Enhanced Recovery After Surgery (ERAS) in gynecologic oncology: System-wide implementation and audit leads to improved value and patient outcomes.

OBJECTIVE: Enhanced recovery pathways have been shown to reduce length of stay without increasing readmission or complications in numerous areas of surgery. Uptake of gynecologic oncology ERAS guidelines has been limited. We describe the effect of ERAS guideline implementation in gynecologic oncology on length of stay, patient outcomes, and economic impact for a province-wide single-payer system. METHODS: We compared pre- and post-guideline implementation outcomes in consecutive staging and debulking patients at two centers that provide the majority of surgical gynecologic oncology care in Alberta, Canada between March 2016 and April 2017. Clinical outcomes and compliance were obtained using the ERAS Interactive Audit System. Patients were followed until 30 days after discharge. Negative binomial regression was employed to adjust for patient characteristics. RESULTS: We assessed 152 pre-ERAS and 367 post-ERAS implementation patients. Mean compliance with ERAS care elements increased from 56% to 77.0% after implementation (p < 0.0001). Median length of stay for all surgeries decreased from 4.0 days to 3.0 days post-ERAS (p < 0.0001), which translated to an adjusted LOS decrease of 31.4% (95% CI = [21.7% - 39.9%], p < 0.0001). In medium/high complexity surgery median LOS was reduced by 2.0 days (p = 0.0005). Complications prior to discharge decreased from 53.3% to 36.2% post-ERAS (p = 0.0003). There was no significant difference in readmission (p = 0.6159), complications up to 30 days (p = 0.6274), or mortality (p = 0.3618) between the cohorts. The net cost savings per patient was $956 (95%CI: $162 to $1636). CONCLUSIONS: Systematic implementation of ERAS gynecologic oncology guidelines across a healthcare system improves patient outcomes and saves resources.

Safety and dose modification for patients receiving niraparib.

Background: Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose ∼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day. ClinicalTrials.gov ID: NCT01847274.

Expression of DNA damage response proteins in cervical cancer patients treated with radical chemoradiotherapy.

OBJECTIVE: The management of locally advanced cervical cancer has improved significantly with the advent of cisplatin-based chemoradiotherapy (CRT) as the primary treatment regimen. Nevertheless, a significant proportion of patients fail to respond or relapse on this treatment and have a very poor prognosis. Our goal was to determine the prognostic value of a panel of proteins involved in detection and repair of DNA damage. METHODS: We performed fluorescence immunohistochemistry, and used software analysis to assess expression of DNA damage response proteins ATM, DNA-PKcs, PARP-1, Ku70 and Ku86 in 117 pre-treatment specimens from patients with locally advanced cervical cancer. We compared expression to clinicopathologic correlates to determine prognostic significance. RESULTS: Five-year progression-free survival was significantly lower in the low expressors than in high expressors of ATM (35% vs. 58%, p=0.044) and PARP-1 (24% vs. 61%, p=0.003), and showed a trend to significance for DNA-PKcs (30% vs. 60%, p=0.050). Low expression of the same proteins also correlated significantly with lower overall survival. In multivariable analysis, adjusted for FIGO stage and tumor size, low ATM and PARP-1 expression was significantly associated with both poorer progression-free and overall survival. Pairwise analyses indicated that expression levels of these proteins were correlated. CONCLUSIONS: Expression of DNA damage response proteins in cervical cancer is associated with outcome in patients treated with CRT. Immunohistochemical analysis of these proteins may be useful in guiding treatment decisions in such patients.

The cost-effectiveness of bevacizumab for the treatment of advanced ovarian cancer in Canada.

BACKGROUND: The overall survival (os) analysis of the icon7 trial demonstrated that frontline ovarian cancer patients with a high risk of progression (stage iii suboptimally debulked, and stage iii or iv with unresectable disease) benefited from the addition of bevacizumab to standard chemotherapy compared with standard chemotherapy alone. The objective of the present study was to investigate the cost-effectiveness, from a Canadian publicly funded perspective, of adding bevacizumab to frontline treatment of ovarian cancer at high risk of progression. METHODS: An area-under-the-curve, Markov-structured model was used to estimate the cost-effectiveness of the treatments. Long-term progression-free survival (pfs) and os were extracted from the icon7 trial (subgroup at high risk of relapse) and extrapolated by parametric time-to-event functions over a time horizon of 10 years. Canadian pfs health state utility values were obtained from the EQ-5D (EuroQoL Group, Rotterdam, Netherlands) questionnaires in the icon7 high-risk patient population. Canadian post-progression utility values were consistent with those for other gynecologic cancers. Cost inputs were informed by public sources. An annual 5% efficacy and cost discount rate was applied. A probabilistic sensitivity analysis and one-way sensitivity analyses were conducted. RESULTS: Ovarian cancer patients at high risk of progression receiving bevacizumab plus standard chemotherapy experienced a mean incremental quality-adjusted life year (qaly) gain of 0.374 years. At an additional cost of $35,901.54, the incremental cost-effectiveness ratio (icer) for the addition of bevacizumab to standard chemotherapy, relative to standard chemotherapy alone, was $95,942 per qaly. CONCLUSIONS: No formal health technology assessment willingness-to-pay threshold exists in Canada. However, at a threshold of $100,000 per qaly, bevacizumab in addition to chemotherapy is a cost-effective alternative for ovarian cancer patients who are at high risk of progression (stage iii suboptimally debulked, and stage iii or iv with unresectable disease). Using the $100,000 per qaly threshold in a probabilistic sensitivity analysis, it was determined that, compared with standard chemotherapy, the addition of bevacizumab to chemotherapy is cost-effective in 56% of tested scenarios.

Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study.

BACKGROUND: We investigated the association of BRCA1 and XPG mutations with response rate (RR), progression-free survival (PFS) and overall survival (OS) in a subset of patients from a phase 3 clinical trial comparing the efficacy and safety of trabectedin + pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with recurrent ovarian cancer. PATIENTS AND METHODS: A candidate array was designed based on the Breast Cancer Information Core database for BRCA mutation analyses. An exploratory analysis of BRCA1/XPG mutation status was conducted using a two-sided log-rank test and 0.05 significance in germline DNA samples from 264 women with failed first-line platinum-based chemotherapy, randomized (1 : 1) to trabectedin + PLD or PLD alone. RESULTS: Overall, 41 (16%) of the 264 women had BRCA1(mut) (trabectedin + PLD: n = 24/135, 18%; PLD: n = 17/129; 13%) and 17 (6%) had XPG(mut) (trabectedin + PLD: n = 8/135, 6%; PLD: n = 9/129, 7%). A higher RR was observed in BRCA1(mut) patients (20/41; 49%) versus BRCA1(wt) patients (62/223; 28%). Within the BRCA1(mut) group, trabectedin + PLD-treated patients had longer PFS and longer OS than PLD-treated patients (median PFS 13.5 versus 5.5 months, P = 0.0002; median OS 23.8 versus 12.5 months, P = 0.0086), whereas in BRCA1(wt) patients, OS was not significantly different (median OS: 19.1 versus 19.3 months; P = 0.9377). There were no differences in OS or PFS of patients with XPG(mut) between the two treatment arms. However, trabectedin + PLD-treated patients with XPG(mut) had a trend toward shorter PFS (median PFS: 1.9 versus 7.5 months; P = 0.1666) and OS (median OS: 14.5 versus 20.7 months; P = 0.1774) than those with XPG(wt). CONCLUSIONS: In this exploratory analysis, patients with recurrent ovarian cancer carrying the BRCA1(mut) had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Phase I/II study of sagopilone (ZK-EPO) plus carboplatin in women with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: Sagopilone is the first fully synthetic epothilone in clinical development and has demonstrated promising preclinical activity. This phase I/II, prospective, open-label trial investigated the efficacy and safety of sagopilone plus carboplatin in patients with recurrent platinum-sensitive ovarian cancer (OC). METHODS: In phase I (dose-escalation stage), patients with OC recurring at least 6 months after platinum-containing chemotherapy received 3-h infusions of sagopilone (initial dose of 12 mg m(-2)) followed by carboplatin every 3 weeks, for 2-6 treatment courses. Patients enrolled in phase II received 3-h infusions of 16 mg m(-2) sagopilone. Efficacy was assessed using modified Response Evaluation Criteria in Solid Tumors (modRECIST) and Gynecologic Cancer InterGroup CA125 criteria. The safety and tolerability of sagopilone were also evaluated. RESULTS: In all, 45 patients received sagopilone at 12 mg m(-2) or 16 mg m(-2). There were 29 confirmed tumour responses (21 modRECIST and 8 CA125) across both treatment groups, indicating that the primary objective of the study was reached. The main adverse events (AEs) reported were peripheral neuropathy (75.6%), fatigue (71.1%) and nausea (64.4%). Grade ≥3 AEs occurred in 35 patients (77.8%). No deaths related to the study drug were reported. CONCLUSION: Sagopilone in combination with carboplatin was effective and toxicities were manageable in patients with recurrent platinum-sensitive OC.

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective.

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer.Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention.

Advanced ovarian cancer: phase III randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel vs carboplatin-paclitaxel.

