Cost-effectiveness of prophylaxis treatment strategies for febrile neutropenia in patients with recurrent ovarian cancer

Objective

Evaluate the cost-effectiveness of primary prophylaxis (PP) or secondary prophylaxis (SP) with pegfilgrastim, filgrastim (6-day and 11-day), or no prophylaxis to reduce the risk of febrile neutropenia (FN) in patients with recurrent ovarian cancer receiving docetaxel or topotecan.

Methods

A Markov model was used to evaluate the cost-effectiveness of PP vs SP from a US payer perspective. Model inputs, including the efficacy of each strategy (relative risk of FN with prophylaxis compared to no prophylaxis) and mortality, costs, and utility values were estimated from public sources and peer-reviewed publications. Incremental cost-effectiveness was evaluated in terms of net cost per FN event avoided, incremental cost per life-year saved (LYS), and incremental cost per quality-adjusted life-year (QALY) gained over a lifetime horizon. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted.

Results

For patients receiving docetaxel, the incremental cost-effectiveness ratio (ICER) for PP vs SP with pegfilgrastim was $7900 per QALY gained, and PP with pegfilgrastim dominated all other comparators. For patients receiving topotecan, PP with pegfilgrastim dominated all comparators. Model results were most sensitive to baseline FN risk. PP vs SP with pegfilgrastim was cost effective in 68% and 83% of simulations for docetaxel and in > 99% of simulations for topotecan at willingness-to-pay thresholds of $50,000 and $100,000 per QALY.

Conclusions

PP with pegfilgrastim should be considered cost effective compared to other prophylaxis strategies in patients with recurrent ovarian cancer receiving docetaxel or topotecan with a high risk of FN.     

Evaluation of the Patient-Generated Subjective Global Assessment (PG-SGA) as a predictor of febrile neutropenia in gynecologic cancer patients receiving combination chemotherapy: a pilot study

Objective

Determine if pre-treatment Patient-Generated Subjective Global Assessment (PG-SGA) predicts febrile neutropenia (FN) in gynecologic cancer patients receiving primary combination chemotherapy.

Methods

Following IRB approval, clinicopathologic variables, pre-treatment laboratory values and PG-SGA were recorded from eligible patients. Bone marrow toxicity (CTC 3.0) divided groups of patients: (1) No grade 3 or 4 neutropenia, (2) grade 3 or 4 neutropenia, (3) FN. Statistical analysis with Kruskal–Wallis one-way analysis of variance and a receiver operating characteristic (ROC) curve were performed.

Results

58 patients met study inclusion: 25 in group 1, 28 in group 2, and 5 in group 3. Mean age was 61 and the majority, 42 (72%), had ovarian cancer. Median PG-SGA scores were: 6 (group 1) vs. 7 (group 2) vs. 14 (group 3) (p = 0.019). Both median albumin: (1) 4.2 vs. (2) 4.0 vs. (3) 3.4 g/dl (p = 0.041), and hemoglobin: (1) 12.1 vs. (2) 11.75 vs. (3) 10.6 g/dl (p = 0.05) differed between the groups. The overall AUC of the ROC curve for PG-SGA was 0.831 ± 0.064 (95% CI = 0.706 to 0.956, p = 0.015). Using the ROC, selecting a PG-SGA score of 7.5 to be predictive of febrile neutropenia yields a sensitivity of 100% and a specificity of 60%. When the cutoff value is set at 12.5, the specificity improves to 81% while decreasing sensitivity to 80%.

Conclusions

PG-SGA scores were higher for patients experiencing FN and may be a reasonably predictive marker of FN in patients receiving multi-agent primary chemotherapy and likely benefactors of prophylactic GCSF.     

