Comprehensive overview of ovarian Cancer: staging, diagnosis, risk stratification and treatment

1. OVARIAN CANCER
Ahmed Zeeneldin

2. Anatomy

3. Tis/0 T1abc T2abc T3abc M1=IV
TNM staging
N0 0 Iabc IIabc IIIabc
N1=IIIC IIIC
M1=IV IV
¨ T1: Limited
¤ to one(a) or both(b) ovaries
¤ + ruptured capsule,
tumor on ovarian surface,
+ve cells in peritoneum (C)
¨ T2: Pelvic extension
¤ Tubes or uterus (a),
¤ other pelvic organs (b)
¤ +ve cells in peritoneum (C)
¨ T3: Extra-pelvic extension
¤ microscopic (a),
¤ macroscopic <2cm(b),
¤ macroscopic >2cm(c)
¨ No T4:
¨ N1: +ve LNs
¨ M1 Distant mets
¨ Grade: 1,2,3

4. Notes
¨ Liver capsule metastasis is T3/Stage III; liver
parenchymal metastasis, M1/Stage IV.
¨ Pleural effusion must have positive cytology for
M1/Stage IV.
¨ Primary peritoneal adenocarcinoma and Fallopian
tube carcinomas are staged using the ovarian
staging system

5. Prognosis
¨ Stage:
¤ T
¤ N
¤ M
¨ Grade
¨ Response to initial therapy
¤ No benefit from two consecutive regimens is very poor
¨ Recurrence
¨ Time to recurrence:
¤ Recurrence less than 6 m of end of chemo (P resistant) is very poor
¤ Give non-paltinum non-taxane drug
¨ Others: old age, comorbidities, poor PS

6. Incidence

7. Incidence
¨ US:
¤ Median age : 63y
¤ Incidence: 22000/y
¤ Mortality: 15000/y
¤ Only 40% are cured
¤ Late clinical presentation in 70%:
n bloating,
n Pains
n Early satiety
n Urinary symptoms

8. NCI-Egypt
8
Ahmed Zeeneldin

9. Screening
¨ No proven value
¨ Whether one or more of the following is used:
¤ CA12-5
¤ US: conventional or transvaginal
¤ CT
¤ human epididymis protein 4 (HE4)

10. Risk factors
¨ Younger age at pregnancy and first birth (25 y)
¨ Oral contraceptives ,
¨ breast-feeding.
¨ Family history
¤ BRCA1 and BRCA2
¤ HNPCC

11. Workup
¨ History including family history
¨ Abdominal/pelvic exam
¨ Imaging:
¤ Ultrasound and/or abdominal/pelvic CT
¤ Chest imaging
¨ Lab:
¤ CA-125 or other tumor markers as clinically indicated
¤ CBC
¤ Chemistry profile with LFT’s
¤ Institutional pathology review
¨ GI evaluation if clinically indicated

12. Ovary cystoadenoma mucinous

13. Mucinous borderline tumor of ovary

14. Histology
serous adenocarcinoma

15. Histology
serous adenocarcinoma

16. Histology
serous adenocarcinoma

17. Histology
serous adenocarcinoma

18. Treatment
¨ Multidisciplinary team:
¤ Gynecological oncological Surgeon
¤ Medical Oncologist
¨ Modalities
¤ Surgery: extensive vs limited
¤ Chemotherapy: IV vs IP
¤ RT: limited role if any
n Whole abd RT consolidation in low-bulk stage III
n Palliative RT: for local and distant symptomatic disease
¨ Stages:
¤ I
¤ II-III-IV

19. Surgery

20. Surgery
¨ Staging laparotomy with Maximum cytoreduction:
¨ By gynecologic oncologist
¨ Indications: operable stages I through IV
¤ aspiration of ascites or peritoneal lavage
¤ All peritoneal surfaces should be visualized,
¤ any peritoneal surface or adhesion suspicious should be excised or biopsied
¤ TH/BSO
n USO with uterine preservation but with full staging laparotomy
n Preserve fertility in young women
n Indications:
n stage I tumors and/or
n low-risk tumors (early-stage invasive tumors, or LMP)
¤ Omentectomy
¤ Lymphadenectomy: ↑ DFS but not OS
n Aortic
n pelvic

21. Surgery for fertility preservation (FP)
¨ FP not an option or MMT (carcinosarcoma), or
stage II-IV EOC or stromal tumor: classic surgery
¨ FP is an option à frozen section àif (Indications)
¤ stage I tumors and/or
¤ low-risk tumors (early-stage invasive carcinoma or
stromal tumor & LMP)
¤ Germ cell tumors à limited surgery

22. Role of neoadjuvant chemotherapy
¨ How? Cisplatin based chemo CB
¤ CBx 3 àsurgeryàCBx3
¨ Role:
¤ Standardin inoperable bulky stage II to IV
¤ Controversial in operable disease:
n same DFS and OS
n (Vergote et al , 2008)

