Publications by authors named "Ludy C Lutgens"

30 Publications

  • Page 1 of 1

Defining Substantial Lymphovascular Space Invasion in Endometrial Cancer.

Int J Gynecol Pathol 2021 Jul 13. Epub 2021 Jul 13.

Departments of Pathology (E.E.M.P., A.L.-C., V.T.H.B.M.S., T.B.) Radiation Oncology (C.C., R.N.), Leiden University Medical Center, Leiden Department of Radiation Oncology, Utrecht University Medical Center, Utrecht (I.M.J.S.) Department of Radiotherapy, Medisch Spectrum Twente, Enschede (J.J.J.) Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam (J.W.M.M.) Maastricht Radiation Oncology Clinic, Maastricht (L.C.H.W.L.) Radiotherapy Group, Arnhem (E.M.V.D.S.-B.), The Netherlands Department of Pathology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev (M.B., E.H.) Department of Gynecology, Copenhagen University Hospital, Rigshospitalet, Copenhagen (C.H., G.O.), Denmark.

Lymphovascular space invasion (LVSI) occurs in a minority of endometrial cancer (EC) cases, and the extent of LVSI is an important risk factor for recurrence and/or metastases. Our aim was to improve the reproducibility of measuring clinically meaningful LVSI by performing a quantitative analysis of the correlation between LVSI and the risk of pelvic lymph node recurrence in EC. EC samples from PORTEC-1 and PORTEC-2 trials were retrieved and used to collect quantitative data, including the number of LVSI-positive vessels per H&E-stained slide. Using a predefined threshold for clinical relevance, the risk of pelvic lymph node recurrence risk was calculated (Kaplan-Meier method, with Cox regression) using a stepwise adjustment for the number of LVSI-positive vessels. This analysis was then repeated in the Danish Gynecological Cancer Database (DGCD) cohort. Among patients in PORTEC-1 and PORTEC-2 trials who did not receive external beam radiotherapy, the 5-yr pelvic lymph node recurrence risk was 3.3%, 6.7% (P=0.51), and 26.3% (P<0.001), respectively when 0, 1 to 3, or ≥4 vessels had LVSI involvement; similar results were obtained for the DGCD cohort. Furthermore, both the average number of tumor cells in the largest embolus and the number of LVSI-positive H&E slides differed significantly between focal LVSI and substantial LVSI. On the basis of these results, we propose a numeric threshold (≥4 LVSI-involved vessels in at least one H&E slide) for defining clinically relevant LVSI in EC, thereby adding supportive data to the semiquantitative approach. This will help guide gynecologic pathologists to differentiate between focal and substantial LVSI, especially in borderline cases.
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http://dx.doi.org/10.1097/PGP.0000000000000806DOI Listing
July 2021

Development of a Management Algorithm for Acute and Chronic Radiation Urethritis and Cystitis.

Urol Int 2021 Jun 15:1-12. Epub 2021 Jun 15.

Department of Urology, St. Antonius Hospital, Gronau, Germany.

Objective: The purpose of this review was to summarize the current literature on the assessment and treatment of radiation urethritis and cystitis (RUC) for the development of an evidenced-based management algorithm.

Material And Methods: The PubMed/MEDLINE database was searched by a multidisciplinary group of experts in January 2021.

Results: In total, 48 publications were identified. Three different types of RUC can be observed in clinical practice: inflammation-predominant, bleeding-predominant, and the combination of inflammation- and bleeding-RUC. There is no consensus on the optimal treatment of RUC. Inflammation-predominant RUC should be treated symptomatically based on the existence of bothersome storage or voiding lower urinary tract symptom as well as on pain. When bleeding-predominant RUC has occurred, hydration and hyperbaric oxygen therapy (HOT) should be used first and, if HOT is not available, oral drugs instead (sodium pentosane polysulfate, aminocaproic acid, immunokine WF 10, conjugated estrogene, or pentoxifylline + vitamin E). If local bleeding persists, focal therapy of bleeding vessels with a laser or electrocoagulation is indicated. In case of generalized bleeding, intravesical installation should be initiated (formalin, aluminium salts, and hyaluronic acid/chondroitin). Vessel embolization is a less invasive treatment with potentially less complications and good clinical outcomes. Open- or robot-assisted surgery is indicated in patients with permanent, life-threatening bleeding, or fistulae.

Conclusions: Treatment of RUC, if not self-limiting, should be done according to the type of RUC and in a stepwise approach. Conservative/medical treatment (oral and topic agents) should primarily be used before invasive (transurethral) treatments.
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http://dx.doi.org/10.1159/000515716DOI Listing
June 2021

Patients' and clinicians' preferences in adjuvant treatment for high-risk endometrial cancer: Implications for shared decision making.

Gynecol Oncol 2021 Jun 10;161(3):727-733. Epub 2021 Mar 10.

Department of radiation oncology, Leiden University Medical Centre, Leiden, the Netherlands.

Background: Decision making regarding adjuvant therapy for high-risk endometrial cancer is complex. The aim of this study was to determine patients' and clinicians' minimally desired survival benefit to choose chemoradiotherapy over radiotherapy alone. Moreover, influencing factors and importance of positive and negative treatment effects (i.e. attribute) were investigated.

Methods: Patients with high-risk endometrial cancer treated with adjuvant pelvic radiotherapy with or without chemotherapy and multidisciplinary gynaecologic oncology clinicians completed a trade-off questionnaire based on PORTEC-3 trial data.

