Oncology Flashcards
1
Q
What happens when there is a loss of heterozygosity at vHL locus on Chromosome 3?
A
Overproduction of VEGF.
2
Q
Compare and contrast sunitinib and sorafenib
A
Essentially they are both TKIs, however sorafenib is a ‘dirtier’ drug in a sense that it acts upon multiple TKs such as VEGF, PDGF, FGF, C/B-raf.
Used as a second line agent.
Similar side effect profile as sunitinib.
3
Q
How is tamoxifen metabolized?
A
CYP2D6 is necessary to form its two most important active metabolites.
Therefore strong inhibitors such as fluoxetine, paroxetine and bupropion should be avoided.
4
Q
In early breast cancer pre-menopausal patients, who benefits from addition of ovarian suppression?
A
Ovarian suppression can be achieved via oophorectomy, GnRH agonist or pelvic radiation.
Addition of ovarian suppression to either AI and tamoxifen improves disease free survival ONLY in women <35 and those who received chemotherapy (ie, high risk disease)
5
Q
Role of prophylactic salpingo-oophorectomy in high risk (ie, BRCA1/2) and average risk patients
A
In high risk groups, prophylactic BSO reduces ovarian and breast cancer risk.
In average risk group however, long term complications from BSO outweighs benefits - significantly increased risk of CVD, osteoporosis (as ovary continues to produces androstenedione and testosterone in significant amounts after menopause. These are converted to estrogen in local tissues)
Therefore ovarian conservation until at least age 65 improves long term survival in women at average risk of ovarian cancer when undergoing hysterectomy for benign disease.
6
Q
What constitutes moderately increased CRC risk (category 2)?
What is the recommended screening?
A
Represents 1-2% of population.
1st degree relative with CRC diagnosed <55, or
2x 1st/2nd degree relatives with CRC at any age
Colonoscopy every 5 years from age 50, or
10 years younger than age of first diagnosis of bowel cancer in the family, whichever comes first.
7
Q
What proportion of breast cancers are directly attributable to BRCA1/2?
A
5-10% cases only.
8
Q
Chemotherapy option in metastatic cholangiocarcinoma/gall bladder cancer
A
First line therapy is low dose cisplatin and gemcitabine.
Also sensitive to 5FU and derivatives, oxaliplatin and irinotecan.
Combination with radiotherapy can be considerd especially in R1 or N+ disease.
9
Q
4 features of carcinoid syndrome
A
Diarrhoea
Bronchospasm
Triscuspid stenosis
Pellagra
Carcinoid syndrome is mainly related to metastatic tumours originating in the midgut (distal small intestine, proximal colon)
Other sites such as foregut/hindgut rarely produces carcinoid syndrome as they lack DOPA decarboxylase
10
Q
General chemotherapy regime in SCLC?
A
Platinum based chemotherapy with etoposide.
11
Q
Causes of hand-foot syndrome
A
- Capecitabine/5-FU
- Vemurafenib/dabrafenib
- Pegylated doxorubicin
- Cytarabine
12
Q
4 major risk factors for RCC
A
- Smoking
- Obesity
- Hypertension
- vHL - 2-3% of cancers are familial
13
Q
Mechanism of HPV causing cervical cancer?
A
HPV 16/18 produces oncogenes E6 and E7 respectively.
E6 - inhibits the p53 tumour suppressor gene
E7 - inhibits RB suppressor gene
14
Q
Main toxicity related to trastuzumab
A
Cardiac toxicity with reversible reduction in EF, improves after cessation of treatment. Needs 3 monthly measurements of EF whilst on treatment.
15
Q
Which targeted therapy may be beneficial in gastric cancer?
A
Trastuzumab.
15% of gastric cancers are HER2 positive.
16
Q
Follow up schedule for non-metastatic CRC stage II to III
A
High recurrence rates - 50% by 2 years, 80% by 3 years.
Most powerful way of determining the future recurrence risk is to examine the resected tumour after resection.
Therefore patients are usually followed up for 5 years with following schedules:
Follow up with:
- Initial perioperative colonoscopy to exclude synchronous lesion, then repeat colonoscopy at 12-18 months to identify new lesions, then 3-5 yearly
- CT chest/abdo/pelvis yearly for 3 years
- CEA - 3 monthly for 2 years, then 6 monthly
17
Q
What constitutes high volume metastatic prostate cancer?
Management?
A
Visceral metastases OR greater than 4 bone metastases.
Metastatic prostate cancer is now managed with upfront chemohormonal therapy consisting of ADT with docetaxel based on CHAARTED and STAMPEDE trial.
18
Q
Side effects of vemurafenib?
A
BRAF inhibitor used in V600E mutation positive melanoma patients.
25% develop cutaneous SCCs Arthralgia Rash Fatigue Photosensitivity Alopecia
19
Q
What constitutes high CRC risk? (category 3)
What is the recommended screening?
A
Represents <1% of population.