Quality of life evaluations in patients with ovarian cancer during chemotherapy treatment

OBJECTIVES: To examine the impact of treatment- and disease-related factors on the quality of life of patients with ovarian cancers undergoing chemotherapy. PATIENTS AND METHODS: Over 18 months period, all patients with ovarian cancer receiving chemotherapy at the Saskatoon Cancer Center were recruited. The Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire was used to assess patients' quality of life before each chemotherapy cycle. Platinum-based chemotherapy was used initially or in patients with a platinum-free interval of more than 6 months in a recurrence setting. After progression on the platinum-based regimens, liposomal doxorubicin, topotecan, and cisplatinum/etoposide were used as salvage chemotherapy pending on drug availability and convenience of administration to patients. Regression analysis was used to identify significant disease and treatment-related factors that can significantly affect patients' quality of life measures. RESULTS: Seventy-two patients participated in the study providing 270 separate observations. The mean age was 57.81 years with a standard deviation of 13.40. The median duration of chemotherapy-free interval for patients with recurrent disease was 7 months. All patients had stage 3 or 4 disease. About half (52.2%) of the patients had optimal surgical resection with small (<1 cm) residual cancer masses before primary adjuvant chemotherapy. Seventy percent of the patients had either a first diagnosis or a first recurrence of cancer with the other 30% previously treated with two or more chemotherapy regimens. Sixty-two percent had an initial complete response to platinum-based chemotherapy. Multivariate regression analysis showed the use of topotecan or cisplatinum/etoposide, patients' poor responses to chemotherapy, experience with two or more previous line of chemotherapy treatment, and younger ages were significant predictors of poor quality of life during chemotherapy. CONCLUSION: There were significant differences in side effects of commonly used chemotherapy regimens on patients' quality of life. Quality of life assessments should be routinely incorporated in selecting specific chemotherapy to be used. Future research should be carried out to identify the best strategies to further integrate the results of quality of life assessments in cancer treatment protocols and to examine the long-term effects of cancer and its treatment on patients and their families.     

Current standards of care for chemotherapy of optimally cytoreduced advanced epithelial ovarian cancer

There has been limited change in evidence-based primary chemotherapeutic management of optimal residual advanced ovarian cancer for more than a decade. The backbone of therapy remains a platinum agent (generally carboplatin) and a taxane (generally paclitaxel). Phase 3 randomized trial data provide support for the use of weekly paclitaxel in this setting (compared to the traditional every 3-week schedule) and the addition of bevacizumab as a component of primary management. Recently available data provide increasingly solid support for a role of regional platinum administration in at least a subset of patients with optimal residual advanced ovarian cancer and an important retrospective analysis has suggested a novel biomarker that may predict for the utility (or lack thereof) of this method of drug delivery.     

Chemotherapy delay after primary debulking surgery for ovarian cancer

Objective

To determine the association of chemotherapy delay with overall survival (OS) and investigate predictors of delay among a population-representative American ovarian cancer cohort.

Intraperitoneal chemotherapy for advanced ovarian cancer

Treatment of patients with advanced ovarian cancer who have failure of first-line chemotherapy is rarely effective. Preliminary pharmacokinetic and phase II clinical studies established the feasibility of delivering relatively high concentrations of cisplatin intraperitoneally via a semipermanent catheter, while using intravenous sodium thiosulfate as a neutralizing agent to decrease the nephrotoxicity of cisplatin. Sixty patients with advanced ovarian cancer, all of whom had failure of first-line chemotherapy (including cisplatin in 56 of 60), were treated with high-dose intraperitoneal cisplatin in combination with doxorubicin and/or cytarabine. Of the 46 patients evaluable for response, 19 (42%) showed an objective response, most often (12/19) disappearance of malignant ascites. No serious drug-associated morbidity was observed aside from three cases of intestinal obstruction which may have been due in part to drug-induced adhesions. It is felt that prospective studies to compare the efficacy of intraperitoneal chemotherapy with other forms of "salvage" therapy, as well as its use as initial chemotherapy for advanced ovarian cancer, need to be done.     

Chemotherapy-induced neutropenia as a biomarker of survival in advanced ovarian carcinoma: An exploratory study of the Gynecologic Oncology Group

Objective

To determine whether chemotherapy-induced neutropenia (C-iN) is associated with improved survival in a population of primary advanced ovarian cancer and peritoneal carcinoma patients treated with a carboplatin plus paclitaxel chemotherapy backbone.

Methods

A post-hoc exploratory analysis of Gynecologic Oncology Group (GOG) protocol 182 was performed. Landmark analysis was conducted on all patients with progression-free survival > 18 weeks from the time of study entry. Neutropenia was defined as the absolute neutrophil count < 1000 mm³. The occurrence of C-iN was analyzed according to demographic, clinicopathologic, and therapeutic intent, including age, body surface area, and treatment arm. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The Cox proportional hazards model was used to evaluate independent prognostic factors and to estimate their effects on PFS and OS.

