gopalan031607
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http://hematology.wustl.edu/conferences/presentations/gopalan031607.pptTRANSCRIPT
Ovarian Cancer
Priya Gopalan3/16/07
Epidemiology
• 8th most common cancer type in women (estimated 22,430 new cases )
• 5th most common cause of cancer death in women (estimated 15,280 deaths )
• Average lifetime risk for women: 1 in 70
• Median age 60• 68% are metastatic at time of diagnosis• 45% 5-yr survival rate for all stages (10-30% for metastatic disease)
From: Jemal et al., CA Cancer J Clin 2007; 57:43-66
Risk factors
• Family history of ovarian/breast cancer
• Personal history of breast cancer (esp. at young age)
• Infertility/nulliparity/uninterrupted ovulation– OCP use, pregnancy, lactation and tubal ligation reduce risk
Genetics of ovarian cancer
• Genetic syndromes account for 10-15% of ovarian cancers
• BRCA1– Germline mutation - in women, confers lifetime risk of:• ovarian cancer: 16-44%• breast cancer: 56-87%
• BRCA2– Germline mutation - in women, confers lifetime risk of:• ovarian cancer: 10%• breast cancer: ~60-85%
Genetics
• Lynch syndrome II– HNPCC (hereditary nonpolyposis colorectal cancer)
– Also have endometrial, ovarian, GU, other GI cancers
– Germline mutations in DNA mismatch repair genes, such as MSH2 or MLH1
Symptoms
• Nonspecific• Lower abdominal discomfort, nausea, bloating, constipation, lower back pain, fatigue
• Abdominal fullness, increased abdominal girth, early satiety
• Dyspnea • Pelvic pain• Sx of small bowel obstruction• Sx of urinary tract obstruction, hydronephrosis
Symptoms
• Paraneoplastic findings– Hypercalcemia (particularly clear cell)
– Subacute cerebellar degeneration – Trousseau’s syndrome – Sign of Leser-Trelat
Physical Exam
• Solid, fixed, irregular pelvic mass
• Ascites
Work-up of Ovarian Mass
• Pelvic ultrasound • CBC, LFTs• CT abdomen/pelvis• CXR• Tumor markers• NO NEEDLE BIOPSIES - risk of tumor spillage into peritoneal cavity
Tumor Markers
• CA-125 – Elevated in 50% of stage I and 80-90% of stage II- IV tumors
– Non-specific increase in benign ovarian tumors, fibroids, adenocarcinomas (e.g. breast)
– Follow for efficacy of treatment, to detect recurrence
• CA 15-3
Tumor Markers
• FP (alpha fetoprotein)- in germ cell tumors
• -hCG (human chorionic gonadotropin)- in germ cell tumors
• Inhibin - in stromal tumors• YKL-40 - secreted glycoprotein
– Elevated in 36/50 CA pts, while 23/50 had elevated CA125 (p<0.008)*
*Dupont JCO 2004
Screening
• Routine CA-125 and endovaginal ultrasound not useful for screening of general population*
– UK pilot study** - 20,000 women- survival for those detected with ovarian CA: 73 mo (screened) vs. 43 mo (unscreened)
– F/U study with 200,000 women - CA125 (then U/S) has PPV 21%•OS?
* NIH consensus conf. JAMA 1995** Jacobs et al., Lancet 1999
Screening/prevention in high-risk patients
• BRCA-1 and BRCA-2 germline mutation– prophylactic BSO
• Also reduces risk of breast CA• Can still be at risk for primary peritoneal carcinoma
– oral contraceptives - controversial – close screening (not proven to be effective in high-risk patients)• Frequent pelvic exams• CA125 q6-12 mo• Transvaginal Ultrasound q6-12 mo
• HNPCC– prophylactic TAH/BSO
Pathology
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are needed to see this picture.
From Up-to-date
3 main histological types
Pap.
