Clinical trial

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INTERNATIONAL JOURNAL OF
PORTEC-­4a: international randomized trial of
GYNECOLOGICAL CANCER
Original research

Editorials

Joint statement

Society statement
molecular profile-­based adjuvant treatment
for women with high-­intermediate risk
Meeting summary

Review articles

Consensus statement

Clinical trial

Case study

Video articles

Educational video

endometrial cancer
lecture

Corners of the world

Commentary

Letters

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Anne Sophie V M van den Heerik ‍ ‍,1 Nanda Horeweg ‍ ‍,1 Remi A Nout,2 Ludy C H W Lutgens,3
Elzbieta M van der Steen-­Banasik,4 G Henrike Westerveld,5 Hetty A van den Berg,6 Annerie Slot,7
Friederike L A Koppe,8 Stefan Kommoss,9 Jan Willem M Mens,2 Marlies E Nowee,10 Stefan Bijmolt,11
David Cibula,12 Tanja C Stam,13 Ina M Jurgenliemk-­Schulz,14 An Snyers,15 Moritz Hamann,16
Aleida G Zwanenburg,17 Veronique L M A Coen,18 Katrien Vandecasteele,19 Charles Gillham,20
Cyrus Chargari,21 Karen W Verhoeven-­Adema,22 Hein Putter,23 Wilbert B van den Hout,24
Bastiaan G Wortman,1 Hans W Nijman,25 Tjalling Bosse,26 Carien L Creutzberg1

For numbered affiliations see HIGHLIGHTS

end of article. • PORTEC-­4a is the first trial to introduce molecular factors in the adjuvant treatment of endometrial cancer.
• Randomization between standard or individualized treatment based on the molecular risk profile.
Correspondence to • PORTEC-­4a will show if omitting treatment in cases of favorable molecular profiles is safe and cost-­effective.
Anne Sophie V M van den
Heerik, Radiotherapy, Leiden
Universitair Medisch Centrum, ABSTRACT invasion; (iii) stage IB, grade 3 without lymph-­vascular
2333 ZA Leiden, Zuid-­Holland, Background Vaginal brachytherapy is currently space invasion; or (iv) stage II (microscopic and grade 1).
Netherlands; a​ .​v.m
​ .​van_d​ en_​
recommended as adjuvant treatment in patients with high-­ Endpoints The primary endpoint is vaginal recurrence.
heerik@​lumc.​nl Secondary endpoints are recurrence-­free and overall
intermediate risk endometrial cancer to maximize local
control and has only mild side effects and no or limited survival; pelvic and distant recurrence; 5-­year vaginal
impact on quality of life. However, there is still considerable control (including treatment for relapse); adverse events
Accepted 17 August 2020
overtreatment and also some undertreatment, which and patient-­reported symptoms and quality of life; and
Published Online First
12 October 2020 may be reduced by tailoring adjuvant treatment to the endometrial cancer-­related healthcare costs.
patients’ risk of recurrence based on molecular tumor Sample size 500 eligible and evaluable patients.
characteristics. Estimated dates for completing accrual and presenting
Primary objectives To compare the rates of vaginal results Estimated date for completing accrual will be late
recurrence in women with high-­intermediate risk 2021. Estimated date for presentation of (first) results is
endometrial cancer, treated after surgery with molecular-­ expected in 2023.
integrated risk profile-­based recommendations for either Trial registration The trial is registered at ​clinicaltrials.​
observation, vaginal brachytherapy or external pelvic gov (NCT03469674) and ISRCTN (11659025).
beam radiotherapy or with standard adjuvant vaginal
brachytherapy
Study hypothesis Adjuvant treatment based on a INTRODUCTION
molecular-­integrated risk profile provides similar local
control and recurrence-­free survival as current standard The cornerstone of treatment for endometrial
adjuvant brachytherapy in patients with high-­intermediate cancer is surgery, consisting of a total abdominal or
risk endometrial cancer, while sparing many patients the laparoscopic hysterectomy and bilateral salpingo-­
morbidity of adjuvant treatment and reducing healthcare oophorectomy. Based on clinicopathologic risk factors
costs. such as age, stage, histological type, grade, depth of
Trial design A multicenter, international phase III myometrial invasion, and presence of lymph-­vascular
randomized trial (2:1) of molecular-­integrated risk profile-­ space invasion, patients are considered to be at
based adjuvant treatment (experimental arm) or adjuvant low- to low-­intermediate risk (approximately 50% of
vaginal brachytherapy (standard arm). patients), high-­intermediate risk (30%–35%), or high
Major inclusion/exclusion criteria Women aged risk (15%–20%) for disease recurrence (Table 1).1
© IGCS and ESGO 2020. 18 years and over with a histological diagnosis of high-­
Re-­use permitted under CC BY. Adjuvant treatment has increasingly been tailored to
intermediate risk endometrioid endometrial cancer after
Published by BMJ.
total abdominal or laparoscopic hysterectomy and bilateral these prognostic factors.
To cite: van den Heerik ASVM, salpingo-­oophorectomy. High-­intermediate risk factors are Multiple randomized trials have established that in
Horeweg N, Nout RA, defined as: (i) International Federation of Gynecology and stage I endometrial cancer with risk factors, adjuvant
et al. Int J Gynecol Cancer Obstetrics stage IA (with invasion) and grade 3; (ii) stage external pelvic radiotherapy provides a significant
2020;30:2002–2007. IB grade 1 or 2 with age ≥60 and/or lymph-­vascular space reduction of vaginal and pelvic recurrence. However

