Incidence, treatment, and survival trends in older versus younger women with epithelial ovarian cancer from 2005 to 2018: A nationwide Danish study.

OBJECTIVE: To examine clinical trends in Denmark for younger and older epithelial ovarian cancer (EOC) patients, focusing on incidence, treatment, and survival changes. METHODS: We included a nationwide cohort diagnosed with EOC from 2005 to 2018. We described age-standardized incidence, surgical patterns, residual disease trends, and cancer-specific survival stratified by age (<70 and ≥ 70 years), stage, and period (2005-09, 2010-13, 2014-18). RESULTS: We included 7522 patients. The incidence decreased from 16.3 (2005) to 11.4 (2018) per 100,000 woman-years, driven by the younger cohort. While the proportion of patients with stage IIIC-IV disease undergoing primary debulking surgery (PDS) decreased, the proportion of patients having interval debulking surgery (IDS) and no debulking surgery increased significantly. In 2014-18, 36% and 24% had PDS for younger and older patients, respectively, compared to 72% and 62% in 2005-09. In both age cohorts, the proportion of patients debulked to no residual disease increased significantly among patients with stage IIIC-IV and in the total cohort. Two-year cancer-specific survival increased from 75% (2005-09) to 84% (2014-18) for younger patients and from 53% to 66% for older patients. After adjusting for potential confounders, age ≥ 70 was associated with a 1.4-fold increased risk of cancer-specific death (95% confidence interval: 1.2,1.5). CONCLUSIONS: The proportion of patients with advanced EOC not undergoing PDS or IDS increased significantly. During the same period, patients debulked to no residual disease, and cancer-specific survival increased. However, a survival gap in favor of the younger patients remains after adjusting for potential confounders.

Neoadjuvant Chemotherapy Reduces the Treatment-free Interval After First-line Treatment in Patients With Advanced Ovarian Cancer.

BACKGROUND/AIM: The aim of the study was to compare platinum resistance and treatment-free interval (TFI) following treatment with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or primary debulking surgery (PDS) in women with advanced epithelial ovarian cancer (EOC). PATIENTS AND METHODS: The study included patients diagnosed with primary EOC, stage IIIC or IV, between 2005 and 2013. Patients were grouped according to first-line treatment (PDS vs. NACT-IDS). Date of second-line treatment initiation was used to evaluate platinum sensitivity. RESULTS: The study population included 521 patients, of which 371 (71%) and 150 (29%) underwent PDS and NACT-IDS, respectively. We found no difference in platinum resistance between groups. Platinum-sensitive patients treated with NACT-IDS had a shorter median TFI (372 vs. 497 days, p=0.042). Similarly, patients with no residual tumor after IDS had a shorter median TFI (280 vs. 302 days, p=0.005). CONCLUSION: NACT-IDS may shorten the TFI after first-line platinum-based chemotherapy.

A novel index for preoperative, non-invasive prediction of macro-radical primary surgery in patients with stage IIIC-IV ovarian cancer-a part of the Danish prospective pelvic mass study.

The purpose of this study was to develop a novel index for preoperative, non-invasive prediction of complete primary cytoreduction in patients with FIGO stage IIIC-IV epithelial ovarian cancer. Prospectively collected clinical data was registered in the Danish Gynecologic Cancer Database. Blood samples were collected within 14 days of surgery and stored by the Danish CancerBiobank. Serum human epididymis protein 4 (HE4), serum cancer antigen 125 (CA125), age, performance status, and presence/absence of ascites at ultrasonography were evaluated individually and combined to predict complete tumor removal. One hundred fifty patients with advanced epithelial ovarian cancer were treated with primary debulking surgery (PDS). Complete PDS was achieved in 41 cases (27 %). The receiver operating characteristic curves demonstrated an area under the curve of 0.785 for HE4, 0.678 for CA125, and 0.688 for age. The multivariate model (Cancer Ovarii Non-invasive Assessment of Treatment Strategy (CONATS) index), consisting of HE4, age, and performance status, demonstrated an AUC of 0.853. According to the Danish indicator level, macro-radical PDS should be achieved in 60 % of patients admitted to primary surgery (positive predictive value of 60 %), resulting in a negative predictive value of 87.5 %, sensitivity of 68.3 %, specificity of 83.5 %, and cutoff of 0.63 for the CONATS index. Non-invasive prediction of complete PDS is possible with the CONATS index. The CONATS index is meant as a supplement to the standard preoperative evaluation of each patient. Evaluation of the CONATS index combined with radiological and/or laparoscopic findings may improve the assessment of the optimal treatment strategy in patients with advanced epithelial ovarian cancer.

