2
Alkylating Agents
NITROGEN MUSTARDS
What are the chemotherapy agents in the nitrogen mustard class?
• Mechlorethamine (Mustargen®)
• Cyclophosphamide (Cytoxan®)
• Ifosfamide (Ifex®)
• Bendamustine (Treanda®)
• Chlorambucil (Leukeran®)
• Melphalan (Alkeran®)
What malignancies are each agent FDA approved for?
FDA-Approved Uses of Nitrogen Mustard Alkylating Agents
Agent |
FDA Approval |
Mechlorethamine |
Chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Hodgkin’s lymphoma (HL), lymphosarcoma, mycosis fungoides, polycythemia vera, squamous cell carcinoma of the bronchus |
Cyclophosphamide |
Acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), breast cancer, Burkitt’s lymphoma, CLL, CML, HL, malignant histiocytosis, malignant lymphoma—mixed small and large cell, malignant lymphoma—small lymphocytic, mantle cell lymphoma, multiple myeloma (MM), mycosis fungoides, neuroblastoma (disseminated disease), non-Hodgkin’s lymphoma (NHL) |
Ifosfamide |
Testicular cancer (germ cell tumor) |
Bendamustine |
CLL, NHL (indolent B cell) |
Chlorambucil |
CLL, HL, mycosis fungoides, NHL |
Melphalan |
Ovarian cancer (unresectable/palliative), MM |
Abbreviation: FDA, U.S. Food and Drug Administration.
How do the nitrogen mustards work?
• Summary: Form cross-links with DNA, inhibiting DNA replication and causing apoptosis
• Nitrogen mustards form reactive, positively charged aziridinium rings by loss of a chloride ion (Figure 2.1). The aziridinium ring then reacts with the nucleophilic centers on DNA (most commonly N-7 of guanine) to form the initial alkylated product. A second aziridinium ring is then formed, which binds to another DNA base, producing a DNA cross-link
• Cyclophosphamide and ifosfamide are prodrugs that are activated to their active metabolites via CYP450 enzymes in the liver
• Bendamustine causes extensive, durable DNA damage due to additional effects on mitotic checkpoints and DNA repair pathways. It is has also been hypothesized that the benzimidazole ring may act as a purine analogue and function as an antimetabolite (Figure 2.2), although this has yet to be proven clinically
• Cross-linking via nitrogen mustards is primarily interstrand
• Cell cycle nonspecific
What are the common mechanisms of resistance to nitrogen mustard therapy?
• Reduced cellular uptake of the drug. Melphalan uptake is dependent on transport via the choline transport system and melphalan is transported via amino acid transport systems. High levels of amino acids, such as leucine, can compete with melphalan for active transport into malignant cells
FIGURE 2.1. Cyclophosphamide and ifosfamide metabolic pathway: Both cyclophosphamide and ifosfamide act as prodrugs and are metabolized via CYP enzymes to a 4-OH-metabolite. This exists as a tautomer with the aldophosphamide form. The aldophosphamide metabolite either is metabolized via aldehyde dehydrogenase (ALDH) to the inactive carboxy metabolites or undergoes spontaneous breakdown in cells to the active metabolite phosphoramide mustard and the acrolein metabolite, which is responsible for hemorrhagic cystitis. Mercaptoethane sulfonate (mesna) is used to inactivate the acrolein metabolite and prevent bladder irritation and hemorrhagic cystitis. Of note, CYP enzymes also convert cyclophosphamide and ifosfamide to the chloroacetaldehyde metabolite, which is thought to be responsible for central nervous system (CNS) toxicity as well as potential nephrotoxicity.
• Inactivation of alkylating agents via increased expression of glutathione and glutathione S-transferase
• Increased expression of aldehyde dehydrogenase (ALDH) within malignant cells may increase the conversion of cyclophosphamide and ifosfamide to inactive carboxy metabolites (Figure 2.1)
• Enhanced DNA repair pathways including nucleotide excision repair (NER) and homologous recombination repair
• Defective cell checkpoint function and apoptotic pathways in response to DNA damage
FIGURE 2.2. Bendamustine structure: Bendamustine contains a mechlorethamine group that is responsible for its nitrogen mustard alkylating agent activity as well as a benzimidazole ring that mimics the structure of purine analogues, and has been theorized to act as an antimetabolite.
