updated overview in management of ovarian cancer

recentupdated management in ovarian cancer as per NCCN

1. EPITHELIAL OVARIAN CANCER : AN UPDATED MANAGEMENT DR. LIZA KHOSHIN PHASE B RESIDENT DEPARTMENT OF ONCOLOGY

2. CONTENTS EPIDEMIOLOGY ANATOMY CLASSIFICATION RISK FACTORS DIAGNOSIS STAGING MANAGEMENT

3. EPIDEMIOLOGY 12 th most common cancer in Bangladesh as per GLOBOCAN 2018 11th most common cancer-related cause of death in Bangladesh Average life time risk : 1 in 70 Median age at diagnosis : 63 years Epithelial tumors : 90 % of ovarian tumors Common histologic subtype : High grade serous  Endometrioid  Clear cell  Mucinous tumors

4. ORIGIN OF THE OVARIAN TUMORS

5. WHO CLASSIFICATION OF MALIGNANT OVARIAN TUMORS A) COMMON EPITHELIAL TUMORS: B) SEX CORD STROMAL TUMORS: MALIGNANT SEROUS TUMOR : Adenocarcinoma, papillary adenocarcinoma, papillary cystadenocarcinoma Surface papillary carcinoma Malignant adenofibroma , cystadenofibroma MALIGNANT MUCINOUS TUMOR Adenocarcinoma, cystadenocarcinoma Malignat adenofibroma , cystadenofibroma MALIGNANT ENDOMETRIOID TUMOR: Adenocarcinoma Adenoacanthoma Malignant adenofibroma , cystadenofibroma Endometrioid stromal sarcoma Mesodermal ( mullerian ) mixed tumor OTHER : Clear cell ( mesonephroid ) tumor, malignant Brenner tumor, malignant Mixed epithelial tumor Undifferentiated carcinoma GRANULOSA – STROMAL TUMOR : Granulosa cell tumor Tumor in the thecoma -fibroma group Fibroma Unclassified ANDROBLASTOMA : SERTOLI - LEYDIG CELL TUMOR Well differentiated Tubular androblastoma , Sertoli leydig tumor (Tubular adenoma of Pick) Tubular androblastoma with lipid storage, Sertoli cell tumor with lipid storage Sertoli – Leydig cell tumor (tubular adenoma with Leydig cells) Leydig cell tumor, hilus cell tumor Of intermediate differentiation Poorly differentiated ( sarcomatoid ) With heterologous elements Gynandroblastoma Lipid (lipoid) cell tumors Unclassified

6. C) GERM CELL TUMOR : Dysgerminoma Endodermal sinus tumor Embryonal carcinoma Polyembryoma Choriocarcinoma Immature teratoma Mature dermoid cyst with malignant transformation Monodermal and highly specialized Struma ovarii Carcinoid Struma ovarii and carcinoid Others Mixed forms D) GONADOBLASTOMA : Pure Mixed with dysgerminoma or other form of germ cell tumor

7. RISK FACTORS Increased risk factors Decreased ris k factors : Patient characteristics: Increasing age Personal history of breast cancer Inflammatory- PID, Endometriosis Hormonal : OCP Progestins Genetic factor : Family h/o Ovarian cancer BRCA 1 / 2 mutations Hereditary non polyposis colorectal cance r Surgery Hysterectomy Tubal ligation Reproductive factors : Nulliparity Early menarche / late menopause Infertility PCOS Endometriosis Ovulation inducing drugs HRT Reproductive factors : Multiparity Breast feeding Environmental factors: Obesity and high fat diet Talc exposure Cigarette smoking (for mucinous ovarian cancer)

8. DIAGNOSIS Usually asymptomatic Acute presentation : Pleural effusion - SOB Bowel obstruction – severe nausea vomiting Subacute presentation : Adnexal mass Pelvic and abdominal symptoms : Bloating Urinary urgency or frequency Difficulty eating or feeling full quickly Pelvic or abdominal pain Palpable inguinal/cervical lymphadenopathy  uncommon Paraneoplastic syndromes : Cerebellar degeneration, polyneuritis, dermatomyositis , hemolytic anemia, DIC, acanthosis , nephrotic syndrome