Results

Neutropenic data was available for 3447 patients. Neutropenic (n = 3196) and non-neutropenic groups (n = 251) were similar in demographic and clinicopathologic characteristics. Neutropenic patients experienced significantly improved survival compared to non-neutropenic patients with the adjusted hazard ratio (HR) for death being 0.86 (95% confidence interval 0.74–0.99; p = 0.041). There was no survival benefit associated with any of the treatment arms among patients with C-iN.

Conclusion

These data suggest that C-iN may represent a clinical biomarker associated with a survival advantage for patients with untreated advanced ovarian cancer. The absence of C-iN may indicate under-dosing and ultimately attenuated anti-neoplastic effect in vulnerable populations.     

Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum

OBJECTIVE: Previously reported data have suggested the lack of complete cross-resistance between docetaxel and paclitaxel in ovarian cancer. We wished to evaluate the biological and clinical activity of docetaxel in a patient population with well-characterized platinum and paclitaxel-refractory ovarian cancer. METHODS: In this single-institution phase 2 trial, 30 women with advanced ovarian cancer whose disease had either failed to respond to primary platinum-paclitaxel chemotherapy or where the cancer had progressed within 3 months of their last treatment with both a platinum agent and paclitaxel were treated with single agent docetaxel (75 mg/m(2) q 3 weeks). Due to a prior history of excessive chemotherapy-induced neutropenia, 3 patients initiated treatment at a dose of 60 mg/m(2). RESULTS: The median number of courses of docetaxel delivered on this protocol was 3 (range 1-7), with 7 patients requiring dose reductions due to treatment-related side effects. The most common toxicities included grade 4 neutropenia, neutropenic fever, and grade >/=2 fatigue experienced by 9 (30%), 2 (7%), 5 (17%) patients, respectively. Three patients (10%) achieved both an objective response (by CA-125 criteria) and symptomatic improvement (e.g., decrease in pain and ascites). The durations of responses were 3, 4, and 6 months. CONCLUSION: Single-agent docetaxel has modest, but definite activity in patients with well-characterized platinum and paclitaxel-resistant ovarian cancer. Use of this drug should be considered a rational management approach in appropriately selected patients in this clinical setting.     

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.     

Guidelines for the management of ovarian cancer during pregnancy

Adnexal masses may be detected during prenatal ultrasound, and ovarian cancer may be suspected during pregnancy. Even though such masses are rarely malignant (1/10,000 to 1/50,000 pregnancies), the possibility of borderline tumour or cancer must be considered. It is a common assumption by both patients and physicians that if an ovarian cancer is diagnosed during pregnancy, treatment necessitates sacrificing the well-being of the fetus. However, in most cases, it is possible to offer appropriate treatment to the mother without placing the fetus at serious risk.     

Clinical disease course during the last year in ovarian cancer

OBJECTIVE(S): The objective was to determine whether there were changes in the pattern and nature of hospitalizations during the last year that could be used in the assessment of whether chemotherapy should be continued. METHODS: Retrospective data were collected from patients who died from ovarian cancer between 1/2000 and 12/2001. Charts from four hospitals were reviewed to abstract chemotherapy, reason for hospitalization, and the incidence of three significant clinical events (bowel obstruction, pleural effusion requiring thoracentesis, and abdominal ascites requiring paracentesis). Data were analyzed in 3-month intervals. RESULTS: Sixty-two patient charts were reviewed. Quarterly admissions increased linearly over the year (7, 18, 27, and 47, P < 0.0001). Hospitalizations for ascites, bowel obstruction, and pleural effusion began increasing around 6 months preceding death. Twenty-two patients did not receive chemotherapy during the last 3 months. Of the 40 patients receiving chemotherapy in the last 3 months, over half were not hospitalized during the period 4-6 months before death, and a further 20% were hospitalized for nonsignificant clinical events. Approximately one-quarter of the patients, however, continued to receive chemotherapy following hospitalization for a significant clinical event. CONCLUSION(S): There were significant changes in the pattern and nature of hospitalization during the last 6 months that included hospitalizations for bowel obstruction, pleural effusion, or ascites. The occurrence of these events suggests that further chemotherapy should be realistically evaluated with the patient, which may reduce the number of patients who receive chemotherapy during their last few months of life.     

