Clinical outcome of patients with endometrial cancer in Norway after omission of radiotherapy and the evaluation of L1CAM as a prognostic factor

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Clinical outcome of patients with endometrial cancer in Norway after omission of radiotherapy and the evaluation of

L1CAM as a prognostic factor

Elisabeth Smogeli MD

2021

Thesis for the degree of Philosophiae doctor (PhD) Faculty of Medicine, University of Oslo

Department of Gynecologic Oncology Division of Cancer Medicine The Norwegian Radium Hospital

Oslo University Hospital

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© Elisabeth Smogeli, 2021

Series of dissertations submitted to the Faculty of Medicine, University of Oslo

ISBN 978-82-8377-903-5

reproduced or transmitted, in any form or by any means, without permission.

Cover: Hanne Baadsgaard Utigard.

Photo cover: BT Stokke

Print production: Reprosentralen, University of Oslo.

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ACKNOWLEDGEMENT

This thesis was carried out at the Department of Gynecological Oncology, Division of Cancer Medicine at The Norwegian Radium Hospital—Oslo University Hospital from 2014 to 2021. I was a doctoral research fellow and a consultant at this department.

I would like to thank Radiumhospitalets legater for the contribution in the first part of the project and the Kolbjørn Brambanis` cancer-research scholarship for the financial support to finish this thesis.

I would also like to thank my main supervisor Associate Professor Kristina Lindemann for introducing me to this project. You have helped me and pushed me through all phases of this PhD project. Your commitment to the field of endometrial cancer and your courage and determination have been my inspiration and motivation. This thesis would not have been possible without your help and guidance.

A warm thank you to the former head of my department and my cosupervisor Professor Emeritus Gunnar Kristensen. Despite your busy schedule and heavy workload, you always found time to answer my questions, guide me through surgery, and bring me to see interesting cases in the clinic. Your broad experience, knowledge, and engagement in the field of gynecological oncology made me interested in this field.

I would like to extend my special thanks to my cosupervisor Professor Ben Davidson for the support, feedback, and invaluable contribution. Moreover, great thank you to my other cosupervisor Professor Milada Cvancarova Småstuen for giving me important statistical insight and support while I was writing this thesis.

I would like to thank my coauthors Arild Holth for teaching me the immunohistochemistry process, Bjørn Risberg and Betina Katz for contribution in review of slides, Yun Wang for helping me with the validation, Yunyoung Wang for the support in database management, and Karin Skogsfjord for the support in database administration.

A special thanks to all my colleagues at the Department of Gynecological Oncology. I appreciate all of the discussions, support, and inspiration from all of you. You made our department a nice place to work. A special thank you to Tone Skeie-Jensen for her kindness and for being a role model. I would also like to thank Erik Rokkones for the understanding and support, Ameli Tropè for the positivity and the nice moments sharing office together and for giving me advice in the beginning of the project, Alda Birgisdottir for helping with validation and for all conversations during coffee breaks and lunches, Taran Paulsen Hellebust for the contribution in collecting data in Paper III, and Kjersti Bruheim and Esten Nakken for their contribution and for sharing their knowledge in oncology and radiation therapy.

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The collaboration with Haukeland University Hospital in Paper III is highly appreciated. A sincere thanks to Henrica Werner for her engagement, patience, and advice during the last part of the project, Professor Jone Trovik for validating the data, and Terje Nordberg for collecting the radiotherapy information.

Thank you to all of the patients who participated in my studies.

I would like to thank my parents Per Ove and Vivi-Ann for the continuous support and for always believing in me, Tone, Kristian David, and Kristina for helping me go through though periods and for sharing great times these years, and Reidun and Paul for their limitless help in our everyday life and for being the best grandparents.

Finally, the most important thank you goes to Pål Jacob for standing by my side patiently and for helping me see things in perspective.

To my children Frederikke and Christian for the love and happiness—you are my everything.

Gran, February 2021 Elisabeth Smogeli

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LIST OF PAPERS

Paper I

Smogeli Elisabeth, Davidson Ben, Cvancarova Milada, Holth Arild, Katz Betina, Risberg Bjørn, Kristensen Gunnar, Lindemann Kristina.

L1CAM as a prognostic marker in stage I endometrial cancer: A validation study.

BMC Cancer. 2016 Aug 4;16:596. doi: 10.1186/s12885-016-2631-4.

Paper II

Smogeli Elisabeth, Cvancarova Milada, Wang Yun, Davidson Ben, Kristensen Gunnar, Lindemann Kristina. (2018).

Clinical Outcome of Patients with High-Risk Endometrial Carcinoma After Treatment with Chemotherapy Only.

International Journal of Gynecological Cancer 2018 Nov;28(9):1789-1795.

doi: 10.1097/IGC.0000000000001356.

Paper III

Lindemann Kristina, Smogeli Elisabeth, Bruheim Kjersti, Småstuen Milada Cvancarova, Nordberg Terje, Trovik Jone, Kristensen Gunnar, Werner Henrica, Nakken Esten.

Salvage radiation for pelvic relapse after surgically treated endometrial cancer.

Submitted to Cancers (2021)

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ABBREVIATIONS

abn Abnormal

AP Anthracycline and platinum (doxorubicin and cisplatin) ASR Age-standardized incidence rate

BD Ben Davidson

BMI Body mass index (kg/m²)

BSO Bilateral salpingo-oophorectomy

C-RT Chemoradiotherapy (or sequential chemotherapy and radiotherapy) CDH1 Cadherin 1

CIs Confidence intervals CN Copy number

CRT Classification and regression decision tree

CT Computed tomography

CTNNB1 Catenin beta-1/beta catenin

DCE Dynamic contrast-enhanced imaging DFS Disease-free survival

DEMCA Danish Endometrial Cancer DWI Diffusion-weighted imaging EBRT External-beam radiation therapy EC Endometrial cancer

EEC Endometrioid endometrial carcinomas

EORTC European Organization for the Research and Treatment of Cancer ER Estrogen receptor

ErbB Erythroblastic leukemia viral oncogene

ESGO European Society for Gynaecological Oncology ESMO European Society for Medical Oncology

ESTRO European Society for Radiotherapy and Oncology FDG ¹⁸F-flurordeoxyglucose

FFS Failure-free survival

FFPE Formalin-fixed paraffin-embedded FGFR Fibroblast-growth-factor receptor

FIGO International Federation of Gynecology and Obstetrics G1–3 Grade of differentiation 1–3

GOG Gynecological Oncology Group

Gy Gray (J/kg)

H&E Hematoxylin and eosin

Her-2/neu Human epidermal growth-factor receptor-2 HIR High intermediate risk

HR Hazard ratio

HRP Horseradish peroxidase HRT Hormone replacement therapy HUH Haukeland University Hospital IHC Immunohistochemistry

Ki-67 Marker of proliferation Ki-67 KRAS Kirsten Rat Sarcoma virus L1CAM L1 cell adhesion molecule 1 LIR Low intermediate risk

