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ROLE OF CHEMOTHERAPY IN OVARIAN MALIGNANCIES

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Information about ROLE OF CHEMOTHERAPY IN OVARIAN MALIGNANCIES
Science-Technology

Published on March 2, 2014

Author: drraj12319

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ROLE OF CHEMOTHERAPY IN OVARIAN MALIGNANCIES DR. R. RAJKUMAR M.D., D.M. MEDICAL ONCOLOGIST : ROLE OF CHEMOTHERAPY IN OVARIAN MALIGNANCIES DR. R. RAJKUMAR M.D., D.M. MEDICAL ONCOLOGIST What do you know about ovarian cancer?: What do you know about ovarian cancer? “its rare in men” :  Editorial Inadequate Treatment of Ovarian Cancer By THE EDITORIAL BOARD Published: March 13, 2013 A new study has found widespread failure among doctors to follow clinical guidelines for treating ovarian cancer, which kills 15,000 women a year in this country. In the case of ovarian cancer, the consequences of inadequate care are tragic. Among those with advanced cancer, the stage at which ovarian cancer is usually first found, 35 percent of the women treated in accordance with the guidelines survived at least five years compared with 25 percent for those whose care fell short. OVARIAN CANCER: OVARIAN CANCER 1/71 lifetime risk 1 5-year survival rates (by year of diagnosis) 2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. INCIDENCE RATES: INCIDENCE RATES RISK FACTORS: RISK FACTORS Family history (primarily 2 or more first degree relatives) Age ( besides family history, this is the most important risk factor ) Nulliparity Early menarche, late menopause Late childbirth (age <35) Environmental factors not yet defined RISK OF OVARIAN CANCER: Baseline 1.5% risk 2 + relatives 3% risk One 1 o relative 5% risk Two 1 o relatives 7% risk BRCA2 mutation 25% risk BRCA1 mutation 40% risk RISK OF OVARIAN CANCER PowerPoint Presentation: INTERVENTIONS TO  MORTALITY? Time Disease Volume Prevention Screening Current point of diagnosis and initiation of treatment SCREENING – US AND CA 125: “…there is no evidence available yet that the current screening modalities of CA 125 and ultrasonography can be effectively used for widespread screening to reduce mortality from ovarian cancer…” SCREENING – US AND CA 125 Screening (CA125): Screening (CA125) Tumor associated antigen Not expressed in mucinous tumors Normal value in 50-70% of stage I tumors and 20-25% of advanced tumors Associated with a variety of common, benign conditions including: endometriosis, fibroids, PID, adenomyosis, pregnancy and possibly menstruation Better predictive value in postmenopausal patients Abnormal >35 u/ml: postmenopausal >200 u/ml: premenopausal RISK REDUCTION: RISK REDUCTION OCP’s Several Case-controlled studies have documented that OCP users have a 30-60% smaller chance of developing EOC than non-users WHO study documented a RR 0.75 Greater reduction in risk with nulliparous women and increased duration of use Breast Feeding Tubal ligation Risk reducing oophorectomy HEREDITARY OVARIAN CANCER: HEREDITARY OVARIAN CANCER Account for 10% of EOC BRCA1, BRCA2 (Hereditary Breast and Ovarian Cancer –HBOC) Estimated 1/300 to 1/800 individuals carry a BRCA 1 or 2 mutation Estimated 1/40 Ashkenazi Jews carry a BRCA 1 or 2 mutation Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Lynch II Colorectal Cancer before age 50 Endometrial cancer before age 50 2 or more “Lynch” family members: colorectal, endometrial, ovarian, ureter /renal pelvis, gastric, biliary tract, small bowel, pancreatic, brain and sebaceous adenoma HEREDITARY OVARIAN CANCER: HEREDITARY OVARIAN CANCER BRCA 1 Germline Mutations Tumor suppressor gene on 17q21 (long arm) Autosomal dominant 65 to 74% Breast Cancer risk 39-46% Ovarian Cancer risk For women with Breast