Results: In total, 171 patients and 63 clinicians completed the questionnaire. Median minimally desired benefit to make chemoradiotherapy worthwhile was significantly higher for patients versus clinicians (10% vs 5%, p = 0.02). Both patients and clinicians rated survival benefit most important during decision making, followed by long-term symptoms. Older patients (OR 0.92 [95%CI 0.87-0.97]; p = 0.003) with comorbidity (OR 0.34 [95% CI 0.12-0.89]; p = 0.035) had lower preference for chemoradiotherapy, while patients with better numeracy skills (OR 1.2 [95%CI 1.05-1.36], p = 0.011) and chemoradiotherapy history (OR 25.0 [95%CI 8.8-91.7]; p < 0.001) had higher preference for chemoradiotherapy.

Conclusions: There is a considerable difference in minimally desired survival benefit of chemoradiotherapy in high-risk endometrial cancer among and between patients and clinicians. Overall, endometrial cancer patients needed higher benefits than clinicians before preferring chemoradiotherapy.
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http://dx.doi.org/10.1016/j.ygyno.2021.03.004DOI Listing
June 2021

Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer.

J Natl Cancer Inst 2021 Mar 6. Epub 2021 Mar 6.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction, however the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined PORTEC-1,-2 and -3 trial cohort.

Methods: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into three groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were two-sided.

Results: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to ≤ 60 or ≤ 70 years would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses. Five-year recurrence-free survival (RFS) was 91.7% (95% confidence interval [CI] = 83.1-100%; hazard ratio [HR] = 0.45, 95%CI =0.16-1.24, p = .12) for LS, 95.5% (95% CI = 90.7-100%; HR = 0.17, 95% CI = 0.05-0.55, p = .003) for 'other' versus 78.6% (95% CI = 73.8-83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95%CI = 0.0-24.7%), 1.5% (95%CI = 0.0-4.3%) and 7.0% (95%CI = 3.0-10.9%) within the LS, 'other' and MLH1-hypermethylated MMRd-EC groups.

Conclusion: The LS prevalence in the PORTEC-trial population was 2.8%, and among MMRd-ECs 9.5%. Patients with LS-associated ECs showed a trend towards better RFS and higher risk for second cancers compared to patients with MLH1-hypermethylated MMRd-EC.
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http://dx.doi.org/10.1093/jnci/djab029DOI Listing
March 2021

Long-Term Toxicity and Health-Related Quality of Life After Adjuvant Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial Cancer in the Randomized PORTEC-3 Trial.

Int J Radiat Oncol Biol Phys 2021 03 28;109(4):975-986. Epub 2020 Oct 28.

Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL).

Methods And Materials: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed.

Results: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population.

Conclusions: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2020.10.030DOI Listing
March 2021

PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer.

Int J Gynecol Cancer 2020 12 12;30(12):2002-2007. Epub 2020 Oct 12.

Radiation Oncology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.

Background: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics.

Primary Objectives: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs.

Trial Design: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm).

Major Inclusion/exclusion Criteria: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1).

Endpoints: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs.

Sample Size: 500 eligible and evaluable patients.

Estimated Dates For Completing Accrual And Presenting Results: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023.

Trial Registration: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).
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http://dx.doi.org/10.1136/ijgc-2020-001929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788476PMC
December 2020

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer.

Cancer Immunol Res 2020 12 30;8(12):1508-1519. Epub 2020 Sep 30.

Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.

Optimum risk stratification in early-stage endometrial cancer combines clinicopathologic factors and the molecular endometrial cancer classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning, image-based algorithm to quantify density of CD8 and CD103 immune cells in tumor epithelium and stroma in 695 stage I endometrioid endometrial cancers from the PORTEC-1 and -2 trials. The relationship between immune cell density and clinicopathologic/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular endometrial cancer classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate, and low densities, with highly significant variation in the proportion of molecular endometrial cancer subgroups between them. Univariable analysis revealed intraepithelial CD8 cell density as the strongest predictor of endometrial cancer recurrence; multivariable analysis confirmed this was independent of pathologic factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair-deficient cancers. Thus, this work identified that quantification of intraepithelial CD8 cells improved upon the prognostic utility of the molecular endometrial cancer classification in early-stage endometrial cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0149DOI Listing
December 2020

Persistence of Late Substantial Patient-Reported Symptoms (LAPERS) After Radiochemotherapy Including Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: A Report From the EMBRACE Study.

Int J Radiat Oncol Biol Phys 2021 01 25;109(1):161-173. Epub 2020 Aug 25.

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Vienna, Austria.

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC).

Methods And Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated.

Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event.

Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.044DOI Listing
January 2021

Confirmation of thermal dose as a predictor of local control in cervical carcinoma patients treated with state-of-the-art radiation therapy and hyperthermia.

Radiother Oncol 2019 11 11;140:150-158. Epub 2019 Jul 11.

Erasmus MC, University Medical Center Rotterdam, Department of Radiation Oncology, The Netherlands. Electronic address:

Background: Addition of deep hyperthermia results in improved local control (LC) and overall survival (OS) compared to radiotherapy alone in patients with cervical carcinoma. Previously, we showed that the thermal dose of hyperthermia significantly correlates with LC and disease specific survival (DSS). Over the last decade, new radiation techniques were introduced resulting in improved LC.

Aim: To validate the effect of thermal dose in a more recent cohort of patients treated with modern radiotherapy techniques, including image guided brachytherapy (IGBT).

Methods: We analyzed primary cervical carcinoma patients treated with a combination of radiotherapy and deep hyperthermia between 2005 and 2016 at our institute. Data on patient, tumor and treatment were collected including the thermal dose parameters TRISE and CEM43T90. Follow-up data on LC, disease free survival, DSS, OS as well as late toxicity data were collected. Data were analyzed using the Cox proportional hazard and Kaplan-Meier analyses.