> 3 1st/2nd degree relatives with CRC and multiple CRCs in 1 person, or
CRC <50 and at least 1 relative with endometrial or ovarian cancer
Suspected FAP in a relative with CRC.
Recommendations:
- Genetic counselling and testing
- If FAP - total colectomy and ileorectal anastomosis, sigmoidoscopy from age 12-15, duodenal screening froma ge 25 or at time of colectomy.
- If HNPCC - colonoscopy 1-2 yearly from age of 25 or 5 years younger than familial case.
20
Q
Indications for adjuvant chemotherapy in breast cancer
A
- Axillary node involvement
- Node negative tumour with size >1cm
- Other adverse prognostic markers (age <35, negative ER/PR status, high grade tumour)
21
Q
What are the treatment options in RCC refractory/not amenable to surgical therapy?
A
First line - sunitinib
Second line - sorafenib/axitinib
Third line - Bevacizumab
Fouth line - mTOR inhibitors such as everolimus in patients with progressive disease on VEGFR-TKI
22
Q
Bowel cancer screening in Australia
A
FOBT every 2 years from 50-70 age
FOBT detects human Hb
Proven to decrease mortality by 20% in 3 large clinical trials.
23
Q
Duke’s classification of CRC.
A
A - limited to mucosa/submucosa
B - through muscularis propria and into or through serosa
C - involvement of regional LN
D - distant metastasis
24
Q
Pre-operative management of rectal cancer
A
MRI to assess local extent of the cancer
If surgical margins are threatened, neoadjuvant chemoradiotherapy.
No strong evidence for post operative adjuvant chemotherapy currently.
25
How is BRCA 1/2 transmitted?
Autosomal dominant.
26
In adult intussusception, what diagnosis would you consider?
Metastatic melanoma until proven otherwise.
27
What options do you have as an adjuvant therapy in Stage 3 melanoma after surgery and lymphadenectomy +/- radiation?
At present, NONE.
No trials have shown evidence that adjuvant therapy in melanoma improves survival.
Therefore current option in adjuvant setting is observation only or enrolling in a clinical trial.
28
What constitutes average CRC risk (category 1)?
What is the recommended screening?
Asymptomatic, no history of CRC/UC, no family history.
FOBT every 2 years from age of 50
Can consider sigmoidoscopy every 5 years from 50 age
29
Describe 4 side effects of 5FU/capecitabine used in colon cancer.
1. Diarrhoea and mucositis
2. Hand foot syndrome (plantar-palmar erythema)
3. Cardiac toxicity secondary to coronary vasospasm
4. Myelosuppression
capecitabine has more PPE
30
Match the following skin manifestations with the associated cancers:
```
Erythroderma
Sweet Syndrome
Migratory thrombophlebitis
Acanthosis nigricans
Dermatomyositis
```
Erythroderma - lymphoma
Sweet's syndrome - MDS, other haematological disorder
Migratory thrombophlebitis - pancreatic cancer
Acanthosis nigricans - gastric cancer
Dermatomyositis - ovarian, lung ca
31
What does terrestrial UV radiation consist of?
5% - UVB which is mostly absorbed by epidermis
95% are UVA which can penetrate below the dermis.
UVA may be more damaging tot he skin by free radical generation, photoageing, immunosuppression and photocarcinosis.
32
What other cancers are associated with HNPCC?
Especially endometrial Ca and second CRC primary
Others include ovarian, stomach, small bowel, hepatobiliary, and renal cancers.
33
When would you consider post-mastectomy chest wall radiotherapy?
1. >5cm breast cancer
| 2. Lymph node involvement
34
How are breast cancers divided into 4 groups according to tumour biology and how do the treatments differ?
Luminal A - strongly ER/PR positive, HER2 negative with low proliferation. Endocrine treatment only.
Luminal B - ER/PR positive, HER2 negative, high proliferation. Chemotherapy and endocrine treatment
HER2+ - ER/PR negative, HER2 positive. Chemotherapy with Herceptin +/- endocrine therapy
Basal like - triple negative with high proliferation. Only treatment option is chemotherapy.
35
What is the significance of ulceration in melanoma?
Heralds high risk for metastatic disease.
Upstages the prognosis of all such patients compared to patients with melanoma of equivalent thickness without ulceration.
36
How does PARP inhibitors work in relation to BRCA1/2 mutations?
BRCA1/2 genes produce critical co factors in repair of dsDNA breaks.
Single strand DNA repair processes are mediated by PARP.
Therefore in tumour cells deficient in BRCA, inhibition of PARP results in inability to repair DNA as they have no other methods of DNA repair (unlike normal cells which will still have dsDNA repair mechanisms intact)
37
When would you consider axillary node dissection?
1. If clinically node positive pre-op
| 2. SNB positive
38
Cancers associated with PTEN mutation (Cowden Syndrome)
1. Breast
2. Thyroid
3. Endometrial
4. GU
39
What is the role of everolimus in metastatic breast cancer?
