Sweatman - Testicular Cancer

Question 1

How is testicular cancer staged? Mets?

Answer 1

• 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

Question 2

Epi and risk factors for testicular cancer?

Answer 2

• 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 1^o sites, but managed in the same way)
• RISK FACTORS: personal/family history of GCT, cryptorchidism, testicular dysgenesis, Klinefelter syndrome

Question 3

How successful is testicular cancer tx, generally?

Answer 3

• One of the most chemo-sensitive, and CURABLE solid malignancies
• 95% 5-yr survival overall, and <400 cancer-related deaths yearly in the US

Question 4

What are the important serum tumor markers for testicular cancer? How are they useful?

Answer 4

• 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

Question 5

What are the treatment options for testicular cancer?

Answer 5

• 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

Question 6

What is the difference in probability of mets for seminomas vs. non-seminomas?

Answer 6

• 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

Question 7

Why do malignant cells lose their sensitivity to Cisplatin (CDDP) with repeated administration?

Answer 7

• 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

Question 8

What is the MOA of Bleomycin?

Answer 8

Binds DNA in presence of iron with ferrous oxide-mediated DNA strand breakage

Question 9

What is the MOA of Cisplatin?

Answer 9

Nuclear and mitochondrial DNA damage + redox stress

Question 10

What is the MOA of Carboplatin?

Answer 10

• Slower reaction with nuclear DNA
• Less potent than Cisplatin -> give higher dose

Question 11

What is the MOA of Etoposide?

Answer 11

Stabilizes DNA and topo II complexes, resulting in strand breakage

Question 12

What is the MOA of Ifosfamide?

Answer 12

Metabolically-activated alkylating agent producing intra- and inter-strand DNA crosslinks

Question 13

What is the MOA of Paclitaxel?

Answer 13

Promotes microtubule assembly, and stabilizes their formation by INH depolymerization

Question 14

What is the MOA of Vinblastine?

Answer 14

• Binds to low-affinity sites on tubulin, resulting in splitting of the microtubules into spiral aggregates of protofilaments
• Leads to disintegration of the microtubule

Question 15

What is the MOA of Mesna?

Answer 15

• Forms acrolein-mesna thioether complexes that are inactive and eliminated in urine w/o causing hemorrhagic cystitis
• Some formulations alreadhy combined with Ifosfamide

Question 16

What dose-limiting AE is common to most of the cytotoxic chemo agents? Support?

Answer 16

• 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

Question 17

What is the toxicity of Bleomycin?

Answer 17

• Late-developing skin toxicity, e.g., erythema, unspecified rash, striae, vesiculation, skin hyper-pigmentation, pruritis
• Dose-limiting pulmonary fibrosis
• Interstitial pneumonitis

Question 18

What is the toxicity of Cisplatin?

Answer 18

• 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

Question 19

What is the toxicity of Carboplatin?

Answer 19

• Less nausea, neurotoxicity, ototoxicity, and nephrotoxicity than Cisplatin
• Dose-limiting thrombocytopenia

Question 20

What is the toxicity of Etoposide?

Answer 20

• Dose-limiting leukopenia
• N/V, stomatitis, diarrhea complicate tx in about 15% of patients
• Hepatic toxicity after high doses

Question 21

What is the toxicity of Ifosfamide?

Answer 21

• Dose-limiting myelosuppression
• Neurotoxicity: coma, seizures, ataxia from release of chloroacetaldehyde
• Hemorrhagic cystitis w/o Mesna

Question 22

What is the toxicity of Paclitaxel?

Answer 22

• Dose-limiting bone marrow suppression (Filgastrim protectant)
• Peripheral neuropathy, esp. disabling in pts with underlying diabetic neuropathy

Question 23

What is the toxicity of Vinblastine?

Answer 23

• Dose-limiting neuropathy with all Vinca alkaloids, esp. Vincristine

Question 24

What is the toxicity of Mesna?

Answer 24

• Dysgeusia: foul, salty, rancid, or metallic taste sensation will persist in the mouth
• Soft stools
• Headache

Question 25

What does Cisplatin do? Kidney?

Answer 25

• 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

Question 26

How does Cisplatin cause ototoxicity? Prevention?

Answer 26

• 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

Question 27

What active pump mechs are involved in Cisplatin transport? Why does this matter?

Answer 27

• 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

Question 28

How can Bleomycin affect the skin and lungs?

Answer 28

• 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

Question 29

Short-hand combo chemo for testicular cancer?

Answer 29

Platin (Cis or Carbo) + an MT-INH (taxane or vinca), an alkylator (Ifosfamide) or DNA-strand breaker (Bleo, Etoposide)

Question 30

What is the achilles heel of Cisplatin?

Answer 30

Relatively rapid appearance of drug resistant phenotypes

Question 31

Which drugs used to tx testicular cancer do NOT produce dose-limiting myelosuppression?

Answer 31

• Bleomycin
• Cisplatin (but NOT Carboplatin
• Vinblastine

Question 32

Amifostine reduces the toxicity of…?

Answer 32

Cisplatin

Question 33

What two drugs have unusual toxicities that arise from ancillary effects unrelated to their principal mech for anti-tumor activity? What are they?

Answer 33

• 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