Results: 227 patients were included. In multivariate analysis, histology, FIGO stage, lymphadenopathy, TRISE, CEM43T90 and IGBT had a significant effect on LC. In the patients treated with IGBT, the thermal dose parameter TRISE remained to have a significant effect on LC in univariate analysis.

Conclusions: The positive association between thermal dose and clinical outcome is replicated in an independent, recent cohort of cervical carcinoma patients. Importantly, in patients receiving IGBT, the effect of thermal dose on clinical outcome is still observed.
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http://dx.doi.org/10.1016/j.radonc.2019.06.021DOI Listing
November 2019

Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.

Lancet Oncol 2018 03 12;19(3):295-309. Epub 2018 Feb 12.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.

Background: Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer.

Methods: PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.

Results: 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1-73·1). 5-year overall survival was 81·8% (95% CI 77·5-86·2) with chemoradiotherapy versus 76·7% (72·1-81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54-1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3-79·9) versus 68·6% (63·1-73·4; HR 0·71, 95% CI 0·53-0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity.

Interpretation: Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival.

Funding: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.
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http://dx.doi.org/10.1016/S1470-2045(18)30079-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840256PMC
March 2018

Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts.

Clin Cancer Res 2016 Aug 22;22(16):4215-24. Epub 2016 Mar 22.

Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.

Purpose: Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy.

Experimental Design: Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, β-catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n = 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared.

Results: Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53-mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high-intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% L1CAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTNNB1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant).

Conclusions: Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. Clin Cancer Res; 22(16); 4215-24. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2878DOI Listing
August 2016

Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial.

Radiother Oncol 2016 09 17;120(3):378-382. Epub 2016 Feb 17.

Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Department of Hyperthermia, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Background: Chemoradiation (RT-CT) is standard treatment for locally advanced cervical cancer (LACC). This study tried to establish if radiotherapy combined with hyperthermia (RT-HT) should be preferred in bulky and/or FIGO-stage ⩾III.

Methods: In this open-label, multicenter randomized trial, patients with LACC were randomly assigned by a computer-generated, biased coin minimization technique to RT-CT or RT-HT. Central randomization was done with stratification by FIGO-stage, tumour diameter and nodal status. Primary endpoint was event free survival (EFS). Secondary endpoints were pelvic recurrence free survival (PRFS), overall survival (OS) and treatment related toxicity. Analysis was done by intention to treat.

Results: The trial was closed prematurely (87 of 376 planned patients enrolled: 43 RT-CT; 44 RT-HT). Median follow-up time was 7.1 years. The cumulative incidence of an event was 33% in the RT-CT group and 35% in the RT-HT group. The corresponding hazard rate (HR) for EFS was 1.15 (CI: 0.56-2.36, p=0.7). Also the hazards for PRFS (0.94; CI 0.36-2.44) and OS (1.04; CI 0.48-2.23) at 5 years were comparable between both treatment arms as was grade ⩾3 radiation related late toxicity (6 RT-CT and 5 RT-HT patients).

Conclusion: After 25% of intended accrual, data suggest comparable outcome for RT-CT and RT-HT.
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http://dx.doi.org/10.1016/j.radonc.2016.02.010DOI Listing
September 2016

Long-Term Impact of Endometrial Cancer Diagnosis and Treatment on Health-Related Quality of Life and Cancer Survivorship: Results From the Randomized PORTEC-2 Trial.

Int J Radiat Oncol Biol Phys 2015 Nov 18;93(4):797-809. Epub 2015 Aug 18.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: To evaluate the long-term health-related quality of life (HRQL) after external beam radiation therapy (EBRT) or vaginal brachytherapy (VBT) among PORTEC-2 trial patients, evaluate long-term bowel and bladder symptoms, and assess the impact of cancer on these endometrial cancer (EC) survivors.

Patients And Methods: In the PORTEC-2 trial, 427 patients with stage I high-intermediate-risk EC were randomly allocated to EBRT or VBT. The 7- and 10-year HRQL questionnaires consisted of EORTC QLQ-C30; subscales for bowel and bladder symptoms; the Impact of Cancer Questionnaire; and 14 questions on comorbidities, walking aids, and incontinence pads. Analysis was done using linear mixed models for subscales and (ordinal) logistic regression with random effects for single items. A two-sided P value <.01 was considered statistically significant.

Results: Longitudinal HRQL analysis showed persisting higher rates of bowel symptoms with EBRT, without significant differences in global health or any of the functioning scales. At 7 years, clinically relevant fecal leakage was reported by 10.6% in the EBRT group, versus 1.8% for VBT (P=.03), diarrhea by 8.4% versus 0.9% (P=.04), limitations due to bowel symptoms by 10.5% versus 1.8% (P=.001), and bowel urgency by 23.3% versus 6.6% (P<.001). Urinary urgency was reported by 39.3% of EBRT patients, 25.5% for VBT, P=.05. No difference in sexual activity was seen between treatment arms. Long-term impact of cancer scores was higher among the patients who had an EC recurrence or second cancer.

Conclusions: More than 7 years after treatment, EBRT patients reported more bowel symptoms with impact on daily activities, and a trend for more urinary symptoms, without impact on overall quality of life or difference in cancer survivorship issues.
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http://dx.doi.org/10.1016/j.ijrobp.2015.08.023DOI Listing
November 2015

Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer--A pooled analysis of PORTEC 1 and 2 trials.

Eur J Cancer 2015 Sep 3;51(13):1742-50. Epub 2015 Jun 3.

