Vaginal changes, sexual functioning and distress of women with locally advanced cervical cancer treated in the EMBRACE vaginal morbidity substudy.

OBJECTIVE: The EMBRACE-vaginal morbidity substudy prospectively evaluated physician-assessed vaginal changes and patient-reported-outcomes (PRO) on vaginal and sexual functioning problems and distress in the first 2-years after image-guided radio(chemo)therapy and brachytherapy for locally advanced cervical cancer. METHODS: Eligible patients had stage IB1-IIIB cervical cancer with ≤5 mm vaginal involvement. Assessment of vaginal changes was graded using CTCAE. PRO were assessed using validated Quality-of-Life and sexual questionnaires. Statistical analysis included Generalized-Linear-Mixed-Models and Spearman's rho-correlation coefficients. RESULTS: 113 eligible patients were included. Mostly mild (grade 1) vaginal changes were reported over time in about 20% (range 11-37%). At 2-years, 47% was not sexually active. Approximately 50% of the sexually active women reported any vaginal and sexual functioning problems and distress over time; more substantial vaginal and sexual problems and distress were reported by up to 14%, 20% and 8%, respectively. Physician-assessed vaginal changes and PRO sexual satisfaction differed significantly (p ≤ .05) between baseline and first follow-up, without further significant changes over time. No or only small associations between physician-assessed vaginal changes and PRO vaginal functioning problems and sexual distress were found. CONCLUSIONS: Mild vaginal changes were reported after image-guided radio(chemo)therapy and brachytherapy, potentially due to the combination of tumors with limited vaginal involvement, EMBRACE-specific treatment optimization and rehabilitation recommendations. Although vaginal and sexual functioning problems and sexual distress were frequently reported, the rate of substantial problems and distress was low. The lack of association between vaginal changes, vaginal functioning problems and sexual distress shows that sexual functioning is more complex than vaginal morbidity alone.

Microcystic elongated and fragmented (MELF) pattern of invasion: Molecular features and prognostic significance in the PORTEC-1 and -2 trials.

OBJECTIVE: Microcystic, elongated fragmented (MELF) pattern of myometrial invasion is a distinct histologic feature occasionally seen in low-grade endometrial carcinomas (EC). The prognostic relevance of MELF invasion was uncertain due to conflicting data, and it had not yet appropriately been studied in the context of the molecular EC classification. We aimed to determine the relation of MELF invasion with clinicopathological and molecular characteristics, and define its prognostic relevance in early-stage low/intermediate risk EC. METHODS: Single whole tumor slides of 979 (85.8%) out of 1141 (high)intermediate-risk EC of women who participated in the PORTEC-1/-2 trials were available for review. Clinicopathological and molecular features were compared between MELF invasion positive and negative cases. Time-to-event analyses were done by Kaplan-Meier method, log-rank tests and Cox' proportional hazards models. RESULTS: MELF invasion was found in 128 (13.1%) cases, and associated with grade 1-2 histology, deep myometrial invasion and substantial lymph-vascular space invasion (LVSI). 85.6% of MELF invasion positive tumors were no-specific-molecular-profile (NSMP) EC. NSMP EC with MELF invasion were CTNNB1 wild type in 92.2% and KRAS mutated in 24.4% of cases. Risk of recurrence was lower for MELF invasion positive as compared to MELF invasion negative cases (4.9% vs. 12.7%, p = 0.026). However, MELF invasion had no independent impact on risk of recurrence (HR 0.65, p = 0.30) after correction for clinicopathological and molecular factors. CONCLUSIONS: MELF invasion has no independent impact on risk of recurrence in early-stage EC, and is frequently observed in low-grade NSMP tumors. Routine assessment of MELF invasion has no clinical implications and is not recommended.

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

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

Radiotherapy Quality Assurance in the PORTEC-3 (TROG 08.04) Trial.

