The potential of RAS/RAF/MEK/ERK (MAPK) signaling pathway inhibitors in ovarian cancer: A systematic review and meta-analysis.

BACKGROUND: The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events. METHODS: We conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model. RESULTS: We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I2 = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAFv600 mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81-92%, I2 = 0%) and 27% (95%-CI 10-48%, I2 = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients. CONCLUSIONS: MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAFv600 mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.

Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100.

OBJECTIVE: This prespecified exploratory analysis evaluated the association of gene expression signatures, tumor mutational burden (TMB), and multiplex immunohistochemistry (mIHC) tumor microenvironment-associated cell phenotypes with clinical outcomes of pembrolizumab in advanced recurrent ovarian cancer (ROC) from the phase II KEYNOTE-100 study. METHODS: Pembrolizumab-treated patients with evaluable RNA-sequencing (n = 317), whole exome sequencing (n = 293), or select mIHC (n = 125) data were evaluated. The association between outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and gene expression signatures (T-cell-inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures), TMB, and prespecified mIHC cell phenotype densities as continuous variables was evaluated using logistic (ORR) and Cox proportional hazards regression (PFS; OS). One-sided p-values were calculated at prespecified α = 0.05 for TcellinfGEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-TcellinfGEP signatures; all but TcellinfGEP and TMB were adjusted for multiplicity. RESULTS: No evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and TcellinfGEP-adjusted glycolysis (PFS, adjusted-p = 0.019; OS, adjusted-p = 0.085) and hypoxia (PFS, adjusted-p = 0.064) signatures. TMB as a continuous variable was not associated with outcomes (p > 0.05). Positive associations were observed between densities of myeloid cell phenotypes CD11c+ and CD11c+/MHCII-/CD163-/CD68- in the tumor compartment and ORR (adjusted-p = 0.025 and 0.013, respectively). CONCLUSIONS: This exploratory analysis in advanced ROC did not find evidence for associations between gene expression signatures and outcomes of pembrolizumab. mIHC analysis suggests CD11c+ and CD11c+/MHCII-/CD163-/CD68- phenotypes representing myeloid cell populations may be associated with improved outcomes with pembrolizumab in advanced ROC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02674061.

Efficacy and safety of durvalumab with olaparib in metastatic or recurrent endometrial cancer (phase II DOMEC trial).

BACKGROUND: Patients with advanced endometrial cancer have a poor prognosis, and treatment options are limited. The investigator-initiated, multicenter, phase II DOMEC trial (NCT03951415) is the first trial to report data on efficacy and safety of combined treatment with PD-L1 and PARP inhibition for advanced endometrial cancer. PATIENTS AND METHODS: Patients with metastatic or recurrent endometrial cancer were enrolled. Patients received durvalumab 1500 mg intravenously q4w and olaparib 300 mg 2dd until disease progression, unacceptable toxicity, or patient withdrawal. Patients with at least 4 weeks of treatment were evaluable for analysis. The primary endpoint was progression-free survival at 6 months. Evidence for efficacy was defined as progression-free survival at 6 months in ≥50% of patients. Secondary endpoints included safety, objective response and overall survival. RESULTS: From July 2019, through November 2020, 55 patients were enrolled. At data cut-off (September 2021), 4 of the 50 evaluable patients were still on treatment. Seventeen patients (34%) were progression-free at 6 months. Objective response rate was 16% (95% CI, 8.3 to 28.5) with 1 complete and 7 partial responses. With a median follow-up of 17.6 months, median progression-free survival was 3.4 months (95% CI, 2.8 to 6.2) and median overall survival was 8.0 months (95% CI, 7.5 to 14.3). Grade 3 treatment-related adverse events occurred in 8 patients (16%), predominantly anemia. There were no grade 4 or 5 treatment-related adverse events. CONCLUSION: The combination of durvalumab and olaparib was well tolerated, but did not meet the prespecified 50% 6-month progression-free survival in this heterogeneous patient population with advanced endometrial cancer.

The psychological impact of gestational trophoblastic disease: a prospective observational multicentre cohort study.