Cancer, the 10-year actuarial risk of developing Ovarian Cancer is 12% Predominately high grade, serous or endometrioid adenocarcinoma Integrating the models of serous carcinogenesis – a binary model: Integrating the models of serous carcinogenesis – a binary model Levanon, Crum, and Drapkin, JCO, 2008 PATHOLOGY: PATHOLOGY Epithelial (65%) Serous (80%) – Tubal Mucinous (10%) – Intestinal Clear cell – Endocervical Endometrioid – Endometrial Brenner – Transitional cell Benign = Cystadenoma Invasive = Cystadenocarcinoma Borderline = Tumor of LMP OVARIAN CANCER STAGING: OVARIAN CANCER STAGING Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases OVARIAN CANCER FIGO STAGING SYSTEM: OVARIAN CANCER FIGO STAGING SYSTEM Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging: Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy PRINCIPLES OF OVARIAN CANCER SURGERY: PRINCIPLES OF OVARIAN CANCER SURGERY Purpose of Surgery Staging of disease Prognosis and treatment depend upon surgical findings and subsequent stage Debulking ( cytoreduction ) Overall reduction of tumor burden to less than 1 cm (preferably no gross residual disease) improves survival Palliation of symptoms Goldie- Coldman Hypothesis Resistance to chemotherapy will develop in fraction of remaining viable cells PRINCIPLES OF OVARIAN CANCER SURGERY: PRINCIPLES OF OVARIAN CANCER SURGERY Midline, vertical incision Careful inspection of all peritoneal surfaces: liver, spleen, large and small bowel, stomach, diaphragms Any ascites is collected for cytology. If no ascites, then pelvic washings should be obtained If no gross disease beyond ovaries: systematic biopsies of peritoneal surfaces and diaphragms Pelvic and para aortic lymph node sampling Infra-colic omentectomy If gross disease beyond ovaries: Tumor debulking is ideal (goal is to leave no residual tumors or implants) PRINCIPLES OF OVARIAN CANCER SURGERY: PRINCIPLES OF OVARIAN CANCER SURGERY In most cases, hysterectomy with bilateral salpingo-oophorectomy is indicated If fertility is a consideration, the contra-lateral ovary and uterus may be left in-situ if tumor is Stage IA, IC, IIA and appropriate counseling UPSTAGING: UPSTAGING Incomplete surgical staging is a common issue Complete surgical staging offers a more accurate diagnosis and in some cases determines the need for adjuvant chemotherapy. Young RC et al. Staging laparotomy in early ovarian cancer. JAMA 1983; 250: 3072-6. 31% of patient were upstaged after a second surgery 77% of patients actually had Stage III disease 25% of patients had an inadequate incision to properly perform staging ( Pfannenstiel ) McGowan L et al. Misstaging of ovarian cancer. Obstet Gynecol 1985; 65: 568-72. Examined completeness of staging in 291 women 46% had inadequate staging GO 97% correct GYN 52% correct Surgeon 35% correct Initial Stage N % upstaged IA 37 16 IB 10 30 IC 2 0 IIA 4 100 IIB 38 39 IIC 9 33 Total 100 31 DOES CYTOREDUCTION MATTER?: DOES CYTOREDUCTION MATTER ? Optimal Suboptimal Response Rate Clinical CR 95% 75% Pathologic CR 50% 25% Progression free interval (mo) 34 13 Survival (mo) 50 36 10-yr survival 35% 15% ONCOLOGY SPECIALIST MOST LIKELY TO PERFORM COMPREHENSIVE SURGERY: ONCOLOGY SPECIALIST MOST LIKELY TO PERFORM COMPREHENSIVE SURGERY *Ovarian Cancer Surgery by: Surgeon Surgeon Specialty Rate of Comprehensive Surgery Gynecologic oncologist 75.7% Obstetrician gynecologist 37.3% General surgeon 38.5% Goff BA et al. Cancer. 