Quality assurance of radiation therapy after breast-conserving surgery among patients in the BOOG 2013-08 trial.

BACKGROUND AND PURPOSE: In the BOOG 2013-08 trial (NCT02271828), cT1-2N0 breast cancer patients were randomized between breast conserving surgery with or without sentinel lymph node biopsy (SLNB) followed by whole breast radiotherapy (WBRT). While awaiting primary endpoint results (axillary recurrence rate), this study aims to perform a quality assurance analysis on protocol adherence and (incidental) axillary radiation therapy (RT) dose. MATERIALS AND METHODS: Patients were enrolled between 2015 and 2022. Data on prescribed RT and (in 25% of included patients) planning target volumes (PTV) parameters were recorded for axillary levels I-IV and compared between treatment arms. Multivariable linear regression analysis was performed to determine prognostic variables for incidental axillary RT dose. RESULTS: 1,439/1,461 included patients (98.5%) were treated according to protocol and 87 patients (5.9%) received regional RT (SLNB 10.9%, no-SLNB 1.5 %). In 326 patients included in the subgroup analysis, the mean incidental PTV dose at axilla level I was 59.5% of the prescribed breast RT dose. In 5 patients (1.5%) the mean PTV dose at level I was ≥95% of the prescribed breast dose. No statistically or clinically significant differences regarding incidental axillary RT dose were found between treatment arms. Tumour bed boost (yes/no) was associated with a higher incidental mean dose in level I (R2 = 0.035, F(6, 263) = 1.532, p 0.168). CONCLUSION: The results indicate that RT-protocol adherence was high, and that incidental axillary RT dose was low in the BOOG 2013-08 trial. Potential differences between treatmentarms regarding the primary endpoint can thus not be attributed to different axillary radiation doses.

Health-related quality of life after interval cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with stage III ovarian cancer.

INTRODUCTION: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improves recurrence-free (RFS) and overall survival (OS) in patients with FIGO stage III ovarian cancer. We evaluated the effect of HIPEC on patient's health-related quality of life (HRQoL) in the OVHIPEC trial. MATERIALS AND METHODS: OVHIPEC was a multicentre, open-label, randomized phase III trial for patients with stage III ovarian cancer. Patients were randomly assigned (1:1) to receive interval CRS with or without HIPEC with cisplatin. HRQoL was assessed using the EORTC QLQ-C30, and the ovarian (QLQ-OV28) and colorectal cancer (QLQ-CR38) modules. HRQoL questionnaires were administered at baseline, after surgery, after end of treatment, and every three months thereafter. HRQoL was a secondary endpoint, with the prespecified focus on the QLQ-C30 summary score and symptom scores on fatigue, neuropathy and gastro-intestinal symptoms. HRQoL was analysed using linear and non-linear mixed effect models. RESULTS: In total, 245 patients were randomized. One-hundred-ninety-seven patients (80%) completed at least one questionnaire. No significant difference over time in the QLQ-C30 summary scores was observed between the study arms (p-values for linear and non-linear growth: p > 0.133). The pattern over time for fatigue, neuropathy and gastro-intestinal symptoms did not significantly differ between treatment arms. CONCLUSION: The addition of HIPEC to interval CRS does not negatively impact HRQoL in patients with stage III ovarian cancer who are treated with interval CRS due to the extent of disease. These HRQoL results, together with the improvement in RFS and OS, support the viability of HIPEC as an important treatment option in this patient population. CLINICALTRIALS. GOV NUMBER: NCT00426257. EUDRACT NUMBER: 2006-003466-34.

The effect of the peritoneal tumor microenvironment on invasion of peritoneal metastases of high-grade serous ovarian cancer and the impact of NEOADJUVANT chemotherapy.