OBJECTIVE: To evaluate the short-term psychological consequences of gestational trophoblastic disease (GTD). DESIGN: A prospective observational multicentre cohort study. SETTING: Nationwide in the Netherlands. POPULATION: GTD patients. METHODS: Online questionnaires directly after diagnosis. MAIN OUTCOME MEASURES: Hospital Anxiety and Depression Scale (HADS), Distress Thermometer (DT), Impact of Event Scale (IES) and Reproductive Concerns Scale (RCS). RESULTS: Sixty GTD patients were included between 2017 and 2020. Anxious feelings (47%) were more commonly expressed than depressive feelings (27%). Patients experienced moderate to severe adaptation problems in 88%. Patients who already had children were less concerned about their reproductivity than were patients without children (mean score 10.4 versus 15.0, P = 0.031), and patients with children experienced lower distress levels (IES mean score 25.7 versus 34.7, P = 0.020). In addition, patients with previous pregnancy loss scored lower for distress compared with patients without pregnancy loss (IES mean score 21.1 versus 34.2, P = 0.002). DISCUSSION: We recommend that physicians monitor physical complaints and the course of psychological wellbeing over time in order to provide personalised supportive care in time for patients who have high levels of distress at baseline. CONCLUSIONS: GTD patients experience increased levels of distress, anxiety and depression, suggesting the diagnosis has a substantial effect on the psychological wellbeing of patients. The impact of GTD diagnosis on intrusion and avoidance seems to be ameliorated in patients who have children or who have experienced previous pregnancy loss. TWEETABLE ABSTRACT: Patients with gestational trophoblastic disease (GTD) experience short-term psychological consequences such as distress, anxiety and depression, suggesting that the diagnosis GTD has a substantial effect on the psychological wellbeing of patients. Various patient characteristics affect the impact of GTD diagnosis.

Risk factors for second-line dactinomycin failure after methotrexate treatment for low-risk gestational trophoblastic neoplasia: a retrospective study.

OBJECTIVE: To find risk factors for second-line dactinomycin failure in patients with low-risk gestational trophoblastic neoplasia (GTN). DESIGN: Retrospective multicentre study. SETTING: Tertiary reference centre. POPULATION: Patients with low-risk GTN, treated with dactinomycin after methotrexate (MTX) failure. METHODS: Retrospective analysis of 45 patients with low-risk GTN treated with dactinomycin after MTX failure, registered between 2006 and 2018. MAIN OUTCOME MEASURES: Treatment outcome and risk factors for second-line dactinomycin failure. RESULTS: Thirty patients (66.7%) were cured and 15 patients (33.3%) required third-line therapy. Type of antecedent pregnancy and hCG levels pre-dactinomycin were risk factors for failure in univariate analysis (odds ratio [OR] 19.30, 95% CI 2.04-182.60, P = 0.01 and OR 2.77, 95% CI 1.18-6.50, P = 0.02, respectively). Level of hCG pre-dactinomycin remained a significant risk factor in multivariate analysis (OR 2.93, 95% CI 1.02-8.40, P = 0.045). Complete remission (CR) was achieved in 83.3% of patients with pre-dactinomycin hCG levels <10 ng/ml, in 75% with hCG levels between 10 and 20 ng/ml, in 66.7% with hCG levels between 20 and 30 ng/ml, and in 50% with hCG levels between 30 and 40 ng/ml. No patients with hCG levels >40 ng/ml achieved CR. Patients with dactinomycin failure were treated surgically and/or with multi-chemotherapy; all except one achieved CR. CONCLUSIONS: Treatment with dactinomycin after MTX failure in patients with low-risk GTN resulted in CR in 66.7%. Chance of curative treatment with dactinomycin is strongly related to the hCG level. TWEETABLE ABSTRACT: Chance of curative treatment with dactinomycin after MTX failure in GTN patients is strongly related to the level of hCG pre-dactinomycin.

Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study.

