Effect of chemotherapy delays and dose reductions on progression free and overall survival in the treatment of epithelial ovarian cancer

Introduction

Hematologic, gastrointestinal, and neurologic complications are common side effects of the platinum and taxane-based chemotherapy used in the primary treatment of epithelial ovarian cancer (EOC). These side effects and the impact of the resultant chemotherapy dose modification on disease free interval have not been extensively studied. The goal of this study was to determine the effect of chemotherapy delays and dose reductions on progression free survival (PFS) and overall survival (OS).

Methods

A review of patients with primary epithelial ovarian, peritoneal, and fallopian tube carcinoma treated between 1/2000 and 12/2007 was performed. Inclusion criteria were advanced stage disease and first line chemotherapy with a platinum and taxane regimen. Cox proportional hazard models were used to determine the effect of chemotherapy reductions and delays on PFS and OS.

Results

One hundred and fifty seven patients met the inclusion criteria. Patients were divided into four groups: no delays or reductions (48%), delay only (27%), reduction only (8%), and both delay and reduction (18%). The mean number of delays/reductions per patient was 1.1 (range = 0-5) and therapy was delayed a mean of 8 days. The most common reasons for delays/reductions were neutropenia (n = 51), thrombocytopenia (n = 45), and neuropathy (n = 18). There were no differences detected in PFS or OS between groups.

Conclusions

There were no differences detected in survival between patients who required dose adjustments and treatment delays and those who did not. The lack of association between survival and chemotherapy alterations suggests that in specific circumstances patients with advanced ovarian cancer should have individualized treatment plans.     

nm23 gene polymorphisms are associated with survival of patients with epithelial ovarian cancer but not with susceptibility to disease

Objective

nm23, a tumor metastasis suppressor gene, has been linked to protection against tumorigenesis and tumor metastasis. This study evaluated whether genetic variants in the nm23 gene were associated with susceptibility to epithelial ovarian cancer (EOC) or the clinical outcome of patients.

Methods

A case-control study was performed with 302 patients with epithelial ovarian cancer and 302 control women. According to the genotypes, the outcome in 213 EOC patients was compared. Progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier plots and Cox models adjusted for clinical factors.

Results

The case-control analysis showed that the rs16949649 and rs2302254 polymorphisms in the nm23 gene promoter were not associated with the risk of developing EOC. In contrast, survival analysis showed that the rs2302254 C/T polymorphism was related to the prognosis of EOC patients. Compared with patients carrying the C/C genotype, patients carrying the T/T genotype had a shorter median PFS and median OS by Kaplan-Meier plots and Cox models adjusted for clinical factors. For rs16949649 T/C polymorphisms, Kaplan-Meier analysis indicated that patients carrying the homozygous C/C genotype had shorter PFS and OS than those carrying the T allele (T/T + T/C genotype). The Cox proportional hazard model analysis suggested that this relationship was only retained in OS when adjusted for clinical factors.

Conclusion

Our studies suggest that rs16949649 and rs2302254 polymorphisms in the nm23 gene promoter may influence the prognosis of patients with epithelial ovarian cancer.     

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.     

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.     

A phase II study of a urokinase-derived peptide (A6) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study

Purpose

This multi-institutional phase II trial assessed the activity and tolerability of the anti-metastatic A6 peptide that binds CD44 in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (EOC/FTC/PPC).

Patients and methods

Women with persistent or recurrent EOC/FTC/PPC were eligible for participation if they had measurable disease defined by RECIST criteria, good performance status, and good overall organ function. Patients must have received one prior platinum-based chemotherapeutic regimen and were allowed to have received one additional cytotoxic regimen for the management of recurrent or persistent disease. Women received a 150 mg twice daily subcutaneous dose of A6 and continued on treatment until disease progression or unacceptable toxicity. Primary measures of clinical efficacy were objective tumor response and progression-free survival (PFS) at 6 months. The association of CD44 in archival tissue specimens with clinical outcome was investigated.

Results

Thirty-one eligible patients were evaluated. No responses were observed. Two patients (6.5%) were progression free for at least 6 months. The median PFS was 2.0 months, and median overall survival has not yet been reached. One patient died of hemorrhage which was possibly study related. There were no grade 4 toxicities. The most common grade 3 toxicities were constitutional (2/31; 6.5%). Archival specimens were available for 27 patients, and 5 (18.5%) were CD44 positive by immunohistochemistry. CD44 expression was not associated with the 6-month PFS (p = 0.342).