Can be used to overcome endocrine resistance.
BOLERO-2 study showed that when everolimus was added to exemestane (AI), improvement in progression free survival was seen. However due to high dose of everolimus used, side effects were common, which were mucositis, diarrhoea, hyperglycaemia/hyperlipidaemia, pneumonitis.
40
Colonoscopy in HNPCC
Lifelong colonoscopy 1-2 yearly.
41
What characterizes limited stage SCLC?
All disease within one radiation field: ie ipsilateral lung and hilar/mediastinal lymph nodes. Curable in 20-30% with concurrent chemoradiotherapy.
42
Breast screening - when does it start and what is its impact?
2 yearly breast mammogram from age of 50 to 74.
Impact of survival mainly in younger women - 40% reduction in mortality in women between ages of 39-49. Non significant 18% survival in women aged 50-59.
43
Adjuvant treatment options for resected pancreatic cancer
Current recommendation is gemcitabine plus capecitabine (5FU derivative)
Combination therapy is better than single agent.
Radiotherapy increases toxicity, not useful in pancreatic cancer when combined with chemotherapy
44
5 factors in determining a 'high risk' breast cancer
1. Multiple relatives with breast or ovarian cancer
2. Early onset of disease in Pt/family
3. >1 primary cancer (contralateral breast or ovarian cancer)
4. Vertical transmission including men
5. Rare malignancies in family history: eg sarcomas and breast cancer in Li-Fraumeni syndrome
All women <70 with ovarian cancer should be screened for BRCA. (15%)
45
Risk factors for ovarian cancer
1. Age
2. Nulliparity
3. Carrier of BRCA1/2
Risk is reduced by OCP use
46
When would you consider pneumonectomy over lobectomy in surgically resectable lung cancer?
Pneumonectomy if proximal cancer - ie <2cm to the carina
47
BRCA1/2 mutations as it relates to breast cancer:
1. Histology
2. Grade
3. Steroid receptors
4. HER2 expression
1. Histology - medullary carcinomas are more common in BRCA1, but majorities are ductal ca of no special type
2. Grade - generally higher grade than general population
3. Steroid receptors - BRCA1 more likely to be ER/PR negative. BRCA 2 has no difference to gen pop
4. HER2 expression - BRCA1/2 generally negative to HER2 expression
48
What are the risk reduction strategies available for BRCA carriers?
1. Bilateral BSO once childbearing is complete (preferably before age 40) - reduces risk of brast cancer by 50% and ovarian cancer by 90%
2. Bilateral mastectomy - reduces risk of breast cancer by 90%
If the patient does not want bilateral mastectomy, screening is available from age of 25 in forms of:
1. Breast self examination
2. Annual mammogram from age of 40 (or 5 years younger than the relative with breast cancer)
3. MRI breast from age of 25
4. Chemoprevention with Tamoxifen in pre/post menopausal, or aromatase inhibitors in post menopausal women
5. OCP can also be considered to reduce ovarian ca risk but may increase breast cancer risk
49
Side effects of cetuximab
Side effects of bevacizumab
Hypersensitivity reaction
Skin toxicity
Magnesium wasting
Bevacizumab SE: Hyptertension, haemorrhage and perforation due to tumour necrosis, 2x VTE risk
50
Significance of dihydropyrimidien dehydrogenase deficiency
Predicts intolerance to 5FU and its pro drug capecitabine.
51
What does BRCA mutation in ovarian cancer predict?
>90% of the tumours will be high grade serous ovarian cancer.
Predict response to platinum based therapy'o
52
What is the function of BRCA 1/2?
DNA repair gene.
53
What should all patients with breast conserving surgery have?
Adjuvant radiotherapy. Long term follow up of breast-conservation trials confirm significantly increased rates of local relapse when radiotherapy is omitted approaching 30%
54
Main side effect of EGFR antibodies such as cetuximab
Facial rash - however development of facial rash is predictive of eventual treatment response.
55
What is the role of bevacizumab in stage 4 NSCLC?
Results from the ECOG 4599 phase III trial demonstrated that in non-SCC NSCLC patients, median survival was significantly longer for those who received chemotherapy plus bevacizumab 15 mg/kg every 3 weeks than for those who received chemotherapy alone (12.3 months vs 10.3 months).[6] Patients with SCC are not eligible for bevacizumab, because of the risk of pulmonary hemorrhage.
56
Causes of false negative PET CT
1. Hyperglycaemia - FDG and glucose compete for some receptor
2. Small tumours <7mm in diameter
3. Tumours with slow growth or metabolism
57
How do you grade neuroendocrine tumours?
How does grade of the tumour influence staging?
Depends on Ki67 and mitotic count.
Staging scans depend on the grade of the tumour.
Grade 1/2 - DOTATATE PET/CT with assessment of somatostatin receptor density - checks suitability for somatostatin analogue treatment and potentially for peptide radionucleotide receptor therapy (PRRT).