– Loss of mismatch repair (MMR) proteins, which initiate apoptosis
– Loss of normal p53 function
– Upregulation of antiapoptotic proteins (eg, BCL-2, BCL-XL)
What are the common dosing ranges for each nitrogen mustard?
• Mechlorethamine: 6 mg/m2 intravenous (IV) on days 1 and 8 q28 days (MOPP regimen for Hodgkin’s lymphoma [HL])
• Cyclophosphamide: Wide range of dosing, see common examples in the following text
– CyBORD (multiple myeloma [MM]): 300 mg/m2 orally (PO) days 1, 8, 15, and 22 of a 28-day cycle
– AC (breast cancer): 600 mg/m2 IV day 1 q21 days
– CHOP (lymphoma): 750 mg/m2 IV day 1 q21 days
– CALGB8811 (acute lymphoblastic leukemia [ALL]): 1,200 mg/m2 IV day 1 of a 28-day cycle
– HyperCVAD (ALL, lymphoma): 300 mg/m2 IV q12h days 1 to 3
• Ifosfamide:
– ICE (lymphoma): 5 g/m2 IV continuous infusion day 2 of a 14- to 21-day cycle
– Sarcoma, lymphoma, testicular (several different regimens): 1 to 3 g/m2 IV × 3 to 5 days
• Bendamustine: 70 to 120 mg/m2 days 1 and 2 of a 21- to 28-day cycle
• Chlorambucil: 0.1 to 0.2 mg/kg PO daily × 3 to 6 weeks; larger doses may be given less frequently (ex: 0.5 mg/kg PO every 2 weeks)
• Melphalan:
– MM (with prednisone): 4 to 6 mg/m2/day for 7 days every 4 weeks
– MM (conditioning for autologous stem cell transplant): 140 to 200 mg/m2 IV × 1
Are nitrogen mustards metabolized/eliminated renally or hepatically?
• Cyclophosphamide and ifosfamide are prodrugs, which are metabolized via CYP450 enzymes (2B6, 2C9, 2C19, 3A4) to active metabolites. Both drugs are eliminated renally (mostly as metabolites, including active metabolites and the acrolein metabolite responsible for hemorrhagic cystitis)
– Hepatic dysfunction may decrease production of active phosphoramide mustard metabolites, potentially decreasing efficacy
– Ifosfamide requires dosage adjustment for renal dysfunction; cyclophosphamide may be used safely in cases of renal dysfunction, although caution should be exercised in patients with severe renal impairment
• Chlorambucil and bendamustine are metabolized hepatically. Bendamustine possesses two active metabolites (formed via CYP1A2 metabolism), although metabolite concentrations are significantly lower in plasma than parent drug, indicating only a minor contribution to the cytotoxic activity of bendamustine
• Melphalan undergoes chemical hydrolysis. A small component is eliminated unchanged in urine; thus, in high doses, dosage adjustment may be required for renal impairment
• Mechlorethamine undergoes rapid inactivation in the plasma via hydrolysis
Are there drug interactions with any of the nitrogen mustards?
• Cyclophosphamide/ifosfamide: CYP450 inducers (eg, carbamazepine, phenytoin, rifampin) may increase the production of active metabolites and enhance toxicity. CYP450 inhibitors (eg, azole antifungals, amiodarone, clarithromycin) may decrease the production of active metabolites and compromise efficacy.
• Use of aprepitant/fosaprepitant: may enhance the risk of neurotoxicity with ifosfamide via CYP induction. Because aprepitant and fosaprepitant are also CYP inhibitors, efficacy of cyclophosphamide/ifosfamide may also be compromised.
• Bendamustine: allopurinol may increase the risk of skin reactions with bendamustine, including rash, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Inhibitors or inducers of CYP1A2 will alter the production of active minor metabolites of bendamustine. The clinical impact of this interaction is unknown.
What are the class adverse effects of the nitrogen mustards?
• Myelosuppression
• Nausea/vomiting
• Infertility (depends on dose and agent used)
• Mucositis
• Secondary malignancies:
– Treatment-related acute myeloid leukemia (AML) is typically associated with deletions in chromosome 5 or 7 and usually occurs 4 to 7 years after exposure
What unique side effects are present with each nitrogen mustard?
