Key words
endometrial cancer - radiotherapy - chemotherapy
The first full publication of the international Post-Operative-Radiation-Therapy-in-Endometrial-Cancer (PORTEC)-3 trial one year ago attracted considerable attention. Adjuvant simultaneous
radiochemotherapy followed by adjuvant chemotherapy ([Table 1]) did not lead to a significant improvement in the overall survival of women with
high-risk endometrial cancer compared to radiotherapy alone [1]. However, the data were still immature [1]. Additional chemotherapy only achieved an improvement in failure-free survival after
5 years. The side effects of the additional chemotherapy were substantial [1].
Table 1 Recent, randomized, controlled studies on adjuvant therapy for endometrial cancer.
|
Patients
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Treatment
|
Toxicity
|
Recurrence
|
Overall survival
|
|
PORTEC: Postoperative Radiation Therapy in Endometrial Cancer; EC: endometrial cancer;
AUC: area under the curve; OS: overall survival; GOG: Gynecologic Oncology Group
|
|
PORTEC-3 [1], [5]
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Endometrioid EC:
stage IA, G3 + LVSI; stage IB, G3; stage II – IIIC; Serous or clear cell EC stage
I – III
n = 660
|
Percutaneous 48.5 Gy ± brachytherapy + 2 × cisplatin 50 mg/m2 followed by 4 × carboplatin AUC 5 + paclitaxel 175 mg/m2 versus radiotherapy alone (percutaneous ± brachytherapy)
|
Acute: 60 vs. 12% neuropathies (≥ grade 2)
After 5 years: 6 vs. 0%
|
Failure-free survival after 5 years: 76.5 vs. 69.1% (adjusted HR: 0.70; p = 0.016)
More significant effect in stage III and for serous EC
|
5-year OS: 81.4 vs. 76.1% (adjusted HR: 0.7; p = 0.034)
More significant effect in stage III and on serous EC
|
|
GOG-258 [6]
|
Stage III and IV a EC (all histological types), residual tumor < 2 cm or serous/clear
cell EC
Stage – II with positive cytology
n = 736
|
Percutaneous pelvic irradiation ± paraaortic field ± brachytherapy + 2 × cisplatin
50 mg/m2 followed by 4 × carboplatin AUC 6 + paclitaxel 175 mg/m2 vs. 6 × carboplatin AUC 6 + paclitaxel 175 mg/m2
|
Side effects ≥ grade 3 in 58% (chemo/radiotherapy) vs. 63% (chemotherapy alone)
|
Recurrence-free 5- year survival: 59 vs. 58% (HR: 0.90; 90% CI = 0.74 – 1.10)
Fewer vaginal and pelvic/paraaortic recurrences but more distant metastases in the
chemo/
radiotherapy group
|
Data too immature
|
|
GOG-249 [7]
|
FIGO I – II:
endometrioid EC with “high-intermediate risk” or serous or clear cell EC with negative cytology
n = 601
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Vaginal brachytherapy + 3 × carboplatin AUC 6 + paclitaxel 175 mg/m2 vs. percutaneous irradiation (45 – 51 Gy) ± vaginal brachytherapy
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Acute toxicity higher in the brachytherapy/chemotherapy arm Late toxicity the same
for both groups
|
Recurrence-free 5-year survival:
76 vs. 76%; vaginal and distant metastasis the same; pelvic and paraaortic lymph node
recurrence somewhat more common in the brachytherapy/chemotherapy group (9 vs. 4%)
|
5-year OS: 85% (brachytherapy + chemotherapy) vs. 87% (percutaneous radiotherapy)
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The German Society for Radio-Oncology (DEGRO) concluded that radiotherapy alone would
remain the treatment of choice in this setting. A combination of chemotherapy and
radiotherapy should only be considered for patients with high-risk stage III tumors
or serous cell carcinoma [2].
The Uterus Commission of the AGO interpreted the results of the PORTEC-3 trial slightly
more cautiously than DEGRO did and did not see any need to amend the current S3-guideline
“Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer” [3] as long as no mature survival data from the PORTEC-3 trial were available [4]. According to the current S3-guideline, the basis of adjuvant therapy to treat patients
with lymph node involvement, involvement of the uterine serosa, the adnexa, the vagina,
bladder or rectum (stage III – IV a disease) is chemotherapy. Postoperative pelvic
irradiation may be carried out in addition to improve local control [3], [4].
A post-hoc survival analysis of the PORTEC-3 trial has now been published, which shows
that after a median follow-up time of 72.6 months, additional chemotherapy led to
a significant improvement in overall survival [5].