(90%)
Psammoma Body
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From: Indiana University Dept. of Pathology and Laboratory Medicine (erl.pathology.iupui.edu)
Staging for Epithelial Ovarian Cancer
From: Cannistra S. N Engl J Med 2004;351:2519-2529
I - OvariesII - Pelvic visceraIII - Peritoneal implants, liver serosa, small bowel, omentumIV - Distant mets (liver parenchyma)
Treatment
• Exploratory Laparotomy - Diagnosis, Staging and Treatment– Goal: Maximal debulking (try to remove all visible disease)• Optimal debulking = No tumor mass > 1cm• Suboptimal debulking
– Follow GOG surgical protocol to definitively stage
– Best done in an “expert center”
Surgery
• TAH/BSO• Visual examination of all peritoneal surfaces
• Visual inspection/palpation of liver• Omentectomy• Para-aortic lymph node biopsy• Peritoneal washings• Random biopsies of clinically uninvolved areas
Surgical debulking of advanced disease
• Meta-analysis of 53 studies published 1989-1998
• Patients were stages III/IV• Underwent initial cytoreduction (debulking), followed by platinum-based chemo
• Maximal cytoreduction occurred if residual disease measured ≤ 3 cm in largest diameter
Bristow RE et al. JCO 2002, 20:1248-59.
Copyright © American Society of Clinical Oncology
Bristow, R. E. et al. J Clin Oncol 2002; 20:1248-1259.
Favorable Prognostic Factors
• Age (< 65)• Good performance status• Stage (I or II)• No ascites• Optimal surgical debulking • Non-clear cell type• Well-differentiated (Grade I or II)• Diploid tumor (no aneuploidy)• Low post-op CA125
Adjuvant chemotherapy• Standard chemo regimens
– Carboplatin(AUC 5-6)/paclitaxel (175mg/m2) q21d x 6 cycles
– Cisplatin (75mg/m2)/paclitaxel (135mg/m2) q21d x 6 cycles
– Carboplatin (AUC 5-6)/docetaxel (60-75mg/m2) q21d x 6 cycles
*Ozols et al. JCO 2003, 21:3194-3200.**Vasey et al. JNCI 2004, 96:1682-91.
Adjuvant Chemotherapy
• Cisplatin and carboplatin have equal efficacy in combination with paclitaxel*
• Paclitaxel and docetaxel have equal efficacy in combination with carboplatin**
*Ozols et al. JCO 2003, 21:3194-3200.**Vasey et al. JNCI 2004, 96:1682-91.
Alternative Adjuvant Chemo
• Platinum/cyclophosphamide• Doxorubin/cyclophosphamide • 3-drug combinations
– Two phase III trials comparing 3 drugs to carbo/taxol showed no additional benefit (Bookman ASCO 2006, Scarfone ASCO 2006)
Current controversies in chemo
• First-line intraperitoneal chemotherapy
• Chemo in “high-risk” early stage disease
• Maintenance chemotherapy
Intraperitoneal chemotherapy
• Rationale: Since the peritoneal cavity is the principal site of disease, direct administration of chemo into the peritoneum will permit exposure to high concentrations of chemo for a prolonged period of time, while reducing generalized toxicities from intravenous administration.
Phase III trials of intraperitoneal
cisplatin/paclitaxelTrial
Chemo-contro
l
Chemo-study
PFS OS %receiving IP
Alberts
IV cytoxan + IV cis
IV cytoxan + IP cis
---
IV:41 moIP:49 mo(p=0.02)
18% ≤ 2 IP
MarkmanIV taxol + IV cis
IV carbo x 2, IV taxol + IP cis
IV:22 moIP:28 mo (p=0.01)
IV:52 moIP:63 mo(p=0.05)
18% ≤ 2 IP
Armstrong
IV taxol + IV cis
IV taxol + IP cis,IP taxol on d8
IV:18 moIP:24 mo(p=0.05)
IV:50 moIP:66 mo(p=0.03)
42% got 6 IP(41% ≤ 2 IP)
Alberts et al, NEJM 1996Markman et al, JCO 2001Armstrong et al, NEJM 2006
Intraperitoneal chemo
• Grade 3 and 4 toxicities more common in IP group
• Pain, fatigue, myelotoxicity, GI, neurologic• Quality of life worse in IP group during and immediately after treatment, but equivalent at one year
• Rec: Consider in women with stage III tumor and small-volume residual disease after maximal debulking– Taxol 135 mg/m2 IV + Cis 100mg/m2 IP + (day 8) Taxol 60mg/m2 IP
Chemo in “high-risk” early stage patients
• Stage IA or IB with grade 2 or 3, stage IC, stage IIA, stage I-IIA clear-cell
• ICON1 trial and EORTC-ACTION trial – After surgery, randomized to platinum-based chemo or observation
– ACTION trial had strict guidelines on patient eligibility, surgical staging and chemo
– Improved PFS and OS with chemo– Most effective in suboptimally debulked patients
ICON1. JNCI, 2003, 95:125-32.Trimbos et al. JNCI, 2003, 95:113-124.