2002 van den Heerik ASVM, et al. Int J Gynecol Cancer 2020;30:2002–2007. doi:10.1136/ijgc-2020-001929
 Clinical trial

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Table 1 Risk groups of endometrial cancer and current treatment recommendations
Risk group ESMO-­ESGO-­ESTRO consensus1 Common treatment recommendations
Low risk Stage I EEC, grade 1–2,<50% No adjuvant treatment
myometrial invasion, LVSI negative
Low-­intermediate risk Stage I EEC, grade 1–2,≥50% Vaginal brachytherapy
myometrial invasion, LVSI negative (consider observation if age <60 years)
High-­intermediate risk Stage I EEC, grade 3, Vaginal brachytherapy
<50% myometrial invasion, any LVSI Consider pelvic external beam radiotherapy if LVSI is unequivocally
Stage I EEC, grade 1–2, positive, especially if no lymph node dissection or sentinel node has
LVSI unequivocally positive, any been performed.
myometrial invasion
High risk Stage I EEC, grade 3, External beam radiotherapy
≥50% myometrial invasion, any LVSI Consider vaginal brachytherapy if no LVSI
Stage II EEC Vaginal brachytherapy if grade 1–2 and LVSI negative
Stage III EEC Pelvic radiotherapy if :
►► Stage II, grade 3
►► LVSI unequivocally positive
►► Stage III
Stage III: combined adjuvant radiotherapy and chemotherapy
(PORTEC-3 schedule or sequential)
NEEC stage I–III (serous, clear Vaginal brachytherapy if serous/clear cell, stage IA after full surgical
cell or undifferentiated cancers; staging, LVSI negative
carcinosarcoma) Stage IB–III: combined adjuvant pelvic radiotherapy and
chemotherapy

EEC, endometrioid endometrial cancer; ESGO, European Society of Gynecological Oncology; ESMO, European Society for Medical
Oncology; ESTRO, European Society; LVSI, lymph-­vascular space invasion; NEEC, non-­endometrioid endometrial cancer; PORTEC,
post operative radiation therapy endometrial cancer.