2007;109(10):2031-2042. * South Carolina admissions HIGH VOLUME SURGEONS MOST LIKELY TO PERFORM COMPREHENSIVE SURGERY: HIGH VOLUME SURGEONS MOST LIKELY TO PERFORM COMPREHENSIVE SURGERY Ovarian Cancer Surgery by: Surgeon Surgery Volume Percentage of Cases Rate of Comprehensive Surgery Very Low 1 case/year 25.2% 55.2% Low / Medium 2-9 cases/year 22.7% 65.1% High ≥ 10 cases/year 52.1% 75.2% LESS THAN HALF OF OVARIAN CANCER SURGERY IS AT HIGH VOLUME HOSPITAL: LESS THAN HALF OF OVARIAN CANCER SURGERY IS AT HIGH VOLUME HOSPITAL Ovarian Cancer Surgery by: Hospital Surgery Volume Percentage of Cases Rate of Comprehensive Surgery Low 1-9 cases/year 33.3% 57.4% Medium 10-19 cases/year 18.1% 69.5% High ≥ 20 cases/year 48.6% 73.7% Goff BA et al. Cancer. 2007;109(10):2031-2042. SIGNIFICANTLY HIGHER SURVIVAL RATES WITH ONCOLOGY SPECIALISTS: SIGNIFICANTLY HIGHER SURVIVAL RATES WITH ONCOLOGY SPECIALISTS Study Gynecologic Oncologists Gynecologists/General Surgeons p value Eisenkop 1992 35 months 17 months <0.001 Junor 1999 18 months 13 months <0.005 Carney 2002 26 months 15 months <0.01 Tingulstad 2003 21 months 12 months 0.01 SUMMARY OF EARLY OVARIAN CANCER: SUMMARY OF EARLY OVARIAN CANCER Observation: Stage IA, grade 1-2 Stage IB, grade 1-2 Chemotherapy (3-6 cycles) Stage IA, grade 3 Stage IB, grade 3 Stage IC any grade Stage II FDA-APPROVED DRUGS IN OVARIAN CANCER: FDA-APPROVED DRUGS IN OVARIAN CANCER 1978 Cisplatin 1989 Carboplatin 1990 Altretamine 1992 Paclitaxel 1996 Topotecan 1999 Liposomal doxorubicin (accelerated) 2005 Liposomal doxorubicin (full) 2006 Gemcitabine 1978 2008 FIRST-LINE THERAPY – STANDARD TREATMENT Options: FIRST-LINE THERAPY – STANDARD TREATMENT Options Platinum + Taxane Chemotherapy ( Carboplatin + Paclitaxel ) Surgery with maximum cytoreduction effort <1cm residual disease CHEMOTHERAPY: CHEMOTHERAPY Standard front-line chemotherapy today is carboplatin , AUC 6 to 7.5, paclitaxel 175 mg/m 2 every 21 days for 6 cycles Result of several studies over last decade GOG 111 1 and OV 10 2 - paclitaxel / cisplatin vs cyclophosphamide / cisplatin GOG 158 3 and AGO OVAR-3 4 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie THE ROLE OF PACLITAXEL IN FIRST-LINE THERAPY FOR OVARIAN CARCINOMA: THE ROLE OF PACLITAXEL IN FIRST-LINE THERAPY FOR OVARIAN CARCINOMA Study # Pts Regimen Median PFS (mo) Median OS (mo) GOG 132 1 377 III suboptimal-IV Cisplatin/ Paclitaxel (24 h) x 6 14.1 26.3 Cisplatin 100 mg/m 2 x 6 16.4 30.2 Paclitaxel 200 mg/m 2 (24 h)* 10.8 25.9 ICON3 2 2074 I-IV Carboplatin/ Paclitaxel (3 h) 17.3 36.1 Carboplatin or CAP 16.1 35.4 CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 THE SCHEDULE OF PACLITAXEL IN FIRST-LINE THERAPY FOR OVARIAN CARCINOMA: THE SCHEDULE OF PACLITAXEL IN FIRST-LINE THERAPY FOR OVARIAN CARCINOMA Study # Pts Regimen Median PFS (mo) Median OS (mo) GOG 158 1 792 III optimal Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 (24 h) 19.4 48.8 Carboplatin AUC 7.5 Paclitaxel 175 mg/m 2 (3 h) * 20.7 56.7 * RR progression 0.88 (95% CI) and RR death 0.86 (95% CI) HR =0.86 (99% CI) AGO 2 798 IIB-IV Cisplatin 75 mg/m 2 Paclitaxel 185 mg/m 2 (24 h) 19.1 44.1 Carboplatin AUC 6 Paclitaxel 185 mg/m 2 (3 h) 17.2 43.3 HR = 1.050 (95% CI) HR =1.045 (95% CI) More toxicity with the cisplatin regimens 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk SCOTROC: TRIAL: Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m 2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m 2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: TRIAL Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: RESULTS: SCOTROC: RESULTS Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: CONCLUSION:  SCOTROC: CONCLUSION PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia / myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel / carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin GOG 182-ICON5 INTERNATIONAL STUDY FOR STAGE III/IV: Regimen I (control) Paclitaxel 175 mg/m 2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m 2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m 2 /d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m 2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m 2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m 2 /d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m 2 /d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m 2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m 2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 INTERNATIONAL STUDY FOR STAGE III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: PROGRESSION-FREE SURVIVAL: GOG0182-ICON5: PROGRESSION-FREE SURVIVAL Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: OVERALL Survival: GOG0182-ICON5: OVERALL Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan HISTORICAL GOG trials: HISTORICAL GOG trials Points Cisplatin/Paclitaxel became standard of care for ovarian cancer in 1996 (GOG #111) Platinum agents are the single most effective agents (GOG #132) Carboplatin/Paclitaxel is not inferior to Cisplatin/Paclitaxel; in fact, it might be superior (GOG #158) Docetaxel/Carboplatin can be substituted for Paclitaxel/Carboplatin without compromising efficacy (SCOTROC) The addition of a third chemotherapy does not improve OS or PFS (GOG #182 ) INTRAPERITONEAL CHEMOTHERAPY: INTRAPERITONEAL CHEMOTHERAPY Conclusions IP chemotherapy had a significantly better PFS and OS for women with optimally cytoreduced Stage III EOC Significant toxicity with IP chemotherapy (only 40% of women completed 6 cycles) Most patients had abdominal port/catheter issues that resulted in conversion to IV carboplatin rather than IP chemotherapy Opponents of IP chemotherapy argue that the IP regimen is not being compared to the current standard of care (Carboplatin and Taxol) Proponents argue that Cisplatin and Taxol is equally effective as Carboplatin and Taxol (GOG #158) CONVENTIONAL VS DOSE-DENSE TC (NOVEL): STUDY DESIGN:  CONVENTIONAL VS DOSE-DENSE TC (NOVEL): STUDY DESIGN Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m 2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m 2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. DOSE-DENSE CHEMOTHERAPY: DOSE-DENSE CHEMOTHERAPY Conclusions Dose-dense paclitaxel significantly improved PFS and OS 29% lower risk of progression 25% lower risk of death Low toxicity (anemia) Median follow-up 42 months, median over-all survival has not yet been reached in either group OVARIAN CANCER: NATURAL HISTORY: OVARIAN CANCER: NATURAL HISTORY Symptoms Diagnosis Chemotherapy #1 Staging Evaluation ? SLL Progression Chemo #2 Chemo #3+ Supportive Care Death Secondary Surgery Maintenance Duration Progression-Free Survival (12-28 mos) Post Progression Survival (12-38 mos) RECURRENT OVARIAN CANCER: MAGNITUDE OF THE CLINICAL PROBLEM: Stage I/II Essentially all patients will achieve a clinical CR after surgery and chemotherapy 20% to 25% will relapse Optimal stage III > 90% will achieve a clinical CR 75% will recur Suboptimal stage III and IV 50% will achieve a clinical CR > 90% will recur RECURRENT OVARIAN CANCER: MAGNITUDE OF THE CLINICAL PROBLEM THERAPEUTIC GOALS IN RECURRENT OVARIAN CANCER: Manage symptomatic patients Delay progression of disease PFS Increase survival Maintain quality of life THERAPEUTIC GOALS IN RECURRENT OVARIAN CANCER PATTERNS OF RECURRENCE: Serologic relapse Rising CA-125 only evidence of disease Localized recurrence Disseminated intraperitoneal disease Extraperitoneal metastases Recurrences can be symptomatic or asymptomatic PATTERNS OF RECURRENCE CONTROVERSIES IN RECURRENT OVARIAN CANCER: Management of an asymptomatic rise in CA-125 in patients without evidence of disease on CT scan or on physical examination Role of secondary cytoreduction Optimal chemotherapy Platinum-sensitive disease Platinum-resistant disease Use of in vitro sensitivity