Search

Objectives: The aim of this study was to analyze morbidity and survival after pelvic exenteration for gynecologic malignancies and evaluate prognostic factors influencing postoperative outcome. Methods: We retrospectively reviewed all patients who underwent a pelvic exenteration at the departments of gynecologic oncology of three tertiary care centers in the Netherlands, the Leiden University Medical Centre, the Amsterdam University Medical Centre, and the Netherlands Cancer Institute, during a 20-year period. We determined postoperative morbidity, 2- and 5-year overall survival (OS) and 2- and 5-year progression free survival (PFS), and investigated parameters influencing these outcomes. Results: A total of 90 patients were included. The most common primary tumor was cervical cancer (n = 39, 43.3%). We observed at least one complication in 83 patients (92%). Major complications were seen in 55 patients (61%). Irradiated patients had a higher risk of developing a major complication. Sixty-two (68.9%) required ≥1 readmission. Re-operation was required in 40 patients (44.4%). Median OS was 25 months and median PFS was 14 months. The 2-year OS rate was 51.1% and the 2-year PFS rate was 41.5%. Tumor size, resection margins and pelvic sidewall involvement had a negative impact on OS (HR = 2.159, HR = 2.376, and HR = 1.200, respectively). Positive resection margins and pelvic sidewall involvement resulted in decreased PFS (HR = 2.567 and HR = 3.969, respectively). Conclusion: Postoperative complications after pelvic exenteration for gynecologic malignancies are common, especially in irradiated patients. In this study, a 2-year OS rate of 51.1% was observed. Positive resections margins, tumor size, and pelvic sidewall involvement were related to poor survival outcomes. Adequate selection of patients who will benefit from pelvic exenteration is important.

The extent of peritoneal metastases (PM) largely determines the possibility of complete or optimal cytoreductive surgery in advanced ovarian cancer. An objective scoring system to quantify the extent of PM can help clinicians to decide whether or not to embark on CRS. Therefore several scoring systems have been developed by different research teams and this review summarizes their performance in predicting a complete or optimal cytoreduction in patients with advanced ovarian cancer. A systematic search in the MEDLINE database revealed 19 articles that described a total of five main scoring systems to predict the completeness of CRS in patients with FIGO stage III-IV ovarian cancer based on the surgical exploration of the abdominal cavity; PCI, PIV, Eisenkop, Espada, and Kasper. The Peritoneal Cancer Index (PCI) and the Predictive Index Value (PIV) were mentioned most frequently and showed AUCs of 0.69-0.92 and 0.66-0.98, respectively. Due to the use of different cut-offs sensitivities and specificities greatly varied. Therefore with the current data, no scoring system could be identified as best. An objective measure of the extent of disease can be of great clinical use for identifying ovarian cancer patients for which a complete (or optimal) CRS is achievable, however due to local differences in treatment strategies and surgical policy a widely adopted objective scoring system with a standard cutoff value is not feasible. Nevertheless, objective scoring systems can play an important role to guide treatment decisions. (C) 2021 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

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.

Detection of peritoneal metastases (PM) is key in the staging and management of gastrointestinal and ovarian cancer patients. The purpose of this meta-analysis was to determine the diagnostic performance of CT, PET(CT), and (DW)MRI in detecting PM. A literature search in Pubmed, Embase (Ovid), and Scopus was performed (January 1997–May 2018) to identify studies reporting on the accuracy of imaging PM in the diagnostic workup of gastrointestinal or ovarian cancers. Inclusion criteria were region-based or patient-based studies comprising > 15 patients, surgery/histology/radiological follow-up as a reference standard, and sufficient data to construct a 2 × 2 contingency table. Two observers performed data extraction. The sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated using a bivariate random-effects model and hierarchical summary operating curves (HSROC) were generated. Of 3457 citations retrieved, twenty-four articles met all inclusion criteria. Thirty-seven datasets could be extracted for analysis including 20 for CT, 10 for PET(CT), and 7 for (DW)MRI. The pooled sensitivity, specificity, and DOR for the detection of PM for region-based studies for CT were 68% (CI, 46–84%), 88%(CI, 81–93%), and 15.9 (CI, 4.4–58.0) respectively; 80% (CI, 57–92%), 90% (CI, 80–96%), and 36.5 (CI, 6.7–199.5) for PET(CT), respectively; 92% (CI, 84–96%), 85% (CI, 78–91%), 63.3 (CI, 31.5–127.3) for (DW)MRI. In the patient-based group, not enough studies were included to make a pooled analysis for (DW)MRI and PET(CT). (DW)MRI and PET(CT) showed comparable diagnostic performance for the detection of peritoneal metastases in ovarian and gastrointestinal cancer patients. Since MRI is more widely available than PET(CT) in clinical practice, this potentially is the imaging method of choice in most centers in the future. • Detection of peritoneal metastases plays an important role in the accurate staging of cancer patients, however, there is no accepted reference standard for the imaging of peritoneal metastases • This meta-analysis shows that (DW)MRI provided the highest sensitivity for the detection of peritoneal metastases in ovarian and gastrointestinal cancer patients • Although (DW)MRI and PET(CT) show a comparable overall diagnostic performance, (DW)MRI seems to be the imaging method of choice since it is more available in daily practice than PET(CT).

