1. ADJUVANT THERAPY IN EARLY ENDOMETRIAL CANCER
WHEN TO GO ?
K.S.Reddy
Pondicherry

2. CANCER INCIDENCE - ESTIMATES

3. Accts for 1.1% of all cancers as compared to 7% in USA
GLOBOCAN, IARC
YEAR
Age Group
INDIA
USA
CERVIX UTERI
CORPUS UTERI
2012*
AGE < 65
107287
9178
10545
29041
AGE > 65
15557
3147
2421
20604
2015*
115060
9985
10819
30341
17254
3492
2676
22859
Accts for 1.1% of all cancers as compared to 7% in USA

4. Introduction
EC usually diagnosed at early stage (up to 80% diagnosed as stage I, 13% as stage II)
5-year OS as high as 88% in stage I disease.
Subgroups of patients with early stages have significantly decreased 5-OS rates, based on various prognostic factors, such as
Myometrial invasion & grade 3 have a 5-OS of 66%.

5. Endometrial cancer is often divided into 2 subtypes:
Type I (75% of cases) etiologically related to
unopposed estrogens and occurs mostly in
Hyperplastic Endometrium - Estrogen related.
Younger, Perimenopausal and Heavier patients
Better prognosis
Type II (10% of cases) occurs mostly in
Atrophic Endometrium with 3 atypical
histological subtypes such as clear cell,
papillary serous cancer and poorly differentiated
Associated with high virulence,
advanced stage at diagnosis and poor prognosis.
Unrelated to estrogen stimulation
Occurs in older & thinner women

6. Surgery is the primary treatment of both localized and advanced disease, Adequate surgical staging and pathological review are the prerequisites for any discussion about individual need for an adjuvant therapy

7. Peritoneal Cytology is done, does not affect staging
Staging FIGO – FIGO 2010
I A: Tumor limited to endometrium
I B: Invasion to < 50% of myometrium
I C: Invasion to > 50% of myometrium
II A: Cervical glandular involvement only
II B: Cervical stromal invasion
III A: Tumor invades serosa and/or adnexa and/or positive peritoneal cytology
III B: Vaginal metastases
III C: Metastases to pelvic or para aortic nodes
IV A: Tumor invasion of bladder and/or bowel mucosa
IV B: Distant metastases, including abdominal metastases and/or inguinal lymph nodes
I: Tumor confined to the corpus uteri I A: No or < half myometrial invasion I B: Invasion ≥ half of myometrium II: Cervical stromal invasion but not beyond the uterus III: Local and/or regional spread III A: Tumor invades the serosa of the corpus uteri and/or adnexa III B: Vaginal and/or parametrial inv III C: Metastases to pelvic and /or PA LN C1: Pelvic node involvement C2: PA LN involvement ± pelvic lymph node involvement IV A: Tumor invades bladder and/or bowel mucosa, B: Distant metastases (abd mets/ inguinal LN mets)
Peritoneal Cytology is done, does not affect staging

8. Proposed definition of ‘risk’ RISK GROUPS (1)
Low risk:
Grade 1–2 histology, with invasion through less than 50% of the myometrium.
Grade 3 without myometrial invasion.
Disease confined to the uterine fundus.
No lympho-vascular space invasion (LVSI)
No evidence of metastases.

9. RISK GROUPS (2)
High-intermediate
Moderately-poorly differentiated tumor
Presence of LVSI
More than 50% myometrial invasion
Age >50 with any 2 risk factors above
Age >70 with any 1 risk factor
No evidence of metastases
All others considered as “Low intermediate risk.”