no overall survival advantage was observed and pelvic radio- copy-­number-­high group, with highly frequent TP53-­mutations, has
therapy is associated with treatment-­related toxicities, predom- an unfavorable prognosis.9 Several independent groups have devel-
inantly gastrointestinal.2–4 Since most relapses occurred in the oped and validated surrogate markers for these subgroups that can
vaginal vault, the PORTEC-2 trial was initiated to evaluate vaginal be assessed on paraffin-­embedded tissues. A molecular-­integrated
brachytherapy as compared with pelvic radiotherapy in patients risk model was defined by integrating the molecular subgroups
with high-­intermediate risk endometrial cancer.3–5 The conclusion with L1-­CAM overexpression, substantial lymph-­vascular space
from the PORTEC-2 trial was that vaginal brachytherapy should invasion, and CTNNB1-­exon 3 mutations.10–12 L1-­CAM is an inde-
be the adjuvant treatment for patients with high-­intermediate risk pendent risk factor of locoregional and distant spread and associ-
disease because of similar efficacy compared with pelvic radio- ated with TP53-­mutations, high tumor grade, and lymph-­vascular
therapy, with lower toxicity and better health-­related quality of space invasion.12 13 CTNNB1-­ exon 3 mutations are prognostic
life.5 However, adjuvant brachytherapy of all patients with high-­ for higher risk of recurrence, especially in the copy-­number-­low
intermediate risk features can still be considered overtreatment group.11 By applying this molecular-­integrated risk profile to the
as there are effective salvage treatments for vaginal relapse in high-­intermediate risk cohorts of the PORTEC-1 and −2 trials, three
patients who are not previously irradiated.6 A long-­term analysis of risk categories (favorable, intermediate, and unfavorable) were
the PORTEC-2 trial showed that a small subgroup of patients with defined with a significantly different recurrence-­free survival.11 It
high-­risk factors might actually benefit from adjuvant pelvic radio- is hypothesized that use of this molecular-­integrated risk profile
therapy to maximize pelvic control. These risk factors are substan- to determine the adjuvant treatment would reduce overtreatment
tial lymph-­ vascular space invasion, L1-­ Cell Adhesion Molecule in many patients and reduce undertreatment in a small propor-
(L1-­CAM) overexpression, and p53 mutant expression, which are tion, with similar vaginal control and recurrence-­free survival. The
all associated with higher risk of both pelvic and distant relapse.6–8 PORTEC-­4a trial is the first study worldwide to evaluate the clinical
The comprehensive genomic analysis of endometrial cancer by role of molecular risk factors in decision making on adjuvant treat-
The Cancer Genome Atlas (TCGA) has led to important novel insights ment in patients with endometrial cancer.
in the genomic landscape of endometrial cancer. The TCGA defined
four molecular subgroups based on mutational burden and copy
number alterations. The ultramutated POLE-­mutant subgroup is
characterized by mutations in the exonuclease domain of DNA poly- METHODS
merase epsilon and is associated with an excellent prognosis. The Trial design
hypermutated subgroup with microsatellite instability (or mismatch-­ The PORTEC-­ 4a trial is a prospective, multicenter phase III
repair deficiency) and the copy-­number-­low group are both asso- study, led by the Dutch Gynaecologic Oncology Group. A total of
ciated with an intermediate (stage-­ dependent) prognosis. The 500 eligible and evaluable women with high-­intermediate risk

van den Heerik ASVM, et al. Int J Gynecol Cancer 2020;30:2002–2007. doi:10.1136/ijgc-2020-001929 2003
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Figure 1 Study design PORTEC-­4a trial. Reprinted from 'Molecular-­integrated risk profile to determine adjuvant radiotherapy
in endometrial cancer: evaluation of the pilot phase of the PORTEC-­4a trial' by Wortman et al., 2018, Gynecologic Oncology
151; 69–75. A: trial design of the PORTEC-­4a trial; B: decision tree for the molecular-­integrated profile; CTNNB1, β-catenin;
EBRT, external beam radiotherapy; LVSI; lymph-­vascular space invasion; HIR, high-­intermediate risk; L1-­CAM, L1-­cell adhesion
molecule; POLE, polymerase-ɛ * stage I (with invasion) disease, grade 3 tumor; stage IB disease, grade 1 or 2 tumor, with either
age 60 years or older or substantial LVSI; stage IB disease, grade 3 tumor, without LVSI; or stage II (microscopic) disease,
grade 1 tumor.