LR Low risk

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LVSI Lymphovascular space invasion

MaNGO Gynaecological Oncology group at the Mario Negri Institute MIS Minimally invasive surgery

MMR Mismatch Repair

MoMaTEC Molecular Markers in the Treatment of Endometrial Cancer MRD Mismatch-repair deficient

MRI Magnetic resonance imaging MSI Microsatellite instability

NEEC Nonendometrioid endometrial carcinoma NCCN National Comprehensive Cancer Network NCT National Clinical Trial

NRH The Norwegian Radium Hospital

NSGO The Nordic Society of Gynecologic Oncology NSMP No specific molecular profile

OS Overall survival

OUH Oslo University Hospital

p16 Protein 16 (also TP16 tumor protein 16) p53 Protein 53 (also TP53 tumor protein 53) PET Positron emission tomography

PFS Progression-free survival

PIK3CA Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit p110alpha POLE DNA polymerase epsilon catalytic subunit ultramutated

PORTEC Postoperative Radiation Therapy in Endometrial Cancer trial PR Progesterone Receptor

ProMisE Proactive Molecular Risk Classifier for Endometrial Cancer PTEN Phosphatase and tensin homolog

QoL Quality of life

RCE The Regional Committee for Medical Research Ethics RCT Randomized controlled trial

RT Radiation therapy

SEPAL Survival effect of para-aortic lymphadenectomy SGO Society of Gynecologic Oncology

SN Sentinel node technique

SPSS Statistical Software Package for the Social Sciences

STATEC Selective Targeting of Adjuvant Therapy for Endometrial Cancer

TAP Taxane, anthracycline, and platinum (paclitaxel, doxorubicin, and cisplatin) TC Taxol (paclitaxel) and carboplatin

TCGA The Cancer Genome Atlas TVU Transvaginal ultrasound UUH Ullevål University Hospital VBT Vaginal brachytherapy WAI Whole abdominal irradiation WHO World Health Organization

wt Wild type

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SUMMARY

Endometrial carcinoma (EC) is the most common gynecological malignancy and is on the rise due to the increase in obesity, an aging population, and other risk factors. Most cases are diagnosed at an early stage, where the disease is confined to the corpus uteri. Patients with early-stage disease will often have an excellent prognosis. Surgery is the mainstay of initial treatment and is curative in many cases. However, some patients with early-stage disease may have a poor prognosis due to the presence of high-risk factors for recurrence such as poor grade of differentiation, deep myometrial invasion, or nonendometrioid histology. According to this risk of recurrence, patients are stratified into three risk categories: Low-, intermediate-, and high-risk groups, each having a distinct prognosis and indication for adjuvant therapy.

Nevertheless, these traditional risk factors are not sufficiently accurate to predict clinical outcomes and are, in part, prone to inter- and intraobserver variability. Novel markers are therefore needed to predict the individual risk of recurrence and to better tailor both surgical and adjuvant treatments to avoid over- and undertreatment. In 2013, L1CAM was reported as a strong prognostic biomarker for identifying aggressive tumors associated with increased risk of recurrence and death for patients with EC. We aimed to validate this finding in an independent cohort of patients at Oslo University Hospital, and this work is described in Paper I of this thesis.

High-risk EC comprises a heterogeneous group of patients with early-stage disease with poor prognostic uterine factors, as well as advanced stages and nonendometrioid histology, and includes approximately 15%–20% of all cases. This population has an increased risk of distant metastasis and disease-related death. These patients are offered adjuvant treatment.

Historically, these patients have been treated with adjuvant radiotherapy, but convincing data on the survival benefit of adjuvant radiotherapy when compared with other systemic approaches such as chemotherapy are lacking. Thus, for decades, the treatment strategy has been subject for discussion. A higher incidence of pelvic recurrence has been reported with chemotherapy given alone compared with radiotherapy alone or with radiotherapy given in combination with chemotherapy. On the other hand, less distant recurrence has been reported when adjuvant chemotherapy was given compared with radiotherapy. In Norway, radiotherapy has been omitted in primary treatment, and patients with high-risk disease are offered adjuvant chemotherapy as a standard treatment instead. In Paper II of this thesis, we report the clinical outcome in terms of patterns of recurrence and survival of the patients with high-risk disease treated at Oslo University Hospital (Norwegian Radium Hospital). Further, for patients with low- and intermediate-risk EC, there is no consensus on the optimal treatment after surgery. In Norway, these patients are offered observation alone based on data indicating that the risk of relapse is low, and that the majority of recurrence will occur in the pelvis where they are amendable to salvage radiotherapy at the time of recurrence. This will spare many women from unnecessary adjuvant treatment and side effects. We aimed at evaluating the clinical outcome of radiotherapy-naïve patients with pelvic relapse after surgical treatment for EC at two university hospitals in Norway, and this work is discussed in Paper III.

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INTRODUCTION

ENDOMETRIAL CARCINOMA

This thesis covers endometrial carcinoma (EC), with focus on the treatment and clinical outcome of this disease. Endometrial carcinoma arises from the epithelial lining of the uterus and comprises approximately 90% of all uterine cancers. Other tumors are classified as mesenchymal or mixed epithelial/mesenchymal tumors and may develop in the muscular layer of the uterus, the myometrium. In 2020, the 5th edition of the World Health Organization Classification of Tumours of the uterine corpus was published. It also included a new molecular classification system for ECs and its relation to traditional histomorphologic classification. In Table 1, a modified overview of the histopathological types of uterine cancer is listed based on this WHO classification¹.

Table 1. Modified overview of the histopathological types of uterine cancer according to WHO International Society of Gynecological Pathology classification¹

CLASSIFICATION OF UTERINE CANCER Epithelial tumors

Endometrioid adenocarcinoma

• POLE-ultramutated

• Mismatch repair-deficient (MRD)

• P53-mutant

• No specific molecular profile (NSMP) Serous adenocarcinoma

Clear cell adenocarcinoma Carcinoma, undifferentiated Mixed cell adenocarcinoma Mesonephric adenocarcinoma Squamous cell carcinoma

Mucinous carcinoma, intestinal type Mesonephric-like adenocarcinoma Carcinosarcoma

Mesenchymal tumors Leiomyoma

Leiomyosarcoma

Endometrial stromal sarcoma

Mixed epithelial and mesenchymal tumors Adenomyoma

Atypical polypoid adenomyoma Adenosarcoma

Miscellaneous tumors

Primitive neuroectodermal tumors Germ cell tumors

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Epidemiology

Cancer is a leading cause of death worldwide and is responsible for 9.6 million deaths in 2018². EC is the sixth most common cancer in women globally² and the most common gynecological malignancy. After cancers of the breast, lung, colon and skin is EC the fifth most common cancer in Norway³. In 2019, 828 women in Norway were diagnosed with uterine cancer³. The national age-standardized incidence rate (ASR) of EC from 2015 to 2019 was 27.6 per 100.000, and it was 28.2 per 100.000 in 2019. The disease is mainly found in developed countries, with the highest incidence of EC in North America and Central and Eastern Europe and with the lowest in Southern and Eastern Asia and most of Africa^2,4 (Figure 1).

