4. The Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1)
trial was the first to randomly compare pelvic external-beam radiotherapy(EBRT)
to no additional treatment (NAT).
Between 1990 and 1997, 715 patients
Median follow-up was 13.3 years
5.
6.
7. Impact of low grade toxicity on HRQL are lacking in this
trials
Conformal techniques are not used
8.
9. Randomised trial undertaken in 19 Dutch radiation oncology centres
427 patients with stage I or IIA endometrial carcinoma with features of high-
intermediate risk were randomly assigned by a computer-generated system.
The primary endpoint was vaginal recurrence.
Secondary endpoints were
locoregional recurrence (pelvic or vaginal, or both)
distant metastases
overall and disease-free survival
treatment-related toxic effects and quality of life
10.
11. VBT is very effective in ensuring local control keeping to a minimum risk of vaginal
recurrence.
VBT achieves excellent vaginal control and rates of locoregional recurrence.
Overall survival, and disease-free survival that are similar to EBRT
Quality of life and gastrointestinal toxic effects are significantly better with VBT.
VBT should be the adjuvant treatment of choice for patients with uterine confined-
endometrial carcinoma of high intermediate risk
12. Number of patients is low that under powers the study
Change in grade I and grade II diseases in central pathological review.
44% to 79% in grade I
44% to 9% in grade II
13% In Retrospect were ineligible for trial
It did not consider LVSI in risk factors
It underscored the role of pathologists in the diagnosis of carcinoma endometrium
14. Phase III, international, open-label,multicentre, randomised trial at 103 centers
686 patients of high risk endometrial cancer enrolled
Nov 2006 to Dec 2013
Randomised to CHEMORADIOTHERPY vs RADIOTHERPAY alone (1:1)
Medain follow-up 60.2 months
15. Pelvic external beam radiotherapy has been the standard adjuvant treatment for women with
high-risk endometrial cancer for many decades, although there is a paucity of evidence on
improvement of survival.
Randomised trials( lissoni et al ,susumu et al) have compared adjuvant chemotherapy with
external beam radiotherapy.
Radiotherapy was shown to delay pelvic recurrence and chemotherapy was shown to delay
distant metastases, but no differences in survival were found.
16. Retrospective studies reported substantial rates of pelvic recurrence if high-risk
patients were treated without radiotherapy, supporting the combined use of
pelvic radiotherapy with adjuvant chemotherapy, as first explored in the RTOG
9708 phase 2 trial
Because the combination of radiotherapy and chemotherapy
(chemoradiotherapy) seemed more effective than either treatment alone, and
because data for toxicity and quality of life were lacking,
the randomised PORTEC-3 trial was initiated to evaluate the benefit of
chemoradiotherapy versus radiotherapy alone for women with high-risk
endometrial cancer
17. Inclusion criteria
Histologically confirmed endometrial carcinoma,
with one of the following postoperative FIGO 2009
stages and grade:
1. stage IA ,grade 3 with documented LVSI
2. stage IB grade 3
3. stage II
4. stage IIIA or IIIC; or IIIB if parametrial invasion
only
5. stage IA, IB, II, or III with serous or clear cell
histology
WHO-performance status 0-2
WBC ≥ 3.0 x 109/L. Platelets ≥ 100 x 109/L.
Bilirubin ≤ 1.5 x UNL ASAT/ALAT ≤ 2.5 x UNL
Written informed consent
AGE ≥18, without upper limit
Exclusion criteria
Uterine sarcoma (including carcinosarcoma)
Previous malignancy < 10 yrs
Previous pelvic radiotherapy, Hormonal therapy
or chemotherapy for this tumor
Bulky cervical involvement with radical
hysterectomy
Inflammatory bowel disease
Residual macroscopic tumor after surgery
Impaired cardiac function, prohibiting the infusion
of large amounts of fluid during cisplatin therapy
Peripheral Neuropathy > grade 2
Hearing impairment > grade 3, or born deaf
18.
19. Surgery comprised total abdominal or laparoscopic hysterectomy with bilateral salpingo-
oophorectomy.
Lymphadenectomy, whether systemic or sampling, was left to the discretion of
participating centres,
while lymph node debulking and para-aortic lymph-node sampling were recommended
in cases of macroscopic positive pelvic nodes or para-aortic nodes (or both).
20. Given in both treatment group
Total dose 48.6 Gy 1.8 Gy fractions , 5 days a week
Proximal vagina,Parametrial tissue
Internal, external, and common iliac node upto L5- S1(with a margin of ≥2 cm above the highest
involved lymph node).
In case of cervical involvement (glandular, stromal, or both), a brachytherapy boost was given to
the vaginal vault.