AIMS: Quality assurance in radiotherapy (QART) is essential to ensure the scientific integrity of a clinical trial. This paper reports the findings of the retrospective QART assessment for all centres that participated in PORTEC-3; a randomised controlled trial that compared pelvic radiotherapy with concurrent chemoradiotherapy to the pelvis followed by adjuvant chemotherapy. The trial showed an overall survival benefit for the addition of the chemotherapy in the management of women with high-risk endometrial cancer. MATERIALS AND METHODS: Clinicians were invited to upload a randomly selected case/s treated at each of the participating sites. Panel reviewers analysed the contours to certify that the target volumes and organ at risk structures were contoured according to guidelines. The results were categorised into acceptable, minor variation, major variation or unevaluable. The radiotherapy plans were dosimetrically evaluated using the well-established Trans-Tasman Radiation Oncology Group (TROG) protocol. RESULTS: Between August 2010 and January 2018, data from 146 patients of 686 consecutively treated patients were retrospectively reviewed. All 16 Australia and New Zealand and 71 of 77 international centres uploaded data for evaluation. In total, 3514 dosimetric and contour variables were reviewed. Of these, 3136 variables were deemed acceptable (89.2%), with 335 minor (9.6%) and 43 major variations (1.2%). Major contour variations included the clinical target volume vaginal vault, clinical target volume parametria and differential planning target volume vault expansion. CONCLUSION: The results of the QART assessment confirmed high uniformity and low rates of both minor and major deviations in contouring and dosimetry in all sites. This supports the safe introduction of the PORTEC-3 treatment protocol into routine clinical practice.

Brachytherapy quality assurance in the PORTEC-4a trial for molecular-integrated risk profile guided adjuvant treatment of endometrial cancer.

OBJECTIVE: The PORTEC-4a trial investigates molecular-integrated risk profile guided adjuvant treatment for endometrial cancer. The quality assurance programme included a dummy run for vaginal brachytherapy prior to site activation, and annual quality assurance to verify protocol adherence. Aims of this study were to evaluate vaginal brachytherapy quality and protocol adherence. METHODS: For the dummy run, institutes were invited to create a brachytherapy plan on a provided CT-scan with the applicator in situ. For annual quality assurance, institutes provided data of one randomly selected brachytherapy case. A brachytherapy panel reviewed and scored the brachytherapy plans according to a checklist. RESULTS: At the dummy run, 15 out of 21 (71.4%) institutes needed adjustments of delineation or planning. After adjustments, the mean dose at the vaginal apex (protocol: 100%; 7 Gy) decreased from 100.7% to 99.9% and range and standard deviation (SD) narrowed from 83.6-135.1 to 96.4-101.4 and 8.8 to 1.1, respectively. At annual quality assurance, 22 out of 27 (81.5%) cases had no or minor and 5 out of 27 (18.5%) major deviations. Most deviations were related to delineation, mean dose at the vaginal apex (98.0%, 74.7-114.2, SD 7.6) or reference volume length. CONCLUSIONS: Most feedback during the brachytherapy quality assurance procedure of the PORTEC-4a trial was related to delineation, dose at the vaginal apex and the reference volume length. Annual quality assurance is essential to promote protocol compliance, ensuring high quality vaginal brachytherapy in all participating institutes.

Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy.

BACKGROUND: PORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis. METHODS: 427 women with HIR endometrial cancer were randomised between 2002-2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis. RESULTS: Median follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors. CONCLUSION: Long-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.

Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial.

OBJECTIVE: The Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-4a trial is a randomized trial for women with high-intermediate risk endometrial cancer (EC), comparing individualized adjuvant treatment based on a molecular-integrated risk profile to standard adjuvant treatment; vaginal brachytherapy. To evaluate patient acceptability and pathology logistics of determining the risk profile, a pilot phase was included in the study. METHODS: PORTEC-4a is ongoing and the first 50 patients enrolled were included in the pilot phase. Primary endpoints of the pilot phase were patient acceptance, evaluated by analyzing the screening logs of the participating centers, and logistical feasibility of determination of the risk profile within 2 weeks, evaluated by analyzing the pathology database. RESULTS: In the first year, 145 eligible women were informed about the trial at 13 centers, of whom 50 (35%) provided informed consent. Patient accrual ranged from 0 to 57% per center. Most common reasons for not participating were: not willing to participate in any trial (43.2%) and not willing to risk receiving no adjuvant treatment (32.6%). Analysis of the pathology database showed an average time between randomization and determination of the molecular-integrated risk profile of 10.2 days (1-23 days). In 5 of the 32 patients (15.6%), pathology review took >2 weeks. CONCLUSIONS: The PORTEC-4a trial design was proven feasible with a satisfactory patient acceptance rate and an optimized workflow of the determination of the molecular-integrated risk profile. PORTEC-4a is the first randomized trial to investigate use of a molecular-integrated risk profile to determine adjuvant treatment in EC.

Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer.

Background: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation. Patients and methods: A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ). Results: In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70). Conclusion: Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved. This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138).

Markers of the p53 pathway further refine molecular profiling in high-risk endometrial cancer: A TransPORTEC initiative.

BACKGROUND: The morphological classification of high-risk endometrial cancer is of limited prognostic value. Recent attempts to stratify tumours according to molecular signatures have shown considerable promise. Here we attempted to further refine molecular classifications using markers of the p53 pathway. METHODS: We analysed the expression of p53 as well as three downstream markers of the p53 pathway, p21, mdm2 and phospho-p63 (pp63), by immunohistochemistry in a series of 114 endometrial cancers (86 endometrioid, 28 non-endometrioid subtype) with high-risk features (such as high tumour grade and deep myometrial invasion) and correlated results with clinical outcome. The Cancer Genome Atlas (TCGA) data were used to analyse TP63 mutations and copy-number alterations using cBioPortal. TP53 was silenced in two endometrial cancer cell lines to study its effect on p21 and p63. RESULTS: About half of the tumours showed a p53 mutant phenotype and there was a strong negative correlation with p21 expression. Being marker positive for pp63 or mdm2 was associated with a significantly increased likelihood of dying, [hazard ratios 5.93 (95% CI 2.37-7.27) and 7.48 (95% CI 3.04-9.39), respectively]. These findings were seen in both p53 wildtype and p53 mutant tumours. Only 11% of TCGA endometrial cancers had a functional TP63 alteration. Upon silencing of TP53, p21 expression was decreased in one cell line, but no effects on p63 were observed. CONCLUSION: Markers of the p53 pathway improve stratification of endometrial cancers and provide novel insights into the role of this pathway in the disease.

Less-favourable prognosis for low-risk endometrial cancer patients with a discordant pre- versus post-operative risk stratification.

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.

Practical guidance for mismatch repair-deficiency testing in endometrial cancer.

Background: Mismatch repair (MMR)-deficiency analysis is increasingly recommended for all endometrial cancers, as it identifies Lynch syndrome patients, and is emerging as a prognostic classifier to guide adjuvant treatment. The aim of this study was to define the optimal approach for MMR-deficiency testing and to clarify discrepancies between microsatellite instability (MSI) analysis and immunohistochemical (IHC) analysis of MMR protein expression. Patients and methods: Six hundred ninety- six endometrial cancers were analyzed for MSI (pentaplex panel) and MMR protein expression (IHC). Agreement between methodologies was calculated using Cohen's Kappa. MLH1 promoter hypermethylation, dinucleotide microsatellite markers and somatic MMR and POLE exonuclease domain (EDM) gene variants (using next-generation/Sanger sequencing) were analyzed in discordant cases. Results: MSI was found in 180 patients. Complete loss of expression of one or more MMR proteins was observed in 196 cases. A PMS2- and MSH6-antibody panel detected all cases with loss of MMR protein expression. The results of MSI and MMR protein expression were concordant in 655/696 cases (kappa = 0.854, P < 0.001). Ambiguous cases (n = 41, 6%) included: subclonal loss of MMR protein expression (n = 18), microsatellite stable or MSI-low cases with loss of MMR protein expression (n = 20), and MSI-low or MSI-high cases with retained MMR protein expression (n = 3). Most of these cases could be explained by MLH1 promoter hypermethylation. Five of seven cases with solitary loss of PMS2 or MSH6 protein expression carried somatic gene variants. Two MSI-high cases with retained MMR protein expression carried a POLE-EDM variant. Conclusion: MSI and IHC analysis are highly concordant in endometrial cancer. This holds true for cases with subclonal loss of MMR protein expression. Discordant MMR-proficient/MSI-high cases (<1%), may be explained by POLE-EDM variants.

