Updates in Ovarian Cancer Treatment Diamantis I. Tsilimigras¹, 6 th year Medical Student ¹ 1 st Department of Obstetrics & Gynecology “Alexandra’’ General Hospital, Athens, Greece HELLENIC REPUBLIC National and Kapodistrian University of Athens SCHOOL OF MEDICINE 1 st DEPARTMENT OF OBSTETRICS & GYNECOLOGY “ALEXANDRA” GENERAL HOSPITAL CHAIRMAN: PROFESSOR D. LOUTRADIS Supervisor: Ass. Prof. Konstantinos Kallianidis

Introduction The 2 nd most common cancer of the female genital tract BUT The most common cause of gynecologic cancer death Lack of effective screening test Atypical signs & symptoms

Ovarian neoplasms >65% of ovarian tumors >90% of ovarian cancers

Epidemiology  Greece: 9/ ovarian cancer incidence  Median age of diagnosis: 61 yrs, 2/3 >55 yrs  Hereditary cancers:~10 yrs earlier than nonhereditary

Risk factors

Symptoms Most often asymptomatic OR Vague, nonspecific complaints Abdominal distention, bloating, early satiety Anorexia, fatigue, back pain, constipation (late symptoms)

Surgical Staging: FIGO guidelines (2014) Int J Gynaecol Obstet. 2014; 124(1):1-5

Survival rates Overall, 5-year survival rate: 20% for epithelial ovarian cancer. Stage I: 80-95% Stage II: 40-70% Stage III: 30% Stage IV: <10% ~75% of ovarian cancers present with stage III or IV disease

Treatment Current approach: Surgery + chemotherapy  Primary Tumor Reductive Surgery (PDS) ◦ Surgery  Chemotherapy  Neoadjuvant Chemotherapy (NACT) ◦ Chemotherapy  Surgery  Chemotherapy  Goal of Surgery  remove all visible disease  Goal of Chemotherapy  kill all cancer cells

Treatment (I) Surgery: mainstay of staging and treatment Primary staging: TAHBSO (total abdominal hysterectomy, bilateral salpingo-oophorectomy), omentectomy, peritoneal washings, Pap smear of diaphragm, sampling of pelvic and para-aortic lymph nodes Debulking/cytoreduction: Gold standard even in advanced ovarian cancer (Stage III & IV) Optimal: no visible tumor or residual tumor ≤1cm Suboptimal: residual tumor ≥1cm

Treatment (II) Combination chemotherapy (IV): Carboplatin & Paclitaxel (treatment of choice) Other options: Abdominal & pelvic radiotherapy Intraperitoneal cisplatin and paclitaxel chemotherapy usually combined with IV chemo: ↑overall survival, ↑side effects

Criteria for implementing the appropriate treatment: PDS or NACT?? Symptoms / Physical Exam / Tumor Marker Imaging (CT scan) Fagotti Score –Laparoscopic Assessment ◦ Anderson Algorithm

Fagotti score - laparoscopic index value to determine disease distribution

Anderson algorithm: presumed stage III/IV disease → Two-surgeon laparoscopic evaluation Nick et al. Nat Rev Clin Oncol April ; 12(4): 239–245

Anderson algorithm Nick et al. Nat Rev Clin Oncol April ; 12(4): 239–245 Benefits: 1) upfront debulking only in those pts most likely to achieve R0, 2) utilization of time between lap and TRS to evaluate novel agents (WOO: window of opportunity trials) among those assigned to primary debulking, 3) application of tumor collected at the time of ICS to evaluate novel combinations of therapeutic agents

PCS or NACT: Is there enough evidence? 4 RCTs (1-4) 1922 patients Stage IIB-IV 958 NACT/ 964 PDS Included studies: 1. Kehoe et al. Lancet. 386, 249–257 (2015) 2. Vergote, I. et al. N. Engl. J. Med. 363, 943–953 (2010) 3. Rose et al. N. Engl. J. Med. 351, 2489–2497 (2004) 4. van der Burg, M. E. et al. N. Engl. J. Med. 332, 629–634 (1995) Endpoints: OS PFS No residual disease Residual disease ≤1cm Optimal cytoreduction rate