Peritoneal metastases of high-grade serous ovarian cancer (HGSOC) are small-sized deposits with superficial growth toward the peritoneal cavity. It is unknown whether integrity of the peritoneal elastic lamina (PEL) correlates with the peritoneal tumor microenvironment (pTME) and whether neoadjuvant chemotherapy (NACT) affects the pTME. We explored integrity of PEL, composition of pTME, effects of NACT, and the prognostic implications in patients with extensive peritoneal metastases of HGSOC. Peritoneal samples (n = 69) were collected during cytoreductive surgery between 2003 and 2016. Clinical data were collected from medical charts. Integrity of PEL was evaluated with elastic stains. T cell (CD3, CD8) and M2-macrophage markers (CD163) were scored using algorithms created in definiens tissue studio. Patients with a disrupted PEL (n = 39; 57%), more often had residual disease after surgery (p = 0.050), compared to intact PEL. An intact PEL was associated with increased intraepithelial (ie) CD8+ cells (p = 0.032), but was not correlated with improved survival. After NACT, increased ieCD3+ cells were shown, compared to no-NACT (p = 0.044). Abundance of total CD3+ and CD8+ cells were associated with PFS (multivariate HR 0.40; 95%CI 0.23-0.69 and HR 0.49; 95%CI 0.29-0.83) and OS (HR 0.33; 95%CI 0.18-0.62 and HR 0.36; 95%CI 0.20-0.64). M2-macrophage infiltration was not correlated with survival. NACT increases abundance of ieCD3+ cells in peritoneal metastases of HGSOC. Increase of CD3+ and CD8+ cells is associated with improved PFS and OS. This suggests that CD3+ and CD8+ cells may function as prognostic biomarkers. Their role as predictive biomarker for chemotherapy or immunotherapy response in HGSOC warrants further research.

Perioperative change in CA125 is an independent prognostic factor for improved clinical outcome in advanced ovarian cancer.

OBJECTIVE: Despite being the most important prognostic factor for prolonged overall survival in epithelial ovarian cancer (EOC), the measurement of residual disease is hampered by its subjective character. Additional assessment tools are needed to establish the success of cytoreductive surgery in order to predict patients' prognosis more accurately. The aim of this study is to evaluate the independent prognostic value of perioperative CA125 change in advanced stage EOC patients. STUDY DESIGN: We identified all patients who underwent primary cytoreductive surgery for advanced stage (FIGO IIB-IV) EOC between 2008 and 2015, from the Netherlands Cancer Registry. The relative perioperative change in CA125 was categorized into four groups; increase, <50% decline, 50-79% decline and ≥80% decline. Overall survival (OS) was analyzed using Kaplan-Meier survival curves and multivariable cox regression models. RESULTS: We included 1232 eligible patients with known pre- and postoperative CA125 serum levels. Patients with a decline of ≥80% in CA125 levels experienced improved OS compared to those with a decline of <50% (univariable Hazard Ratio (HR) 0.45, 95%CI 0.36-0.57). The prognostic effect of perioperative CA125 change was independent of patient- and treatment characteristics, such as the extent of residual disease after cytoreductive surgery (multivariable HR≥80% 0.52(0.41-0.66)). CONCLUSIONS: This study shows that the perioperative change in CA125 is an independent prognostic factor for overall survival after primary surgery for EOC patients. This pleads for the use of a combined model, consisting of perioperative CA125 change and the outcome of residual disease, in order to predict the prognosis of EOC patients more accurately.

Overview of non-epithelial ovarian tumours: Incidence and survival in the Netherlands, 1989-2015.

INTRODUCTION: About 5% of ovarian tumours have a non-epithelial histology, including germ cell tumours (GCTs), sex cord-stromal tumours (SCSTs) and sarcomas. Because these non-epithelial ovarian tumours are rare and population-based studies are scarce, the aim of this population-based study is to describe trends in the incidence, treatment and survival of women with these tumours in the Netherlands. METHODS: All women diagnosed with non-epithelial ovarian malignant tumours in the Netherlands between 1989 and 2015 were identified from the Netherlands Cancer Registry. Data on demographics, tumour characteristics and initial treatment were collected, and overall survival was analysed. RESULTS: A total of 1258 non-epithelial ovarian tumours were identified comprising 752 GCTs (60%), 341 SCSTs (27%) and 165 sarcomas (13%). The European age-standardised incidence rate (ESR) was 0.4 per 100,000 persons per year for GCTs, 0.2 for SCSTs and 0.1 for sarcomas. Approximately 97% of patients underwent surgical resection for the primary tumour, 31% received systemic treatment and 3% radiotherapy. Between the late 1980s and 2015, five-year overall survival improved for all histologic subtypes: GCTs rose from 73% to 88% (p = 0.03), SCSTs from 64% to 81% (p = 0.57) and sarcomas from 20% to 29% (p = 0.14). CONCLUSION: Malignant GCTs and SCSTs are rare, and their incidence has not significantly changed over recent decades. They have a good prognosis, which also improved slightly during this period. Primary sarcomas of the ovary are extremely rare and still have a poor prognosis.

