This document summarizes the key findings of the PORTEC-3 trial, which compared concurrent chemoradiation (C-RT) to radiation alone (RT) in high-risk endometrial cancer patients. The trial found that C-RT improved 5-year overall survival by 5.1% and 5-year failure-free survival by 6.9% compared to RT. Patients with stage III disease saw the greatest benefits from C-RT, with an over 11% improvement in failure-free survival. However, C-RT also resulted in significantly more adverse events, especially neuropathy, during and after treatment.

1. Journal Club
Dr. Varshu Goel
Second Year Post-Graduate Resident
Department of Radiation Oncology
Maulana Azad Medical College, Delhi
Lancet Oncol 2018

2. FIGO StagingFor UterineCarcinoma
2
AJCC Cancer Staging Manual, 8th ed.
FIGO
stage
Definition
I Tumor confined to corpus uteri, including endocervical glandular
involvement
IA Tumor limited to endometrium or invades less than one-half of the
myometrium
IB Tumor invades one-half or more of the myometrium
II Tumor invades stromal connective tissue of the cervix but does
not extend beyond uterus (does not include endocervical
glandular involvement)
IIIA Tumor involves serosa and/or adnexa (direct extension or
metastasis)
IIIB Vaginal involvement (direct extension or metastasis) or
parametrial involvement

3. FIGO StagingFor UterineCarcinoma
3
AJCC Cancer Staging Manual, 8th ed.
FIGO
stage
Definition
IIIC1 Regional lymph node metastasis to pelvic lymph nodes
IIIC2 Regional lymph node metastasis to para-aortic lymph nodes, with
or without positive pelvic lymph nodes
IVA Tumor invades bladder mucosa and/or bowel mucosa (bullous
edema is not sufficient to classify a tumor as IVA)
IVB Distant metastasis (includes metastasis to inguinal lymph nodes
intraperitoneal disease, or lung, liver, or bone. It excludes
metastasis to para-aortic lymph nodes, vagina, pelvic serosa, or
adnexa)

4. Histopathology: Degreeof Differentiation
4
AJCC Cancer Staging Manual, 8th ed.
Grade Definition
G1 5% or less of a nonsquamous or nonmorular solid growth pattern
G2 6-50% of a nonsquamous or nonmorular solid growth pattern
G3 More than 50% of a nonsquamous or nonmorular solid growth
pattern. Papillary serous, clear cell, and carcinomasarcomas are
considered high grade.
• Notable nuclear atypia exceeding that which is routinely expected for the
architectural grade increases the tumor grade by 1 (i.e., 1 to 2 and 2 to 3).
• Serous, clear cell, and mixed mesodermal tumors are high risk and considered
grade 3.
• Adenocarcinomas with benign squamous elements (squamous metaplasia) are
graded according to the nuclear grade of the glandular component.

5. FIGO StagingFor UterineSarcoma
5
AJCC Cancer Staging Manual, 8th ed.
FIGO
stage
Leiomyosarcoma and
Endometrial Stromal Sarcoma
Adenosarcoma
I Tumor limited to the uterus Tumor limited to the uterus
IA Tumor 5 cm or less in greatest
dimension
Tumor limited to the
endometrium/ endocervix
IB Tumor more than 5 cm Tumor invades to less than half of
the myometrium
IC Tumor invades more than half of
the myometrium
II Tumor extends beyond the
uterus, within the pelvis
Tumor extends beyond the
uterus, within the pelvis
IIA Tumor involves adnexa Tumor involves adnexa
IIB Tumor involves other pelvic
tissues
Tumor involves other pelvic
tissues

6. FIGO StagingFor UterineSarcoma
6
AJCC Cancer Staging Manual, 8th ed.
FIGO
stage
Leiomyosarcoma and
Endometrial Stromal Sarcoma
Adenosarcoma
III Tumor infiltrates abdominal
tissues
Tumor infiltrates abdominal
tissues
IIIA One site One site
IIIB More than one site More than one site
IIIC Regional lymph node metastasis Regional lymph node metastasis
IVA Tumor invades bladder or
rectum
Tumor invades bladder or rectum
IVB Distant metastasis (excluding
adnexa, pelvic and abdominal
tissues)
Distant metastasis (excluding
adnexa, pelvic and abdominal
tissues)

7. 7
Perez & Brady’s Principles and Practice of Radiation Oncology, 7e
LN metastases

