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Flashcards in Gynaecological cancers Deck (59)
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1

Describe ovarian cancer pathology

-  types of histopathology

mainly based on histopathology

 

4 types;

- mucinous invasive; most commonly metastasis from GI tract. sometimes rare primary mucinous ovarian cancers

- endometrial; from endometriosis

- clear cell; from endometriosis

- high grade serous; most common. likely from distal end of fallopian tube

2

Describe genomic landscape of ovarian cancer

deficiency in high grade serous ovarian cancers 

4 different molecular subtypes (AOCS, TCGA, NCI, Norway) were prognostic 

3

germline deficiencies; BRCA1/2

predicted for better outcome at 5 years with germline mutations than non carriers.

BRCA2 better than BRCA1 & non carriers outcome in 10 years

 

 

4

Describe genetic testing recommendation in ovarian cancer

 

ALL women diagnosed at ≤ 70 years of age with highgrade non-mucinous epithelial ovarian, fallopian tube or primary peritoneal cancer should be referred for BRCA1/2 testing

5

Describe when people usually present with ovarian cancer

usually Stage III/IV at initial presentation, due to non specific symptoms of early stage. 

 

6

Describe primary mx of ovarian cancer

1. debulking surgery to acheive R0 (presence of residual disease at time of surgery known to be a poor prognostic factor)

2. primary chemotherapy (6x Carbo/Taxol q3w)

3. first clinical remission

7

Describe mx of recurrent ovarian cancer

recurrence occurs in 80% of patients post 1st clinical remission

determined by platinum free interval

1. if platinum sensitive >6 months; better outcome -> usually 2nd/additional clinical remission -> but can recurr again

2. if platinum resistant (recurs in less than 6 months), poorer outcome -> likely recurrence/progression.

 

8

Describe overview of clinical course of ovarian cancer mx

9

Describe chemotherapy trials in ovarian cancer

Carbo/Taxol

no difference in treatment arms

15.4-16.4month median progression-free survival (PFS)

weekly (instead of Q3week) carbo/taxol: significant improvement in PFS & overall survival in high risk populations (suboptimal debulked/stage 4 patients) in only one study. but not validated in further many studies. 

10

Describe neoadjuvant therapy in ovarian cancer

3 weeks of chemo before debulking surgery

similar progression free and overall survival

adopted globally as one of the options if lots of symptoms, ascites requiring treatment quickly. chemo can reduce symptoms and improve performance status prior to surgery 

11

Describe intraperitoneal chemotherapy in ovarian cancer

controversial

can improve PFS & overall survival

benefit restricted to those who could go through all 6 cycles

 

Significant Gr 3/4 toxicity

 

12

Describe mx of ovarian cancer targeting angiogenesis

mAB targeting angiogensis e.g. tyrosine kinase inhibitor

e.g. bevacizumab

when bevacizumab added to usual chemotherapy, improved PFS & overall survival but again limited to those with high risk population

 

Questions remain: front line vs. recurrent setting, duration & dose, combination with IP/Dose dense schedule, bevacizumab vs. other antiangiogenic agentes, cost effectiveness, biomarkeres 

13

Describe PARP inhibitors in ovarian cancer

inhibit DNA repair pathway

PARP inhibition -> impairs base excision repair -> if HR-deficient tumour cell (e.g. BRCA deficient), impaired HR mediated DNA repair -> tumour selective cell death (synthetic lethality). 

Normal cells with functional homologous recombination can replicate DNA & have HR-mediated DNA repair leading to cell survival. 

i.e. PARP inhibitors only lead to tumour selective cell death by affecting base excision repair in HR/BRCA deficient tumour cell

  • in recurrent settings
  • great for those with mutations
  • dramatic improvement in PFS (overall survival too premature)
  • improved progression free survival even as first line
  • PFS 41.4 months (c.f. 13.8 in placebo) in BRCA1. Benefit greater if BRCA2 mutation.  

14

Describe mx of ovarian cancer front line setting

- optimally debulked pt

- suboptimally debulked pt/ stage IV

- stage III/IV germline or somatic BRCA1/2 mutant

 

  • Optimally debulked (no macroscopic residual disease):
    • If suitable, consider IP chemotherapy
    • If not, IV Carbo/Taxolq3w
  • Suboptimally debulked/Stage IV
    • Carbo/Taxol q3w + Bevacizumab (total 18 doses)
    • If Bevacizumab contra-indicated, consider Carbo q3w + weekly Taxol
  • Stage III/IV germline or somatic BRCA1/2mutant
    • Carbo/Taxol q3w -> maintenance olaparib(maximal duration of therapy 2 years)

Refer to germline testing. if BRCA1/2 mutation, then eligible for olaparib. 

15

Mx of platinum resistant vs. sensitive recurrent ovarian tumours

1. platinum resistant if <6 months platinum-free interval

use non-platinum single agent; 

- liposomal doxorubicin

- weekly paclitaxel

- gemcitabine

- topotecan

- oral cyclophosphamide

 

2. Platinum sensitive if >6 months platinum-free interval

use platinum single agent or doublet;

- liposomal doxorubicin

- paclitaxel

- gemcitabine 

 

Gooe symptom mx is critical. 

16

Describe recurrent disease in ovarian cancer

isolated recurrent disease; may have improved PFS with surgery rather than no surgery. 

 

markers only vs. symptomatic progression. CA125 rising, in absence of clinical detectable symptoms/radiologically detectable disease. no difference in chemo between those treated for biochemical disease, vs. treated once symptomatically/radiologically detectable. hence don't usually treat biochemically only 

platinum sensitivity; important prognostic factor for those with recurrent disease. not a binary system. sensitivity if disease free >6 months.

