Sweatman - Testicular Cancer Flashcards
1
Q
How is testicular cancer staged? Mets?
A
- Tx most successful if the tumor is detected early, when confined to the originating organ
- Metastatic disease via lymphatic spread: most common site is the lymph nodes in the abdomen
1. Lungs, liver, bones, and brain also possible
2
Q
Epi and risk factors for testicular cancer?
A
- 2% of all human malignancies, but most common solid tumor in men 15-34
1. Worldwide incidence has more than doubled in the past 40 years - 95% germ cell tumors (GCTs) in testes: seminoma or non-seminoma (occasionally in extragonadal 1o sites, but managed in the same way)
- RISK FACTORS: personal/family history of GCT, cryptorchidism, testicular dysgenesis, Klinefelter syndrome
3
Q
How successful is testicular cancer tx, generally?
A
- One of the most chemo-sensitive, and CURABLE solid malignancies
- 95% 5-yr survival overall, and <400 cancer-related deaths yearly in the US
4
Q
What are the important serum tumor markers for testicular cancer? How are they useful?
A
- Alpha-fetoprotein (AFP)
- Lactate dehydrogenase (LDH)
- Beta-human chorionic gonadotropin (hCG)
- Useful for monitoring all stages of non-seminomas and metastatic seminomas bc elevated marker levels is the early sign of relapse
1. Should be determined before, during, and after tx, and throughout the F/U period - Critical in 1) diagnosing GCTs, 2) determining prognosis, and 3) assessing tx outcome
5
Q
What are the treatment options for testicular cancer?
A
- Surgery curative for organ-confined disease (removal of one testis will NOT have appreciable effect on fertility)
- Stage 2: radiotherapy (5d/wk for 5-6wks) and chemo in adjunctive manner
- All of the treatment options involve a PLATINUM agent -> while Cisplatin is an effective agent in the tx of many solid tumors, it loses effectiveness w/repeated admin
6
Q
What is the difference in probability of mets for seminomas vs. non-seminomas?
A
- Seminomas: grow slowly, and do NOT spread rapidly to other areas of the body
- Non-seminomas: more likely to spread through the bloodstream to other parts of the body -> liver, lungs, and brain
7
Q
Why do malignant cells lose their sensitivity to Cisplatin (CDDP) with repeated administration?
A
- Wide panel of genetic/epigenetic defects that can:
1. Affect processes preceding CDDP binding to its targets (pre-target resistance)
2. Potentiate the ability of cells to repair the molecular damage (on-target resistance)
3. Impair transmission of signals that normally relay CDDP-induced damage to cell senescence or apoptosis (post-target resistance)
4. Stimulate delivery of pro-survival signals that antagonize CDDP cytotoxicity, although they are not normally elicited by this drug (off-target resistance) - Generally multifactorial, explaining lack of effective strategies to avoid resistance
8
Q
What is the MOA of Bleomycin?
A
Binds DNA in presence of iron with ferrous oxide-mediated DNA strand breakage
9
Q
What is the MOA of Cisplatin?
A
Nuclear and mitochondrial DNA damage + redox stress
10
Q
What is the MOA of Carboplatin?
A
- Slower reaction with nuclear DNA
- Less potent than Cisplatin -> give higher dose
11
Q
What is the MOA of Etoposide?
A
Stabilizes DNA and topo II complexes, resulting in strand breakage
12
Q
What is the MOA of Ifosfamide?
A
Metabolically-activated alkylating agent producing intra- and inter-strand DNA crosslinks
13
Q
What is the MOA of Paclitaxel?
A
Promotes microtubule assembly, and stabilizes their formation by INH depolymerization
14
Q
What is the MOA of Vinblastine?
A
- Binds to low-affinity sites on tubulin, resulting in splitting of the microtubules into spiral aggregates of protofilaments
- Leads to disintegration of the microtubule
15
Q
What is the MOA of Mesna?
A
- Forms acrolein-mesna thioether complexes that are inactive and eliminated in urine w/o causing hemorrhagic cystitis
- Some formulations alreadhy combined with Ifosfamide
16
Q
What dose-limiting AE is common to most of the cytotoxic chemo agents? Support?
A
- Most produce a dose-limiting blood dyscrasia
- Some patients may get “support” from agents like GCSF (granulocyte colony-stimulating factor, Filgrastim)
1. Promotes a more rapid recovery from the drug-induced nadir
17
Q
What is the toxicity of Bleomycin?
A
- Late-developing skin toxicity, e.g., erythema, unspecified rash, striae, vesiculation, skin hyper-pigmentation, pruritis
- Dose-limiting pulmonary fibrosis
- Interstitial pneumonitis
18
Q
What is the toxicity of Cisplatin?