BACKGROUND: Advanced recurrent ovarian cancer (ROC) is the leading cause of gynecologic cancer-related death in developed countries and new treatments are needed. Previous studies of immune checkpoint blockade showed low objective response rates (ORR) in ROC with no identified predictive biomarker. PATIENTS AND METHODS: This phase II study of pembrolizumab (NCT02674061) examined two patient cohorts with ROC: cohort A received one to three prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12 months and cohort B received four to six prior lines with a PFI/TFI of ≥3 months. Pembrolizumab 200 mg was administered intravenously every 3 weeks until cancer progression, toxicity, or completion of 2 years. Primary end points were ORR by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded independent central review by cohort and by PD-L1 expression measured as combined positive score (CPS). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Cohort A enrolled 285 patients; the first 100 served as the training set for PD-L1 biomarker analysis. Cohort B enrolled 91 patients. ORR was 7.4% for cohort A and 9.9% for cohort B. Median DOR was 8.2 months for cohort A and not reached for cohort B. DCR was 37.2% and 37.4%, respectively, in cohorts A and B. Based on the training set analysis, CPS 1 and 10 were selected for evaluation in the confirmation set. In the confirmation set, ORR was 4.1% for CPS <1, 5.7% CPS ≥1, and 10.0% for CPS ≥10. PFS was 2.1 months for both cohorts. Median OS was not reached for cohort A and was 17.6 months for cohort B. Toxicities were consistent with other single-agent pembrolizumab trials. CONCLUSIONS: Single-agent pembrolizumab showed modest activity in patients with ROC. Higher PD-L1 expression was correlated with higher response. CLINICAL TRIAL NUMBER: Clinicaltrials.gov, NCT02674061.

Early tumor regrowth is a contributor to impaired survival in patients with completely resected advanced ovarian cancer. An exploratory analysis of the Intergroup trial AGO-OVAR 12.

OBJECTIVE: Surgical assessment of residual tumor provides the strongest prognostic information in advanced ovarian cancer (AOC), with the best outcome observed after complete resection. Postoperative radiological assessment before initiation of chemotherapy can supplement the information obtained by surgical assessment; however, it may also reveal conflicting findings. METHODS: Patients with AOC enrolled in the AGO-OVAR 12 trial underwent baseline imaging before the first chemotherapy cycle. The findings from surgical and radiologic assessment for disease extend were compared. Additionally, an integrated approach was assessed. RESULTS: Complete data from all 3 assessment methods were available for 1345 patients. Of 689 patients with complete resection, tumor was observed in 28% and 22% of patients undergoing radiologic and integrated assessment, respectively. Patients with surgical- radiological and surgical-integrated concordant findings showed a 5-year overall survival (5Y-OS) of 72% and 71%, whereas patients with surgical-radiological and surgical-integrated discordant results showed inferior 5Y-OS of 47% and 49%, respectively. Patients with surgically assessed residual disease had a 5-YOS of 37%. The interval between surgery and baseline assessment was independently associated with discordance between assessment methods, which might reflect early tumor regrowth. CONCLUSIONS: Baseline tumor assessment before chemotherapy provides information that stratifies patients with complete resection into different prognostic groups. Integrating the data from different assessment methods might lead to improved definitions of prognostic groups. Further investigation to determine if earlier initiation of chemotherapy after debulking surgery could increase survival of patients with early tumor regrowth is warranted.

Presence of gastro-intestinal symptoms in ovarian cancer patients during survivorship: a cross-sectional study from the PROFILES registry.

