January 1994 and December 2003 were retrospectively identified. Apparent early-stage EOC was defined as gross disease that appeared confined to the pelvis without abdominal spread at the time of initial exploration. Demographics, pathologic findings, staging procedures performed, and clinical impression at surgery were analyzed. Patterns of lymph node positivity and risk factors associated with upstaging were assessed.

Results

One hundred and ninety patients with apparent early-stage EOC undergoing primary surgical staging met criteria for inclusion. All patients had at least some pathologic assessment of lymph nodes, with 115 having both bilateral pelvic and paraaortic lymphadenectomy performed. After review of pathology and operative reports, the final FIGO staging within the cohort was 54 IA (28.4%), 10 IB (5.3%), 51 IC (26.8%), 1 IIA (0.5%), 4 IIB (2.1%), 37 IIC (19.5%), 8 IIIA (4.2%), 25 IIIC (13.2%). Overall 25/190 (13%) had lymph nodes metastasis as follows: 8 (32%) had positive pelvic nodes, 12 (48%) had positive paraaortic nodes, and 5 (20%) had both positive pelvic and paraaortic lymph nodes. Significant risk factors for lymph node metastasis included bilateral vs. unilateral primary lesion (26.8% vs. 7.5%, p < 0.001), positive cytologic washings vs. negative (22.4% vs. 9.1%, p = 0.012), ascites vs. no ascites (28.2% vs. 9.3%, p = 0.002), serous vs. other histology (28% vs. 9%, p = 0.001), grade 1 vs. grade 2 vs. grade 3 disease (2.7% vs. 1.9% vs. 23.2%, p < 0.001), and preoperative CA 125 levels of > 35 vs. ≤ 35 U/ml (22.4% vs.0% p = 0.006). No patients with mucinous cancers (n = 29) had lymph node metastases. Patterns of LN metastases were largely independent of laterality of primary lesions: among those with unilateral lesions and positive nodes (n = 10), 5 (50%) had ipsilateral lymph node involvement, 4 (40%) had bilateral involvement, and 1 (10%) had isolated contralateral lymph nodes positive.

Conclusions

Complete surgical staging in EOC patients with gross disease confined to the ovaries and pelvis should include bilateral pelvic and paraaortic lymphadenectomy.Even in patients with unilateral lesions, lymph node metastases are commonly bilateral. Bilateral ovarian lesions, positive cytology, presence of ascites, high grade histology, and serous histology are risk factors for lymph node involvement. This information may be helpful in counseling patients presenting for consideration of re-staging after unexpected findings of malignancy.     

Should stage IIIC ovarian cancer be further stratified by intraperitoneal vs. retroperitoneal only disease?: a Gynecologic Oncology Group study

Objective

To examine whether clinical outcomes varied with intraperitoneal (IP) and/or retroperitoneal (RP) involvement in stage IIIC epithelial ovarian cancer (EOC) patients with microscopic residual disease after cytoreduction.

Methods

Retrospective review was performed for EOC patients enrolled in Gynecologic Oncology Group (GOG)-182 who underwent primary cytoreduction to microscopic residual disease. Patients were divided into 3 groups: stage IIIC by lymphadenopathy with < 2 cm IP spread (RP); > 2 cm IP spread and negative nodes (IP/RP−); and > 2 cm IP dissemination and positive lymphadenopathy (IP/RP+). Product-limit and multivariate proportional hazards modeling were used.

Results

Analyses included 417 stage IIIC women who underwent primary cytoreduction with lymphadenectomy to microscopic residual. There were 203, 123, and 91 in the RP, IP/RP−, and IP/RP+ groups, respectively. IP/RP+ and IP/RP− were associated with worse progression-free survival (PFS) (Hazard Ratio (HR) 1.68, 95% confidence interval (CI) 1.23-2.30; HR 1.38, 95% CI 1.04-1.84) vs. RP only. IP/RP+ was associated with worse overall survival (OS) (HR 1.79, 95% CI 1.24-2.57) while IP/RP− trended towards worse OS (HR 1.21, 95% CI 0.85-1.73) vs. RP only. Median PFS for IP/RP+ and IP/RP− groups was 21 and 29 months, respectively, vs. 48 months in the RP group (p = 0.0007) and median OS of 63 and 79 months vs. “not reached,” respectively (p = 0.0038).

Conclusions

Among EOC patients surgically cytoreduced to microscopic residual disease, those upstaged to IIIC by retroperitoneal involvement demonstrated significant improvement in PFS and OS compared to patients with intraperitoneal tumor, suggesting that these women may represent a unique subset of FIGO stage IIIC patients.     

Outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC)

Objective

To describe the outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC) so as to define the criteria for patient selection for palliative surgery.

Methods

90 women with relapsed EOC underwent palliative surgery for bowel obstruction between 1992 and 2008.

Results

Median age at time of surgery for bowel obstruction was 57 years (range, 26 to 85 years). All patients had received at least one line of platinum-based chemotherapy. Median time from diagnosis of primary disease to documented bowel obstruction requiring surgery was 19.5 months (range, 29 days-14 years). Median interval from date of completed course of chemotherapy preceding surgery for bowel obstruction was 3.8 months (range, 5 days-14 years). Ascites was present in 38/90(42%). 49/90(54%) underwent emergency surgery for bowel obstruction. The operative mortality and morbidity rates were 18% and 27%, respectively. Successful palliation, defined as adequate oral intake at least 60 days postoperative, was achieved in 59/90(66%). Only the absence of ascites was identified as a predictor for successful palliation (p = 0.049). The median overall survival (OS) was 90.5 days (range, < 1 day-6 years). Optimal debulking, treatment-free interval (TFI) and elective versus emergency surgery did not predict survival or successful palliation from surgery for bowel obstruction (p > 0.05).

Conclusion

Surgery for bowel obstruction in relapsed EOC is associated with a high morbidity and mortality rate especially in emergency cases when compared to other gynaecological oncological procedures. Palliation can be achieved in almost two thirds of cases, is equally likely in elective and emergency cases but is less likely in those with ascites.     

Surgical staging of early stage epithelial ovarian cancer: results from the CDC-NPCR ovarian patterns of care study

Objectives

The objectives of this study were to determine the adequacy of surgical staging performed on surgically treated epithelial ovarian cancer (EOC) patients with apparent early stage disease and to determine if receipt of surgical staging had an influence on survival.

Methods

Detailed surgical staging information was collected from medical records for 721 patients diagnosed between 1998 and 2000 with EOC. Patients resided in California or New York and were identified through population-based cancer registries.

Results

Nearly 90% of patients had removal of the omentum and evaluation of bowel serosa and mesentery but only 72% had assessment of retroperitoneal lymph nodes and the majority of patients did not receive biopsies of other peritoneal locations. Only lymph node assessment (as well as node assessment combined with washings and omentectomy) had a statistically significant association with improved survival. The 5-year survival for women with node sampling was 84.2% versus 69.6% for those without this surgical procedure, and patients who did not have lymph node assessment had nearly twice the risk of death as those who did. When patients were stratified by receipt of chemotherapy, lack of node sampling had an effect only on patients who also had no chemotherapy (adjusted HR = 2.2, CI = 1.0-4.5).

Conclusions

The results of this population-based study confirm the prognostic importance of surgical staging for women with EOC, and the important role of gynecologic oncologists in treating these patients. Adjuvant chemotherapy does not appear to further improve survival for those women who receive adequate surgical staging.     

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 (60-70 mg/m²) on days 1, 8, 15, and 22 of a 28 day cycle and those treated with weekly paclitaxel and bevacizumab (10-15 mg/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. 6.2 months, p < .01). There was a trend towards improved OS for paclitaxel/bevacizumab (median OS 20.6 vs. 9.1 months; 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.     

Video-assisted thoracic surgery (VATS) evaluation of intrathoracic disease in patients with FIGO III and IV stage ovarian cancer

Objectives

The aim of this study was to assess the influence of video-assisted thoracic surgery (VATS) on our treatment decisions in FIGO III and IV ovarian cancer patients.

Methods

Patients with ovarian cancer and suspected supra-diaphragmatic involvement (pleural effusions, pleural carcinomatosis, lung metastasis, or enlarged supra-diaphragmatic lymph nodes) at chest computer tomography (CT) scan underwent VATS with or without laparoscopy (LSC) to decide for primary cytoreduction or neoadjuvant chemotherapy. Operation time, VATS complications (intrapleural hematoma, secondary hemorrhage with intervention, pneumonia and empyema) and shift in the therapeutic strategy due to VATS were evaluated.