Department of Radiotherapy, Leiden University Medical Center, The Netherlands. Electronic address:

Background: Lymph-vascular space invasion (LVSI) is an important adverse prognostic factor in endometrial cancer (EC). However, its role in relation to type of recurrence and adjuvant treatment is not well defined, and there is significant interobserver variation. This study aimed to quantify LVSI and correlate this to risk and type of recurrence.

Methods: In the post operative radiation therapy in endometrial carcinoma (PORTEC)-trials stage I EC patients were randomised to receive external beam radiotherapy (EBRT) versus no additional treatment after surgery (PORTEC-1, n=714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n=427). In tumour samples of 926 (81.2%) patients with endometrioid tumours LVSI was quantified using 2-, 3- and 4-tiered scoring systems. Cox proportional hazard models were used for time-to-event analysis.

Results: Any degree of LVSI was identified in 129 cases (13.9%). Substantial LVSI (n=44, 4.8%) using the 3-tiered approach had the strongest impact on the risk of distant metastasis (hazard ratio (HR) 4.5 confidence interval (CI) 2.4-8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment) substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2 CI 2.4-16), distant metastasis (HR 3.6 CI 1.9-6.8) and overall survival (HR 2.0 CI 1.3-3.1). Only EBRT (HR 0.3 CI 0.1-0.8) reduced the risk of pelvic regional recurrence.

Conclusions: Substantial LVSI, in contrast to focal or no LVSI, was the strongest independent prognostic factor for pelvic regional recurrence, distant metastasis and overall survival. Therapeutic decisions should be based on the presence of substantial, not 'any' LVSI. Adjuvant EBRT and/or chemotherapy should be considered for stage I EC with substantial LVSI.
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http://dx.doi.org/10.1016/j.ejca.2015.05.015DOI Listing
September 2015

Nomograms for prediction of outcome with or without adjuvant radiation therapy for patients with endometrial cancer: a pooled analysis of PORTEC-1 and PORTEC-2 trials.

Int J Radiat Oncol Biol Phys 2015 Mar 30;91(3):530-9. Epub 2015 Jan 30.

Department of Radiation Oncology, MAASTRO, GROW, University Medical Centre Maastricht, Maastricht, The Netherlands.

Background: Postoperative radiation therapy for stage I endometrial cancer improves locoregional control but is without survival benefit. To facilitate treatment decision support for individual patients, accurate statistical models to predict locoregional relapse (LRR), distant relapse (DR), overall survival (OS), and disease-free survival (DFS) are required.

Methods And Materials: Clinical trial data from the randomized Post Operative Radiation Therapy for Endometrial Cancer (PORTEC-1; N=714 patients) and PORTEC-2 (N=427 patients) trials and registered group (grade 3 and deep invasion, n=99) were pooled for analysis (N=1240). For most patients (86%) pathology review data were available; otherwise original pathology data were used. Trial variables which were clinically relevant and eligible according to data constraints were age, stage, given treatment (pelvic external beam radiation therapy (EBRT), vaginal brachytherapy (VBT), or no adjuvant treatment, FIGO histological grade, depth of invasion, and lymph-vascular invasion (LVSI). Multivariate analyses were based on Cox proportional hazards regression model. Predictors were selected based on a backward elimination scheme. Model results were expressed by the c-index (0.5-1.0; random to perfect prediction). Two validation sets (n=244 and 291 patients) were used.

Results: Accuracy of the developed models was good, with training accuracies between 0.71 and 0.78. The nomograms validated well for DR (0.73), DFS (0.69), and OS (0.70), but validation was only fair for LRR (0.59). Ranking of variables as to their predictive power showed that age, tumor grade, and LVSI were highly predictive for all outcomes, and given treatment for LRR and DFS. The nomograms were able to significantly distinguish low- from high-probability patients for these outcomes.

Conclusions: The nomograms are internally validated and able to accurately predict long-term outcome for endometrial cancer patients with observation, pelvic EBRT, or VBT after surgery. These models facilitate decision support in daily clinical practice and can be used for patient counseling and shared decision making, selecting patients who benefit most from adjuvant treatment, and generating new hypotheses.
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http://dx.doi.org/10.1016/j.ijrobp.2014.11.022DOI Listing
March 2015

[Rectal bleeding after radiotherapy for prostate cancer].

Ned Tijdschr Geneeskd 2014 ;158:A7698

Maastricht Universitair Medisch Centrum, Maastricht.

This clinical lesson, based on two case histories, illustrates a complication seen after manipulation of the rectal wall in patients who have undergone radiotherapy for localised prostate cancer. Rectal bleeding, which is feared by patients, can be the first sign of radiation proctitis. Manipulation of the rectal wall, for example by taking biopsies or Argon plasma coagulation, should be done with caution and only if absolutely necessary, because it can lead to fistula formation.
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April 2015

Improved risk assessment of endometrial cancer by combined analysis of MSI, PI3K-AKT, Wnt/β-catenin and P53 pathway activation.

Gynecol Oncol 2012 Sep 15;126(3):466-73. Epub 2012 May 15.

Department of Clinical Oncology, Leiden University Medical Center, The Netherlands.

Objective: To investigate if analysis of genetic alterations in the main pathways involved in endometrioid type carcinogenesis (PI3K-AKT, Wnt/β-catenin, P53-activation and MSI) improves the current risk assessment based on clinicopathological factors.