OBJECTIVE: To assess the association between gastro-intestinal (GI) symptoms and health-related quality of life (HRQoL) in ovarian cancer (OC) survivors. METHODS: Women diagnosed with OC between 2000 and 2010 as registered in the Netherlands cancer registry (n = 348), received a questionnaire on socio-demographic characteristics, HRQoL (EORTC-QLQ-C30), ovarian cancer-specific symptoms including GI (EORTC-QLQ OV28), and psychological distress (HADS). Data collection took place in 2012. RESULTS: Of 348 women diagnosed with ovarian cancer, 191 (55%) responded. Of all participants, 69% were eligible for analysis (n = 131). In 25% of all women, high level GI symptoms occurred (n = 33). In 23% of all women, recurrence of OC occurred (n = 30). Regression analysis showed that presence of high levels of GI symptoms during survivorship was associated with lower functioning on all HRQoL domains (except for emotional functioning), more symptoms, and higher levels of distress. QoL was negatively affected in those who had few and high levels of GI symptoms. QoL of those with recurrent disease was worse than those without recurrent disease. CONCLUSION: A substantial proportion of OC survivors experience GI symptoms, regardless of the recurrence of disease. Health care professionals should be aware of GI symptoms during survivorship in order to refer their patients for supportive care interventions to reduce symptoms or help survivors to cope. Further research should examine the cause of GI symptoms during OC survivorship among those with non-recurrent disease.

Localization of distant metastases defines prognosis and treatment efficacy in patients with FIGO stage IV ovarian cancer.

BACKGROUND: Patients with ovarian cancer who are diagnosed with Federation of Gynecology and Obstetrics (FIGO) stage IV disease are a highly heterogeneous group with possible survival differences. The FIGO staging system was therefore updated in 2014. OBJECTIVE: To evaluate the 2014 changes to FIGO stage IV ovarian cancer on overall survival. METHODS: We identified all patients diagnosed with FIGO stage IV disease between January 2008 and December 2015 from the Netherlands Cancer Registry. We analyzed the prognostic effect of FIGO IVa versus IVb. In addition, patients with extra-abdominal lymph node involvement as the only site of distant disease were analyzed separately. Overall survival was analyzed by Kaplan-Meier curves and multivariable Cox regression models. RESULTS: We identified 2436 FIGO IV patients, of whom 35% were diagnosed with FIGO IVa disease. Five-year overall survival of FIGO IVa and IVb patients (including those with no or limited therapy) was 8.9% and 13.0%, respectively (p=0.51). Patients with only extra-abdominal lymph node involvement had a significant better overall survival than all other FIGO IV patients (5-year overall survival 25.9%, hazard ratio 0.77 [95% CI 0.62 to 0.95]). CONCLUSION: Our study shows that the FIGO IV sub-classification into FIGO IVa and IVB does not provide additional prognostic information. Patients with extra-abdominal lymph node metastases as the only site of FIGO IV disease, however, have a better prognosis than all other FIGO IV patients. These results warrant a critical appraisal of the current FIGO IV sub-classification.

Association between information provision and supportive care needs among ovarian cancer survivors: A cross-sectional study from the PROFILES registry.

OBJECTIVE: To examine the association between satisfaction with perceived information provision during diagnosis and treatment and supportive care needs in ovarian cancer survivors. METHODS: In 2012, women (n = 348) diagnosed with ovarian cancer, as registered between 2000 and 2010 in the Netherlands Cancer Registry, received a questionnaire including questions on the perceived level of, and satisfaction with, information received (EORTC QLQ-INFO25) and supportive care needs (Cancer Survivors' Unmet Needs Measure). RESULTS: Of 348 women, 191 (55%) responded. Of all participants, 35% were not satisfied (n = 65) with the perceived amount of information received. Participants who were satisfied with the amount of information reported significantly higher levels of perceived information on disease, medical tests, treatment, and other services. Patients not satisfied with information provision had a higher total number of needs and a higher number of unmet needs than women satisfied with information provision. Multivariable linear regression analysis showed that satisfaction with information provision was negatively associated with the total number of unmet needs (ß = -0.20, P = .03) after adjustment for potential confounding clinical and sociodemographic factors. CONCLUSION: Ovarian cancer survivors satisfied with the information provision during treatment reported fewer unmet needs during survivorship. Optimization of information provision for ovarian cancer patients during initial diagnosis and treatment may contribute to a decrease in unmet needs during survivorship.

Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia be simplified? A new retrospective analysis from a nationwide dataset.

