![Tumor Markers (young women <35)
CA-125, Inhibin,
Alpha-fetoprotein
[AFP],
Beta– human chorionic
gonadotropin [beta-
hCG])](https://image.slidesharecdn.com/metastaticovariancancer-180616161940/85/Metastatic-ovarian-cancer-13-320.jpg)
![PFS favored platinum and paclitaxel
1-year progression-free
survival of 10% (50 vs
40% [4-15])
Median progression-free
survival of 3 months (13
vs 10 months [1-5]).](https://image.slidesharecdn.com/metastaticovariancancer-180616161940/85/Metastatic-ovarian-cancer-55-320.jpg)
![MITO-11
PFS was increased in the
paclitaxel/pazopanib arm when
compared with paclitaxel alone
(median 6.35 months [95% CI,
5.36–11.02] vs. 3.49 months
[2.01–5.66]](https://image.slidesharecdn.com/metastaticovariancancer-180616161940/85/Metastatic-ovarian-cancer-63-320.jpg)
Metastatic ovarian cancer
- 2. HPI 56 F PMH asthma glaucoma, was first seen by her gynecologist for a right ovarian mass palpable on her routine gynecologic exam in May, 2015 for DUB and underwent ultrasound. Showed bilateral complex adnexal masses with the left ovary with 9.5 x 8 cm solid and cystic mass and a 7.8 x 7.4 cm mass at the left ovary. Fluid and implants were also seen in the cul-de- sac. In retrospect, she had noted abdominal bloating and had to get larger pants. Patient also reported a decreased appetite.
- 3. History PMH : Glaucoma, asthma, fibroid, chronic back ache PSH : D&C fibroids, wisdom teeth extraction Social history: Occasional alcohol drinker, non-smoker. No children, (because of late marriage). She works at Macy’s. Family History: Father with bladder and lung Ca, +h/o smoking, 2 brothers- no h/o cancer
- 4. Physical Exam General: Well-developed, well-nourished 55 y.o. female in no apparent distress HEENT: Pupils are equal and reactive to light, extraocular movement intact, sclera is anicteric. No lymphadenopathy Neck: Supple, no JVD Respiratory: Clear to auscultation.. Cardiovascular: Regular rate and rhythm, normal S1 and S2 Abdomen: Soft, nontender. No hepatosplenomegaly is appreciated, no masses. Extremities: No edema, clubbing or cyanosis is noted. Skin: Unremarkable Lymph Nodes: No lymphadenopathy is noted. Neuro: Alert and oriented ×3, nonfocal.
- 8. Epidemiology Fifth most common cause of cancer related mortality in women Most common gynecologic cancer in the US In 2018, estimated 22,240 new diagnoses expected 14,070 deaths expected <40% are cured 5 year survival 46% Median age- 63 70% cases are diagnosed with advanced disease
- 9. Epidemiology Nulliparity Older age at first pregnancy (>35yrs) PID Postmenopausal hormone therapy BRCA1/BRCA2; Lynch Syndrome Inverse correlation with- Younger age at first pregnancy (<25yrs) No association with obesity
- 10. Symptoms Bloating, Pelvic or abdominal pain, Difficulty eating/early satiety, Urinary symptoms (urgency or frequency), If these symptoms are new and frequent (>12 d/mo) Literature does not support routine screening for ovarian cancer in the general population
- 12. Workup Abdominal/pelvic ultrasound (Initial evaluation) 1 Abdominal/pelvic CT/MRI scan (to assess for metastasis) 2 Tumor markers 3 Biopsy (?) 4
- 13. Tumor Markers (young women <35) CA-125, Inhibin, Alpha-fetoprotein [AFP], Beta– human chorionic gonadotropin [beta- hCG])
- 14. Caution Fine-needle aspiration (FNA) should be avoided for presumed early-stage disease if possible To prevent rupturing the cyst and spilling malignant cells into the peritoneal cavity; however, FNA may be necessary in patients with bulky disease
- 17. Primary Treatment TAH/BSO + Debulking Systemic chemotherapy Surgeon should describe the following in the operative report: 1) the extent of initial disease; 2) the amount of residual disease; and 3) whether a complete or incomplete resection (including a description of the lesions) was achieved
- 18. Fertility Preservation Unilateral salpingo-oophorectomy (USO) (preserving the uterus and contralateral ovary) may be adequate for Unilateral stage I tumors (stage 1A and 1C, but not stage 1B) low-risk ovarian tumors (ie, early-stage, grade 1 tumors; borderline tumors). Stage IB tumors who wish to maintain fertility, a BSO (preserving the uterus) and comprehensive surgical staging are needed.