Conclusion

A6 was well tolerated but had minimal activity in patients with persistent or recurrent EOC/FTC/PPC.     

Pre-treatment tumor expression of ERCC1 in women with advanced stage epithelial ovarian cancer is not predictive of clinical outcomes: a Gynecologic Oncology Group study

Objective

Excision repair cross-complementation group 1 (ERCC1) is required for the repair of platinum-induced DNA damage. This study sought to assess the prognostic value of ERCC1 expression, measured by immunohistochemistry (IHC) using a highly specific antibody, in advanced epithelial ovarian cancer (EOC) patients treated with platinum-based chemotherapy.

Methods

Formalin-fixed, paraffin-embedded tumors were collected from two GOG phase III trials (GOG-172 and GOG-182) of patients with stage III/IV EOC treated with platinum-based chemotherapy. ERCC1 was detected by (IHC) using FL297 polyclonal antibody and tumors were categorized as negative or positive, based on nuclear staining of tumor cells. ERCC1 genotyping was performed as previously reported. Associations between ERCC1 expression and clinical characteristics, platinum responsiveness, progression-free survival (PFS) or overall survival (OS) were evaluated.

Results

Of 408 eligible patients, 27% had tumors that were ERCC1 positive. ERCC1 expression was not associated with clinical characteristics or platinum-responsiveness. Women with ERCC1-positive versus -negative tumors had similar median PFS (17.9 months versus 17.5 months, respectively, p = 0.59), median OS (52.0 months versus 47.0 months, respectively, p = 0.30), risk of disease progression (adjusted hazard ratio [HR] = 0.90, 95% confidence interval (CI): 0.71-1.15, p = 0.41), and risk of death (adjusted HR = 0.81, 95% CI: 0.61-1.07, p = 0.14). ERCC1 expression, as measured by IHC, was not associated with single nucleotide polymorphisms (SNPs), in codon 118 and C8092A, of the ERCC1 gene.

Conclusions

ERCC1 expression, measured by IHC in pre-treatment tumor specimens, using a highly specific antibody, has limited clinical value in patients with advanced EOC treated with platinum and taxane based chemotherapy.     

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.     

Impact of obesity on chemotherapy dosing for women with advanced stage serous ovarian cancer in the Australian Ovarian Cancer Study (AOCS)

Objectives

Obesity is an increasing health problem that is reported to influence chemotherapy dosing. The extent to which this occurs and whether this affects outcomes in ovarian cancer was unclear.To describe chemotherapy dosing practices in normal, overweight and obese patients treated for FIGO Stage III/IV serous ovarian cancer in the Australian Ovarian Cancer Study (AOCS).To evaluate the relationship between body mass index (BMI), dose intensity of chemotherapy received, overall survival (OS) and progression free survival (PFS).

Methods

Patient characteristics including age, height, weight, FIGO stage, serum creatinine, primary chemotherapy received and outcome data were extracted from medical records and entered into the AOCS database. Outcomes were analysed against BMI and relative dose intensity (RDI) received, based on calculations derived from a standard regimen (carboplatin AUC 5 and paclitaxel 175 mg/m²).

Results

333 women were included in the analysis. 27% were overweight and 21% were obese. In cycle 1 66% of obese patients received carboplatin doses more than 5% below their optimal calculated dose, and 32% received sub-optimal paclitaxel doses, compared to 25% and 13% of normal weight patients respectively. Obese women were more likely to have received < 85% RDI for carboplatin compared to normal weight women (p < 0.001). BMI group and RDI of carboplatin and paclitaxel were not predictors of OS. Women who received less than 85% RDI for carboplatin had a worse PFS (univariate analysis, median PFS 11 versus 15 months; p = 0.04). There was no significant association between RDI and OS or PFS in multivariate analysis.

Conclusions

Obesity is common in ovarian cancer patients, and commonly results in lower chemotherapy dosing than recommended. Analysis of chemotherapy dosing from this study suggests that reduced dose intensity of carboplatin, which was more common in obese women, may impact on PFS in patients with advanced serous ovarian cancer.     

