Ovary Part 2

Medical StudentsResidentsOvarian Cancer
Written By Sydney Oesch

Episode Notes

Surgical Intervention

  1. Defining residual disease after cytoreduction

    1. Optimal cytoreduction: < 1 cm gross residual disease in any single location/implant

    2. R0: no visible/gross residual disease

    3. Otherwise, suboptimal

  2. GOG 172 , GOG 182/ICON 5

    1. Subgroups with R0 cytoreduction improved OS ≥ 24 mo compared to pts w/ residual disease

  3. Lymphadenectomy

    1. Panici 2005

      1. N = 427

      2. Randomized to systematic lymph node dissection vs removal of bulky lymph nodes in optimally debulked advanced ovarian cancer

      3. Improved staging accuracy, no oncologic benefit to systematic lymphadenectomy

      4. Conflicting retrospective analyses and meta-analysis showed OS benefit with systematic lymphadenectomy

    2. LION

      1. Stage IIB-IV ovarian cancer with clinically negative lymph nodes and complete surgical cytoreduction

      2. PPaLND vs no LND

      3. No difference in OS or PFS

      4. Longer surgery, higher blood loss/transfusion, higher repeat laparotomy, readmission, and death rates within 60 days in PPaLND group

    3. LION trial established that systematic lymphadenectomy for patients with advanced stage EOC does not improve outcomes and shouldn’t be done, even though it does detect some microscopic metastases.  One caveat does exist, which is that bulky lymph nodes should be resected in all patients, if surgically feasible, as with all other bulky disease!

  4. Chemotherapy

    1. GOG 158

      1. Established carbo/taxol as SOC

      2. 2003, n = ~800

      3. Carboplatin + paclitaxel vs cisplatin + paclitaxel

      4. PFS and OS not different

      5. Worse GI, GU, leukopenia, and metabolic toxicities w/ cisplatin

      6. Thrombocytopenia worse w/ carboplatin

    2. Alternative Agents?

      1. MITO-2

        1. Carboplatin + liposomal doxorubicin vs carboplatin + paclitaxol

        2. No differences in OS or PFS

        3. Carbo/doxil: less neurotoxicity, alopecia; more hematologic adverse events

      2. SCOTROC 1

        1. Docetaxel + carboplatin vs paclitaxol + carboplatin

        2. No difference in PFS, OS, ORR

        3. Docetaxel/carbo: less neurotoxicity, more G3-4 neuropenia

      3. GOG182/ICON5

        1. Evaluated whether adding a third agent to carbo/taxol improves outcomes

        2. Extra agent included doxil, topotecan, gemcitabine in two dosing regiments

        3. No improvement in PFS or OS in any arm

    3. Alternative Dosing?

      1. JGOG 3016, Katsumata

        1. Dose dense weekly taxol (80 mg/m2) w/ carboplatin AUC 6 every 3 weeks vs carbo/taxol (180 mg/m2) at standard q3 week dosing

        2. ddChemo toxic - 36% discontinued treatment early; 60% of discontinuations d/t hematologic toxicity

          1. Thus, lower dose intensity of carboplatin dd group, but dose intensity of taxol higher in dd group

        3. ddChemo improved PFS to 28 vs 17 mo, 3 year OS 72 vs 65%

      2. MITO-7

        1. Attempted to corroborate results

        2. Carbo/taxol standard dosing vs weekly carboplatin AUC 2 + taxol 60 mg/m2 weekly x 18 weeks

        3. PFS not different

        4. QOL and toxicity scores worse in standard q3 wk regimen

        5. This regimen is often used in patients that are more frail/may not tolerate standard chemo dosing, in an effort to reduce treatment-related QOL and toxicity

      3. ICON8

        1. Standard dosing carbo/taxol, MITO-7 carbo/taxol, dose-dense taxol + standard carboplatin (JGOG 3016)

        2. No difference in PFS or OS

        3. Caused ddChemo to fall out of favor in US

      4. GOG 262

        1. carbo/taxol +/- bevacizumab vs carbo + dose dense paclitaxel +/- bevacizumab

        2. No difference in outcomes

      5. GOG 252

        1. IV carbo + ddTaxol + bev vs IP carbo + ddTaxol + bev vs IP cisplatin + IP taxol + IV taxol on day 1.

        2. 43% of patients on trial w/ suboptimal debulking

        3. No difference in PFS between 3 groups

    4. Maintenance Therapy

      1. Single-agent paclitaxel

        1. GOG 178

          1. 3 cycles vs 12 cycles of taxol maintenance

          2. Improved PFS from 21 mo in 3 cycle group to 28 mo in 12 cycle group

      2. Bevacizumab

        1. GOG 218

          1. carbo/taxol +/- bev in pts w/ stage 3 suboptimally debulked or stage IV EOC disease