Results

17 patients were included into this study (1 patient with FIGO stage IIIb, 1 with IIIc and 15 with stage IV). The median operation time for VATS only was 46.5 min (range: 20-50 min, n = 3). Perioperatively, no complications occurred. After surgical staging, the tumor was confined to the abdomen in four patients in whom primary cytoreduction was attempted. All other 13 patients underwent neoadjuvant chemotherapy. VATS altered the therapeutic management in 6/17 ovarian cancer patients (3 times upstaging, 3 times downstaging). Negative predictive values (NPV) for local and diffuse pleural carcinomatosis ranged between 0.5 and 0.71.

Conclusion

In this case series, VATS in addition to LSC showed negligible morbidity related to surgery and a short operation time. We were able to improve the accuracy of the FIGO staging and assessed operability more reliably in these patients than through imaging techniques alone.     

Carcinosarcoma of the ovary: a case-control study

Introduction

Carcinosarcoma of the ovary is a rare tumor with a grim prognosis. Chemotherapy for these tumors is chosen according to guidelines established for epithelial ovarian cancer (EOC). The purpose of this study is to compare response to chemotherapy and survival in patients with advanced stage carcinosarcoma of the ovary.

Methods

We identified women with advanced carcinosarcoma of the ovary who underwent first-line platinum and taxane-based chemotherapy. Each case was matched to two women with serous EOC. Cases and controls were matched by age, stage, and year of diagnosis. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model.

Results

Fifty women treated with first line platinum and taxane-based chemotherapy had advanced carcinosarcoma of the ovary and were selected as cases. The response rates to chemotherapy for cases and controls were 62% and 83% (P = 0.03), respectively. Median progression-free survival was 11 months (95% CI, 8 to 14 months) versus 16 months (95% CI, 12 to 21 months; P = 0.02) and median overall survival was 24 months (95% CI, 18 to 29 months) versus 41 months (95% CI, 33 to 49 months; P = 0.002) for cases and controls, respectively.

Conclusion

Patients with advanced carcinosarcoma of the ovary have a poorer response to platinum and taxane-based first-line chemotherapy and worse survival, compared to patients with serous EOC. Aggressive surgical treatment may play an important role. However, other alternative systemic therapeutic approaches should be sought for patients with carcinosarcoma of the ovary.     

Impact of beta blockers on epithelial ovarian cancer survival

Objective

Stress may promote ovarian cancer progression through mechanisms including autonomic nervous system mediators such as norepinephrine and epinephrine. Beta blockers, used to treat hypertension, block production of these adrenergic hormones, and have been associated with prolonged survival in several malignancies. We sought to determine the association between beta blocker use and epithelial ovarian cancer (EOC) disease progression and survival.

Methods

We performed an institutional retrospective review of patients with EOC treated between 1996 and 2006. Patients underwent cytoreductive surgery followed by platinum-based chemotherapy. Women were considered beta blocker users if these medications were documented on at least two records more than 6 months apart. Statistical tests included Fisher's exact, Kaplan-Meier, and Cox regression analyses.

Results

248 met inclusion criteria. 68 patients used antihypertensives, and 23 used beta blockers. Median progression-free survival for beta blocker users was 27 months, compared with 17 months for non-users (p = 0.05). Similarly, overall disease-specific survival was longer for beta blocker users (56 months) compared with non-users (48 months, p = 0.02, hazard ratio = 0.56). Multivariate analysis identified beta blocker use as an independent positive prognostic factor, after controlling for age, stage, grade, and cytoreduction status (p = 0.03). Overall survival remained longer for beta blocker users (56 months) when compared with hypertensive patients on other medications (34 months) and patients without hypertension (51 months) (p = 0.007).

Conclusions

In this cohort of patients with EOC, beta blocker use was associated with a 54% reduced chance of death compared with that of non-users.     

Expression of 67-kDa laminin receptor was associated with tumor progression and poor prognosis in epithelial ovarian cancer

Objective

67-kDa laminin receptor (67LR) has been identified as a prognostic biomarker for a variety of human cancers. We investigated the clinical significance of 67LR expression and its functional role in epithelial ovarian cancer (EOC).

Methods

67LR expression was evaluated by immunohistochemistry in 62 patients with EOC. We assessed the correlation of 67LR expression with clinical characteristics. In vitro experiment was performed for 67LR with inhibition using siRNA to evaluate its role in cell survival, apoptosis, and invasion in EOC cells.

Results

67LR was predominantly expressed on the cell membrane in the majority of EOC samples (45/62, 73%). 67LR expression was significantly correlated with advanced stage (P = 0.001). Patients with 67LR expression had shorter progression-free survival among all the patients (P = 0.010) and in particular among patients with advanced stages (P = 0.046). When 67LR expression was inhibited by siRNA in EOC cells (HeyA8 and A2780), there was a significant decrease of cell proliferation and invasion as well as increase of apoptosis.