23. Non-optimal initial surgery
¨ Occurs in:
1.Uterus intact
2. Adnexa intact
3. Omentum not removed
4. Documentation of staging incomplete
5. Residual disease, potentially resectable
¨ What to do:
¨ Depends on stage, grade, planned further therapy
and is there a resectable residual
¤ With resectable residual: complettion of surgical staging
¤ With irresectable residual: chemox3-6àcompetion
surgeryàcomplete the 6-8 courses

24. Non-optimal initial surgery

25. Systemic therapy

26. Role
¨ Neoadjuvant
¨ Adjuvant
¨ Post-adjuvant
¨ Maintenance

27. Role of neoadjuvant chemotherapy
¨ How? Cisplatin based (CB) chemo IV
¤ CBx 3 àsurgeryàCBx3
¨ Role:
¤ Standardin inoperable bulky stage II to IV
¤ Controversial in operable disease:
n same DFS and OS
n (Vergote et al , 2008)

28. Adjuvant therapy

29. Post-adjuvant therapy

30. Chemotherapy in ovarain CA
¨ Systemic (IV) q 3w:
¤ Docetaxel plus carboplatin (DC):
n D: 60-75 mg/m2 & C: AUC of 5-6
¤ Paclitaxel plus carboplatin (TC)
n C: AUC of 5-7.5 & T: 75 mg/m2 3-hour IV infusion
¤ Paclitaxel plus Cisplatin (TP)
n T 135 mg/m2 IV 24-h IV infusion & Cisplatin (P) 75 mg/m2
¨ Combined (intraperitoneal IP+IV) q 3w:
¤ D1: T 135 mg/m2 IV 24-h IV infusion
¤ D2: P 100 mg/m2 IP
¤ D8: T 60 mg/m2 (max BSA 2.0 m2)

31. IV vs IP
Armstrong et al, N Engl J Med 2006;354:34-43
¨ Stage III & residual <= 1cm
¨ 6 cycles
¨ Longest MOS: 67 m vs 50 m

32. IV vs IP
Armstrong et al, N Engl J Med 2006;354:34-43

33. IV vs IP
Armstrong et al, N Engl J Med 2006;354:34-43

34. IV vs IP
¨ IV is the standard
¨ Till more data accumulate, IP is an option for stage III
with residual <=1cm, if tolerable
¨ Needs catheter and experience
¨ Expected poor tolerance to IP:
¤ Poor PS
¤ Comorbidities
¤ Old age
¤ Stage IV disease
¨ If you start IP and intolerant, continue with IV

35. High-dose chemo and autoBMT
Möbus et al, J Clin Oncol 2007;25(27):4187-4193
¨ RCT
¨ Cyclo-pacli x 6
¨ Cyclo-paclix2 à HD
carbo-paclix3 with
stem cell support

36. Toxicity of HD arm

37. PFS and OS: non-significant

38. Maintenance therapy
Markman et al J Clin Oncol 2003;21:2460-2465
¨ In complete clinical
remission:
¤ Negative clinical exam
¤ Negative CA125
¤ Negative CT with LN <1cm
¨ After 6-8 cycles of taxane-
carbo
¨ Pacli 175 q4w
¤ X 3 vs x 12
¨ PFS: 21 vs 28 m
¨ Stopped early for
superiority

39. PFS curve

40. Follow-up Recommendations
¨ by:
¤ H&P
¤ CA125
¤ Other lab and imaging when necessary
¨ Fequency:
¤ Q2-4m x 2y
¤ 63-6m x 3y
¤ Q12m thereafter

41. Clinical questions
¨ WAHAT TO DO WITH
¤ Non-optimal initial surgery
¤ No or Partial response to initial chemo
¤ Complete response then:
n Recurrence within 6 m
n Recurrence 6-12 m
n Recurrence > 12 m
¤ Biochemical failure: rising CA125 with no clinical or
radiological evidence or progression.

42. Biochemical failure: rising CA125 with no clinical or radiological
(CT/MRI +/- PET) evidence or progression.
¨ Clinically relapse within 2-6 m
¨ Options:
¤ Priorchemo: treat as new
¤ No-prior chemo:

43. Biochemical relapse

44. Response to intial therapy

45. Recurrence after complete response

46. ACCEPTABLE RECURRENCE THERAPIES
Preferred Agents Other Agents
¨ Cytotoxic Therapy ¨ Cytotoxic Therapy
¤ Combination if platinum sensitive ¤ Altretamine
n Carboplatin/paclitaxel (category 1) ¤ Capecitabine
n Carboplatin/docetaxel ¤ Cyclophosphamide, Ifosfamide
n Carboplatin/gemcitabine ¤ Irinotecan
n Cisplatin/gemcitabine ¤ Melphalan
n Carboplatin/weekly paclitaxel ¤ Oxaliplatin
n Carboplatin/liposomal doxorubicin ¤ Paclitaxel
¤ Single-agent if platinum sensitive ¤ Vinorelbine
Carboplatin, Cisplatin, oxaliplatin
n
¨ Hormonal Therapy:
¤ Single-agent non-platinum based if ¤ Anastrozole , Letrozole
platinum resistant
¤ Tamoxifen
n Docetaxel, Paclitaxel, weekly
n Etoposide, oral Gemcitabine ¤ Megestrol acetate
n Liposomal doxorubicin ¤ Leuprolide
n Pemetrexed Topotecan ¨ Palliative localized radiation therapy
¨ Targeted Therapy: Bevacizumab