          2. three arms to the study: carboplatin + palitaxel vs carboplatin + paclitaxel  + bevacizumab (bev-concurrent) in cycles 2-6 vs carboplatin + paclitaxel + bevacizumab in cycles 2-22 (bev-concurrent plus maintenance)

          3. PFS improved from 10.3 to 14.1 months in the group receiving bevacizumab maintenance

          4. OS, HR for progression or death not different

          5. Did not find BRCA status predictive of bevacizumab activity

        2. ICON7

          1. carbo/taxol/bev vs carbo/taxol

          2. PFS improved, but only by 1.5 mo

            1. Benefit peaked at 12 mo, but by 24 mo, effect no longer seen and then actually became worse for the bev group vs standard group

          3. In high risk of progression group - stage IV or suboptimally debulked/inoperable stage II disease - PFS 18 mo w/ bev vs 14.5 w/o and OS 36.6 mo w/ bev vs 28.8 mo w/o

          4. The beneficial effect of bevacizumab in exploratory analyses suggested that patients with the largest residual tumor burden would most greatly benefit

        3. Boost

          1. PDS followed by 6 cycles standard treatment -> bev x 15 cycles vs 30 cycles

          2. No difference between arms

        4. To synthesize the results of the above trials, it seems that bevacizumab is best for patients with “high risk for progression of disease”.  This is generally designed as suboptimally debulked stage III disease, inoperable stage III disease, or stage IV disease.

        5. KELIM

          1. stands for the modeled CA-125 elimination rate constant K

          2. calculated by using at least three CA-125 values during the first 100 days of neoadjuvant or adjuvant therapy

          3. Colomban et al, 2020

            1. found among the patients with high-risk disease, those with favorable standardized KELIM of at least 1.0 (46.7%) had no survival benefit from bevacizumab, whereas those with unfavorable KELIM less than 1.0 (53.2%) derived the highest OS benefit, with an absolute difference of 9.1 months.

    5. Neoadjuvant Chemotherapy

      1. EORTC 55971

        1. NACT versus PDS followed by chemo in patients with stage III-IV EOC

        2. Optimal debulking was achieved in 81% of patients with NACT and 42% with PDS

        3.  HR for progression and death were both noninferior.  Notably, PFS and OS were only about 12 months and 30 months respectively in both groups.

        4.  After this trial, the question still remained - if the rate of optimal debulking was increased, why were we not seeing a concomitant increase in overall survival with neoadjuvant chemotherapy?

      2. CHORUS

        1. NACT followed by IDS vs PDS followed by CT in stage III or IV EOC

        2. Optimal cytoreduction in 24% PDS and 34% in IDS

        3. PFS and OS not different

      3. SCORPION

        1. PDS w/ CT vs NACT w/ IDS

        2. All patients got laparoscopic evaluation w/ Fagotti score prior to assignment

        3. With this system, really high rates of optimal debulking were achieved - 93% in the primary debulking and 99% in the interval debulking groups!

        4. PFS and OS not different

      4. JCOG0602

        1. NACT w/ IDS vs PDS w/ CT

        2. NACT doubled chance of optimal debulking

        3. No difference in PFS or OS

      5. Takeaway: no trial can prove a progression or survival benefit of neoadjuvant chemotherapy versus primary debulking surgery, but it does seem to improve the likelihood of an optimal debulking and possibly reduce the rate of complications/surgical morbidity

    6. PARP Inhibitors

      1. FDA approvals for the following PARP inhibitors for up front maintenance therapy

        1. olaparib for germline or somatic BRCA mutated

        2. olaparib with bevacizumab in germline or somatic BRCA mutated or HRD

        3. niraparib for patients with any BRCA or HRD status

      2. SOLO-1

        1. patients with advanced high grade serous or endometrioid ovarian cancer with BRCA mutations

        2. carboplatin + paclitaxel vs carboplatin + paclitaxel followed by olaparib for 2 years

        3. HR for PFS in the olaparib maintenance group was 0.30 and the median PFS was not reached.

      3. PRIMA

        1. stage III or IV high grade serous or endometrioid ovarian cancer with prior first-line platinum therapy with partial or complete response with or without a BRCA mutation

        2. hierarchical design: first analyzed whether the tumor had HRD via a BRCA mutation or “mychoice” score of > 42.  If positive, they were moved to an intention to treat analysis.  

