ADJUANT TREATMENT IN ENOMETRIAL CANCER

Dr Paul George

• Based on retrospective histopathological analyses and prospective adjuvant studies three risk groups were characterized: low, intermediate, and high risk

Overall the 5-year survival rates for all grades and histologic subtypes are approximately

• 78%-90% for stage I, • 74% for stage II,• 36%-57% for stage III, and • 20% stage IV

LOW RISK

• Stage IA, Grade 1-2Stage IB, Grade 1

• Well or MD• Meta analysis of 8 studies• 2nd malignancy (hazard ratio [HR], 2.02• higher risk of mortality (HR, 1.36)and• had experienced lower quality of life from

significant radiation toxicity

• Therefore, patients in the low risk category do not generally receive adjuvant treatment, but are followed-up carefully during the surveillance period

INTERMEDIATE RISK

RESULTS Adj RT Stage I, II

PORTEC GOG-99RISK FACTORS AGE >60

G - 3MYO INV >50%

<50/ <60/<70 2-3>66%LVI +

HIGH intermediate RISK 2 OUT OF 3 ANY AGE + 3 FACTORS>50 + 2 FACTORS>70 + 1 FACTOR

RESULTS 10 Yr LRRRT- 5 %NO Rx- 23%

4 yr resultRT- LRR- 5%, 13% ANY SITENO Rx- LRR- 13%, 27 % ANY

INTERMEDIATE RISK• Based on GOG 99 & PORTEC• LOW IR Stage IA, grade 3 Stage IB, grade 2 Stage IIA, grade 1-2, <50% MI

• HIR Stage IB, grade 3 Stage IC, grade 1-2

Stage IIA, grade 3, <50% MIStage IIA, grade 1-2,

>50% MI +/-+LVSI G2-3,LVI, >66%MI 1/3 above w/ age >70

2/3 above w/ age <503/3 above w/age <50

Adjuant Pelvic RT in Early EC

ALDERS ET AL 1980PORTEC1GOG99ASTEC/EN5

• Adjuant pelvic RT improves local control but failed to show a survival advantage

• In all studies, adjuvant PRT was associated with significant radiation-related toxicities including diarrhea, fecal leakage, urinary frequency and urgency, which negatively affected quality of life.2nd malignancies

To circumvent adverse effects related to radiotherapy, while not compromising outcomes, a subsequent trial, PORTEC-2 compared vaginal brachytherapy (VBT) to PRT

• the VBT group suffered significantly lesser toxicities compared to the PRT group.

• The rate of acute grade 1-2 gastrointestinal (GI) toxicity was significantly lower in the VBT vs. PRT group (12.6% vs. 53.8%).

• These results support using VBT for patients with patients with HIR early stage EC.

Role of chemo

• JGOG 2033 PRT vs Cisplatin based chemo• EORTC 55991• Maggi et al• All studies showed that the use of chemotherapy lowered

the risk of distant metastasis, but did not improve OS in the overall study population

• Protocols JGOG 2033 and EORTC 55991 demonstrated an improvement in OS with the use of chemotherapy in the higher risk subgroup defined as either stage II-IIIA or stage IC, grade 3 and/or age >70 (73.6% vs. 89.7%, p=0.006 in JGOG 2033; 75% vs. 82%, p=0.046 in EORTC 55991

• To definitively address whether chemotherapy improves survival in early stage uterine cancer, protocols PORTEC-3 and GOG 249 were designed

The highly anticipated results of these studies will definitively answer whether or not systemic chemotherapy has a place in the management of high risk early stage EC

HIGH RISK

• Stage IC, grade 3• Stage IIA, grade 3, >50% MI

• Stage IIB, any grade• UPSC• CCC• Stage III-IV

TREATMENT FOR ADVANCED STAGE ENDOMETRIAL CANCER

• WAI/CHEMO• 1983 Greer and Hamberger shows fiirst series

of adjuant WAI improves OS• Other retrospective studies have shown that

most of the disease relapses systemically• The results of these studies reiterated the

concept that stage III &above EC should be considered a systemic disease, for which effective systemic therapy is required

Role of Multiagent chemo

• GOG 107 & 163 showed improved response rate for AP regimen in metastatic & recurrent EC

GOG122

This trial set a new standard for patients with locally advanced EC, bringing systemic chemotherapy to the forefront of EC managementHowever 18% of patients treated on the AP arm developed pelvic recurrence as the first site of relapse despite improved systemic control compared to WAI, local control remains insufficient

TripletGOG 177 TAP vs APBetter RR , PFS & OS in metastatic setting

• GOG184

These results suggested that TAP although highly active in the metastatic setting, is not superior to the doublet regimen omitting paclitaxel and is too toxic to be administered routinely after tumor volume directed radiotherapy in the adjuvant setting.