9. INVESTIGATION For diagnosis : Tumor marker Transabdominal / Transvaginal ultrasonography For confirmation of diagnosis : Surgical exploration & biopsy Tumor molecular testing (BRCA1/2, MSI, dMMR ) For staging : CT scan of abdomen, pelvis and chest MRI of abdomen PET CT scan Routinely: CBC CXR P/A view RFT LFT

10. TUMOR MARKER IN OVARIAN MASSES TUMOR MARKER OVARIAN NEOPLASM CA 125 Epithelial ovarian cancer CEA Mucinous ovarian cancer HCG Embryonal carcinoma Choriocarcinoma INHIBIN A OR INHIBIN B Granulosa cell tumor LDH Dysgerminoma AFP Endodermal sinus tumor Embryonal carcinoma

11. FIGO staging FIGO STAGE I Tumor limite d to ovaries (one or both) or fallopian tube(s) IA Tumor limited to one ovary (capsule intact) or fallopian tube, no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings IB Tumor limited to both ovaries; (capsule intact) or fallopian tube surface ; no malignant cells in ascites or peritoneal washings IC Tumor limited to one or both ovaries or fallopian tubes, with any of the following: IC1 Surgical spill IC2 Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface IC3 Malignant cells in ascites or peritoneal washings II Tumor involves one or both ovaries or fallopian tubes with pelvic extension below pelvic brim or primary peritoneal cancer IIA Extension and/or implants on the uterus and / or fallopian tube(s) and/or ovaries IIB Extension to and/or implants on other pelvic tissues

12. III Tumor involves one or both ovaries or fallopian tubes, or primaryperitoneal cancer, with microscopically confirmed peritoneal metastasis outside the pelvis and/ oor metastasis to the retroperitoneal (pelvic and/or para -aortic) lymph nodes IIIA1 Positive retroperitoneal lymph nodes only ( histologically confirmed) IIIA2 Microscopic extrapelvic (above the pelvic brim)peritoneal involvement +/- retroperitoneal lymph nodes IIIB Macroscopic peritoneal metastasis beyond pelvis 2cm or less in greatest dimension +/- metastasis to the retroperitoneal lymph nodes IIIC Macroscopic peritoneal metastasis beyond the pelvis >2cm in greatest dimension +/- metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ) IV IVA Pleural effusion with positive cytology IVB Liver or splenic parenchyma metastases, metastases to extraabdominal organs (including inguinal LN and lymph nodes outside the abdominal cavity); transmural involvement of intestine

13. MANAGEMENT Epithelial Ovarian tumor Primary peritoneal carcinomatosis Fallopian tube cancer

14. TREATMENT MODALITY SURGERY SYSTEMIC THERAPY CHEMOTHERAPY TARGETED THERAPY HORMONAL THERAPY IMMUNOTHERAPY

15. SURGERY AIMS: Histopathological confirmation of the disease (primary/ secondary ) Staging laparatomy (to determine the extent) Debulking : Primary debulking Interval debulking Second cytoreduction Goal of surgery Ro resection margins or optimal cytoreduction (≤1cm diameter residual tumor) / debulking

16. PRIMARY CYTOREDUCTION : • Debulking surgery prior to administration of 1 st line CT • S tandard approach for suspected epithelial ovarian cancer INTERVAL CYTOREDUCTION : D ebulking procedure performed after several cycles of chemotherapy have been administered Done in those who had a suboptimal cytoreduction at the time of initial surgery

17. EXPLORATORY LAPATOROTOMY A large midline incision required to inspect the peritoneal cavity, including the upper abdomen, retroperitoneal spaces and lymph nodes Fluid sample from ascitic fluid, peritoneal surfaces, pelvic and paracolic spaces collected and sent for cytological examination If intraperitoneal carcinomatosis absent, ovarian tumor is resected first and surgical staging done to avoid the rupturing of ovarian mass

18. Grossly normal opposite ovary biopsy or excision of any benign appearing cyst Pelvic and paraaortic retroperitoneal lymph nodes sampling if not involved. But if involved, should be removed An infracolic omentectomy if gross disease is not present in omentum . But if present ( omental cake )  completely excised as completely as possible Careful examination of both diaphragm, liver serosa, liver parenchyma, spleen