Introduction/Background* The role of HIPEC in ovarian cancer has been the subject of significant debate. The publication of the OVIHIPEC trial has provided evidence to support the use of HIPEC in the interval cytoreduction setting with a complete or near partial macroscopic resection1. It is clear from many of the recent surgical trials in advanced and recurrent ovarian cancer that the international gynaecological oncology community has not been successful in implementing standardised surgical approaches to advanced ovarian cancer cytoreductive surgery (CRS). This includes the role, accreditation and operational protocols for HIPEC. Methodology Our aim was to ascertain the global interest of centres practising CRS for ovarian cancer and HIPEC of contributing to an International Data Registry with a view to implement a Delphi process to address these vital issues in ovarian cancer surgery. A SurveyMonkey invitation was distributed to centres already involved within the Peritoneal Surface Oncology Group International (PSOGI) database. Invitation was voluntary and consent obtained to become involved with the registry. A short 5 question survey was initially issued to assess referral levels and accreditation requirements. Result(s)* 40 of 98 centres replied to the survey. 78% consented to become involved in an international registry. 63% of centres who replied receive between 50 - >100 referrals of ovarian cancer per year and 90% perform HIPEC in ovarian cancer. 79% (31/40) stated they had been practising CRS & HIPEC for >10 years. The number of CRS with HIPEC per year performed was 50 in 4%. 21% of centres held international accreditation for ovarian cancer CRS and 51% held national accreditation. Of interest was that 82% reported that no certification was required for the administration of HIPEC in their country. Conclusion* Given the multiple reports demonstrating variations in practice across the globe we believe this could be a very important opportunity for implementing change for women with ovarian cancer. For centres that consented to participation a further survey will be issued focusing on operating standards for CRS in ovarian cancer and protocols for HIPEC administration.

Introduction/Background* The COVID-19 pandemic caused drastic healthcare changes worldwide. To date, the impact of these pandemic-induced alterations in gynaecological oncology healthcare is unknown. We assessed the impact of the COVID-19 pandemic on gynaecological oncology healthcare in the Netherlands by analysing data of the Dutch Gynaecological Oncology Audit (DGOA). Methodology All patients in The Netherlands undergoing surgery for ovarian, vulvar, endometrial or cervical cancer are registered in the DGOA since 2014. To evaluate whether the COVID-19 pandemic influenced care, we compared the following parameters that are available in the DGOA: surgical volume, time to first treatment (TTFT), length of hospital stay (LOHS), postoperative complications and 30-day mortality. Four periods were identified in 2020 based on incidence of COVID-19 infections in The Netherlands: ‘Pre-COVID-19’, ‘First wave’, ‘Interim period’ and ‘Second wave’. Using descriptive statistics, results from 2020 were compared with the same four periods of 2018-2019 combined. Result(s)* A total of 12.447 surgical procedures were analysed. Analysing the four periods in 2020, compared to the average volumes of 2018-2019, the surgical volume for the four tumour types decreased during the first COVID-19 wave and interim period (figure 1). This was due to a decrease in surgical volume for cervical cancer only (17.2% in 2020), while volumes for ovarian, vulvar and endometrial cancer remaining stable. Moreover, during the interim period, only 51% of the expected cervical cancer procedures were performed. A significantly shorter median TTFT was observed in all four malignancies in 2020, compared to 2018-2019 (table 1). No differences in LOHS, postoperative complications and 30-day mortality were observed (table 1). Conclusion* The COVID-19 pandemic clearly impacted gynaecological oncology healthcare in The Netherlands. During the first COVID-19 wave, surgical volume for gynaecological oncological procedures dropped considerably, mainly due to a substantial drop in surgical volume for cervical cancer. This is probably caused by the temporary interruption of the population screening program. During the COVID-19 pandemic, waiting time to start therapy was shorter. The quality of perioperative healthcare was not negatively impacted by the pandemic.

Results of the PlaComOv-study, a randomized, controlled trial in the Netherlands Introduction/Background* The most important prognostic factor for patients with advanced-stage ovarian cancer is complete cytoreductive surgery (CRS). Standard surgical treatment with electrosurgery cannot always result in complete CRS, especially when many small metastases are found on the mesentery and intestinal surface. We investigated whether adjuvant use of the PlasmaJet® Device will help increase the complete cytoreduction rate. Methodology 327 patients with FIGO stage IIIB-IV epithelial ovarian cancer (EOC) who underwent primary or interval CRS were assigned to either surgery with PlasmaJet (intervention) or without PlasmaJet (control group). Primary outcome was the percentage of complete CRS. Secondary outcomes were duration of surgery, blood loss, number of bowel resections and colostomies, hospitalization, 30 day-morbidity and quality of life (QoL). Result(s)* Complete CRS was achieved in 119 patients (75.8%) of the intervention group and in 115 patients (67.6%) of the control group (P=0.131). A per-protocol analysis was performed in which data of 27 patients with unresectable disease were excluded, considering that the aim of the study was to examine the effectiveness of the use of the PlasmaJet in achieving CRS. Complete CRS was obtained in 85.6% in the intervention group and in 71.5% in the control group (absolute difference 14.1%, 95% confidence interval [CI], 0.047 to 0.230; P=0.005). The number of colostomies was lower in the intervention group (6.5% versus 12.7%) but did not differ significantly (P=0.169). Patient-reported QoL six months after surgery differed between groups in favor of PlasmaJet surgery (95% CI, 0.455 to 8.350; P=0.029). Other secondary outcomes did not differ significantly. Conclusion* The adjuvant use of the PlasmaJet during CRS for advanced stage ovarian cancer resulted in a significant higher proportion of complete CRS in patients with resectable disease and a higher QoL six months after surgery. (Funded by ZonMw, Trial Register NL62035.078.17.)