10. RISK GROUPS (3)
High risk:
Serosal involvement ( any Grade )
Positive Peritoneal Cytology
IC Gr. 3
Adnexal involvement
Pelvic or Para aortic nodal metastases (any Grade and MMI)

11. Radiotherapy in high-risk early endometrial cancer
Complex
Controversial
Confusing

12. PORTEC-1
PORTEC-1 study group ( ) aimed to Determine the impact of pelvic irradiation without additional brachytherapy on the outcome in patients with early stage endometrial cancer The surgical procedure was a simple total abdominal hysterectomy and bilateral salpingo oophorectomy (TAH-BSO) without any lymphadenectomy. 714 patients - IBG2, IBG3, ICG1, ICG2 (ICG3 specifically NOT included) Randomized to NAT vs 46 Gy pelvic RT No brachytherapy

13. Role of RT in non-formally staged EC?
PORTEC - 1
(Creutzberg CL et al, J Clin Oncol 2004, Scholten IJROBP 2005)
10 yr LR failure rate: S – 14%, S+RT – 5% (p < 0.001)
73% of LRF’s were isolated vaginal
Subgroup Analysis of risk factors
Risk factors – age ≥ 60, Gr 3, ≥ 50% myometrial inv.
If at least 2 of 3 risk factors present
10 yr. LRF rate: S- 23.1%, S+RT – 4.6%
Late toxicity - 5 yr. actuarial rates
All grades: S – 4%, S+RT – 26% (p < )
Grade 1: S - 4%, S+RT – 17%
Grade 3-4: S+RT – 3%

14. FIFTEEN-YEAR RADIOTHERAPY OUTCOMES OF THE RANDOMIZED PORTEC-1 TRIAL
CREUTZBERG et al.
IJROBP 81(4), 2011

15. Radiation therapy
Pelvic EBRT was administered with a target volume that included the parametrial tissues, the proximal two thirds of the vagina, and lymphatic drainage regions along the internal iliac vessels up to the promontory. The superior field border was at the L5–S1 disc.
The total dose was 46 Gy in 2-Gy daily fractions.
The PORTEC trial was done before three dimensional conformal treatment planning techniques had been introduced. Radiation was delivered by
AP-PA opposed fields(30%), three-field (18%) or
four-field techniques (52%)
Calculation of the dose distribution on the central axis and specification at isocenter or midplane

16. Role of RT in surgically staged EC GOG # 99 (2004)

17. GOG # 99 (2004)
Complete surgical staging including pelvic and para-aortic node sampling
Surgical stage IB, IC, IIA (occult) and IIB (occult)
All histologic types except serous papillary and clear cell
Randomized to pelvic RT vs. no further therapy

18. GOG 99 (2004) – at 4 years (Keys, et al Gynecol Oncol 2004) No RT arm (N = 202)WPRT arm (N = 190)
Vaginal Rec.
Pelvic Rec.
Distant Rec.
Over all survival
EBRT
No RT
2(1.1%)
13(6.4%)
1(0.5%)
5(2.5%)
10(5.3%)
92%
86%
Statistically significant
Statistically not significant

19. GOG #99: CONCLUSION
Adjunctive RT in early stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit a “high intermediate risk” definition.
“Use of adjunctive RT in women with intermediate risk EC decreases the risk of recurrences but has an inappreciable effect on overall survival”
Keys et al. Gynecol Oncol 2004; 92:

20. Patterns of failure in early endometrial cancer undergoing surgery only– implications for treatment
The majority of pelvic failures in both PORTEC and GOG 99 were isolated vaginal
Are non-radiated isolated vaginal failures curable?
Predictors of vaginal relapse
Gr 3 histology, LVSI+
(Mariani, Gyn Oncol 2005)
Can adjuvant vaginal brachytherapy address potential vaginal failures, and improve the therapeutic index?

