Key words
endometrial cancer - adjuvant therapy - chemotherapy - radiotherapy - recurrence
The data on the adjuvant therapy of endometrial cancer (EC) are inconsistent. In the
past year, the results of two important studies, GOG-258 and GOG-249, were presented
at the conferences of the American Society of Clinical Oncology (ASCO) and the American
Society for Radiation Oncology (ASTRO) [1], [2]. In addition, the results of the PORTEC-3 study were published in full [3]. With this statement, the Uterus Committee wishes therefore to interpret the new
data and discuss them against the background of the recently published S3 guideline
[4].
In the Postoperative Radiotherapy in Endometrial Cancer (PORTEC)-1 study published
in 2011, doctors in the Netherlands showed that locoregional control is significantly
improved by percutaneous pelvic radiation with 46 Gray (Gy) after hysterectomy and
bilateral adnexa extirpation in women with unknown lymph node status and an intermediate
or high-intermediate risk level (Fédération Internationale des Gynécologues et Obstétriciens
[FIGO] endometrioid EC stage IA (in the current version) with < 50% myometrial infiltration
depth, G2 or G3, or FIGO stage IB with > 50% myometrial infiltration depth, G1 or
G2 (vaginal recurrence: 11 vs. 2.5%). The rates of pelvic recurrence, distant recurrence
and overall survival were not improved by adjuvant radiation [5].
The PORTEC-2 study investigated whether vaginal brachytherapy alone with 3 × 7 Gy
or 30 Gy can achieve locoregional, especially vaginal, tumour control comparable to
that achieved with external-beam pelvic radiation with 46 Gy and 3-D radiation planning
in patients with so-called “high-intermediate” risk endometrioid EC (FIGO stage IA
in the current version [< 50% myometrial infiltration] > 60 years or G3 or FIGO stage
IB [> 50 myometrial infiltration], G1 or G2, or FIGO stage II with endocervical gland
involvement, G1 or G2 and < 50% myometrial infiltration. The vaginal, locoregional
and distant recurrence rates did not differ significantly in the two study arms. Likewise,
the overall and disease-free survival did not differ significantly, but the side effect
profile was better in the brachytherapy group [6].
In the recently published PORTEC-3 study, an international group in 103 centres investigated
the benefit of additional chemotherapy during and after percutaneous adjuvant radiotherapy
([Table 1]) [3]. The study included women with high-risk EC (endometrioid adenocarcinoma, FIGO IB
with G3, IA with G3 and lymphatic invasion; endometrioid adenocarcinoma, FIGO II or
III; serous or clear-cell EC FIGO I – III). The patients received either teletherapy
of 48.6 Gy only or were given cisplatin (50 mg/m2) twice in addition, in the first and fourth weeks of radiation, followed by 4 cycles
of carboplatin (AUC5) and paclitaxel (175 mg/m2). 660 patients were included in the final analysis. The average follow-up period
was 60.2 months. Just under 60% of the patients had lymphadenectomy, about 45% were
FIGO stage III, 27% had endometrioid EC graded G3, and 25% had serous or clear-cell
EC. Failure-free survival (FFS), defined as recurrence or death due to EC or therapy,
and overall survival were selected as primary co-endpoints for the study.
Table 1 Recent studies on adjuvant radio-chemotherapy schemes in women with high-risk endometrial
cancer.
|
Name
|
Source
|
n
|
Inclusion criteria
|
Therapy
|
Freedom from recurrence
|
Overall survival
|
Comments
|
|
PORTEC-3
|
De Boer 2018 Lancet Oncol
|
686
|
Endometrioid adenocarcinoma: FIGO stage IB and G3 or L1, FIGO stage II – III
serous or FIGO stage I – III clear-cell adenocarcinoma
|
48.6 Gy à 1.8 Gy
versus
48.6 Gy à 1. 8 Gy and 2 × cisplatin 50 mg/m2 followed by 4 × carboplatin AUC-5 + paclitaxel 175 mg/m2
|
Failure-free survival after 5 years: 68.6 vs. 75.5%; adjusted HR: 0.71 (95% CI: 0.53 – 0.95),
p = 0.022
|
After 5 years: 76.7 vs. 81.8%; adjusted HR: 0.76 (95% CI: 0.54 – 1.06), p = 0.109,
interim data
|
1. Overall survival was calculated using interim data, as required number of events
will only be achieved at the end of 2018.
