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Role of Chemotherapy For Endometrial Carcinoma

IGCS council, GCIG executive board Sapporo Railway Hospital Vice-director Sapporo Japan. Role of Chemotherapy For Endometrial Carcinoma. Satoru Sagae MD PhD. IGCS 10,2006. Endometrial Cancer - Treatment Plan. Surgical Staging. Low Risk IA: G1-2 No treatment. Intermediate Risk

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Role of Chemotherapy For Endometrial Carcinoma

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  1. IGCS council, GCIG executive board Sapporo Railway Hospital Vice-director Sapporo Japan Role of Chemotherapy For Endometrial Carcinoma Satoru Sagae MD PhD IGCS 10,2006

  2. Endometrial Cancer - Treatment Plan Surgical Staging Low Risk IA: G1-2 No treatment Intermediate Risk IA: G3 IB, IC: G1-3 IIA, IIB: G1-3 Pelvic RT +/- cuff RT High Risk/ Recurrent IIIA, IIIB, IIIC: G1-3 IVA, IVB: G1-3 Pelvic RT +/- cuff RT Aortic RT (+) ALN &/or Chemotherapy < 5%* 5-10%* IIIA + cytology > 10%* No treatment/Chemo/RT? *Recurrence risk ?*

  3. Up-to-date adjuvant therapy for endometrial cancer IA/ IB , G1 / 2 No treatment Low–risk Low? IA/ B G3，IC High? II, LVI (+) IIIa cytol(+) Ser., Clear Early stage Radiation （PRT ）orChemotherapy Intermediate -risk Surgical Staging →GOG99 →JGOG2033 Chemotherapy or Radiation Advanced stage High–risk III / IVA / B →GOG 122 Chemotherapy or Radiation Recurrence Concurrent Chemo-Radiation

  4. Radiotherapy versus Observation in early-stage endometrial cancer GOG 99＊ PORTEC NRH Number of Patients 540 717 448 Local Recurrence Obs >RT Obs >RT Obs >RT Distant Metastasis NS NS NS PFS NS NS NS OS NS NS NS GOG99; high intermediate risk: G2/G3, Lymph Vas Inv, Myomet Inv >2/3 with 1) over 70 years old + 1 factor, 2) over 50 y.o. + 2 factors, 3) all3 factors.

  5. JGOG 2033 Phase III ( CAP vs PRT ) ＊ 1994 to 2000 for 7 years 103 member institutions ＊Evaluable n=385 Regimen I Pelvic Radiation Therapy Randomize • - Endometrial ca. • Hysterectomy + BSO • ( complete resection ) • - Myometrial inv. ≧ 1 / 2 Regimen II CPA 333 mg / m2 Doxorubicin 40 mg / m2 CDDP 50 mg / m2 q 3 - 4 weeks, x 3 < Sagae et al. ASCO 2005 abstr # 5002

  6. JGOG 2033Patient Characteristics Sagae et al. ASCO 2005 abstr # 5002

  7. SUBGROUP ANALYSIS WITH NEW CRITERIA FOR INTERMEDIATE RISK Low intermediate risk (LIR) stage IC patients under 70 years of age and with G1/2 endometrioid adenocarcinoma High intermediate risk (HIR) (1) stage IC patients over age 70 years or having G3 endometrioid adenocarcinoma (2) stage II or IIIA (positive cytology) patients with deeper than 50% myometrial invasion in the corpus. Sagae et al. ASCO 2005 abstr # 5002

  8. SITES OF INITIAL RECURRENCE *Include multiple recurrences Sagae et al. ASCO 2005 abstr # 5002

  9. JGOG 2033 CONCLUSIONS • Both pelvic radiation therapy and chemotherapy were equally effective with 85% of 5 year survival in all 374 pts with stage Ic (75%) through stage II, IIIc (25%). • In subgroup analysis, among 184 pts with low intermediate risk, the survival of both treatments was over 90% without any statistical significance. 3. However, among 119 pts with high intermediate risk, CAP arm significantly 15% improved PFS and OS when compared with PRT. Sagae et al. ASCO 2005 abstr # 5002

  10. GOG 122 Phase III ( AP vs WAI ) Regimen I • - Endometrial ca. • - Surgical stage III / IV • - Hysterectomy + BSO • - PAN ( - ) • - PAN ( + ) • with negative scalene • node and • negative chest CT Whole Abdomen Radiation Therapy Randomize Regimen II Doxorubicin 60 mg / m2 CDDP 50 mg / m2 q 4 weeks Randall ME, et al. J Clin Oncol 24:36,2006

  11. Randall ME, et al. J Clin Oncol 24:36,2006

  12. GOG #122 • Adjuvant chemotherapy appears to benefit all substages and histologic subtypes of stage III disease (not analyzed by grade) • Hazard ratio for death with chemotherapy for all stage III disease combined is 0.68 • 5 year PFS for stage III disease is 50%-60% • 5 year OS for stage III disease is 55%-65% • 35% of recurrences on chemotherapy arm were initially limited to the pelvis Randall ME, et al. J Clin Oncol 24:36,2006

  13. Effects of Single agent Agent Response rate (%) Doxorubicin ( ADM ) Epirubicin Pirarubicin 37 26 10 20 24 Cisplatin Carboplatin 14 15 Cyclophosphamide Ifosphamide 18 8 Vincristine Vinblastine Etoposide (oral ) 14 Medroxyprogesterone acetate Tamoxifen 25 10

  14. Effects ofADM- base therapy Regimen Mean response rate ( range ) ADM + CPA 39% ( 31 - 46% ) CPA 500 mg/m2 + ADM 60 mg/m2 ADM +CDDP 58% ( 33 - 81% ) CDDP 50-60 mg/m2 + ADM 50-60 mg/m2 ADM + CPA + CDDP 46% ( 26 - 56% ) CDDP 50-60 mg/m2 + ADM 40-50 mg/m2 + CPA 400-600 mg/m2

