The EORTC QLU-C10D is a valid cancer-specific preference-based measure for cost-utility and health technology assessment in the Netherlands.

BACKGROUND: Cost-utility analysis typically relies on preference-based measures (PBMs). While generic PBMs are widely used, disease-specific PBMs can capture aspects relevant for certain patient populations. Here the EORTC QLU-C10D, a cancer-specific PBM based on the QLQ-C30, is validated using Dutch trial data with the EQ-5D-3L as a generic comparator measure. METHODS: We retrospectively analysed data from four Dutch randomised controlled trials (RCTs) comprising the EORTC QLQ-C30 and the EQ-5D-3L. Respective Dutch value sets were applied. Correlations between the instruments were calculated for domains and index scores. Bland-Altman plots and intra-class correlations (ICC) displayed agreement between the measures. Independent and paired t-tests, effect sizes and relative validity indices were used to determine the instruments' performance in detecting clinically known-group differences and health changes over time. RESULTS: We analysed data from 602 cancer patients from four different trials. In overall, the EORTC QLU-C10D showed good relative validity with the EQ-5D-3L as a comparator (correlations of index scores r = 0.53-0.75, ICCs 0.686-0.808, conceptually similar domains showed higher correlations than dissimilar domains). Most importantly, it detected 63% of expected clinical group differences and 50% of changes over time in patients undergoing treatment. Both instruments showed poor performance in survivors. Detection rate and measurement efficiency were clearly higher for the QLU-C10D than for the EQ-5D-3L. CONCLUSIONS: The Dutch EORTC QLU-C10D showed good comparative validity in patients undergoing treatment. Our results underline the benefit that can be achieved by using a cancer-specific PBM for generating health utilities for cancer patients from a measurement perspective.

Laparoscopy for diagnosing resectability of disease in women with advanced ovarian cancer.

BACKGROUND: This is an update of a Cochrane Review that was originally published in 2014, Issue 2.The presence of residual disease after primary debulking surgery is a highly significant prognostic factor in women with advanced ovarian cancer. In up to 60% of women, residual tumour of > 1 cm is left behind after primary debulking surgery (defined as suboptimal debulking). These women might have benefited from neoadjuvant chemotherapy (NACT) prior to interval debulking surgery instead of primary debulking surgery followed by chemotherapy. It is therefore important to select accurately those women who would best be treated with primary debulking surgery followed by chemotherapy from those who would benefit from NACT prior to surgery. OBJECTIVES: To determine if performing a laparoscopy, in addition to conventional diagnostic work-up, in women suspected of advanced ovarian cancer is accurate in predicting the resectability of disease. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) in the Cochrane Library; MEDLINE via Ovid, Embase via Ovid, MEDION and Science Citation Index and Conference Proceedings Citation Index (ISI Web of Science) to July 2018. We also checked references of identified primary studies and review articles. SELECTION CRITERIA: We included studies that evaluated the diagnostic accuracy of laparoscopy to determine the resectability of disease in women who are suspected of advanced ovarian cancer and planned to receive primary debulking surgery. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently assessed the quality of included studies using QUADAS-2 and extracted data on study and participant characteristics, index test, target condition and reference standard. We extracted data for two-by-two tables and summarised these graphically. We calculated sensitivity and specificity and negative predictive values. MAIN RESULTS: We included 18 studies, reporting on 14 cohorts of women (including 1563 participants), of which one was a randomised controlled trial (RCT). Laparoscopic assessment suggested that disease was suitable for optimal debulking surgery (no macroscopic residual disease or residual disease < 1 cm (negative predictive values)) in 54% to 96% of women who had macroscopic complete debulking surgery (no visible disease at end of laparotomy) and in 69% to 100% of women who had optimal debulking surgery (residual tumour < 1 cm at end of laparotomy).Only two studies avoided partial verification bias by operating on all women independent of laparoscopic findings, and provided data to calculate sensitivity and specificity. These two studies had no false positive laparoscopies (i.e. no women had a laparoscopy indicating unresectable disease and then went on to have optimal debulking surgery (no disease > 1 cm remaining)).Due to the large heterogeneity pooling of the data was not possible for meta-analysis. AUTHORS' CONCLUSIONS: Laparoscopy may be a useful tool to identify those women who have unresectable disease, as no women were inappropriately unexplored. However, some women had suboptimal primary debulking surgery, despite laparoscopy predicting optimal debulking and data are at high risk of verification bias as only two studies performed the reference standard (debulking laparotomy) in test (laparoscopy)-positive women. Using a prediction model does not increase the sensitivity and will result in more unnecessarily explored women, due to a lower specificity.