The effect of adjuvant chemotherapy on survival in patients with FIGO stage I high-grade serous ovarian cancer.

OBJECTIVE: The benefit of adjuvant chemotherapy for FIGO stage I, high-grade serous ovarian cancer (HGSOC) after optimal staging is a matter of debate. We investigated the effect of adjuvant chemotherapy on recurrence-free survival (RFS) and overall survival (OS) in a population-based cohort study. METHODS: All patients diagnosed in the Netherlands between 2002 and 2014 with FIGO stage I HGSOC who underwent surgical staging were included. Data on clinical characteristics, histopathology, completeness of staging and survival were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. Recurrence data was collected from hospital files. We used Kaplan-Meier methods to estimate RFS and OS and Cox-proportional hazard analyses to control for differences in baseline characteristics between patients who did or did not receive chemotherapy. RESULTS: We identified 223 patients who underwent optimal staging procedures including lymph node sampling. Events of disease recurrence occurred in 21 of the 101 patients (21%) who received adjuvant chemotherapy and in 46 of the 122 patients (38%) who did not (multivariable hazard ratio (HR), 0.37; 95%CI 0.22-0.64; p < 0.01). Five-year RFS was 81% after staging plus chemotherapy and 59% after staging only. At a median follow-up of 105 months, 21 patients (21%) in the chemotherapy group and 38 patients (31%) in the no-chemotherapy group had died (multivariable HR 0.50; 95%CI 0.28-0.89; p = 0.02). Ten-year OS was 78% with chemotherapy and 62% without chemotherapy. CONCLUSIONS: Adjuvant chemotherapy improves long-term RFS and OS in patients with FIGO stage I HGSOC after optimal staging.

Outcome of surgery in advanced ovarian cancer varies between geographical regions; opportunities for improvement in The Netherlands.

INTRODUCTION: The care for patients with epithelial ovarian cancer(EOC) is organised in eight different geographical regions in the Netherlands. This situation allows us to study differences in practice patterns and outcomes between geographical regions for patients with FIGO stage IIIC and IV. METHODS: We identified all EOC patients who were diagnosed with FIGO stage IIIC or IV between 01.01.2008 and 31.12.2015 from the Netherlands Cancer Registry. Descriptive statistics were used to summarize treatment and treatment sequence(primary cytoreductive surgery(PCS) or neoadjuvant chemotherapy and interval cytoreductive surgery(NACT-ICS)). Moreover, outcome of surgery was compared between geographical regions. Multilevel logistic regression was used to assess whether existing variation is explained by geographical region and case-mix factors. RESULTS: Overall, 6,741 patients were diagnosed with FIGO IIIC or IV disease. There were no differences in the percentage of patients that received any form of treatment between the geographical regions(range 80-86%, P = 0.162). In patients that received cytoreductive surgery and chemotherapy, a significant variation between the geographical regions was observed in the use of PCS and NACT-ICS(PCS: 24-48%, P < 0.001). The percentage of complete cytoreductive surgeries after PCS ranged from 10 to 59%(P < 0.001) and after NACT-ICS from 37 to 70%(P < 0.001). Moreover, geographical region was independently associated with the outcome of surgery, also when adjusted for treatment sequence(P < 0.001). CONCLUSION: We observed a significant variation in treatment approach for advanced EOC between geographical regions in the Netherlands. Furthermore, the probability to achieve no residual disease differed significantly between regions, regardless of treatment sequence. This may suggest that surgical outcomes can be improved across geographical regions.

The prognostic value of residual disease after neoadjuvant chemotherapy in advanced ovarian cancer; A systematic review.