Predictors of suboptimal surgical cytoreduction in women treated with initial cytoreductive surgery for advanced stage epithelial ovarian cancer

OBJECTIVE: The purpose of this study was to determine if a suboptimal cytoreduction can be predicted preoperatively in women with advanced ovarian cancer. STUDY DESIGN: All women with stage III/IV epithelial ovarian cancer treated with initial surgery at our hospital between January 1, 1995 and January 1, 2003 were eligible; 56 patients met inclusion criteria and underwent retrospective chart review. Statistical analysis was performed using SPSS. RESULTS: Twenty-nine women (52%) had optimal cytoreduction (OC), and 27 (48%) had suboptimal cytoreduction (SC). Women in the SC group had higher median CA-125 values at surgery (954 SC vs 597 OC, P = .07). Three sites of disease on preoperative CT were reported more frequently in the SC patients; omentum (P = .007), parietal peritoneum (P = .096), and ascites (P = .093). CONCLUSION: A suboptimal cytoreduction confers no survival advantage to women with advanced ovarian cancer. Thus, these patients may be the best candidates for initial chemotherapy, and identifying them preoperatively becomes important.     

Predictors of surgical outcome and survival among elderly women diagnosed with ovarian and primary peritoneal cancer

OBJECTIVE: To identify perioperative variables that will predict surgical outcome and survival among elderly women diagnosed with ovarian and primary peritoneal cancer. METHODS: A retrospective review of 78 women>or=75 years treated for ovarian and primary peritoneal cancer from 1/1/90 to 06/30/04 was performed. Patients were categorized in two groups based on optimal versus suboptimal cytoreductive surgery. Perioperative variables were compared across the two groups by univariate and multivariate logistic regression analysis to evaluate the impact on survival. RESULTS: The median age at the time of diagnosis was 79.3 years. Overall, 50% of the patients underwent optimal cytoreductive surgery. Patients with low perioperative serum albumin levels were associated with a 2.4-fold increased risk of suboptimal cytoreductive surgery (95% CI 1.02-5.88, p=0.04). Median survival of patients that underwent cytoreductive surgery was 19 months. As expected, survival analysis showed that patients with suboptimal cytoreductive surgery had a lower survival (median=17 months) than patients with optimal surgery (median=62 months, p=0.00). Patients>or=80 years were associated with a nearly 2-fold increase in the risk of mortality (95% CI 1.05-3.54, p=0.03), while albumin levels of >or=3.7 g/dl were associated with a 40% reduction in risk of mortality (95% CI 0.41-0.89, p=0.01). CONCLUSIONS: Optimal cytoreductive surgery is feasible in many elderly patients. Women>or=80 years and with poor nutritional status are associated with a poor survival outcome. Perioperative variables such as these can be used to identify the elderly patients that are most likely to be suboptimally cytoreduced and thus have a dismal survival outcome.     

Somatic hypermutation and outcomes of platinum based chemotherapy in patients with high grade serous ovarian cancer

Objective

The standard treatment for high grade ovarian serous cancer (HG-OSC) is aggressive cytoreductive surgery followed by platinum based chemotherapy. However, approximately 30% of patients exhibit platinum resistance, and those patients show aggressive clinical courses. Currently, it is difficult to predict which HG-OSC patients will respond to platinum-based chemotherapy.

Methods

We analyzed whole exome sequences for 174 HG-SOC patients using data obtained from The Cancer Genome Atlas (TCGA) data portal regarding platinum response. Patients were categorized as having either hypermutation or hypomutation according to the number of mutations in their sample.

Results

HG-SOC showed multiple somatic mutations in individual patients with an average mutated gene number of 61.9. The mean mutation number per patient significantly differed between the platinum sensitive and resistant groups (P < 0.001). Patients who were platinum sensitive were more likely to have somatic hypermutation in their cancer cells and multivariate logistic regression analysis revealed that somatic hypermutation was an independent factor for risk estimation of platinum sensitivity (odds ratio [OR] = 3.616; P = 0.002). In multivariate Cox hazard analysis, we identified that somatic hypermutation, as well as platinum response and surgical outcome, were independent prognostic factors in HG-OSC (overall survival, P = 0.012; progression free survival, P = 0.036).