endometrioid endometrial cancer will be randomized (2:1) to the fractions of 7 Gy each within an overall time of 2 weeks). About
experimental arm with molecular-­ integrated risk profile-­based 5%–10% will have an unfavorable profile and receive pelvic radio-
adjuvant treatment: observation in case of a favorable risk profile, therapy (45–48.6 Gy in 1.8–2 Gy fractions) (see Figure 1).11 Patients
vaginal brachytherapy in case of intermediate risk, and pelvic radi- are clinically evaluated during alternating follow-­up visits to their
otherapy in case of an unfavorable risk profile; or to the standard gynecologist and radiation oncologist every 3 months for the first 3
arm with adjuvant vaginal brachytherapy. After informed consent years for early detection of local recurrence, and at 6-­month inter-
and randomization, histopathological slides and a representative vals until 5 years. For long-­term information, vital status and events
tumor tissue block are sent for expert gynecopathology review and are also recorded at 7 years. Toxicity is evaluated using Common
determination of the molecular-­integrated risk profile. Microscopy Terminology Criteria for Adverse Events (CTCAE) version 4.0. and
is used to confirm histological type, grade and invasion, and, espe- patient-­reported health-­related quality of life is evaluated using
cially, evaluation and semi-­quantification of lymph-­vascular space the European Organization for Research and Treatment of Cancer
invasion. Immunohistochemistry is needed to determine L1-­CAM, Quality-­of-­life Questionnaire Core 30 questionnaire (EORTC QlQ-­
p53, and mismatch-­repair protein expression (MLH1, PMS2, MSH2, C30)and the endometrial cancer-­specific module (EN24). In case
and MSH6). Pathogenic POLE-­mutations and CTNBB1-­exon 3 status of (suspected) recurrence or metastasis, full evaluation is required
are determined by DNA sequencing. In a small subgroup (3%–6%) and treatment with curative intention is initiated if appropriate.
of cases the tumor will have more than one classifying feature Currently, a total of 22 sites in Belgium, Czech Republic, Germany,
(combinations of POLE-mutations, mismatch-­repair deficiency, and France, Ireland, and The Netherlands are open for inclusion and
p53-­abnormal staining).14 Risk profiles for these so-­called ‘multiple another eight are preparing for participation. The study is supported
classifiers’ are assigned as follows, based on a previous extensive by the Dutch Cancer Society (UL2011-5336 and UL20).
analysis: favorable in case of a POLE-­mutation irrespective of other
classifiers; intermediate if both mismatch-­repair deficiency and
p53 abnormal staining, but unfavorable if also substantial lymph-­ Participants
vascular space invasion or L1-­CAM overexpression is found.In any Patients aged 18 years or older with a WHO performance status
other case the least favorable factor will determine the risk profile of 0–2 with a histological diagnosis of endometrioid endometrial
(see Figure 1).14 cancer with high-­intermediate risk features (as listed in Box 1) are
In each participating country, at least one pathology laboratory eligible after surgery, consisting of a total abdominal or laparoscopic
has been validated for review and determination of the molecular-­ hysterectomy and bilateral salpingo-­oophorectomy. Lymphadenec-
integrated risk profile. tomy, lymph node sampling, or sentinel node procedure are not
Based on previous analysis it is expected that approximately required but permitted as per center standard protocol.
50%–55% of patients with high-­ intermediate risk endometrial Patients diagnosed with malignancy (except for non-­melanoma
cancer have a favorable molecular profile.11 In the experimental skin cancer) in the past 5 years and/or previous pelvic radiotherapy
arm this subgroup will receive no adjuvant treatment and will be are excluded. In addition, patients are not eligible if the interval
observed. An estimated 40% of patients have an intermediate between date of surgery and start of radiotherapy is expected to
profile and will receive vaginal brachytherapy (21 Gy in three exceed 8 weeks.

