응급실에서 흔히 보는 항암제 부작용의 진단과 치료

응급실에서 흔히 보는 항암제 부작용의 진단과 치료

성균관대학교 의과대학 내과학교실

박 준 오

학습목표

- 항암제의 정의, 종료 및 항암제 흔한 부작용의 종류 - 항암제 부작용의 원인 및 기전

- 항암제 부작용과 관련된 종양응급의 진단 및 치료

서 론

1. 항암제란?

항암제란 세포내의 DNA에 직, 간접적으로 DNA의 복제 (replication), 전사(transcription), 번역(translation)을 차단 혹은 핵산 합성의 대사 경로에 개입하여 핵산 합성을 방해하거나, microtubule에 작용하여 세포분열을 저해함으로써 암세포에 대한 세포 독성을 나타내는 약제를 총칭한다

2. 항암제의 역사

항암제의 전신투여로 암을 치료하겠다는 개념은 역사적 으로 크게 3가지의 관찰을 통하여 시작되었다. 첫째는, 19세 기 Paul Ehrlich는 여러 종료의 염색물질이 각각의 다른 세포 및 조직에 반응하는 것을 관찰하였고, 이에 근거해서 종양과 특이적으로 결합하여 항암효과를 나타낼 수 있는 물질, 즉

“Magic bullets” 존재의 가능성을 가설로 세웠다. 둘째는 1차 대전 당시 독가스로 사용된 mustard gas가 골수기능을 억압 한다는 사실을 관찰하게 되었고, 저용량의 mustard gas로 골 수에서 기원한 종양의 치료로 사용할 수 있을 거라는 아이디 어를 얻게 되었다. 마지막으로, 난소절제시 유방암과 같이 호르몬에 반응하는 종양의 경우 크기가 줄어드는 현상과 같 이, 우리 몸에 종양의 성장을 촉진시키는 물질이 존재하며 이를 억제하여 종양을 치료할 수 있다는 개념을 발전시켰다.

항암제의 종류 및 분류

항암제 작용기전에 따라서 크게 1) DNA에 작용하는 것과 2) microtubules에 작용하는 것으로 나눌 수 있다 (Table 1, 그 Fig.1, 2 참조).

1. 세포주기와 항암제

DNA 합성 및 복제는 주로 S-phase에서 이루어지며, 복제 된 DNA의 염색체는 M-phase 에서 분리된다. 전통적으로 항 암제는 작용하는 세포주기에 따라서 세포주기의 어느 싯점 이나 작용하는 “phase-nonspecific” agents 혹은 세포주기의 특 정한 곳에서만 최대 효과를 내는 “phase-specific” agents로 구 분된다. 일단 항암제가 작용을 하면 세포는 세포주기의

“checkpoint”에서 DNA 손상을 복구하거나 혹은 세포사멸로 진행된다. 이러한 checkpoint 기능은 p53과 같은 종양억제유 전자에 의해서 조절된다(Fig. 1).

Figure 1. 세포주기 및 항암제.

Drug Toxicity Interactions, Issues Direct DNA-Interacting Agents

Alkylating agent: Alkylating agents break down to reactive intermediates that covalently modify bases in DNA. This leads to cross-linkage of DNA strands or the appearance of breaks in DNA as a result of repair efforts. “Broken” or cross-linked DNA is intrinsically unable to complete normal replication or cell division; in addition, it is a potent activator of cell cycle checkpoints and further activates cell-signaling pathways that can precipitate apoptosis

Cyclophosphamide Marrow (relative platelet sparing) Cystitis

Common alkylator Cardiac (high dose)

Liver metabolism required to activate to phosphoramide mustard + acrolein

Mesna protects against “high-dose” bladder damage Alopecia, pulmonary, infertility + teratogenesis

Mechlorethamine Marrow

Vesicant Nausea

Topical use in cutaneous lymphoma

Chlorambucil Marrow

Common alkylator

Alopecia, pulmonary, infertility + teratogenesis

Melphalan Marrow (delayed nadir)

GI (high dose)

Decreased renal function delays clearance

Carmustine (BCNU) Marrow (delayed nadir) GI, liver (high dose) Renal

Lomustine (CCNU) Marrow (delayed nadir) 　