Methods: Formalin fixed paraffin embedded (FFPE) primary tumor samples of 65 patients with FIGO-stage I endometrioid type endometrial cancer (EEC) were selected from the randomized PORTEC-2 trial. Tumors were stained by immunohistochemistry for P53, PTEN and β-catenin. Tumor DNA was isolated for sequence analysis of TP53 (exons 4 to 8), hotspot mutation analysis of KRAS (exon 1) and PI3K (exon 9 and 20) and microsatellite-instability (MSI) analysis including MLH1 promotor-methylation status. Univariate and multivariate analyses for disease-free survival (DFS) using Cox regression models were performed.

Results: P53 status (HR 6.7, 95%CI 1.75-26.0, p=0.006) and MSI were the strongest single genetic prognostic factors for decreased DFS, while high PI3K-AKT pathway activation showed a trend and β-catenin was not prognostic. The combination of multiple activated pathways was the most powerful prognostic factor for decreased DFS (HR 5.0; 95%CI 1.59-15.6 p=0.006). Multiple pathway activation, found in 8% of patients, was strongly associated with aggressive clinical course. In contrast, 40% of patients had no alterations in the investigated pathways and had a very low risk of disease progression.

Conclusions: Activation of multiple oncogenic pathways in EEC was the most powerful prognostic factor for decreased DFS, resulting in an individual risk assessment superior to the current approach based on clinicopathological factors.
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http://dx.doi.org/10.1016/j.ygyno.2012.05.012DOI Listing
September 2012

Five-year quality of life of endometrial cancer patients treated in the randomised Post Operative Radiation Therapy in Endometrial Cancer (PORTEC-2) trial and comparison with norm data.

Eur J Cancer 2012 Jul 14;48(11):1638-48. Epub 2011 Dec 14.

Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.

Background: The PORTEC-2 trial showed efficacy and reduced side-effects of vaginal brachytherapy (VBT) compared with external beam pelvic radiotherapy (EBRT) for patients with high-intermediate risk endometrial cancer. The current analysis was done to evaluate long-term health related quality of life (HRQL), and compare HRQL of patients to an age-matched norm population.

Methods: Patients were randomly allocated to EBRT (n=214) or VBT (n=213). HRQL was assessed using EORTC QLQ-C30 and subscales from PR25 and OV28 (bladder, bowel, sexual symptoms); and compared to norm data.

Findings: Median follow-up was 65 months; 348 (81%) patients were evaluable for HRQL (EBRT n=166, VBT n=182). At baseline, patient functioning was at lowest level, increasing during and after radiotherapy to reach a plateau after 12 months, within range of scores of the norm population. VBT patients reported better social functioning (p=0.005) and lower symptom scores for diarrhoea, faecal leakage, need to stay close to a toilet and limitation in daily activities due to bowel symptoms (p⩽0.001), compared to EBRT. There were no differences in sexual functioning or symptoms between the treatment groups; however, sexual functioning was lower and sexual symptoms more frequent in both treatment groups compared to the norm population.

Interpretation: Patients who received EBRT reported clinically relevant higher levels of bowel symptoms and related limitations in daily activities with lower social functioning, 5 years after treatment. VBT provides a better HRQL, which remained similar to that of an age-matched norm population, except for sexual symptoms which were more frequent in both treatment groups.
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http://dx.doi.org/10.1016/j.ejca.2011.11.014DOI Listing
July 2012

Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma.

Int J Radiat Oncol Biol Phys 2011 Nov 2;81(4):e631-8. Epub 2011 Jun 2.

Department of Clinical Oncology, Leiden University Medical Center, The Netherlands.

Purpose: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers.

Patients And Methods: The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat.

Results: 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02).

Conclusions: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.
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http://dx.doi.org/10.1016/j.ijrobp.2011.04.013DOI Listing
November 2011

Long-term outcome and quality of life of patients with endometrial carcinoma treated with or without pelvic radiotherapy in the post operative radiation therapy in endometrial carcinoma 1 (PORTEC-1) trial.

J Clin Oncol 2011 May 28;29(13):1692-700. Epub 2011 Mar 28.

Department of Clinical Oncology, Leiden University Medical Center, PO PO Box 9600, 2300 RC Leiden, The Netherlands.

Purpose: To determine the long-term outcome and health-related quality of life (HRQL) of patients with endometrial carcinoma (EC) treated with or without pelvic radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial.

Patients And Methods: Between 1990 and 1997, 714 patients with stage IC grade 1 to 2 or IB grade 2 to 3 EC were randomly allocated to pelvic external-beam radiotherapy (EBRT) or no additional treatment (NAT). HRQL was evaluated with the Short Form 36-Item (SF-36) questionnaire; subscales from the European Organisation for Research and Treatment of Cancer (EORTC) PR25 module for bowel and bladder symptoms and the OV28 and CX24 modules for sexual symptoms; and demographic questions. Analysis was by intention-to-treat.

Results: Median follow-up was 13.3 years. The 15-year actuarial locoregional recurrence rates were 5.8% for EBRT versus 15.5% for NAT (P < .001), and 15-year overall survival was 52% versus 60% (P = .14). Of the 351 patients confirmed to be alive with correct address, 246 (70%) returned the questionnaire. Patients treated with EBRT reported significant (P < .01) and clinically relevant higher rates of urinary incontinence, diarrhea, and fecal leakage leading to more limitations in daily activities. Increased symptoms were reflected by the frequent use of incontinence materials after EBRT (day and night use, 42.9% v 15.2% for NAT; P < .001). Patients treated with EBRT reported lower scores on the SF-36 scales "physical functioning" (P = .004) and "role-physical" (P = .003).

Conclusion: EBRT for endometrial cancer is associated with long-term urinary and bowel symptoms and lower physical and role-physical functioning, even 15 years after treatment. Despite its efficacy in reducing locoregional recurrence, EBRT should be avoided in patients with low- and intermediate-risk EC.
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http://dx.doi.org/10.1200/JCO.2010.32.4590DOI Listing
May 2011

Synopsis of partial-body radiation diagnostic biomarkers and medical management of radiation injury workshop.