INTRODUCTION: The ability to minimize residual disease during primary cytoreductive surgery is the strongest predictor for improved overall survival in advanced ovarian cancer. But while the probability to achieve a macroscopic complete resection increases if surgery is preceded by neoadjuvant chemotherapy (NACT), survival rates after NACT are similar to those observed after primary surgery. This may suggest that the prognostic effect of residual disease is altered after NACT. More specifically, randomized data suggest that there is no difference between optimal (0.1-1 cm) and suboptimal (>1 cm) cytoreductive surgery after NACT. Therefore, the aim of the current review is to establish the prognostic effect of the amount of residual disease after interval cytoreductive surgery (ICS) on overall survival. METHODS: Potential articles for inclusion in the current review were systematically searched through Medline, Embase and Cochrane in September 2017. Median overall survival (mOS) was summarized by the outcome of ICS per study. In addition, mOS was summarized for all studies together stratified by the outcome of ICS, based on the principle of a weighted average. RESULTS: In total, 3677 unique manuscripts were individually screened on title and abstract, which resulted in 11 individual studies that comprised a total of 2178 patients. MOS was 41 months for patients with no residual disease (range 33-54 months), 27 months for patients with 0.1-1 cm of residual disease (range 19-38 months) and 21 months with >1 cm of residual disease (range 14-27 months). Six studies showed significant differences between optimal and suboptimal ICS, while five studies showed no differences. CONCLUSION: The summary of the currently available literature showed that after NACT, patients with optimal cytoreductive surgery experience lengthened survival compared to patients with suboptimal cytoreductive surgery. Patients with no macroscopic residual disease have, however, the most favorable survival outcomes, similar to what is seen after primary cytoreductive surgery.

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.

Interval between debulking surgery and adjuvant chemotherapy is associated with overall survival in patients with advanced ovarian cancer.

OBJECTIVE: Treatment for advanced epithelial ovarian cancer (EOC) consists of debulking surgery and (neo)adjuvant platinum-based chemotherapy. The aim of this study was to evaluate whether the time from surgery to adjuvant chemotherapy (TTC) was associated with clinical outcome. METHODS: We identified all Dutch patients who received optimal or complete debulking surgery for primary EOC (FIGO IIb-IV) between 2008 and 2015 from the Netherlands Cancer Registry. TTC was divided into three groups based on the interquartile range (IQR). Early (<25%) and prolonged (>75%) TTC were compared to intermediate TTC (25-75%). Logistic regression was used to identify factors associated with a prolonged TTC and multivariable Cox regression to evaluate the independent effect of treatment interval on overall survival (OS). Patients receiving primary debulking surgery (PDS) and patients receiving interval debulking surgery (IDS) were analyzed separately. RESULTS: 4097 patients were included, 1612 underwent PDS and 2485 IDS. Median TTC was 29 days (IQR 24-37). Age ≥ 65, complete debulking surgery, postoperative complications, and hospitalization ≥10 days were independently associated with a longer TTC for both PDS and IDS. TTC in the longest quartile was associated with poor OS after both PDS (Hazard Rate (HR) 1.43, 95% CI 1.09-1.88) and NACT-IDS (HR 1.22 (1.02-1.47)) when compared to the intermediate TTC, but only in patients with no macroscopic residual disease after surgery. CONCLUSIONS: Our study provides evidence that delayed initiation of adjuvant chemotherapy is an independent prognostic factor for worse overall survival after complete (interval)debulking surgery. We advise to start adjuvant chemotherapy within five to six weeks after debulking surgery.

Identifying pathologic complete response of the breast after neoadjuvant systemic therapy with ultrasound guided biopsy to eventually omit surgery: Study design and feasibility of the MICRA trial (Minimally Invasive Complete Response Assessment).

PURPOSE: Improvements in neoadjuvant systemic therapy (NST) for breast cancer patients have led to increasing rates of pathologic complete response (pCR). The MICRA trial (NTR6120) aims at identifying pCR with post-NST biopsies. Here, we report the study design and feasibility. METHODS: The MICRA-trial is a multi-center prospective cohort study. Patients with a pre-NST placed marker and radiologic complete (rCR) or partial response on MRI after NST are eligible for inclusion. Ultrasound guided biopsy of the original tumor area is performed. Pathology results of the biopsies and surgery specimens are compared. The primary endpoint is false-negative rate of biopsies in identifying pCR. RESULTS: During the first year of the trial 58 patients with rCR were included. One patient was a screening failure and excluded for analysis. Twenty-one percent had hormone receptor (HR)+/HER2- tumors, 21% HR+/HER2+ tumors, 18% HR-/HER2+ tumors and 40% TN tumors. Overall pCR was 68%. In seven patients biopsies could not be obtained: in 6 patients, the marker could not be identified on ultrasound in the OR and in 1 patient there were technical difficulties. A median of eight biopsies was obtained (range 4-9). The median of histopathological representative biopsies was 4 (range 1-8). CONCLUSION: Ultrasound guided biopsy of the breast in patients with excellent response on MRI after NST is feasible. Accuracy results of the MICRA trial will be presented after inclusion of 525 patients to determine if ultrasound guided biopsy is an accurate alternative to surgical resection for assessment of pCR after NST.