BACKGROUND: Topotecan has single-agent activity in recurrent ovarian cancer. It was evaluated in a novel combination compared with standard frontline therapy. METHODS: Women aged 75 years or younger with newly diagnosed stage IIB or greater ovarian cancer, Eastern Cooperative Oncology Group Performance Status of 1 or less, were stratified by type of primary surgery and residual disease, treatment center, and age; then randomly assigned to one of the two 21-day intravenous regimens. Patients in arm 1 (n = 409) were administered four cycles of cisplatin 50 mg/m(2) on day 1 and topotecan 0.75 mg/m(2) on days 1-5, then four cycles of paclitaxel 175 mg/m(2) over 3 hours on day 1 followed by carboplatin (area under the curve = 5) on day 1. Patients in arm 2 (n = 410) were given paclitaxel plus carboplatin as in arm 1 for eight cycles. We compared progression-free survival (PFS), overall survival, and cancer antigen-125 normalization rates in the two treatment arms. A stratified log-rank test was used to assess the primary endpoint, PFS. All statistical tests were two-sided. RESULTS: A total of 819 patients were randomly assigned. At baseline, the median age of the patients was 57 years (range = 28-78); 81% had received debulking surgery, and of these, 55% had less than 1 cm residual disease; 66% of patients were stage III and 388 (47.4%) patients had measurable disease. After a median follow-up of 43 months, 650 patients had disease progression or died without documented progression and 406 had died. Patients in arm 1 had more hematological toxicity and hospitalizations than patients in arm 2; PFS was 14.6 months in arm 1 vs 16.2 months in arm 2 (hazard ratio = 1.10, 95% confidence interval = 0.94 to 1.28, P = .25). Among patients with elevated baseline cancer antigen-125, fewer in arm 1 than in arm 2 had levels return to normal by 3 months after random assignment (51.6% vs 63.3%, P = .007) CONCLUSIONS: Topotecan and cisplatin, followed by carboplatin and paclitaxel, were more toxic than carboplatin and paclitaxel alone, but without improved efficacy. Carboplatin plus paclitaxel remains the standard of care for advanced epithelial ovarian cancer.

Use of systemic therapy in women with recurrent ovarian cancer--development of a national clinical practice guideline.

OBJECTIVE: To develop a guidance document concerning the use of systemic therapy for women with recurrent ovarian cancer that would be applicable for the Canadian health care system. This will be done using a standardized systematic review process, guideline evaluation instruments, multi-disciplinary expert consensus opinion and evidence-rating systems. DATA SELECTION: The primary data sources were MEDLINE, National Guideline Clearinghouse and Cochrane Library. METHODS: Clinical practice guidelines, technology assessments, systematic reviews and randomized controlled trials addressing systemic therapy for women with recurrent ovarian cancer were eligible. DATA EXTRACTION: Data was identified and extracted by the methodology team and reviewed by the authors. Results were reviewed and discussed by members of an expert working group comprised of a multidisciplinary and geographic divergent group of practitioners. DATA SYNTHESIS: The existing 7 practice guidelines underwent formal evaluation for quality, currency and content using the AGREE tool. Recommendations with evidence-ratings were developed. This data was used by a pan-Canadian panel in an informal consensus process, which resulted in the initial draft of a guideline. The guideline team reviewed the draft and made further edits to ensure the guideline's appropriateness for a national context. Practitioner feedback was requested from 165 health care providers who treat ovarian cancer from across Canada. Overall response rate was 37% and was very positive. Comments were reviewed and the guideline was edited appropriately. CONCLUSION: The development of a national practice guideline on the use of systemic therapy for recurrent ovarian cancer was feasible using systematic literature review, expert consensus, guideline evaluation instruments, evidence-rating systems, independent internal and external review measures and final approval by a national discipline specific society (GOC). Recommendations for practice are offered.

Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: an NCIC clinical trials group study (NCIC IND.116).

OBJECTIVE: ISIS 5132 is a 20-base phosphorothioate DNA oligonucleotide against human c-raf kinase, a downstream effector of ras oncogene function. C-raf kinase is a molecule in the MAP kinase signaling cascade which is essential for cellular proliferation, the overexpression of which leads to malignant expression. Activity of this compound was documented in a woman with ovarian cancer in a Phase I study. METHODS: We evaluated ISIS 5132 at a dose of 4 mg/kg/day by continuous venous infusion, administered for 21 days q 4 weeks in 22 patients with recurrent ovarian cancer in a standard two-stage Phase II design. Three patients were ineligible; 19 patients are evaluable for toxicity and 16 for response. All patients had previously received systemic therapy for ovarian cancer (6 had one and 13 had two prior regimens). Patients were treated with a median of two cycles and 79% of the patients received >90% planned dose intensity. RESULTS: ISIS 5132 was well tolerated with no episodes of Grade 3 or 4 hematologic or biochemical (creatinine, AST, bilirubin) toxicity. There were six episodes of grade 3 nonhematologic toxicity in 4 patients thought to be treatment related (lethargy 2; anorexia 1; abdominal pain 2; shortness of breath 1). No responses were seen in the 16 patients who are evaluable for response; 4 had stable disease for a median of 3.8 months and 12 patients had documented progressive disease. CONCLUSION: ISIS 5132 at 4 mg/kg/day as a single agent did not show activity in recurrent ovarian cancer.

