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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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)