• Cyclophosphamide:
– Hemorrhagic cystitis (more common with higher doses)
– Syndrome of inappropriate antidiuretic hormone (SIADH; more common with higher doses)
– Cardiotoxicity (serious hemorrhagic myocarditis, which is infrequent and seen at higher doses for stem cell transplant)
• Ifosfamide:
– Neurotoxicity/encephalopathy (wide spectrum of signs and symptoms, including sedation, confusion, hallucinations, cerebellar symptoms, seizures, and coma)
– Hemorrhagic cystitis (more common than cyclophosphamide at equivalent doses)
– Renal impairment
• Bendamustine and chlorambucil: skin rashes, hypersensitivity reactions
• Melphalan:
– Mucositis with high doses (conditioning for autologous stem cell transplant; can use ice chips during infusion to lower the risk of severe mucositis)
– SIADH
What are the premedications required?
• Cyclophosphamide/ifosfamide: mercaptoethane sulfonate (mesna)—dose varies depending on regimen
– Continuous infusion (typically 100% of ifosfamide/cyclophosphamide dose)
– Intermittent dosing (60%–100% of ifosfamide/cyclophosphamide dose given with/prior to dose, and 4 and 8 hours after dose)
– When using oral mesna, dose should be doubled to account for approximately 50% bioavailability
What is the emetogenicity level of the nitrogen mustards?
• High: cyclophosphamide (≥1,500 mg/m2), mechlorethamine
• Moderate: cyclophosphamide (<1,500 mg/m2), ifosfamide, melphalan, bendamustine
• Minimal: chlorambucil
Are the nitrogen mustards vesicants or irritants?
• Vesicant: mechlorethamine
• Irritant: bendamustine, melphalan, ifosfamide
NON-NITROGEN MUSTARDS
What are the chemotherapy agents in the non-nitrogen mustard alkylating agent class?
Alkyl alkane sulfonates
• Busulfan (Busulfex®, Myleran®)
Nitrosoureas
• Carmustine (BCNU, BiCNU®, Gliadel®)
• Lomustine (CCNU, CeeNU®)
• Streptozocin (Zanosar®)
Aziridines
• Altretamine (Hexalen®)
• Thiotepa (Tepadina®)
Methylating agents
• Dacarbazine (DTIC-Dome®)
• Procarbazine (Matulane®)
• Temozolomide (Temodar®)
What malignancies are each agent FDA approved for?
FDA-Approved Uses of Non-Nitrogen Mustard Alkylating Agents
Agent |
FDA Approval |
Busulfan |
Chronic myeloid leukemia (CML) |
Carmustine |
Brain tumors, multiple myeloma, Hodgkin’s lymphoma (HL; relapsed/refractory), non-Hodgkin’s lymphomas (NHL; relapsed/refractory) |
Lomustine |
Brain tumors, HL (relapsed/refractory) |
Streptozocin |
Metastatic islet cell carcinoma of the pancreas |
Altretamine |
Ovarian cancer (persistent/recurrent) |
Thiotepa |
Bladder cancer, breast cancer, ovarian cancer, intracavitary effusions due to metastatic tumors |
Dacarbazine |
Malignant melanoma, HL |
Procarbazine |
HL |
Temozolomide |
Anaplastic astrocytoma (refractory), glioblastoma multiforme (newly diagnosed) |
Abbreviation: FDA, U.S. Food and Drug Administration.
How do the alkylating agents work?
• Summary: form cross-links with DNA, inhibiting DNA replication and causing apoptosis
• Alkylating agents form reactive intermediates that react with nucleophilic centers on DNA (most commonly N-7 of guanine) but also may bind to proteins, amino acids, and nucleotides
• Alkylating agents with two reactive groups (bifunctional alkylating agents) form DNA cross-links
– Streptozocin is a nitrosourea that contains a glucose moiety, which may explain its selectivity toward pancreatic beta cells
• Methylating agents (procarbazine, dacarbazine, temozolomide) transfer a single methyl group to DNA bases
– Procarbazine and dacarbazine primarily create O-6 methylguanine adducts. Temozolomide primarily methylates N–7 of guanine; adducts to the O-6 of guanine are critical for cytotoxicity
– Procarbazine and dacarbazine are metabolized in the liver to active metabolites. Temozolomide spontaneously converts to its active metabolite [3-methyl-(triazen-1-yl)imidazole-4-carboxamide—MTIC] in aqueous solution
• DNA cross-linking and alkylation inhibits DNA synthesis. Attempts at repair of DNA alkylation and cross-linking lead to DNA strand breakage
• Cell cycle checkpoint proteins recognize the DNA damage, halt cell cycle progression, and initiate apoptosis
• Cross-linking with bifunctional alkylating agents is primarily interstrand
• Cell cycle nonspecific
What are the common mechanisms of resistance to alkylating agent therapy?