8. • Review Of Literature
• Observation vs pelvic RT (Norwegian trial,PORTEC1, GOG 99,
MRC/NCIC)
• Observation versus IVRT (Sorbe)
• Pelvic RT vs IVRT (PORTEC-2, Swedish trial by Sorbe et al)
• Pelvic RT vs CT (GOG 122, JGOG, and the Italian study)
• C-RT vs RT (Finland, NSGO/MaNGO, GOG249, PORTEC-3)
• C-RT vs CT (GOG 258)
• Ongoing Trials
• Article Proper
• Conclusion
Contents
8

9. 9
PelvicRT vs Observation

10. 10
PORTEC-1

11. • Multicenter RCT involving 19 institutions of Netherlands
• 715 patients of FIGO stage I EC recruited from 1990 to 1997
• 354 patients were randomly assigned to EBRT & 361 to NAT
• 5 yr and 15 yr results published in 2000(Lancet) and 2011(IJROBP)
• Median FU= 13.3 years
• EBRT-46Gy/23#/4.5 weeks delivered by AP-PA parallel opposed fields
(30%), 3-field (18%) or 4-field techniques (52%)
11
PORTEC-1

12. 12
PORTEC-1: LocoregionalRelapse

13. • No difference in overall survival with EBRT
• Reduction in locoregional recurrence in HIR group receiving EBRT
• No significant difference in LRR in LIR group receiving adjuvant
radiation
• In view of the long-term negative impact of EBRT, the absence of
survival benefit, and the presence of effective salvage treatment, the
rationale for the abandonment of EBRT for intermediate-risk EC has
been confirmed.
13
PORTEC-1: Results

14. 14
GOG 99
Key et al. Gynecol Oncol 2004; 92: 744-751.

15. • 392 patients with stage IB, IC, IIA, all grades (surgical LN-ve)
• TAH+BSO and selective lymph node dissection
• Adjuvant EBRT vs observation
• Risk Factors : increasing age, moderate to poorly diff tumor grade, presence
of LVSI, and outer-third myometrial invasion.
• 2yr recurrence  3% vs 12% in favour of EBRT (p< 0.01)
Outcome EBRT (%) Observation (%)
Vag recurrence 1 6.4
Distant failure 5.3 6.4
2yr recurrence (HIR) 6 26
4yr OS 92 86
15
GOG 99
Key et al. Gynecol Oncol 2004; 92: 744-751.

16. • 905 patients with intermediate or high risk early disease
• Randomly assigned after surgery to observation (453) or to
external beam radiotherapy (452); vaginal brachytherapy was
used in 52% in both groups
16
MRC ASTEC/NCICCTG EN.5 Trial
Blake et al. Lancet 2009; 373: 137–46.

17. • Median follow-up 58 months
• 5-year overall survival  84% in both groups
• LRR 7% vs. 4% in favour of EBRT (p=0.038)
• Conclusion : Adjuvant EBRT cannot be recommended as part
of routine treatment to improve survival for women with EEC
at intermediate or high risk of recurrence, and brachytherapy
might be preferred for local control
17
MRC ASTEC/NCICCTG EN.5 Trial
Blake et al. Lancet 2009; 373: 137–46.

18. 18
PelvicRT vs VBT

19. 19

20. AdjuvantRT
Creutzberg et al. Curr Oncol Rep 2011;13:472-478.
20

21. 21
AdjuvantRT vs CT

22. 22
396 pts of St III/IV EC with post-op residuum <2cm
194 : chemo
Inj CDDP-50mg/m2 and Inj
Doxorubicin-60mg/m2 q 3 wks X 7
cycles f/b 1 cycle Cisplatin
202 : WAI
30Gy/20#/4wks to WA
15Gy/8#/1.5wks boost to pelvis ±
paraaortic area
HR for disease progression 0.71 favoring AP arm (p<0.01)
HR for death0.68 favoring AP arm (p<0.01)
Chemotherapy with AP significantly improved progression-free and overall
survival compared with WAI.
GOG 122

23. RTOG9708
23

24. 24

25. • Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and
MaNGO ILIADE-III) were undertaken to clarify if sequential
combination of chemotherapy and radiotherapy improves PFS in
high-risk endometrial cancer.
• 534 patients, high risk post op EC stage I-III with no residual tumor
• NSGO/EORTC study = the combined modality treatment was
associated with 36% reduction in the risk for relapse or death
• GOG/MaNGO study pointed in the same direction (HR 0.61), but was
not significant
• Neither study showed significant differences in the overall survival
• Conclusion : Addition of adjuvant chemotherapy to radiation
improves progression-free survival
25
EORTC55991/ManGOIliade Trial

26. 26
Hogberget al.