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.     

A phase II trial of thalidomide in patients with refractory uterine carcinosarcoma and correlation with biomarkers of angiogenesis: A Gynecologic Oncology Group study

Objectives

To evaluate the efficacy and adverse events of thalidomide in previously-treated, measurable, persistent or recurrent carcinosarcoma of the uterus, and to explore associations between angiogenic markers with patient demographics and clinical outcome.

Methods

Eligible, consenting patients were treated until disease progression or toxicity intervened with daily starting dose of 200 mg thalidomide/day that was increased by 200 mg every 2 weeks to a target dose of 1000 mg/day. Endpoints included progression-free survival (PFS) ≥ 6 months (primary), toxicity, response, overall PFS and survival. Pre- and post-treatment plasma were evaluated for a panel of angiogenic biomarkers and assessed against clinical outcomes.

Results

Of 55 enrolled patients, 45 were evaluable for toxicity and survival. Two patients (4%; 90% CI 1-13%) experienced a partial response, and 8 (18%; 90% CI 9-30%) had PFS ≥ 6 months. Median PFS was 1.9 months and median survival was 5.9 months. Grade 2-3 sensory neuropathy was noted in 6 patients, and 4, 3, and 3 patients experienced grade 3 sedation, fatigue, and constipation, respectively. Three patients had grade 4 adverse events (2 thromboembolic, 1 anemia). High pre-treatment VEGFA levels were associated with poorer PFS and survival.

Conclusions

Treatment with thalidomide met the protocol specified goal of prolonging PFS at 6 months. However, based on results with newer agents, the activity was insufficient to support further investigation. Association between pre-treatment VEGFA and prognosis in this population supports further evaluation of anti-angiogenic therapies in uterine carcinosarcoma.     

Prognosis of ovarian clear cell carcinoma compared to other histological subtypes: a meta-analysis

Objective

To compare the survival outcome between clear cell carcinoma (CCC) and other histological subtypes in epithelial ovarian carcinoma (EOC).

Methods

From January 1974 to February 2011, we identified a total of 31,800 (CCC; 2152, non-CCC; 29648) patients from 12 studies meeting the inclusion criteria.

Results

Heterogeneity tests demonstrated significant between-study variation (I² = 92.1%) with no significant difference in hazard ratio (HR) for death between CCC and non-CCC (HR; 1.16, 95% CI; 0.85-1.57, random-effects model). Comparing the HR based on stage I + II, and stage III + IV, between CCC and non-CCC, showed that CCC patients had a higher hazard rate for death than those with non-CCC of the ovary (stage I + II; HR; 1.17, 95% CI; 1.01-1.36, stage III + IV; HR; 1.65, 95% CI; 1.52-1.79). In a comparison of CCC and serous EOC, advanced stage (III and IV) CCC only showed a poorer hazard rate for death than serous EOC (HR; 1.71, 95% CI; 1.57-1.86).

Conclusion

This analysis suggests that ovarian CCC patients had poorer prognosis than those with other histological subtypes of EOC, especially in advanced EOC stages. Different treatment strategies may be needed for patients with ovarian CCC.     

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.     

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.     

Perinatal audit using the 3-delays model in western Tanzania

Objective

To audit intrapartum fetal and early neonatal deaths of infants weighing ≥ 2000 g in a regional hospital in western Tanzania.

Methods

The 3-delays methodology was applied to a cohort of perinatal deaths from July 2002 to July 2004.

Results

The overall perinatal mortality rate in the hospital was 38 per 1000 live births, and in just over half of these cases the birth weight was ≥ 2000 g. The leading clinicopathologic causes of death were birth asphyxia (19.0%), prolonged or obstructed labor (18.5%), antepartum hemorrhage (11.5%), and uterine rupture (9.0%). First delays occurred in 19.0% of the cases, second delays occurred in 21.5%, and third delays occurred in 72.5%.

Conclusion

For women who delivered in this hospital, most of the substandard care occurred after admission to the health facility. The improvement of institutional health care may have a significant impact on the decision to attend health institutions and, thereby, reduce first delays.     