• Inactivation of alkylating agents via increased expression of glutathione and glutathione S-transferase
• Enhanced DNA repair pathways, including base excision repair, enzymes that catalyze the removal of alkyl groups from guanine bases (alkylguanine-O6-alkyltransferase [AGT], encoded by the O6-methylguanine methyltransferase [MGMT] gene), NER, and homologous recombination repair
– Lower AGT levels due to methylation of the promoter region of the MGMT gene lead to enhanced sensitivity of tumors to alkylating agents (eg, improved survival of glioblastoma patients with methylated MGMT promoters receiving temozolomide and radiation therapy)
– AGT is the primary mechanism of resistance to the methylating agents temozolomide, procarbazine, and dacarbazine, and this enzyme contributes resistance to lomustine and carmustine as well
• Defective cell checkpoint function and apoptotic pathways in response to DNA damage
– Induction of the Akt signaling pathway, which inhibits apoptotic pathways
– Loss of MMR proteins, which initiate apoptosis
– Loss of normal p53 function
– Upregulation of antiapoptotic proteins (eg, BCL-2, BCL-XL)
What are the common dosing ranges for each alkylating agent?
• Busulfan:
– 3.2 to 4 mg/kg/day IV (may be given in divided dosing) × 2 to 4 days (bone marrow transplant [BMT] conditioning)
– 1 to 8 mg/day PO (chronic myeloid leukemia [CML], essential thrombocythemia [ET], polycythemia vera [PV])
• Carmustine:
– 150 to 200 mg/m2 IV q6–8 weeks (may be given over 2 days)
– Autologous hematopoietic stem cell transplantation (HSCT): 300 to 600 mg/m2 prior to transplant (eg, BEAM, CBV regimens)
– Glioblastoma multiforme: Up to eight wafers (61.6 mg) in resection cavity
• Lomustine: 100 to 130 mg/m2 PO × 1 q6 weeks
• Streptozocin:
– 500 mg/m2/day × 5 days q6 weeks
– 1,000 to 1,500 mg/m2 once weekly
• Altretamine:
– 260 mg/m2 daily in four divided doses × 14 to 21 days of a 28-day cycle
• Thiotepa:
– BMT conditioning: 250 mg/m2/day × 3 days or 150 mg/m2 q12h × 6 doses
– Ovarian/breast cancer: 0.3 to 0.4 mg/kg q1–4 weeks
– Intravesicular: 60 mg in 30 to 60 mL normal saline (NS) retained for 2 hours weekly × 4 weeks
– Intrathecal (leptomeningeal metastases): 10 mg twice a week (days 1 and 4) × 8 weeks
• Dacarbazine:
– ABVD: 375 mg/m2 days 1 and 15 q28 days
– Metastatic melanoma: 250 mg/m2/dose days 1 to 5 q3 weeks or 1,000 mg/m2 IV every 3 to 4 weeks
• Procarbazine: 60 to 100 mg/m2 PO × 7 to 14 days
• Temozolomide:
– Glioblastoma (newly diagnosed, concomitant radiotherapy): 75 mg/m2 PO daily × 42 days
– 150 mg/m2 PO daily × 5 days every 28 days (increase to 200 mg/m2 next cycle if nadir blood counts acceptable)
Are alkylating agents metabolized/eliminated renally or hepatically?