47. Notes
¨ primarily progress on two consecutive regimens
without evidence of clinical benefits have
diminished likelihood of benefiting from additional
therapy. Decisions to offer supportive care,
additional therapy, or clinical trials should be made
on a highly individual basis.
¨ Platinum-based combination therapy should be
considered for platinum-sensitive recurrences.
¨ Combination therapy with bevacizumab may be
considered.

48. Optimal chemotherapy of recurrent ovarian cancer:
Metanalysis of 13 trials
Fung-Kee-Fung et al Curr Oncol 2007;14(5):195-208.
¨ In five of the thirteen trials in which 100% of patients were
considered sensitive to platinum-containing chemotherapy, further
platinum-based combination chemotherapy significantly improved
response rates (two trials), progression-free survival (four trials), and
overall survival (three trials) when compared with single-agent
chemotherapy involving carboplatin or paclitaxel. Only two of these
randomized trials compared the same chemotherapy regimens:
carboplatin alone versus the combination of carboplatin and
paclitaxel. Both trials were consistent in reporting improved survival
outcomes with the combination of carboplatin and paclitaxel. In one
trial, the combination of carboplatin and gemcitabine resulted in
significantly higher response rates and improved progression-free
survival when compared with carboplatin alone. Median survival
with carboplatin alone ranged from 17 months to 24 months in four
trials.

49. Optimal chemotherapy of recurrent ovarian cancer:
Metanalysis of 13 trials
Fung-Kee-Fung et al Curr Oncol 2007;14(5):195-208.
¨ 5 trials in chemosensitive disease: significant
¤↑ RR in 2 trials
¤ ↑ PFS in 4 trials
¤ ↑ OS in 3 trials
¨ If combination platinum-based chemotherapy is not
indicated, then a single platinum agent should be
considered.

50. Optimal chemotherapy of recurrent ovarian cancer:
Metanalysis of 13 trials
Fung-Kee-Fung et al Curr Oncol 2007;14(5):195-208.
¨ Platinum-refractory or platinum-resistant disease:
¤ Monotherapy should be considered because no advantage
appears to accrue to the use of non-platinum-containing
combination chemotherapy.
¤ Single-agent paclitaxel, topotecan, or pegylated liposomal
doxorubicin have demonstrated activity in this patient
population and are reasonable treatment options.
¤ No evidence either supports or refutes the use of more than
one line of chemotherapy.
¤ Many treatment options have shown modest response rates,
but their benefits over best supportive care have not been
studied in clinical trials

51. Borderline Epithelial Ovarian Cancer
¨ primary epithelial ovarian lesion with cytological
characteristics suggesting malignancy, but without
frank invasion
¨ clinically indolent course and good prognosis.
¨ Five-year survivals exceed 80%.
¨ peritoneal implants characterises OC

52. Borderline Epithelial Ovarian Cancer
¨ Treatment:
¤ Surgery as OC
¤ With peitoneal implants:
n Non-invasive: observation
n Invasive: observation or chemotherapy

53. Less Common Ovarian Histopathologies
¨ germ cell neoplasms,
¨ carcinosarcoma (MMMT), and
¨ ovarian stromal tumors.
¨ Early stage
¨ Fertility preservation
¨ Tumor markers: CA125, inhibin, AFP, BHCG

54. Germ Cell Tumors
¨ Young age <35 y
¨ Surgery: extensive or conservative
¨ Post surgery:
¤ Observation in stage I dysgerminoma or immature
teratoma
¤ Chemo (3-4 PEB):
n embryonal or endodermal sinus tumors;
n stages II-IV dysgerminoma or immature teratoma

55. Ovarian Stromal Tumors (Sex cord-stromal tumors)
¨ Surgery (conservative in stage I or else extensive)
¨ Post surgery treatment:
¨ Stage I low risk: observation
¨ Stage I high risk: observation, RT, PB chemo (BEP-TC)
n Tumor rupture,
n stage 1C,
n poorly differentiated tumor,
n tumor size greater than 10-15 cm132
¨ Stage II-IV: radio or PB chemo,

56. Carcinosarcoma (Malignant Mixed Müllerian Tumors)
¨ Surgery
¨ Post surgical therapy
¤ Stage I:
n Ifosfamide-based regimens
¤ Stage II-IV or recurrence:
¤ As ovarian CA