BACKGROUND: Worldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible. PATIENTS AND METHODS: Between January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified. RESULTS: Of the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5-10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7-44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0-16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3-3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9-12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4-30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system. CONCLUSION: Our simplified alternative using only five of the FIGO prognostic factors appears to be an accurate system for discriminating patients requiring single as opposed to multi-agent chemotherapy. Further work is urgently needed to validate these findings.

The added value of hysterectomy in the management of gestational trophoblastic neoplasia.

BACKGROUND: Despite the undoubted effectiveness of chemotherapeutic treatment in gestational trophoblastic neoplasia (GTN), problems related to toxicity of chemotherapy and chemo-resistant disease have led to reconsideration of the use of hysterectomy. Aim of the present study was to evaluate indications for and outcome of hysterectomy in patients with GTN in a nation-wide cohort. METHODS: Between 1977 and 2012, we identified all patients diagnosed with GTN and treated with hysterectomy from the Dutch national databases. Demographics, clinical characteristics and follow-up were recorded retrospectively. RESULTS: One hundred and nine patients (16.5% of all registered patients with GTN) underwent hysterectomy as part of their management for GTN. The majority of patients was classified as low-risk disease (74.3%), post-molar GTN (73.5%) and disease confined to the uterus (65.1%). After hysterectomy, complete remission was achieved in 66.2% of patients with localized disease and in 15.8% of patients with metastatic disease. For patients with localized disease, treated with primary hysterectomy, treatment duration was significantly shorter (mean 3.2weeks and 8.0weeks respectively, p=0.01) with lower number of administered chemotherapy cycles (mean 1.5 and 5.8 respectively, p<0.01) than patients in a matched control group. CONCLUSION: In selected cases, a hysterectomy may be an effective means to either reduce or eliminate tumor bulk. Primary hysterectomy should mainly be considered in older patients with localized disease and no desire to preserve fertility, whereas patients with chemotherapy-resistant disease may benefit from additional hysterectomy, especially when disease is localized. For patients with widespread metastatic disease, the benefit of hysterectomy lies in the removal of chemotherapy-resistant tumor bulk with subsequent effect on survival.

Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.

BACKGROUND: Gestational trophoblastic disease (GTD) represents a heterogeneous group of disorders. Wide variations in incidence rates are reported worldwide, probably explained by a lack of centralized databases and heterogeneity in case definition. The aim of the present study was to determine the trends in incidence of GTD in the last 20 years with the use of population-based data. PATIENTS AND METHODS: Data on patients with pathologically confirmed diagnosis of GTD between 1994 and 2013 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. RESULTS: In the 20-year period 6343 cases were registered with GTD, representing an overall incidence rate of 1.67 per 1000 deliveries per year. An initial rise in incidence rate was seen over the first 10 years (0.075 per year, 95% CI 0.040-0.109), followed by a stabilization from 2004 to 2013 (increase per year 0.011, 95% CI -0.017-0.040). Although partial hydatidiform mole (HM) was more common in earlier years, complete and partial HM reached comparable incidence rates of 0.68 and 0.64 per 1000 deliveries respectively from 2009 onwards. In the last decade, unspecified HM diagnosis declined significantly from 0.14 per 1000 deliveries in 2003 to 0.03 per 1000 deliveries (per year -0.011, CI -0.016-0.06), suggesting improved diagnostic analyses. CONCLUSION: After an initial rise in GTD incidence in the Netherlands rates remained steady from 2004 onwards. As pathological confirmation is currently the norm and advanced pathological techniques are now widely available, true steady incidence rates may have been reached.

Trends in quality of non-Hodgkin's lymphoma care: is it getting better?

