1) The PORTEC-1 and PORTEC-2 trials compared pelvic radiotherapy to no additional treatment or vaginal brachytherapy for patients with endometrial carcinoma. PORTEC-1 found pelvic radiotherapy reduced vaginal recurrence while PORTEC-2 found vaginal brachytherapy achieved excellent vaginal control with fewer side effects compared to pelvic radiotherapy. 2) The PORTEC-3 trial randomized 686 patients with high risk endometrial cancer to chemoradiotherapy or radiotherapy alone. It found chemoradiotherapy improved failure-free survival compared to radiotherapy alone, especially for stage III patients, but with increased toxicity. 3)

1. Lancet oncology : February 12,2018
Dr . Muneer .A
Dept of Radiation oncology

2.  What is
 PORTEC 1?
 PORTEC 2?

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

7.  Impact of low grade toxicity on HRQL are lacking in this
trials
 Conformal techniques are not used

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

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

13. Lancet oncology : February 12,2018

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

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%)

27. CHEMORADIOTHERAPY
81・8%
RADIOTHERAPY
76・7%
p= 0.109

28. CHEMORADIOTHERAPY
75.5 %
RADIOTHERAPY
68.6 %
p= 0.02

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.

30. OVER ALL SURVIVAL

31. FAILURE FREE
SURVIVAL

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 )

34. Chemoradiotherapy, n=330
 GRADE 2 OR Worse
 GRADE 3 or worse
 Grade 2 or worse
senosry neuropathy
 3year
 5 year
Radiotherapy, n=330
 308 (93%)
 198 (60%)
 20 (8%)
 12 (9%)
 144 (43%)
 41 (12%) p=.0001
 1(1%) p=.0001
 0 p=.0001

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