Grade 3 - FDG PET used
58
Match the class to the following drugs:
```
Leuprolide/Goserelin
Flutamide
Cyproterone acetate
Abiraterone acetate
Enzalutamide
```
Leuprolide/Goserelin - GnRH agonist
Flutamide - steroidal anti-androgen
Cyproterone acetate - antiandrogen
Abiraterone acetate - blocks biosynthesis of androgens at ALL sites including testes, adrenal glands and prostate tumour cells.
Enzalutamide - androgen receptor antagonist (extremely high affinity). Crosses blood brain barrier.
59
What are the three most important pro-angiogenic factors in angiogenesis?
VEGF, PDGF, bFGF (basic fibroblast GF)
All are ligands for receptor tyrosine kinases
Hence multikinase inhibitors such as sorafenib are effective especially in treatment of RCCs.
Hypertension is a marker of response in VEGF inhibitors.
60
Action of Sunitinib
TKI which inhibits VEGF/PDGF receptors
Also inhibits c-kit oncogene.
Currently standard of care in first line treatment of RCC.
Superior to IFN.
61
How do you distinguish between seminomas and NSGCT?
AFP.
AFP will be high in NSGCT while as AFP will be normal in seminomas.
bHCG and LDH can be raised in both.
62
4 cancer causes of raised CEA
1. Gastric cancer
2. Colorectal
3. Lung
4. Breast
63
Causes of false positive PET CT result
Any inflammatory or infective lesion which can produce substantial FDG accumulation - ie, any granulomatous disease such as TB, sarcoidosis, rheumatoid nodule, surgery or infection such as pneumonia.
64
What is the benefit of regular use of sunscreen?
Prevents development of pre-cancerous actinic keratoses and skin cancers (SCC and melanoma)
65
What are the adjuvant options after radical inguinal orchidectomy of stage 1 NSGCT?
1. Active surveillance - preferred option
2. RPLND - no difference in survival compared with surveillance. If node positive then...
3. Chemotherapy - 1-2x cycles of BEP or EP.
Must include the platinum component.
Associated SE such as hair loss, pancytopenia, pneumonitis, cisplatin associated toxicities such as ototoxicity, peripheral neuropathy etc
66
What are the 5 prognostic factors in CRC?
1. Serosal involvement
2. Presence or absence of LN involvement based on MINIMUM of 12 LN sampling
3. Distant metastasis
4. Degree of penetration through the bowel wall
5. MSI (HNPCC) - associated with improved survival independent of tumour stage.
67
SERMs such as tamoxifen have differing effect on different tissues. Describe the differing effects on breast, bone, uterus and liver.
Antagonist on ER in breast tissue therefore usefula s a adjuvant endocrine therapy.
Agonist in uterus, liver and bone. Therefore improves bone health (ONLY in post menopausal women), however increases risk of uterine cancer. Also increased risk of VTE.
68
What proportion of CRCs are familial?
<5% of caes make up FAP/HNPCC.
69
Genetic defects in Lynch Syndrome (HNPCC)
MLH1, MSH2, MSH6, PMS1/2, MLH3
| Can be identified by immunohistochemistry on tumour specimen
70
What is the most important prognostic factor in stage 1/2 melanoma?
Breslow thickness +/- ulceration.
71
What is the role of neoadjuvant therapy in setting of prostate cancer?
Currently nil.
No reduction in LN metastasis or improvement in overall survivial seen.
No evidence that it improves resectability.
72
Amsterdam criteria for HNPCC
- 3 or more relatives with an associated cancer (colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis);
- 2 or more successive generations affected;
- 1 or more relatives diagnosed before the age of 50 years;
- 1 should be a first-degree relative of the other two;
- Familial adenomatous polyposis (FAP) should be excluded in cases of colorectal carcinoma
73
Outline the options of hormonal treatment in metastatic prostate cancer
1st line - GnRH agonist +/- Docetaxel depending on sites of disease.
2nd line - Total androgen blockade with GnRH agonist and testosterone antagonist
3rd line - inhibitors of adrenal steroidal synthesis, such as ketoconazole, or newer agents such as abiraterone acetate
74
Side effects of sunitinib
Lethargy
Hypertension - good prognostic factor. 2x survival compared to normal BP (due to increased vasoconstriction leading to systemic vascular resistance)
Diarrhoea and vomiting
Hand-foot syndrome
75
What agent would you use in ALK+ metastatic lung cancer?
Crizotinib. Inhibitor of ALK phosphorylation.
| ROS-1 fusion mutation cancers also respond to crizotinb.
76
How would you manage metastatic testicular cancers?
BEP chemotherapy 3-4 cycles
| Resect residual masses - residual benign teratomas can undergo malignant transformation therefore needs to be excised.
77
What is the action of aromatase inhibitors such as anastrozole/letrozole?
Blocks DHEA conversion to oestrogen and effectively reduces oestrogen levels to zero.
Therefore reduces BMD.