Trimbos, J. B. et al. J. Natl. Cancer Inst. 2003 95:113-125.
OS, optim. debulked
OS, suboptim. debulked
RFS, optim. debulked
RFS, suboptim. debulked
* *
Maintenance Chemotherapy
• Single-agent paclitaxel– Enrolled women with complete response to platinum/paclitaxel combination - 262 evaluable
– Received 3 vs. 12 additional cycles of paclitaxel (175 mg/m2) q28d
– Closed early because of significant diff. in PFS (21 for 3 cycles vs. 28 months for 12 cycles, p=0.0023)• No difference in OS at time of study closure
• Rec: Discuss results of this trial and give pt. option of receiving maintenance paclitaxel
Markman et al. JCO 2003, 21:2460-65.
Role of radiation
• No longer used as part of primary treatment in U.S.– May be used in platinum-resistant disease
• Occasionally used for large pelvic recurrences, brain and bone mets
• NCCN guidelines: option for microscopic Stage III disease (category 3 recommendation)
Stage I
• Favorable prognostic factors (Stage IA and IB, grade 1 and ?2)– Treat with surgery alone (5-yr. survival 90-95%)
• Unfavorable prognostic factors (grade ?2 and 3, stage IC)– Surgery then 6 cycles of chemo
Stage II
• Favorable prognostic factors– Surgery then chemo (?3-4 cycles)
• Unfavorable prognostic factors– Surgery then 6 cycles of chemo
Stages III, IV
• Surgery then 6 cycles of chemo– ?Maintenance therapy - 12 cycles of paclitaxel
Routine Monitoring
• >50% patients with surgery and chemo get complete CR (normal exam, CA125 and CT)
• Monitor with exams and CA125• Use of “second-look” laparotomy not supported (Ozols JCO 2003)
Recurrent/persistent disease• Majority of patients with advanced disease
relapse• Often see tumor marker increase ~ 3 months before clinical/radiological detection
• “Secondary cytoreduction” might be helpful in patients with >6-12 month first remission (Hoskins Gynecol Oncol 1989)
• Usually responds to series of different chemo regiments– Response rate to each drug 10-20%– Can see 5-10 yr. survivals after recurrence, with good quality of life
Treatment of asymptomatic recurrence
• Consider tamoxifen or aromatase inhibitor for patients with asymptomatic recurrence (tumor marker-only recurrence)– Markman M et al. Gynecol Oncol 1996; Bowman et al. Clin Cancer Res 2002)
– Fewer than 20% have response to hormonal therapy, but occ. see marked decrease in CA125 and prolonged stable disease
2nd Line Chemotherapy
• Usually single agent chemo• Clinical trial• Carbo/cis if platinum-sensitive (≥ 6 months since last dose)– Response rate ≥ 30% (Cannistra et al. JCO 2002)
– >60% response rate if ≥ 2 years since prior treatment (Cannistra et al. JCO 2002, Markman et al. JCO 1991)
– Add taxol, if taxane-sensitive
2nd line Chemotherapy (cont’d)
• Liposomal doxorubicin• Topotecan• Gemcitabine• Taxotere, paclitaxel• 5-FU• Oral etoposide• Vinorelbine• Hexamethylmelamine (alkylating agent)
Biological agents
•Trials with VEGF and EGFR inhibitors in progress–Newly-diagnosed disease–Tumor marker-only relapse–Several phase II trials with bevacizumab as 2+ line therapy in advanced disease
Summary
• Surgery is important for diagnosis, staging and treatment.
• Surgery is initial treatment for all stages (even metastatic).
• Platinum/taxane combinations are standard regimen, usually for 6 weeks.
• “High risk” early stage disease benefits from chemo if suboptimally debulked.
• Intraperitoneal chemotherapy is beneficial, and used routinely for stage III patients.
Treatment of non-epithelial cancers
• Germ cell tumors - Surgery, then…– Stage I dysgerminoma/Stage I (Grade 1) immature teratoma - OBSERVE
– Everything else - CHEMO (BEP = Bleo, Etoposide, Cis)
• Stromal tumors - Surgery, then…– Stage I low risk - OBSERVE– Stage I high risk (Stage IC or grade 3) - Observe or cis-based chemo or RT
– Stage II-IV - • Limited disease - RT• Otherwise, platinum-based chemo (BEP or carbo/taxol or etoposide/carbo ± doxorubicin)