  15. Chemotherapy for Endometrial cancer GOG 48 GOG 107 RR.PFS NS ADM CA EORTC 55872 NS AP AT GOG 163 Standard regimen = ADM + CDDP

  16. ADM + CDDP vsADM+ TXL + CDDP GOG 177 Phase III study Regimen I Doxorubicin 60 mg / m2 CDDP 50 mg / m2 - Endometrial ca. - Stage III / IV or Recurrent disease - Measurable disease - No prior cytotoxic chemotherapy Randomize q3 weeksx 7 G-CSF Regimen II Doxorubicin 45 mg / m2 CDDP 50 mg / m2 Paclitaxel 160 mg / m2 q3 weeksx 7 G-CSF

  17. Results of GOG 177 Regimen CR (%) Alive without PD (%) OR (%) AP 6.8 33.3 8.3 TAP 21.6 * 56.7 * 23.9 * Treatment may have contributed to the death of 5 patientson the TAP regimen. Treatment and disease may have contributed to the death of 5 patients on the TAP regimen. * p < 0.05

  18. Chemotherapy for Endometrial cancer GOG 48 GOG 107 ADM CA EORTC 55872 AP AT GOG 163 Toxic ! GOG 177 TAP

  19. GOG 209 TAP vs TC Phase III study Regimen I Doxorubicin 45 mg / m2 CDDP 50 mg / m2 day 1 Paclitaxel 160 mg / m2 day 2 G-CSF • - Endometrial ca. • - Surgical stage III / IV or • Recurrent • - Measurable disease • - ER, PR status Randomize Regimen II Paclitaxel 175 mg / m2 CBDCA AUC = 6 day 1 Ongoing with GOG Japan (JGOG)

  20. Japanese Phase II studies - Advance, Recurrent Endometrial cancer Paclitaxel ( Taxol ) 210 mg / m2 q 3 weeks - Prior CT or RT - 23 Pts. RR = 30.4 % Hirai et al. Gynecol Oncol 94;471,2004 - Advance, Recurrent Endometrial cancer Docetaxel ( Taxotere ) 70 mg / m2 q 4 weeks - Prior CT or RT - 32 Pts. RR = 31.3 % Katsumata et al. Br J Cancer 93;999,2005

  21. Option of Taxanes / Platinum Taxanes Platinum Docetaxel CBDCA Paclitaxel CDDP SCOTROC, SGCTC, OV-10, GOG 111, AGO, GOG 158, JGOG 3016, JGOG P II study 2041, JGOG P III study 2043

  22. JGOG 2041 Arm 1 : DP Randomized phase II Docetaxel 70 mg/m2 CDDP 60 mg/m2 Randomize - Advance, recurrent endometrial cancer - Measurable disease - Prior CT, RT Arm 2 : DC Docetaxel 60 mg/m2 CBDCA AUC = 6 Arm 3 : TC Total 90 Pts Closed 2004 Paclitaxel 180 mg/m2 CBDCA AUC = 6

  23. JGOG 2041 monitoring report(Oct, 2006) AE(>G3) DP (n=24) DC (n=30) TC (n=28) GI 20.8 3.3 0.0 Neuro 0 0 7.1 Hb 8.3 31.0 28.6 WBC 75.0 89.7 82.1 Neutro 83.3 89.7 82.1 Platelet 4.2 10.3 25.0 RR 51.7% 48.3%60.0% 95%CI32.5-70.6%29.5-67.5%40.6-77.3%

  24. New RCT Phase III JGOG2043 Randomized comparative phase III Arm 1 : AP Doxorubicin 60 mg/m2 CDDP 50 mg/m2 • - Intermediate risk I/II • - Advanced III/IV • - Adjuvant • First-line chemo. • Primary endpoint • PFS • Secondary endpoint • OS, AE, Tx, LN • - About 600 patients Randomize Arm 2 : DP DOC 70 mg/m2 CDDP 60 mg/m2 Arm 3 : TC Paclitaxel 180 mg/m2 CBDCA AUC = 6

  25. Future direction of Adjuvant Chemotherapy JGOG PIII 2043 GOG163 AP AP or AT ？? GOG 177 TC DP TAP ？? ？? GOG 209 Taxane AnthracyclinePlatinum

  26. PTEN/MMAC-1 43% endometrial cancers Loss of function increases AKT, increase mTOR mTOR: Iº-70%, Rec-50% EGF-R over expressed in 60-80% (UPSC) mTOR inhibitors RAD001 CCI-779 (NCIC) (5/16 PR, 31%, Oza) EGF-R Targeted therapy Gefitinib (GOG 229-C) Trastuzumab（GOG 181b) Erlotinib, OSI-774 (NCIC) 7% response rate Biologic Therapies in Clinical Trials

  27. Conclusions 1.Chemotherapy may be an alternative modality with radiation therapy for high intermediate-risk and high-risk endometrial cancer. 2. Optimal chemotherapeutic agents are AP, TAP, TC and others with current investigations. 3. Biologics as Future directions are including with Gefitinib, Trastuzumab, Erlotinib, CCI-779 and others.

  28. Endometrial Cancer State of the Science MeetingNCRI,UK NCI-US GCIG Manchester, UK November 28-29,2006 • Review of molecular biology • Role of surgery, radiotherapy, chemotherapy, endocrine therapy,biologic therapy • Potential trials in early stage disease • Potential trials in advanced or recurrent disease • Potential trials in clear cell and papillary serous histologies • Potential translational research

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