However no icnreased risk of VTE/uterine cancer.
Slightly more effective than tamoxifen at reducing recurrence.
78
Why do you need to give steroids with abiraterone acetate?
Abiraterone acetate is an androgen biosynthesis inhibitor.
Prevents DHEA conversion to androstenedione to testosterone/DHT etc
However also blocks conversion of 17-OH-pregnenolone to cortisol as well.
Excess Pregnenolone is converted to aldosterone.
Hence excess aldosterone formation occurs with decreased testosterone and cortisol.
Need to give prednisone to prevent addisonian crisis.
79
Describe action of following molecules:
1. Cetuximab
2. Trastuzumab
3. Erlotinib
4. Sunitinib
1. Recombinant chimeric monoclonal antibody which binds to EGFR, which inhibits proliferation and induces apoptosis of tumour cells that over-expresses EGFR.
2. Recombinant humanized monoclonal antibody that binds to HER2. Small-modest risk of cardiotoxicity.
3. Reversible TKI acting on EGFR. Used in NSCLC and pancreatic cancer.
4. TKI acting on vEGF receptors 2 and 3, PDGFR B, FLT-3 and c-KIT. All play a role in tumour angiogenesis and tumour cell proliferation. Used in RCC, GIST, pancreatic neuroendocrine tumour.
80
Compare the efficacy of tamoxifen vs aromatase inhibitors such as letrozole in post menopausal women with breast cancer
Aromatase inhibitors are more effective than SERMs with lower 10 year mortality (12.1 vs 14.2%)
81
What chemotherapy regimen is available for METASTATIC CRCs?
FOLFOX
FOLFIRI - Folinic acid, 5FU, IRInotecan
82
Name 3 cancers where BRAF mutations are observed.
1. Melanoma 50%
2. Colorectal 10%
3. Papillary thyroid cancer
83
Which CRCs benefit from EGFR inhibitors such as cetuximab and Panitumumab?
>75% CRCs are positive for EGFR mutations by IHC but there is no correlation between presence or intensity of IHC staining and clinical response to EGFR inhibitors.
K-ras activating mutations are found in 40-45% of CRCs and are associated with resistance to EGFR targeting agents.
Therefore need to be EGFR positive AND wild-type K-ras in order to be eligible for EGFR inhibitors.
84
When should you consider adjuvant chemotherapy in CRC?
In Duke's C CRC, proven survival benefit.
In Duke's B CRC, consider adjuvant chemotherapy if following high risk features are present:
1. Inadequate LN sampling
2. T4 disease - direct invasion of other organs/structures
3. Involvement of visceral peritoneum
4. Bowel obstruction/perforation
5. Poorly differentiated histology
85
List the common to least common types of lung cancer
1. Adenocarcinoma 40%
2. Squamous cell 20%
3. Small cell 13%
4. Large cell 7%
Others 20% - bronchoalveolar, carcinoid
86
What is the standard of care for Her2 positive metastatic breast cancer?
Chemotherapy (taxane based) + Trastuzumab and Pertuzumab.
Addition of pertuzumab improved overall survival without increase in cardiac toxicity.
87
What is the significance of LDH in stage 4 metastatic melanoma?
Confers a poor prognosis.
| Regardless of where the metastasis are, if you have high LDH, you are automatically classified as Stage 4M1c.
88
Match the following tumour markers with appropriate tumour:
```
CEA
CA125
CA15.3
CA19.9
aFP
```
```
CEA - colon cancer
CA125 - ovarian
CA15.3 - breast
CA19.9 - pancreas, biliary
AFP - germ cell tumours, HCC
```
89
What are the 3 adjuvant chemotherapy regime available for CRC?
FOLFOX - FOLinic acid + 5FU + OXaliplatin every 14 days for 6 months
XELOX - Capecitabine (XELoda) + OXaliplatin for 6 months
FOLFIRI - FOLinic acid, 5FU, IRInotecan
FOLFOX and XELOX are generally used in stage 2-3 CRC.
FOLFOX and FOLFIRI are standard first line therapies in metastatic CRC.
Capecitabine alone - used in frail elderly but inferior to combination therapy
90
Describe 6 situations when you would think about BRCA screening in breast cancer
1. Young breast cancer ie age <50
2. Triple negative breast cancer age <60
3. 2 or more breast cancer in one patient
4. Ovarian or primary peritoneal cancer
5. Male breast cancer (often BRCA 2)
6. Patients with 1st or 2nd degree relatives with ovarian/breast cancer before age of 50
91
What cancers are associated with asbestos exposure?
Highest risk for mesothelioma - 10-20x risk
| But also increases NSCLC risk
92
What is the significance of APC gene mutation on Chr 5?
FAP.
Autosomal dominant.
<1% of all CRCs
CRCs develop by age 45 in 90% of untreated individuals.