Ifosfamide Myelosuppressive

Cystitis Neurologic Metabolic acidosis

Analogue of cyclophosphamide Must use mesna for uro-protection

Greater activity vs testicular neoplasms and sarcomas 　

Procarbazine Marrow

Nausea Neurologic Common alkylator

Liver and tissue metabolism required Disulfiram-like effect with ethanol Acts as MAOI

HBP after tyrosinase-rich foods

Alopecia, pulmonary, infertility + teratogenesis

Dacarbazine (DTIC) Marrow

Nausea Flulike

Metabolic activation

Temozolomide Nausea/vomiting

Headache/fatigue Constipation

Infrequent myelosuppression

Altretamine (formerly hexamethyl-melamine)

Nausea

Neurologic (mood swing)

Liver activation

Barbiturates enhance/cimetidine diminishes Table 1. 작용기전에 따른 항암제의 분류 및 대표적인 부작용

2. 작용기전에 따른 항암제의 분류(Fig. 2)

REFERNCES

1. Kasper D, Fauci AS, Hauser S, et al. Harrison 's principles of internal medicine. 19^th ed. New York: McGraw-Hill (2015).

2. Goldman L, Schafer AI. Goldman-Cecil Medicine. 25^th ed.

Philadelphia: Elsevier (2016).

Drug Toxicity Interactions, Issues Neuropathy

Marrow (less)

　 　 Cisplatin: Only the

cis

configuration is active as an antitumor agent. It is hypothesized that in the intracellular environment, a chloride is lost from each position, being replaced by a water molecule. The resulting positively charged species is an efficient bifunctional interactor with DNA, forming Pt-based cross-links.

Nausea

Neuropathy - stocking & glove sensorimotor neuropathy Auditory

Marrow platelets > WBCs Nephropathy + Renal Mg2+, Ca2+

Maintain high urine flow; osmotic diuresis, monitor intake/output K+, Mg2+

Emetogenic—prophylaxis needed

Full dose if CrCl >60 mL/min and tolerate fluid push

Carboplatin Marrow platelets > WBCs, more

frequent than cisplatin Nausea

Renal (high dose)

Reduce dose according to CrCl: to AUC of 5–7 mg/mL per min (AUC

= dose/[CrCl + 25])

Oxaliplatin Neuropathy

Nausea Anemia

Acute reversible neurotoxicity; chronic sensory neurotoxicity cumulative with dose; reversible laryngopharyngeal spasm

Antitumor Antibiotics and Topoisomerase Poisons: Antitumor antibiotics are substances produced by bacteria that in nature appear to provide a chemical defense against other hostile microorganisms. As a class, they bind to DNA directly and can frequently undergo electron transfer reactions to generate free radicals in close proximity to DNA, leading to DNA damage in the form of single-strand breaks or cross-links. Topoisomerase poisons include natural products or semisynthetic species derived ultimately from plants, and they modify enzymes that regulate the capacity of DNA to unwind to allow normal replication or transcription.

Bleomycin Pulmonary

Skin effects Raynaud’s Hypersensitivity

Fever and chills, facial flush Little myelosuppression

Pulmonary fibrosis, which increases in incidence at >300 cumulative units administered and is minimally responsive to treatment (e.g., glucocorticoids).

Inactivate by bleomycin hydrolase (decreased in lung/skin) O2 enhances pulmonary toxicity

Cisplatin-induced decrease in CrCl may increase skin/lung toxicity Reduce dose if CrCl <60 mL/min

Dactinomycin Marrow

Nausea Mucositis Vesicant Alopecia

Radiation recall

Etoposide (VP16-213) Marrow (WBCs > platelet) Alopecia

Hypotension

Hypersensitivity (rapid IV) Nausea

Mucositis (high dose)

Hepatic metabolism—renal 30%

Reduce doses with renal failure

Schedule-dependent (5-day schedule better than 1-day)

Late leukemogenic - When given at high doses or very frequently, topoisomerase II inhibitors may cause acute leukemia associated with chromosome 11q23 abnormalities in up to 1% of exposed patients