27. 27
AdjuvantChemovs RT

28. • Arms: Adjuvant VBT + chemotherapy vs adjuvant pelvic RT
• At a median follow-up of 53 months, 82% of patients were alive and
recurrence-free at 3 years.
• Adjuvant pelvic radiation should remain the standard of care for high-
risk, early-stage endometrial cancer patients
GOG 249
28
VBT + chemotherapy Pelvic RT
3-yr OS 88% 91%
Pelvic and para-aortic
nodal recurrence at 5 yrs
9.2% 4.4%
http://www.ascopost.com/News/58092

29. N= 680, stages III-IVA (<2 cm residual disease) or FIGO 2009 stage I/II
serous or clear cell UC and positive cytology
333 : C-RT
cisplatin and tumor volume
directed irradiation followed by 4
cycles of carboplatin and
paclitaxel
347 : CT
6 cycles of carboplatin and paclitaxel
for optimally debulked, advanced
endometrial carcinoma
Conclusion :
• no increase in recurrence-free survival, RFS
• low incidence of vaginal, pelvic and paraaortic recurrences, but distant
recurrences were more common with C-RT vs. CT
29
NCT00942357
GOG 258

30. • 15% patients have high-risk features for distant metastases and cancer
related deaths:
• EEC stage I, grade 3 with deep invasion or with lymph-vascular space
invasion (LVSI)
• stage II or III EEC
• non-endometrioid (serous or clear cell) histology = aggressive and
worse prognosis
WhyThis Article
30

31. • 103 centres
• November 23, 2006 to December 20, 2013
• Participating groups were:
• Dutch Gynaecology Oncology Group (DGOG, Netherlands)
• National Cancer Research Institute (NCRI; UK)
• Australia and New Zealand Gynaecologic Oncology Group (ANZGOG;
Australia and New Zealand)
• Mario Negri Gynaecologic Oncology Group (MaNGO; Italy)
• Canadian Cancer Trials Group (CCTG; Canada)
• Fedegyn (France).
Methods
31
https://www.clinicalresearch.nl/portec3

32. • Aged 18 years and above (No upper age limit)
• Histologically confirmed endometrial carcinoma, with one of the
following postoperative FIGO 2009 stages and grade:
• stage IA with myometrial invasion, grade 3 with documented LVSI
• stage IB grade 3
• stage II
• stage IIIA or IIIC; or IIIB if parametrial invasion only
• stage IA (with myometrial invasion), IB, II, or III with serous or clear
cell histology
Inclusion Criteria
32

33. • Uterine sarcoma (including carcinosarcoma)
• Previous malignancy (except for non-melanomatous skin cancer) < 10 yrs
• Previous pelvic radiotherapy, hormonal therapy or chemotherapy for this
tumor
• Macroscopic stage II for which Wertheim type hysterectomy (eligible if stage
II grade 3 or stage III at pathology)
• Prior diagnosis of Crohn’s disease or ulcerative colitis
Exclusion Criteria
33

34. • Residual macroscopic tumor after surgery
• Creatinine clearance ≤ 60 ml/min (Cockroft) or ≤ 50 ml/min (EDTA clearance,
or measured creatinine clearance)
• 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
Exclusion Criteria
34

35. 660 patients underwent TAH/TLH + BSO
330 : pelvic RT (standard
arm)
(48.6 Gy in 1.8 Gy daily #,
5x per week), BT boost in
case of cervical
involvement with
EQD2 = 14 Gy
330 : Experimental Arm
same RT schedule
2 cycles of cisplatin 50 mg/m2 given
concurrently with RT at a 21-day interval
followed by 4 additional cycles of adjuvant
chemotherapy: carboplatin AUC 5 and
paclitaxel 175 mg/m2 (over 3
hours) at 21-day intervals
• Toxicity evaluated before treatment (baseline), at completion of RT, at
each chemo cycle and at each follow-up.
• Quality of life evaluated before treatment (baseline), at completion of
RT, and at 6, 12, 18, 24, 36 and 60 months from the date of
randomisation.
35
Protocol
Within 4-6 weeks of surgery
Total RT duration = 50 days