2. It should be noted that the authors had to report an adjusted HR value.
|
|
GOG-249
|
Randall # LBA-1 ASTRO 2017
|
601
|
FIGO stage I – II, either high-intermediate endometrioid adenocarcinoma or serous
or clear-cell adenocarcinoma
|
Percutaneous pelvic radiation (44.0–54.0 Gy) versus
vaginal brachytherapy followed by 3 × carboplatin AUC-6 + paclitaxel 175 mg/m2
|
Cumulative incidence of recurrence and metastasis after 5 years: 18% in both groups
|
After 3 years: 91 vs. 88% (p = 0.57), interim data
|
Percutaneous radiotherapy selected as the standard even though data from PORTEC-2
show that vaginal brachytherapy is equi-effective and better tolerated.
|
|
GOG-258
|
Matei # 5505 ASCO 2017
|
813
|
Endometrioid adenocarcinoma FIGO stage III/IV, residual tumor < 2 cm or serous or
clear-cell adenocarcinoma FIGO stage I – II
|
6 × carboplatin + paclitaxel 175 mg/m2
versus
percutaneous pelvic radiation with 2 × cisplatin 50 mg/m2 followed by 4 × carboplatin AUC-6 + paclitaxel 175 mg/m2
|
Recurrence-free survival after 5 years: HR: 0.9 (95% CI: 0.74 – 1.1)
|
After 5 years: 73 versus 70%, interim data
|
Chemotherapy arm was viewed as the standard when designing the study.
|
The 5-year overall survival rate was 81.8% (95% confidence interval [CI] 77.5 – 86.2)
with chemoradiotherapy vs. 76.7% (95% CI 72.1 – 81.6) with radiotherapy alone (adjusted
hazard ratio [HR] 0.76; 95% CI 0.54 – 1.06; p = 0.11). The 5-year FFS was significantly
better in the chemoradiotherapy group than in the group that had radiotherapy alone
(75.5% [95% CI 70.3 – 79.9] vs. 68.6% [95% CI 63.1 – 73.4]; adjusted HR 0.71 [95%
CI 0.53 – 0.95]; p = 0.02). Without adjustment, the difference in FFS was not significant
(HR 0.76 [95% CI 0.57 – 1.02]; p = 0.067). The effects of chemoradiotherapy were seen
most clearly in patients with FIGO stage III (increase in the 5-year overall survival
from 69.8 to 78.7%; adjusted p value 0.074; improvement in the 5-year FFS 69.3 vs.
58.0%, unadjusted p value 0.031). No statistically significant difference was found
in the small subgroup of patients with serous carcinoma (5-year FFS of 58% after chemoradiotherapy
and 48% after radiotherapy (HR 0.63 [95% CI 0.36 – 1.12]; p = 0.11). Side effects
≥ grade 3 occurred in 60% of patients with chemoradiotherapy compared with only 12%
of patients who had radiotherapy alone (p < 0.0001). Persistent neuropathies (≥ grade
2) were observed after 3 years in 8% of women after chemoradiotherapy compared with
only 1% after radiotherapy (p < 0.0001).
Even if one of the two study endpoints (FFS) was reached after statistical adjustment,
the authors conclude from these results that chemoradiotherapy cannot be recommended
as the new standard for patients with high-risk EC in FIGO stage I and II. However,
this therapy can be discussed with patients in stage III, bearing in mind the considerable
toxicity [3]. Moreover, it must be mentioned that the number of events for calculating the overall
survival was lower than planned and only 69% of the required events were observed.
Sufficient statistical events to allow a final evaluation of the overall survival
data will probably be available only at the end of 2018.
The Uterus Committee of the AGO is of the opinion that adjuvant combined chemoradiotherapy
with sequential chemotherapy cannot be regarded currently as the new standard in high-risk
EC based on the available results of the PORTEC-3 study.