Figure 1. Shows age-standardized incidence rates of corpus uteri cancer using data from GLOBOCAN 2020.

During the last decades, the incidence rates of uterine cancer have increased across the western world in line with the rising prevalence of risk factors such as aging, obesity, diabetes, and reduced physical activity⁵. Other risk factors are early menarche, late-onset menopause (after 55 years of age), nulliparity, Polycystic ovarian syndrome (chronic ovulation), unopposed estrogen therapy, long-term use of tamoxifen, Lynch syndrome, Cowden syndrome (defect in PTEN tumor suppressor gene) and family history of EC, breast, ovarian, or colon cancer.

The median age at diagnosis is 63 years⁴, but there has also been a nonsignificant trend toward increased incidence among premenopausal women⁶.

Estimated age-standardized incidence rates (World) in 2020, corpus uteri, all ages

< 2.6 2.6–5.3 5.3–8.9 8.9–14.2

≥ 14.2

No data Not applicable ASR (World) per 100 000

All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for which there may not yet be full agreement.

Data source: GLOBOCAN 2020 Graph production: IARC (http://gco.iarc.fr/today)

World Health Organization © International Agency for

Research on Cancer 2021

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Prognosis and survival

EC is generally associated with good prognosis partly because it is often detected at an early stage because of the symptom of postmenopausal bleeding. The prognosis of EC is closely related to stage and other prognostic factors like tumor type, grade, lymphovascular space invasion (LVSI), and age. When all stages of cancer were included, the 5-year survival rate for EC in Norway was 86.6% for the period 2015–2019³.

Over the same period, for patients with stage I EC, the 5-year relative survival rate was as high as 97.2%. This is not the case for the group of patients who are diagnosed with high-risk or advanced disease. The prognosis for patients with regional disease and distant metastasis is poor, with 5-year relative survival rates of 68.1% and 43.8%, respectively, in the period 2015–

2019³. However, a substantial number of patients with EC die from other health conditions as the majority of these women are elderly and have several comorbidities. Figure 2 shows the steady increase in EC incidence and survival in Norway over the past 50 years.

Figure 2. Incidence (per 100000) and 5-year relative survival (%).

Figure adapted from Cancer in Norway 2019.

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Histopathology

ECs occur mostly sporadically and have traditionally been classified into two broad categories according to histopathological patterns: Type I tumors and Type II tumors. Bokhman described these two pathogenic types of EC in 1983⁷. Type I tumors represents 70%–80% of all cases and is associated with unopposed estrogen stimulation. They are mostly endometrioid adenocarcinomas, and they are often preceded by hyperplasia of the endometrium. They are also often low-grade, diploid, and hormone-sensitive tumors and are more common in obese women⁵.

Type II tumors are of nonendometrioid histology and account for 10% to 20% of EC. They consist mostly of serous carcinomas (50%–75%), clear cell carcinomas (12%–14%), undifferentiated carcinomas, and mixed elements of serous, clear cell, or endometrioid carcinomas. Carcinosarcomas account for the remaining type II endometrial epithelial malignancies. They are all known to be poorly differentiated and often hormone receptor negative, are seen more frequently in nonobese and older women, and are associated with a higher risk of metastasis and poor prognosis⁸.

Even though this dual classification has been incorporated in clinical decisions over the years, we now know that there is a considerable overlap among the biological, pathological, and molecular characteristics and prognosis within these tumor types. Some Type I ECs, such as those with poor differentiation, have a poor prognosis, whereas some Type II ECs may present with a fairly good prognosis. These differences may, in part, be explained by the overlap in molecular characteristics. Table 2 provides an overview of the most commonly reported molecular alterations in subgroups of EC.

In Type I tumors, the PIK3CA pathway is the most frequently altered, but mutations in KRAS and FGFR2 have also been reported^9,10. Type II tumors often display aberrant expression of p53, PTEN alterations, and to some degree, ERBB and FGFR alterations^11-13. However, poorly differentiated endometrioid ECs also express aberrant p53 in about 23% of the cases¹⁴, which explains the poor prognosis of these patients.

Consequently, evolving classification systems and clinical guidelines have tried to distinguish the subgroups of EC by combining histology, grading, molecular markers, and immunohistochemical profiles instead. This will be discussed in more detail in the chapter

“Preoperative and postoperative staging” of this thesis.

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Table 2. Molecular alterations of endometrial cancer by histology. With permission from The Lancet.

Grading

In addition to the histological subtype, the tumor’s grading is another central feature of prognostic significance. This grading is used together with myometrial invasion and LVSI to predict the risk of lymph node involvement and to tailor the surgical and adjuvant treatments.

Endometrioid endometrial carcinomas (EEC) are graded histologically according to the solid growth pattern in the tumor tissue seen under the microscope. Grade 1 (G1) tumors are well differentiated with a glandular pattern and only £5% of nonsquamous solid growth pattern, Grade 2 (G2) tumors have less well-defined glands and have a 6%–50% nonsquamous solid growth pattern, and Grade 3 (G3) tumors are poorly differentiated and have more than 50%

solid nonsquamous growth pattern.

Endometrioid carcinomas represent the largest group of ECs, and in particular, endometrioid Grades 1 and 2 are more frequently confined to the uterus. Grade 3 endometrioid carcinomas as well as the poor histological type (serous, clear cell, and carcinosarcoma) have a much greater tendency for nodal involvement and advanced disease⁸. Nonendometrioid tumors are high grade by definition.

There is increasing evidence for the molecular and prognostic similarities of EEC G3 tumors and nonendometrioid endometrial carcinoma (NEEC)^15,16. We have also considered this in the subgroup analysis of Paper II, where these tumors were studied as one subgroup.

Another challenge is to accurately grade a tumor to determine the need for surgical staging.

Studies have shown discordance between the diagnosis of the preoperative biopsies and the final hysterectomy specimen. The lowest agreement is found in G2 EC, where 14% of the patients were upgraded to G3 or nonendometrioid tumors. In G3 tumors, there is a risk of upgrading to nonendometrioid histology^17,18. There is also some degree of downgrading from G3 to G2 and from G2 to G1. A meta-analysis performed to assess the agreement between the

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preoperative endometrial biopsy and the final diagnosis after hysterectomy concluded that there was only moderate agreement between pathologists when analyzing the grade of differentiation with a pooled estimate of Cohen`s k 0.45¹⁷.

In a retrospective study at our institution, we compared the preoperative centrally reviewed histology with the postoperative hysterectomy specimen. There was good agreement between the two, and patients were correctly classified as Type I EC in 455/477 (95%) of the cases.

