Lights, camera, (Mechanism of) action
What is the name of the enzyme that methotrexate inhibits?
Dihydrofolate reductase (DHFR)
s/o to Mounika!
Before administering eculizumab what immunization must be given?
Vaccinate with meningococcal vaccines at least 2 weeks prior to initiation of treatment
What is the proper sequencing when giving taxanes and platinums?
Taxane first then platinum ('pay your TAXes first')
Limits myelosuppression, enhances efficacy
Which of the following can increase risk of pulmonary toxicity with bleomycin?
A) Living at high altitude
B) G-CSF use
C) Concurrent steroid use
D) Use of CPAP
E) Underlying hepatic dysfunction
B) G-CSF use
Bleomycin can cause life threatening pulmonary fibrosis in up to 10% of patients receiving the drug. Risk factors: age > 70, cumulative dose > 400 units, poor renal function, prior RT, concurrent O2, smoking, G-CSF use
Name two drugs that can accumulate in third space fluids.
Methotrexate, pemetrexed. Ideally drain effusions prior to starting therapy.
In which cell cycle does cyclophosphamide work?
A) S phase
B) G2 phase
C) M phase
D) G1 phase
E) It is cell cycle non specific
E) Cyclophosphamide and other alkylating agents are cell cycle non specific
Which medication below is most likely to cause GU/renal toxicity?
A) Doxorubicin
B) Vincristine
C) Paclitaxel
D) Ifosfamide
E) Irinotecan
D) Ifosfamide
Metabolites acrolein and chloroacetaldehyde can cause hemorrhagic cystitis and nephrotoxicity, respectively.
To avoid: aggressive hydration, mesna, frequent bladder emptying
Which population has reduced clearance of gemcitabine?
A) Men
B) Women
C) African American
D) Asian
B) Women
Women and elderly patients may have reduced clearance. No specific modifications suggested but monitor closely for adverse effects.
52M is on second line FOLFIRI + panitumumab for metastatic left-sided KRAS WT colorectal cancer. He has been on therapy for 3 months and interval scans show reduction in radiographically lesions of 20%. He presents to you with a rash. He is asymptomatic but on exam he has a macular rash on his face and torso. You classify as grade 1. What do you recommend?
A) Oral antibiotics with minocycline
B) Oral prednisone x 7d
C) Hydrocortisone topical cream 1%
D) No treatment needed, continue current therapy
E) Dose reduce the current regimen
D) No treatment needed, continue current therapy
For grade 1 rash no modifications to treatment are required. Could consider clindamycin gel and hydrocortisone cream 2.5%.
For grade 2 use hydrocortisone cream 2.5% + oral minocycline/doxycycline.
For grade 3 dose reduction, hydrocortisone cream 2.5%, minocycline/doxycycline, oral prednisone 0.5mg/kg x 7d, consider isotretinoin 30mg daily
For grade 4 likely needs IV antibiotics
Capecitabine has a serious drug-drug interaction with which of the following meds?
A) Clindamycin
B) Warfarin
C) Keppra
D) Ibuprofen
E) Fluoxetine
Bonus: What is the interaction?
B) Warfarin
There is a black box warning for capecitabine-warfarin interaction.
Postmarketing reports have shown clinically significant increases in PT and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced.
Which of the following drugs is NOT an anti-folate?
A) Methotrexate
B) Pemetrexed
C) Pralatrexate
D) Capecitabine
D) Capecitabine
Capecitabine is a pyrimidine analogue. The others are folate antagonists.
Which if the following is a unique side effect of crizotinib?
A) Pancreatitis
B) Pulmonary fibrosis
C) Visual disturbance
D) Hemorrhage
E) Proteinuria
C) Visual disturbance
Commonly reported disturbances include the appearance of shimmering, flashing, or trailing lights; appearance of streamers, strings, or floaters; and overlapping shadows or afterimages. Occurs within 2 weeks of initiating therapy. Generally grade 1, generally resolves on its own. Consider referral to ophtho and dose reduction if grade 2 and above.
58F with recently diagnosed metastatic TNBC presents to discuss starting treatment. Additional testing reveals CPS 0, BRCA 1/2 WT. She is very interested in taking an oral chemotherapy.
You discuss capecitabine 1000mg/m2 BID 2 weeks on 1 week off. Her LFTs are normal but she has diabetic nephropathy with baseline CrCl 20. She is taking HCTZ and metformin. What should you do?