2004 van den Heerik ASVM, et al. Int J Gynecol Cancer 2020;30:2002–2007. doi:10.1136/ijgc-2020-001929
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pooled PORTEC-1 and 2 trials, the expected 5-­year rates of vaginal
Box 1 Inclusion and exclusion criteria of the PORTEC-­4a
recurrence are 2.0% in the vaginal brachytherapy arm and 4.625%
trial
in the molecular profile arm. The null hypothesis states that the
5-­year cumulative incidence of vaginal recurrence in the molecular
Inclusion criteria*
• Women aged 18 years and over
profile-­directed treatment arm exceeds that of the standard vaginal
• Surgery consisting of a total abdominal or laparoscopic hysterecto- brachytherapy arm by more than an equivalence margin of 7%:
my and bilateral salpingo-­oophorectomy the null hypothesis will be rejected if the upper bound of the one-­
• Endometroid endometrial cancer with high-­ intermediate risk sided 95% Wald confidence interval of the difference (molecular
features: arm minus standard arm) does not exceed the equivalence margin.
–– Stage IA (with invasion), grade 3 (any age, with or without The inclusion period was estimated to be 4 years, with a follow-­up
lymph-­vascular space invasion) period of 3 years after inclusion of the last patient. For a total of 500
–– Stage IB, grade 1 or 2 and age >60 years evaluable patients, with 167 patients in the standard arm and 334
–– Stage IB, grade 1 or 2 with documented lymph-­vascular space in the molecular arm, a power of 84.4% is achieved. An additional
invasion power calculation was performed for a subgroup analysis among
–– Stage IB, grade 3 without lymph-­vascular space invasion
all patients with a favorable risk profile to determine the difference
• Stage II (microscopic), grade 1
• Treatment with curative intent
in vaginal recurrence between the experimental group (no adju-
vant treatment) and the standard treatment group (brachytherapy).
Exclusion criteria These groups will be compared using a non-­inferiority design
• Any diagnosis of malignancy <5 years ago (except non-­melanoma with an equivalence margin of 8.5%. The power will depend on
skin cancer) the actual difference between the arms. For example, if the 5-­year
• Previous pelvic radiotherapy
cumulative incidence of vaginal recurrence would be 4% in the
• WHO performance status 3–4
experimental arm and 1.5% in the standard arm, the power will be
• Expected interval between surgery and start of adjuvant treatment
exceeding 8 weeks
89.7%: for 5% vs 1.5% this would be 75%. The main aim of this
analysis is to estimate the difference in vaginal recurrence in the
*International Federation of Gynecology and Obstetrics stage favorable subgroups with sufficient precision (SE of the difference
below 2.4%).
The pilot phase (first 50 patients) of the PORTEC-­4a trial has
Primary and secondary endpoints
been completed and showed that the trial design is acceptable for
The primary endpoint is vaginal recurrence. Secondary endpoints
patients and feasible in terms of the logistics for determining the
are 5-­year recurrence-­free and overall survival; vaginal control
molecular profile within 2 weeks.13 Currently, 366 patients have
(including treatment for relapse); pelvic and distant recurrence;
been included. Monitoring of safety is done by the Data and Safety
adverse events; patient-­ reported symptoms and health-­ related
Monitoring Board. Annual safety reviews of serious adverse events,
quality of life; and endometrial cancer-­related healthcare costs.
deaths, and recurrences are presented confidentially to the Data
Translational research is an integral part of this molecular-­
and Safety Monitoring Board, which is free in its recommendations
integrated risk profile-­based trial. Therefore, a tumor tissue block
to the study coordinators and confidential recommendations to the
of all patients is collected and stored in the dedicated tissue bank
study statistician.
at Leiden University Medical Center for further analysis.

Randomization Statistical methods

The study is an open-­label phase III trial with (2:1) randomized allo- All analyses concerning treatment effects will be performed
cation to either molecular-­integrated risk profile-­directed adjuvant according to the intention-­to-­treat principle. Time-­to-e­ vent
treatment (experimental arm) or adjuvant vaginal brachytherapy analyzes will be performed with date of randomization as a starting
(standard arm). Central randomization is done by a web-­based point. Formal tests for the differences in relapse and survival rates
randomization application with stratification for participating center, between the two arms will be done with the Kaplan–Meier method,
tumor grade (1 vs 2 vs 3), and type of surgery (lymphadenectomy the log-­rank test, and Cox regression analysis. The competing risk
yes or no) using a biased coin minimization procedure. The trial method will be used, with competing risks of death, pelvic recur-
number and result of randomization are immediately obtained via rence, and distant recurrence for analysis of vaginal recurrence,
the randomization system and confirmed by email. and competing risk of death for analyses of pelvic and distant
recurrence. Analysis of toxicity will be based on treatment received.
Sample size P-­values<0.05 will be considered statistically significant.
It is hypothesized that the experimental treatment strategy leads to For the cost-­utility analysis, endometrial cancer-­related health-
less overtreatment, which would yield less morbidity and a better care costs will be considered. This includes in both arms of the
quality of life. As treatment will be deescalated in a substantial part trial the costs of: primary treatment, care associated with adverse
of the patients in the experimental arm, a non-­inferiority design events, and first treatment for relapse and/or metastasis. Health-
was chosen to estimate vaginal recurrence in both groups with care use across the follow-­up period will be converted to costs
sufficient precision and to exclude a clinically relevant difference using standard prices, discounted over time. The difference in
with an equivalence margin of 7%. Other first recurrences (pelvic quality-­adjusted life years and costs between the two arms will be
and distant) and death are considered competing risks. Based on compared according to the intention-­to-­treat principle, using t-­tests
data from the PORTEC-2 trial and the molecular analysis from the with, if appropriate, multiple imputation of missing data.