Postoperative chemotherapy in advanced ovarian granulosa cell tumors.

The objective of this research is to assess the use of first-line postoperative chemotherapy in patients with advanced ovarian granulosa cell tumor (GCT). A retrospective population-based case series identified 60 women with stage IC or greater ovarian GCT over a 25-year period. Five patients were excluded because of incomplete information. None of the patients had received chemotherapy or radiotherapy prior to the diagnosis of advanced GCT. All patients had, at a minimum, a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pathology was centrally reviewed and the diagnosis confirmed. Of the 55 eligible patients, the 21 women with stage III and IV disease were the main focus of the study. Clinical outcomes and survival were compared between 13 women who received combination chemotherapy and eight who did not. Univariate analysis was conducted to assess the impact of age at diagnosis, size of residual disease, and adjuvant use of radiation therapy on prognosis. For the 55 patients, median age at diagnosis was 54 years (range 22-79). Median length of follow-up was 4.4 years (range 0.3-23.3). Median time to progression was 2.3 years (range 0.3-5.3). Sixty percent of those with no macroscopic disease after primary surgery recurred within 4.5 years of diagnosis. All patients with gross residual disease (>2 cm) were dead within 4 years of diagnosis. Overall 5 years survival rate was 61.6% (95% CI (49.3-76.9)). Among stage III and IV patients, there were no differences with respect to age at diagnosis and use of radiation therapy between those who did and did not receive chemotherapy. The only statistically significant difference was the presence of macroscopic residual disease (82% vs. 22%). Although there was no statistical significant difference in overall survival, there was a trend toward a poorer outcome in the group that received chemotherapy. Survival of patients with macroscopic residual disease was not influenced by use of chemotherapy (P = 0.976). We conclude that the presence of macroscopic residual disease after primary surgery was the most important prognostic factor. Although these patients were more likely to receive postoperative chemotherapy, there was no evidence to document a beneficial effect of systemic therapy in this group of women.

Urolithiasis following formation of a continent urostomy: case report and review of the literature.

BACKGROUND: Formation of urinary stones in a continent urostomy (Indiana pouch) has been described as a late complication. Management of a patient with symptomatic multiple large stones and review of the literature are outlined. CASE REPORT: A 32-year-old woman presented with recurrent urinary tract infections and pyelonephritis 6 years after a total pelvic exenteration and creation of a continent urostomy for central recurrent carcinoma of the cervix after radical pelvic radiation. Multiple large stones were found to be the underlying etiology. Laparotomy, enterocystotomy, and removal of stones were performed without apparent complication. CONCLUSION: It is recommended that for single calculi or multiple small stones, electroshock wave lithotripsy or the percutaneous endoscopic approach be considered. For larger stones the use of laparotomy and enterocystostomy may be appropriate.

Factor analysis of false-negative second-look laparotomy.

From January 1976 through December 1987, 155 patients with ovarian epithelial malignancy underwent a second-look laparotomy. Seventy-seven (50%) had a negative second-look. Recurrence after negative second-look occurred in 15 patients (19.5%). Of the factors analyzed, serous histology and residual disease after initial laparotomy were found to be of significance. Grade of tumor, stage, and ascites were not found to be of significance.

Human papillomavirus types 16 and 18 sequences in early cervical neoplasia.

A total of 100 colposcopic biopsies from patients with abnormal Papanicolau's tests were surveyed for the presence of human papillomavirus (HPV) types 16 and 18 sequences by spot-blot hybridization. HPV 16 and 18 DNA sequences were detected in 58% of the biopsies. None of the cervical intraepithelial neoplasia grade I (CIN I) contained HPV 16 while 50% of the CIN III lesions (carcinoma in situ, CIS) contained HPV 16. HPV 18-related sequences were equally represented in CIN I, II, and III. Southern-blot hybridization of total undigested cellular DNA revealed the presence of HPV DNA sequences only in an episomal form. While the restriction enzyme patterns in HPV 16-positive samples were mostly identical to the originally cloned sequence, the restriction enzyme pattern for HPV 18-positive samples were different from that of HPV 18 but identical to each other. Furthermore, this DNA hybridized more strongly to HPV 18 under nonstringent conditions, suggesting a new type.