Do stage of disease, comorbidity or access to treatment explain socioeconomic differences in survival after ovarian cancer? - A cohort study among Danish women diagnosed 2005-2010.

AIMS: In order to reduce social inequality in cancer survival, knowledge is needed about where in the cancer trajectory disparities occur, and how social and health-related aspects may interact. We aimed to determine whether socioeconomic factors are related to cancer diagnosis stage, and whether socioeconomic disparities in survival after ovarian cancer can be explained by socioeconomic differences in cancer stage, comorbidity, treatment or lifestyle factors. METHODS: In the Danish Gynaecological Cancer Database we identified 2873 cases of ovarian cancer diagnosed between 2005 and 2010. From this data we retrieved information on prognostic factors, treatment information and lifestyle factors. Age, vital status, comorbidity, education, income and cohabitation status were ascertained from nationwide administrative registers. Associations were analyzed with logistic regression and Cox regression models. RESULTS: Educational level was weakly associated with cancer stage. Short education, lower income and living without a partner were related to poorer survival after ovarian cancer. Among women with early cancer stage, HR (95% CI) for death was 1.75 (1.20-2.54) in shorter compared to longer educated women. After adjustment for comorbid conditions, cancer stage, tumour histology, operation status and lifestyle factors, socioeconomic differences in survival persisted. CONCLUSIONS: Socioeconomic disparities in survival after ovarian cancer were to some extent, but not fully explained by differences in important prognostic factors, suggesting further investigations into this problem, however implying that socially less advantaged ovarian cancer patients should receive attention during cancer treatment and rehabilitation.

Differences in regional diagnostic strategies and in intended versus actual first-line treatment of patients with advanced ovarian cancer in Denmark.

BACKGROUND: Triage of patients with ovarian cancer to primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT) is challenging. In Denmark, the use of NACT has increased, but substantial differences in the use of NACT or PDS exist among centers. We aimed to characterize the differences between intended and actual first-line treatments in addition to the differences in the triage process among the centers and to evaluate the different diagnostic modalities and the clinical aspects' influence in the triage process. MATERIALS AND METHODS: From 4 centers, forms containing data about the diagnostic process and intended treatment were prospectively collected and merged with data from the Danish Gynecological Cancer Database and medical records. RESULTS: Of the 671 completed forms, 540 patients had stage IIIC or IV epithelial ovarian cancer. Of the 238 (44%) referred to PDS, 91% received PDS and 4% never had debulking surgery. Of the 288 patients (53%) referred to NACT, 44% were never debulked. Fourteen patients (3%) were referred to palliative treatment. The use of different imaging modalities, diagnostic laparoscopy, and laparotomy varied significantly among the centers. Diagnostic surgical procedures were considered to be most influential in the triage process. Regardless of the intended first-line treatment or center, the tumor size and dissemination was the most influential clinical aspect. CONCLUSIONS: In Denmark, substantial differences exist between intended and actual first-line treatments as well as in the diagnostic process and use of NACT, calling for further discussion on diagnostic strategy and therapeutically approach for patients with advanced ovarian cancer.

Biomarkers for predicting complete debulking in ovarian cancer: lessons to be learned.