van den Heerik ASVM, et al. Int J Gynecol Cancer 2020;30:2002–2007. doi:10.1136/ijgc-2020-001929 2005
Clinical trial

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Health-­
related quality of life analysis will be performed for Author affiliations
1
patients with a valid baseline measurement and at least one Radiation Oncology, Leiden University Medical Center, Leiden, Zuid-­Holland, The
Netherlands
follow-­up measurement. To evaluate the differences between the 2
Radiation Oncology, Erasmus Medical Center - Cancer Institute, Rotterdam, Zuid-­
treatment groups with respect to the effect of treatment burden on Holland, The Netherlands
life quality during and up to 5 years after treatment, the repeated 3
Radiation Oncology, Maastricht University Medical Centre+, Maastricht, Limburg,
measures of the scales of the quality of life questionnaires will be The Netherlands
4
analyzed using mixed ANOVA models. Single items will be analyzed Radation Oncology, Radiotherapy Group, Arnhem, Gelderland, The Netherlands
5
Radiation Oncology, Amsterdam University Medical Centers, University of
using logistic regression at different timepoints.
Amsterdam, Amsterdam, Noord-­Holland, The Netherlands
6
Radiation Oncology, Catharina Hospital, Eindhoven, Noord-­Brabant, The
Netherlands
7
Radiation Oncology, Radiotherapy Institute Friesland, Leeuwarden, Friesland, The
DISCUSSION Netherlands
8
Several randomized trials, such as the GOG-99, ASTEC, and Radiation Oncology, Institute Verbeeten, Tilburg, Noord-­Brabant, The Netherlands
9
Women's Health, Universitätsklinikum Tübingen, Tübingen, Baden-­Württemberg,
PORTEC-1 and −2 trials, have established recommendations
Germany
for the adjuvant treatment of endometrial cancer based on clin- 10
Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Noord-­Holland,
icopathological risk factors.2–5 Current international guidelines The Netherlands
recommend adjuvant vaginal brachytherapy for women with early 11
Radiation Oncology, University Medical Centre Groningen, University of Groningen,
stage high-­intermediate risk endometrial cancer, while those with Groningen, Groningen, The Netherlands
12
low- and low-­intermediate risk disease are recommended to be Gynecologic Oncology Centre, Department of Obstetrics and Gynaecology, First
Faculty of Medicine, Charles University and General University Hospital, Prague,
observed after surgery.1–5 The molecular classification of endome- Czech Republic
trial cancer, as first defined by TCGA and subsequently validated 13
Radiation Oncology, Haaglanden Medical Center, Den Haag, Zuid-­Holland, The
by the use of surrogate markers which makes the molecular tests Netherlands
14
available in daily clinical practice, has profoundly altered the risk Radiation Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands
15
classification. The PORTEC-­4a trial is the first randomized trial Radiation Oncology, Radboudumc, Nijmegen, Gelderland, The Netherlands
16
Women's Health, Rotkreuzklinikum Munchen, Munchen, Bayern, Germany
to implement the use of molecular factors to determine adjuvant 17
Radiation Oncology, Isala Klinieken, Zwolle, Overijssel, The Netherlands
treatment. The molecular-­integrated risk profile includes both the 18
Radiation Oncology, Zuidwest Radiotherapeutic Institute, Vlissingen, Zeeland, The
molecular groups and other essential risk factors such as substan- Netherlands
tial lymph-­vascular space invasion and L1-­CAM overexpression.7 12 19
Radiation Oncology, University Hospital Ghent, Gent, Oost-­Vlaanderen, Belgium
20
The PORTEC-­4a trial will provide essential information on whether 21
Radiation Oncology, St. Luke's Hospital Dublin, Dublin, Ireland
vaginal brachytherapy can be safely omitted in patients with a Radiation Oncology, Institut Gustave-­Roussy, Villejuif, Île-­de-­France, France
22
Comprehensive Cancer Centre Utrecht, Utrecht, The Netherlands
favorable molecular-­integrated risk profile, and whether patients 23
Medical Statistics, Leiden University Medical Center, Leiden, Zuid-­Holland, The
with an unfavorable risk profile would benefit from more intensive Netherlands
adjuvant treatment. If local control rates in the molecular-­integrated 24
Biomedical Data Sciences, Leiden University Medical Center, Leiden, Zuid-­
risk profile-­directed adjuvant treatment arm are not significantly Holland, The Netherlands
