ADJUVANT THERAPY IN EARLY ENDOMETRIAL CANCERWHEN TO GO ?

K.S.ReddyPondicherry

CANCER INCIDENCE - ESTIMATES

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GLOBOCAN, IARC

YEAR AGE GROUP

INDIA USA

CERVIX UTERI

CORPUS UTERI

CERVIX UTERI

CORPUS UTERI

2012* AGE < 65 107287 9178 10545 29041

AGE > 65 15557 3147 2421 20604

2015* AGE < 65 115060 9985 10819 30341

AGE > 65 17254 3492 2676 22859

Accts for 1.1% of all cancers as compared to 7% in USA

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%.

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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 5

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

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Staging FIGO – 1988 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)

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Peritoneal Cytology is done, does not affect staging

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.

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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.”

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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)

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Radiotherapy in high-risk early endometrial cancer

• Complex• Controversial • Confusing

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PORTEC-1PORTEC-1 study group (1990-97) 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

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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 < 0.0001)• Grade 1: S - 4%, S+RT – 17%• Grade 3-4: S+RT – 3%

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FIFTEEN-YEAR RADIOTHERAPY OUTCOMES OF THE RANDOMIZED PORTEC-1 TRIAL

CREUTZBERG et al.IJROBP 81(4), 2011

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Radiation therapyPelvic 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

Role of RT in surgically staged ECGOG # 99 (2004)

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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

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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 EBRT No RT EBRT No RT EBRT No RT

2(1.1%) 13(6.4%) 1(0.5%) 5(2.5%) 10(5.3%) 13(6.4%) 92% 86%

Statistically significant

Statistically not significant

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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; 92:744-751.

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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?

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Two important phase III randomized trials reported in 2007-2008

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Trial design for ASTEC/EN.5

Surgery

High risk pathology and no macroscopic disease

RANDOMIZE

No external beam RT External beam RT

Primary endpoint: Overall survival

Secondary endpoint: Recurrence-free survival

905 cases

453 cases 452 cases

(51% Brachytherapy) (52% Brachytherapy)

71% TAH BSO29% TAH BSO PLN

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Outcomes of ASTEC/EN.5

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Outcomes of ASTEC/EN.5EBRT: N-452 OBSERVATION: N-453

Vag. Rec. Pelvic Rec. Distant Rec. Over all survival

EBRT OBSE EBRT OBSE EBRT OBSE EBRT OBSE

7 (1.5%)

17 (3.8%)

6 (1.3%)

12 (2.6%)

34 (7.5%)

31 (6.8%)

84% 84%

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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.

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• 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.

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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

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PORTEC – 2 Design

TAH / BSO no LNDEligibility:

High intermediate risk group-age>60+ IC G1-2 or IB G3

-stage IIaN=427 pts

EBRTN=214

BrachytherapyN=213

Primary endpoint: rate of vaginal relapseSecondary endpoints: OS, QOL

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PORTEC – 2 Trial Results

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%

Median F/U 36 months

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PORTEC – 2 Toxicity Results

EBRT

QOL Diarrhea ~30%

Impairment in: ~30%

daily activities

Decreased social: ~20%

functioning

G1-2 GI toxicity: 54%

G1-2 GU toxicity: 27%

Skin toxicity: 20%

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)

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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?

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GOG # 99 vs PORTEC-2

GOG # 99

(2004)

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.

PORTEC-2

(2008)

Brachytherapy should be the treatment of choice for patients with high intermediate risk endometrial carcinoma.

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Cost of therapy

• IVBT less costly than external beam RT

• Patient convenience

• Ancillary costs– Time to recovery

– Time away from home/employment

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NSGO 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. 2010 September ; 46(13): 2422–2431. doi:10.1016/j.ejca.2010.06.002. 36

NSGO EC-9501/EORTC-55991

Radical surgery　 TAH+BSO　 (+PLA)

RT+CT

RT

CT+RTOR

Randomization

Primary endpoint　　 Progression-free survival (PFS)

Surgical stage I, II, IIIA ( positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only)

Endometrioid Type – 61%Serous, clear cell, or anaplastic carcinomas (39%) were eligible regardless of other risk factors

44 Gy XRT ± optional brachytherapy (BT:39%)

196 cases

186 cases

382 cases

May 1996 to January 2007

(BT:44%)

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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 o Doxorubicin/epirubicin 50 mg/m2 and cisplatin

50 mg/m2 every four weeks.o Amendment in Aug 2004 (291 patients

included) allowed alternative CT regimens, including:

o Paclitaxel 175 mg/m2+epirubicin 60 mg/m2 or o Doxorubicin 40 mg/m2+carboplatin AUC 5 ; oro Paclitaxel 175 mg/m2+carboplatin AUC 5-6

every three weeks.

NSGO EC-9501/EORTC-55991Results

• 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

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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).

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• 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;59:168-173.

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Key Question #1: Which patients with endometrioid endometrial cancerrequire no additional therapy after hysterectomy?• Following total abdominal hysterectomy with or without node

dissection, no radiation therapy is a reasonable option for patients with

1) 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

1) 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).

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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

1) grade 1 or 2 cancers with ≥50% myometrial invasion or

2) 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).

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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

(Grade: strong recommendation, high-quality evidence).

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Key Question #3B: Which women with stage III-IVA endometrial cancer shouldreceive 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.

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Key Question #4: When should brachytherapy be used in addition toexternal 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).

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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.

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