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Chemotherapeutic agents, also referred to as antineoplastic agents, are used to directly or indirectly inhibit the uncontrolled growth and proliferation of cancer cells. They are classified according to their mechanism of action and include alkylating agents, antimetabolites, topoisomerase inhibitors, antibiotics, mitotic inhibitors, and protein kinase inhibitors. Chemotherapy is associated with a range of adverse effects (e.g., nausea, vomiting, immunosuppression, and impaired growth of healthy cells), and some agents increase the risk of secondary neoplasm development. For some chemotherapeutic agents, specific detoxifying agents can be administered to avert preventable side effects (e.g., leucovorin after application of methotrexate, mesna after cyclophosphamide application).

For further information of management chemotherapy-related complications, see “Principles of cancer care.”

Basics of chemotherapeutic agents action [1][2]

Kinetics
- Chemotherapeutic agents are most active on cells with a high growth fraction, i.e., cells actively undergoing division (including normal cells, such as epithelial or bone marrow cells, as well as cancer cells)
- The log-kill hypothesis is a mathematical model of chemotherapeutic agent action, according to which a given dose of a certain chemotherapeutic agent eliminates a constant fraction of cancer cells regardless of tumor size. [3]
Cell cycle specificity
- Cell cycle-specific antineoplastic agents act on proliferating cells only during a specific phase of the cell cycle. There is no cell-cycle specific antineoplastic agent that acts during the resting (G0) phase.
- Cell cycle-nonspecific antineoplastic agents act on cells at any phase of the cell cycle, including the resting (G0) phase.
Resistance mechanisms: cancer cells can develop resistance to chemotherapeutic agents via the following mechanisms
- Mutations or altered expression of target cells (e.g., increased expression of dihydrofolate reductase can result in resistance of cancer cells to methotrexate)
- Increased rate of DNA repair (e.g., this mechanism can cause resistance to alkylating agents)
- Drug inactivation (e.g., some cancer cells can increase the synthesis of glutathione and other antioxidants, thus counteracting anthracyclines, which act through the generation of reactive oxygen species)
- Alteration of apoptotic pathways (e.g., leukemic cells can increase the expression of antiapoptotic molecules such as Bcl-2 to escape chemotherapy-induced apoptosis)
- Drug efflux (e.g., cancer cells can increase the expression of the MDR1 gene coding for P-glycoprotein which acts as the efflux transporter)

Basics of chemotherapy

For more information, see “Antineoplastic therapy” in “General oncology.”

Combination therapy

Chemotherapeutic agents are usually used in combination (combined chemotherapy regimens).

Advantages
- Increased log-kill
- Prevention and counteraction of cancer drug resistance
- Targeting both dividing and resting cells (in combination of cell cycle-specific and cell cycle-nonspecific agents)
- Synergistic effects allow for lower doses and, subsequently, less toxicity
Examples
- CHOP (or R-CHOP) for the treatment of non-Hodgkin lymphomas
- ABVD for the treatment of Hodgkin lymphomas
- FOLFOX, FOLFIRI, or XELOX for the treatment of colorectal cancer.

Routes of administration

The most common route of administration for chemotherapy is intravenous; other important methods of delivery include oral, intrathecal, and topical application.

Topical
- Used in the treatment of cancerous or precancerous skin lesions
- Chemotherapeutic agents that can be administered topically include 5-FU and mitomycin.
Intrathecal administration
- The aim of intrathecal administration is to prevent the need for cerebral radiation therapy and to treat meningeal disseminated diseases (e.g., meningeal leukemia/lymphoma)
- Chemotherapeutic agents that can be injected intrathecally include methotrexate and cytarabine.
Oral administration
- Allows for ambulatory treatment, e.g., maintenance therapy, palliative treatment
- Chemotherapeutic agents that can be administered orally include idarubicin, capecitabine, temozolomide, etoposide, methotrexate, 6-MP.

Efficacy of treatment

Individual influencing factors
- Patient factors (e.g., overall health, bone marrow capacity, liver and kidney function, age, compliance)
- Cancer factors (e.g., growth fraction, cancer doubling time, type and stage of cancer, resistance)
Blood-brain barrier
- Many chemotherapeutic agents cannot cross the blood-brain barrier, which reduces their effectiveness in the treatment of malignant CNS diseases
- Fat-soluble agents (e.g., carmustine, lomustine), however, can be transported across the blood-brain barrier via diffusion and are, therefore, used in the treatment of brain tumors.

Common adverse effects of chemotherapy

Chemotherapeutic agents damage actively dividing cells, but can also affect tissues with a low mitotic potential (e.g., neurons).