Overall survival

Progression-free survival

Extent of surgical debulking

Conclusions NAC:  reasonable treatment for FIGO stage III & IV ovarian cancer  non-inferior OS and PFS compared with PDS  higher rate of optimal debulking

Trends in the use of NACT for advanced ovarian carcinoma in the US National Cancer Database: Overall number of pts (stage III/IV): ,032 (66.4%) PDS + adjuvant chemo 5429 (13.3%) NACT + IDS 5844 (15.4%) surgery only 2389 (5.9%) chemo only  NACT : 8.6%→22.6% (p<0.001)  PDS + chemo: 68.1%→60.8% (p<0.001)  Surgery only: 17.8%→9.9% (p<0.001) Melamed et al. Gynecol Oncol November;143(2):

SGO/ASCO Guidelines(2016): NACT in stage IIIc/IV ovarian cancer Wright et al. Journal of Clinical Oncology 34, no. 28 (October 2016)

Recommendations: NACT: women with a high risk profile or a low likelihood of achieving cytoreduction to <1 cm Primary cytoreductive surgery is recommended over NACT for women with high likelihood to achieve cytoreduction <1 cm with good and acceptable morbidity. For women who are fit for primary cytoreductive surgery, with potentially resectable disease, either NACT or primary cytoreductive surgery may be offered. Histologic confirmation (core biopsy preferred) of an invasive ovarian, fallopian tube, or peritoneal cancer should be obtained before NACT is initiated. Platinum/taxane doublet is preferred for NACT; alternate regimens, containing a platinum agent, may be selected based on individual patient factors. Interval cytoreductive surgery should be performed after ≤4 cycles of NACT with a response to chemotherapy or stable disease. In women with progressive disease on NACT, surgery is indicated only for palliation (eg, relief of a bowel obstruction). Other treatment options include alternative chemotherapy regimens, clinical trials, and/or initiation of end-of-life care. Wright et al. Journal of Clinical Oncology 34, no. 28 (October 2016)

The future: Targeted therapies

Treatment Strategies related to Cancer Function

PARP Poly ADP-ribose polymerase (DNA Repair Enzyme)

Lynparza ™ –> Olaparib (PARP inhibitor) FDA-approved (2014)- For advanced serous ovarian cancer with BRCA gene mutations Clinical Cancer Advances 2016 J Clin Oncol Mar 20; 34(9): 987–1011

Criteria for Testing / Treatment FDA approved for women who have received three or more chemotherapy treatments for ovarian cancer. Not approved for anyone who has a BRCA mutation Initial Diagnosis and 2 separate recurrences FDA did not approve olaparib for maintenance treatment.

Angiogenesis Inhibitors Block the growth of blood vessels in a tumor, starving the cancer of the nutrition and oxygen it needs to survive Bevacizumab (iv) Pazopanib Cediranib (oral)

Take-home messages Ovarian cancer is an aggressive tumor, usually presents with stage III/IV disease, highly lethal (- 20% 5-year survival rate) Most often asymptomatic or vague, nonspecific complaints- high index of suspicion Surgery is the mainstay of treatment Staging PCS → Adjuvant chemo ( Paclitaxel + Carboplatin) ICS ( after NACT) Second look operation Secondary cytoreduction

PCS or NACT : Anderson algorithm (Fagotti score) OR SGO/ASCO Guidelines(2016): NACT: women with a high risk profile or a low likelihood of achieving cytoreduction to <1 cm Primary cytoreductive surgery is recommended over NACT for women with high likelihood to achieve cytoreduction <1 cm with good and acceptable morbidity. Future strategies: Targeted therapies (PARP inhibitors, Angiogenesis inibitors etc)

Thank you