traditional chemotherapy: alkylating agents

Primary chemotherapy

used for many hematologic cancers and advanced solid tumors for which no alternative treatment exists

curative in a small number or patients with advanced metastatic disease, palliative for many others

Neoadjuvant chemotherapy

for patients with localized diseases where other therapy such as surgery can be used

goal is to reduce size of tumor to increase effectiveness of surgery

Adjuvant chemotherapy

used for many patients alongside local treatments such as surgery or radiation

goal of reducing local and systemic recurrence

Log (1st order) kill hypothesis

chemo at a certain dose kills a constant fraction of tumor cells, rather than a constant number

Cell cycle-specific (CCS) drugs

kill cells in a specific phase of replication

Cell cycle-nonspecific (CCNS) drugs

kill cells in both resting and replicating phases

Glutathione

produced by cancer cells as a resistance mechanism

traps chemo-drugs to prevent their activity

Alkylating agents

cyclophosphamide, carmustine, platinum analogs, mitomycin

Anthracyclines

doxorubicin, daunorubicin, mitoxantrone

Cell cycle-nonspecific (CCNS) drugs

alkylating agents, anthracyclines

Alkylating agents

form reactive molecular species affecting nucleophilic groups on DNA bases, particularly N-7 position on guanine

Alkylating agents

myelosuppression, N/V/D, mucosistis, hair loss, increased risk of secondary malignancies

Cyclophosphamide

metabolized to form cytotoxic metabolites

Cyclophosphamide

high oral bioavailability, also given IV

used for leukemia, non-Hodgkin’s lymphoma, ovarian cancers, and neuroblastoma

Phosphoramide mustard

active metabolite of cyclophosphamide

Acrolein

inactive, toxic metabolite of phosphamides

Hemorrhagic cystitis

caused by build up of acrolein causing genitourinary bleeding

Chloroacetaldehyde

neurotoxic metabolite of phosphamides produced by CYP3A4

MESNA

given prophylactically to counteract acrolein toxicitiy

Neurotoxicity

risk factors: renal/hepatic dysfunction, low serum albumin, old age

Methylene blue

thought to reverse neurotoxicity by inhibiting MAO, which prevents formation of chloroacetaldehyde

Ifosfamide

makes extremely high amounds of acrolein

MESNA

given with high dose cyclophosphamide and all doses of ifosfamide

Melphalan

dose-limiting myelosuppression, mucositis (canker sores in entire mouth)

extremely hot feeling during infusion (give ice chips or cold blanket)

Melphalan

given orally or IV

used in stem cell transplant conditioning regiments

Mustard alkylators

myelosuppression, alopecia, GI toxicity, gonadal toxicity

Nitrosoureas (carmustine, lomustine), temozolamide (TMZ)

lipophilic drugs that require nonenzymatic decomposition to form active drugs

Temozolamide

orally administered

standard of care for high-grade gliomas

Nitrosoureas

delayed nadir of 42 days, administered q6w

Carmustine

administered IV or implanted intracranial wafer

ethanol used as IV vehicle

pulmonary toxicity (fibrosis)

Lomustine

administered orally

less risk of pulmonary toxicity (fibrosis)

Busulfan

misc alkylating agent

causes dose-limiting pancytopenia

must give with seizure prophylaxis (usually levetiracetam)

Mitomycin

misc alkylating agent, mostly used palliatively

causes dose limiting myelosuppression, especially thrombocytopenia and leukopenia

vesicant: can cause severe tissue necrosis

turns urine blue-green

Platinum analogs

cisplatin, carboplatin, oxaliplatin

Cisplatin

absolute max dose of 100 mg/m² per cycle due to nephrotoxicity

also must hydrate with magnesium/potassium pre and post infusion

can also induce ototoxicity and neuropathy with dose accumulation

Carboplatin

dosed with Calvert formula

dose (mg) = target AUC (4-6) * (eGFR + 25)

eGFR capped at 125

Carboplatin

dose limiting myelosuppression, moderate emetogenic potential, hypersensitivity with exposure > 6 cycles

Oxaliplatin

dose limiting chronic peripheral neuropathy, myelosuppression, moderate emetogenic potential

extreme cold sensitivity that triggers neuropathy (reaching into freezer for a popsicle can trigger it)