- 19. Debulking Surgery Remove all gross disease, Aspiration of ascites with peritoneal lavage Hysterectomy and BSO should be performed. Encapsulated mass should be removed intact, Omentectomy. Suspicious and/or enlarged nodes should be resected, if possible. Bilateral pelvic and para- aortic lymph node is recommended for those patients with tumor
- 20. Neoadjuvant Chemotherapy Stage III to IV disease deemed unlikely to be completely cytoreduced to R0 Gynecologic oncologist should make this assessment Before initiation of neoadjuvant chemotherapy- Histologic confirmation of ovarian cancer should be obtained (by FNA, biopsy, or paracentesis); Core biopsy is preferred.
- 22. OV21/PETROC Multicenter, two-stage, phase II trial. Eligible patients with stage IIB–IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (<1 cm) debulking surgery were randomized to treatment arms: (i) i.v. carboplatin/paclitaxel, or (ii) i.p. carboplatin plus i.v./i.p. paclitaxel. The primary end point was 9-month progressive disease rate (PD9). The analysis compared i.v. carboplatin/paclitaxel (n = 101) with i.p. carboplatin, i.v./i.p. paclitaxel (n = 102). The intention to treat PD9 was lower in the i.p. carboplatin arm compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%) versus 38.6% (95% CI 29.1% to 48.1%) P = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57–1.17); P = 0.27 and OS HR 0.80 (95% CI 0.47–1.35) P = 0.40.
- 25. Retrospective analysis of the EORTC-NCIC trial Stage IIIC patients with metastatic tumours ⩽45 mm benefited more from primary surgery Stage IV patients with metastatic tumours >45 mm benefited more from neoadjuvant chemotherapy. Stage IIIC patients with larger metastatic tumors and in stage IV patients with less extensive metastatic tumours both treatments were equally effective. We estimated that the potential five-year survival rate in the population of treated patients would be 27.3% (95% confidence interval (CI) 21.9–33.0), 7.8% higher than if all were treated with primary surgery, and 5.6% higher if all were treated with neoadjuvant chemotherapy.
- 26. Neoadjuvant vs PDS Large (586 patients) single-institution study in the United States reported that patients with advanced ovarian cancer who had standard debulking surgery had improved median overall survival (71.7 months) when compared with those who had neoadjuvant chemotherapy (42.9 months). A report of more than 14,000 patients reported that median survival is improved by almost 2 years in those receiving upfront debulking surgery when compared with those receiving neoadjuvant chemotherapy (69 vs. 45 months). A recent retrospective Italian study in women in complete response after primary treatment reported better outcomes with upfront surgery (n = 322) when compared with neoadjuvant therapy followed by surgery (n = 62); overall survival at 2 years, 5 years, and 7 years was 96.4%, 69.3%, and 50.4% for upfront surgery versus 87.1%, 41.8%, and 32.6% for neoadjuvant therapy (P =.001)
- 29. Adjuvant Chemotherapy IV/IP chemotherapy regimen (IP chemotherapy) is recommended for patients with stage III cancer with optimally debulked (<1 cm residual) disease based on randomized controlled trials (category 1).1 In women with stage III cancer, survival was increased by 16 months after IP therapy using cisplatin/paclitaxel when compared with standard intravenous therapy GOG 172 trial
- 37. Postremission Therapy Paclitaxel (category 2B) is a postremission therapy option for patients with stages II to IV epithelial ovarian cancer, Fallopian tube cancer, or primary peritoneal cancer who have had complete clinical remission after first-line therapy. Maintenance (or postremission) therapy an option based on the results from GOG 178 (No OS difference)
- 41. Median overall survival was no different between the groups, at 54.8 months with surveillance, 51.3 months with paclitaxel, and 60 months with PP. The hazard ratio (HR) for paclitaxel vs surveillance was 1.104 (97.5% CI, 0.884–1.38); for PP vs surveillance, it was 0.979 (97.5% CI, 0.781–1.23).
- 45. Management of an Increasing CA-125 Level A multi-institutional European trial assessed the use of CA-125 for monitoring for ovarian cancer recurrence after primary therapy The data suggest that treating recurrences early (based on detectable CA-125 levels in patients who are asymptomatic) is not associated with increase in survival and is associated with a decrease in quality of life
- 48. Rising CA-125 Refer for a clinical trial Delaying treatment (ie, observation) until clinical symptoms arise, or Immediate treatment (category 2B) Tamoxifen, other hormonal agents are acceptable recommendations for this clinical situation (category 2B for all)
- 49. 105 patients with Stage III or IV epithelial ovarian cancer Tamoxifen (20 mg orally twice daily) and evaluated for response. 18% responded: 10% demonstrated a complete response (CR) and 8% showed a partial response (PR). 38% had short-term disease stabilization. CR had a median duration of 7.5 months, with the longest lasting 17 months. Patient with CR- 89% had elevated estrogen receptor levels. This contrasts with patients who had stable or progressive disease as only 59% of them had measurable estrogen receptors (P = 0.16)
- 50. Recurrent Disease Prognosis is poor either 1) for patients who progress after 2 consecutive chemotherapy regimens without ever sustaining a clinical benefit (refractory) 2) for those whose disease recurs in less than 6 months (platinum resistant) Patients who relapse 6 months or more after initial chemotherapy are termed platinum sensitive. Combination platinum-based chemotherapy for a total of 6 cycles is preferred for first recurrence (category 1) in patients with platinum-sensitive disease
- 51. Secondary cytoreductive surgery can be considered for patients who recur (ie, radiographic and/or clinical relapse) after a long disease-free interval (6 months or more) Re-evaluation should follow after 2 to 4 cycles of chemotherapy (depending on the agent) to determine if patients benefited from chemotherapy. Patients who primarily progress on 2 consecutive chemotherapy regimens without evidence of clinical benefit may not benefit from additional therapy. Platinum-based combination chemotherapy is recommended (category 1) for a total of 6 cycles for platinum-sensitive recurrence For patients with platinum-sensitive disease who cannot tolerate combination therapy, the preferred single agent is carboplatin or cisplatin.