Regarding grading, our result was comparable to published studies with 12% of the G2 patients being upregulated to G3. Of the G1 cases, 15% were upgraded to G2, and only 2% were upregulated to G3. For the G3 patients, 23% were downgraded to G2 on final histology. For low-risk patients, the positive predicted value was 87%, which is important as low-risk patients in Norway are surgically treated in their local hospital with hysterectomy and bilateral salpingo- oophorectomy (BSO) alone (See the chapter: “Related research in the PhD-period,” abstract presented at the annual meeting for the Norwegian Society of Gynecology and Obstetrics in 2017). The difficulties in an accurate preoperative diagnosis to tailor surgical treatment warrant feasible and reproducible assessments that can be performed preoperatively.

PREOPERATIVE INVESTIGATION

The most common symptom of EC is abnormal uterine bleeding. Approximately 90% of all EC patients will present with postmenopausal bleeding¹⁹. This is one of the reasons why the disease is detected at an early stage. These women are recommended prompt investigation with pelvic examination, transvaginal ultrasound (TVU), and endometrial biopsy. Furthermore, it is important to collect both the patient’s family and medical history to identify risk factors for this disease.

Endometrial sampling

An endometrial biopsy or pipelle sampling is an adequate method to achieve preoperative histology in an outpatient office. With sensitivity of over 90% and specificity of up to 98%^17,20, this method gives a more accurate diagnosis for postmenopausal women than for premenopausal women according to estimates from a meta-analysis²⁰. An adequate biopsy is important as the preoperative diagnosis determines the extent of surgical staging. In cases where there is insufficient material from the pipelle sampling, we can use dilation and curettage or biopsy under hysteroscopy instead. Hysteroscopy is the gold standard in many institutes as it gives a more precise diagnosis than a blind dilation and curettage¹⁷.

It is crucial to collect sufficient tissue to enable histologic evaluation, especially when assessing the tumor grade; otherwise, the solid growth pattern may be missed.

Imaging

TVU is the gold standard, together with pipelle sampling, in evaluating women who experience abnormal uterine bleeding. An endometrial thickness of >3 mm in women with postmenopausal bleeding has been suggested as a cutoff value to investigate further to exclude EC²¹. In asymptomatic women without hormone replacement therapy (HRT), however, a screening for

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EC on endometrial thickness is not advisable because it is not sufficiently sensitive as a diagnostic tool²².

With diagnostic sensitivity of 98%, TVU is just as accurate as magnetic resonance imaging (MRI) when assessing myometrial and cervical involvement: that is assuming the TVU is performed by an experienced practitioner²³. When TVU and endometrial biopsy are combined, the resulting sensitivity can detect up to 100% of EC. Although ultrasound costs less than MRI, TVU is not suitable in detecting lymph node metastasis.

MRI is one of the best imaging techniques used for preoperative staging, with an overall staging accuracy of 83%–92%^24-26. MRI is primarily used to evaluate the local tumor spread, infiltration of the myometrium, and invasion to the cervical stroma as well as the lymph node status.

Diffusion-weighted imaging (DWI) can further improve the accuracy of assessing myometrial invasion^24,26. At Oslo University Hospital, pelvic dynamic contrast-enhanced (DCE) MRI is the standard diagnostic workup to evaluate the myometrial depth of the tumor, cervical involvement, and lymph node status in the pelvis. This is performed together with TVU and a representative endometrial biopsy (pipelle or curettage). In addition, computed tomography (CT) of the thorax, abdomen, and pelvis is performed to detect lymph node metastasis outside the pelvis and extrauterine or distant disease.

A remaining challenge is how to best utilize preoperative imaging to detect lymph node metastases. Even though imaging techniques are useful, MRI lacks specificity, and some institutions in Norway have implemented FDG-PET/CT to select patients for lymphadenectomy because FDG-PET or PET/CT improves diagnostic accuracy²⁷.

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PREOPERATIVE AND POSTOPERATIVE STAGING

Preoperative staging is used to guide the optimal surgical strategy, whereas postoperative staging is used to tailor adjuvant treatment.

Preoperative risk classification of stage I EC

In Norway, stage I ECs are preoperatively classified as low, intermediate, and high risk for lymph node metastasis and extrauterine spread based on histological subtype, grading, and myometrial invasion (Table 3)^28,29. How a patient’s EC is classified will determine both where the patient is treated, i.e., at a local hospital vs the regional university hospital, and what surgical procedure is performed. EC patients preoperatively assessed as low risk are managed at a local hospital with hysterectomy and BSO, whereas intermediate- or high-risk cases are referred to the regional university hospital for pelvic and para-aortic lymphadenectomy and omentectomy as indicated.

Table 3. Classification of FIGO stage I tumors across all risk categories²⁹.

Postoperative risk classification

Various risk stratification systems have evolved over the past 20 years to guide adjuvant treatment^30-33 (Table 4). The ultimate aim is to identify high-risk patients in need of multimodality treatment and patients at low risk of recurrence, where adjuvant treatment can be de-escalated. The ESMO modified classification, which is based on Federation of Gynecology and Obstetrics (FIGO) stage, depth of myometrial invasion, grade, and LVSI, has been used until the new incorporation of molecular markers came in the late 2020³⁴. Bendifallah et al. investigated the role of LVSI as a risk factor for recurrence and lymph node metastasis, concluding that in early-stage EC, LVSI seems to be particularly predictive of recurrence, especially for the intermediate-risk group³⁵. LVSI was therefore included in the ESMO classification to improve its accuracy. New biomarkers, including L1CAM, have been shown to be negative prognostic markers for early-stage EEC^36.37, and this biomarker, which we evaluated in Paper I, will be discussed further in the chapter “Biomarkers.”

Histological subtype FIGO stage Ia FIGO stage Ib Endometrioid Grades 1–2 Low risk Intermediate risk Endometrioid Grade 3 (High-)Intermediate risk High risk Nonendometrioid (Type II) High risk High risk

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Table 4. Variation in classification of risk factors according to trials and society guidelines. Printed with permission from The Lancet.

Molecular classification

Acknowledging the limitations of the accuracy of prognostic clinical and histopathological characteristics, molecular markers have been studied to develop a more reliable classification system and effectively triage patients to optimal adjuvant treatment.

The Cancer Genome Atlas (TCGA) project has been the most extensive molecular study to date, collecting genomic data from 232 endometrial carcinomas³⁸. The researchers combined whole genome sequencing, exome sequencing, microsatellite instability (MSI) assays, and copy number analysis. On the basis of these molecular data, they classified endometrioid and serous endometrial cancers into the following four groups: DNA polymerase epsilon catalytic subunit (POLE) ultramutated, MSI hypermutated, copy number (CN) low, and CN high tumors. The four groups were shown to be of predictive significance for progression-free survival (PFS).