Brachytherapy dose was equivalent to 14 Gy in 2 Gy fractions (with recommended scheme of 10
Gy high-dose rate [HDR] in fractions of 5 Gy), specified at 5 mm from the vaginal vault surface.
start within 4–6 weeks of surgery, but no later than 8 weeks.
21. two cycles of intravenous cisplatin 50 mg/m2 in the first and fourth week of external
beam pelvic radiotherapy, followed by four cycles of intravenous carboplatin AUC5
and paclitaxel 175 mg/m2 at 21-day intervals
Adjuvant chemotherapy started within 3 weeks after completion of external beam
pelvic radiotherapy, and with a 28-day interval from the second concurrent cycle
22. cisplatin was postponed for 1 week. If recovery required more than 1 week
cisplatin was discontinued neuropathy of grade 2 or worse
Carboplatin was postponed or stopped in case of severe haematological toxicity.
Paclitaxel was postponed for grade 2 neuropathy and stopped if recovery
exceeded 1 week or grade 3 neuropathy developed
23. PRIMARY ENDPOINTS
OVERALL SURVIVAL (time from date of
randomisation to date of death from any
cause).
FAILURE-FREE SURVIVAL.(any
relapse or death related to endometrial
cancer or treatment, time from
randomisation to date of first failure-free
survival event. )
SECONDARY ENDPOINTS
vaginal, pelvic, or distant recurrence
treatment-related toxicity
health-related quality of life
Abdominal recurrences outside the
pelvic area (peritoneal carcinomatosis,
liver, and para-aortic lymph nodal
metastases) were considered distant
metastases
24. Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
baseline (after surgery),
at completion of radiotherapy,
each chemotherapy cycle,
at 6-month intervals from randomisation until 5 years,
At 3 years ,7 years and 10 years
25. Chemoradiotherapy, n=330
Median follow up
Median age
Lymphadenectomy,lymp
hnode sampling or full
surgical staging
EBRT completion
Vaginal brachy
Radiotherapy, n=330
60.0 months
62 years
190 patients (58%)
329 patients (100%)
151 (46%)
60.7 months
62 years
192 patients (58%)
325 patients (99%)
158 (48%)
26. Both cycles of concurrent cisplatin were completed by 304 (92%) of 330 patients in
the chemoradiotherapy group.
Adjuvant chemotherapy was started by 304 (92%) patients, while 262 (79%)
patients completed all four cycles of carboplatin and 233 (71%) patients completed
all four cycles of paclitaxel.
At least one dose reduction of cisplatin (to 40 mg/m2) was recorded for five (2%)
patients, of carboplatin (from AUC5 to AUC4) for 36 (11%) patients, and of paclitaxel
(from 175 mg/m2 to 135 mg/m2) for 50 (15%) patients.
Chemotherapy was discontinued in 61 (18%) patients; in 31 (9%) because of
toxicity, patient decision in 20 (6%), disease progression in seven (2%), other
reason (3%)
29. SUBGROUP ANALYSIS,
women with stage III endometrial cancer had significantly lower overall survival
and failure-free survival than those with stage I–II disease
patients with stage III endometrial cancer who have the highest frequency of
recurrence, also had the greatest absolute benefit from the combined treatment.
The smaller failure-free survival improvement for patients with stage I–II disease
seems not to outweigh the cost in terms of toxicity and quality-of-life impairment.
Pelvic control was high (91%) with radiotherapy alone.
32. In multivariable analysis for failure-free survival, only age group was found to be
predictive of treatment effect, with a strong treatment-by-age effect (p=0・012)
Women aged 70 years or older had the greatest benefit from chemoradiotherapy
than younger women.
Age is a well-known risk factor for endometrial cancer and a greater benefit of
chemotherapy in older women has been reported previously.( susumu et al,
colombo et al)
(although selection of fitter older women in this randomised trial might have
occurred )
35. treatment with chemoradiotherapy significantly
improved 5-year failure-free survival for patients with high-risk endometrial cancer
compared with radiotherapy alone but there was no significant difference in overall
survival.
women with stage III endometrial cancer, a significant improvement in failure free
survival was found
For each patient, the cost in terms of increased toxicity and longer treatment duration
should be weighed against the benefit in terms of improvement in failure-free
survival.
36. Final analysis was time based rather than event based
( median follow-up: 5 years ).
Studies regarding molecular characteristics and targeted agents
needed to individualise treatment of women with high risk endometrial
cancer.
37. Randomised Phase III Trial Comparing Vaginal Brachytherapy (two doses
schedules: 21 or 15 Gy HDR in 3 fractions) and Observation after Surgery in
patients with Endometrial Carcinoma with High-Intermediate Risk Features
A Dutch Gynaecological Oncology Group trial
Result not yet published