• Busulfan: Extensively hepatically metabolized; dose adjust for hepatic dysfunction
• Carmustine: Metabolized hepatically to active metabolites and excreted in the urine; dose adjust for renal dysfunction and severe hepatic dysfunction
• Lomustine: Metabolized hepatically to active metabolites and excreted in the urine; dose adjust for renal dysfunction and severe hepatic dysfunction
• Streptozocin: Metabolized hepatically and excreted in the urine; dose adjust for renal dysfunction and severe hepatic dysfunction
• Altretamine: Metabolized hepatically to active metabolites and excreted in the urine; dose adjust for renal dysfunction and severe hepatic dysfunction
• Thiotepa: Metabolized hepatically to active and inactive metabolites and excreted in the urine; dose adjust for renal and severe hepatic dysfunction
• Dacarbazine: Hepatically metabolized to active metabolites and excreted in the urine; dose adjust for renal dysfunction and/or severe hepatic dysfunction
• Procarbazine: Hepatically oxidized to active metabolites (further metabolized to inactive metabolites); dose adjust for hepatic dysfunction
• Temozolomide: Eliminated renally; dose adjust for severe renal dysfunction
Are there drug interactions with any of the alkylating agents?
• Procarbazine inhibits monoamine oxidase (MAO); avoid tyramine-containing foods, sympathomimetics (eg, dopamine), tricyclic antidepressants, other serotonin and norepinephrine concentration modifying drugs (selective serotonin reuptake inhibitors [SSRIs], serotonin–norepinephrine reuptake inhibitors [SNRIs], linezolid), and other MAO inhibitors to prevent risk of hypertensive crisis and serotonin syndrome
• Procarbazine may produce a disulfiram-like reaction when taken with alcohol
• Procarbazine/dacarbazine: Metabolized via CYP enzymes to active metabolite. CYP450 inducers (eg, carbamazepine, phenytoin, rifampin) may increase the production of active metabolites and enhance toxicity. CYP450 inhibitors (eg, azole antifungals, amiodarone, clarithromycin) may decrease the production of active metabolites and compromise efficacy
• Busulfan is metabolized primarily by conjugation via glutathione S-transferase and partially via CYP450 metabolism. Interactions resulting in increased busulfan concentrations have been reported with azole antifungals (itraconazole), acetaminophen, metronidazole, phenytoin, and phenytoin. Phenytoin concentrations should also be monitored in patients receiving busulfan, as reductions in phenytoin levels have been observed
– Although the IV formulation has improved delivery of busulfan, due to variability in busulfan pharmacokinetics, first-dose therapeutic drug monitoring may be useful in select patients
• Cimetidine has been reported to enhance myelosuppression due to carmustine and lomustine (mechanism unknown)
• Altretamine used in combination with MAO inhibitors increases the risk of severe orthostatic hypotension
What are the class adverse effects of the alkylating agents?
• Myelosuppression
• Nausea/vomiting
• Infertility (depends on dose and agent used)
• Secondary malignancies
– Treatment-related AML is typically associated with deletions in chromosome 5 or 7 and usually occurs 4 to 7 years after exposure
What unique side effects are present with each alkylating agent?
• Procarbazine: hemolysis (in G6PD-deficient patients), neurotoxicity (central nervous system [CNS] depression—avoid other CNS-depressing agents—dizziness, drowsiness, confusion), hypersensitivity reactions (rash, pneumonitis [rarely])
• Dacarbazine: flulike syndrome (fevers, chills, myalgias for several days after therapy), photosensitivity
• Temozolomide: myelosuppression (primarily lymphopenia—prophylaxis for Pneumocystis pneumonia (PCP) should be initiated for those receiving concomitant temozolomide and radiation therapy and in those who become lymphopenic)
• Busulfan: mucositis, skin hyperpigmentation and rash, alopecia, pulmonary fibrosis (“busulfan lung”), hepatotoxicity (veno-occlusive disease [VOD]), neurotoxicity (CNS depression, anxiety, headache, confusion, dizziness, seizures; use prophylactic anticonvulsants when using for BMT conditioning)
• Carmustine: mucositis, pulmonary fibrosis (risk increases at cumulative doses >1,400 mg/m2), hepatotoxicity (VOD), neurotoxicity (ataxia, dizziness, headache), alcohol intoxication with high doses (formulated with ethanol), facial flushing, skin irritation and injection site pain, hypotension (infuse over >2 hours to minimize injection site pain, flushing, and hypotension), skin hyperpigmentation and pain (after skin contact), alopecia
• Lomustine: pulmonary fibrosis (uncommon at doses <1,100 mg/m2), neurotoxicity (confusion, ataxia, lethargy, disorientation), nephrotoxicity
• Streptozocin: hyperglycemia/glucose intolerance (due to pancreatic beta cell toxicity), nephrotoxicity, pain/irritation at injection site, liver function test (LFT) elevations (usually transient)
• Altretamine: peripheral sensory neuropathy, neurotoxicity (mood disturbances, somnolence, agitation, depression, dizziness)
• Thiotepa: mucositis, alopecia, dermatologic changes (dermatitis, erythema, pruritus, pigmentation changes), hepatotoxicity (VOD), neurotoxicity (dizziness, headache, seizures, confusion), hypersensitivity reactions, pneumonitis
What are the premedications required?