93
Genetic syndromes associated with pancreatic cancer
1. BRCA - 5% lifetime risk
2. HNPCC
3. Familial pancreatic cancer
4. Peutz Jeghers syndrome
5. CF and SPINK1 mutation
94
What agent would you use in metastatic lung cancer which is EGFR positive?
TKIs such as Gefitinib or Erlotinib. More effective than platinum doublet chemotherapy as a first line treatment in patients with EGFR mutation.
95
What is the action of irinotecan?
Describe 3 notable SE.
Topoisomerase I inhibitor.
Diarrhoea, myelosuppression and cholinergic effect.
96
Mechanism of action of Aprepitant
Belongs to a class of drugs called substance P antagonists (SPA). It mediates its effect by blocking the neurokinin 1 (NK1) receptor.
Used in prevention of chemotherapy induced nausea and vomiting - platinum based, anthracyclines.
97
What are the adjuvant options of treatment for stage 1 seminoma following radical inguinal orchidectomy?
1. Active surveillance - preferred option. 15% recurrence rate however still salvageable 98% of the time if captured early
2. Radiotherapy - dog leg or PA strip
However associated with impaired fertility, increased secodnary testicular cancers, cardiac disease
3. Adjuvant chemotherapy with cisplatin
Equivalent efficacy to XRT however associated with peripheral neuropathy, ototoxicity, nausea and vomiting
98
Most common 3 side effects of VEGF inhibitors such as sorafenib?
1. Hypertension
2. PRES
3. Proteinuria
99
How is GIST treated?
Resection followed by 3 years of adjuvant imatinib if high risk disease (determined by size of the tumour and mitotic rate)
In metastatic incurable disease, imatinib is first line, followed by sunitinib, then regorafenib.
100
Lynch syndrome (HNPCC) - associated mutations and cancer risks
Germline mutation in MLH1, MSH2, MSH6, PMS2 or EPCAM resulting in methylation of the promotor region of MSH2.
Increased lifetime risk for CRC, endometrial cancer, gastric cancer, ovarian cancer.
101
What is the significance of development of rash in patient with adenocarcinoma who is on EGFR TKIs such as erlotinib?
Higher grade rash has higher probability of response.
Rash therefore is a predictive marker of response.
102
SE profile of mTOR inhibitors
Hyperglycaemia, hyperlipidaemia
Pneumonitis in 2%
Rash
Asthenia, mucositis
103
What is the optimal duration of paclitaxel and carboplatin for metastatic NSCLC?
The role of maintenance chemotherapy in patients with metastatic NSCLC is unclear. Randomized studies did not show a survival advantage with prolonged chemotherapy (>6 cycles) as compared with standard-length therapy (4-6 cycles).[7] Accordingly, giving another four cycles of chemotherapy or providing continuous maintenance therapy with paclitaxel would not be recommended. Currently, only switch-maintenance therapy with pemetrexed and erlotinib has been approved by the US Food and Drug Administration (FDA)
104
What is the difference between vemurafenib and Dabrafenib in treatment of melanoma?
Both are BRAF inhibitors, however:
Vemurafenib - selective targeting of V600E mutation, but no activity in CNS
Dabrafenib - inhibits all V600 mutations, has activity in CNS.
105
Role of BRAF mutations in determining the cause of MMR deficient CRCs.
MMR deficient CRCs make up 15% of all CRCs and most are due to MLH1 methylation. 3% are due to germline MMR mutation (ie, Lynch syndrome). They are commonly R sided, poorly differentiated with lymphocytic infiltrates.
BRAF mutations are RARE with germline mutations of MMR genes, therefore presence of BRAF mutation in CRCs suggest that it is due to somatic methylation mutation.
106
What is the most common melanoma type in asians?
Acral Lentiginous Melanoma.
Occurs in palms, soles and under nails.
Poor prognosis.
107
Side effect of trastuzumab?
Reversible cardiomyopathy (unlike anthracyclines which are irreversible)
108
When would you consider using Lapatinib in breast cancer?
CNS involvement in trastuzumab refractory disease (trastuzumab does not have any CSF penetration but Lapatinib does)
109
What does Sun Protection Factor (SPF) mean on sunscreen?
Based on effectiveness of the sunscreen in blocking the UVB. Does not measure effectiveness against UVA.
SPF of 15 means that it takes 10min for skin to start to burn without sunscreen compared to 150min with that sunscreen.
110
What is the impact of increased intake of fruit and vegetables in CRC?
Reduced incidence.
111
What are the three most important prognostic factors in stage 3 melanoma? (ie, locoregional advanced disease)
1. Number of metastatic nodes
2. Micro vs macrometastatic disease
3. Third most significant factor being presence of ulceration.
112
Effects of tamoxifen
Selective estrogen receptor modifier.
Anti-estrogen effect in mammary tissue
Oestrogen receptor agonist in bone and inhibits osteoclast - bone protection
Partial estrogen receptor agonist in endometrium - increases the risk of endometrial cancer by 2-4x
113
2 mutations commonly found in GIST
1. c-KIT
| 2. PDGFR alpha mutation
114
Minimum duration of imatinib therapy for GIST after complete resection
>36 months
115
Scanning modality in stage 2-4 melanoma
MRI brain and PET CT whole body.
| No further imaging is required in stage 1 disease.