Since this initial work, two other research groups have further developed the methodology to evaluate the molecular features of ECs mainly to allow the analysis of standard formalin-fixed paraffin-embedded tissue and to facilitate clinical implementation. In the Vancouver group, Talhouk et al. categorized the patients into four groups using a stepwise approach. First, the Mismatch Repair (MMR)-deficient proteins were identified using immunohistochemistry (IHC). Then, those tumors with loss of expression were designated MMR-deficient (MMR-D) (1). The MMR with intact proteins was termed MMR intact and further sequenced using digital PCR to identify POLE exonuclease domain mutation (EDM) (2). Finally, cases were assessed with IHC for p53, (3) p53 wild type (wt), and (4) p53 abnormal (abn) with null or missed mutations. This resulted in the molecular classification “Proactive Molecular Risk Classifier for EC (ProMisE)”^15,39.

The ProMisE has since been validated⁴⁰ by Stelloo et al. Their group used the PORTEC-3 study population of 116 patients to define the four prognostic subgroups using a parallel approach to account for potential multiple classifiers⁴¹. In group 1, p53 mutation was identified by p53 IHC

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and validated by sequencing. For group 2, the researchers used the Promega microsatellite instability (MSI) analysis system (MSI assay validated by IHC) to determine the MSI, and for group 3, the team identified POLE EDM hotspot mutations using Sanger sequencing. The last group, group 4, had no specific molecular profile (NSMP). The groups were consistently shown to be of prognostic impact, and Figure 3 summarizes two of the models (TCGA and ProMisE) and the survival curves of TCGA, Leiden classification and ProMisE.

Figure 3. TCGA, Leiden and Vancouver group characterizations, and cumulative recurrence-free survival by molecular group. Reprinted from McAlpine JN, et al. Endometrial cancer: Not your grandmother’s cancer⁴². With permission from Wiley & Sons.

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In December 2020, the European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) proposed new guidelines for the management of patients with endometrial carcinoma to include these molecular biomarkers⁴³ (Table 5).

Table 5. ESGO/ESTRO/ESP definition of prognostic risk groups. Reprinted from the International Gynecologic Cancer Society & European Society of Gynaecological Oncology with permission from BMJ Publishing Group

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TREATMENT

Surgery is the mainstay for treating EC and is curative in most cases. The disease is surgically staged using the International FIGO staging system (Figure 4)⁴⁴.

Stage I: Tumor is confined to the uterus.

Stage Ia: None or less than half myometrial infiltration.

Stage Ib: Infiltration in half or more than half of the myometrium.

Stage II: Cervical stromal invasion, but not extending beyond the uterus.

Stage III: Local and/or regional spreading of tumor.

Stage IIIa: Infiltration of the serosa and/or adnexa

Stage IIIb: Metastasis to the vagina and/or parametrial infiltration

Stage IIIc: Metastasis to retroperitoneal lymph nodes in the pelvis and/or para-aortal Stage IIIc1: Metastasis to pelvic lymph nodes

Stage IIIc2: Metastasis to para-aortic lymph nodes

Stage IV: Tumor infiltrates the bladder and/or intestinal mucosa and/or distant metastasis Stage IVa: Infiltration of the bladder or intestinal mucosa

Stage IVb: Distant metastasis, including intra-abdominal metastases and/or inguinal node metastases.

Figure 4: Endometrial cancer is staged surgically according to the International Federation of Gynaecology and Obstetrics (FIGO) criteria, revised in 2009⁴⁴. Reprinted with permission from Kreftlex.no.

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Presumed stage I

Total hysterectomy and bilateral removal of tubes and ovaries with or without lymphadenectomy are the standard treatments for stage I EC. In premenopausal women, preservation of the ovaries may be discussed with the patient with the prerequisite of macroscopic normal appearance of the ovaries and no signs of extrauterine disease.

Retrospective studies have not found a significant impact of ovarian preservation on survival⁴⁵. The omentum and peritoneum are always carefully evaluated. In cases of serous, clear cell, undifferentiated histology or carcinosarcoma, an omentectomy is also performed. In selected cases, with Grade 1 endometrioid carcinoma and no signs of myometrial invasion or lymph node metastasis, fertility-preserving treatment options can be considered⁴⁶. The role of lymphadenectomy in patients with stage I disease is described below.

Presumed stage II

Until recently, in Norway, radical hysterectomies were performed in patients with suspected cervical stroma invasion. However, this practice has now been abandoned in the absence of a proven survival benefit compared with a simple hysterectomy⁴⁷.

Minimally invasive surgery

In many institutions, minimally invasive surgery (MIS), laparoscopy, or robot-assisted surgery are the standard treatment in nonbulky (i.e., not FIGO stages IIIa–IVa). Compared with laparotomy, MIS offers the advantages of fewer infections, reduced interoperative blood loss, shorter duration of hospitalization, and fewer postoperative complications. Laparoscopy has been shown to be noninferior to laparotomy, with no significant difference in survival between these two methods (either for disease-free or overall survival)^48-50. Another important advantage of MIS is the superior quality of life (QoL) up to six months after surgery compared with laparotomy^51,52.

Robotic surgery may have some advantages in the treatment of obese women. Laparoscopy outcomes for obese women are found to match those for normal-weight women for measures such as completeness of surgery, recurrence rate, and survival. However, for women with high body mass index (BMI), surgery still poses a higher risk due to wound infections and longer operative time^53,54.

Lymphadenectomy

The surgical staging according to FIGO 2009 criteria (Figure 3) requires a full assessment of the lymph node status in the pelvis and abdomen⁴⁴. This recommendation is based on the assumption that lymphadenectomy provides a therapeutic benefit, in addition to allocating women to poorer prognosis groups.

The therapeutic role of lymphadenectomy has been studied in two randomized trials^55,56. Neither trial demonstrated a benefit for disease-free survival nor overall survival, but these studies were also limited by the extent of lymphadenectomy and the representativeness for patients with high-risk disease. Lymphadenectomy was associated with a significantly higher risk of surgically related systemic morbidity and lymphoedema/lymphocyst formation⁵⁷. For that reason, a risk stratified approach has been developed to spare patients with low risk of

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lymph node metastasis from lymphadenectomy to decrease the risk of surgical morbidity.

Metastasis to the pelvic lymph nodes was reported by the Gynecology Oncology Group (GOG)- 210 to occur in approximately 4% of G1, in 7% of G2, and 18% of G3 ECs⁸. Simultaneous metastases to the para-aortic lymph nodes were seen in 2% of G1, 4% of G2, and 9% of G3 cases. For the NEEC, the risk of metastasis to pelvic lymph nodes is 20%–25%, and for para- aortic lymph nodes, the risk is 12%–18%. Myometrial invasion predicted a higher risk of lymph node metastasis across all grades of EC. For G1 EC with superficial or endometrium involvement, the risk of metastasis to pelvic lymph nodes was only 0.8%, but with myometrial involvement of the outer half, the metastatic rate was much higher at 15%. This association was even more pronounced in G3 EC, where the risk of lymph node metastasis was 3% for endometrium-only involved cases but was 28% when the outer half of the myometrium was involved. The Norwegian national guidelines are in line with the ESMO guidelines that do not recommend lymphadenectomy in patients with endometrioid carcinoma Grades 1–2 with less than 50% myometrial invasion. The retrospective SEPAL study compared outcomes of intermediate- and high-risk EC patients undergoing systematic pelvic lymphadenectomy or combined pelvic and para-aortic lymphadenectomy. The result was a significantly better overall survival in high-risk patients who had pelvic and para-aortic lymph node dissection. The authors therefore recommended combined pelvic and para-aortic lymphadenectomy for patients with intermediate or high risk of recurrence³³, which was the standard of care for patients treated in the period discussed in this thesis.

