Oncology 2 - Urological and Gastrointestinal Cancers Flashcards
What is the incidence of RCC?
2-3% of all cancers in adults
7th most common cancer in men
9th most common cancer in women
Incidence is increasing
What are risk factors for RCC?
Smoking
Obesity
Hypertension
2-3% are familial (von hippel lindau)
What is the pathogenesis of vHL disease?
TSG on chromosome 3, loss of heterozygosity leads to overproduction of VEGF, important in tumour angiogenesis.
Autosomal dominant
What is the predominant type of RCC?
75% are clear cell
What are VEGF inhibitors used in RCC?
mAbs - Bevacizumab
TKIs - sunitinib/sorafenib/pazopanib/axitinib
What are mTOR inhibitors used in the treatment of RCC?
temsirolimus
everolimus
What is 1st line therapy in metastatic renal cell cancer?
Sunitinib
- inhibits VEGF, PDGF, c-kit oncogene
- ORR 39% vs 8%, improved median PFS, non-sig increase in OS
What are AEs of sunitinib?
Lethargy Hypertension Diarrhoea/vomiting stomatitis hypothyroidism skin and hair discolouration hand-foot syndrome neutropenia and thrombocytopenia LV dysfunction
(pazopanib is similar)
What is the MOA of sorafenib?
TKI of: VEGF PDGF FGF C-raf B-raf
- similar SEs to sunitinib - 2nd line therapy
What is the MoA of bevacizumab?
MAb against VEGF - binds and neutralises
Better than IFN alone when used in RCC, with RR increased, and improved PFS. No change in OS
What is mTOR and it’s function?
mammalian target of rapamycin
master regulator of cell
transduces extracellular signals that promote growth and survival
key component in intracellular signals for proliferation, growth, survival and angiogenesis
activated in many tumours
exacerbates loss of vHL function
increases HIF-1alpha, increases expression of genes required for tumour cell growth in hypoxic environment, including VEGF
What is the function of mTOR inhibitors in RCC?
temsirolimus
in both treated and untreated advanced disease - improved median OS and median PFS
What are SEs of temsirolimus?
asthenia, mucositis infection, anaemia nausea, anorexia rash decreased PO2 hyperglycaemia, hyperlipidaemia pneumonitis in
What is epidemiology of prostate cancer?
leading site of new cancer dx in men ranks 2nd for cancer deaths in males incidence stable 1/8 will develop prostate cancer in their lifetime median age at Dx is 69 risk increases with age
- prostate, 2. bowel, 3. melanoma
What is the function of PSA and DRE in prostate cancer?
At age 40, DRE and PSA can predict likely lifetime risk of prostate cancer.
what is the rationale of treatment of prostate cancer?
Localised:
- surgery
- radiotherapy
Advanced
- hormonal therapy
- chemotherapy
- supportive therapy
- radio Tx
- bisphosphonates
- palliative care
What are the results of neoadjuvant therapy in prostate cancer?
no reduction in LN mets
no improvement in OS
does reduce positive resection margins
What are treatment options of early prostate cancer?
Little conclusive data:
- active surveillance
- radical prostatectomy
- EBRT/brachytherapy
What are predictors of relapse/metastatic disaease?
gleason score - 5-7 vs 8-10
PSA doubling time - 10 months
What are adjuvant therapy options in locally advanced disease?
surveillance
Hormone therapy/androgen ablation
radiotherapy (EBRT)
combined modality therapy
What are significant toxicities of adjuvuant therapy in advanced prostate cancer?
loss of libido host flushes fatigue anaemia loss of muscle mass weight gain depression osteoporosis
What does adjuvant XRT achieve in advanced prostate cancer?
immediate post of XRT improves local control in men with pT3 disease, and those with positive resection margins
What does the addition of ADT to EBRT achieve in prostate cancer?
improvement in local control, distal control and overall survival compared to EBRT alone
What are 1st, 2nd, 3rd and 4th line therapies for hormonal treatment of prostate cancer?
1st line - GnRH agonists +/- docetaxel
2nd line - total androgen blockade - GnRH agonist + testosterone antagonist
3rd line - abiraterone acetate (inhibition of adrenal steroid synthesis)
4th line - clinical trials
What are examples and MoA of GnRH agonists?
