NEW ASPECTS OF ADJUVANT THERAPY IN ENDOMETRIAL CANCER

NEW ASPECTS OF ADJUVANT THERAPY IN ENDOMETRIAL CANCER (update of our current treatment policy) Zvi Bernstein MD. ONCOLOGY DIVISION Staff Meeting, November 26, 2008 1 EC FIGO STAGE Staff Meeting, November 26, 2008 2 2007: CLINICAL CANCER ADVANCES • Major Clinical Cancer Advances in 2007- 6 major clinical cancer advances and a further 18 that are considered "notable“, in independent annual review. • In Gynecologic Oncology: Only 1 finding was considered as "notable" advance: – External-beam radiation does not improve outcomes in endometrial cancer. Staff Meeting, November 26, 2008 3 ASCO 2007 Comprehensive Conclusion: “COMBINING EBRT WITH SURGERY IS NOT EFFECTIVE AND WILL LIKELY END ANY DEBATE ABOUT CONTINUED USE EBRT FOR PATIENTS WITH ENDOMETRIAL CANCER” Staff Meeting, November 26, 2008 4 Introduction (1) • EC usually diagnosed at early stage (up to 80% diagnosed as stage I, 13% with 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 IC and grade 3 only a 5-OS of 66%. Staff Meeting, November 26, 2008 5 Introduction (2) Endometrial cancer is often divided into 2 subtypes: • Type I etiologically related to unopposed estrogens and occurs mostly in hyperplasic endometrium and better prognosis. • Type II occurs mostly in atrophic endometrium with 3 atypical histological subtypes such as clear cell, papillary serous cancer (UPSC), and poor differentiated, and associated with high virulence, advanced stage at diagnosis and poor prognosis. Staff Meeting, November 26, 2008 6 Introduction (3) Surgery is the primary treatment of both localized and advanced disease, the adequate surgical staging and pathological review are the prerequisites for any discussion about individual need for an adjuvant therapy Staff Meeting, November 26, 2008 7 SURGICAL STAGING “Probably the most controversial aspect of this is the component of lymphadenectomy,” Staff Meeting, November 26, 2008 8 Lymphadenectomy (ACOG & ASGO,NCCN) “Complete dissection should be the gold standard!” “90% of involved nodes are only microscopically positive and the extent of dissection influences survival. ” Staff Meeting, November 26, 2008 9 Lymphadenectomy (FIGO) • Pelvic LN sampling. • Para-aortic LN sampling indications: -suspicious para-aortic or common iliac LN -grossly positive adnexa -grossly positive pelvic LN -full thickness myometrial invasion -high grade tumors -clear cell, serous papillary, carcinosracoma histologic subtype Staff Meeting, November 26, 2008 10 2000: TRENDY SLOGAN “MORE SURGERY – LESS RADIOTHERAPY!” Staff Meeting, November 26, 2008 11 Number of Nodes Removed Over Time Abu-Rustum et al. Gyn Oncol 103:714-718, 2006 Staff Meeting, November 26, 2008 12 Lymphedema Risk vs. Number of Nodes Removed Abu-Rustum et al. Gyn Oncol 103:714-718, 2006 Staff Meeting, November 26, 2008 13 NCCN GUIDELINES Staff Meeting, November 26, 2008 14 Completely Surgically Staged Patient ? “AT LEAST 8 LN (4 FROM THE EACH SIDE OF THE PELVIS)” Perry W. Grigsby, M.D. Mallinckrodt Institute of Radiology Washington University Staff Meeting, November 26, 2008 15 Lymph Nodes Assessment Staff Meeting, November 26, 2008 16 Risk Factors for Recurrence GOG#33 (1987) Prospective surgical-pathological study (1180 patients) • • • • • • Uterine Factors Grade Depth of MMI LVS invasion Cervical extension Histologic type Tumor location • • • • • Extrauterine Factors Pelvic / PA nodes mts. Adnexal mts. +-ve peritoneal cytology (?) Extension through serosa Peritoneal implants Morrow, Gyn Oncol 40:55-65,1991 17 Staff Meeting, November 26, 2008 FIGO Degrees of Risk within Stage I EC GOG#33 (1987) Staff Meeting, November 26, 2008 18 Staff Meeting, November 26, 2008 19 GOG # 99 (2004) Staff Meeting, November 26, 2008 20 