The American GOG-258 trial, which considered chemotherapy alone to be the standard
for patients with stage III and IVa EC, reported in the first full publication of
its results that additional radiotherapy did not lead to any improvement in recurrence-free
survival [6].
The first full publication of the results of the GOG-249 trial, which compared adjuvant
radiotherapy ± brachytherapy with brachytherapy plus 3 cycles of carboplatin/paclitaxel
to treat high/intermediate risk EC stage I and II, is now available [7].
Based on all of these new data [5], [6], [7], it is now possible to issue more reliable recommendations than one year ago.
Current Status of the PORTEC-3 Trial
Current Status of the PORTEC-3 Trial
This trial investigated patients (n = 660) with high-risk EC ([Table 1]). Approximately 45% of patients had stage III disease, 26% had stage IIIC, i.e.,
had lymph node metastasis. 25% of patients had serous or clear cell (type 2) EC, 32%
had poorly differentiated (G3) endometrioid EC [5]. When looking at the total patient population, the most recent analysis (median
follow-up: 72.6 months) reported a 5-year overall survival rate of 81.4% (95% CI = 77.2 – 85.8)
for the group which received chemo- and radiotherapy vs. 76.1% (71.6 – 80.9) for the
group which received radiotherapy alone (HR: 0.7; 95% CI = 0.51 – 0.97; p = 0.034).
The 5-year failure-free survival rate was 76.5% (95% CI = 71.5 – 80.7) vs. 69.1% (63.8 – 73.8;
HR: 0.7; 95% CI = 0.52 – 0.94; p = 0.01). In most patients, distant metastasis was
the first manifestation of recurrence. Distant metastasis occurred in 21.4% of women
in the chemo/radiotherapy group and in 29.1% of women in the group which received
radiotherapy alone [5]. A subgroup analysis of patients with stage I and II EC found no significant differences
in overall survival and failure-free survival for patients who additionally received
chemotherapy. However, in the subgroup of patients with stage III EC or serous EC,
the addition of chemotherapy resulted in a significant improvement in the 5-year overall
survival rate: 78.5 vs. 68.5% (stage III; p = 0.043) and 71.4 vs. 52.8% (serous EC;
p = 0.037) as well as in the failure-free survival rate: 70.9 vs. 58.4% (stage III;
p = 0.011) and 59.7 vs. 47% (serous EC; p = 0.008) [5].
The most recent analysis found that after 5 years the side effects were similar in
both groups. Only sensory neuropathies were more common in the chemo/radiotherapy
arm [5]. The authors concluded that combined chemo/radiotherapy, consisting of pelvic irradiation
with 2 simultaneous administrations of cisplatin, followed by 4 cycles of carboplatin/paclitaxel
should be recommended to patients with serous and/or stage III EC [5]. This includes all patients with pelvic and/or paraaortic lymph node metastasis,
irrespective of the local spread of the primary tumor.
Current Status of the GOG-258 Trial
Current Status of the GOG-258 Trial
Based on the results of its earlier randomized trials, the American Gynecologic Oncology
Group considers systemic chemotherapy to be the most useful adjuvant therapy to treat
high-risk EC in patients with resected locally advanced EC [6]. In contrast to adjuvant radiotherapy, chemotherapy was able to improve survival
in earlier studies [6]. However, the administration of chemotherapy alone was associated with a high rate
of locoregional recurrence. The aim of the GOG-258 trial was therefore to determine
whether standard therapy (6 cycles of adjuvant chemotherapy with carboplatin/paclitaxel)
could be improved by combining it with external radiotherapy based on the extent of
tumor spread (adjuvant radiochemotherapy with cisplatin, followed by 4 cycles of adjuvant
chemotherapy with carboplatin/paclitaxel) [6].