A) Do not give capecitabine
B) Discontinue HCTZ
C) Reduce capecitabine by 25%
D) Reduce capecitabine by 50%
E) Change the schedule to 1 week on 1 week off
A) Do not give capecitabine
Capecitabine is c/i in CrCl < 30
53M with history of GBM presents to the ED with cough and dyspnea x 4 weeks He is s/p debulking surgery for a 6cm GBM. Pathology showed tumor was MGMT methylated and IDH mutated. He recently completed adjuvant temozolomide with radiation.
He just got back from a trip to Arizona. CT chest shows diffuse interstitial infiltrates. What is the most likely etiology?
A) GBM metastasized to lung
B) Invasive aspergillosis
C) Pneumocystis Jiroveci
D) Coccidiomycosis
E) Pulmonary fibrosis
C) Pneumocystis Jiroveci
Temozolomide is an alkylating agent that can cause significant myelosuppression and prolonged lymphopenia. Patients should be on PCP ppx until lymphocyte recovery.
Name some side effects of BRAF/MEK inhibitors. Bonus if you can name a combination and indication.
Pyrexia, QTc prolongation, cardiomyopathy, fatigue, arthralgias.
Dabrafenib/trametinib: BRAF V600E+ mNSCLC
Vemurafenib/Cobimetinib: BRAF V600E melanoma
Encorafenib/Binimetinib: BRAF V600E melanoma. Encorafenib + chemo for mCRC
What is the name of the enzyme that converts capecitabine to 5FU in the tumor cell?
A) Thimidylate synthase
B) Dihydrofolate reductase
C) Thimidylate phosphorlyase
D) Dihidropyrimidine dehydrogenase
E) Cytidine deaminase
C) Thimidylate phosphorlyase
Capecitabine is an orally bioavailable prodrug that is converted to 5FU through several enzymatic steps.
1. Converted to 5'DFCR in the liver by carboxylesterase
2. Converted to 5'DFUR in the tissue by cytidine deaminase
3. Converted to 5FU in the tumor cell by thimidylate phosphorylase
Pemetrexed inhibits thimidylate synthase. Methotrexate inhibits DHFR.
78M with newly diagnosed metastatic pancreatic cancer is started on gemcitabine nab-paclitaxel. He is tolerating the treatment well and at his 3 mo scans has good response on imaging.
You receive a call from the ED that the patient has presented there with fatigue and renal failure. Other labs notable for Hb 7.4, Plt 70k, LDH 1000, Tbili 5, Cr 3.2 (bl 1). Coags are normal. What is the likely etiology?
A) DIC from pancreatic cancer
B) HUS from gemcitabine
C) Trousseou's syndrome
D) ATN from nab-paclitaxel
E) Stauffer's syndrome
B) HUS from gemcitabine
Mechanism of HUS due to gemcitabine is unclear as is ideal management, but must discontinue immediately. Consider steroids, FFP, plasmapheresis, dialysis.
55F presents with de novo metastatic TNBC with metastases to the liver and lungs. She has normal renal function but bilirubin is 2.5.
She is seen by GI but they are unable to deploy a stent as her hyperbilirubinemia is due to extrinsic compression of bile ducts by tumor. She needs to start chemotherapy soon to rescue her from visceral crisis. Which chemotherapy should NOT be used?
A) Capecitabine
B) Carboplatin
C) Cisplatin
D) Cyclophosphamide
E) Docetaxel
E) Docetaxel
Docetaxel is the only drug listed that is primarily metabolized by the liver. It has a black box warning for hepatotoxicity and should not be used if bili > ULN, AST/ALT > 1.5x ULN or ALP > 2.5x ULN.
35F presents to the ED with fatigue and bruising. On admission she was found to have wbc 15k with frequent blasts in the periphery, Hb 6.5, plt 10k. Her smear is concerning for auer rods and bone marrow biopsy and cytogenetics confirm APL. She is started on ATRA/arsenic. On day 7 of treatment she is febrile and reports dyspnea. Her blood pressure is 90/50. What is the likely etiology of her presentation?
A) Septic shock due to neutropenia
B) Differentiation syndrome
C) Pulmonary embolism
D) Pulmonary hemorrhage
E) Acute cardiac failure due to volume overload
B) Differentiation syndrome
Occurs in 25-50% of patients with APL within 2 to 21 days after initiation of treatment and is seen more frequently in patients with high WBC count at diagnosis (ie > 10k). Patients at increased risk should be prophylaxed with steroids. Treatment is steroids and supportive care.