17

Describe novel combinations in ovarian cancer

Niraparib + PD-1 inhibitor -> significnat response rate 23% in platinum resistant/refractory high grade serous ovarian cancer

18

Describe novel agents in recurrent ovarian cancer mx

1. antiangiogenic agents

  • bevacizumab 
  • cediranib
  • trebananib

2. PARP inhibitors

  • olaparib
  • rucaparib
  • niraparib

3. novel agents

  • Immunotherapy
  • Restoring p53
  • Other DNA repair agents
  • Combinations

19

Summary of ovarian cancer

- ?homogenous ?heterogenous disease

- primary mx

- new front line mx in first line setting

- anti angiogenic agents & PARP inhibitors

- recurrent disease mx

 

  • Ovarian cancer is a heterogeneous disease
  • Primary treatment consists of debulkingsurgery and chemotherapy with Carboplatin/Paclitaxel
  • Neoadjuvant chemotherapy, dose-dense chemotherapy and intra-peritoneal chemotherapy are all potential treatment options in first line setting
  • Anti-angiogenic agents and PARP inhibitors have a role in the first line and recurrent setting
  • In recurrent disease, platinum sensitivity, BRCA status and patient symptoms are all important factors

20

In recurrent ovarian cancer, what are important factors?

platinum sensitivity

BRCA status

patient symptoms

21

Describe endometrial cancer

- prevalence

- median age at diagnosis

- mortality rate

 

  • Most common gynaecologicalmalignancy
  • 5th most common cancer in women
  • Increasing incidence related to increasing prevalence of obesity and metabolic syndrome
  • Median age of diagnosis is 63yo
  • Majority are diagnosed at early stage
  • Mortality rate of 1.7-2.4 per 100,000 women

22

Describe risk factors for endometrial cancer

 

  • Unopposed oestrogen
    • Nulliparity, early menarche, late menopause
    • Obesity -> excessive peripheral conversion of androgens to oestrogens
    • Chronic anovulation state eg. polycystic ovarian syndrome
    • Tamoxifenuse
  • Age
  • Lynch syndrome and other familial cancer syndromes. Account for ~5% of endometrial cancers, particularly at younger age
  • Protective factors –OCP 

23

Describe types of endometrial cancer

 

Type I –most common, accounts for ~80%

  • Endometrioid adenocarcinomas, Grade 1-2
  • Typically arise from atypical endometrial hyperplasia
  • Oestrogen dependent
  • Good prognosis

 

Type II

  • High grade endometrioid, serous, clear cell
  • Oestrogen independent, different biology
  • Less chemo-sensitive, poor prognosis

24

Describe 5 year overall survival in endometrial cancer based on staging

Stage I: 80-90%

Stage II: 65-80%

Stage III: 50-65%

Stage IV: 20-25%

25

Clinical px of endometrial cancer

 

  • ~90% present with abnormal PV bleeding
    • Post-menopausal, post-coital bleeding
  • Pelvic/abdominal pain, bloating and systemic symptoms such as nausea, fatigue, and loss of appetite/weight usually indicate advanced disease
  • Investigate with transvaginal US +/-pipelle. Should be performed by a specialist gynaecological US
  • May require hysteroscopy/D+C
  • Pre-operative MRI used to determine local invasion and potential nodal involvement. No evidence for routine pre-operative CT Chest or PET scan

26

Describe surgical mx in endometrial cancer

 

  • Total hysterectomy and bilateral salpingo-oopherectomy +/- sentinel lymph node sampling is standard for presumed early stage endometrial cancer
  • Laparoscopic and/or robotic surgery is associated with shorter hospital stay and lower post-op complications
  • Includes careful assessment of peritoneal surfaces and omental biopsies may be required
  • Role of lymph node clearance is controversial
  • Fertility sparing treatment may be appropriate in some patients

27

Describe adjuvant therapy in endometrial cancer

adjuvant therapy post surgery controversial

depends on risk stratification

  • FIGO stage
  • Histological subtype and grade
  • Lymphovascular invasion
  • Depth of myometrial invasion
  • Age

 

Mx based on risk stratification 

  • Low risk: observation alone
  • Intermediate: brachytherapy or observation
  • High-intermediate: controversial. depends on extent of surgical lymphadenectomy. brachytherapy vs. external beam pelvic radiotherapy vs. observation
  • High: controversial. pelvic radiotherapy plus brachytherapy. possible benefit of concurrent chemotherapy + adjuvant chemotherapy for stage III disease. 

28

  Basic principles of advanced disease mx of endometrial cancer

- what factors are considered

 

  • Patient factors: symptoms, performance status, co-morbidities, previous treatment
  • Tumour factors: sites of disease, tempo of disease
  • Biomarkers/Molecular factors: ER/PR status, mismatch repair (MMR) protein status 
  • Easy to do at most pathology labs by immunohistochemistry on FFPE material (eg. archival surgical specimen)
  • Surgical cytoreduction can be considered where possible
  • PORTEC-3 style treatment for patients with residual disease post-op if within a radiotherapy field
  • Palliative radiation to sites of symptomatic disease
  • Hormonal therapy with progestogens/tamoxifen can offer long-term disease control for patients with Type I endometrial cancer

29

Describe systemic chemotherapy in endometrial cancer

 

  • GOG209 (only in abstract form)
    • Carboplatin + Paclitaxel vs Cisplatin + Doxorubicin + Paclitaxel
    • Response rate of ~60%
    • Non-inferior in terms of OS and PFS
    • Doublet much better tolerated compared to triplet
  • No proven second line therapy
    • Multiple chemotherapy and novel agents tested

30

Describe microsattelite instability and immunotherapy in endometrial cancer

mismatch repair protein status

typically higher tumor mutational burden respond better to immunotherapy esp immune checkpoint inhibitors compared to those with microsatellite stability

e.g. avelumab, durvalumab