A nurse-led sexual rehabilitation intervention after radiotherapy for gynecological cancer.

PURPOSE: Although vaginal dilator use after combined pelvic radiation therapy and brachytherapy (RT/BT) is recommended to prevent vaginal shortening and stenosis, women fail to use them and experience sexual problems. A nurse-led sexual rehabilitation intervention targeting sexual recovery and vaginal dilatation was developed. Its feasibility was investigated during a prospective, longitudinal, observational pilot study. METHODS: Four oncology nurses were specifically trained to conduct the intervention. Gynecologic cancer patients treated with RT/BT were assessed using (i) questionnaires on frequency of dilator use (monthly), sexual functioning, and sexual distress (at baseline and 1, 6, and 12 months) and psychological and relational distress (at 1, 6, and 12 months); (ii) semi-structured interviews (between 6 and 12 months); and (iii) consultation recordings (a random selection of 21 % of all consults). RESULTS: Twenty participants were 26-71 years old (mean = 40). Eight participants discontinued participation after 3 to 9 months. At 6 months after RT, 14 out of 16 (88 %), and at 12 months 9 out of 12 (75 %), participants dilated regularly, either by having sexual intercourse or by using dilators. Sexual functioning improved between 1 and 6 months after RT, with further improvement at 12 months. Most participants reported that the intervention was helpful and the nurses reported having sufficient expertise and counseling skills. CONCLUSIONS: According to the pilot results, the intervention was feasible and promising for sexual rehabilitation and regular dilator use after RT. Its (cost-)effectiveness will be investigated in a randomized controlled trial.

Sexual distress and associated factors among cervical cancer survivors: A cross-sectional multicenter observational study.

BACKGROUND: To assess whether sexual distress among cervical cancer (CC) survivors is associated with frequently reported vaginal sexual symptoms, other proposed biopsychosocial factors and whether worries about painful intercourse mediate the relation between vaginal sexual symptoms and sexual distress. METHODS: A cross-sectional study was conducted among 194 sexually active partnered CC survivors aged 25 to 69 years. Sexual distress, vaginal sexual symptoms, sexual pain worry, anxiety, depression, body image concerns, and relationship dissatisfaction and the sociodemographic variables age, time since treatment, and relationship duration were assessed by using validated self-administrated questionnaires. RESULTS: In total, 33% (n = 64) of the survivors scored above the cut-off score for sexual distress. Higher levels of sexual distress were shown to be associated with higher levels of vaginal sexual symptoms, sexual pain worry, relationship dissatisfaction, and body image concerns. Furthermore, the results showed that sexual pain worry partly mediated the association between vaginal sexual symptoms and sexual distress, when controlling for relationship dissatisfaction and body image concerns. CONCLUSIONS: Appropriate rehabilitation programs should be developed for CC survivors to prevent and reduce not only vaginal sexual symptoms but also sexual pain worry, relationship dissatisfaction, and body image concerns to reduce sexual distress.

Risk factors and treatment for recurrent vulvar squamous cell carcinoma.

Recurrent disease occurs in 12-37% of patients with vulvar squamous cell carcinoma (VSCC). Decisions about treatment of recurrent VSCC mainly depend on the location of the recurrence and previous treatment, resulting in individualized and consensus-based approaches. Most recurrences (40-80%) occur within 2 years after initial treatment. Currently, wide local excision is the treatment of choice for local recurrences. Isolated local recurrence of VSCC has a good prognosis, with reported 5-year survival rates of up to 60%. Groin recurrences and distant recurrences are less common and have an extremely poor prognosis. For groin recurrences, surgery with or without (chemo) radiotherapy is a treatment option, depending on prior treatment. For distant recurrences, there are only palliative treatment options. In this review, we give an overview of the available literature and discuss epidemiology, risk factors, and prognostic factors for the different types of recurrent VSCC and we describe treatment options and clinical outcome.

Tumour-free margins in vulvar squamous cell carcinoma: Does distance really matter?