• Busulfan: prophylactic anticonvulsants should be utilized with BMT (seizures usually occur during administration or within 24 to 48 hours after the last dose)
• All other non-nitrogen mustard alkylating agents do not require premedications
What is the emetogenicity level of the alkylating agents?
• High: procarbazine, dacarbazine, carmustine (>250 mg/m2), streptozocin, altretamine, thiotepa (≥300 mg/m2 in children)
• Moderate: temozolomide, busulfan, carmustine (≤250 mg/m2), lomustine, thiotepa (adults; <300 mg/m2 in children)
Are the alkylating agents vesicants or irritants?
• Dacarbazine, busulfan, carmustine, and streptozocin are irritants
• All other agents are neither vesicants nor irritants
PLATINUMS
What are the chemotherapy agents in the platinum class?
• Cisplatin (Platinol®)
• Carboplatin (Paraplatin®)
• Oxaliplatin (Eloxatin®)
What malignancies are each platinum FDA approved for?
FDA-Approved Uses of Platinum Alkylating Agents
Agent |
FDA Approval |
Cisplatin |
Advanced bladder cancer, metastatic testicular cancer, metastatic ovarian cancer |
Carboplatin |
Advanced ovarian cancer |
Oxaliplatin |
Stage III colon cancer, advanced colorectal cancer |
Abbreviation: FDA, U.S. Food and Drug Administration.
How do the platinums work? (See Figure 2.3)
• Form cross-links between purine nucleosides (guanine and adenine) of DNA (~95% intrastrand), causing DNA kinking, interference with normal DNA function, and ultimately cell death
• Cross-linking of DNA triggers DNA repair via the NER pathway and double-strand break repair process. When DNA cross-links are not effectively repaired, cell death occurs
• May also bind RNA and various cellular proteins; however, majority of cytotoxicity thought to be related to DNA intrastrand cross-links
• Binding to nuclear and cytoplasmic proteins may result in cytotoxic effects
• Synergistic with radiation (a radiosensitizer) and other DNA-damaging agents
• Cell cycle–nonspecific agent
FIGURE 2.3. Platinum structure and mechanism of action.
What are the common mechanisms of resistance to platinum therapy?
• Increased activity of DNA repair pathways (eg, NER)
• Inactivation of drug by binding to sulfhydryl groups on cytosolic proteins (eg, glutathione)
• Reduced uptake into or active efflux out of cells via copper transport pathways (CTR1, ATP7A, ATP7B)
• Decreased apoptosis in response to DNA damage
– Loss of MMR proteins, which initiate apoptosis
What are the common dosing ranges for each platinum?
• Cisplatin: 50 to 100 mg/m2 every 3 to 4 weeks
• Carboplatin: Use Calvert equation to calculate dose (usual area under the curve [AUC] 5–6). If estimating glomerular filtration rate (GFR), FDA recommends considering capping GFR at 125 mL/min
– Dose = Target AUC (GFR + 25)
• Oxaliplatin: 85 to 130 mg/m2 every 2 to 3 weeks
Are the platinums metabolized/eliminated renally or hepatically?
• Platinums are eliminated via the kidney and require dose adjustments
– Carboplatin is dosed via GFR and the Calvert equation
• Platinums do not require dosage adjustment for hepatic dysfunction
Are there drug interactions with the platinums?