Accentuate antimetabolite action

Topotecan Marrow

Mucositis Nausea Mild alopecia

Reduce dose with renal failure No liver toxicity

　 　 Irinotecan Diarrhea: “early onset” with cramping,

flushing, vomiting (Acute cholinergic syndrome) + “late onset”

after several doses Marrow

Alopecia Nausea Vomiting Pulmonary

Prodrug requires enzymatic clearance to active drug “SN- 38”

Early diarrhea likely due to biliary excretion

Late diarrhea, use “high-dose” loperamide (2 mg q2–4 h)

Doxorubicin (and daunorubicin):

Intercalate into DNA, thereby altering DNA structure,

Marrow Mucositis Alopecia

Cardiovascular acute/chronic

Heparin aggregate; coadministration increases clearance Acetaminophen, BCNU increase liver toxicity

Cumulative doses >550 mg/m² are associated with a 10% incidence of chronic cardiomyopathy.

Drug Toxicity Interactions, Issues replication, and topoisomerase II

function

Vesicant Doxorubicin’s cardiotoxicity is increased when given together with trastuzumab.

Radiation recall

Idarubicin Marrow

Cardiac (less than doxorubicin)

None established

Epirubicin Marrow

Cardiac

None established

Mitoxantrone Marrow

Cardiac (less than doxorubicin) Vesicant (mild)

Blue urine, sclerae, nails

Interacts with heparin

Less alopecia, nausea than doxorubicin Radiation recall

Less alopecia, nausea than doxorubicin Indirectly DNA-Interacting Agents

Antimetabolites: A broad definition of antimetabolites would include compounds with structural similarity to precursors of purines or pyrimidines, or compounds that interfere with purine or pyrimidine synthesis. Some antimetabolites can cause DNA damage indirectly, through misincorporation into DNA, abnormal timing or progression through DNA synthesis, or altered function of pyrimidine and purine biosynthetic enzymes. They tend to convey greatest toxicity to cells in S-phase, and the degree of toxicity increases with duration of exposure. Common toxic manifestations include stomatitis, diarrhea, and myelosuppression. Second malignancies are not associated with their use.

Deoxycoformycin Nausea

Immunosuppression Neurologic Renal

Excretes in urine

Reduce dose for renal failure Inhibits adenosine deaminase Reduce dose for renal failure 6-Mercaptopurine (6-MP) Marrow

Liver Nausea 　

Variable bioavailability Metabolize by xanthine oxidase Decrease dose with allopurinol

Increased toxicity with thiopurine methyltransferase deficiency

6-Thioguanine Marrow

Liver Nausea

Variable bioavailability

Increased toxicity with thiopurine methyltransferase deficiency 　

Azathioprine Marrow

Nausea Liver

Metabolizes to 6-MP; therefore, reduce dose with allopurinol Increase toxicity with thiopurine methyltransferase deficiency

2-Chlorodeoxyadenosine Marrow Renal Fever

Notable use in hairy cell leukemia

Hydroxyurea Marrow

Nausea Mucositis Skin changes

Rare renal, liver, lung, CNS

Decrease dose with renal failure Augments antimetabolite effect

Methotrexate: MTX inhibits dihydrofolate reductase, which regenerates reduced folates from the oxidized folates produced when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates, cells die a “thymine-less”

death.

Marrow Liver/lung Renal tubular Mucositis

Toxicity lessened by “rescue” with leucovorin – LV can bypass this block and rescue cells from methotrexate, which is maintained in cells by polyglutamylation

Excreted in urine - high-dose regimens require alkalinization of urine with increased flow by hydration.

Decrease dose in renal failure; NSAIDs increase renal toxicity 　

5-Fluorouracil (5FU): 5FU originated from the observation that tumor cells incorporate radiolabeled uracil more efficiently into DNA than normal cells, especially gut. 5FU is metabolized in cells to 5´FdUMP, which inhibits thymidylate synthetase (TS). In addition, misincorporation can lead to single-strand breaks, and RNA can aberrantly incorporate FUMP.

Marrow Mucositis Neurologic Skin changes

Intravenous administration of 5FU leads to bone marrow suppression after short infusions but to stomatitis after prolonged infusions.