Conclusion

These findings suggest that 67LR expression may play an important role in tumor progression into advanced stage with poor prognosis in EOC and down-regulation of 67LR on tumor cells may be a therapeutic target in those patients.     

Interaction between preoperative CA-125 level and survival benefit of neoadjuvant chemotherapy in advanced epithelial ovarian cancer

Objective

This study aims to determine whether neoadjuvant chemotherapy (NAC) has survival benefit in selected patients with advanced epithelial ovarian cancer (EOC) who have high risk of suboptimal cytoreduction which is represented by high serum CA-125 level.

Methods

We retrospectively reviewed records of 314 patients with EOC including 94 patients who received NAC. After stratification by preoperative CA-125 levels, the progression-free survival (PFS) was compared between the NAC group and the primary debulking surgery (PDS) group.

Results

The NAC group had more FIGO stage IV disease (P < 0.001) and higher CA-125 levels (P < 0.001). Although suboptimal resection rate was higher in the PDS group (50% vs. 18%, P < 0.001), however, NAC was not associated with increased PFS in multivariate Cox analysis (P = 0.334). Nevertheless, after stratification according to CA-125 levels, NAC showed survival benefit in the subgroup with high CA-125 levels (> 2000 U/ml; HR 0.62, P = 0.037).

Conclusion

Our preliminary data suggests the possible interaction between CA-125 levels and survival benefit of NAC. The randomized trial data about NAC should be stratified by the reproducible and relevant criteria such as preoperative serum CA-125 level to elucidate true survival benefit of NAC in ovarian cancer.     

Lymphovascular space invasion is an independent risk factor for nodal disease and poor outcomes in endometrioid endometrial cancer

Objective

Adjuvant radiotherapy improves local control but not survival in women with endometrial cancer. This benefit was shown in staged patients with “high intermediate risk” (HIR) disease. Other studies have challenged the need for systematic staging including lymphadenectomy. We sought to determine whether LVSI alone or in combination with other histologic factors predicts lymph node (LN) metastasis in patients with endometrioid endometrial cancer.

Methods

A retrospective review was conducted of patients with endometrioid endometrial carcinoma who had confirmed presence/absence of LVSI and clinicopathologic data necessary to identify HIR criteria. Kaplan-Meier curves were generated and univariate and multivariate analyses performed as appropriate.

Results

We identified 757 eligible patients and 628 underwent systematic lymphadenectomy for staging purposes. In the surgically staged group, 242 (38%) patients met uterine HIR criteria and 196 (31%) had LVSI. Both HIR and LVSI were significantly associated with LN metastasis. Among the HIR positive group, 59 had LN metastasis (OR 4.46, 95% CI 2.72-7.32, P < 0.0001). Sixty-six LVSI positive patients had nodal metastasis (OR 11.04, 95% CI 6.39-19.07, P < 0.0001). The NPV of LVSI and HIR negative specimens was 95.6% and 93.4% respectively. In multivariate analysis, PFS and OS were significantly reduced in both LVSI positive (P < 0.0001) and HIR patients (P < 0.0001) when compared to patients who were LVSI and HIR negative.

Conclusions

HIR status and LVSI are highly associated with LN metastasis. These features are useful in assessing risk of metastatic disease and may serve as a surrogate for prediction of extrauterine disease.     

A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies

Objectives

Protein kinase C (PKC) activation contributes to proliferation and angiogenesis in epithelial ovarian or primary peritoneal carcinoma (EOC/PPC). A multi-institutional phase II trial was conducted to evaluate the efficacy and safety of PKCβ inhibitor enzastaurin in persistent or recurrent EOC/PPC and to explore potential prognostic and predictive biomarkers.

Methods

Eligible women with measurable platinum-sensitive and resistant EOC/PPC were treated with continuous administration of oral enzastaurin until disease progression or unacceptable toxicity. A two-stage sequential design was used to evaluate progression-free survival (PFS) ≥ 6-months, tumor response, and toxicity. Translational studies included sequencing of the TP53, PTEN, PIK3CA and PKCβII genes for somatic mutations, quantitative PCR assays for AKT2 and PTEN copy number alterations, and measurement of circulating VEGF-A plasma levels.