Introduction/Background* Based on the results of the randomized controlled OVHIPEC-1 trial, Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with cisplatin has been incorporated in Dutch evidence based guidelines and is considered routine treatment in patients with stage III epithelial ovarian cancer following complete or optimal interval cytoreductive surgery (CRS). Differences in patient selection criteria, technical aspects and perioperative management exist between the ten Dutch centers that perform HIPEC for ovarian cancer. As part of an implementation process, we aim to standardize these important aspects using a consensus-based Delphi approach. Methodology This consensus study comprised a two-phase modified Delphi approach involving 40 experts with experience in performing the HIPEC procedure for ovarian cancer (gynecological oncologists, medical oncologists, oncological surgeons and anesthesiologists). Key aspects of HIPEC were identified in panel discussions. Next, the expert panel completed a survey consisting of various statements and questions about these aspects. During a subsequent consensus meeting, survey outcomes were discussed considering the available scientific evidence. Consensus was defined as ≥75% agreement on a statement or question. Statements with Result(s)* In the first round, the response rate was 98% and consensus was seen for 45% of statements and questions. Highest agreement was present for selected statements on CRS and postoperative care. For those statements consensus was reached, agreement varied from 78-100% (statements on CRS) and 78-95% (statements on postoperative care). Items on patient selection, setting the indication, preoperative workup, and technical aspects of HIPEC required more panel discussion and revision. Results of the second round will be available by July 2021. Conclusion* A Dutch expert panel reached substantial agreement on a number of statements regarding HIPEC for ovarian cancer. Lack of consensus was generally associated with absence of robust scientific evidence. The results of this consensus study can help to align treatment protocols and minimize practice variation. These efforts will ensure optimal and safe introduction of HIPEC in the Netherlands, result in a safe treatment for all eligible patients and may guide the research agenda on HIPEC for 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

Introduction: The Dutch Gynecological Oncology Audit (DGOA) was initiated in 2014 to serve as a nationwide audit, which registers the four most prevalent gynecological malignancies. This study presents the first results of clinical auditing for ovarian cancer in the Netherlands.Methods: The Dutch Gynecological Oncology Audit is facilitated by the Dutch Institute of Clinical Auditing (DICA) and run by a scientific committee. Items are collected through a web-based registration based on a set of predefined quality indicators. Results of quality indicators are shown, and benchmarked information is given back to the user. Data verification was done in 2016. Results: Between January 01, 2014 and December 31, 2018, 6535 patients with ovarian cancer were registered. The case ascertainment was 98.3% in 2016. The number of patients with ovarian cancer who start therapy within 28 days decreased over time from 68.7% in 2014 to 62.7% in 2018 (p < 0.001). The percentage of patients with primary cytoreductive surgery decreased over time (57.8%-39.7%, P < 0.001). However, patients with complete primary cytoreductive surgery improved over time (53.5%-69.1%, P < 0.001). Other quality indicators did not significantly change over time.Conclusion: The Dutch Gynecological Oncology Audit provides valuable data on the quality of care on patients with ovarian cancer in the Netherlands. Data show variation between hospitals with regard to pre-determined quality indicators. Results of 'best practices' will be shared with all participants of the clinical audit with the aim of improving quality of care nationwide.(c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/).