In certain risk situations (e.g., FIGO stage III and IV after surgery with no or minimal
residual tumour), chemotherapy forms the basis of adjuvant therapy [4]. The benefit of additional radiotherapy must be clarified. The benefit of adjuvant
chemotherapy combined with vaginal brachytherapy for tumours with a high recurrence
risk compared with percutaneous radiotherapy is unclear. Two studies by the Gynecologic
Oncology Group (GOG) addressed this topic, though they are not yet available as a
full publication ([Table 1]). In the GOG-258 study, 813 patients with EC stage III or IVa and postoperative
residual tumour < 2 cm or patients with serous histology in FIGO stage I and II were
treated with 6 × carboplatin (AUC5) plus paclitaxel (175 mg/m2) (standard arm) or with chemoradiotherapy according to the protocol of the PORTEC-3
study [1]. The recurrence-free survival and overall survival were similar in both groups (5-year
overall survival rate 70 vs. 73%). Vaginal recurrences (3 vs. 7%) and pelvic and para-aortic
recurrences (10 vs. 19%) were significantly more frequent after 5 years in the group
that had chemotherapy alone, but distant metastases were significantly more seldom
(27 vs. 21%). The final data regarding overall survival are still awaited.
Initial results of the GOG-249 study are currently available as an abstract ([Table 1]) [2]. This study included 601 patients with EC FIGO stages I and II with high-intermediate
risk and endometrioid EC or with serous or clear-cell EC. They received either percutaneous
pelvic radiation (44 Gy/25 fractions or 54 Gy/28 fractions) or vaginal brachytherapy
followed by 3 cycles of carboplatin (AUC6) and paclitaxel 175 mg/m2. The 3-year overall survival (91 vs. 88%) and the number of vaginal recurrences and
of distant metastases (18 vs. 18%) were similarly high in both groups after 5 years.
Pelvic and para-aortic recurrences were more frequent in the combined brachytherapy/chemotherapy
group (4 vs. 9%), as was toxicity (≥ grade 3 events in 62 vs. 11%).
For a final interpretation of the three cited studies, the full publications and final
survival data are required. With hindsight, it might perhaps have been useful in the
GOG-249 study to combine the brachytherapy with the usual 6 instead of 3 cycles of
carboplatin/paclitaxel to achieve the full efficacy of the chemotherapy. In the GOG-258
study, locoregional control might possibly have been improved in the chemotherapy
arm by additional brachytherapy. There is therefore a danger that the PORTEC-3, GOG-249
and GOG-258 studies will not allow conclusive recommendations on the use of adjuvant
radio- and chemotherapy in EC even after publication of the final survival data.
The current S3 guideline “Diagnosis, treatment and follow-up of patients with endometrial
cancer” [4] recommends the following procedure:
-
“Adjuvant chemotherapy can be given to patients with type II EC and to patients with
type I EC G3, pT1b and stage pT2 (all pN0) (Level of Evidence [LoE] 2).”
-
“Patients with EC stage pT3 and/or pN1 should receive adjuvant chemotherapy (LoE1).”
-
“Patients with EC stage pT4a who were macroscopically tumour-free after surgery or
have a maximum residual tumour under 2 cm should receive chemotherapy (LoE1).”
-
“Patients with stage pT1b, pNx, G3 or stage pT2 pNx, endometrioid EC (type I) should
receive vaginal brachytherapy. Alternatively, percutaneous radiotherapy can be given
(expert consensus, strong consensus 96%).”
-
“Patients who have had systematic lymphadenectomy in stage pT1b, pN0, G3 or stage
pT2, endometrioid EC (type I), should receive vaginal brachytherapy. Percutaneous
radiotherapy should not be given here (consensus 92%).”
-
“Patients with stage pT1, pNx (any grading) with ‘substantial lymphatic invasion’
(highest grade in a 3-level grading of lymphatic invasion) can receive percutaneous
pelvic radiation instead of vaginal brachytherapy (expert consensus 93%).”
-
“For patients with involved lymph nodes, involvement of the uterine serosa, adnexa,
vagina, bladder or rectum (that is, FIGO stages III–IVa) with endometrioid EC (type
I), postoperative external pelvic radiation can be given in addition to chemotherapy
to improve local control (expert consensus 93%).”
-
“The indication for postoperative vaginal brachytherapy or external pelvic radiation
in type II EC (serous or clear-cell histology) should be guided by the recommendations
for type I EC (endometrioid adenocarcinoma, G3) of the same stage (expert consensus
95%).”
These guideline recommendations are valid even after publication of the PORTEC-3 study.
A change in the recommendations above based on the results of the PORTEC-3 study published
to date is not required. In the opinion of the guideline group, a review will be useful
when the final survival data of PORTEC-3, GOG-258 and GOG-249 are published in full.
The first update of the S3 guideline “Diagnosis, treatment and follow-up of patients
with endometrial cancer” is planned for the end of 2019. Until then, the guideline
group will continue to check all recommendations for updates.