Leuprolie, goserelin
decrease LH production and in turn testicular androgens
What are examples of antiandrogens?
flutamide and bicalutamide (Steroidal) cyproterone acetate (non-steroidal)
What must be prescribed prior to and after the commencement of GnRH agonist in patients w prostate ca?
must admin a testosterone antagonist for 7 days pre and post to prevent flare phenomenon.
What do current guidelines recommend re: complete andogen blockade in metastatic prostate cancer?
Do no recommend complete androgen blockade over and above monotherapy
What are options in castrate resistant prostate cancer?
Can switch to 2nd line hormonal therapy:
- cessation of antiandrogens if on CAB or addition of antiandrogen (withdrawal responses in 20%)
- can add ketoconazole
- Corticosteroids reduce pituitary ACTH which reduces adrenal steroidogenesis
- response is generally only 4-6 months
What chemotherapy agents are used in CRPC?
Generally docetaxel - which has been shown to have higher RR, and 2 month overall survival - now 1st line std of care in mCRPC
what is the MoA and SEs of docetaxel?
taxane chemotherapy agent - inhibits disassembly of microtubules during cell cycle progression, also inactivates bcl-2 - leading to apoptosis.
SEs: hair loss, NV, pancytopenia, diarrhoea, lethargy, fluid retention, hypersensitivity reactions, myalgias, arthralgias, peripheral neuropathy and nail changes
What is the indication for cabazitaxel in CRPC?
in patients with docetaxel resistant disease, shown to have improved OS vs mitozantrone.
Significant toxicity:
myelosupppression esp febrile neutropenia
diarrhoea
mucositis
What is the MoA of abiraterone Acetate?
When is it indicated?
What are SEs?
Blocks the synthesis of testosterone in the adrenal gland
Post docetaxel chemo - abiraterone shown to improve OS
AEs: fluid retention, hypokalemia (due to increased aldosterone) - shunts steroid synthesis to mineralocorticoid pathway.
What must be given with abiraterone acetate?
Cortisol - blocks production of cortisol and DHT, shunts to aldosterone.
What is the MoA of enzalutamide?
androgen receptor antagonist.
Phase III trials show improved OS vs. placebo.
What are uses of bisphosphonates in prostate ca?
Prevention of osteopenia with ADT
prevention/delay of skeletal complications with bone mets
relieve pain from bone mets
What is initial 1st line Rx for pt with bone mets?
Commence zoledronic acid + calcium + vit D.
Dose adjust for renal impairment, not recommended for CrCL
What evidence supports the use of Bispho in Prostate cancer?
delays skeletal complications.
only marginally improves pain vs control groups.
denosumab similar.
What are SEs of bispho in prostate ca?
Flare in pain
Myalgia/arthralgia
Renal impairment
ONJ
What are common complications of prostate cancer?
acute urinary retention bilateral ureteric obstruction spinal cord compression pancytopenia from BM infiltration bilateral lower limb lymphoma 2ndary to pelvic obstruciton
What are complications of hormone therapy in prostate cancer?
impotence decreased libido metabolic syndrome - CVD, IHD, Strokes - hyperglycaemia, diabetes - obesity Osteoporosis
What are common complications of chemotherapy treatment in Prostate Ca?
Chemotherapy
- Taxane therapy -fluid retention, peripheral neuropathy, lethargy/fatigue
common:
alopecia, mucositis, diarrhoea, febrile neutropenia
What is key epidemiology of testicular cancer?
Comparatively rare
75% occur in
What are good prognostic factors in Testicular ca?
Seminoma - any primary site - non pulmonary visceral mets - Markers: normal aFP, any BhCG, any LDH, NSGCT NSGCT: - testicular or retroperitoneal primary - Markers: - aFP
What are intermediate prognostic factors in Testicular Ca?
Seminoma: - testicular or retroperitoneal primary - nonpulmonary visceral mets - Markers: - normal AFP - any BhCG - Any LD NSGCT: - testicular or retroperitoneal primary - non-pulmonary visceral mets - markers: - aFP 1000-10000 (indicative of NSGCT) - BhCG 5000-50,000 - LD 1.5-10.0x ULN
What are poor prognostic factors in Testicular Ca?