Objectives. The challenge when performing cytoreductive surgery (CRS) is to balance the benefits and risks. The aim of this study was to report short term postoperative morbidity and mortality in relation to surgical outcome in patients undergoing primary debulking surgery (PDS) or interval debulking (IDS) surgery in the Netherlands. Methods. The Dutch Gynecological Oncology Audit (DGOA) was used for retrospective analysis. Patients undergoing PDS or IDS between January 1st, 2015 -December 31st, 2018 were included. Outcome was frequency of postoperative complications. Median time to adjuvant chemotherapy and severity of complications were related to outcome of CRS. Complications with Clavien-Dindo >= 3 were analyzed per region and case mix corrected. Statistical analysis was performed with R.Studio. Results. 1027 patients with PDS and 1355 patients with IDS were included. Complications with re-invention were significantly higher in PDS compared to IDS (5.7% vs. 3.6%, p = 0.048). Complete cytoreduction was 69.7% in PDS and 62.1% IDS, p < 0.001. Time to adjuvant chemotherapy was 49 days in patients with complete CRS and a complication with re-intervention. Regional variation for severe complications showed one region outside confidence intervals. Conclusions. Higher complete cytoreduction rate in the PDS group indicates that the correct patients have been selected, but is associated with a higher percentage of complication with re-intervention. As result, time to start adjuvant chemotherapy is longer in this group. Maintaining a balance in aggressiveness of surgery and outcome of the surgical procedure with respect to severe complications is underlined. Bench marked data should be discussed nationally to improve this balance. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Introduction The Dutch Gynaecological Oncology Audit (DGOA) was initiated in 2013 where all patients with a gynaecological malignancy are registered. The aim of this study is to present the first results of clinical auditing from the DGOA for ovarian-, cervical-, endometrial- and vulvar cancer. Methods The DGOA is facilitated by the Dutch Institute of Clinical Auditing and run by its own scientific committee. Items are collected through a web-based registration based on a set of quality indicators. Results are frequently updated and benchmarked information is given back to the user. Data verification was done in 2016 where the accuracy and completeness was checked. Results Between 01 January 2014 and 31 December 2018, a total of nearly 18.000 patients were registered. Case ascertainment was 98.3% in 2016. Percentage of patients with ovarian cancer waiting less than 28 days to start with any form of therapy decreased over time from 57.3% in 2014 to 40.9% in 2018 (p Conclusion The DGOA provides valuable data on the quality of care for patients diagnosed with a gynaecological malignancy. Data shows variation between hospitals with regard to pre-determined quality indicators. The results of the so called ‘best practices’ are shared with participants of the clinical audit with the aim of improving quality of care in the Netherlands.

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. ispartof: VIRCHOWS ARCHIV vol:477 issue:4 pages:535-544 ispartof: location:Germany status: published

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. (C) 2016 Elsevier Ltd. All rights reserved

Introduction/Background Introduction: GROINSS-V II investigated whether radiotherapy is a safe alternative for inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). Methodology Methods: In GROINSS-V II, a prospective multicentre phase II trial, patients were included with early-stage squamous cell carcinoma (SCC) of the vulva (diameter Results From December 2005 until October 2016, 1552 eligible patients were registered. SN-metastasis occurred in 324/1552 (21%) patients. After 54 months of inclusion the stopping-rule for SN-positive patients was activated; interim analysis showed an increased risk for groin recurrence in case of SN-metastasis >2 mm and/or extranodal extension (ENE). After amendment of the protocol only patients with SN-micrometastasis ≤2 mm received radiotherapy, while those with SN metastasis >2 mm underwent IFL (with radiotherapy if >1 metastasis or ENE). Final analysis after ≥2 years of follow-up revealed six isolated groin recurrences in 157 patients with a SN-micrometastasis (3.8%). Four could not be considered radiotherapy failures: two developed recurrence in the contralateral (SN-negative) groin, two refused radiotherapy. Twenty-eight patients did not get radiotherapy (2 recurrences;7.1%). Among 129 patients who received radiotherapy to the groin(s) only two isolated groin recurrences were diagnosed (1.6%: 95%CI:0–3.8%). The combination of radiotherapy with SN was associated with minimal toxicity: 5/118(4.2%) grade 3 toxicity, no grade 4 or 5 toxicity. In 38/1222 SN-negative patients (3.1%: 95%CI:2.1–4.1%) isolated groin recurrences were diagnosed with clear protocol violations in 6 patients: incomplete treatment of the groin (n=3); primary tumor >4cm (n=1); not all SNs visualized on the lymphoscintigram removed (n=2). After exclusion of these protocol violations an isolated groin recurrence rate of 2.6% (95%CI:1.7–3.5%) was observed. Conclusion Radiotherapy to the groins is a safe alternative for IFL in patients with SN metastasis ≤2 mm, with minimal toxicity. We further established the safety of omitting IFL in patients with SCC of the vulva 2 mm, radiotherapy with a total dose of 50Gy was no safe alternative for IFL; dose escalation and/or chemoradiation should be investigated in these patients. Disclosure Funded by Dutch Cancer Society.

Introduction/Background Presence of residual disease (RD) after interval debulking surgery (IDB) is an important negative prognostic factor for patients with advanced stage epithelial ovarian cancer (EOC). Surgery is of limited benefit when the diameter of RD is >1 cm. RD is difficult to predict before surgery. The multivariate model Cancer Ovarii Non-invasive Assessment of Treatment Strategy (CONATS) index, based on serum biomarker Human Epididymis 4 (HE4), age and WHO performance status (PS), predicted no visible RD in patients undergoing primary debulking surgery with an AUC of 0.85. The AUC of predicting RD >1 cm was not reported, although this can be of importance for pre-operative decision making especially in fragile patients. We tested this model for predicting RD >1 cm in patients undergoing IDB. Methodology We retrospectively included patients with advanced EOC who underwent IDB between 2010 and 2017 in two tertiary centers in the Netherlands. HE4 was measured with electrochemiluminescence in pre-operative samples. The CONATS-index was used to predict RD. Areas under the curve (AUC) were calculated to predict RD >1 cm. Results Two-hundred-seventy-three patients were included. Mean age was 64 years (SD 11 years). Following surgery, 232 patients (85%) had RD ≤1 cm and 41 patients (15%) had RD >1 cm. The AUC was 0.80 for predicting RD >1 cm. In patients ≥70 years of age the AUC was 0.82. Conclusion The CONATS-index can help to predict surgical outcome after IDB in addition to radiologic parameters and can be useful in counseling patients about the chance whether a meaningful IDB can be achieved. This could be especially helpful in counseling elderly patients in whom surgery has an increased risk of complications. Disclosure Nothing to disclose.