AIM: We aimed to construct and validate a model based on biomarkers to predict complete primary debulking surgery for ovarian cancer patients. PATIENTS AND METHODS: The study consisted of three parts: Part I: Biomarker data obtained from mass spectrometry, baseline data and, surgical outcome were used to construct predictive indices for complete tumour resection; Part II: sera from randomly selected patients from part I were analyzed using enzyme-linked immunosorbent assay (ELISA) to investigate the correlation to mass spectrometry; Part III: the indices from part I were validated in a new cohort of patients. RESULTS: Part I: The area under the receiver operating characteristic curve (AUC) was 0.82 for both indices. Part II: Linear regression analysis gave an R(2) value of 0.52 and 0.63 for transferrin and ß2-microglobulin, respectively. Part III: The AUC of the two indices decreased to 0.64. CONCLUSION: Our validated model based on biomarkers was unable to predict surgical outcome for patients with ovarian cancer.

Does neoadjuvant chemotherapy impair long-term survival for ovarian cancer patients? A nationwide Danish study.

OBJECTIVE: In Denmark, the proportion of women with ovarian cancer treated with neoadjuvant chemotherapy (NACT) has increased, and the use of NACT varies among center hospitals. We aimed to evaluate the impact of first-line treatment on surgical outcome and median overall survival (MOS). METHODS: All patients treated in Danish referral centers with stage IIIC or IV epithelial ovarian cancer from January 2005 to October 2011 were included. Data were obtained from the Danish Gynecological Cancer Database, the Danish National Patient Register and medical records. RESULTS: Of the 1677 eligible patients, 990 (59%) were treated with primary debulking surgery (PDS), 515 (31%) with NACT, and 172 (10%) received palliative treatment. Of the patients referred to NACT, 335 (65%) received interval debulking surgery (IDS). Patients treated with NACT-IDS had shorter operation times, less blood loss, less extensive surgery, fewer intraoperative complications and a lower frequency of residual tumor (p < 0.05 for all). No difference in MOS was found between patients treated with PDS (31.9 months) and patients treated with NACT-IDS (29.4 months), p = 0.099. Patients without residual tumor after surgery had better MOS when treated with PDS compared with NACT-IDS (55.5 and 36.7 months, respectively, p = 0.002). In a multivariate analysis, NACT-IDS was associated with increased risk of death after two years of follow-up (HR: 1.81; CI: 1.39-2.35). CONCLUSIONS: No difference in MOS was observed between PDS and NACT-IDS. However, patients without residual tumor had superior MOS when treated with PDS, and NACT-IDS could be associated with increased risk of death after two years of follow-up.

HE4 and CA125 levels in the preoperative assessment of endometrial cancer patients: a prospective multicenter study (ENDOMET).

OBJECTIVE: To evaluate whether human epididymis protein 4 (HE4) and CA125 correlate with known high-risk prognostic factors for endometrial cancer. DESIGN: Prospective multicenter study. SETTING: Three Danish tertiary gynecological oncology centers. POPULATION: A total of 352 patients with endometrial cancer and atypical endometrial hyperplasia consecutively referred between 1 September 2009 and 1 January 2012. METHODS: Preoperative blood samples were obtained from all patients. Biomarker levels were correlated with pathological characteristics of hysterectomy specimens. MAIN OUTCOME MEASURES: FIGO stage, depth of myometrial invasion, cervical involvement, lymph node metastases, and histological type and grade of tumor. RESULTS: We found that both HE4 and CA125 were significantly positively correlated with histological grade (HE4: p = 0.002 and CA125: p = 0.027), lymph node metastases (HE4: p = 0.013 and CA125: p < 0.0001), myometrial invasion (p < 0.0001) and cervical involvement (p < 0.0001). Furthermore, a significant increase was found with increasing FIGO stage for both markers (p < 0.0001). In a combined index including age, the diagnostic value increases. Area under the receiver operating characteristics curves were higher for the index compared with the markers individually for all our endpoints. The calculated plots for the combined index may assist gynecologists in predicting the risk of deep myometrial invasion, cervical involvement and lymph node metastases. The analyses emphasize that the combined markers should be used in the prediction of prognostic factors. CONCLUSION: This study confirmed that the markers are significantly elevated in patients with prognostic high-risk factors and may, therefore, be used as an additional tool in combination with imaging and clinical information when planning the treatment of endometrial cancer patients.