Cost-effectiveness of laparoscopy as diagnostic tool before primary cytoreductive surgery in ovarian cancer.

OBJECTIVE: To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1cm residual disease) in patients suspected of advanced stage ovarian cancer. METHODS: An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patient's response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices. RESULTS: We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility=0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were € 1400 per intervention, making the overall costs of both strategies comparable (difference € -80 per patient (95% CI -470 to 300)). Findings were consistent across various sensitivity analyses. CONCLUSION: In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life.

Laparoscopy to Predict the Result of Primary Cytoreductive Surgery in Patients With Advanced Ovarian Cancer: A Randomized Controlled Trial.

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.

Prognostic Value of Residual Disease after Interval Debulking Surgery for FIGO Stage IIIC and IV Epithelial Ovarian Cancer.

Although complete debulking surgery for epithelial ovarian cancer (EOC) is more often achieved with interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT), randomized evidence shows no long-term survival benefit compared to complete primary debulking surgery (PDS). We performed an observational cohort study of patients treated with debulking surgery for advanced EOC to evaluate the prognostic value of residual disease after debulking surgery. All patients treated between 1998 and 2010 in three Dutch referral gynaecological oncology centres were included. The prognostic value of residual disease after surgery for disease specific survival was assessed using Cox-regression analyses. In total, 462 patients underwent NACT-IDS and 227 PDS. Macroscopic residual disease after debulking surgery was an independent prognostic factor for survival in both treatment modalities. Yet, residual tumour less than one centimetre at IDS was associated with a survival benefit of five months compared to leaving residual tumour more than one centimetre, whereas this benefit was not seen after PDS. Leaving residual tumour at IDS is a poor prognostic sign as it is after PDS. The specific prognostic value of residual tumour seems to depend on the clinical setting, as minimal instead of gross residual tumour is associated with improved survival after IDS, but not after PDS.

Laparoscopy for diagnosing resectability of disease in patients with advanced ovarian cancer.