Platinums should be administered after taxane derivatives to limit myelosuppression and enhance efficacy
• Cisplatin/carboplatin—concomitant nephrotoxic drugs, IV thiosulfates may inactivate drug, phenytoin, lithium (due to cation wasting with nephrotoxicity)
• Oxaliplatin—synergistic with 5-fluorouracil (5-FU), must be prepared in dextrose solutions (other platinums are stabilized by NS)
What are the class adverse effects of the platinums?
• Nephrotoxicity—cisplatin > carboplatin > oxaliplatin
• Nausea/vomiting—cisplatin > carboplatin/oxaliplatin
• Neuropathy
• Myelosuppression—carboplatin > cisplatin > oxaliplatin
• Acute hypersensitivity (usually occurs after 6th–8th exposure to the drug)
What are the most common adverse effects of each platinum?
• Cisplatin—Nausea/vomiting (highly emetogenic), nephrotoxicity with cation wasting (hypomagnesemia, hypokalemia, hypocalcemia), myelosuppression (more thrombocytopenia), ototoxicity (high tone loss), peripheral neuropathy, hypersensitivity
• Carboplatin—Myelosuppression (more thrombocytopenia and neutropenia), nausea/vomiting (moderate), nephrotoxicity, peripheral neuropathy, hypersensitivity
• Oxaliplatin—Acute neuropathy (usually within 7 days) commonly triggered by cold exposure (patients should avoid cold beverages/foods to prevent laryngopharyngeal dysesthesia), cumulative and chronic neuropathy, nausea/vomiting (moderate), myelosuppression (less than other platinums—likely related to concomitant 5-FU use), and hepatotoxicity
What are the premedications required?
• Premedications (other than antiemetics) are generally not required for platinum derivatives
• Prior to cisplatin administration, hydration with 1 to 2 L of fluid is recommended; adequate hydration should be maintained for 24 hours after administration
• Do not give ice chips or cold beverages/foods during (or within 7 days) of oxaliplatin infusion
What is the emetogenicity level of the platinums?
• Cisplatin—high
• Carboplatin/oxaliplatin—moderate
Are the platinums vesicants or irritants?
• Platinums are classified as irritants
ANTITUMOR ANTIBIOTICS
What are the chemotherapy agents in this class?
• Bleomycin (Blenoxane®)
• Dactinomycin (Cosmegen®, actinomycin D)
• Mitomycin C (Mutamycin®, MMC)—Streptomyces caespitosus
What malignancies are the antitumor antibiotics FDA approved for?
FDA-Approved Uses of Antitumor Antibiotics
Agent |
FDA Approval |
Bleomycin |
Head and neck cancers, Hodgkin’s lymphoma, malignant pleural effusions, testicular and other germ cell tumors |
Dactinomycin |
Choriocarcinoma, pediatric sarcomas, Wilms’ tumor, neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma |
Mitomycin |
Anal carcinomas and bladder instillation in bladder cancer |
Abbreviation: FDA, U.S. Food and Drug Administration.
How do the antitumor antibiotics work?
• Bleomycin: A2 peptide
– Generates free radicals by binding to Fe, causing single and double DNA strand breaks
Oxygen binds to iron leading to the formation of Fe(II)-bleomycin-O2
The complex binds in the minor groove to guanosine-cytosine–rich portions of DNA by forming an “S” tripeptide and partial intercalation of the bithiazole rings. This will stabilize the Fe(II)-bleomycin-O2 complex. In the absence of DNA, the complex will self-destruct
Reactive oxygen species (ROS) will cause double and single DNA strand breaks
Inhibits RNA and protein synthesis to a lesser degree
• Dactinomycin
– Intercalation of double-stranded DNA by chromophore of dactinomycin, inserts between the guanine-cytidine base pairs
– Binds to single-stranded DNA, prevents reannealing of DNA, and stabilizes unusual hairpins resulting in inhibition of transcription
• Mitomycin
– Forms DNA adducts by cross-linking complementary double-stranded and single-stranded DNA (alkylator) → inhibits DNA replication
Binds different parts of guanine depending on the way it formed a ROS
– Anaerobic: Undergoes reduction reaction to form reactive unstable intermediates, which forms a covalent monoadduct with DNA
– Aerobic: DT-diaphorase (DTD) enzyme and nicotinamide adenine dinucleotide phosphate (NADPH) metabolize MMC to reactive cytotoxic species (prodrug)
What are common mechanisms of resistance to each agent?