Sentinel node technique

In the absence of a proven therapeutic benefit of lymphadenectomy, procedures with a lower risk of surgical complications have been explored. The sentinel node technique (SN) has been evaluated prospectively in a FIRES study of 340 patients with stage I disease across all risk groups⁵⁸. In all patients, the SN procedure was followed by a full lymphadenectomy. In 14%

of the patients, the SN technique was not successful. The sensitivity to detect node-positive disease was 97.2%, and the negative predictive value was 99.6%, confirming the feasibility and accuracy of this procedure. The safety of SN in obese patients has also been confirmed by other studies^59-61.

Advanced disease

Surgery is the preferred modality for patients with bulky disease (FIGO stages IIIa–IVa) if complete resection of macroscopic disease can be achieved³⁴. A small retrospective study found that primary surgical cytoreduction is associated with longer survival⁶². Patients with stage IV EEC who had no gross residual disease after primary cytoreduction was associated with a median OS of 42 months compared with median OS of 19 months for patients with residual disease, and 2,2 months for patients without cytoreduction. For patients not eligible for primary surgery, neoadjuvant chemotherapy followed by interval debulking can be considered⁶³. Palliative surgery may be offered to patients where resection of the tumor can relieve or reduce specific symptoms.

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ADJUVANT TREATMENT

Adjuvant treatment is added to primary therapy to enhance its potency by treating any microscopic disease that remains after surgery. The aim is to decrease the risk of later recurrence. However, there is currently no consensus on the optimal adjuvant treatment for patients with early-stage EC. Therefore, adjuvant treatment varies widely, especially with regard to the administration of radiotherapy, whether alone or in combination with chemotherapy.

Adjuvant radiotherapy

Adjuvant radiotherapy can be administered as external beam radiation therapy (EBRT) or as vaginal brachytherapy (VBT). Traditionally, EBRT was the adjuvant treatment of choice for early-stage disease, and it has been extensively studied in randomized controlled trials (RCTs)31,32,64,65. These RCTs primarily included patients with low- and/or intermediate-risk disease, and the results have been summarized in a Cochrane review by Kong et al.⁶⁶. They all consistently showed a reduction in vaginal and pelvic recurrence but without any significant survival benefit. In a PORTEC-1 study on patients with low- or intermediate-risk, EBRT reduced the frequency of relapse at 5 years from 14% in the surgery alone group to 4% in the group with postoperative EBRT. In the group that did not receive EBRT, 73% of relapses were vaginal. The occurrence of distant metastases and EC-related death was similar in the two groups³¹. In GOG-99, EBRT given to patients in the high-intermediate-risk (HIR) group showed a cumulative incidence of recurrence at 2 years of 3% in the EBRT group compared to 12% in the control group (no additional treatment). Most of this reduction of recurrence occurred in the HIR group³². On the basis of these studies, EBRT was only beneficial to a subgroup of patients with high-intermediate-risk (HIR) features. This HIR group of patients has been defined by both PORTEC-1 and GOG-99 with slightly different risk factors (Table 4).

However, there are still concerns regarding the negative impact on QoL due to both short- and long-term toxicity after radiotherapy. Long-term follow-up of the PORTEC-1 patients confirmed that irradiation caused bladder and bowel symptoms (such as urgencies, leakage, diarrhea, and incontinence) as long as 15 years after treatment⁶⁷. Onsrud et al. published the long-term follow up of the Oslo study of 568 early-stage EC patients, mainly low- and intermediate-risk EC patients, who were randomized to postoperative RT or observation-only after their vaginal mucosa was irradiated with radium⁶⁸. This update still showed no statistically significant improvement in survival for the EBRT group. However, patients aged <60 years had shortened survival times after EBRT and an increased risk of a second cancer.

To avoid the adverse effect of EBRT, vaginal brachytherapy (VBT) has been explored.

PORTEC-2 aimed to compare these two adjuvant options in a noninferiority, multicenter randomized trial of 427 HIR EC patients. The trial showed decreased side effects from VBT compared to pelvic RT but no statistical significance in local or extrapelvic recurrence rates.

There was no significant difference in disease-free survival (DFS) nor overall survival (OS) between the two groups⁶⁹. However, the QoL was better for patients in the VBT-group because of lower toxicity. VBT was therefore recommended as an effective adjuvant treatment for patients with HIR EC⁷⁰. By restricting the adjuvant EBRT to the HIR subgroup, approximately 50% of women could be spared from unnecessary treatment and unwanted side effects31,32,67,71.

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With the help of novel molecular markers, this HIR subgroup has been further subdivided into favorable and unfavorable types. In the PORTEC-2 population, risk factors such as substantial LVSI, L1CAM expression, and p53-mutant were all found to be strongly associated with the risk of recurrence (whether pelvic and distant) and EC-related survival⁷¹. Furthermore, women with HIR disease and with one of these unfavorable biomarkers had lower rates of pelvic recurrence if they received EBRT rather than VBT. PORTEC 4a is an ongoing trial that randomizes (2:1) women with HIR EC using these unfavorable biomarkers in a molecular- integrated risk profile. In the experimental arm, observation is performed in case of a favorable risk profile; VBT, in case of an intermediate-risk profile; and EBRT, in case of an unfavorable risk profile. In the standard arm, adjuvant VBT is administered⁷².

The ESMO–ESGO–ESTRO guidelines from 2016 acknowledged the uncertain benefit of adjuvant radiotherapy³⁴. For low-risk EC, the guidelines recommend omitting adjuvant RT but leaving VBT optional for intermediate-risk EC, with the aim of reducing vaginal recurrence, especially in women aged >60 years. For not surgically staged patients with HIR EC, adjuvant EBRT is recommended for patients with unequivocally positive LVSI, and adjuvant VBT is recommended for G3 and negative LVSI patients.

In Norway, no adjuvant treatment is given to patients with low- or intermediate-risk stage I EC.

The rationale in omitting radiotherapy in Norway is grounded in the presumed low number of relapses and supported by the outcome of the patients in the PORTEC-I trial who developed vaginal and/or pelvic relapse. Patients who were radiotherapy-naïve had improved survival rates⁷³. Hence, we spare radiotherapy to those with local recurrence in order to improve their chance of a cure.