21. Two important phase III randomized trials reported in 2007-2008

23. Trial design for ASTEC/EN.5
71% TAH BSO
29% TAH BSO PLN
Surgery
High risk pathology and no macroscopic disease
RANDOMIZE
905 cases
452 cases
453 cases
No external beam RT
External beam RT
In this study, after hysterectomy and BSO, pelvic lymphadenectomy was performed in about 30%, patients with high risk pathology without macroscopic desease was enrolled into randomization into noexternal beam radiation therapy and external beam radiation therapy.
Primary endpoint was overall survival and secondary endpoint was recurrence-free survival.
(51% Brachytherapy)
(52% Brachytherapy)
Primary endpoint: Overall survival
Secondary endpoint: Recurrence-free survival

24. Outcomes of ASTEC/EN.5

25. Outcomes of ASTEC/EN.5 EBRT: N-452 OBSERVATION: N-453
Vag. Rec.
Pelvic Rec.
Distant Rec.
Over all survival
EBRT
OBSE
7 (1.5%)
17 (3.8%)
6 (1.3%)
12 (2.6%)
34 (7.5%)
31 (6.8%)
84%

26. ASTEC/EN.5 CONCLUSION
Overall morbidity (which included documented postsurgical complications) was greater in the radiation therapy study arm (60% vs 26%).
No differences in recurrence-free, disease-specific, or overall survival (hazard ratio 1.01; P = 0.98)
Although it was not a primary end point of the study (Not randomized to receive or not)
Vault brachytherapy
Decreased the risk of isolated recurrence in the vagina
(hazard ratio: 0.53; P = .038).
This reduction in local recurrence did not influence survival.

27. ASTEC/EN.5 CONCLUSION (2)
EBRT alone is not indicated in the treatment of women with early-stage endometrial cancer at intermediate risk of relapse
Further refinement of which subgroups of women might benefit from treatment would require an individual patient data meta-analysis.

29. PORTEC – 2 (2008)
Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk endometrial cancer: Results of the randomized PORTEC-2 trial
R. A. Nout, H. Putter, I. M. Joergenliemk-Schulz, J. J. Jobsen, L. C. Lutgens, E. M. van der Steen-Banasik, J. W. Mens, A. Slot, V. T. Smit and C. L. Creutzberg
Leiden University Medical Center, Leiden, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands; Medisch Spectrum Twente, Enschede, Netherlands; MAASTricht Radiation Oncology Clinic, Maastricht, Netherlands; Radiotherapy Institute Arnhem, Arnhem, Netherlands; Daniel den Hoed Cancer Center, Rotterdam, Netherlands

30. PORTEC – 2 Design TAH / BSO no LND EBRT Brachytherapy Eligibility:
High intermediate risk group
-age>60+ IC G1-2 or IB G3
-stage IIa
N=427 pts
EBRT
N=214
Brachytherapy
N=213
Primary endpoint: rate of vaginal relapse
Secondary endpoints: OS, QOL

31. PORTEC – 2 Trial Results
Median F/U 36 months
EBRT Vaginal relapse: 1.9% Loco reg. relapse: 2.5% Distant relapse: 5.7% Pelvic relapse: 0.6% No deaths: 20 pts DFS: 89% OS: 90%
BT P
0.9% (p = 0.97)
4% (p = 0.15)
6.3% (p = 0.37)
3.5% (p = 0.03)
20 pts
89%
90%

32. PORTEC – 2 Toxicity Results
EBRT
QOL Diarrhea ~30%
Impairment in: ~30%
daily activities
Decreased social: ~20%
functioning
G1-2 GI toxicity: %
G1-2 GU toxicity: %
Skin toxicity: %
BT P
~10% (p = 0.001)
~13% (p = 0.03)
~10% (p=0.001)
13% (p = 0.001)
22% (p=0.1)
2% (p = 0.001)

33. Treat at recurrence or treat upfront?
PORTEC – 2 Conclusions
VBT as effective as EBRT for intermediate high risk EC. Despite the slightly but significantly increased pelvic failure rate in the VBT arm.
OS and RFS were similar.
QOL significantly better with brachytherapy
VBT should be the treatment of choice for patients with high-intermediate risk EC.
Remaining question:
Treat at recurrence or treat upfront?