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 Staff Meeting, November 26, 2008 21 GOG # 99 (Patients) • 392 evaluable patients • 58.5% IB, 32.1% IC, only 9.4% stage II(occult) • 82.3% inner and middle third invasion, only 17.6% outer third invasion • 81.6% grade 1 and 2, only 18.4% grade 3 Staff Meeting, November 26, 2008 22 GOG # 99 (Results) Recurrence Pattern Surgery Surgery+EBRT Vagina, by randomization 13/172 (7.6%) 2/179 (1.1%) Vagina, by treatment 15/172 (8.7%) 1/179 (0.6%) received Total pelvic failure, by 20/172 (12%) 3/179 (1.7%) randomization Total pelvic failure, by 22/172 (13%) 1/179 (0.6%) treatment received Surgery Surgery +EBRT Alive (4 years) 86% 92% Dead of disease 15/202 (7.4%) 8/190 (4.2%) Intercurrent deaths 18/202 (8.9%) 14/190 (7.4%) Staff Meeting, November 26, 2008 23 PROBLEMS WITH GOG # 99 • The number of events was smaller than expected and approximately 50% of deaths were due to intercurrent disease and the study was insufficiently powered to demonstrate a statistically significant survival difference. • Recognized during study that patient population being accrued was mostly low risk. Therefore, “low intermediate” and “high intermediate” risk groups were defined based on GOG #33 data base. Staff Meeting, November 26, 2008 24 RISK GROUPS (1) GOG # 99 (2004) • • • • • 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 lymphovascular involvement. No evidence of metastases. Staff Meeting, November 26, 2008 25 RISK GROUPS (2) GOG # 99 (2004) 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 Others considered “Low intermediate risk.” Staff Meeting, November 26, 2008 26 GOG # 99 (2004) Risk of recurrence at 2 year: High intermediate risk ( 132 pts. ) - 27% Low intermediate risk ( 260 pts. ) - 6% GOG #33 (1987) Staff Meeting, November 26, 2008 27 RISK GROUPS (3) GOG # 99 (?) High risk: • Serosal involvement ( any Grade ) • Positive Peritoneal Cytology (IC Gr. 3) • Adnexal , pelvic or P/A metastases (any Grade and MMI) Staff Meeting, November 26, 2008 28 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. Keys et al. Gynecol Oncol 2004; 92:744-751. Staff Meeting, November 26, 2008 29 Staff Meeting, November 26, 2008 30 Three important phase III randomized trials in 2007-2008 Staff Meeting, November 26, 2008 31 Staff Meeting, November 26, 2008 32 Trial design for ASTEC/EN.5 Surgery 71% TAH BSO 29% TAH BSO PLN EN.5: July 1996ASTEC: July 1998- High risk pathology and no macroscopic disease 83% - Endometrioid 17% - SPC 29% - any LND 453 cases RANDOMIZE 905 cases 452 cases No external beam RT 2% EBRT, 51% Brachytherapy External beam RT 98% EBRT, 52% Brachytherapy Primary endpoint: Overall survival Secondary endpoint: Recurrence-free survival Staff Meeting, November 26, 2008 33 Outcomes of ASTEC/EN.5 Staff Meeting, November 26, 2008 34 Outcomes of ASTEC/EN.5 Staff Meeting, November 26, 2008 35 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, diseasespecific, 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. Staff Meeting, November 26, 2008 36 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 metaanalysis. Staff Meeting, November 26, 2008 37 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. Staff Meeting, November 26, 2008 38 NSGO EC-9501/EORTC-55991 May 1996 to January 2007 RT Randomization 44 Gy XRT ± optional brachytherapy (BT:39%) 196 cases 382 cases Radical surgery TAH+BSO (+PLA) RT+CT OR 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 (BT:44%) 186 cases CT+RT CT : intially AP Later AP, TP, TAP, TEP Primary endpoint Progression-free survival (PFS) 39 Staff Meeting, November 26, 2008 NSGO EC-9501/EORTC-55991 2008 Updated Results (1) • Median follow-up: 4.3 years • Statistically significant improvement in progression-free survival (hazard ratio 0.62; P = .03) in