116
Role of sentinel lymph node biopsy and total lymph node dissection in melanoma
In stage II disease, SLN biopsy is indicated after surgical resection of primary melanoma.
If SLN shows positive lymph node involvement, then stage II disease becomes stage III disease, and TLND is indicated.
There are no RCT evidence to show that TLND confers survival benefit, however significant number of patients attain 5 year survival and palliative benefit of TLND are considerable. Therefore it is still done.
117
Management of metastatic disease in melanoma
If no extensive locoregional disease and metastasis confined to a single site is found, then metastatectomy is of benefit.
Sites including lung, adrenal, brain benefit from metastatectomy.
In brain, if multiple brain metastasis, whole brain radiotherapy still confers a survival benefit.
118
Side effects of vemurafenib (selective V600E BRAF inhibitor)
1. SCC
2. Arthralgia
3. Rash
4. Photosensitivity
5. Fatigue
119
Name 3 major immune related side effects of CTLA-4 inhibitors
First and foremost GI - immune related colitis with diarrhoea
Skin - pruritis, erythema, vitiligo
Hepatitis
Endocrine including adrenal crisis
Mostly managed with corticosteroids and if severe, TNF blockade or mycophenolate
However one upside of IRAE is that grade III/IV IRAEs had a significantly higher rate of tumour regression than those without IRAE.
120
Predictive marker of efficacy for following:
1. VEGF/PDGFR inhibitors such as sunitinib and sorafenib
2. EGFR TKIs such as erlotinib/gefetinib
3. CTLA-4 inhibitors such as ipilimumab
1. Hypertension
2. Rash
3. IRAE such as colitis, skin reactions
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4 risk factors for RCCs
1. Smoking
2. Obesity
3. Hypertension
4. Familial - 2-3% related to VHL
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2 important side effects of RCC specific mTOR inhibitor, temsirolimus
1. HTN, hyperlipidaemia, which reflects role of mTOR in glucose and lipid metabolic pathway
2. Pneumonitis - therefore in patients with SOB with mTOR inhibitors, do HRCT!
123
Define castrate resistant prostate cancer
Patients being managed with ADT who have evidence of disease progression (increasing serum PSA, new clinical metastases, progression of existing metastases) in the presence of adequately depressed serum testosterone are considered to have castration resistant disease
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Situations where abiraterone and enzalutamide cannot be used
Abiraterone - cannot be used in severe liver disease
Enzalutamide - increased risk of falls, decreases warfarin level
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Mechanism of action of abiraterone
Abiraterone is an orally administered small molecule that irreversibly inhibits the products of the CYP17 gene (including both 17,20-lyase and 17-alpha-hydroxylase). I
In doing so, abiraterone blocks the synthesis of androgens in the tumor as well as in the testis and adrenal glands. Patients treated with abiraterone are at risk for adrenal insufficiency and require concurrent steroid replacement therapy
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Mechanism of action of enzalutamide
Enzalutamide is an orally administered agent that acts at multiple sites in the androgen receptor signaling pathway:
1. Blocking the binding of androgen to the androgen receptor
2. Inhibition of nuclear translocation of the androgen receptor
3. Inhibition of the association of the androgen receptor with nuclear DNA.
Unlike abiraterone, concurrent treatment with steroids is not required.
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When should you consider using mitoxantrone?
Mitoxantrone was the first chemotherapy agent approved for use in men with castration resistant prostate cancer. Mitoxantrone was approved based upon improvement in symptoms, and not a prolongation of survival.
Its use now is generally limited to patients requiring chemotherapy who have progressed on or are not candidates for taxane chemotherapy.
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3 most important tumour markers in testicular cancer
Three serum tumor markers have established roles in testicular cancer: alpha fetoprotein (AFP), the beta subunit of human chorionic gonadotropin (beta-hCG, since the alpha subunit is common to several pituitary hormones), and lactate dehydrogenase (LDH).
Serum levels of AFP and/or beta-hCG are elevated in 80 to 85 percent of men with NSGCTs, even when nonmetastatic.
By contrast, serum beta-hCG is elevated in less than 20 percent of testicular seminomas, and AFP is not elevated in pure seminomas
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Compare and contrast NSGCT and seminomas:
Compared with NSGCTs, seminomas:
1. More localized disease (80% confined to testes, 15% have stage 2 disease in that they are limited to RPLN)
2. Rarely spread via the bloodstream to other areas (eg, liver, lung, bones, or brain). This occurs more commonly in men with NSGCTs.
3. Are exquisitely sensitive to radiation therapy (RT), while NSGCTs are more radioresistant.
4. NSGCTs are marked by rise in bHCG and AFP, while as only 20% of seminomas have rise in bHCG and AFPs are completely normal.