Neoadjuvant chemotherapy or primary debulking surgery in FIGO IIIC and IV patients; results from a survey study in the Netherlands.

INTRODUCTION: Primary debulking surgery (PDS) followed by adjuvant chemotherapy is historically recommended as first line treatment for advanced stage ovarian cancer. Two randomized controlled trials, however, showed similar efficacy and reduced toxicity with neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS). Nevertheless, uptake of NACT-IDS varies widely between hospitals, which cannot be explained by difference in patient populations. In this survey, we therefore aimed to evaluate the views on NACT-IDS among all Dutch gynaecologists and medical oncologists involved in the treatment of ovarian cancer. STUDY DESIGN: An e-mail link to the online questionnaire was sent to all medical oncologists and gynaecologists in the Netherlands, regardless of their (sub)specializations. The data was analysed using descriptive statistics and chi-square tests were used to analyse differences between groups. RESULTS: Three-hundred-forty physicians were invited to fill out the questionnaire. After two reminders, 167 of them responded (49%). Among the responders, 82% of the gynaecologists versus 93% of the medical oncologists considered the available evidence sufficiently convincing to treat advanced stage ovarian cancer patients with NACT-IDS (p = 0.076). Moreover, 33% of gynaecologists and 62% of medical oncologists preferred NACT-IDS to PDS as first line treatment (p = 0.001). While most responders (86%) indicated that selecting the right patients for NACT-IDS is difficult, those with bulky disease, FIGO stage IV or metastases near the porta hepatica were most likely to undergo NACT-IDS. CONCLUSION: The majority of Dutch gynaecologists and medical oncologists adopted NACT-IDS as an alternative treatment approach for advanced stage primary ovarian cancer. About two-thirds of medical oncologists and one-third of gynaecologists prefer NACT-IDS to PDS as first line treatment in this setting. Improving patient selection is considered of paramount importance.

No improvement in long-term survival for epithelial ovarian cancer patients: A population-based study between 1989 and 2014 in the Netherlands.

AIM: This study investigates changes in therapy and long-term survival for patients with epithelial ovarian cancer (EOC) in the Netherlands. METHODS: All patients with EOC, including peritoneal and fallopian tube carcinoma, diagnosed in the Netherlands between 1989 and 2014 were selected from the Netherlands Cancer Registry. Changes in therapy were studied and related to overall survival (OS) using multivariable Cox regression models. RESULTS: A total of 32,540 patients were diagnosed with EOC of whom 22,047 (68%) had advanced stage disease. In early stage, lymph node dissection as part of surgical staging procedures increased over time from 4% in 1989-1993 to 62% in 2009-2014 (P < 0.001). In advanced stage, the number of patients receiving optimal treatment with surgery and chemotherapy increased from 55% in 1989-1993 to 67% in 2009-2014 (P < 0.001). Five-year survival rates improved in both early stage (74% versus 79%) and advanced stage (16% versus 24%) as well as in all patients combined (31% versus 34%). Ten-year survival rates, however, slightly improved in early stage (62% versus 67%) and advanced stage (10% versus 13%) but remained essentially unchanged at 24% for all patients combined. CONCLUSION: Despite intensified treatment and staging procedures, long-term survival for women with EOC has not improved in the last 25 years. The observed improvements in 5-year OS reflect a more prolonged disease control rather than better chances for cure. Furthermore, the apparent better long-term outcome, when early and advanced stage patients are analysed separately, is largely due to improved staging procedures and the ensuing stage migration. These effects disappear in a combined analysis of all patients.

Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013-08).