Radiat Res 2010 Feb;173(2):245-53

Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889, USA.

Radiation exposures from accidents, nuclear detonations or terrorist incidents are unlikely to be homogeneous; however, current biodosimetric approaches are developed and validated primarily in whole-body irradiation models. A workshop was held at the Armed Forces Radiobiology Research Institute in May 2008 to draw attention to the need for partial-body biodosimetry, to discuss current knowledge, and to identify the gaps to be filled. A panel of international experts and the workshop attendees discussed the requirements and concepts for a path forward. This report addresses eight key areas identified by the Workshop Program Committee for future focus: (1) improved cytogenetics, (2) clinical signs and symptoms, (3) cutaneous bioindicators, (4) organ-specific biomarkers, (5) biophysical markers of dose, (6) integrated diagnostic approaches, (7) confounding factors, and (8) requirements for post-event medical follow-up. For each area, the status, advantages and limitations of existing approaches and suggestions for new directions are presented.
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http://dx.doi.org/10.1667/RR1993.1DOI Listing
February 2010

Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial.

J Clin Oncol 2009 Jul 22;27(21):3547-56. Epub 2009 Jun 22.

Department of Clinical Oncology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.

PURPOSE Studies on quality of life (QOL) among women with endometrial cancer have shown that patients who undergo pelvic radiotherapy report lower role functioning and more diarrhea and fatigue. In the Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trial, patients with endometrial carcinoma were randomly assigned to receive external-beam radiotherapy (EBRT) or vaginal brachytherapy (VBT). QOL was evaluated by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and subscales from the prostate cancer module, PR-25, and the ovarian cancer module, OV-28. PATIENTS AND METHODS PORTEC-2 accrued 427 patients between 2002 and 2006, of whom 214 were randomly assigned to EBRT, and 213 were randomly assigned to VBT. Three-hundred forty-eight patients (81%) were evaluable for QOL. QOL outcomes were analyzed at a median follow-up of 2 years. Results At baseline after surgery, patient functioning was at the lowest level, and it increased during and after radiotherapy to reach a plateau after 12 months. Patients in the VBT group reported better social functioning (P < .002) and lower symptom scores for diarrhea, fecal leakage, the need to stay close to the toilet, and limitation in daily activities because of bowel symptoms (P < .001). At baseline, 15% of patients were sexually active; this increased significantly to 39% during the first year (P < .001). Sexual functioning and symptoms did not differ between the treatment groups. CONCLUSION Patients who received EBRT reported significantly higher levels of diarrhea and bowel symptoms. This resulted in a higher need to remain close to a toilet and, as a consequence, more limitation of daily activities because of bowel symptoms and decreased social functioning. Vaginal brachytherapy provides a better QOL, and should be the preferred treatment from a QOL perspective.
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http://dx.doi.org/10.1200/JCO.2008.20.2424DOI Listing
July 2009

Radiotherapy and hyperthermia for treatment of primary locally advanced cervix cancer: results in 378 patients.

Int J Radiat Oncol Biol Phys 2009 Jan 5;73(1):242-50. Epub 2008 Nov 5.

Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.

Purpose: To report response rate, pelvic tumor control, survival, and late toxicity after treatment with combined radiotherapy and hyperthermia (RHT) for patients with locally advanced cervical carcinoma (LACC) and compare the results with other published series.

Methods And Materials: From 1996 to 2005, a total of 378 patients with LACC (International Federation of Gynecology and Obstetrics Stage IB2-IVA) were treated with RHT. External beam radiotherapy (RT) was applied to 46-50.4 Gy and combined with brachytherapy. The hyperthermia (HT) was prescribed once weekly. Primary end points were complete response (CR) and local control. Secondary end points were overall survival, disease-specific survival, and late toxicity. Patient, tumor, and treatment characteristics predictive for the end points were identified in univariate and multivariate analyses.

Results: Overall, a CR was achieved in 77% of patients. At 5 years, local control, disease-specific survival, and incidence of late toxicity Common Terminology Criteria for Adverse Events Grade 3 or higher were 53%, 47%, and 12%, respectively. In multivariate analysis, number of HT treatments emerged as a predictor of outcome in addition to commonly identified prognostic factors.

Conclusions: The CR, local control, and survival rates are similar to previously observed results of RHT in the randomized Dutch Deep Hyperthermia Trial. Reported treatment results for currently applied combined treatment modalities (i.e., RT with chemotherapy and/or HT) do not permit definite conclusions about which combination is superior. The present results confirm previously shown beneficial effects from adding HT to RT and justify the application of RHT as first-line treatment in patients with LACC as an alternative to chemoradiation.
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http://dx.doi.org/10.1016/j.ijrobp.2008.03.072DOI Listing
January 2009

Is the treatment of keloid scars still a challenge in 2006?

Ann Plast Surg 2007 Feb;58(2):186-92

Department of Plastic and Reconstructive Surgery, University Hospital of Maastricht, Maastricht, The Netherlands.

Background: Several options are described to treat keloid scars, none of them being 100% successful. Radiotherapy is suggested to have the most significant effect on recurrence rate.

Objectives: The aim of the study is to confirm the effectiveness of iridium brachytherapy combined with surgery and to evaluate patient satisfaction.

Patients And Methods: We retrospectively enrolled 24 patients with 30 keloids, treated by surgical excision and iridium 192 high-dose-rate (HDR) brachytherapy.