19. Paracolic spaces and large bowel are inspected and if there is threat for intestinal obstruction then resection may be required The small intestine and mesentery are evalutaed and any tumor implants are removed as much as possible Hysterectomy and Salpingoophorectomy – If fertility is not needed then TAH + BSO done If fertility is desired in case of young women with stage I A(early), low malignant potential lesion, then unilateral salpingo-ophorectomy or bilateral salpingo ophorectomy

20. ROLE OF APPENDICECTOMY Routinely for mucinous ovarian tumor as primary mucinous appendiceal tumor may metastasize to ovary Routine appencectomy for all staging procedure for ovarian cancer is controversial

21. The standard staging procedure is Extrafascial hysterectomy with BSO with omentectomy with pelvic and paraaortic lymph node dissection with cytology of peritoneal cavity and any suspected lesions either by laparotomy (preferred) or laparoscopy

22. TIMING OF TREATMENT INITIATION Started as soon as feasible, usually within 2-4 weeks from the surgery No high-quality data about the optimal timing for the initiation of first-line chemotherapy, but limited data suggest that a delay of greater than approximately 1 month in instituting chemotherapy associated with a poorer outcome

23. SYSTEMIC THERAPY CHEMOTHERAPY : Neoadjuvant -   For women with advanced EOC who are poor candidates to withstand an aggressive initial surgery For those with extensive disease where optimal cytoreduction is not possible Unresectable disease Adjuvant chemotheapy : S tage 1A/B(grade3,clear cell ),1C, II, III, IV ovarian cancer Palliative chemotherapy

24. UNRESECTABLE DISEASE   Most experts agree that criteria for unresectability include patients with the following : ●Diffuse and/or deep infiltration of the small bowel mesentery. ●Diffuse carcinomatosis involving the stomach and/or large parts of the small or large bowel ●Infiltration of the duodenum and/or parts of the pancreas (not limited to the pancreatic tail) ●Involvement of the large vessels of the hepatoduodenal ligament, celiac trunk or behind the porta hepatis ●Involvement of the liver parenchyma

25. ANGIOGENESIS INHIBITORS  A ngiogenesis inhibitors not used in combination with initial CT for advanced EOC, as only modest benefits have been demonstrated in randomized trials . B evacizumab is approved by the US Food and Drug Administration and used in addition to conventionally dosed IV CT (Cat 2B), in select patients without a known mutation in  BRCA1   / BRCA2   who have a high risk of recurrence ( eg : those with pleural effusions or ascites )

26. BEVACIZUMAB : First targeted agent to show significant single agent activity in ovarian carcinoma Used during adjuvant carboplatin /paclitaxel and for maintenance therapy  (Cat 2B)

27. GOG 218 FOR BEVACIZUMAB AS AN ADJUVANT AFTER SURGERY Bevacizumab+ standard ct vs Bevacizumab alone PFS 14.1vs 10.3 month, (p value < 0.001) PFS was not significantly increased in patient who did not receive maintenance Bevacizumab vs chemotherapy alone There was no improvement in OS with bevacizumab

28. IMMUNOTHERAPY OLAPARIB : (PARP inhibitor) In December 2014, olaparib was approved for use as a single agent by   FDA .   The FDA approval is for germline BRCA mutated ( gBRCAm ) advanced  ovarian cancer   as a maintenance who has received 3 or more prior lines of chemotherapy( recurent /progressive disease)

29. RADIOTHERAPY Limited use only for : - Palliative setting for symptom control in patients with recurrent disease

30. SUSPICIOUS OVARIAN MASS Abdominal and pelvic examination Imaging study- TVS / USG / CT / MRI CBC and complete metabolic panel Tumor marker GI evaluation as indicated and family history for germline mutation Clinical staging

31. CLINICAL STAGING Stage IA (Fertility desired) Stage IB ( Ferility desired) Stage IA – IV , surgical candidate, optimal cytoreduction ( fertility not desired) Poor surgical candidate or low likelyhood of optimal cytoreduction USO + CSS BSO + CSS TAH + BSO + CSS + debulking as required Neoadjuvant therapy Further treatment as Pathological staging Clinical stage Primary treatment