25
worse than in the standard arm, then patients will have the benefit Obstetrics & Gynecology, University Medical Centre Groningen, University of
Groningen, Groningen, Groningen, The Netherlands
of less overtreatment, with an expected substantial reduction in 26
Pathology, Leiden University Medical Center, Leiden, Zuid-­Holland, The
morbidity and a better quality of life. Netherlands
The acceptance and implementation of the molecular-­integrated
risk profile in standard care will be facilitated if the cost-­utility Correction notice Since the online publication of this article, the authors have
analysis shows that molecular-­integrated risk profile-­tailored adju- noticed that the author name ‘G Henrieke Westerveld’ is incorrect. This has now
vant treatment leads to similar or even reduced healthcare costs. been corrected to 'G Henrike Westerveld'.
Even though the costs in the experimental group will be higher Twitter Nanda Horeweg @NandaHoreweg
due to determination of the molecular-­integrated risk profile by Contributors ASVMvdH drafted the original manuscript, all authors contributed in
next-­generation sequencing, about 50%–55% of the patients with reviewing, editing, and approving the final manuscript.
a favorable profile will receive no adjuvant treatment which will Funding This study was funded by KWF Kankerbestrijding (UL2011-5336 and
substantially reduce costs. However, the costs of any additional 12376).
recurrence in the experimental arm may partially counterbalance Competing interests ASVMvdH and NH report a research grant from the Dutch
this effect. In addition, it is expected that a substantial reduction in Cancer Society, during the conduct of the PORTEC-­4a study. HWN reports non-­
financial support from Merck, grants from the Dutch Cancer Society, grants from
the cost of the molecular profile will be realized as cheaper targeted AIMM, outside the submitted work. RAN reports grants from the Dutch Cancer
POLE sequencing methods are being developed. Society, grants from the Dutch Research Council, grants from Elekta, grants from
During the trial both national and international pathology labo- Varian, grants from Accuray, outside the submitted work. CC reports non-­financial
ratories are being validated for determination of the molecular-­ support from Roche, non-­financial support from TherAguix, personal fees from
Elekta, personal fees from MSD, personal fees from GSK, outside the submitted
integrated risk profile, leading to early and rapid dissemination and work. CLC reports grants from the Dutch Cancer Society, non-­financial support
optimization of the molecular techniques and logistical processes. from Elekta-­Nucletron, during the conduct of the PORTEC-­4a study. SK reports
If cost-­utility is confirmed, it is expected that molecular-­integrated personal fees from GSK, personal fees from Roche, personal fees from MSD,
risk profile-­directed adjuvant treatment will rapidly be accepted personal fees from AstraZeneca, outside the submitted work.
as the standard approach in clinical practice and used in future Patient consent for publication Not required.
studies. Provenance and peer review Not commissioned; internally peer reviewed.

2006 van den Heerik ASVM, et al. Int J Gynecol Cancer 2020;30:2002–2007. doi:10.1136/ijgc-2020-001929
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inferiority, randomised trial. Lancet 2010;375:816–23.
Open access This is an open access article distributed in accordance with the 6 Creutzberg CL, Nout RA, Lybeert MLM, et al. Fifteen-­year
Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits radiotherapy outcomes of the randomized PORTEC-1 trial
others to copy, redistribute, remix, transform and build upon this work for any for endometrial carcinoma. Int J Radiat Oncol Biol Phys
purpose, provided the original work is properly cited, a link to the licence is given, 2011;81:e631–8.
and indication of whether changes were made. See: https://​creativecommons.​org/​ 7 Bosse T, Peters EEM, Creutzberg CL, et al. Substantial lymph-­
licenses/​by/​4.0​ /. vascular space invasion (LVSI) is a significant risk factor for
recurrence in endometrial cancer – a pooled analysis of PORTEC 1
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Nanda Horeweg http://​orcid.​org/​0000-​0002-​8581-​4753
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