Diagnostic accuracy of risk of malignancy index in predicting complete tumor removal at primary debulking surgery for ovarian cancer patients.

Ovarian cancer patients in whom complete tumor removal is impossible with primary debulking surgery (PDS) may benefit from neoadjuvant chemotherapy and interval debulking surgery. However, the task of performing a pre-operative evaluation of the feasibility of PDS is difficult. We aimed to investigate whether the risk of malignancy index (RMI) was a useful marker for this evaluation. RMI and surgical outcome were investigated in 164 patients, 49 of whom had no residual tumor after PDS. The receiver operating characteristic curve showed an area under the curve of 0.72 (confidence interval: 0.64-0.80). The possibility of complete tumor removal decreased with increasing RMI and there was a tendency towards higher RMI in patients with residual tumor after PDS, but no single cut-off value of RMI produced useful clinical predictive values. In conclusion, RMI alone is not an optimal method to determine whether complete tumor removal is possible with PDS.

SUVmax of 18FDG PET/CT as a predictor of high-risk endometrial cancer patients.

OBJECTIVE: To evaluate SUVmax in the assessment of endometrial cancer preoperatively with particular focus on myometrial invasion (MI), cervical invasion (CI), FIGO stage, risk-stratification and lymph node metastases (LNM). METHODS: A total of 268 women with endometrial cancer or atypical endometrial hyperplasia underwent FDG PET/CT imaging before surgical treatment. SUVmax of the primary tumour was compared with histological prognostic factors. RESULTS: SUVmax was significantly higher in patients with high FIGO stages (p<0.0001), deep MI (p=0.002), CI (p=0.04), LNM (p=0.04) and high risk tumours (p=0.003). Linear regression found that SUVmax was dependent of MI (p=0.001, 95% CI 2.863-11.098), CI (p=0.001, 95% CI 2.896-11.499), risk (p=0.004, 95% CI 0.077-0.397), LNM (p=0.04, 95% CI 0.011-0.482) and FIGO stage (p<0.0001, 95% CI 0.158-0.473). CONCLUSIONS: Preoperative PET/CT scanning and SUVmax measurements of the primary tumour may provide additional clinical and prognostic information about MI, CI, LNM and high risk disease in patients with endometrial cancer and allow for individualization of patient care. However, the sensitivity and specificity of the SUVmax in staging endometrial cancer is not high enough to reliably replace surgical staging.

MRI, PET/CT and ultrasound in the preoperative staging of endometrial cancer - a multicenter prospective comparative study.

OBJECTIVES: The aim of this prospective multicenter study was to evaluate and compare the diagnostic performance of PET/CT, MRI and transvaginal two-dimensional ultrasound (2DUS) in the preoperative assessment of endometrial cancer (EC). METHODS: 318 consecutive women with EC were included when referred to three Danish tertiary gynecological centers for surgical treatment. Preoperatively they were PET/CT-, MRI-, and 2DUS scanned. The imaging results were compared to the final pathological findings. This study was approved by the National Committee on Health Research Ethics. RESULTS: For predicting myometrial invasion, we found sensitivity, specificity, PPV, NPV, and accuracy for PET/CT to be 93%, 49%, 41%, 95% and 61%, for MRI to be 87%, 57%, 44%, 92%, and 66% and for 2DUS to be 71%, 72%, 51%, 86% and 72%. For predicting cervical invasion, the values were 43%, 94%, 69%, 85% and 83%, respectively, for PET/CT, 33%, 95%, 60%, 85%, and 82%, respectively, for MRI, and 29%, 92%, 48%, 82% and 78% for 2DUS. Finally, for lymph node metastases, the values were 74%, 93%, 59%, 96%, and 91% for PET/CT and 59%, 93%, 40%, 97% and 90% for MRI. When comparing the diagnostic performance we found PET/CT, MRI and 2DUS to be comparable in predicting myometrial invasion. For cervical invasion and lymph node metastases, however, PET/CT was the best. CONCLUSIONS: None of the modalities can yet replace surgical staging. However, they all contributed to important knowledge and were, furthermore, able to upstage low-risk patients who would not have been recommended lymph node resection based on histology and grade alone.