Seminoma - N/A
NSGCT:
- mediastinal primary
- non-pulmonary visceral mets
- Markers:
- aFP >10,000
- BhCG >50,000
- LD >10x ULN
Management of Stage 1 NSGCT?
Inguinal orchidectomy then:
1) active surveillance
- markers
- radiology (Alternate CXR and CT CAP)
- q1m 1st year
- q2m 2nd year
- q3m 3rd year
- then early
2) Can perform Retroperitoneal LND (no difference in survival vs. active surveillance)
3) Chemotherapy - 1-2 cycles of BEP or EP (bleomycin, etoposide, cisplatin)
What are SEs of BEP?
NV, hair loss, lethargy pancytopenia Hypersensitivity reaction to bleomycin Pneumonitis due to bleomycin Peripheral neuropathy, tinnitus and renal impairment due to cisplatin.
What are adjuvant treatment options in stage I seminoma?
Active surveillance
15% recurrence rate
Salvage rates high if detected early (no impact on mortality)
Tumour markers and CT ever 4 months for 3-4 years
Radiotherapy
Adjuvant chemo possible - single agent carboplatin reduces recurrence
What is the management of metastatic testicular cancer?
70% curable with standard chemotherapy:
usually 3-4 cycles of BEP
Most fibrotic tissue or teratoma - risk of malignant transformation with teratoma (requires resection of residual mass 3-6/12 post)
What is the management of relapsed/refractory disease?
Relapse within 4 weeks = cisplat resistant disease.
Progression wihtout initial Cr - worse prognosis
Histology -seminoma does better than NSGCT
Alternate chemo includes - VIN (vinplastine, ifostfamide, cisplat) or TIP (paclitaxel, ifosfamide, cisplatin)
Can do sequential hi dose chemo with mini-autografts w reasonable response rates.
What is the incidence of CRC in Aus?
2nd for new cancers and 3rd for cancer deaths in Aust
>50% are over 70y of age
1/28F and 1/18M will develop bowel cancer in their lifetime
5 year survival rate is 63% overall
What is duke’s classification for CRC?
Duke A = limited to mucosa and submucosa
B = through muscularis propria and into or through serosa
C = involvement of regional lymph nodes
D = distant metastases
What are prognostic factors for CRC?
Degree of penetration through bowel wall Serosal involvement Independent of T stage Presence or absence of LN involvement - based on minimum of 12 LNs Presence or absence of distant mets - MSI (HNPCC) associated with improved survival independent of tumours stage
What is the most important indicator of prognosis in CRC?
Pathological stage at presentation.
Poor prognostic indicators - bowel obstruction/perforation, extramural LVI
What are risk factors for CRC?
Most sporadic vs. familial FAP and HNPCC 50yo Reduced fruit and vegetable intake Personal/FHx of sporadic cancers/polyps IBD - UC 5-15x risk, CD less risk Obesity 1.5x risk T2DM - 30% higher in non-diabetics Modest increase w EtOH
What are features of FAP?
FAP:
AD
Germline mut in APC on Chr 5
What are features of HNPCC?
AKA lynch’s syndrome
AD
2-4% of CRCs
Defects in DNA Mismatch repair genes
- MSH2, MLH1, PMS1, PMS2, MSH6, MLH3
- can be identified by IHC on tumour specimen
High risk of extracolonic tumours and second CRC primary
- esp endometrial Ca
- also ovarian, stomach, small bowel, hepatobiliary, renal pelvis/ureter
What are screening recommendations for those at average risk of CRC?
ASx with nil FHx, nil CRC or UC.
FOBT every 2 years from age 50
? sigmoidoscopy every 5 years from 50.
What are screening recommendations for those at moderately increased risk of CRC?
1st Deg relative with CRC
What are screening recommendations for high risk screening?
> 3 1st/2nd degree relatives with CRC or suspect HNPCC
2 1st/2nd degree relatives with CRC or multiple CRC in 1 person
CRC
What is the advantage of bowel cancer screening?
reduces mortality by 15-33% in detection of precancerous lesions in CRC.
What agents are appropriate adjuvant chemo is CRC?
5FU
Capecitabine
Oxaliplatin
What is the MoA and SEs of 5FU?