favor of the combined modality. • Absolute difference in 5-year progression-free survival: 7% (79% vs. 72%). Staff Meeting, November 26, 2008 40 NSGO EC-9501/EORTC-55991 2008 Updated Results (2) • 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 Staff Meeting, November 26, 2008 41 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 Staff Meeting, November 26, 2008 42 PORTEC – 2 Design TAH / BSO no LND 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 Staff Meeting, November 26, 2008 43 PORTEC – 2 Trial Results Median F/U 36 months Vaginal relapse: Locoreg. relapse: Distant relapse: Pelvic relapse: No deaths: DFS: OS: EBRT 1.9% 2.5% 5.7% 0.6% 20 pts 89% 90% Staff Meeting, November 26, 2008 BT 0.9% 4% 6.3% 3.5% 20 pts 89% 90% P (p = 0.97) (p = 0.15) (p = 0.37) (p = 0.03) 44 PORTEC – 2 Toxicity Results EBRT ~30% ~30% BT ~10% ~13% P (p = 0.001) (p = 0.03) QOL Diarrhea Impairment in: daily activities Decreased social: functioning G1-2 GI toxicity: G1-2 GU toxicity: Skin toxicity: ~20% 54% 27% 20% ~10% 13% 22% 2% (p=0.001) (p = 0.001) (p=0.1) (p = 0.001) 45 Staff Meeting, November 26, 2008 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? Staff Meeting, November 26, 2008 46 GOG # 99 vs PORTEC-2 GOG # 99 (2004) PORTEC-2 (2008) Brachytherapy should be the treatment of choice for patients with highintermediate risk endometrial carcinoma. 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. Staff Meeting, November 26, 2008 47 JGOG 2033 Randomized phase III trial of pelvic RT versus cisplatin-based chemotherapy in patients with intermediate risk endometrial carcinoma S. Sagae, N. Susumu, Y. Udagawa, K. Niwa, R. Kudo, S. Nozawa, for the Japan Gynecologic Oncology Group Gynecologic Oncology 108 (2008) 226–233 Staff Meeting, November 26, 2008 48 Trial design for JGOG 2033 Enrollment: Jan 1994 - Dec 2000 Surgery TAH BSO+ PLN (95.3%) >1/2 myometrial invasion, no residual tumor FIGO stage IC, IIA, IIB, IIIA, IIIB, IIIC RANDOMIZE 238 pts. 475 pts. 237 pts. Pelvic Radiation Therapy (PRT) 193 pts. PRT:45-50Gy, PART (5.7%), Brachytherapy (3.1%) Chemotherapy (CAP) 192 pts. Cyclophosphamide 333 mg/m2 Doxorubicin 40 mg/m2 Cisplatin 50 mg/m2 Every 4 weeks for 3 or more courses Primary endpoint: Overall Survival Secondary endpoints: PFS, toxicity Staff Meeting, November 26, 2008 49 TREATMENT Comparison Completed Tx Median No. of courses Median duration of Tx Stopped Tx due to toxicity PRT 98.9% 5.1 wks 1.6% CAP 97.3% 3 ( 3-7 ) 11.4 wks 4.8% Staff Meeting, November 26, 2008 50 Adverse Effects Toxicity Grade 0-2 3-4 PRT (n=193) 190 (98.4%) 3 ( 1.6%) CAP (n=192) 181(95.3%) 9 (4.7%) Tx-related death 0 (0%) 0 (0%) Staff Meeting, November 26, 2008 51 JGOG 2033 RESULTS Staff Meeting, November 26, 2008 52 JGOG 2033 Conclusion Adjuvant chemotherapy may be a useful alternative to radiotherapy for intermediate-risk endometrial cancer. Staff Meeting, November 26, 2008 53 ADVANCED ENDOMETRIAL CARCINOMA Staff Meeting, November 26, 2008 54 422 PTS. 202 – WAI, 194 - PA Staff Meeting, November 26, 2008 55 Whole abdominal irradiation vs. doxorubicin/cisplatin (60/50) regimen for stage III/IV endometrial cancer (GOG #122) Clinical data No. of patients No. of patients alive WAI 202 38% CT 194 51% Treatment-related death Deaths from cancer 60-Month PFS (corrected for stage) 60-Month survival (corrected for stage) 4 100 38% 42% 8 78 60% 55% 56 Staff Meeting, November 26, 2008 Staff Meeting, November 26, 2008 57 Conclusions Patients with surgical stage III or IV Endometrial Carcinoma treated with AP experienced a statistically significant improvement in survival when compared with patients who received WAI, but also experienced more frequent and more severe acute toxicity. Staff Meeting, November 26, 2008 58 An overview about the performed