BACKGROUND: Studies showed that axillary lymph node dissection can be safely omitted in presence of positive sentinel lymph node(s) in breast cancer patients treated with breast conserving therapy. Since the outcome of the sentinel lymph node biopsy has no clinical consequence, the value of the procedure itself is being questioned. The aim of the BOOG 2013-08 trial is to investigate whether the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients treated with breast conserving therapy. METHODS: The BOOG 2013-08 is a Dutch prospective non-inferiority randomized multicentre trial. Women with pathologically confirmed clinically node negative T1-2 invasive breast cancer undergoing breast conserving therapy will be randomized for sentinel lymph node biopsy versus no sentinel lymph node biopsy. Endpoints include regional recurrence after 5 (primary endpoint) and 10 years of follow-up, distant-disease free and overall survival, quality of life, morbidity and cost-effectiveness. Previous data indicate a 5-year regional recurrence free survival rate of 99% for the control arm and 96% for the study arm. In combination with a non-inferiority limit of 5% and probability of 0.8, this result in a sample size of 1.644 patients including a lost to follow-up rate of 10%. Primary and secondary endpoints will be reported after 5 and 10 years of follow-up. DISCUSSION: If the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients undergoing breast conserving therapy, this study will cost-effectively lead to a decreased axillary morbidity rate and thereby improved quality of life with non-inferior regional control, distant-disease free survival and overall survival. TRIAL REGISTRATION: The BOOG 2013-08 study is registered in ClinicalTrials.gov since October 20, 2014, Identifier: NCT02271828. https://clinicaltrials.gov/ct2/show/NCT02271828.

Serum HE4 is correlated to prognostic factors and survival in patients with endometrial cancer.

The extent of surgery and the decision for adjuvant treatment in patients with endometrial cancer (EC) depend on the presence of risk factors for lymph node metastases and disease recurrence. Postoperative markers such as myometrial infiltration and specific mutations can select patients for adjuvant treatment but will not influence surgical planning. A biomarker stratifying patients into low-risk and high-risk groups before surgery could identify patients who benefit from more extensive surgery. Therefore, we evaluated the correlation of serum biomarker HE4 with clinical and recently identified prognostic pathological variables and survival. Patients treated for endometrial cancer between 1994 and 2014 were included. Serum HE4 concentration was measured in preoperatively obtained samples. A total of 88 patients were eligible for analysis. The majority (64%) was diagnosed with endometrioid-type adenocarcinoma. Serum HE4 concentration is significantly associated with stage of disease (p = 0.001), deep myometrial invasion (p < 0.001), exact depth of myometrial invasion (≥4 mm) (p = 0.01), tumour-free distance to serosa (≤7 mm) (p < 0.001), extensive lymph vascular space invasion (p = 0.04) and cervical involvement (p = 0.001). HE4 concentration and nodal involvement were correlated, although not significant (p = 0.17). Serum HE4 is an independent prognostic factor for recurrence-free survival (HR 5.12 per 10-fold increase in HE4, 95% CI 1.54-17.1) and overall survival (HR 7.48 per 10-fold increase in HE4, 95% CI 1.76-31.7). HE4 is a prognostic marker in endometrial cancer and is helpful in addition to other variables for the preoperative risk stratification of patients with endometrial cancer.

The histophysiology and pathophysiology of the peritoneum.

The peritoneum is an extensive serous organ with both epithelial and mesenchymal features and a variety of functions. Diseases such as inflammatory peritonitis and peritoneal carcinomatosis can induce disturbance of the complex physiological functions. To understand the peritoneal response in disease, normal embryonic development, anatomy in healthy conditions and physiology of the peritoneum have to be understood. This review aims to summarize and discuss the literature on these basic peritoneal characteristics. The peritoneum is a dynamic organ capable of adapting its structure and functions to various physiological and pathological conditions. It is a key element in regulation of inflammatory responses, exchange of peritoneal fluid and prevention of fibrosis in the abdominal cavity. Disturbance of these mechanisms may lead to serious conditions such as the production of large amounts of ascites, the generation of fibrotic adhesions, inflammatory peritonitis and peritoneal carcinomatosis. The difficulty to treat diseases, such as inflammatory peritonitis and peritoneal carcinomatosis, stresses the necessity for new therapeutic strategies. This review provides a detailed background on the peritoneal anatomy, microenvironment and immunologic responses which is essential to generate new hypotheses for future research.

Incidence of lymph node metastases in clinical early-stage mucinous and seromucinous ovarian carcinoma: a retrospective cohort study.