resistance assays Determine length of treatment Role of biologic/targeted therapy CONTROVERSIES IN RECURRENT OVARIAN CANCER MANAGEMENT OF A RISING CA-125 IN A PATIENT WHO IS CLINICALLY DISEASE FREE: Rising CA-125 is highly predictive of a clinical relapse Median time of 4-6 months before symptoms develop and/or a clinical recurrence (physical exam or imaging studies) is documented [1,2] Patient/physician preference about instituting chemotherapy is similar (~ 50%) No evidence that delaying chemotherapy until clinical relapse is detrimental Randomized trial in progress in Europe 1. Niloff JM, et al. Am J Obstet Gynecol. 1986;155:56-60. 2. Vergote IB, et al. Tumour Biol. 1992;13:168-174. MANAGEMENT OF A RISING CA-125 IN A PATIENT WHO IS CLINICALLY DISEASE FREE OVARIAN CANCER AT FIRST RELAPSE DEFINITION OF SENSITIVITY: Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” OVARIAN CANCER AT FIRST RELAPSE DEFINITION OF SENSITIVITY Defined as measurable recurrence, not biochemical (CA-125) recurrence TREATMENT OF PLATINUM-SENSITIVE DISEASE: ICON-4/AGO-OVAR-2.2 Randomization “Platinum” vs paclitaxel/carboplatin AGO, NCIC-EORTC Randomization Carboplatin vs gemcitabine/carboplatin Ongoing trial: AGO-OVAR 2.9 (CALYPSO trial) Randomization Carboplatin + PLD vs carboplatin + paclitaxel TREATMENT OF PLATINUM-SENSITIVE DISEASE CONCLUSIONS: PLATINUM-SENSITIVE RECURRENT OVARIAN CANCER: CONCLUSIONS: PLATINUM-SENSITIVE RECURRENT OVARIAN CANCER Carboplatin is key drug Carboplatin combinations are superior to single-agent carboplatin Choice of carboplatin / gemcitabine vs carboplatin / paclitaxel based on toxicity considerations Results of carboplatin /PLD vs carboplatin / paclitaxel will be available soon TREATMENT OF PLATINUM-RESISTANT DISEASE : TREATMENT OF PLATINUM-RESISTANT DISEASE DRUGS USED FOR THE TREATMENT OF PLATINUM-RESISTANT DISEASE: DRUGS USED FOR THE TREATMENT OF PLATINUM-RESISTANT DISEASE PLD Gemcitabine Topotecan GCIG CALYPSO Trial: GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E PLD 30 mg/m 2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m 2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual Completed (Target accrual 864 pts) PFS 1° endpoint Treatment Free Interval: Traditional Model: Treatment Free Interval: Traditional Model Time from last platinum exposure (TFI) Treatment Completion 6 mos Platinum Resistant/Refractory Platinum Sensitive Non-Platinum Treatment Platinum Retreatment SECONDARY CYTOREDUCTION: SECONDARY CYTOREDUCTION Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval HOW LONG TO TREAT PATIENTS WITH RECURRENT DISEASE?: HOW LONG TO TREAT PATIENTS WITH RECURRENT DISEASE? Only a minority of patients will achieve a clinical CR with chemotherapy In platinum-sensitive disease: 6% to 15% In platinum-resistant disease: 2% to 3% The majority of patients will have residual disease after 6 cycles of chemotherapy What to do? Continue with same chemotherapy if patient is asymptomatic? Stop after 6 cycles (“drug holiday”) if patient is asymptomatic? Switch to another chemotherapy? ANSWERS: ANSWERS No RCTs in recurrent disease directly address this issue In previously untreated patients, RCTs have failed to show any benefit for either continuing with the same chemotherapy or switching to a non – cross-resistant regimen In recurrent disease, the same could be expected Currently, this is a personal choice issue with patient/physician Toxicity is key Some patients will choose more therapy as long as there is evidence they are not in a remission — “ psychochemotherapy ” Benefit of “drug holidays” Why are YOU here ???:  Why are YOU here ??? Why am I here ???: Why am I here ??? Why are WE here ???: Why are WE here ??? Thanks!: Thanks!

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