Neoadjuvant chemotherapy as ovarian cancer treatment: ever more used with major regional differences.

INTRODUCTION: The traditional first-line treatment for patients with advanced ovarian cancer with primary debulking surgery (PDS) and adjuvant chemotherapy is controversial as some authors report a potential benefit from the alternative treatment with neoadjuvant chemotherapy (NACT) and interval debulking surgery. The aim of this study was to investigate the use of NACT in Denmark in regard to increased use and regional differences. MATERIAL AND METHODS: Stage IIIC and IV ovarian cancer patients treated in the five Danish tertiary referral centres in the 2005-2010-period were included. The study is based on validated data from The Danish Gynaecological Cancer Database. RESULTS: Of the 1,367 eligible patients 1,069 were treated with PDS and 298 with NACT. In 2005-2007, 11% of patients were treated with NACT. In 2008-2010, this percentage had risen to 30% (p < 0.00001). Between the five referral centres, the use of NACT ranged from 6% to 41% in 2005-2010 (p < 0.00001); from 1 % to 31% in 2005-2007 (p < 0.00001); from 10% to 48% in 2008-2010 (p < 0.00001) and from 9% to 48% in 2010 (p < 0.0008). Patients treated with NACT were significantly older, had inferior ASA scores and Eastern Cooperative Oncology Group performance status compared with the patients from the PDS group. There was no difference between treatments in regard to body mass index, stage IV disease or patients with no co-morbidity. CONCLUSION: The use of NACT as first-line treatment tripled from 2005-2010, but the regional variability was large which calls for a uniform agreement on treatment principles and evaluation. FUNDING: This study was financially supported by grants from The Copenhagen University Hospital Research Foundation, Manufacturer Einar Willumsens Memorial Trust, The Capital Region of Denmark Research Foundation, The Arvid Nilsson Foundation, The King Christian X Foundation, The Dagmar Marshall Foundation, The Danish Research Foundation, and The Hans and Nora Buchard Foundation. TRIAL REGISTRATION: not relevant.

Centralized treatment of advanced stages of ovarian cancer improves survival: a nationwide Danish survey.

OBJECTIVE: This retrospective, nationwide, observational study was designed to compare treatment in tertiary referral centers vs. regional hospitals on overall survival for patients with stage IIIC and IV ovarian cancer. MATERIAL AND METHODS: The study took place in all gynecological departments in Denmark, involving a total of 1,160 patients with stage IIIC or IV ovarian cancer. Data were extracted for 2,024 patients with all stages of ovarian cancer recorded in the Danish Gynecological Cancer Database between 1 January 2005 and 31 December 2008. The main outcome measure was overall survival. RESULTS: No difference was found between tertiary centers and regional hospitals with regard to age, body mass index, American Society of Anesthesiologists score or comorbidity. Patients in regional hospitals had poorer Eastern Cooperative Oncology Group performance status, i.e.1.0 vs. 2.0 (p= 0.005). Patients in referral centers presented more often with stage IIIC and IV disease, i.e. 59.7 vs. 51.7% (p < 0.001). Patients with stage IIIC and IV disease in regional vs. tertiary hospitals had a higher rate of primary cytoreductive surgery, i.e. 89.5 vs. 82.5% (p= 0.004), a poorer rate of complete cytoreductive surgery following primary cytoreductive surgery, i.e. 13.9 vs. 25.2% (p < 0.001), a lower rate of neoadjuvant chemotherapy, i.e. 5.5 vs. 13.4% (p < 0.001), and more often underwent acute surgery, i.e. 17.0 vs. 9.2% (p < 0.001). Patients treated in referral centers had better overall survival (p= 0.021). Treatment in a referral center was an independent prognostic factor for overall survival hazard ratio, 0.83 (confidence interval 0.70-0.98). CONCLUSION: Patients with stage IIIC and IV ovarian cancer benefit from treatment in a tertiary referral center.