• Bleomycin: bleomycin hydrolase enzyme hydrolyzes terminal amine, inhibiting the iron-binding capacity (and cytotoxic activity) of the drug
– Enzyme protects normal tissue, but is in low concentration in the skin and lungs
• Dactinomycin: efflux by P170 glycoprotein pump encoded by the MDR gene
• Mitomycin: loss of MMC activation capacity, increased DNA repair mechanisms, P170 efflux pump
What are the common dosing ranges for each agent?
• Bleomycin
– HL
ABVD: 10 units/m2 on days 1 and 15 of each 28-day cycle
BEACOPP: 10 units/m2 on day 8 of each 21-day cycle
Stanford 5: 5 units/m2 weeks 2, 4, 6, 8, 10, and 12
– Testicular cancer and other germ cell tumors, BEP: 30 units/week × 12 doses
– Intrapleural or intraperitoneal injections for malignant effusions to breast, lung, and ovarian cancers: 60 units/m2 in 50 to 100 mL of NS
• Dactinomycin
– Pediatric dosing: 12 to 15 mcg/kg/day × 5 days each cycle
– Adult dosing: 300 to 600 mcg/m2/day × 5 days each cycle
• Mitomycin
– Stomach and pancreas adenocarcinoma: 20 mg/m2 every 6 to 8 weeks
– Anal carcinoma: 10 mg/m2 every 4 weeks
– Intravesicular instillation for bladder cancer: 40-mg dose × 1 or 20 mg weekly × 6 weeks, then monthly for 3 years
Are the agents metabolized/eliminated renally or hepatically?
• Bleomycin: renal
• Dactinomycin: renal and biliary
• Mitomycin: hepatic metabolism, renal elimination
Are there drug interactions with any of the agents?
• Bleomycin
a. Will form complexes with copper, cobalt, iron, zinc, and manganese
b. Cisplatin decreases bleomycin clearance
c. Radiation therapy produces additive free radical damage to DNA resulting in additive pulmonary toxicity
d. Brentuximab and filgrastim/pegfilgrastim can increase lung toxicity when given with bleomycin
• Dactinomycin: radiosensitizer
• Mitomycin: radiosensitizer
What are the adverse effects of each agent?
• Bleomycin: Thrombophlebitis, rash, blisters, hyperkeratosis, hyperpigmentation, fevers, hypersensitivities (chills, fever, anaphylaxis; test dose not predictive), pulmonary dysfunction (pneumonitis, fibrosis), Raynaud’s disease, very low likelihood for myelosuppression
a. Pulmonary fibrosis (dose-limiting toxicity [DLT], cumulative above 400 units)
i. Develops slowly; usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles, and chest x-ray infiltrates
ii. Causes direct inflammatory response, epithelial apoptosis, and progressive deposition of collagen over 1 to 2 weeks → pulmonary fibrosis
iii. Increased risk with age >70 (>40 for germ cell tumor patients), underlying pulmonary dysfunction, or chest radiation therapy, decreased renal function, growth factors (filgrastim/pegfilgrastim), single doses >25 units/m2
iv. Due to lack of bleomycin hydrolase in lung
v. Associated with single high doses versus smaller daily doses
• Dactinomycin: Myelosuppression (DLT), nausea/vomiting, diarrhea, alopecia, rare VOD, radiation recall, interstitial pneumonitis
• Mitomycin: Gastrointestinal (GI) side effects are mild and infrequent, hemolytic uremic syndrome, interstitial pneumonitis, cardiomyopathy, rare VOD
a. Myelosuppression
i. Common with low daily doses, less common with boluses every 4 to 8 weeks
ii. Rare <50 mg/m2; at higher doses, thrombocytopenia is more common than anemia and leukocytopenia
What are the premedications required?
• Bleomycin: some investigators advocate for test doses for lymphoma patients due to rare instances of allergic reactions
• Antiemetics
What is the emetogenicity level of the antitumor antibiotics?
• Bleomycin: minimal
• Dactinomycin: moderate
• Mitomycin: low
Are the antitumor antibiotics vesicants or irritants?
• Bleomycin: nonvesicant, nonirritant
• Dactinomycin: vesicant—requires cold compress
• Mitomycin: vesicant—requires cold compress and dimethyl sulfoxide (DMSO)