A
- Renally eliminated: active accumulation in renal cells (5x serum concentration), INH breakdown of lipids to generate metabolic energy
- Dose-limiting renal toxic (AMIFOSTINE)
- Ototoxic
- Neurotoxic
19
Q
What is the toxicity of Carboplatin?
A
- Less nausea, neurotoxicity, ototoxicity, and nephrotoxicity than Cisplatin
- Dose-limiting thrombocytopenia
20
Q
What is the toxicity of Etoposide?
A
- Dose-limiting leukopenia
- N/V, stomatitis, diarrhea complicate tx in about 15% of patients
- Hepatic toxicity after high doses
21
Q
What is the toxicity of Ifosfamide?
A
- Dose-limiting myelosuppression
- Neurotoxicity: coma, seizures, ataxia from release of chloroacetaldehyde
- Hemorrhagic cystitis w/o Mesna
22
Q
What is the toxicity of Paclitaxel?
A
- Dose-limiting bone marrow suppression (Filgastrim protectant)
- Peripheral neuropathy, esp. disabling in pts with underlying diabetic neuropathy
23
Q
What is the toxicity of Vinblastine?
A
- Dose-limiting neuropathy with all Vinca alkaloids, esp. Vincristine
24
Q
What is the toxicity of Mesna?
A
- Dysgeusia: foul, salty, rancid, or metallic taste sensation will persist in the mouth
- Soft stools
- Headache
25
What does Cisplatin do? Kidney?
- Binds with high affinity to nuclear DNA via nucleophilic **N7** sites on purines
- Interacts with several cytoplasmic nucleophiles, incl mitochondrial DNA (mtDNA) and multiple mito and extra-mito proteins:
1. Favors reticular and **oxidative stress**
2. Elicits signal transduction cascade involving pro-apoptotic BCL-2 family members **BAK1 and BAX** + voltage-dependent ion channel 1 (VDAC-1)
3. Activating cytoplasmic pool of **p53**
- KIDNEY: accumulated in renal epi cells by _active pump mechs_; redox/ER stress = _interruption of IC energy production_ and cell damage
26
How does Cisplatin cause ototoxicity? Prevention?
- Several areas of cochlea damaged, incl outer hair cells in basal turn, spiral ganglion cells, and stria vascularis
- Mechs involve **production of ROS**, which can trigger cell death; depletion of glutathione and antioxidant enzymes, allowing an INC in lipid peroxidation
- Chemoprevention: **antioxidants** at early stage in ototoxic pathways and application of agents that act further down cell death cascade to prevent apoptosis and hearing loss
27
What active pump mechs are involved in Cisplatin transport? Why does this matter?
- Copper transporters (Ctr1/2): **Ctr 1** seems to be involved in general Cisplatin uptake in tumor and normal cells
- P-type copper transporting ATPases: ATP7A/B
- Organic cation transporter-2 (**OCT2**): restricted to a few cells (like renal, cochlear, nervous), and may have epigenetically down-regulated expression in some tumors -\> _may be a target for protective therapy_
- Multidrug extrusion transporter-1: MATE1
- NOTE: some of these transporters able to accept other platinum derivatives as substrates
28
How can Bleomycin affect the skin and lungs?
- Irritants like silica, asbestos, and Bleo (uric acid liberated from DNA-damaged cells) can injure lung epi cells, and be detected by **Nalp3 inflammasome** in macros
- Stimulates production of **ROS**, chemokines, and cytokines -\> inflam mediators enhance recruitment and activation of leukocytes
- **IL-1B** induces ROS-expressing neutros that can further damage epi cells and promotes production of **TGF-B1**, a profibrotic cytokine that triggers fibroblast proliferation and activation
- TGF-B also targets epi cells, inducing **EMT** (epi mesenchymal transition) and formation of ECM-producing myofibroblasts
1. Exacerbates inflam response by stimulating differentiation of **TH17** cells
29
Short-hand combo chemo for testicular cancer?
Platin (Cis or Carbo) + an MT-INH (taxane or vinca), an alkylator (Ifosfamide) or DNA-strand breaker (Bleo, Etoposide)
30
What is the achilles heel of Cisplatin?
Relatively rapid appearance of drug resistant phenotypes
31
Which drugs used to tx testicular cancer do NOT produce dose-limiting myelosuppression?
- Bleomycin
- Cisplatin (but NOT Carboplatin
- Vinblastine
32
Amifostine reduces the toxicity of...?
Cisplatin
33
What two drugs have unusual toxicities that arise from ancillary effects unrelated to their principal mech for anti-tumor activity? What are they?
- _Bleomycin_: drug-induced generation of cellular stress, leading to a rise in ROS and depletion of cytoprotective antioxidants
- _Cisplatin_: active (pump-mediated) accumulation in renal and cochlear tissues, and drug-induced generation of cellular stress, leading to a rise in ROS and depletion of cytoprotective antioxidants