32. INCIDENTALLY DIAGNOSED OVARIAN CANCER BY PREVIOUS SURGERY Suspected grade I or low grade stage I disease Surgical staging Completion surgery/Surgical staging Reductive surgery CT f/b IDS Findings Primary treatment Obtain family history, genetic risk evaluation, pathological review if required, imaging study if not done , tumor marker if indicated Incomplete previous surgery or staging Suspected grade II stage I disease (non serous) Suspected stage I, high grade serous or clear cell or stage IC Completion surgery/surgical staging/ chemotherapy Stage II - IV No residual disease Potentially resectable residual disease Potentially unresectable residual disease Pathological staging

33. Disease diagnosed by Surgery (Pathological staging) (Stage I) Stage I A / IB / IC disease Grade II endometrioid Observe or Platinum based CT (3-6 cycle) Grade III Endometrioid / High risk serous carcinoma IV platinum based CT Clear cell carcinoma, carcinosarcoma Observe (IA) IV platinum based therapy Mucinous carcinoma Observe or fertility sparing surgery CT (IC) Monitoring and follow up Pathological staging Primary CT/Primary Adjuvant therapy

34. Stage II / III /IV Platinum based CT Completion surgery as indicated by tumor response and potential resectability Maintenance therapy Pathological staging Primary CT / Adjuvant therapy

35. POST PRIMARY TREATMENT (STAGE II – IV) Monitorin and follow up Imaging as clinically indicated (TVS/USG/CT/MRI/PET CT Complete remission Partial remission Progression Stable disease Observed or Orlaparib for BRCA I/II mutation or if Bevacizumab is used in primary therapy then post remisssion Bevacizumab Orlaparib for BRCA I mutation or post remisssion Bevacizumab if used in primary therapy Or treatment as persistent disease Treatment as persistent disease Post remission Bevacizumab Bevacizumab if used in primary therapy or treatment Maintenance therapy

36. MONITORING / FOLLOW UP (STAGE I – IV AFTER PRIMARY TREATMENT) Visit every 2-4 monthly for 2 year  3-6 monthly for 3 year  annnually after 5 year Physical examination include pelvic examination Imaging study of the chest , abdomen and pelvis as indicated BCC and chemistry profile Tumor marker Genetic risk evaluation if not done previously

37. PERSISTANT DISEASE OR RECURRANCE Disease status T herapy Progression on primary,maintenance or recurrance therapy Or Stable or persistant disease(if not on maintenance therapy) Or Complete remission and relapse<6 months after completing chemotherapy Clinical trial And/or Best supportive care And/or Recurrance therapy as platinum resistant Complete remission and relapse≥6 mo after completing prior chemotherapy Radiographic and or clinical relapse Biochemical relapse Consider 2 ND cytoreductive therapy Clinical trial OR Delay treatment until clinical relapse OR Immediate platinum based CT ( 2B) OR Best supportive care Clinical trial AND/OR Platinum based CT ( cat1) for first recurrance OR Recurrance therapy OR Best supportive care

38. NEOADJUVANT VS PRIMARY CYTOREDUCTIVE SURGERY [As compared by Surveillance, Epidemiology and End-Results (SEER) database] NACT PRIMARY CYTOREDUCTIVE SURGERY Ostomies placed 8% 19% Small bowel resections 4% 6% Large bowel resections 11% 21% Reduction in p ostoperative complications : - Infection - Gastrointestinal complications - Pulmonary problems 18% 35% 11% 11% 29% 4%

39. European Organization for the Research and Treatment of Cancer (EORTC) 55971 trial NACT for 3 cycles f/b interval surgical cytoreduction and ACT Primary debulking surgery (PDS) f/b 6 cycles of platinum-based CT Fewer postoperative deaths 0.7% 2.5% Infections 2% 8% Grade 3/4 hemorrhage 4% 7% Thrombotic events O% 2.6% Optimal cytoreduction 81% 42% Median free survival No difference No difference Overall survival (OS) : If no residual disease at the time of surgery - if microscopic residual disease only ( ie , <10 mm residual disease 38 months 27 months 45 months 32 months

40. CHEMOTHERAPY REGIMEN

41. WOMEN WITH OPTIMALLY CYTOREDUCED DISEASE    For patients with optimally cytoreduced EOC, combined (IV/IP therapy) rather than IV treatment alone, IV chemotherapy remains an appropriate alternative Preferred IV/IP therapy regimen  — The most commonly used IV/IP regimen consists of six cycles of IV  paclitaxel  (135 mg/m 2  over 24 hours) on day 1 IP  cisplatin  (100  mg/m 2 ) on day 2 IP  paclitaxel  (60 mg/m 2 ) on day 8 Repeat every 3 weekly for 6 cycles