Intensity-modulated radiation therapy for advanced cervical cancer: a comparison of dosimetric and clinical outcomes with conventional radiotherapy

Objective

The aim of this study is to evaluate the dosimetry, efficacy and toxicity of reduced field intensity-modulated radiation therapy (RF-IMRT) for patients with advanced cervical cancer.

Methods

From August 2005 to August 2010, 60 patients with stage IIB-IIIB cervical cancer underwent reduced field IMRT (RF-IMRT group) and 62 patients treated with conventional radiotherapy (c-RT group) were enrolled. The RF-IMRT plans were as follows: whole pelvic IMRT plan was performed to deliver a dose of 30 Gy firstly, then the irradiated volume was reduced to lymphatic drainage region as well as paracervix and parametrium for an additional 30 Gy boost. Intracavitary brachytherapy and concurrent chemotherapy were performed during external irradiation. The tumor coverage and normal tissue avoidance were evaluated. Treatment response, toxicities and survival were assessed.

Results

The mean dose delivered to the planning target volume was significantly higher in RF-IMRT group than in c-RT group (61.5 vs. 50.8 Gy, P = 0.046). IMRT plans yielded better dose conformity to the target and better sparing of the rectal, bladder and small intestine. The RF-IMRT patients experienced significantly lower acute and chronic toxicities with comparable short-term effects than did those treated with conventional RT (CR: 87.7% vs. 88.3%, P = 0.496; PR: 7.0% vs. 6.7%, P = 0.440). No significant differences were found between treatment groups for 1 year, 3 year, and 5 year overall survival (OS) levels, although the latter approached statistical significance in favor of IMRT, while a significantly higher progression-free survival (PFS; P = 0.031) was seen for IMRT.

Conclusions

RF-IMRT yields improved dose distributions, with lower toxicities, while providing comparable clinical outcomes. The increased PFS may be an advantage.     

Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: a phase I study of the Gynecologic Oncology Group

Objectives

The aim of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of whole abdomen radiation as a chemosensitizer of weekly docetaxel for women with recurrent epithelial ovarian fallopian tube, or peritoneal cancers.

Patients and methods

Women were enrolled on one of three dose levels of docetaxel (20, 25, or 30 mg/m²) administered weekly with concurrent low-dose whole abdominal radiation given as 60 cGy bid 2 days weekly for a total of 6 weeks.

Results

Thirteen women were enrolled and received 70 weekly treatments of docetaxel in combination with radiation therapy. At the first dose level, docetaxel 25 mg/m², grade 3 fatigue and thrombocytopenia were observed. At the next dose level, docetaxel 30 mg/m², grade 3 febrile neutropenia, grade 4 thrombocytopenia with epistaxis, and grade 3 diarrhea were observed. Given these dose-limiting toxicities, a lower dose of docetaxel 20 mg/m² was administered and found to be tolerable. No objective responses were observed among the 10 patients with measurable disease; however, the median progression-free survival (PFS) in all patients was 3.3 months, and 3 of the patients with measurable disease were free of tumor progression after 6 months (30%; 90% confidence interval 8.7-61%).

Conclusions

Twice weekly low-dose whole abdomen radiation during weekly docetaxel 20 mg/m² was well-tolerated. Given the PFS demonstrated in these women with resistant ovarian cancer, further study of whole abdominal radiation and concurrent chemotherapy may be warranted.     

The impact of disease distribution on survival in patients with stage III epithelial ovarian cancer cytoreduced to microscopic residual: a Gynecologic Oncology Group study

Objective

To assess the survival impact of initial disease distribution on patients with stage III epithelial ovarian cancer (EOC) cytoreduced to microscopic residual.

Methods

We reviewed data from 417 stage III EOC patients cytoreduced to microscopic disease and given adjuvant intravenous platinum/paclitaxel on one of three randomized Gynecologic Oncology Group (GOG) trials. We subdivided patients into three groups based on preoperative disease burden: (1) minimal disease (MD) defined by pelvic tumor and retroperitoneal metastasis (2) abdominal peritoneal disease (APD) with disease limited to the pelvis, retroperitoneum, lower abdomen and omentum; and (3) upper abdominal disease (UAD) with disease affecting the diaphragm, spleen, liver or pancreas. We assessed the survival impact of potential prognostic factors, focusing on initial disease distribution using a proportional hazards model and estimated Kaplan-Meier survival curves.