Results

Among 27 eligible and evaluable patients, 3 women with PFS ≥ 6-months (11%) and 2 women with partial responses (7%) were observed. One of them achieved a durable response and remains on the study. No grade 4 adverse events were observed. Most common grade 3 adverse events were constitutional (4) and gastrointestinal (3). Mutations in the TP53 gene and abnormal copy number in the PTEN gene were common (56% and 48% of cases, respectively).

Conclusions

Enzastaurin was tolerable but had insufficient activity to proceed with the second stage of accrual. However, 1 patient has been progression-free for 44 months. No association between a biomarker and response to enzastaurin has been found. Exploratory analysis suggested an association between survival and PTEN copy number losses.     

Prognostic determinants in patients with uterine and ovarian clear carcinoma

Objective

The purpose of this study is to analyze and compare the demographics, treatment, recurrence, and survival rates in patients with uterine clear cell carcinoma (UCCC) and ovarian clear cell carcinoma (OCCC).

Methods

A retrospective review of the Cancer Registry database was performed. All patients with UCCC and OCCC who underwent surgical staging at the two participating institutions, between January, 1995 and December, 2007, were identified. Categorical variables were evaluated by Chi square test. Survival estimates were plotted utilizing the Kaplan-Meier method.

Results

Analysis of 41 women with UCCC and 121 with OCCC was performed. In patients with OCCC, 48.4% had localized disease, 18.9% had regional spread, 31.1% had distant metastasis, and in 1.6% spread is unknown; compared to UCCC, 41.5% had localized disease, 12.2% regional spread, and 46.3% distant metastasis (p = 0.2). The median progression free survival was 31.4 months in women with UCCC, compared to 145 months in patients with OCCC (p = 0.04). UCCC women had a median overall survival of 39.5 months, compared to 155.8 months in patients with OCCC (p = 0.002). In the multivariate Cox regression model, age > 55 years old, tumor extension, optimal cytoreduction, and platinum-based chemotherapy were identified as independent predictors of overall survival. UCCC vs. OCCC was not associated with decreased overall survival in multivariate analysis.

Conclusion

OCCC and UCCC have the same rate of localized disease, regional spread and distant metastasis. After controlling for age, tumor extension, optimal cytoreduction, and platinum based chemotherapy, UCCC was not associated with decreased overall survival compared to OCCC.     

Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers

Objective

There are few validated relapse prediction biomarkers for epithelial ovarian cancer (EOC). We have shown progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) are up regulated, overexpressed survival factors in EOC. We hypothesized they would predict presence of occult EOC.

Method

PGRN, SLPI, and the known biomarker HE4 were measured in EOC patient plasma samples, prospectively collected every 3 months from initial remission until relapse. Clinical data and CA125 results were incorporated into statistical analyses. Exploratory Kaplan-Meier estimates, dividing markers at median values, evaluated association with progression-free survival (PFS) and overall survival (OS). Area-under-the-curve (AUC) statistics were computed from receiver operating characteristic (ROC) curves to evaluate discrimination ability. A Cox proportional hazards model assessed the association between PFS, OS, and biomarkers, adjusting for clinical prognostic factors.

Results

Samples from 23 advanced stage EOC patients were evaluated. PGRN at 3 months was the only biomarker independently associated with PFS (P < 0.0001) and OS (P < 0.003). When used to predict progression by 18 months, sensitivity and specificity were 93% and 100%, respectively, with AUC = 0.944. The Cox model hazard ratio for PFS, divided at 59 ng/ml by ROC analysis and adjusted for clinical factors, was 23.5 (95% CI: 2.49-220). Combinations with SLPI, HE4, and/or CA125 did not improve the model.

Conclusions

We report pilot data indicating a potential independent association of PGRN on EOC patient PFS and OS. A validation study will be required to confirm this finding and to inform whether PGRN warrants evaluation as a potential screening biomarker.     

An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical time period as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy (NACT)

Objective

The recent EORTC-NCIC randomized trial comparing primary debulking surgery (PDS) to neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian carcinoma (EOC) reported a median progression-free survival (PFS) of 12 months and overall survival (OS) of 30 months for both arms. Due to the equivalent survival and decreased morbidity with NACT, many now consider it the preferred approach. We analyzed the outcomes of patients treated with PDS at our institution during the same time period in which the EORTC-NCIC trial was conducted, using identical inclusion criteria.

Methods

We identified all patients undergoing primary treatment for advanced EOC at our institution from 9/98-12/06. Study inclusion and exclusion criteria were identical to those of the EORTC-NCIC trial. Standard statistical tests were used.