Introduction/Background Skeletal muscle depletion in women with advanced ovarian cancer has been associated with adverse clinical outcome and survival. To validate earlier results in a homogenous population, we analyzed whether a decrease in skeletal muscle index (SMI) during neo-adjuvant chemotherapy (NACT) is associated with worse outcome in patients with stage III epithelial ovarian cancer, who were included in the OVHIPEC trial. Methodology Within the phase III OVHIPEC trial, 245 patients with stage III ovarian cancer were randomized after three cycles of NACT with carboplatin and paclitaxel to receive interval cytoreductive surgery (CRS) with or without HIPEC. Randomization was performed after at least stable disease after two cycles of NACT, and when complete or optimal CRS was achieved. CT-scans performed at baseline (timepoint 1), and after two cycles of NACT (timepoint 2) were selected. A slide on the third lumbar level was selected from each CT-scan, and the difference in SMI between both scans (ΔSMI) was calculated using SliceOMatic. Overall and recurrence-free survival of patients with a decrease or increase in ΔSMI were performed using Kaplan-Meier estimates and log-rank tests. Results Of the 245 patients randomized in the OVHIPEC trial, SMI and ΔSMI of scans at both timepoints were available for 212 patients (87%). After a median follow-up of 4.7 years, 116 of 212 patients (55%) had died. In survival analysis, 43 of 74 patients (58%) in the group with a decrease in ΔSMI, and 73 of 138 of the patients (53%) in the group with stable/increase in ΔSMI had died. Median overall survival did not differ significantly(p=0.764). Conclusion A decreasing skeletal muscle index during neo-adjuvant chemotherapy was not associated with worse outcome in patients with stage III ovarian cancer, who were treated with complete/optimal interval CRS and six cycles of chemotherapy within the OVHIPEC trial. Disclosure Nothing to disclose.

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.

Objectives: To determine the diagnostic performance of MRI with diffusion-weighted imaging (DW-MRI) in assessing the peritoneal tumor load and predicting whether a complete cytoreduction can be achieved in patients with epithelial ovarian cancer (EOC).Methods: For this observational prospective study, 25 patients with epithelial ovarian cancer scheduled for cytoreductive surgery were included. Patients underwent a 3 T DW-MRI scan prior to surgery. The MR protocol consisted of a T1 and T2 weighted, a contrast-enhanced T1 weighted, and a diffusion-weighted (b0, b1000) sequence. The Peritoneal Cancer Index (PCI) was determined on DW-MR images (MRI-PCI) by two readers, independently, and was compared to the PCI determined during surgery (S-PCI). The inter-observer agreement between the two radiologists was evaluated. In addition, receiver operating characteristics curves were calculated for predicting complete cytoreduction with the S-PCI and MRI-PCI.Results: Staging with DW-MRI showed a correlation to surgical staging with an intraclass correlation coefficient (ICC) 0.86 and 0.85 for reader 1 and 2, respectively. Inter-observer agreement was excellent with an ICC of 0.90 (95% CI: 0.64-0.96). The MRI-PCI scores of reader 1 (AUC = 0.96), reader 2 (AUC = 0.98), and the S-PCI (AUC = 0.92) showed similar predictive values for complete cytoreduction.Conclusion: DW-MRI is accurate in predicting the S-PCI and can be helpful to predict whether a complete resection in ovarian cancer patients is feasible.

About 5-15% of all malignant ovarian tumors are metastases from other malignancies such as gastrointestinal tumors, breast cancer or melanoma. Also other gynecological tumors can metastasize to the ovaries. It is crucial to differentiate between primary epithelial ovarian cancer (EOC) and ovarian metastases because different treatment is required. The clinical value of human epididymal secretory protein 4 (HE4) as a serum biomarker in primary ovarian cancer has been established. The use of HE4 in the differentiation between primary ovarian cancer and ovarian metastases from other malignancies has never been investigated.HE4, CA125 and CEA were measured in 192 patients with EOC (n=147) or ovarian metastases (n=40). Univariate and multivariate logistic regression analyses were done. Sensitivity, specificity and area under the curve (AUC) were calculated for all markers and ratios hereof using receiver operating characteristics methodology.Median serum HE4 concentration was significantly higher in patients with EOC compared to patients with ovarian metastases (431 pmol/L vs 68 pmol/L, p0.001). HE4 and CEA were independent factors in differentiating between EOC and ovarian metastases (both p0.001) while CA125 was not (p=0.33). The HE4(2.5)/CEA ratio demonstrated the highest discriminative value (ROC-AUC 0.94) compared to HE4, CEA, CA125 or CA125/CEA ratio (0.88, 0.78, 0.80 and 0.89 respectively) and showed a specificity of 82.5% at set sensitivity of 90% in discriminating EOC from ovarian metastases.HE4 can be used in combination with CEA to make the distinction between EOC and ovarian metastases from gastrointestinal origin.