Conclusions

Somatic hypermutation was significantly associated with platinum sensitivity and was an independent prognostic factor in HG-OSC patients treated with platinum based chemotherapy.     

Prognostic significance of the relative dose intensity of chemotherapy in primary treatment of epithelial ovarian cancer

Objective

Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. In this study, we sought to determine the prognostic significance of RDI in patients with epithelial ovarian cancer (EOC).

Methods

A retrospective analysis of chemotherapy naïve patients treated between 2001 and 2008 with intravenous taxane and platinum was performed. RDI was calculated as the delivered dose intensity (total dose delivered/total time of therapy) divided by standard dose intensity calculated for each regimen and compared to progression-free survival (PFS). Multivariate recursive partitioning survival analysis was utilized.

Results

138 EOC patients completed initial taxane/platinum-based chemotherapy following surgical cytoreduction. The most common reasons for dose delays and reductions were thrombocytopenia (38%) and neutropenia (31%). 24% of treatment delays were due to social reasons such as transportation constraints or scheduling conflicts. The average RDI was 90% (range, 24-126%). The mean PFS was 31 months (range, 3-117). Patients that achieved an RDI between 70% and 110% had a mean PFS of 32 months compared to 20 months in patients with an RDI of < 70% or > 110% (p = 0.046). 14 patients (10%) had a RDI of < 70%.

Conclusions

RDI is a significant predictor of survival in patients with EOC. Effort should be made to achieve an RDI of at least 70%. Dose reductions and treatment delays could be minimized by utilizing prophylactic colony stimulating factors and educating patients about the importance of adhering to their treatment schedule.     

Platinum-resistant ovarian cancer: Prematurely stopped phase II Austrian AGO chemotherapy studies

AIM: To report the results of two phase II studies of chemotherapy in patients with platinum-resistant and platinum-refractory ovarian cancer and discuss the current status of systemic therapy in this disease. METHODS: Two subsequent Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) phase II studies have been carried out. Patients either had platinum-refractory or platinum-resistant disease, i.e., disease progression during first line platinum-based therapy or recurrence within 6 mo following the last platinum-containing chemotherapy, respectively. In the first study, 6 cycles of irinotecan at 55 mg/m² and docetaxel 25 mg/m² were both administered on days 1, 8 and 15 of a 4 wk cycle. In the second phase II study, either non-pegylated (PEG) liposomal doxorubicin (L-DXR) 60 mg/m² monotherapy on day 1 and PEG filgrastim on day 2 (arm A) or L-DXR at 50 mg/m² and gemcitabine (GEM) at 650 mg/m² on day 1 and GEM on day 8 (arm B) were administered every 4 wk. Patients in arm B received prophylactic filgrastim 5 μg/kg per day from days 3 to 6 and from days 9 to 12, respectively. RESULTS: Response rates in studies were 14% and 17%, respectively. The progression-free survival was less than 3 mo. Diarrhea was most prevalent in patients treated with irinotecan + docetaxel, while stomatitis/mucositis occurred in a quarter of patients treated with L-DXR +/- GEM + granulocyte colony stimulating factor, respectively. Following treatment with the latter regimen, a total of 11 serious adverse events were recorded among the 12 patients included. The rate of remissions of the regimens used in these two Austrian AGO studies was low and their toxicity significant. Due to their low therapeutic index, neither of these regimens can be recommended in this heavily pretreated patient population with platinum-resistant ovarian cancer exhibiting a high tumor-associated symptom burden. CONCLUSION: The two reported phase II studies of the Austrian AGO in platinum-resistant disease had to be terminated prematurely due to a low therapeutic index. Treatment of this disease remains a clinical dilemma. Bevacizumab seems to be active at this late-stage disease but may be associated with significant bowel toxicity.     

Clinical outcome of neoadjuvant chemotherapy for advanced ovarian cancer

Objective

To evaluate clinical outcome in patients selected to receive neoadjuvant chemotherapy (NACT) compared to primary debulking surgery (PDS).