Results

Of 316 eligible patients, 285 (90%) underwent PDS and 31 (10%) received NACT due to extra-abdominal disease, medical comorbidities, and/or advanced age (> 85 years). Of the 285 patients who underwent PDS, most had carcinoma of ovarian origin (248, 87%); stage IIIC disease (249, 87%); grade 3 tumors (237, 83%); and serous histology (249, 87%). Optimal cytoreduction (≤ 1 cm residual) was achieved in 203 patients (71%). Postoperative platinum-based chemotherapy was given to 281 of 285 patients (99%). The median PFS and OS were 17 and 50 months, respectively.

Conclusion

PDS should continue to be the preferred initial management for patients with bulky stages IIIC-IV ovarian carcinoma. NACT should be reserved for those who cannot tolerate PDS and/or for whom optimal cytoreduction is not feasible.     

BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer

Objective

Our objective was to determine the rate of BRCA1/2 deficiency in platinum-sensitive and platinum-resistant tumors from a cohort of unselect patients with advanced epithelial ovarian cancer (EOH).

Methods

BRCA1/2 mutation analysis was performed in 29 patients with platinum-sensitive EOC and 24 patients with platinum-resistant disease. Germline DNA was analyzed in mutation carriers when normal tissue was available. BRCA expression was ascertained by quantitative rt-PCR. Associations between BRCA mutation status and expression levels and parameters of platinum response were analyzed.

Results

Fifteen of 53 (28.3%) EOC tumors had BRCA1/2 mutations. Twelve mutations were in BRCA1, while 3 involved BRCA2. Of the 12 mutation-carriers with normal tissue available for DNA analyses, 33.3% of the mutations were found to be somatic. Three mutations were novel. The majority of BRCA mutations (73%) were identified in patients with platinum-sensitive disease. In total, 38% of platinum-sensitive tumors were found to have a BRCA mutation, compared to 17% of the platinum-resistant patients. A statistical trend toward platinum-sensitive disease was seen in BRCA mutation carriers (p = 0.079). Nineteen (36%) study patients had some form of BRCA deficiency, and these patients were less likely to have platinum-resistant tumors (OR = 0.29; p value = 0.048).

Conclusions

BRCA mutations occurred more frequently in platinum-sensitive EOC than platinum-resistant disease. The high overall frequency of BRCA deficiency in EOC underscores the importance of tumor profiling as therapies targeting the DNA repair pathway are being investigated.     

Therapy-related myeloid leukemia after treatment for epithelial ovarian carcinoma: an epidemiological analysis

Objective

Therapy related acute myeloid leukemia (t-AML) is a potential late complication of cytotoxic therapy, and it is of particular concern in the treatment of patients with epithelial ovarian carcinoma (EOC) exposed to multiple courses of chemotherapy during the course of their disease. This study examines the incidence, characteristics and clinical outcomes of patients who developed secondary myeloid-type leukemia after a diagnosis of EOC.

Methods

National Cancer Institute's Surveillance, Epidemiology and End Results database was pooled for diagnosis of secondary myeloid leukemia after an initial diagnosis of EOC. This group of patients was compared to patients with de novo AML, and to EOC patients who did not develop secondary myeloid leukemia. Demographic, cytopathological and survival data were recorded. Cox Proportional Hazards model was used to calculate hazard ratios (HR) for developing secondary leukemia and to determine the statistically significant variables impacting survival. Kaplan-Meier estimates of survival were obtained and comparisons between the groups were performed using log-rank test.

Results

One hundred and nine myeloid leukemia cases were identified among 63,359 patients with a prior diagnosis of EOC for an overall incidence of 0.17%. The median latency to development of leukemia was 4 years (range 0-27 years). Median survival from the time of secondary leukemia diagnosis was 3 months and significantly worse than the 6 month median survival in patients with de novo AML (p < 0.001). Age at leukemia diagnosis greater than 65 and development of secondary vs. de novo leukemia had a statistically worse prognosis on multivariate analysis (HR of 2.69, 95%CI 2.60-2.78 and 1.81, 95%CI 1.49-2.20 respectively). The development of secondary leukemia was more common with EOC diagnosis made prior to the platinum/taxane era (HR 6.70, 95%CI 3.69-12.18). There was no difference in median survival between EOC patients who developed AML and those who did not.

Conclusion

Development of t-AML is a rare but lethal event among EOC patients, and its incidence has decreased significantly since the use of platinum/taxane-based chemotherapy became the standard of care.