A total of 736 patients with high-risk EC ([Table 1]), of whom > 97% had stage III disease, 50% had stage IIIC1, 25% had stage IIIC2
and 21% had serous or clear cell EC, received adjuvant treatment after surgery consisting
either of chemotherapy alone or a combination of chemo/radiotherapy in analogy to
treatment in the PORTEC-3 trial. If paraaortic lymph node involvement (IIIC2) was
also present, this region was also irradiated [6]. The median follow-up time was 47 months. The recurrence-free 5-year survival rate
was 59% (95% CI = 53 – 64%) in the chemo/radiotherapy group and 58% (53 – 64%) in
the group treated with chemotherapy alone (HR: 0.9; 90% CI = 0.74 – 1.10). In accordance
with the study hypothesis, additional radiotherapy resulted both in fewer vaginal
recurrences (2 vs. 7%; HR: 0.36; 95% CI = 0.16 – 0.82) and fewer pelvic and paraaortic
lymph node recurrences (11 vs. 20%; HR: 0.43; 95% CI = 0.28 – 0.66). However, distant
metastasis was more common in the group with chemo/radiotherapy compared to the group
which received only chemotherapy (27 vs. 21%; HR: 1.36; 95% CI = 1.00 – 1.86). Side
effects ≥ grade 3 were reported for 58% of patients in the chemo/radiotherapy group
and 63% of patients who had chemotherapy alone. The addition of radiotherapy to chemotherapy
did not improve recurrence-free survival. It remains to be seen in the remaining follow-up
time whether the reduction in the frequency of distant metastasis in the group with
chemotherapy alone will have an impact on overall survival [6].
Current Status of the GOG-249 Trial
Current Status of the GOG-249 Trial
This trial aimed to investigate whether for high/intermediate risk and high-risk patients
with stage I and II EC, adjuvant vaginal brachytherapy followed by shortened chemotherapy
(3 cycles) would be more effective than percutaneous radiotherapy ± brachytherapy
([Table 1]) [7]. High/intermediate risk was defined as age ≥ 70 years plus 1 uterine risk factor,
age ≥ 50 years plus 2 risk factors or age ≥ 18 years plus 3 risk factors. Uterine
risk factors were G2 and G3 tumors, pT1b and lymphatic vessel invasion [7]. Pelvic and paraaortic lymphadenectomy was recommended and carried out in 90% of
patients. Alternatively, CT or MRI was done postoperatively to exclude enlarged lymph
nodes. 21% of patients had endometrioid EC, G3; 20% had serous or clear cell EC [7]. 75% of patients had stage I, 25% had stage II disease. Patients with serous or
clear cell stage I or II EC and positive peritoneal cytology were not admitted to
the GOG-249 trial, and it was recommended that they should participate in the GOG-258
trial instead [7].
After a median follow-up time of 53 months, the recurrence-free 5-year survival rate
of the group which received percutaneous radiotherapy was 76% (95% CI = 0.70 – 0.81)
and that of the brachytherapy/chemotherapy group was 76% (0.70 – 0.81). The hazard
ratio was 0.92 (90% CI = 0.69 – 1.23). The 5-year overall survival rate was 87% (95%
CI = 83 – 91%) for patients treated with percutaneous radiotherapy and 85% (95% CI:
81 – 90%) for the brachytherapy/chemotherapy group (HR: 1.04; 90% CI = 0.71 – 1.52).
Rates of vaginal recurrence and distant metastasis were similar for both groups; pelvic
and paraaortic recurrence was more common in the brachytherapy/chemotherapy group
(9 vs. 4%) [7]. Acute toxicity was higher in the brachytherapy/chemotherapy group, while late toxicity
was similar for both groups.
Interpretation
Interpreting the study results is easier if we take a brief critical look at the sometimes
comparable and sometimes different concepts underpinning the three studies. To start
with, we would like to congratulate both study groups for treating almost 2000 patients
under controlled conditions in these three studies and generating valuable knowledge.
The GOG-249 trial treated patients with carcinomas limited to the uterus (FIGO I or
II and normal cytology), while the GOG-258 trial only included patients with extrauterine
involvement (including positive lavage cytology of type-2 tumors). Supported by corresponding
studies, the detailed description of which would go beyond the scope of this opinion,
both American trials attempted to answer logical questions. The GOG-249 trial addressed
the question whether “a little” chemotherapy combined with vaginal brachytherapy is
better than external pelvic radiotherapy combined with optional vaginal brachytherapy.
The GOG-258 trial investigated whether the addition of radiotherapy to chemotherapy
offers benefits to patients with advanced disease. In contrast, the PORTEC-3 trial
aimed to investigate whether the addition of chemotherapy to radiotherapy is associated
with improved overall survival. In the absence of resilient data on improvements to
overall survival rates, this turning around of the question is particularly important
for radiotherapy. Moreover, the inclusion criteria of the PORTEC-3 trial were far
broader as they permitted the inclusion of patients with stage IA G3 and LVSI EC to
stage IIIC disease.
The repeat evaluation of the PORTEC-3 trial using somewhat more mature data now shows
very clearly that the addition of chemotherapy to percutaneous radiotherapy results
in a significant and, above all, clinically relevant improvement in overall survival,
particularly of patients with stage III or serous EC, compared to radiotherapy alone
[5]. This logically expected outcome was not yet apparent in the first publication of
the PORTEC-3 trial [1], as the data were not yet mature.