Results: We observed a significant difference in scar thickness before and after the treatment (P < 0.001). With regard to patient satisfaction and complaints, 79.1% of them had no pain and irritation after treatment, 79.2% of patients would recommend this treatment to other patients, and 87.5% would undergo this treatment again if necessary.

Conclusions: Our results confirm the effectiveness of surgical keloid excision followed by HDR brachytherapy in primary treatment or if other alternative methods have failed.
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http://dx.doi.org/10.1097/01.sap.0000237761.52586.f9DOI Listing
February 2007

Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review.

Int J Radiat Oncol Biol Phys 2005 Nov 31;63(3):834-8. Epub 2005 May 31.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: In 2000, the results of the multicenter Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial were published. This trial included 714 Stage I endometrial carcinoma patients randomly assigned to postoperative pelvic radiotherapy (RT) or no further treatment, excluding those with Stage IC, Grade 3, or Stage IB, Grade 1 lesions. Radiotherapy significantly decreased the risk of locoregional recurrence (4% vs. 14%), without affecting overall survival. In this report the long-term outcome and results with central pathology review are presented.

Methods And Materials: The slides of 569 patients (80%) could be obtained for pathology review. Median follow-up for patients alive was 97 months. Analysis was done according to the intention-to-treat principle. The primary study endpoints were locoregional recurrence and death.

Results: Ten-year locoregional relapse rates were 5% (RT) and 14% (controls; p < 0.0001), and 10-year overall survival was 66% and 73%, respectively (p = 0.09). Endometrial cancer related death rates were 11% (RT) and 9% (controls; p = 0.47). Pathology review showed a substantial shift from Grade 2 to Grade 1, but no significant difference for Grade 3. When cases diagnosed at review as Grade 1 with superficial myometrial invasion were excluded from the analysis, the results remained essentially the same, with 10-year locoregional recurrence rates of 5% (RT) and 17% (controls; p < 0.0001).

Conclusions: In view of the significant locoregional control benefit, radiotherapy remains indicated in Stage I endometrial carcinoma patients with high-risk features for locoregional relapse.
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http://dx.doi.org/10.1016/j.ijrobp.2005.03.007DOI Listing
November 2005

Monitoring myeloablative therapy-induced small bowel toxicity by serum citrulline concentration: a comparison with sugar permeability tests.

Cancer 2005 Jan;103(1):191-9

Department of Radiation Oncology, Maastricht Radiation Therapy and Oncology Clinic, University Hospital Maastricht, Maastricht, The Netherlands.

Background: Intestinal mucositis is an important cause of cancer treatment-related morbidity and mortality, carrying a serious economic burden. Currently, objective parameters are lacking that would enable the monitoring of gut damage in routine clinical practice, thus hindering the development of clinical studies designed to investigate potential new strategies aimed at reducing or preventing this side effect. The authors investigated the characteristics of serum citrulline concentration compared with sugar permeability tests with respect to its use as a marker for cancer treatment-induced small bowel injury.

Methods: In this prospective study, 10 patients with hematologic malignancies who were receiving myeloablative therapy had gut toxicity assessed with sugar permeability tests. Serum citrulline concentrations also were determined using archival serum samples. The association between both parameters and their respective characteristics were analyzed and compared with data from the literature.

Results: Sensitivity and specificity were better for the citrulline assay compared with sugar permeability tests. Maximum gut damage assessed with the citrulline assay was observed 1-2 weeks earlier compared with the sugar permeability test. Similarly, citrulline indicated recovery of gut damage at 3 weeks after transplantation, whereas most sugar permeability tests remained abnormal.

Conclusions: The simplicity of the method, the low costs, and the lack of drawbacks to the method make the citrulline assay the first choice for measuring and monitoring treatment-related gut damage and provides an objective parameter for cancer treatment-related gut toxicity.
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http://dx.doi.org/10.1002/cncr.20733DOI Listing
January 2005

Plasma citrulline concentration: a surrogate end point for radiation-induced mucosal atrophy of the small bowel. A feasibility study in 23 patients.

Int J Radiat Oncol Biol Phys 2004 Sep;60(1):275-85

Department of Radiation Oncology (MAASTRO), University Hospital Maastricht, Maastricht University, Dr. Tanslan 12, 6229 ET Maastricht, The Netherlands.

Purpose: Plasma citrulline, a nitrogen end product of glutamine metabolism in small-bowel enterocytes, was suggested as a marker of radiation-induced small-bowel epithelial cell loss in mice after single-dose whole-body irradiation. Our objective was to evaluate the feasibility of citrulline as a marker for radiation-induced small-intestinal mucosal atrophy in patients during and after abdominal fractionated radiotherapy.

Methods And Materials: Twenty-three patients were studied weekly during treatment and at intervals of 2 weeks and 3 and 6 months after treatment by postabsorptive plasma citrulline concentration and clinical toxicity grading. The interrelationship between these variables and the correlation with small-bowel dose and volume parameters were investigated.

Results: During fractionated radiotherapy, citrulline concentration significantly decreased as a function of the radiation dose (p < 0.001) and the volume of small bowel treated (p = 0.001). The plasma citrulline concentration correlated with clinical toxicity during the last 3 weeks of treatment. As a whole, citrulline concentration correlated better with radiation dose and volume parameters than clinical toxicity grading.

Conclusions: In patients treated with fractionated radiation therapy for abdominal or pelvic cancer sites, plasma citrulline concentration may be a simple objective marker for monitoring epithelial cell loss, a major event in acute radiation-induced small-bowel toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2004.02.052DOI Listing
September 2004

Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial.

J Clin Oncol 2004 Apr;22(7):1234-41

Department of Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.