Which medication below has not been shown to cause secondary malignancy?
A) Etoposide
B) Everolimus
C) Olaparib
D) Temozolomide
E) Bleomycin
E) Bleomycin
Topoisomeras inhibitors, mTOR inhibitors, PARP inhibitors, alkylating agents as well as anthracyclines are all known to cause secondary malignancies.
Board pearl: Topoisomerase inhibitors/anthracyclines cause M4/M5 AML with 11q23 1-3 years after therapy.
Alkylating agents cause 5q/7q del MDS 4-7 years after therapy.
What is the mechanism of action of Sacituzumab?
Antibody drug conjugate bound to SN-38 (active metabolite of topoisomerase I inhibitor irinotecan)
56M with new diagnosis of inv(16) AML completes induction 7+3 and is undergoing consolidation with high dose cytarabine. On day 2 of his infusion he has sudden onset of confusion and tremor. His blood pressure is 100/50. What is the most likely etiology?
A) Bacterial meningitis due to prolonged neutropenia
B) Cerebellar toxicity from high dose araC
C) Delayed anthracycline toxicity
D) Carcinomatosis meningitis
E) Severe sepsis due to contaminated blood products
B) Cerebellar toxicity from high dose araC
Cerebellar/cerebral toxicity can occur with cytarabine. There is increased risk with high dose (ie 1000mg/m2), age > 40, abnormal LFTs/Cr. It can present with ataxia, dysarthria, nystagmus, tremor within 3h of dose and up to 2 weeks following last dose. Must permanently discontinue the medication.
55F with history of double hit DLBCL is admitted to the hospital to receive high dose methotrexate for CNS prophylaxis. On the day after treatment she has acute renal failure with Cr 5 from baseline of 1. She admits to taking high doses of NSAIDs prior to admission for knee pain. She receives aggressive hydration, urinary alkalinization and leucovorin rescue but has persistent renal failure with oliguria. She is adamantly refusing dialysis. What treatment should be offered to her?
Glucarpidase
Glucarpidase is a recombinant carboxypeptidase for use in MTX toxicity in pts with renal damage despite receiving adequate fluids, urinary alkalinization and leucovorin rescue.
NB: MTX levels are unreliable for 48h after administration and can only be measured by chromatographic method.
54F with history of stage IIIC ovarian cancer. She undergoes R0 resection and is planning to start adjuvant carboplatin/paclitaxel. She is BRCA 1/2 WT.
During her first cycle she develops rash, flushing and chest tightness within minutes of starting the infusion. Her symptoms resolve when the infusion is stopped. What is the causative agent and what do you recommend?
A) Cremophor. Switch to docetaxel.
B) Cremophor. Rechallenge with paclitaxel, slow infusion rate.
C) Polysorbate 80. Switch to docetaxel
D) Polysorbate 80. Rechallenge with paclitaxel, slow infusion rate.
E) Albumin. Rechallenge with paclitaxel, slow infusion rate.
B) Cremophor. Rechallenge with paclitaxel, slow infusion rate.
This patient had a paclitaxel infusion reaction with mild symptoms that resolved with stopping the infusion. She can be re-challenged at a slower rate. If she had severe symptoms or life threatening allergic reaction you would not re-challenge.
59M with history of stage III colon cancer undergoes resection and is recommended to start adjuvant FOLFOX. Five days after starting he presents to the ED with severe mouth pain, diarrhea and fevers. ANC on admission is 100. He admits to taking tylenol 1000mg daily and using St. Johns wort. What is the likely cause of his presentation?
A) Tylenol interacting with 5FU hepatic metabolism prolonging chemotherapy exposure
B) He has a UGT1A1 mutation causing decreased metabolism of oxaliplatin
C) He did not receive neulasta following chemo
D) He has dihydropyrimidine dehydrogenase deficiency
E) St. John's wort increasing activity of cytochrome p450
D) He has dihydropyrimidine dehydrogenase deficiency
DPD deficiency occurs in 3-5% of the population and can lead to severe neutropenia, stomatisis, diarrhea. Reduced enzyme activity increases the half life of 5FU leading to increased toxicity. Reduce dose or avoid based on phenotype.