        3. niraparib maintenance for 36 months after frontline therapy versus placebo maintenance

        4. PFSin the HRD population to be 21.9 months on niraparib vs 10.4 months on placebo.  The median PFS in all comers was 13.8 months vs 8.2 months

        5. exploratory analysis of the study, in the HR proficient population, PFS was improved to 8.1 mo vs 5.4 mo in the niraparib arm

      4. PAOLA-1

        1. all-comers with stage III or IV high grade serous or endometrioid ovarian cancer OR other non-mucinous histologic types if the patient had a germline BRCA mutation

        2. tested for HRD via BRCA mutation or “mychoice” score of > 42

        3. stratified to carboplatin + paclitaxel + bevacizumab x 22 cycles versus carboplatin + paclitaxel + bevacizumab x 22 cycles and olaparib.  This was the first PARP inhibitor trial to include an “active agent” in the control group maintenance period

        4. In the overall population, progression free survival improved to 22.1 mo vs 16.6 mo in favor of the olaparib + bevacizumab group

        5. in patients with BRCA mutation with a PFS benefit of 37.2 vs 21.7 mo, HRD of any kind: 37.2 vs 17.8 mo, HRD + BRCA WT: 28.1 vs 16.6 mo.  

        6. No difference in PFS for patients with HR proficient tumors

References

1. Harter P, Sehouli J, Lorusso D, et al. A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms. New England Journal of Medicine. 2019;380(9):822-832. doi:10.1056/NEJMOA1808424/SUPPL_FILE/NEJMOA1808424_DATA-SHARING.PDF

2. Parmar MKB, Torri V, Bonaventura A, et al. ICON2: Randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. Lancet. 1998;352(9140):1571-1576. doi:10.1016/S0140-6736(98)04119-1

3. McGuire WiP, Hoskins WiJ, Brady MF, et al. Cyclophosphamide and Cisplatin Compared with Paclitaxel and Cisplatin in Patients with Stage III and Stage IV Ovarian Cancer. https://doi.org/101056/NEJM199601043340101. 1996;334(1):1-6. doi:10.1056/NEJM199601043340101

4. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21(17):3194-3200. doi:10.1200/JCO.2003.02.153

5. Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000;92(9):699-708. doi:10.1093/JNCI/92.9.699

6. Parmar MKB, Adams M, Balestrino M, et al. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet. 2002;360(9332):505-515. doi:10.1016/S0140-6736(02)09738-6

7. Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009;27(9):1419-1425. doi:10.1200/JCO.2008.19.1684

8. Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2000;18(1):106-115. doi:10.1200/JCO.2000.18.1.106

9. Pignata S, Scambia G, Ferrandina G, et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. J Clin Oncol. 2011;29(27):3628-3635. doi:10.1200/JCO.2010.33.8566

10. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. The Lancet. 2009;374(9698):1331-1338. doi:10.1016/S0140-6736(09)61157-0

11. Katsumata N, Yasuda M, Isonishi S, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. www.thelancet.com/oncology. 2013;14. doi:10.1016/S1470-2045(13)70363-2

12. Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): A randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2014;15(4):396-405. doi:10.1016/S1470-2045(14)70049-X

13. Clamp AR, James EC, McNeish IA, et al. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(7):919-930. doi:10.1016/S1470-2045(22)00283-2

14. Sivakumaran T, Mileshkin L, Grant P, et al. Evaluating the impact of dose reductions and delays on progression-free survival in women with ovarian cancer treated with either three-weekly or dose-dense carboplatin and paclitaxel regimens in the national prospective OPAL cohort study. Gynecol Oncol. 2020;158:47-53. doi:10.1016/j.ygyno.2020.04.706

15. Chan JK, Brady MF, Penson RT, et al. Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer. New England Journal of Medicine. 2016;374(8):738-748. doi:10.1056/NEJMOA1505067/SUPPL_FILE/NEJMOA1505067_DISCLOSURES.PDF

16. Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21(13):2460-2465. doi:10.1200/JCO.2003.07.013

17. Walker JL, Brady MF, Wenzel L, et al. Randomized trial of intravenous versus intraperitoneal chemotherapy plus bevacizumab in advanced ovarian carcinoma: An NRG oncology/Gynecologic oncology group study. Journal of Clinical Oncology. 2019;37(16):1380-1390. doi:10.1200/JCO.18.01568/SUPPL_FILE/PROTOCOL_JCO.18.01568.PDF