Contains fulltext : 190963.pdf (Publisher’s version ) (Closed access) 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.

Aim To compare outcome of women with ovarian metastasis who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) to outcome of women without ovarian metastasis who underwent CRS-HIPEC. Methods A prospective CRS-HIPEC database was searched to identify women with surgically treated colorectal carcinoma between 2000 and 2012. Patients with ovarian metastasis were identified and patients with peritoneal carcinomatosis but without ovarian metastasis were included as control cases. Results 75 patients with macroscopic ovarian metastasis underwent CRS-HIPEC with curative intent, while 50 female patients without ovarian metastasis were identified who underwent CRS-HIPEC. Patients with ovarian metastasis more often had a primary appendiceal tumour and had a more extensive intra-abdominal tumour load compared to patients without ovarian metastases. Median follow-up time was 45 months (95% confidence interval (CI): 37–53 months). Overall survival (OS) did not differ significantly between the two groups with a median OS in the ovarian metastasis group of 40 months (95% CI 26–54) compared to 64 months (95% CI 17–111, P = 0.478) in the non-ovarian metastasis group. Recurrence patterns did not differ significantly between groups (p = 0.183). Conclusions Patients with ovarian metastasis of colorectal and appendiceal origin who underwent CRS-HIPEC had similar outcome compared to patients without ovarian metastasis. Given the findings of high coincidence of peritoneal metastases with ovarian metastases and ovarian metastases not being an independent factor for survival after CRS-HIPEC, this procedure should be recommended for patients with peritoneal metastases and ovarian metastases of colorectal and appendiceal carcinoma.

Objective Ovarian cancer is the leading cause of death in women with gynecologic cancer. CA125 is the commonly used biomarker in the diagnosis of ovarian cancer, but has limitations in both sensitivity and specificity. Human Epididymal secretory protein (HE4) is a promising biomarker and is included in the Risk of Ovarian Malignancy Algorithm (ROMA) score, which is suggested to further increase the diagnostic accuracy than either marker alone. However, information from ultrasound and CT-scan is not included in this algorithm. This study evaluated the diagnostic accuracy of HE4 in the pre-operative diagnosis of ovarian cancer and the predictive values of biomarkers, ultrasound and CT-scan and combinations hereof. Methods HE4 and CA125 were measured in 361 subjects (34 benign, 147 ovarian cancer and 180 controls). Sensitivity, specificity and area under the curve (AUC) for CA125, HE4, ROMA and RMI scores were calculated using the receiver operating characteristic (ROC) methodology. The additional predictive value of ultrasound or CT-scan to the individual markers was analyzed using logistic regression. Results The sensitivity in predicting ovarian cancer of CA125 was 91% and of HE4 90%. The specificity was 65% and 97% respectively. HE4 demonstrated the highest discrimination (ROC-AUC=0.96), compared to ROMA, RMI and CA125 (AUC=0.95, 0.89 and 0.90 respectively). ROMA did not improve when it was combined with different ultrasound factors. The presence of intra-abdominal metastasis on CT-scan improved the discriminative potential of HE4 (p=0.0004). Conclusion HE4 in combination with CT-scan may be incorporated in the diagnostic work-up in women with a pelvic mass.

Contains fulltext : 174766.pdf (Publisher’s version ) (Closed access) BACKGROUND: Pre-operative risk stratification based on endometrial sampling determines the extent of surgery for endometrial cancer (EC). We investigated the concordance of pre- and post-operative risk stratifications and the impact of discordance on survival. METHODS: Patients diagnosed with EC within the first 6 months of the years 2005-2014 were selected from the Netherlands Cancer Registry (N = 7875). Pre- and post-operative risk stratifications were determined based on grade and/or histological subtype for 3784 eligible patients. RESULTS: A discordant risk stratification was found in 10% of patients: 4% (N = 155) had high pre- and low post-operative risk and 6% (N = 215) had low pre- and high post-operative risk. Overall survival of patients with high pre- and low post-operative risk was less favourable compared to those with a concordant low risk (80% versus 89%, p = 0.002). This difference remained significant when correcting for age, stage, surgical staging and adjuvant therapy (hazard ratio 1.80, 95% confidence interval 1.28-2.53, p = 0.001). Survival of patients with low pre- and high post-operative risk did not differ from those with a concordant high risk (64% versus 62%, p = 0.295). CONCLUSION: Patients with high pre- and low post-operative risk have a less favourable prognosis compared to patients with a concordant low risk. Pre-operative risk stratifications contain independent prognostic information and should be incorporated into clinical decision-making.

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.