34. GOG # 99 vs PORTEC-2 GOG # 99 (2004) PORTEC-2 (2008)
EBRT in early stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit a “high intermediate” risk definition.
Brachytherapy should be the treatment of choice for patients with high intermediate risk endometrial carcinoma.

35. Cost of therapy IVBT less costly than external beam RT
Patient convenience
Ancillary costs
Time to recovery
Time away from home/employment

36. On behalf of NSGO and EORTC
A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early stage high-risk endometrial cancer (NSGO-EC-9501/EORTC 55991)
On behalf of NSGO and EORTC
T. Hogberg1, P. Rosenberg1, G. Kristensen1, CF de Oliviera2, R de Pont Christensen1 B Sorbe1, C Lundgren1, H Andersson1, T Salmi1, NS Reed2. 1Nordic Society of Gynecologic Oncology, Odense, Denmark, 2Europ Org for Research and Treatment of Cancer, Brussels, Belgium.
Eur J Cancer September ; 46(13): 2422–2431. doi: /j.ejca

37. NSGO EC-9501/EORTC-55991 RT Randomization Radical surgery RT+CT CT+RT
May 1996 to January 2007
Randomization
44 Gy XRT ± optional brachytherapy (BT:39%)
382 cases
196 cases
Radical surgery
　TAH+BSO　(+PLA)
RT+CT
(BT:44%) OR
186 cases
Surgical stage I, II,
IIIA ( positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only)
CT+RT
After hysterectomy and BSO was performed, eligibility criteria are defined as patients with surgical stage I or II, or IIIA ( positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only) . In addition, patients with serous, clear cell or anaplastic carcinoma , were eligible regardless of other risk factors.
Patietnts were randomized into radiation group or into radiation plus chemotherapy group. Chemotherapy regimen was either AP, TP, TAP,or TEP.
Primary endpoint was pregression-free survival.
Endometrioid Type – 61%
Serous, clear cell, or anaplastic carcinomas (39%) were eligible regardless of other risk factors
Primary endpoint
　　 Progression-free survival (PFS)

38. Pelvic RT was given according to departmental guidelines (≥44 Gy)
Pelvic RT was given according to departmental guidelines (≥44 Gy). RT was given before CT in the RT-CT arm.
Optional vaginal brachytherapy had to be decided before randomization.
CT consisted of four courses of
Doxorubicin/epirubicin 50 mg/m2 and cisplatin 50 mg/m2 every four weeks.
Amendment in Aug 2004 (291 patients included) allowed alternative CT regimens, including:
Paclitaxel 175 mg/m2+epirubicin 60 mg/m2 or
Doxorubicin 40 mg/m2+carboplatin AUC 5 ; or
Paclitaxel 175 mg/m2+carboplatin AUC 5-6 every three weeks.

39. NSGO EC-9501/EORTC-55991 Results
Cancer-specific overall survival improved in radiation/ chemotherapy group (10% at 5 y. from 78 % to 88 %).
Combined modality improved progression-free but also cancer specific overall survival
No difference of overall survival by randomization between combined modality and radiation alone
RT+CT was better than RT alone.
The next question is if RT+CT better than CT alone

40. Rationale for combining chemotherapy and external beam radiation in patients with high-risk endometrial cancer-RTOG 9708 study (2004)
Combined-modality treatment may be the optimal
approach to minimize the risk of pelvic and distant
recurrence.
Feasibility of this approach was tested by the RTOG 9708 study that treated patients with
Grade 2 or 3 endometrial adenocarcinoma with either >50%MI, Cervical stromal invasion, or
Pelvic-confined extrauterine disease
with concurrent chemoradiation
(Cisplatin 50 mg/m2 on days 1 and28) followed by adjuvant chemotherapy 4 cycles of cisplatin and paclitaxel given at 4-week intervals).

