Renal Cancer Drugs Flashcards
How do you cure renal cancer?
Excise the kidney.
What characteristic of renal cancers indicate chemotherapy and drug intervention as opposed to excision?
Advanced stage or metastasis.
The most common sites for renal metastasis is…..
According to Sweatman, the liver. Accrding to Nichols, the lungs.
Cyclophosphamide dose limiting toxicity.
Hemorrhagic Cystitis
Pretreat with MESNA
Doxorubicin dose limiting toxicity.
Acute and chronic cardiotoxicity
Vincristine dose limiting toxicity.
Peripheral Neuropathy
VHL gene mutations cause what cancer?
Clear Cell Renal Carcinoma
What is the central target of drugs that treat Clear Cell Carcinoma?
VEGF –> the unregulated product of the VHL/HIF pathway’s constitutive activity
What 4 drug classes can you use to treat Clear Cell Carcinoma? (Think molecular mechanism)
VEGF INHIBITION:
- MaBs
- TKIs
- mTOR inhibitors
- Immuno-actovators
Name the MaB used to treat Renal Cell Carcinoma. What does the antibody bind to and inhibit?
Bevacizumab - Anti-VEGF antibody
Can you cure Clear Cell Carcinoma?
No, only prolong survival 10-12 months.
Can cytotoxic therapy work for Clear Cell Carcinoma?
NO. CYTOTOXIC THERAPY WILL NOT WORK. Must use a MaB, TKI, or mTOR inhibitor.
Of the drugs you can use for Clear Cell Renal Carcinoma treatment, which do you administer first? After?
TKI administered first, the followed up with an mTOR inhibitor.
Name the Rapamycin drugs.
Rapamycins are mTOR inhibitors.
TEMSIROLUMUS
EVEROLIMUS
“olimus” = mTOR inhibitor
MOA of mTOR inhibitors.
Bind to FKBP12 and inhibit mTORC1
- Immunosuppressant
- Promotes apoptosis
- Prevents cell-cycle progression and angiogenesis
Why do mTOR inhibitors and TKI’s only prolong the survival of a patient, but not cure?
Resistance develops quickly.
Extra mTOR pathways activated by a second, distinct mTOR (mTORC2)
Drugs are being developed that block BOTH of them. But not yet.
If your patient’s renal cancer is unresponsive to anti-angiogenic drugs, what mTOR inhibitor do you give them first?
Everolimus - prolongs survival in patients who had failed with initial treatment with anti-angiogenic drugs.
(TKI’s, Bevacizumab)
What are the 2 classes of drugs that have CYP3A4 activity?
TKIs and mTOR inhibitors
Which of the mTOR inhibitors is a prodrug? What is its active metabolite?
Temsirolimus is metabolized (assumably by CYPs) to SIROLIMUS, the active form.
How do you administer mTOR inhibitors?
Everolimus = daily oral
Temsirolimus = weekly IV
What odd toxicity is Everolimus associated with?
Pulmonary Infiltrates - watch for shortness of great or coughing in these patients.
Describe TKIs.
Route?
Metabolism?
TKI’s are small molecular weight drugs. Orally administered. CYP substrates.
They bind to the ATP binding site of VEGF tyrosine kinase receptors, preventing the vascular proliferative effects.
Adverse effects of TKIs.
Tyrosine Kinase receptors are all over the body, contributing to the adverse effects.
- Cardiac
- HTN - rapid onset. Adjust dose or take patient off.
- QT prolongation - Pazopanib, Sorafenib
- Thromboembolism
- Hemorrhagic Events
- Blood dyscrasias
- Hepatic - BBW for Pazopanib and Sunitinib - liver failure
- Renal - Proteinurea
- ENDOCRINE DYSFUNCTION - F’s up levels of key hormones
- Hypersensitivity - Stevens Johnsons Syndrome - Sorafenib, Sunitinib
You need to monitor ________ levels in a patient on TKI’s.
Thyroid and Adrenal function
Blood glucose levels
Bone density
TKI’S MAIN TOXICITY IS ENDOCRINE SYSTEM DISRUPTION.
Bevacizumab has a BBW for what?
Hemorrhage
GI perforations
Impaired wound healing
bevacizumab’s normal toxicities mirror those of TKI’s: Thromboembolism, Proteinuria, blood dyscrasias, but instead of HTN, it causes….
Hypotension.
How do you administer Bevacizumab? Do you use it alone or with another drug?
IV (MaB)
Combo with Interferon or Alone.
What classes of drugs produce a more “durable” response in the patient, and what does “durable” mean?
Durable means tolerable by the patient, and degree of life extension. These drugs don’t just allow you to live an extra year. They may cure you.
IFN-alpha
IL-2 Aldesleukin
IMMUNOACTIVE DRUGS
MOA of Aldesleukin.
IL-2
Induces a state of controlled septic shock. Activates your immune system.
Toxicities associated with Aldesleukin.
The MOA of Aldesleukin is pretty much a toxicity….
CAPILLARY LEAK SYNDROME:
- HYPOtension
- Decreased TPR
- Tachycardia
- Hematologic toxicity
- PULMONARY EDEMA (bilateral)
- Renal toxicity
Over 126 adverse effects.
What drugs must be co-administered with Aldesleukin to maintain normal body systems?
Dopamine - maintains renal perfusion
Phenylephrine - maintain BP support
Acetaminophen - Fever/chills
Proton Pump Inhibitor - combats gastric acidity
MOA Interferon-Alpha 2b
IFN-alpha binding its cell-surface receptor activates the JAK/STAT pathway. Results in transcriptional up regulation of genes responsible for antiviral, anti proliferative, and anti tumor activities.
T/F: IFN-alpha is marketed for use in Renal Cell Carcinomas.
FALSE: IFN is used OFF-LABEL for the treatment of renal cancer.
How do you administer IFN-alpha?
3x weekly Subcu
What’s the BBW for IFN?
Neuropsychiatric, autoimmune, and ischemic/infectious disorders.
Most common side effects if IFN:
fatigue, fever, flu-like symptoms (over 95%)
Neutropenia, leukopenia (92%)