36. • Coprimary endpoints were overall survival and failure-free survival
• Overall survival was defined as time from date of randomisation to date
of death from any cause
• Failure-free survival (defined as any relapse or death related to
endometrial cancer or treatment) was defined as time from
randomisation to date of first failure-free survival event
• Secondary endpoints were vaginal, pelvic, or distant recurrence;
treatment-related toxicity; and health-related quality of life
Endpoints
36

37. 37

38. 38

39. 39

40. 40
RecurrenceOutcomes

41. 41

42. 42

43. • 136 deaths till May 1, 2017
• 4 of which were later counted as failure free event
• 186 patients had a failure free survival event (83 in C-RT and 103 in RT
group)
AdverseEvents
43
61 Deaths in C-RT arm 75 Deaths in RT arm
50 : Endometrial Ca 68 : Endometrial Ca
4 : Second malignancy 5 : Second malignancy
3 : Other intercurrent disease 1 : Disease progression or late
treatment complications
2 : Treatment of metastatic
disease
1 : intercurrent disease or late
treatment related toxicity
2 : intercurrent disease or late
treatment related toxicity

44. • 5-year overall survival was 81·8% with C-RT versus 76·7% with RT
• 5-year failure-free survival was 75·5% versus 68·6%
• 11% for stage III
• Women aged 70 years or older had the greatest benefit
• Most recurrences were distant metastases: 22% in C-RT vs 28% in RT
group
• Grade 3 or worse adverse events during treatment occurred in 198 (60%)
of 330 who received C-RT versus 41 (12%) of 330 patients who received
radiotherapy (p<0·0001).
• Neuropathy (grade 2 or worse) persisted significantly more often after C-
RT than after RT (20 [8%] vs one [1%] at 3 years; p<0·0001)
Results
44

45. • 5-year failure-free survival favored the C-RT group with a 7% difference
between the groups
• Patients with stage III disease obtained the greatest benefit with a more
than 11% absolute improvement in failure-free survival and 9%
improvement in 5-year overall survival
• Similar to the pooled results of the NSGO 9501/ EORTC 55991 and
MaNGO-ILIADE 3 trials showing improved failure-free survival but non-
significantly higher overall survival (p=0·07) for patients receiving RT
sequentially with adjuvant CT compared with RT alone
Strengths
45

46. Because of the death and failure-free survival event rates were lower than
expected at the time of trial design, the required number of overall
survival events was not reached and the final analysis was time-based
rather than event based, with final analysis at a median follow-up of 5
years (42 months after inclusion of last patient)
Limitations
46

47. • Improved 5-year failure-free survival, esp. For stage III
• No significant difference in overall survival
• Because pelvic control was high with radiotherapy alone, this
chemoradiotherapy schedule cannot be recommended as a new
standard for patients with stage I–II endometrial cancer but should be
individualized for stage III
Conclusion
47

48. 48
Summary

49. 49
Risk Adjuvant Treatment
Low Observation
Intermedi
ate
• Adjuvant brachytherapy is recommended to decrease vaginal
recurrence
• No adjuvant treatment is an option, especially for patients aged
<60 years
High,inter
mediate
Node Neg
• Adjuvant brachytherapy is recommended to decrease vaginal
recurrence
• No adjuvant treatment is an option
High
intermedi
ate,
No
surgical
nodal
staging
• Adjuvant EBRT recommended for LVSI unequivocally positive
to decrease pelvic recurrence
• Adjuvant brachytherapy alone is recommended for G 3 and
LVSI negative to decrease vaginal recurrence
• Systemic therapy is of uncertain benefit
Summary
ESMO ESTRO Guidelines 2016

50. 50
Risk Adjuvant Treatment
High,
Node Neg
• Adj EBRT with limited fields should be considered to decrease
locoregional recurrence
• Adj brachytherapy may be considered as an alternative to
decrease vaginal recurrence
• Adj systemic therapy is under investigation
High,
No
surgical
nodal
staging
• Adj EBRT is generally recommended for pelvic control and
relapse-free survival
• Sequential adjuvant chemotherapy may be considered to
improve PFS and cancer-specific survival (CSS)
• Adj C-RT
Summary
ESMO ESTRO Guidelines 2016

51. Ongoing Trials
51
NCT01244789

52. Ongoing Trials
52
NCT02566811

53. 53
PORTEC4
• Primary endpoint: vaginal recurrence
• Second primary endpoint: 5-year vaginal control including
treatment for relapse

54. 54
PORTEC4a

55. Thank You
55