- 52. Preferred combinations carboplatin/paclitaxel (category 1), carboplatin/liposomal doxorubicin (category 1) carboplatin/weekly paclitaxel, carboplatin/albumin-bound paclitaxel (for taxane hypersensitivity), carboplatin/docetaxel, carboplatin/gemcitabine (which has been shown to improve PFS) cisplatin/gemcitabine, or carboplatin/gemcitabine/bevacizumab.
- 55. PFS favored platinum and paclitaxel 1-year progression-free survival of 10% (50 vs 40% [4-15]) Median progression-free survival of 3 months (13 vs 10 months [1-5]).
- 61. Conclusions Carboplatin/liposomal doxorubicin has a better PFS compared to carboplatin/paclitaxel. Carboplatin/liposomal doxorubicin is easier to tolerate; (women tend to discontinue therapy with carboplatin/paclitaxel more often than they do with carboplatin/liposomal doxorubicin. )
- 62. Platinum resistant disease Sequential therapy using single agents is typically used Response rate of the following agents appears to be similar: Topotecan, 20%; Gemcitabine, 19%; Liposomal doxorubicin, 26%; Oral etoposide, 27%.356 Docetaxel is 22% and for Weekly paclitaxel is 21%.
- 63. MITO-11 PFS was increased in the paclitaxel/pazopanib arm when compared with paclitaxel alone (median 6.35 months [95% CI, 5.36–11.02] vs. 3.49 months [2.01–5.66]
- 72. BRCA The most common type of ovarian cancer, high grade serous ovarian cancer, frequently has defects in the genes involved in the DNA repair pathway, homologous recombination. Mutations of BRCA1 and BRCA2 occur in 20- 25% of high grade serous carcinomas of the ovary. Sporadic, non-hereditary tumors with defects in homologous recombination display similar features to BRCA mutant tumors, so called “BRCAness
- 73. BRCA BRCA mutated and BRCA like tumors have higher response rates to platinum based chemotherapy than non-BRCA ovarian cancers, with improved overall survival and prolonged treatment-free intervals. With deficient homologous recombination, the other DNA repair pathways become more important and PARP is an integral part of the other pathways.
- 74. Who Should Get Genetic Testing Young age, < 50 Triple negative breast cancer Bilateral breast cancer, or breast and ovarian cancer Ovarian cancer Male breast cancer Ashkenazi Jewish Ancestry Strong family history, two first or second degree relatives > 50, or one < 50.
- 75. PARP inhibitors Poly (ADP Ribose) Polymerase (PARP) is a group of enzymes important in DNA repair. BRCA mutations result in defects in homologous recombination. Tumors with defects in homologous recombination require PARP for cell survival. PARP inhibitors are active in BRCA mutated tumors and tumors with defects in homologous recombination.
- 77. PARP inhibitors There are currently three PARP inhibitors approved for use in different indications in high grade serous ovarian cancer. Olaparib is approved for breast cancer patients with BRCA mutations. There are over 100 clinical trials investigating PARP inhibitors, and taking advantage of synergistic anti- tumor activity.
- 85. Common adverse reactions (≥20%) Anemia, nausea, fatigue (including asthenia), Nasopharyngitis, Diarrhea, Aarthralgia/myalgia, Headache, Cytopenias
- 90. Back to our case Neoadjuvant chemotherapy with carboplatin and weekly paclitaxel x6 , and had an excellent response She underwent debulking surgery, Her CA 125 normalized and her post-treatment CT and PET scans were negative.
- 91. CT followed by PET showed recurrence after her CA 125 was slowly going up.
- 92. Treatment Consented to Carboplatin and Doxil, which she started 10/7/16. She completed 6 full cycles, and her re- staging showed a complete response. Maintenance Niraparib
- 93. Thank you
Editor's Notes
- #31: intravenous paclitaxel plus cisplatin, intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel ;; 410 patients were randomized
- #44: PFS= 12.3 vs 17.9 months; OS= No difference
- #85: HRD= Homologous recombination deficient; ITT= Intent to treat Least benefit with BRCA WT; PFS of 9.7 months