The PORTEC-3 trial does not answer the question whether patients with high-risk EC
who receive sufficient adjuvant chemotherapy even need radiotherapy. The American
GOG-258 trial aimed to answer that question. In an unambiguously high-risk cohort
(97% of patients had stage III disease), adequate chemotherapy (6 × carboplatin/paclitaxel;
no vaginal brachytherapy) was defined as the standard and compared with simultaneous
radiochemotherapy (external beam radiotherapy of the pelvis ± paraaortic field ± vaginal
brachytherapy + 2× cisplatin), followed by 4 cycles of carboplatin/paclitaxel [6]. The additional radiotherapy improved locoregional control; however, distant metastasis
occurred more often than in the group receiving chemotherapy alone [6]. The potential reason for this could be the reduction of full chemotherapy cycles
from 6 to 4 or a delay in starting combination chemotherapy. Additional radiotherapy
certainly did not lead to an improvement in recurrence-free survival. To date, overall
survival is the same for both groups. It remains to be seen whether the reduction
of distant metastasis in the group given chemotherapy alone will result in improved
survival rates.
Consequently, as recommended in the S3-guideline [3], chemotherapy with carboplatin/paclitaxel remains the basis for adjuvant therapy
to treat stage III disease. The recommendation that chemotherapy be used when treating
serous tumors should be made clear.
The recommendation in the S3-guideline that percutaneous radiotherapy “may” be used
to treat stage III EC can be upheld, as radiotherapy improved locoregional control
in the GOG-258 trial but did not affect either overall or recurrence-free survival.
It is worth noting that the recurrence-free 5-year survival rate of the subgroup of
patients with stage III disease in the radiochemotherapy arm of the PORTEC-3 trial
was 71%, a significantly better rate than the 59% reported for patients in the radiochemotherapy
arm (> 97% consisted of patients with stage-III EC) of the GOG-258 trial or 58%, the
rate for its chemotherapy arm. But possible differences in the composition of the
patient populations also need to be taken into account: around 70% of patients in
the GOG-258 trial had stage IIIC1/2 disease compared to only 27% with stage IIIC disease
in the PORTEC-3 trial [5], [6].
If, therefore, a patient is treated with adjuvant chemotherapy in accordance the standard
arm of the GOG-258 trial, additional brachytherapy may be considered to reduce the
rate of vaginal recurrence. If a patient is treated according to the protocol of the
experimental arm of the GOG-258 trial, it is important to discuss with the patient
whether reducing pelvic and paraaortic recurrence by administering percutaneous radiotherapy
justifies the potential increase in distant metastasis, particularly as pelvic and/or
paraaortic recurrence can be treated by secondary irradiation with good outcomes if
no percutaneous irradiation was previously carried out [3], [8]. The ongoing ECLAT trial will show whether lymph node recurrence is as common after
adequate (therapeutic) pelvic and paraaortic lymphadenectomy followed by 6 × carboplatin/paclitaxel
and brachytherapy as the rates reported in the GOG-258 trial, where the median number
of resected lymph nodes was only 13 pelvic and 3 paraaortic lymph nodes [6].
The authors of the GOG-249 trial emphasize that the majority of the patients they
investigated would have been cured by surgery alone without any additional adjuvant
measures. That was why only 3 cycles of chemotherapy were administered [7]. The authors emphasized the importance of determining those patients in this “high/intermediate
risk” group who really need adjuvant therapy. The S3-guideline provides clear recommendations
about the differentiated administration of brachytherapy, percutaneous irradiation
and chemotherapy [3].
The ongoing PORTEC-4a trial will use modern molecular prognostic factors to differentiate
patients in the “high/intermediate risk group” (here: stage IA, G3 to II G1). Combined
with retrospective analysis, this should help to identify those women who probably
do not require any adjuvant therapy and those patients for whom brachytherapy is adequate
as well as the few cases who need percutaneous radiotherapy and/or chemotherapy [9].
The recent full publication of the results of 3 large phase-III trials on the use
of adjuvant chemotherapy and radiotherapy in endometrial cancer does not necessitate
any acute changes to the S3-guideline. The reported study results are entirely compatible
with the current recommendations made in the guideline. The new data place an even
greater emphasis on the benefit of adjuvant chemotherapy, especially when treating
serous EC and stage III EC, than the current guideline. A fundamental analysis of
the guideline and other publications will be carried out by the guideline group at
the beginning of 2020, and the group will also consider to what extent current recommendations
may need to be modified.