BACKGROUND: There is no consensus on the width of tumour-free margins after surgery for vulvar squamous cell carcinoma (VSCC). Most current guidelines recommend tumour-free margins of ≥8 mm. The aim of this study was to investigate whether a margin of <8 mm is associated with an increased risk of local recurrence in VSCC. METHODS: A meta-analysis of the available literature and a cohort study of 148 VSCC patients seen at a referral centre from 2000 to 2012 was performed. The primary end-point of the cohort study was a histologically confirmed ipsilateral local recurrence within 2 years after primary treatment in relation to the margin distance. RESULTS: Based on 10 studies, the meta-analysis showed that a tumour-free margin of <8 mm is associated with a higher risk of local recurrence compared to a tumour-free margin of ≥8 mm (pooled risk ratio, 1.99 [95% confidence interval {CI}: 1.13-3.51], p = 0.02). In the cohort study, we found no clear difference in the risk of local recurrence in the <8 versus ≥8 mm group; however, 40% of the patients in the <8 mm group received additional treatment. Tumour-positive margin was the only independent risk factor for local recurrence in the multivariable analysis (hazard ratio, 0.21 [95% CI: 0.08-0.55]). CONCLUSIONS: This work provides important data to question the commonly used 8-mm margin as a prognosticator for local recurrence. More research is needed to address the question of whether additional treatment improves the prognosis in patients with a tumour-free margin of <8 mm.

Prediction model for regional or distant recurrence in endometrial cancer based on classical pathological and immunological parameters.

BACKGROUND: Adjuvant therapy increases disease-free survival in endometrial cancer (EC), but has no impact on overall survival and negatively influences the quality of life. We investigated the discriminatory power of classical and immunological predictors of recurrence in a cohort of EC patients and confirmed the findings in an independent validation cohort. METHODS: We reanalysed the data from 355 EC patients and tested our findings in an independent validation cohort of 72 patients with EC. Predictors were selected and Harrell's C-index for concordance was used to determine discriminatory power for disease-free survival in the total group and stratified for histological subtype. RESULTS: Predictors for recurrence were FIGO stage, lymphovascular space invasion and numbers of cytotoxic and memory T-cells. For high risk cancer, cytotoxic or memory T-cells predicted recurrence as well as a combination of FIGO stage and lymphovascular space invasion (C-index 0.67 and 0.71 vs 0.70). Recurrence was best predicted when FIGO stage, lymphovascular space invasion and numbers of cytotoxic cells were used in combination (C-index 0.82). Findings were confirmed in the validation cohort. CONCLUSIONS: In high-risk EC, clinicopathological or immunological variables can predict regional or distant recurrence with equal accuracy, but the use of these variables in combination is more powerful.

L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: pooled PORTEC trial results.

BACKGROUND: L1 cell adhesion molecule (L1CAM) expression has been implicated as risk factor for disease recurrence in endometrial cancer (EC), most likely due to its role in promoting tumour cell motility. We tested the performance of L1CAM expression in predicting the risk of recurrence in the randomised post operative radiation therapy in endometrial carcinoma (PORTEC)-1 and -2 trials. METHODS: In the PORTEC trials, stage I EC patients were randomised to external beam radiotherapy (EBRT) versus no additional treatment (PORTEC-1, n=714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n=427). Tumour samples of 865 (75.8%) patients were available for L1CAM expression analysis by immunohistochemistry. An established scoring system for EC was used, with >10% L1CAM staining defined as positive. RESULTS: Positive L1CAM expression was significantly correlated with risk of distant recurrence, with a hazard ratio (HR) of 5.1 (95% confidence interval (CI) 3.1-8.7) but not with vaginal relapse, while a trend for pelvic nodal relapse was found. Tumours with the highest expression levels (>50% positive) had the strongest risk of distant recurrence (HR 5.3, CI 2.7-10.4). In multivariate Cox analysis with the risk factors age, depth of invasion, grade, lympho-vascular space invasion (LVSI) and treatment, L1CAM expression remained an independent prognostic factor for distant recurrence (HR 3.5, CI 1.92-6.30) and overall survival (HR 2.1, CI 1.41-2.98). CONCLUSION: L1CAM expression is a strong independent predictor for distant recurrence and overall survival in stage I endometrial cancer. These results warrant prospective validation of L1CAM as marker for selecting patients who could benefit from more extensive diagnostic and/or therapeutic procedures.