Purpose: Stage IC, grade 3 endometrial cancer is regarded as a high-risk category. Stage IC, grade 3 patients were not eligible for the randomized Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial, but were registered and received postoperative radiotherapy.

Patients And Methods: The PORTEC trial included 715 patients with stage IC, grade 1 or 2, and stage IB, grade 2 or 3 endometrial cancer. Patients were randomly assigned after surgery to receive pelvic radiotherapy (RT) or no further treatment. A total of 104 patients with stage IC, grade 3 endometrial cancer were registered, of whom 99 could be evaluated. Patterns of relapse and survival were compared with PORTEC patients receiving RT. Median follow-up was 83 months.

Results: The actuarial 5-year rates of locoregional relapse were 1% to 3% for PORTEC patients who received RT, compared with 14% for stage IC, grade 3 patients. Five-year distant metastases rates were 3% to 8% for grade 1 and 2 tumors; 20% for stage IB, grade 3 tumors; and 31% for stage IC, grade 3 tumors. Overall survival rates were 83% to 85% for grades 1 and 2; 74% for stage IB, grade 3; and 58% for stage IC, grade 3 patients (P <.001). In multivariate analysis grade 3 was the most important adverse prognostic factor for relapse and death as a result of endometrial cancer (hazard ratios, 5.4 and 5.5; P <.0001).

Conclusion: Patients with stage IC, grade 3 endometrial carcinoma are at high risk of early distant spread and endometrial carcinoma-related death. Novel strategies for adjuvant therapy should be explored to improve survival for this patient group.
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http://dx.doi.org/10.1200/JCO.2004.08.159DOI Listing
April 2004

Citrulline: a physiologic marker enabling quantitation and monitoring of epithelial radiation-induced small bowel damage.

Int J Radiat Oncol Biol Phys 2003 Nov;57(4):1067-74

MAASTRO, Department of Radiation Therapy and Oncology, University Hospital Maastricht/Maastricht University, Maastricht, The Netherlands.

Purpose: Small bowel irradiation results in epithelial cell loss and consequently impairs function and metabolism. We investigated whether citrulline, a metabolic end product of small bowel enterocytes, can be used for quantifying radiation-induced epithelial cell loss.

Methods And Materials: NMRI mice were subjected to single-dose whole body irradiation (WBI). The time course of citrullinemia was assessed up to 11 days after WBI. A dose-response relationship was determined at 84 h after WBI. In addition, citrullinemia was correlated with morphologic parameters at this time point and used to calculate the dose-modifying factor (DMF) of glutamine and amifostine on acute small bowel radiation damage.

Results: After WBI, a time- and dose-dependent decrease in plasma citrulline level was observed with a significant dose-response relationship at 84 h. At this time point, citrullinemia significantly correlated with jejunal crypt regeneration (p < 0.001) and epithelial surface lining (p = 0.001). A DMF of 1.0 and 1.5 was computed at the effective dose 50 (ED50) level for glutamine and amifostine, respectively.

Conclusions: Citrullinemia can be used to quantify acute small bowel epithelial radiation damage after single-dose WBI. Radiation-induced changes in citrullinemia are most pronounced at 3 1/2 to 4 days postirradiation. At this time point, citrullinemia correlates with morphologic endpoints for epithelial radiation damage.
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http://dx.doi.org/10.1016/s0360-3016(03)00781-8DOI Listing
November 2003

Survival after relapse in patients with endometrial cancer: results from a randomized trial.

Gynecol Oncol 2003 May;89(2):201-9

Department of Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

Objective: The aim of this study was to determine the rates of local control and survival after relapse in patients with stage I endometrial cancer treated in the multicenter randomized PORTEC trial.

Methods: The PORTEC trial included 715 patients with stage 1 endometrial cancer, either grade 1 or 2 with deep (>50%) myometrial invasion or grade 2 or 3 with <50% invasion. In all cases an abdominal hysterectomy was performed, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy) or no further treatment.

Results: The analysis was done by intention-to-treat. A total of 714 patients were evaluated. At a median follow-up of 73 months, 8-year actuarial locoregional recurrence rates were 4% in the RT group and 15% in the control group (P < 0.0001). The 8-year actuarial overall survival rates were 71 (RT group) and 77% (control group, P = 0.18). Eight-year rates of distant metastases were 10 and 6% (P = 0.20). The majority of the locoregional relapses were located in the vagina, mainly in the vaginal vault. Of the 39 patients with isolated vaginal relapse, 35 (87%) were treated with curative intent, usually with external RT and brachytherapy, and surgery in some. A complete remission (CR) was obtained in 31 of the 35 patients (89%), and 24 patients (77%) were still in CR after further follow-up. Five patients subsequently developed distant metastases, and 2 had a second vaginal recurrence. The 3-year survival after first relapse was 51% for patients in the control group and 19% in the RT group (P = 0.004). The 3-year survival after vaginal relapse was 73%, in contrast to 8 and 14% after pelvic and distant relapse (P < 0.001). At 5 years, the survival after vaginal relapse was 65% in the control group compared to 43% in the RT group.

Conclusion: Survival after relapse was significantly better in the patient group without previous RT. Treatment for vaginal relapse was effective, with 89% CR and 65% 5-year survival in the control group, while there was no difference in survival between patients with pelvic relapse and those with distant metastases. As pelvic RT was shown to improve locoregional control significantly, but without a survival benefit, its use should be limited to those patients at sufficiently high risk (15% or over) for recurrence in order to maximize local control and relapse-free survival.
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http://dx.doi.org/10.1016/s0090-8258(03)00126-4DOI Listing
May 2003
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