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http://hematology.wustl.edu/conferences/presentations/gopalan031607.ppt

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  • PFS 16 mo for subopt. debulking/stage IV, 24 mo for opt. debulking

gopalan031607 gopalan031607 Presentation Transcript

  • Ovarian Cancer Priya Gopalan 3/16/07
  • 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 From Up-to-date 3 main histological types Pap. (90%)
  • Psammoma Body 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 - Ovaries II - Pelvic viscera III - Peritoneal implants, liver serosa, small bowel, omentum IV - 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.
  • 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/paclitaxel Alberts et al, NEJM 1996 Markman et al, JCO 2001 Armstrong et al, NEJM 2006 IV taxol + IP cis, IP taxol on d8 IV carbo x 2, IV taxol + IP cis IV cytoxan + IP cis Chemo-study 42% got 6 IP (41% ≤ 2 IP) IV:50 mo IP:66 mo (p=0.03) IV:18 mo IP:24 mo (p=0.05) IV taxol + IV cis Armstrong 18% ≤ 2 IP IV:52 mo IP:63 mo (p=0.05) IV:22 mo IP:28 mo (p=0.01) IV taxol + IV cis Markman 18% ≤ 2 IP IV:41 mo IP:49 mo (p=0.02) --- IV cytoxan + IV cis Alberts %receiving IP OS PFS Chemo-control Trial
  • 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.
  • Copyright restrictions may apply. Trimbos, J. B. et al. J. Natl. Cancer Inst. 2003 95:113-125. Copyright restrictions may apply. 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)