Chemotherapy for Chemotherapy for Chemotherapy for Chemotherapy - PowerPoint PPT Presentation

Chemotherapy for Chemotherapy for Chemotherapy for Chemotherapy for Early Stage High Early Stage High-Risk Early Stage High Early Stage High Risk Risk Risk Endometrial Cancer: Endometrial Cancer: Endometrial Cancer: Endometrial Cancer: Opposed Opposed pp pp Hal Hirte Hal Hirte Medical Oncologist Medical Oncologist Juravinski Cancer Centre Juravinski Cancer Centre Juravinski Cancer Centre Juravinski Cancer Centre Hamilton, Hamilton, Ontario Ontario

The The Emperor’s The The Emperor s Emperor’s New Clothing Emperor s New Clothing New Clothing New Clothing

The The Emperor’s The The Emperor s Emperor’s New Chemotherapy Emperor s New Chemotherapy New Chemotherapy New Chemotherapy

Outline Outline Outline Outline � Staging of Endometrial Cancer Staging of Endometrial Cancer � Risk Factors for Recurrence Ri k F Ri k F Risk Factors for Recurrence f f R R � Results of Randomized Studies Results of Randomized Studies � Unanswered Questions Unanswered Questions � Summary and Conclusions Summary and Conclusions Su Su a y a d Co c us o s a y a d Co c us o s

FIGO Staging of Endometrial FIGO Staging of Endometrial Cancer Cancer

Risk Factors For Recurrence Risk Factors For Recurrence � Uterine Uterine � Histologic grade Histologic grade � Depth of myometrial invasion Depth of myometrial invasion � Vascular space invasion Vascular space invasion p � Cervical extension Cervical extension � Extrauterine Extrauterine Extrauterine Extrauterine � Pelvic node metastases Pelvic node metastases � Aortic node metastases � Aortic node metastases Aortic node metastases Aortic node metastases � Adnexal metastases Adnexal metastases � Positive peritoneal cytology � Positive peritoneal cytology Positive peritoneal cytology Positive peritoneal cytology � Gross tumour breakthrough of the uterine serosa Gross tumour breakthrough of the uterine serosa

Histologic Grade and Depth of Histologic Grade and Depth of Invasion Invasion Creasman et al. Cancer 1987; 60:2035

Grade, Depth of Invasion and Grade, Depth of Invasion and Node Metastasis Node Metastasis Node Metastasis Node Metastasis Creasman et al. Cancer 1987; 60:2035

Recurrence Recurrence- -Free Interval and Free Interval and Grade Grade Morrow et al, Gynecol Oncol 1991; 40:55

Recurrence Recurrence- -Free Interval and Free Interval and Depth of Invasion Depth of Invasion Morrow et al, Gynecol Oncol 1991; 40:55

Risk of Recurrence Within Stage I Risk of Recurrence Within Stage I Endometrial Cancer Endometrial Cancer Lukka et al. Gynecol Oncol 2006; 102:361

Results of 4 Randomized Studies Results of 4 Randomized Studies Reported to Date Reported to Date � Radiotherapy Radiotherapy ± ± chemotherapy (2) chemotherapy (2) � Radiotherapy versus chemotherapy (2) R di Radiotherapy versus chemotherapy (2) R di h h h h h h (2) (2)

Morrow et al (GOG Morrow et al (GOG-34) Morrow et al (GOG Morrow et al (GOG 34) 34) 34)

Morrow et al (GOG Morrow et al (GOG-34) Morrow et al (GOG Morrow et al (GOG 34) 34) 34) FIGO clinical Stage I or II (occult): -greater than 50% myometrial invasion r t r th 50% m m tri l i i -pelvic or aortic node metastasis -cervical involvement -adnexal involvement Radiation – 5000 cGy to whole pelvis at 160-180 cGy/day / Chemotherapy – doxorubicin 60 mg/m 2 iv doxorubicin 60 mg/m 2 iv Chemotherapy Control – observation q3weekly to maximum dose of 500 mg/m 2 (N=89) (N=92)

Results Results Results Results

Conclusions Conclusions Conclusions Conclusions � Study was terminated prematurely because of � Study was terminated prematurely because of Study was terminated prematurely because of Study was terminated prematurely because of slow recruitment slow recruitment � 27% of patients randomized to doxorubicin did � 27% of patients randomized to doxorubicin did 27% of patients randomized to doxorubicin did 27% of patients randomized to doxorubicin did not receive it not receive it � No significant difference in OS or PFS N No significant difference in OS or PFS N i i ifi ifi diff diff i OS i OS PFS PFS � Study unable to determine effect of doxorubicin Study unable to determine effect of doxorubicin on recurrence due to protocol violations, small on recurrence due to protocol violations, small sample size and number of patients lost to sample size and number of patients lost to follow follow-up up