Antimetabolite (pyrimidine analogue) Usually given with Folic acid SEs lethargy, NV, minimal hair loss Cardiac tox due to coronary artery spasm Diarrhoea and mucositis Haematological Hand food syndrome Toxicity if dihydropyrimidine dehydrogenase dependent
What are features of capecitabine?
oral fluoropyrimidine (same activity as 5FU) SEs similar to 5FU but more hand-foot syndrome
What are features of oxaliplatin?
Platinum derivative SEs - lethargy NVD - haematological/myelosuppression - peripheral neuropathy - pseudolaryngopharyngeal dysasethesia - hypersensitivity reaction
What are adjuvant regimes in CRC?
FOLFOX - folinic acid, 5FU, Oxaliplatin q14d
XELOX - CApecitabine, Oxaliplatin for 6 months
What are adjuvant chemo options in Stage III/Duke’s C disease?
Proven survival benefit in adjuvant chemo
Oxaliplatin-based regimes now standard of care with increased OS in oxaliplatin arm vs 5FU/FA
When should adjuvant chemo be considered in stage II/Duke’s B disease?
adjuvant controversial - metaanaly suggest 2-4% increased OS
Feat assoc with increased risk of recurrence:
- inadequate LN sampling
- T4 disease (invasion of other structures)
- Involvement of visceral peritoneum
- Peritumoural LVI
- Poorly differentiated including mucinous tumours
- Bowel obstruction or perforation
suggest adjuvant if above present
What is the improvement in survival with chemo in metastatic CRC?
Median OS 2 years with irinotecan/oxaliplatin-cont regimens
5-6m with best supportive care.
30-40% have met dz at Dx
What are standard 1st line therapies in mCRC?
FOLFOX and FOLFIRI
- folinic acid + 5FU, oxaliplatin/Irinotecan
What is the MoA of irinotecan and AEs?
Topoisomerase inhibitor
SEs:
- diarrhoea, myelosuppression, cholinergic effects
- metab by UGT1A1*28 - genetic polymorphisms may increase toxicity
What is the MoA of bevazcizumab and it’s role in mCRC?
Bevacizumab - humanised mAb against VEGF - inhibition of vascularisation and tumour growth.
SEs:
- Hypertension
- GI perforation 1-2%
- Impaired wound healing
- Tumour associated haemorrhage
- 2x increase in arterial thromboembolic events (CVA/TIA/AMI)
Improved outcome in met CRC when combined with oxaliplat/irinotecan regimens, but increased SEs (RR, TTP, OS)
What is the MoA of cetuximab and it’s role in mCRC treatment?
cetuximab - part humanised mAb against EGFR. 75-82% of CRC express EGFR, but no correlation between expression and clinical response.
Inhibits proliferation/causes apoptosis in EGFR positive cells.
Indicated in patients with mCRC, kRAS wild type and whose disease has progressed on 1st line threapy
Improves TTP
SEs - hypersensitivity recation with 1st infusion
skin toxicity
(correlated with response)
What is panitumumab?
fully humanised EGFR mAb - similar SEs and efficacy to cetuximab.
What mutations are associated with resistance to EGFR therapy in CRC?
k-RAS mutations - must shown to be K-RAS wild type to qualify for anti-EGFR therapy
What is the rationale in resection of liver mets in mCRC?
improved 5ys vs chemo alone.
? liver toxicity with resection and oxaliplatin/irinotecan
When is neoadjvant therapy indicated in rectal ca?
in T3/T4 and N+ disease
lower rates of local recurrence.
What are RFs for gastric cancer?
High intake of salt-preserved foods, low consumption of fresh fruit and vegetables.
H. pylori major risk factor
Smoking
GORD
obesity
1-3% are hereditary diffuse gastric tumours
What are features of Gastric Cancer?
only 10-20% localised at presentation
>90% are adenocarcinomas
Adenoca of distal oesophagus = gastric ca
What is the role of surgery and neoadjuvant therapy in gastric Ca?
radical surgery and adjuvant chemotherapy has been shown to improve OS and median survival after 5 years of follow-up. (ECF - epirubicin, cisplatin, 5FU)
? role of radiotherapy
15% benefit from addition of traztuzumab to above, if HER2 +Ve
What are chemotherapy options for pancreatic ca?
adjuvant: 5FU or gemcitibine
metastatic disease: Folfirinox (5FU, irinotecan, oxaliplatin) has been shown to improve survival