• LESS TOXIC CT (Pacli +carbo)GOG209Naakumura et alSeveral other studies confirm that CT is notinferior to TAP and as active as APBetter toxicity profile favours CT as the stdchemotherapy regimen for Advanced EC

• AP, TAP , CT all are active in EC

Combined modality treament in locally advanced EC

30% of patients included in GOG-122 treated with systemic chemotherapyrecurred in the pelvis and in the abdomen.This observation suggested that patients treated with systemic chemotherapy experience a finite rate of local failure, which could compromise in overall survival.

This concern supported including tumor volume directedradiotherapy in the upfront approach of stage III/IVA EC, with the intent of preventing local recurrences. Whether this improved local control translates into an improvement in OS remains unproven

CHEMORADIATION

Several small studiesOnda et alBruzzone et alHogberg et alCombination chemoradiation is superior interms of PFS & OSRTOG phase IIITALIAN study concurrent chemoRT

GOG 184

combined approach yielded a three-year DFS of 62%-64% in this setting

• The ongoing international protocol GOG 258 compares tumor volume-directed radiotherapy administered concurrently with cisplatin and followed by 4 cycles of CT against CT chemotherapy alone

• It is anticipated that GOG 258 will answer critical questions regarding the

• impact of chemo-radiation on OS, • the tolerability of the approach, and • the short- and long-term impact on the quality of life.

• If positive, the combined chemo-radiotherapy approach would become a new standard of care in locally advanced EC

Summarising

GENERAL PRINCIPLE OF MANAGEMENNT

RISK STRATIFICATIONLow risk Int. low risk Int. high risk High risk

Stage IA, Grade 1-2Stage IB, Grade 1

Stage IA, grade 3Stage IB, grade 2

Stage IIA, grade 1-2, <50% MI

Stage IB, grade 3Stage IC, grade 1-2Stage IIA, grade 3, <50% MIStage IIA, grade 1-2, >50% MI +/-+LVSI

G2-3,LVI, >66%MI1/3 above w/ age >702/3 above w/ age <503/3 above w/age <50

Stage IC, grade 3Stage IIA, grade 3, >50% MI

Stage IIB, any grade

UPSCCCC

Stage III-IV

MANAGEMENTLOW RISK LOW

INTERMEDIATEHIGH INTERMEDIATE

HIGH

OBSERVATION

VBT if Age>60LVILower uterine segment involvement

OBSERVATION/VBT VBT ALONE

PELVIC EBRT IF ESS NOT DONE

STAGING LAPAROTOMY+PELVIC EBRT+VBT+CHEMO

Hormone Replacement Theraapy

controversial Reasonable option for Stage I

FOLLOW UP

• Physical examination 3-6months for 2-3years• Annnually thereafter• CA 125 optional• Imaging as indicated• Genetic counselling• Patient education lifestyle, nutrition obesity,

potential recurrence• Sexual health , vaginal dillators/lubricants

66yr old lady who is evaluated for postmenopausal bleeding and diagnosed to have ca endometriumUnderwent staging lap with TAH+ BSO with lymph node sampling

After complete HPEMD Endometroid adenoca stage IC G2 with no LVI

• RISK?????

GENERAL PRINCIPLE OF MANAGEMENNT

RISK STRATIFICATIONLow risk Int. low risk Int. high risk High risk

Stage IA, Grade 1-2Stage IB, Grade 1

Stage IA, grade 3Stage IB, grade 2

Stage IIA, grade 1-2, <50% MI

Stage IB, grade 3Stage IC, grade 1-2Stage IIA, grade 3, <50% MIStage IIA, grade 1-2, >50% MI +/-+LVSI

G2-3,LVI, >66%MI1/3 above w/ age >702/3 above w/ age <503/3 above w/age <50

Stage IC, grade 3Stage IIA, grade 3, >50% MI

Stage IIB, any grade

UPSCCCC

Stage III-IV

Adjuant treatment???

To circumvent adverse effects related to radiotherapy, while not compromising outcomes, a subsequent trial, PORTEC-2 compared vaginal brachytherapy (VBT) to PRT

• chemo????

• To definitively address whether chemotherapy improves survival in early stage uterine cancer, PORTEC-3 and GOG 249 were designed

• Thank you……………..

dr paul george