Maggi et al Maggi et al Maggi et al Maggi et al

Maggi et al Maggi et al Maggi et al Maggi et al FIGO stage IC gr 3, stage IIA-B gr 3 with > 50% myometrial invasion, stage III Randomize Chemotherapy: Pelvic XRT: cyclophosphamide 600 mg/m 2 45-50 Gy in 5-7 weeks doxorubicin 45 mg/m 2 + para-aortics if involved p cisplatin 50 mg/m 2 i l i 50 / 2 (n=166) q4weeks X 5 cycles (n=174)

Results Results Results Results

Conclusions Conclusions Conclusions Conclusions � No improvement in PFS or OS for patients � No improvement in PFS or OS for patients No improvement in PFS or OS for patients No improvement in PFS or OS for patients treated with chemotherapy treated with chemotherapy � Trend for radiotherapy to delay local relapses � Trend for radiotherapy to delay local relapses Trend for radiotherapy to delay local relapses Trend for radiotherapy to delay local relapses and chemotherapy to delay distant relapses and chemotherapy to delay distant relapses

Susumu et al (JGOG Susumu et al (JGOG-2033) Susumu et al (JGOG Susumu et al (JGOG 2033) 2033) 2033)

Susumu et al (JGOG Susumu et al (JGOG Susumu et al (JGOG 2033) Susumu et al (JGOG-2033) 2033) 2033) FIGO stage IC to III with > 50% myometrial invasion Randomize Chemotherapy: Pelvic XRT: cyclophosphamide 333 mg/m 2 45-50 Gy in 4-6 weeks doxorubicin 40 mg/m 2 + para-aortics if involved cisplatin 50 mg/m 2 p g/ (N=186) ( ) q4weeks X 3 or more cycles (N=188)

Results Results Results Results

Conclusions Conclusions Conclusions Conclusions � No improvement in PFS or OS for patients � No improvement in PFS or OS for patients No improvement in PFS or OS for patients No improvement in PFS or OS for patients treated with chemotherapy treated with chemotherapy � Retrospective subgroup analysis of “high to � Retrospective subgroup analysis of high to Retrospective subgroup analysis of “high to Retrospective subgroup analysis of high to intermediate risk” group (stage IC > 70 years, IC intermediate risk” group (stage IC > 70 years, IC grade 3 stage II or IIIA n=120) found that grade 3 stage II or IIIA n=120) found that grade 3, stage II or IIIA n=120) found that grade 3, stage II or IIIA n=120) found that chemotherapy significantly improved PFS and chemotherapy significantly improved PFS and OS however no PFS or OS difference found in OS however no PFS or OS difference found in OS, however no PFS or OS difference found in OS, however no PFS or OS difference found in “high risk” group (stage IIIA “high risk” group (stage IIIA- -IIIC n=75) IIIC n=75)

Hogberg et al (NSGO/EORTC) Hogberg et al (NSGO/EORTC) Hogberg et al (NSGO/EORTC) Hogberg et al (NSGO/EORTC) A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early-stage high-risk di ti (RT) ± h th (CT) i l t hi h i k endometrial cancer (NSGO-EC-9501/EORTC 55991). T. Hogberg, P. Rosenberg, G. Kristensen, C. F. de Oliveira, R. de Pont Christensen, B. Sorbe, C. Lundgren, T. Salmi, H. Andersson, N. S. Reed Journal of Clinical Oncology , 2007 ASCO Annual Meeting Journal of Clinical Oncology , 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 5503

Hogberg et al (NSGO/EORTC) Hogberg et al (NSGO/EORTC) FIGO stage I, II, IIIA (cytology), or IIIC with high risk for recurrence: One or more of - grade 3 tumour d 3 - deep myometrial invasion - non-diploid DNA - serous or clear cell or anaplastic histology p gy Pelvic radiotherapy ± vaginal brachytherapy Pelvic radiotherapy ± vaginal brachytherapy Given to dose of ≥ 44 Gy No chemotherapy Chemotherapy given before OR after XRT: (n=190) - doxorubicin 40 mg/m 2 , cisplatin ±50 mg/m 2 X 4 cycles - epirubicin 75 mg/m 2 , cisplatin ±50 mg/m 2 X 4 cycles paclitaxel 175 mg/m 2 epirubicin 60 mg/m 2 carboplatin AUC5 - paclitaxel 175 mg/m 2 , epirubicin 60 mg/m 2 , carboplatin AUC5 - paclitaxel 175 mg/m 2 , carboplatin AUC5-6 (n=177)

Results Results � Improved PFS on the chemotherapy arm Improved PFS on the chemotherapy arm p p py py � 7% improvement at 5 years, p=0.03 7% improvement at 5 years, p=0.03 � Survival data too early to draw conclusions � Survival data too early to draw conclusions Survival data too early to draw conclusions Survival data too early to draw conclusions