BACKGROUND: The presence of residual tumour after primary debulking surgery is the most important prognostic factor in patients with advanced ovarian cancer. In up to 60% of cases, residual tumour of more than 1 cm is left behind, stressing the necessity of accurately selecting those patients who should be treated with primary debulking surgery and those who should receive neoadjuvant chemotherapy instead. OBJECTIVES: To determine if performing an open laparoscopy after the diagnostic work-up of patients suspected of advanced ovarian cancer is accurate in predicting the resectability of disease. SEARCH METHODS: We searched MEDLINE, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Register of Diagnostic Test Accuracy Studies, MEDION and ISI Web of Science to February 2013. Furthermore, we checked references of identified primary studies and review articles. SELECTION CRITERIA: We included studies that evaluated the diagnostic accuracy of laparoscopy to determine the resectability of disease in patients who are suspected of advanced ovarian cancer and planned to receive primary debulking surgery. DATA COLLECTION AND ANALYSIS: Two review authors assessed the quality of included studies using QUADAS-2 and extracted data on study and patients' characteristics, index test, target condition and reference standard. Data for two-by-two tables were extracted and summarised graphically. Sensitivity and specificity and negative predictive values were calculated. MAIN RESULTS: We included seven studies reporting on six cohorts. Between 27% to 64% of included patients per study were positive on laparoscopy (too extensive disease to warrant laparotomy) and between 36% to 73% were negative (disease suitable for debulking laparotomy). Only two studies avoided partial verification bias and provided data to calculate sensitivity and specificity, which did not justify meta-analysis. These two studies had a sensitivity of 0.70 (95% confidence interval (CI) 0.57 to 0.82) and 0.71 (95% CI 0.44 to 0.90); however, the specificity of both studies was 1.00 (95% CI 0.90 to 1.00). In these two studies there were no false positives, i.e. no patients for whom laparoscopy indicated that major surgery would not be successful and should be avoided, whereas, in reality the patient could be successfully operated upon. Negative predictive values (NPV), for those patients who were diagnosed with having not too extensive disease correctly identified were 0.75 (95% CI 0.55 to 0.86) and 0.96 (95% CI 0.56 to 0.99) due to a different prevalence. Although the studies did report sufficient data to calculate NPVs, we judged these estimates too heterogeneous to meta-analyse.Three studies described the development or validation of a prediction model with a clear cut-off for test positivity. Sensitivity and specificity of these prediction models were 0.30 to 0.70 and 0.89 to 1.00, respectively. However, one of these studies suffered from partial verification bias. AUTHORS' CONCLUSIONS: Laparoscopy is a promising test, but the low number of studies and the differences between the included studies do not allow firm conclusions to be drawn from these data. Due to a difference in prevalence, there is a wide range in negative predictive values between studies. Two studies verified all patients. These imply a high specificity of laparoscopy in diagnosing resectability and have a good sensitivity. Both studies show that the use of criteria for unresectable disease will result in no patients inappropriately unexplored. However, there will still be patients undergoing unsuccessful primary laparotomy. Using a prediction model does not increase the sensitivity and will result in more unnecessarily explored patients, due to a lower specificity.

Laparoscopy to predict the result of primary cytoreductive surgery in advanced ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled study.

BACKGROUND: Standard treatment of advanced ovarian cancer is surgery and chemotherapy. The goal of surgery is to remove all macroscopic tumour, as the amount of residual tumour is the most important prognostic factor for survival. When removal off all tumour is considered not feasible, neoadjuvant chemotherapy (NACT) in combination with interval debulking surgery (IDS) is performed. Current methods of staging are not always accurate in predicting surgical outcome, since approximately 40% of patients will have more than 1 cm residual tumour after primary debulking surgery (PDS). In this study we aim to assess whether adding laparoscopy to the diagnostic work-up of patients suspected of advanced ovarian carcinoma may prevent unsuccessful primary debulking surgery for ovarian cancer. METHODS: Multicentre randomized controlled trial, including all gynaecologic oncologic centres in the Netherlands and their affiliated hospitals. Patients are eligible when they are planned for PDS after conventional staging. Participants are randomized between direct PDS or additional diagnostic laparoscopy. Depending on the result of laparoscopy patients are treated by PDS within three weeks, followed by six courses of platinum based chemotherapy or with NACT and IDS 3-4 weeks after three courses of chemotherapy, followed by another three courses of chemotherapy. Primary outcome measure is the proportion of PDS's leaving more than one centimetre tumour residual in each arm. In total 200 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION: Patients who have disease considered to be resectable to less than one centimetre should undergo PDS to improve prognosis. However, there is a need for better diagnostic procedures because the current number of debulking surgeries leaving more than one centimetre residual tumour is still high. Laparoscopy before starting treatment for ovarian cancer can be an additional diagnostic tool to predict the outcome of PDS. Despite the absence of strong evidence and despite the possible complications, laparoscopy is already implemented in many countries. We propose a randomized multicentre trial to provide evidence on the effectiveness of laparoscopy before primary surgery for advanced stage ovarian cancer patients. TRIAL REGISTRATION: Netherlands Trial Register number NTR2644.