OBJECTIVE: The use of lymph node sampling during staging procedures in clinical early-stage mucinous ovarian carcinoma (MOC) is an ongoing matter of debate. Furthermore, the incidence of lymph node metastases (LNM) in MOC in relation to tumour grade (G) is unknown. We aimed to determine the incidence of LNM in clinical early-stage MOC per tumour grade. DESIGN: Retrospective study with data from the Dutch Pathology Registry (PALGA). SETTING: The Netherlands, 2002-2012. POPULATION OR SAMPLE: Patients with MOC. METHODS: Histology reports on patients with MOC diagnosed in the Netherlands between 2002 and 2012 were obtained from PALGA. Reports were reviewed for diagnosis, tumour grade and presence of LNM. Clinical data, surgery reports and radiology reports of patients with LNM were retrieved from hospital files. MAIN OUTCOME MEASURES: Incidence of LNM, disease-free survival (DFS). RESULTS: Of 915 patients with MOC, 426 underwent lymph node sampling. Cytoreductive surgery was performed in 267 patients. The other 222 patients received staging without lymph node sampling. In eight of 426 patients, LNM were discovered by sampling. In four of 190 (2.1%) patients with G1 MOC, LNM were present, compared with one of 115 (0.9%) patients with G2 MOC and three of 22 (13.6%) patients with G3 MOC. Tumour grade was not specified in 99 patients. Patients with clinical early-stage MOC had no DFS benefit from lymph node sampling. CONCLUSIONS: LNM are rare in early-stage G1 and G2 MOC without clinical suspicion of LNM. Therefore, lymph node sampling can be omitted in these patients. TWEETABLE ABSTRACT: Lymph node sampling can be omitted in clinical early-stage G1 and G2 mucinous ovarian cancer.

Difficulties with diagnosis of malignancies in pregnancy.

Diagnosis and staging of cancer during pregnancy may be difficult due to overlap in physical signs, uncertainties on safety and accuracy of diagnostic tests and histopathology in pregnant women. Tumour markers should be used with caution due to pregnancy-induced elevation. Ionizing imaging and staging techniques such as computed tomography (CT) or positron emission tomography (PET) scans and sentinel node procedures are safe during pregnancy when fetal radiation threshold of 100 mGy is maintained. Ionizing imaging techniques can increasingly be avoided with the technical devolvement of non-ionizing techniques such as magnetic resonance imaging (MRI), including whole body MRI and diffusion-weighted imaging, which hold potentially great opportunities for the diagnostic management of pregnant cancer patients. Pathological evaluation and establishing a diagnosis of malignancy can be difficult in pregnant women, and a note to the pathologist of the pregnant status is essential for accurate diagnosis. This chapter will give an overview of possibilities and difficulties in diagnosing pregnant women with cancer.

The value of completion axillary treatment in sentinel node positive breast cancer patients undergoing a mastectomy: a Dutch randomized controlled multicentre trial (BOOG 2013-07).

BACKGROUND: Trials failed to demonstrate additional value of completion axillary lymph node dissection in case of limited sentinel lymph node metastases in breast cancer patients undergoing breast conserving therapy. It has been suggested that the low regional recurrence rates in these trials might partially be ascribed to accidental irradiation of part of the axilla by whole breast radiation therapy, which precludes extrapolation of results to mastectomy patients. The aim of the randomized controlled BOOG 2013-07 trial is therefore to investigate whether completion axillary treatment can be safely omitted in sentinel lymph node positive breast cancer patients treated with mastectomy. DESIGN: This study is designed as a non-inferiority randomized controlled multicentre trial. Women aged 18 years or older diagnosed with unilateral invasive clinically T1-2 N0 breast cancer who are treated with mastectomy, and who have a maximum of three axillary sentinel lymph nodes containing micro- and/or macrometastases, will be randomized for completion axillary treatment versus no completion axillary treatment. Completion axillary treatment can consist of completion axillary lymph node dissection or axillary radiation therapy. Primary endpoint is regional recurrence rate at 5 years. Based on a 5-year regional recurrence free survival rate of 98 % among controls and 96 % for study subjects, the sample size amounts 439 per arm (including 10 % lost to follow-up), to be able to reject the null hypothesis that the rate for study and control subjects is inferior by at least 5 % with a probability of 0.8. Results will be reported after 5 and 10 years of follow-up. DISCUSSION: We hypothesize that completion axillary treatment can be safely omitted in sentinel node positive breast cancer patients undergoing mastectomy. If confirmed, this study will significantly decrease the number of breast cancer patients receiving extensive treatment of the axilla, thereby diminishing the risk of morbidity and improving quality of life, while maintaining excellent regional control and without affecting survival. TRIAL REGISTRATION: The BOOG 2013-07 study is registered in the register of ClinicalTrials.gov since April 10, 2014, Identifier: NCT02112682 .