5. Seminomas display relatively indolent growth and a longer natural history.
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Management of stage 1 and 2 seminomas
Stage 1 - radical orchidectomy and active surveillance
Stage 2 - if limited RPLN involvement, radiotherapy (since seminomas are sensitive to radiotherapy). If more extensive involvement, cisplatin based chemotherapy.
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3 Risk factors associated with relapse in stage 1 NSGCT
1. Lymphovascular invasion
2. Predominance of an embryonal carcinoma component
3. A T3 or T4 primary tumour
If none of these are present, active surveillance.
If any one of these features are present, could consider RPLND, BEP chemotherapy (bleomycin, etoposide, cisplatin) or active surveillance.
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Efficacy of bevacizumab in metastatic CRCs
Bevacizumab is a recombinant humanized monoclonal Ab that targets VEGF. Inhibits binding of VEGF to its receptor on endothelial cells and decreases vascularisation and causes inhibition of tumour growth.
When bevacizumab is added to FOLFOX or FOLFIRI regime as first line, increased overall survival at the expense of increased side effects which includes hypertension, bowel perforation and impaired wound healing.
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Key characteristic of HER2 positive breast cancers
HER2 positive cancers have higher risk of metastasis and relapse.
Therefore chemotherapy and trastuzumab are indicated for all tumours, except very small tumours (ie, <5mm and node negative tumours)
On immunohistochemistroy, HER2 positivity is defined from 1+ (NEGATIVE), 2+ (equivocal) and 3+ (positive)
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What is the advantage of Lapatinib (TKI) over HER2 agents such as trastuzumab?
Lapatinib has CSF penetration while trastuzumab does not.
Lapatinib has been shown to be beneficial as a single agent or with chemotherapy in treatment of breast cancer in trastuzumab refractory disease
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How does trastuzuamb emtansine work?
It is a conjugate trastuzumab with anti-microtubule agent (DM1), which delivers the anti-microtubule agent directly to the cancer cells. Imporved PFS and less toxicity compared to trastuzumab and taxane.
136
5 poor prognostic factors in small cell lung cancer
1. Poor performance status
2. Extensive stage
3. Hyponatremia
4. Elevated LDH
5. Elevated ALP
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True/False - asbestos by itself can increase the risk of NSCLC
True
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Chemotherapy regime of choice in Stage 4 non-squamous NSCLC?
Cisplatin/carboplatin PLUS Pemetrexed.
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Treatment of choice for EML4-ALK fusion oncogene or ROS-1 fusion positive lung adenocarcinoma
Crizotinib - inhibitor of ALK phosphyorylation. Has high response rates and disease control.
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Investigation of carcinoid tumours/syndromes
1. Measurement of urinary 5-HIAA is most useful - patients need to avoid tryptophan or serotonin rich foods as they can cause false positivity
2. Chromogranin concentration has low specificity therefore should NOT be used as a screening test but can be useful in disease monitoring
3. CT with contrast is generally useful - most carcinoid tumours are vascular
4. MRI is most sensitive for liver metastasis
5. Octreoscan - most carcinoid tumours express high levels of somatostatin receptors therefore can be imaged with radiolabeled form of somatostatin analog octreotide
6. Endoscopy - for ALL patients with metastatic carcinoid with unknown primary site
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When should you offer adjuvant chemotherapy for breast cancer?
Usually offered to early stage hormone receptor positive cancers with high risk characteristics such as:
○ High grade tumour
○ Large tumour size >2cm
○ Pathologically involved lymph nodes
○ High 21 gene recurrence score >31
Also:
Triple negative cancer if size >0.5cm (given that no hormone therapy can be given and chemotherapy is their only option for adjuvant treatment following or before radiotherapy)
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Histological appearances of MMR deficient CRC
1. Mucinous
2. Poor differentiation
3. Right sided
4. Lymphocytic infiltrate
5. Expanding growth pattern
6. Absence of intraglandular neutrophil rich dirty necrosis
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Mechanism of action of 5FU/capecitabine
Inhibits thymidylate synthetase and prevents methylation of deoxyuridic acid to thymidylic in formation of pyrimidines. S phase specific.
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Mechanism of action of cytarabine
Blocks DNA polymerase in formation of DNA. S phase specific.
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Name 4 alkylating agents and describe their mechanism of action
1. Cisplatin
2. Cyclophosphamide
3. Chlorambucil
4. Busulphan
Causes covalent cross-linking between DNA.
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Name 2 antibiotic chemotherapy agents and their mechanism of action
Bleomycin, doxorubicin.
Degrades DNA by formation of free radicals, and intercalate between base pairs and block RNA production.
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How does BRCA mutation influence survival and response to therapy in ovarian cancer?
BRCA mutated women are platinum sensitive and therefore have better PFS and OS. Higher rates of response to second therapy even if early relapse. Therefore consider mutation testing even if no family history, as 15% of high grade cancers are BRCA positive.