LV augments the activity of 5FU by promoting formation of the ternary covalent complex of 5FU, the reduced folate & TS.

Toxicity enhanced by leucovorin; dihydropyrimidine dehydrogenase deficiency increases toxicity; metabolism in tissue

Capecitabine Diarrhea Prodrug of 5FU due to intratumoral metabolism

Drug Toxicity Interactions, Issues Hand-foot syndrome

Cytosine arabinoside Marrow

Mucositis

Neurologic (high dose) Conjunctivitis (high dose) Noncardiogenic pulmonary edema

Enhances activity of alkylating agents

Metabolizes in tissues by deamination but renal excretion prominent at doses >500 mg; therefore, dose reduce in “high-dose” regimens in patients with decreased CrCl

Azacitidine Marrow

Nausea Liver Neurologic Myalgia

Use limited to leukemia

Altered methylation of DNA alters gene expression 　

Gemcitabine Marrow

Nausea Hepatic

Fever/”flu syndrome”

Fludarabine phosphate Marrow

Neurologic Lung

Dose reduction with renal failure

Metabolized to F-ara converted to F-ara ATP in cells by deoxycytidine kinase

Clofarabine Myelosuppression

Mucositis

Rare cardiac/inflammatory

Nelarabine Myelosuppression

Neurologic

T cell ALL; T cell lymphoblastic lymphoma

Asparaginase Protein synthesis; indirect inhibition of DNA synthesis by decreased histone synthesis

Clotting factors Glucose Albumin Hypersensitivity CNS

Pancreatitis/ Hepatic

Blocks methotrexate action

Pemetrexed: Novel folate-directed antimetabolite. It is

“multi-targeted” in that it inhibits the activity of several enzymes, including thymidylate synthetase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, thereby affecting the synthesis of both purine and pyrimidine nucleic acid precursors

Anemia Neutropenia Thrombocytopenia

Supplement folate/B12 to avoid significant toxicity to the normal tissues

Caution in renal failure 　

Pralatrexate Myelosuppression

Mucositis

Active in peripheral T cell lymphoma

Antimitotic Agents: Microtubules are cellular structures that form the mitotic spindle, and in interphase cells, they are responsible for the cellular

“scaffolding” along which various motile and secretory processes occur. Microtubules are composed of repeating noncovalent multimers of a heterodimer of α and β isoform of the protein tubulin.

Vincristine Vesicant

Marrow Neurologic

GI: ileus/constipation; bladder hypotoxicity; SIADH Cardiovascular

Hepatic clearance

Dose reduction for bilirubin >1.5 mg/dL

Acute neuropathic effects include jaw pain, paralytic ileus, urinary retention, and the syndrome of inappropriate antidiuretic hormone secretion.

Prophylactic bowel regimen 　

Vinblastine Vesicant

Marrow – more myelotoxic than VCR Neurologic (less common but similar

spectrum to other vincas) Hypertension

Hepatic clearance

Dose reduction as with vincristine 　

Drug Toxicity Interactions, Issues Raynaud’s

Vinorelbine Vesicant

Marrow

Allergic/bronchospasm (immediate) Dyspnea/cough (subacute)

Neurologic (less prominent but similar spectrum to other vincas)

Hepatic clearance

Paclitaxel: Taxanes differ from the vinca alkaloids in that the taxanes stabilize microtubules against depolymerization. The

“stabilized” microtubules function abnormally and are not able to undergo the normal dynamic changes of microtubule structure and function necessary for cell cycle completion.

Hypersensitivity Marrow Mucositis Alopecia

Sensory neuropathy CV conduction disturbance Nausea-infrequent

Premedication with steroids, H1 and H2 blockers Hepatic clearance

Dose reduction as with vincas 　

Nab-paclitaxel (protein bound) Neuropathy Anemia Neutropenia Thrombocytopenia

A protein-bound formulation of paclitaxel (called

nab-paclitaxel

Caution in hepatic insufficiency

Docetaxel Hypersensitivity

Fluid retention syndrome Marrow

Dermatologic Sensory neuropathy Nausea infrequent Some stomatitis

Premedication with steroids, H1 and H2 blockers