BackgroundDespite much debate, there is little evidence on consequences of consent procedures for residual tissue use. Here, we investigated these consequences for the availability of residual tissue for medical research, clinical practice, and patient informedness. MethodsWe conducted a randomised clinical trial with three arms in six hospitals. Participants, patients from whom tissue had been removed for diagnosis or treatment, were randomised to one of three arms: informed consent, an opt-out procedure with active information provision (opt-out plus), and an opt-out procedure without active information provision. Participants received a questionnaire six weeks post-intervention; a subsample of respondents was interviewed. Health care providers completed a pre- and post-intervention questionnaire. We assessed percentage of residual tissue samples available for medical research, and patient and health care provider satisfaction and preference. Health care providers and outcome assessors could not be blinded. ResultsWe randomised 1,319 patients, 440 in the informed consent, 434 in the opt-out plus, and 445 in the opt-out arm; respectively 60.7%, 100%, and 99.8% of patients’ tissue samples could be used for medical research. Of the questionnaire respondents (N = 224, 207, and 214 in the informed consent, opt-out plus, and opt-out arms), 71%, 69%, and 31%, respectively, indicated being (very) well informed. By questionnaire, the majority (53%) indicated a preference for informed consent, whereas by interview, most indicated a preference for opt-out plus (37%). Health care providers (N = 35) were more likely to be (very) satisfied with opt-out plus than with informed consent (p = 0.002) or opt-out (p = 0.039); the majority (66%) preferred opt-out plus. ConclusionWe conclude that opt-out with information (opt-out plus) is the best choice to balance the consequences for medical research, patients, and clinical practice, and is therefore the most optimal consent procedure for residual tissue use in Dutch hospitals.

Contains fulltext : 172775.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Objectives of this study were to evaluate the effect of changes in patterns of care, for example centralization and treatment sequence, on surgical outcome and survival in patients with epithelial ovarian cancer (EOC). METHODS: Patients diagnosed with FIGO stage IIB-IV EOC (2004-2013) were selected from the Netherlands Cancer Registry. Primary outcomes were surgical outcome (extent of macroscopic residual tumor after surgery) and overall survival. Changes in treatment sequence (primary debulking surgery and adjuvant chemotherapy (PDS+ACT) or neo-adjuvant chemotherapy and interval debulking surgery (NACT+IDS)), hospital type and annual hospital volume were also evaluated. RESULTS: Patient and tumor characteristics of 7987 patients were retrieved. Most patients were diagnosed with stage III-IV EOC. The average annual case-load per hospital increased from 8 to 28. More patients received an optimal cytoreduction (tumor residue/=20 cytoreductive surgeries annually), 80% in medium (10-19 surgeries) and 71% in small hospitals (

Epithelial ovarian cancer (EOC) is the fourth most common gynecologic cancer in Europe and is the leading cause of death among women with gynecologic malignancies. This is due to the fact that the majority of the patients are diagnosed with advanced stage disease. In these stages, extensive intraperitoneal metastases are often present, making therapy more difficult. The current standard treatment involves primary or interval cytoreductive surgery and chemotherapy. However, many patients develop intraperitoneal (IP) recurrences despite complete surgery and chemotherapy. Therefore, alternative ways to deliver chemotherapy have been examined. Administration of the chemotherapy directly into the peritoneal cavity allows high doses of the cytotoxic agent at the site of the cancer, while minimizing the occurrence of systemic side effects. Theoretically, IP administration is most beneficial when only microscopic disease is present since penetration of the drug is limited to a few millimeters. IP chemotherapy can be administered during surgery under hyperthermic conditions (HIPEC) or during regular chemotherapy courses through a catheter placed into the abdominal cavity. IP administration results in an improved survival, although catheter-related morbidity is reported. Hyperthermia potentiates the cytotoxic effect of chemotherapy and may therefore have an additional positive effect on prognosis. Although recent observational studies show encouraging results with respect to effect on survival and rate of complications, it remains a challenge to identify those patients who would benefit most from adding HIPEC to the standard treatment. In this respect, age and timing of HIPEC during treatment might be important factors, although no convincing evidence is available yet. Currently, a total of 18 clinical trials are open and to answer the above-mentioned questions, it is adamant to complete these trials, especially the randomized phase III trials. Accrual is hampered by the fact that HIPEC is currently offered as standard treatment in some centers even though convincing evidence is not yet available. If these phase III trials show positive results in favor of HIPEC, subsequent trials comparing surgery and postoperative IP chemotherapy with surgery and HIPEC seem a logical next step.

The authors regret that reference 5 (Milam et al., 2011) in the original article was included in the reference list incorrectly, and it should not have been included. The authors apologise for any inconvenience caused.

Human papillomavirus type 16 (HPV16)-encoded E7 oncoprotein is constitutively expressed in cervical carcinoma cells and is required for cellular transformation to be maintained. The E7 protein, therefore, forms an attractive target for T-cell-mediated immune intervention to prevent or treat HPV16+ tumors. The authors performed a peptide-based phase I/II vaccination trial to induce anti-tumor immune responses in patients with recurrent or residual cervical carcinoma. Fifteen HLA-A*0201+ patients with HPV16+ cervical carcinoma received vaccinations with synthetic peptides representing 2 HPV16 E7-encoded, HLA-A*0201-restricted cytotoxic T lymphocyte epitopes and a pan-HLA-DR-binding T-helper epitope, PADRE, in adjuvant. No signs of toxicity were observed. Two patients had stable disease for more than 1 year after vaccination, 3 patients died of the disease during or shortly after the vaccination period, and 10 patients maintained progressive cervical carcinoma. Specific immune responses directed against the vaccine components were analyzed in peripheral blood samples. No cytotoxic T lymphocyte responses against the HPV16 E7 peptides were detectable. After vaccination, strong PADRE helper peptide-specific proliferation was detected in 4 of 12 patients. In conclusion, peptide vaccination with 2 HPV16 E7 cytotoxic T lymphocyte epitopes and a universal T helper epitope is well tolerated by patients with advanced cervical carcinoma. Despite a reduction of in vitro cytolytic or proliferative recall responses to some, but not all, conventional antigens in this patient group, peptide-specific proliferative responses were induced in 4 patients. Based on the current study, it is now feasible to perform peptide vaccination in earlier stages of HPV16-induced cervical disease.