42. Support for IV/IP chemotherapy comes from randomized data comparing standard IV therapy with IV/IP treatment following primary cytoreductive surgery In one meta-analysis that included nine randomized trials and over 2100 women, IV/IP therapy was associated with : A reduction in the risk of dying compared with IV treatment (HR 0.81, 95% CI 0.72-0.90) Improvement in disease-free survival (HR for recurrence 0.78, 95% CI 0.70-0.86)

43. WOMEN WITH SUBOPTIMALLY CYTOREDUCED DISEASE   Are not appropriate candidates for IP treatment as it results in limited penetration into larger tumors and reduced effectiveness of treatment. Therefore, IV therapy is recommended

44. DOSE-DENSE VERSUS CONVENTIONALLY DOSED IV THERAPY Dose-dense IV therapy  A dministering CT in a weekly schedule It typically refers to one of two regimens: A) Carboplatin and paclitaxel 3 weekly B) Carboplatin and paclitaxel  administered weekly In general, trials have suggested similar or improved efficacy with dose-dense regimens relative to conventionally dosed therapy, though toxicities are typically higher M ucinous or clear cell carcinoma  does not have improved disease outcomes with dose-dense therapy, so conventionally dosed regimen suggested

45. MAINTENANCE THERAPY (POST REMISSION THERAPY) Limited data to support the routine administration of maintenance for patient with stages II-IV EOC , who have had complete clinical remission after 1 st line therapy Paclitaxel (cat 2B) Pazopanib (Cat 2B),   Bevacizumab   -frontline setting , along with chemotherapy and as maintenance for select patients with a high risk of recurrence   Olaparib -  for women with a germline mutation in  BRCA1  or  BRCA2  and a response to frontline platinum-based therapy has also found to be benifited .

46. Paclitaxel (4 weekly for 12 cycle)(category 2B) PFS : 28 vs 21 month(improved) but no improvement in OS

47. Olaparib vs placebo (SOLO1 trial phase 3 trail) Median follow up At 41 month (60 versus 27 percent; hazard ratio [HR for disease progression or death 0.30, 95% CI 0.23-0.41 three-year rate of freedom from death 84 versus 80 percent (HR for death 0.95, 95% CI 0.60-1.53

48. MAINTENANCE Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom group (AGO-OVAR 16) Pazopanib vs placebo PFS (18 versus 12 months, respectively; hazard ratio [HR] 0.766, 0.64-0.91) significant grade 2 or greater hypertension (52 versus 17 percent) grade 3 or 4 diarrhea (8 versus 1 percent) grade 3 or 4 hepatotoxicities (9 versus <1 percent). only prospective trial to evaluate maintenance angiogenesis inhibition as a single agent at the completion of first-line chemotherapy. However, it provides more evidence that maintenance therapy using an angiogenesis inhibitor can prolong PFS. However, until this is shown to also improve OS, we do not administer angiogenesis inhibitors in this context as part of standard clinical practice.

49. MAINTENANCE Nintedanib vs placebo PFS (17.3 versus 16.6 months; HR 0.84, 95% CI 0.72-0.98) Thrombocytopenia Anemia ●Hypertension ●Hepatic transaminitis (18 versus 6 percent with placebo) (14 versus 7 percent) (5 versus 0.4 percent) (16 versus 3 percent) Further follow-up is ongoing for its impact on OS

50. RECURENCE Likelihood of relapse after initial therapy for all stage EOC 62% 80-85% of stage III and IV relapse even after initial treatment Management of relapse cases are stratified as: Platinum free interval PFI ≥ 6 month indicate Platinum sensitive disease PFI < 6 month indicate Platinum Resistant cases BRCA mutation status Hisological variety

51. RECURRENCE THERAPY

52. REFERENCES NCCN Guidelines Version 1.2019 Epithelial Ovarian cancer / Fallopian tube cancer / Primary peritoneal cancer DeVita , Hellman, and Rosenbergs Cancer Principles and Practice of Oncology - 10E (2015) [PDF] [ UnitedVRG ] AJCC Cancer staging manual, 8 th edition The MD Anderson Manual of Medical Oncology, 3 rd edition Uptodate