Results

The study groups had similar clinicopathologic characteristics. Median overall survival (OS) was not reached in MD patients compared to 80 and 56 months in the APD and UAD groups (P < 0.05). The five-year survival percentages for MD, APD, and UAD were 67%, 63%, and 45%. In multivariate analysis, the UAD group had a significantly worse prognosis than MD and APD both individually and combined (Progression Free Survival (PFS) Hazards Ratio (HR) 1.44; P = 0.008 and OS HR 1.77; P = 0.0004 compared to MD + APD).

Conclusion

Stage III EOC patients with initial disease in the upper abdomen have a worse prognosis despite cytoreductive surgery to microscopic residual implying that factors beyond cytoreductive effort are important in predicting survival.     

Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer

Objective

To identify factors that increase the risk of neutropenic events in women with advanced ovarian carcinoma receiving initial chemotherapy.

Methods

Multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy from 1995 to 2008. Outcomes were severe (SN; absolute neutrophil count [ANC] < 500/mm³) and febrile neutropenia (FN; ANC < 1000/mm³ and temperature > 38.1 °C). Cumulative risk of neutropenic events was estimated by Kaplan Meier method. Multivariate analysis was by Cox proportional hazard regression.

Results

Three hundred twenty-six patients met inclusion criteria. There were 251 SN events among 140 (43%) patients and 24 FN events among 22 (7%) patients. Univariate predictors of SN were body surface area < 2.0 m² (p = 0.03), body mass index (BMI) < 30 kg/m² (p < 0.01), Caucasian race (p < 0.01), treatment on research protocols (p < 0.01), non-carboplatin-containing regimens (p < 0.01), and planned relative dose intensity (RDI) > 85% of standard (p = 0.02). Women over age 60 were more likely to develop FN (p = 0.05). Multivariate predictors of SN were treatment on research protocols (hazard ratio [HR] 1.93; p < 0.01), Caucasian race (HR 2.13; p = 0.01), and planned RDI > 85% (HR 1.69; p = 0.05); predictors of FN were age > 60 (HR 2.84; p = 0.05) and non-carboplatin containing regimens (HR 4.06; p < 0.01).

Conclusion

While SN is fairly common, FN occurs infrequently in women with EOC undergoing taxane and platin-based chemotherapy and primary prophylactic growth factor support is not indicated. However, women older than 60 years of age receiving non-carboplatin containing regimens are at higher risk for FN and warrant closer surveillance.     

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.     

Changes in serum CA-125 can predict optimal cytoreduction to no gross residual disease in patients with advanced stage ovarian cancer treated with neoadjuvant chemotherapy

Objective

To evaluate the predictive power of serum CA-125 changes in the management of patients undergoing neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) for a new diagnosis of epithelial ovarian carcinoma (EOC).

Methods

Using the Cancer Registry databases from our institutions, a retrospective review of patients with FIGO stage IIIC and IV EOC who were treated with platinum-based NACT-IDS between January 2006 and December 2009 was conducted. Demographic data, CA-125 levels, radiographic data, chemotherapy, and surgical-pathologic information were obtained. Continuous variables were evaluated by Student's t test or Wilcoxon-Mann-Whitney test.

Results

One hundred-three patients with stage IIIC or IV EOC met study criteria. Median number of neoadjuvant cycles was 3. Ninety-nine patients (96.1%) were optimally cytoreduced. Forty-seven patients (47.5%) had resection to no residual disease (NRD). The median CA-125 at diagnosis and before interval debulking was 1749 U/mL and 161 U/mL, respectively. Comparing patients with NRD v. optimal macroscopic disease (OMD), there was no statistical difference in the mean CA-125 at diagnosis (1566 U/mL v. 2077 U/mL, p = 0.1). There was a significant difference in the mean CA-125 prior to interval debulking, 92 v. 233 U/mL (p = 0.001). In the NRD group, 38 patients (80%) had preoperative CA-125 ≤ 100 U/mL compared to 33 patients (63.4%) in the OMD group (p = 0.04).

Conclusions

Patients who undergo NACT-IDS achieve a high rate of optimal cytoreduction. In our series, after treatment with taxane and platinum-based chemotherapy, patients with a preoperative CA-125 of ≤ 100 U/mL were highly likely to be cytoreduced to no residual disease.