Objective Predicting survival of patients with epithelial ovarian cancer (EOC) is based on prognosis of the population. Combining prognostic factors could facilitate survival prediction on the level of the individual patient. The aim of this study was to develop a prognostic model to predict five-year disease specific survival in patients with EOC, and to evaluate whether this would add to prediction based on prognosis of the population. Patients and methods A retrospective cohort study was performed of all EOC patients treated with primary debulking and adjuvant chemotherapy or neo-adjuvant chemotherapy and interval debulking surgery in three gynaecological-oncologic centres between 1998 and 2010. Primary outcome was 5-year disease-specific survival. We developed a Cox proportional hazard model using the LASSO-method to select the best combination of characteristics from 12 potential predictors and to correct for overfitting. Performance of the model was expressed as calibration and discrimination (c-statistic). A nomogram was developed to increase the clinical applicability of the model. Results Of 840 patients with EOC 462 (55%) died within 5years due to the disease. A combination of FIGO stage, residual tumour after surgery, primary or interval surgery, histology, performance status, age, amount of ascites and a family history suggestive of breast/ovarian cancer best predicted 5-year survival. The final model showed accurate calibration and the c-statistic was 0.71 (95% CI 0.69–0.74). Conclusions Five-year survival in all stage EOC patients can be predicted accurately using available characteristics. After external validation the model can be used for counselling of patients.

Conventional sentinel node (SN) mapping is performed by injecting a radiocolloid followed by lymphoscintigraphy (and SPECT/CT imaging). An extra intraoperative injection with blue dye can then allow for optical identification of the SN. In order to improve the current clinical standard, the hybrid tracer indocyanine green (ICG)-(99m)Tc-nanocolloid was introduced, a tracer that is both radioactive and fluorescent. This feasibility study aimed to evaluate the value of a multimodal-based SN biopsy in vulvar cancer.Fifteen patients with vulvar cancer (29 groins) scheduled for SN biopsy were peritumorally injected with ICG-(99m)Tc-nanocolloid followed by lymphoscintigraphy and SPECT/CT imaging to identify the SNs. In thirteen patients, shortly before the start of the operation, blue dye was intradermally injected around the lesion. SNs were harvested using a combination of radiotracing, fluorescence imaging, and optical blue dye detection. A portable gamma camera was used before and after SN excision to confirm excision of the preoperatively defined SNs.Preoperative lymphoscintigraphy and SPECT/CT imaging visualized drainage to 39 SNs in 28 groins. During the operation, 98% (ex vivo 100%) of the SNs were radioactive. With fluorescence imaging 96% of the SNs (ex vivo 100%) could be visualized. Only 65% of the SNs had stained blue at the time of excision.ICG-(99m)Tc-nanocolloid can be used for preoperative SN identification and enables multimodal (radioactive and fluorescent) surgical guidance in patients with vulvar cancer. The addition of fluorescence-based optical guidance offers more effective SN visualization compared to blue dye.

Om een endodontische revisie te kunnen uitvoeren, is het noodzakelijk opnieuw toegang te verkrijgen tot de geinfecteerde wortelkanaalinhoud. Daartoe zullen eerder aangebrachte kanaalvullingen, wortelstiften, plastische vulmaterialen en eventueel afgebroken instrumenten moeten worden verwijderd uit de pulpakamer en de wortelkanalen. Soms zal ook een kroon moeten worden doorboord of verwijderd.

A phase I-II clinical trial was performed involving vaccination with HPV16 E7 peptides of patients suffering from HPV16 positive cervical carcinoma which was refractory to conventional treatment. Patients receiving the vaccine were HLA-A(star)0201 positive with HPV16 positive cervical carcinoma. The clinical trial was designed as a dose-escalation study, in which successive groups of patients received 100 mu g, 300 mu g or 1000 mu g of each peptide, respectively. The vaccine consisted of two HPV16 E7 peptides and one helper peptide emulsified in Montanide ISA 51 adjuvant. 19 patients were included in the study, no adverse side-effects were observed. 2 patients showed stable disease for 1 year after vaccination; 15 patients showed progressive disease of whom 1 died during the vaccination treatment due to progressive disease; and 2 patients showed tumour-regression after chemotherapy following vaccination. A relative low count of lymphocytes before and after vaccination was present in 11/19 patients indicating that these patients were immunocompromised. This study shows that HPV16 E7 peptide vaccination is feasible, even in a group of patients with terminal disease. This paves the way for vaccinating patients with less advanced disease, whose immune system is less compromised by progressive disease. (C) 1999 Elsevier Science Ltd. All rights reserved.