CT phaseIII trials of GOG in endometrial cancer Trial Regiment RR (%) PFS (mos) 27 45 46 49 40 44 3.8 5.7 6.5 5.9 7.2 6.0 OS 9.2 9.0 11.2 13.2 12.4 13.6 #107 Dox Dox/Cis #139 Dox/Cis (AC) Circadian (AC) #163 Dox/Cis Pac/Dox+GCSF #177* Dox/Cis (60 45/50) Pac/Dox/Cis+GCSF (160/45/50)---TAP 34 57 5.3 8.3 12.1 15.3 *more toxicity with PFS and OAS no superior to the current standard therapy Staff Meeting, November 26, 2008 59 PROJECT RAMBAM HEALTH CARE CAMPUS Oncology Division Endometrial Cancer Adjuvant Treatment Policy (Updated: November, 2008) Z. Bernstein, A. Amit, E. Gez, S. Billan, R. Abdah-Bortnyak, L. Lowenstein, A. Kuten Based on the Guidelines of the Mallinckrodt Institute of Radiology Washington University (by Perry W. Grigsby, M.D.) Staff Meeting, November 26, 2008 60 Surgically staged patients at least 8 LN evaluated (4 from each side of the Pelvis) Staff Meeting, November 26, 2008 61 STAGE I Stage IA, IB, IC Grades I and II Post-Operative Therapy No further therapy Chemotherapy if ≥ 2/3 Myometrial Invasion Vaginal cuff brachytherapy HDR 700 cGy at ½ cm X 3 IA, IB, IC with Grade III or LVSI Or HDR 350 cGy at ½ cm X 6 And Chemotherapy if ≥ 2/3 Myometrial Invasion Staff Meeting, November 26, 2008 62 STAGE II Stage Post-Operative Therapy Vaginal cuff brachytherapy IIA, IIB HDR 400 cGy at ½ cm X 6 Chemotherapy if ≥ 2/3 Myometrial Invasion Staff Meeting, November 26, 2008 63 STAGE III Stage Post-Operative Therapy Vaginal cuff brachytherapy IIIA, IIIB HDR 350 cGy at ½ cm X 6 Chemotherapy if ≥ 2/3 Myometrial Invasion IMRT plus vaginal cuff brachytherapy 5,120 CTV Final And HDR 200 cGy at ½ cm X 6 (250 cGy for LVSI, 300 cGy for +/close margins) + Chemotherapy Groin irradiation is added if the disease involves the distal 1/3 of the vagina. Pelvic IMRT may be given with negative lymph nodes if the patient’s tumor has features of deep myometrial invasion, high grade, or extensive LVSI. Staff Meeting, November 26, 2008 64 IIIC Pelvis only unless Para-Aortic Nodes Positive SIGNIFICANT PELVIC RECURRENCE IN HIGH-RISK EC AFTER CT ALONE Staged according to the 1988 FIGO criteria (GOG #33) • 143 high-risk endometrial cancer patients received adjuvant chemotherapy alone. • All patients underwent primary surgery consisting of total abdominal hysterectomy and bilateral salpingo-oophor-ectomy. •All patients received 4–6 cycles of chemotherapy as the sole adjuvant therapy, consisting primarily of cisplatin and doxorubicin. • Most patients had Stage III–IV disease (83.7%) or unfavorable histology tumors (74.4%). Staff Meeting, November 26, 2008 65 RESULTS (1) Median follow-up was 27 months (range, 2–96 months). Staff Meeting, November 26, 2008 66 RESULTS (2) Staff Meeting, November 26, 2008 67 Conclusions: PVR is common in high-risk pathologic Stage I–IV endometrial cancer patients after adjuvant chemotherapy alone. These results support the continued use of locoregional RT in patients undergoing adjuvant chemotherapy Staff Meeting, November 26, 2008 68 Incompletely surgically staged patients Stage IA, IB G1, 2 Post-Operative Therapy No further therapy I; G3 (Any myometrial invasion) IC (Any Grade) IMRT plus vaginal cuff brachytherapy 5,120 CTV Final And II, III (Any Grade) HDR 200 cGy at ½ cm X 6 HDR (250 for LVSI, 300 cGy X 6 for +/close margins) + Chemotherapy Groin irradiation is added if the disease involves the distal 1/3 of the vagina. Staff Meeting, November 26, 2008 69 IMRT ON THE WAY Staff Meeting, November 26, 2008 70 SPECIAL THANKS TO: ONCO-GYNECOLOGIC TEAM Amnon Amit Lior Lowenstein RADIATION ONCOLOGY TEAM Abraham Kuten Eliahu Gez Salem Billan Roxoliana Abdah-Bortnyak Alex Nebelski Raquel Bar-Deroma Alison Berniger Gadi Goldstein Staff Meeting, November 26, 2008 71 THANK YOU ! Staff Meeting, November 26, 2008 72