41. The pelvic recurrence rate was only 2% at 4 years.
Toxicity was acceptable and 98% of patients were able to complete the planned treatment regimen.
Overall survival and disease-free survival rates at 4 years were 85% and 81%, respectively.
The pelvic recurrence rate was only 2% at 4 years.
Greven K et al, Preliminary analysis of RTOG 9708: Adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after
surgery for patients with high-risk endometrial cancer.
Int J Radiat Oncol Biol Phys. 2004;59:

48. Key Question #1: Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy?
Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients with
no residual disease in the hysterectomy specimen despite positive biopsy (Grade: strong recommendation, low-quality evidence)
2) grade 1 or 2 cancers with either no invasion or less than 50% myometrial invasion, especially when no other high-risk features are present (Grade: strong recommendation, high-quality evidence).
Patients with the following pathologic features may be reasonably treated with or without vaginal brachytherapy
grade 3 cancers without myometrial invasion (Grade: strong recommendation, low-quality evidence)
2) grade 1 or 2 cancers with less than 50%myometrial invasion and higher risk features such as age greater than 60 and/or lymphovascular space invasion (Grade: strong recommendation, moderate-quality evidence).

49. Key Question #2: Which patients with endometrioid endometrial cancer should receive vaginal cuff radiation?
Vaginal cuff brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence for patients with
grade 1 or 2 cancers with ≥50% myometrial invasion or
grade 3 tumors with <50% myometrial invasion
(Grade: strong recommendation, moderate-quality evidence).
Vaginal cuff brachytherapy is preferred to pelvic radiation in patients with these risk factors particularly in patients who have had comprehensive nodal assessment
(Grade: strong recommendation, low-quality evidence).

50. Key Question #3A: Which women with early stage endometrial cancer should receive postoperative external beam radiation?
Pelvic radiation is an effective means of decreasing pelvic recurrence for early stage patients but has not been proven to improve overall survival. 1) Patients with grade 3 cancer with ≥50% myometrial invasion or cervical stroma invasion may benefit from pelvic radiation to reduce the risk of pelvic recurrence (Grade: strong recommendation, high-quality evidence). 2) Patients with grade1 or 2 tumors with ≥50% myometrial invasion may also benefit from pelvic radiation to reduce pelvic recurrence rates if other risk factors are present such as age > 60 years and/or LVSI

51. Key Question #3B: Which women with stage III-IVA endometrial cancer should receive postoperative external beam radiation?
The use of pelvic radiation has been shown to improve survival in some settings. The best available evidence at this time suggests that a reasonable option for adjuvant treatment of patients with positive nodes, or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum includes external beam radiation therapy as well as adjuvant chemotherapy (Grade: strong recommendation, moderate-quality evidence). Chemotherapy (Grade: weak recommendation, moderate-quality evidence) or Radiation therapy alone (Grade: weak recommendation, low-quality evidence) may be considered for some patients based on pathologic risk factors for pelvic recurrence.

52. Key Question #4: When should brachytherapy be used in addition to external beam radiation?
Prospective data is lacking to validate the use of vaginal brachytherapy after pelvic radiation and retrospective studies show little conclusive evidence of a benefit, albeit with small patient numbers.
Use of vaginal brachytherapy in patients also undergoing pelvic external beam radiation may not generally be
warranted, unless risk factors for vaginal recurrence are ….present
(Grade: weak recommendation, low-quality evidence).

53. Key Question #5: How should radiation therapy and chemotherapy be integrated in the management of endometrial cancer?
The best available evidence suggests that concurrent chemoradiation followed by adjuvant chemotherapy is indicated for patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum (Grade: strong recommendation, moderate-quality evidence). Alternative sequencing strategies with external beam radiation and chemotherapy are also acceptable (Grade: weak recommendation, low-quality evidence). Chemotherapy (moderate-quality evidence) or radiation therapy alone (low-quality evidence) may be considered for some patients based on pathologic risk factors for pelvic recurrence.