The Nordic strategy to minimize adjuvant radiotherapy was evaluated in a population-based study from Denmark. After omission of radiotherapy 6.3% of low-risk and 22% of intermediate-risk patients recurred⁷⁴. Recurrence was predominantly locoregional recurrence in the low- and intermediate-risk cases, whereas nonlocoregional recurrence was prominent in high-risk cases. The reported recurrence rates of up to 22% and the challenges with the reproducibility of our current risk-classification systems warrant research on better prognostic biomarkers in early-stage EC to better tailor adjuvant treatment. For an introduction in potential biomarkers, please see the subchapter “Biomarkers” in this introduction. Paper I of this thesis explores L1CAM as a prognostic marker for early-stage endometrioid EC.

Adjuvant chemotherapy

Patients with high-risk EC have a higher risk of systemic recurrent disease. In Norway, patients with high-risk tumors will therefore be offered six cycles of platinum-based chemotherapy (i.e., carboplatin and paclitaxel). The publication of the GOG-209 study proved the noninferiority of carboplatin/paclitaxel compared to paclitaxel–doxorubicin–cisplatin⁷⁵. The OS results have just recently been published, confirming similar survival in both arms⁷⁶.

Several randomized studies have tried to clarify the role of adjuvant chemotherapy without being able to agree on a common strategy²⁸. Most of these studies included patients with high- risk stage I disease and more advanced disease such as stage III. GOG-122 was the first study to compare chemotherapy with doxorubicin–cisplatin (AP) and radiotherapy (EBRT) in patients with optimally debulked stage III or IVa⁷⁷. The study randomized 202 patients to

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receive whole abdominal irradiation (WAI) and 194 patients to receive AP. At a follow-up time of 74 months, chemotherapy was found to be favorable both in recurrence-free survival (HR, 0.70; 95% CI, 0.55–0.91; p = 0.007) and OS (HR, 0.68; 95% CI, 0.52–0.89; p = 0.004). The 5- year survival rate adjusted for stage was 55% in patients treated with AP compared with 42%

of those who received RT⁷⁷.

The Italian trial in 2006 is a similar study that randomized 345 patients with high-risk EC (stage I G3 with involvement of the serosa, stage II G2 with deep myometrial invasion, and stage III) to adjuvant triple-drug chemotherapy or EBRT⁷⁸. Even though not significant, the study confirmed the trend of radiotherapy playing a role in delaying local recurrence, and chemotherapy may, in particular, reduce the risk of distant metastasis. There was no difference in PFS or OS between the groups. The progression-free rate of 63% after 5 years highlights the need to optimize treatment in these patients. An unplanned subgroup analysis of a Japanese study reported a larger benefit for chemotherapy in high-intermediate-risk (HIR) patients defined as stage Ic, who were aged over 70 years, who had G3 EEC, or who were stage II or IIIa with deeper myometrial invasion⁷⁹. The chemotherapy group had a significantly higher PFS rate (83.8%; HR, 0.44; 95% CI, 0.20–0.97; p = 0.004) and OS rate (89.7%; HR, 0.24; 95%

CI, 0.009–0.69; p = 0.006) when compared to pelvic radiotherapy⁷⁹.

Retrospective studies have raised concerns regarding chemotherapy’s lack of ability to control pelvic recurrence when given alone. In a retrospective study of patients with stage IIIc disease, the pelvic recurrence rates were 39% for chemotherapy alone, 29% for RT alone, and 27% for the two treatments combined⁸⁰. However, most relapses (70%) for patients with high-risk EC occurred outside the pelvis irrespective of the kind of adjuvant treatment given.

Paper II of this thesis is a retrospective analysis of patients with high-risk early-stage and node- positive EC treated with chemotherapy alone at Oslo University Hospital.

Combined adjuvant radiotherapy and chemotherapy

The combination of radiotherapy and chemotherapy could ideally provide both pelvic and distant control of recurrence. A pooled analysis of two randomized trials (NSGOEC- 9501/EORTC-55991 and MaNGO ILIADE-III) showed that the addition of chemotherapy sequential to RT vs RT alone significantly increased DFS by reducing the risk of recurrence or death by 36% (HR, 0.64; 95 CI, 0.41–0.99; p = 0.04)⁸¹. The disease-specific survival also significantly favored the combination treatment (with a 49% reduction in the risk of death from EC), and there was no statistically significant increase in OS. However, the combined chemoradiation (CTRT) was associated with increased morbidity and a higher rate of treatment discontinuation. There was no significant difference in the patterns of recurrence between the arms. The GOG-249 trial compared vaginal brachytherapy and three cycles of chemotherapy with EBRT in patients with high-intermediate or high-risk features. However, there was no significant difference in survival (either recurrence-free or OS)⁸².

The PORTEC-3 trial included women with FIGO 2009 (1) stage Ia endometrioid EC, G3 with LVSI, (2) stage Ib endometrioid EC G3, (3) stage II or III endometrioid EC, or (4) stage I to III with serous or clear cell histology⁸³. Patients were randomized to either EBRT alone or chemoradiation followed by four cycles of platinum-based chemotherapy. In the initial report by de Boer et al., they showed a significant improvement in failure-free survival (FFS) between the two groups but not in OS. The 5-year FFS was 75.5% in the CTRT group vs 68.8% in the

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RT group (HR, 0.71; 95% CI, 0.53–0.95; p = 0.022). The 5-year OS was 81.8% in the CTRT group compared with 76.7% in the RT group (HR, 0.76, 95% CI, 0.54–1.06; p = 0.109). Serous cancers had a significantly poorer outcome than other histological subtypes. They also found that most relapses were distant and there was almost no locoregional recurrence. In an updated post-hoc analysis of that study, CTRT significantly improved OS (HR, 0.70; p = 0.034) compared with RT alone⁸⁴. However, more than half of the patients in the chemoradiotherapy arm reported grade 3 or worse adverse events during treatment compared with only 12% of the patients who received only radiotherapy (p < 0.0001)^83,85. The combination-therapy group also had a higher risk of persisting neuropathy at three years.

The randomized GOG-258 study assigned around 700 patients to receive CTRT or six cycles of paclitaxel and carboplatin (TC). Final results reported no differences in overall or recurrence- free survival. When patients were treated with chemotherapy alone, significantly more relapses were located in the vagina, pelvis, or para-aortic lymph nodes, but the benefit was a lower number of distant metastases compared with the CTRT arm⁸⁶.

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MANAGEMENT OF RECURRENT DISEASE

Most relapses occur between 2 and 3 years after the primary treatment^73,87,88. The overall recurrence rate for EC is about 15%⁸⁹. For the early stages, the recurrence rate varies from 2%

to 15%, and for advanced or nonendometrioid EC, the recurrence rate is up to 50%⁸⁹.

Management of recurrent disease depends on the localization of relapse, prior treatment, and the patient’s comorbidities and preferences.