18. Walker J, Mark B, Moore K, et al. Long Term Survival of GOG 252 ‘Randomized Trial of Intravenous Versus Intraperitoneal Chemotherapy plus Bevacizumab in Advanced Ovarian Carcinoma: An NRG Oncology/GOG Study’ (021). Gynecol Oncol. 2022;166:S16-S17. doi:10.1016/S0090-8258(22)01239-2

19. Burger RA, Brady MF, Bookman MA, et al. Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer. https://doi.org/101056/NEJMoa1104390. 2011;365(26):2473-2483. doi:10.1056/NEJMOA1104390

20. Perren TJ, Swart AM, Pfisterer J, et al. A Phase 3 Trial of Bevacizumab in Ovarian Cancer. New England Journal of Medicine. 2011;365(26):2484-2496. doi:10.1056/NEJMOA1103799/SUPPL_FILE/NEJMOA1103799_DISCLOSURES.PDF

21. Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16(8):928-936. doi:10.1016/S1470-2045(15)00086-8

22. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. Journal of Clinical Oncology. 2014;32(13):1302-1308. doi:10.1200/JCO.2013.51.4489

23. Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. New England Journal of Medicine. 2018;379(26):2495-2505. doi:10.1056/NEJMOA1810858/SUPPL_FILE/NEJMOA1810858_DATA-SHARING.PDF

24. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. New England Journal of Medicine. 2019;381(25):2391-2402. doi:10.1056/NEJMOA1910962/SUPPL_FILE/NEJMOA1910962_DATA-SHARING.PDF

25. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. New England Journal of Medicine. 2019;381(25):2416-2428. doi:10.1056/NEJMOA1911361/SUPPL_FILE/NEJMOA1911361_DATA-SHARING.PDF

26. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. New England Journal of Medicine. 2019;381(25):2403-2415. doi:10.1056/NEJMOA1909707/SUPPL_FILE/NEJMOA1909707_DATA-SHARING.PDF

27. Vergote I, Tropé CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943-953. doi:10.1056/NEJMOA0908806

28. Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): An open-label, randomised, controlled, non-inferiority trial. The Lancet. 2015;386(9990):249-257. doi:10.1016/S0140-6736(14)62223-6

29. Vergote I, Coens C, Nankivell M, et al. Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials. Lancet Oncol. 2018;19(12):1680-1687. doi:10.1016/S1470-2045(18)30566-7

30. Fagotti A, Ferrandina MG, Vizzielli G, et al. Randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer (SCORPION-NCT01461850). Int J Gynecol Cancer. 2020;30(11):1657-1664. doi:10.1136/IJGC-2020-001640

31. Onda T, Satoh T, Ogawa G, et al. Comparison of survival between primary debulking surgery and neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomised trial. Eur J Cancer. 2020;130:114-125. doi:10.1016/J.EJCA.2020.02.020

32. Pfisterer J, Joly F, Kristensen G, et al. Optimal Treatment Duration of Bevacizumab as Front-Line Therapy for Advanced Ovarian Cancer: AGO-OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 Open-Label Randomized Phase III Trial. https://doi.org/101200/JCO2201010. 2022;41(4):893-902. doi:10.1200/JCO.22.01010

33. You B, Purdy C, Copeland LJ, et al. Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study. Journal of Clinical Oncology. 2022;40(34):3965. doi:10.1200/JCO.22.01207

34. Colomban O, Tod M, Peron J, et al. Bevacizumab for Newly Diagnosed Ovarian Cancers: Best Candidates Among High-Risk Disease Patients (ICON-7). JNCI Cancer Spectr. 2020;4(3). doi:10.1093/JNCICS/PKAA026

35. Monk BJ, Parkinson C, Lim MC, et al. ATHENA–MONO (GOG-3020/ENGOT-ov45): A randomized, double-blind, phase 3 trial evaluating rucaparib monotherapy versus placebo as maintenance treatment following response to first-line platinum-based chemotherapy in ovarian cancer. https://doi.org/101200/JCO20224017_supplLBA5500. 2022;40(17_suppl):LBA5500-LBA5500. doi:10.1200/JCO.2022.40.17_SUPPL.LBA5500

36. Monk BJ, Coleman RL, Fujiwara K, et al. ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA-MONO) and rucaparib in combination with nivolumab (ATHENA-COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer. Int J Gynecol Cancer. 2021;31:1589-1594. doi:10.1136/ijgc-2021-002933

Sydney Oesch
Previous

Ovary Part 3
Next

Ovary Part 1