This study outlines trends in quality of delivered non-Hodgkin's lymphoma (NHL) care in the Netherlands between 2007 and 2011 and to what extend this was influenced by the national Visible Care program, which aimed at increasing transparency by providing insight into the quality of healthcare. We analyzed data collected from medical records in two observational studies, combined into 20 validated quality indicators (QIs) of which 6 were included in the national program. A random sample of 771 patients, diagnosed with NHL in 26 Dutch hospitals, was examined. Multilevel regression analyses were used to assess differences in quality of NHL care and to provide insight into the effect of the national program. We reported improved adherence to only 3 out of 6 QIs involved in the national program and none of the other 14 validated QIs. Improvement was shown for performance of all recommended staging techniques (from 26 to 43 %), assessment of International Prognostic Index (from 21 to 43 %), and multidisciplinary discussion of patients (from 23 to 41 %). We found limited improvement in quality of NHL care between 2007 and 2011; improvement potential (<80 % adherence) was still present for 13 QIs. The national program seems to have a small positive effect, but has not influenced all 20 indicators which represent the most important, measurable parts in quality of NHL care. These results illustrate the need for tailored implementation and quality improvement initiatives.

Human chorionic gonadotropin (hCG) regression normograms for patients with high-risk gestational trophoblastic neoplasia treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) chemotherapy.

BACKGROUND: We present normograms for human chorionic gonadotropin (hCG) regression in patients with high-risk gestational trophoblastic neoplasia (GTN) successfully treated with multiagent chemotherapy in order to predict treatment resistance. PATIENTS AND METHODS: We collected data for 46 patients with high-risk GTN treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) who had hCG values available. Patients were classified as having methotrexate (MTX)-resistant disease (n = 22) or primary high-risk disease (n = 24). The 10th, 50th and 90th percentiles of the hCG before every chemotherapy course were calculated and plotted in normograms. RESULTS: Half of the patients treated for MTX-resistant disease and primary high-risk disease had normal hCG levels before the third and sixth course of chemotherapy, respectively. In patients with MTX-resistant disease, the 90th percentile line fell below normal before the start of the fourth course, whereas in patients with primary high-risk disease this was not the case until the eighth course of chemotherapy. CONCLUSION: Resistance to EMA/CO treatment for high-risk GTN, as illustrated by examples, could be predicted using normograms for hCG resistance. Normograms differed depending on the indication for multiagent chemotherapy due to much higher initial hCG values in patients with primary high-risk disease compared with those treated for MTX-resistant disease.

Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia.

OBJECTIVE: Methotrexate (MTX) alternating with folinic acid is a commonly used treatment regimen for low-risk gestational trophoblastic neoplasia (GTN). In The Netherlands, two courses of MTX are administered after normalization of serum human chorionic gonadotrophin (hCG) levels (consolidation courses), whereas in the United Kingdom, three consolidation courses are given. In a retrospective setting we compared relapse rates of women completing MTX therapy for low-risk GTN in The Netherlands and the UK. METHODS: From 1980 to 2008, 351 patients were collected from the Dutch Central Registry for Hydatidiform Moles and records from the Dutch Working Party on Trophoblastic Disease. From the Charing Cross Hospital Trophoblast Disease Centre (London), 600 low-risk GTN patients were identified from 1992 to 2008. RESULTS: In 4.0% of patients relapse occurred after MTX treatment with three consolidation courses, whereas 8.3% of patients relapsed after MTX treatment with two consolidation courses (p=0.006). Although patients from The Netherlands had a higher level of hCG (p<0.001) and more patients had metastases before the start of treatment (p=0.012), the number of courses of MTX to achieve a normal hCG did not differ significantly between patients from The Netherlands and the UK (p=0.375). CONCLUSIONS: Relapse rates were higher in patients treated with two consolidation courses of MTX. Although other factors might have influenced the observed difference in relapse rates, three courses of consolidation chemotherapy may be preferable to two in the treatment of low-risk GTN in order to decrease the risk of disease relapse. A prospective randomized study would be required to confirm these findings.

Fatal cases of gestational trophoblastic neoplasia over four decades in the Netherlands: a retrospective cohort study.