A clinical examination together with a CT of the chest, abdomen, and pelvis as well as a biopsy of the relapse is important to assess the extent of the disease to confirm the diagnosis.

Locoregional recurrence

Local recurrence in EC refers to a relapse in the vaginal vault or in the vaginal cuff, whereas regional recurrence refers to a relapse outside the vaginal vault within the pelvis. For radiotherapy-naïve women with isolated vaginal/central pelvic recurrence, salvage RT is usually recommended.

Many retrospective studies have focused on treating vaginal relapses. Both the type of RT used, and the dose have a significant impact on local control, with the best results seen at higher irradiation dosages (Gy) and a combination of EBRT and brachytherapy to ensure optimal dosing to the tumor^90-93. These studies described a median total radiation dose between 68 and 76 Gy. In Paper III, we used 67 Gy as a cutoff for radical RT.

The PORTEC-1 trial compared adjuvant whole pelvic radiation therapy with observation for patient with low-risk stage I EC^31,73. In the control arm, 10% of the patients experienced vaginal recurrence compared with 2% of those in the radiation arm, also highlighting that pelvic radiation does not completely diminish the local recurrence rates. Most of the patients with isolated vaginal recurrence were treated with curative intent, and 85% of the patients had complete remission with 3-year OS of 70%. Even after 8 years, 67% of the patients were without any sign of the disease⁷³. Complete remission was only 40% for patients with pelvic relapse treated with curative intent. The outcome was also poorer if the relapse involved the pelvic sidewall compared to a centrally located relapse.

Several other retrospective results have reported on the clinical outcome after salvage radiotherapy for pelvic relapse in patients with EC. Most of the studies were single-site studies with a limited number of patients included. Huh et al. evaluated the outcome of 69 stage I EC patients with isolated vaginal recurrence that were prior treated with surgery only. Eighty-one percent of the women were successfully salvaged with radiotherapy. The 5-year OS was 75%⁹⁴. Another retrospective study of salvage RT for local recurrence by Jereczek-Fossa et al. showed rather poor survival rates of 33% and 25% after 3 and 5 years, respectively, for patients undergoing radiotherapy (EBRT, EBRT + VBT, and VBT alone) for local EC recurrence⁹². Complete remission was observed in 43% of patients, and partial remission was observed in 30% of patients. The FIGO stage of the recurrent tumor and the physical total radiotherapy dose were the main factors with a significant impact on both the time to progression and OS⁹². The initial risk group of the tumor has been found to be a significant prognostic factor for the response to the treatment and benefit for survival in these retrospective studies^90-93.

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Paper III is a multicenter retrospective study of patients treated for central pelvic or vaginal relapse to assess treatment outcomes after salvage radiotherapy.

Locoregional recurrence after adjuvant radiotherapy is not common. In the follow-up study of PORTEC-1, 13 patients developed locoregional recurrence after EBRT was administered and 46 patients in the control group, showing 8-year relapse rates of 4% and 15%, respectively⁷³. The patients with prior RT have, in general, a poor prognosis, and only a very selected population will be candidate for curative surgery with pelvic exenteration. For another small proportion of nonsurgical candidates, reirradiation is an option if the technical resources and skills are available. Patients are at a high risk for severe toxicity and complications such as fistula formation, irradiation inflammation in the bowel/bladder/rectum, and stricture formation. These complications may be reduced if stereotactic radiation can be administered⁹⁵. Most commonly, medical treatment is offered to these patients.

Distant recurrence

Recurrence outside the pelvis is considered a distant relapse and is usually incurable, and the treatment is of palliative character. Studies on primary advanced EC often include patients with recurrent disease, and the GOG-209 study that established carboplatin–paclitaxel as a standard of care of these studies is also discussed in the previous section on “Adjuvant treatment.” The options for palliative treatment are systemic cytotoxic or endocrine treatment in addition to supportive care.

Chemotherapy

Several trials have been studying different cytotoxic treatments as described in the chapter

“Adjuvant chemotherapy” above. GOG-177 showed an improved response rate of 57% and statistically significant increased RFS and OS with the cytotoxic combination of paclitaxel, doxorubicin, and cisplatin (TAP) compared to cisplatin/doxorubicin (AP)⁹⁶. The study established a new standard of care for patients with advanced and recurrent disease but at the expense of more adverse effects. The triple regimen had a high toxicity, particularly increased peripheral neuropathy with 12% vs 1%, and the subsequent GOG-209 study could finally establish the noninferiority of carboplatin–paclitaxel, which had a better toxicity profile⁷⁶. Second-line treatments have a poorer response rate, and the choice of cytotoxic treatment depends on prior treatments and the performance status of the patient⁹⁷. Several phase II trials have tried to evaluate the efficacy of the second-line cytotoxic treatment of EC but have failed to find any suitable agent with strong enough activity against the disease⁸⁹.

Retreatment with platinum can be considered for women with a long recurrence-free and platinum-free interval. Doxorubicin, liposomal doxorubicin, and weekly paclitaxel are often used as nonplatinum options, with objective response rates between 9.5% and 11.5% for liposomal doxorubicin and up to as high as 37% for weekly paclitaxel⁸⁸. However, in the phase II trial for paclitaxel, there was no prior exposure to paclitaxel. Thus, this response rate must therefore be interpreted with caution.

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Endocrine treatment

Endocrine treatment is an option for patients with advanced disease or with distant metastasis recurrence where chemotherapy or radiation therapy is not an option. This treatment seems more effective for patients with tumors of endometrioid histology and low grade⁹⁸. Progestins have been shown to be effective against the disease⁹⁹ without detrimental side effects. Recently, a combination of an aromatase inhibitor and cyclin D kinase 4/6 inhibitor has shown encouraging results with a clinically meaningful increase of the progression-free survival of 5.3 months¹⁰⁰.

Targeted options

Novel alternative targeted therapies for EC have emerged during the past decade as we have learned more about molecular mechanisms, identified new molecular pathways, and explored the genomic data of endometrial carcinoma through the TCGA project. These targeted drugs are aimed at blocking the growth of cancer cells by binding to specific molecules needed in carcinogenesis. The signal pathway PI3K/akt/mTOR is a frequently altered pathway in EC and has been extensively studied in multiple phase-II trials but with limited results on recurrence and no impact on the OS¹⁰¹.

EGFR/HER1 and ERBB2/HER2 are found in up to 70% of EC (Table 2). Monoclonal antibodies cetuximab and trastuzumab act directly against HER 1 and HER2, and a survival benefit has been reported in HER2-positive patients¹⁰². Immunotherapy with checkpoint inhibitors has emerged as a promising treatment modality, especially in patients with high mutation burden like POLE hypermutated subtype and patients with d-MMR tumors¹⁰³.

Clinical outcome of patients with endometrial cancer in Norway after omission of radiotherapy and the evaluation of L1CAM as a prognostic factor