OBJECTIVE: To describe fatal cases of gestational trophoblastic neoplasia (GTN) over four decades and evaluate whether treatment was given according to the protocol and reveal possible implications for future management. DESIGN: Retrospective cohort study. SETTING: The Netherlands. POPULATION: Women who died from GTN from 1971 to 2011. METHODS: Records from the Dutch Central Registry for Hydatidiform Moles and the Working Party on Trophoblastic Disease were used to identify fatal cases of GTN. MAIN OUTCOME MEASURES: Disease extent, risk classification, treatment regimens and cause of death. RESULTS: Twenty-six women died from GTN. In five cases GTN developed after a hydatidiform mole and in 19 cases following term pregnancy. Half of the women died between 1971 and 1980, when women were not yet classified as having low-risk or high-risk disease and were therefore not yet treated accordingly. A major decline in the number of deaths was seen after the first decade, with a further decrease from 1981 to 2011. Early death occurred in nine women. In four of these women, death was treatment-related. Women who died more than 4 weeks after the start of treatment mostly died from metastatic tumour (n = 14). CONCLUSIONS: The yearly number of women who died from GTN decreased considerably over the last four decades. Appropriate risk classification is essential to start optimal initial therapy and to prevent therapy resistance. Women with post-term choriocarcinoma represented a large proportion of the dead women and we propose that these women are considered as having high-risk disease.

A prospective monitoring of fatal serious adverse events (SAEs) in a Dutch Colorectal Cancer Group (DCCG) phase III trial (CAIRO) in patients with advanced colorectal cancer.

BACKGROUND: Early and correct assessment of treatment-related mortality is highly important in clinical cancer trials. However, no data are available on the quality of safety monitoring. PATIENTS AND METHODS: An on-site review was carried out by the study coordinators of the individual charts of all patients participating in the Capecitabine-Irinotecan-Oxaliplatin (CAIRO) study who had died within 30 days of the last administration of study drugs when death was accompanied by any other event than disease progression. The relationship between treatment and death was categorized as unrelated, remote, possible, or probable and submitted to an independent data monitoring committee (IDMC). These results were then compared with the initial assessment of the local investigator. RESULTS: Forty of 820 patients qualified for review. The relationship between cause of death and study drugs was changed in 26 patients (65%). A major protocol violation (MPV) was identified in 12 of 14 patients with a probable relationship between cause of death and study treatment. CONCLUSIONS: There was little agreement between the relation as assessed by the local investigator compared with the IDMC. A quality control improves the assessment of safety results and the observed MPVs underscore the importance of educating medical staff and patients.

Effectiveness and toxicity of lenvatinib in refractory thyroid cancer: Dutch real-life data.

OBJECTIVE: The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial. METHODS: From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies. RESULTS: A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04). CONCLUSIONS: PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.

Intraperitoneal treatment for advanced ovarian cancer, the Dutch experience. What did we learn?

BACKGROUND: Combined administration of intravenous (iv) and intraperitoneal (ip) (iv/ip) chemotherapy is an effective adjuvant treatment option after primary debulking surgery (PDS) for advanced ovarian cancer (OC). Increased toxicityand patient burden limit its use in daily practice. OBJECTIVE: To assess toxicity and survival outcomes of iv/ip chemotherapy in daily practice in the Netherlands. METHODS: This retrospective cohort study included 81 women who underwent at least an optimal PDS for FIGO stage III OC followed by iv/ip chemotherapy according to the Armstrong regimen, in four hospitals in the Netherlands between January 2007 and May 2016. We collected information on surgical procedure, abdominal port implantation, toxicity, and recurrence-free and overall survival. RESULTS: All participants underwent PDS, of whom 60 (74%) had their ip catheter implanted during PDS. Most frequently reported all grade toxicity was haematological n = 44 (54%). Forty-four patients (54%) completed all six cycles of iv/ip chemotherapy. The most frequent causes of discontinuation of iv/ip administration were renal dysfunction (12/37 = 32%) and catheter problems (7/37 = 19%). Median recurrence-free survival and overall survival were 24 months (range 0 - 108) and 80 months (range 4-115), respectively. Surgical outcome, completion of more than three courses of treatment and intra-abdominal localisation of recurrent disease were associated with better survival outcomes. CONCLUSION: In daily practice, 54% of patients with advanced OC could complete all scheduled cycles of iv/ ip chemotherapy with acceptable morbidity and toxicity, leading to outcomes comparable with the results of published trials on iv/ip chemotherapy.