Gastrointestinal tract

Chemotherapy-induced nausea and vomiting
Chemotherapy-induced diarrhea
Mucositis (soft tissue erythema of the buccal mucosa, gingival bleeding, multiple shallow ulcerations, and dysphagia)
Constipation
Intestinal perforation
Causative agents include:
- Alkylating agents (e.g., chlorambucil)
- Antifolates (e.g., methotrexate)
- Pyrimidine antagonists (e.g., 5-FU, cytarabine)
- Antibiotics (e.g., dactinomycin)
- Anthracyclines (e.g., doxorubicin, daunorubicin)

Blood

Myelosuppression
- Granulocytopenia and lymphocytopenia (increased risk of infection)
- Thrombocytopenia (increased risk of bleeding)
- Anemia (fatigue)
Most chemotherapeutic agents induce some extent of dose-dependent myelosuppression.
Severe suppression of the hematopoietic system can be caused by:
- Alkylating agents (e.g., cyclophosphamide, busulfan)
- Antifolates (e.g., methotrexate)
- Pyrimidine antagonists (e.g., 5-FU, cytarabine)
- Purine antagonists (e.g., 6-MP), taxanes (e.g., paclitaxel)
- Anthracyclines (e.g., doxorubicin, daunorubicin)

Skin

Hair loss
Causative agents include:
- Pyrimidine antagonists (e.g., 5-FU)
- Antibiotics (e.g., dactinomycin)
- Anthracyclines (e.g., doxorubicin, daunorubicin)

CNS

Centrally induced vomiting
- Mediated by substance-P and neurokinin-1 receptors in the brain
- Associated with delayed emesis after chemotherapy
- Causative agents include e.g., nitrogen mustards (e.g., chlorambucil), nitrosoureas (e.g., carmustine)
Chemotherapy-induced peripheral neuropathy
- Pain, burning, tingling, and loss of sensation in the distal extremities that spread from the hands and feet (stocking-glove pattern).
- Causative agents include:
  - Platinum-based medications (e.g., cisplatin)
  - Taxanes (e.g., paclitaxel)
  - Vinca alkaloids (e.g., vincristine)

Sexual organs

Gonadal damage that may lead to temporary azoospermia, premature ovarian failure, and infertility
Causative agents include alkylating agents (e.g., cyclophosphamide, chlorambucil, procarbazine)

The chemotox woman Chemotherapy side effects

Overview of chemotherapeutic drugs classes

Overview of important chemotherapeutic agents
Drug class	Subgroup	Drug	Cell cycle specificity	Indications
Antimetabolites	Antifolates	Methotrexate	S phase	Neoplastic conditions Breast cancer Head and neck cancers (e.g., squamous cell carcinoma) Lung cancer Leukemias (e.g., acute lymphoblastic leukemia) Lymphomas (e.g., cutaneous T-cell lymphoma, non-Hodgkin lymphomas) Sarcomas Choriocarcinoma Other uses Hydatidiform moles Ectopic pregnancy Medical abortion (in combination with misoprostol) Immunosuppression for autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, psoriasis, vasculitides)
	Antifolates	Pemetrexed		Pleural mesothelioma Non-small cell lung cancer (NSCLC)
	Pyrimidine antagonists	Cytarabine (arabinofuranosyl cytidine)		Leukemias (e.g., AML) Lymphomas
		5-Fluorouracil (5-FU) Capecitabine (prodrug for 5-FU)		Systemic treatment Breast cancer Gastric cancer Colorectal cancer Pancreatic cancer Topical treatment Actinic keratosis Basal cell carcinoma
		Gemcitabine		Pancreatic cancer Breast cancer NSCLC Ovarian cancer
	Purine antagonists	6-Mercaptopurine (6-MP) Azathioprine (prodrug for 6-MP)		Acute lymphoblastic leukemia Immunosuppression Organ transplants Autoimmune diseases (e.g., inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis) that are steroid-resistant or to reduce steroid dose
		Fludarabine		Chronic lymphocytic leukemia (CLL) Myeloablation prior to hematopoietic stem cell transplant
		Cladribine	Nonspecific	Hairy cell leukemia Multiple sclerosis
	Ribonucleotide reductase inhibitors	Hydroxyurea (hydroxycarbamide)	S phase	Myeloproliferative disorders (e.g., chronic myeloid leukemia, polycythemia vera) Sickle cell crisis prophylaxis (by increasing hemoglobin F) Leukostasis syndrome
Alkylating agents	Oxazaphosphorines	Cyclophosphamide	Nonspecific	Neoplastic conditions Solid tumors (e.g., breast cancer, ovarian cancer, small cell lung cancer) Leukemias Lymphomas Multiple myeloma Nonneoplastic conditions Autoimmune diseases (e.g., systemic lupus erythematosus, granulomatosis with polyangiitis) Nephrotic syndrome
	Oxazaphosphorines	Ifosfamide		Solid tumors (e.g., testicular germ-cell cancer, osteosarcoma)
	Nitrogen mustards	Chlorambucil		CLL Hodgkin lymphoma Non-Hodgkin Lymphoma (NHL)
	Nitrogen mustards	Melphalan		Multiple myeloma Ovarian cancer Amyloidosis
	Imidazotetrazines	Temozolomide		Glioblastoma Anaplastic astrocytoma
	Nitrosoureas	Carmustine Lomustine Streptozocin		Brain tumors (e.g., glioblastoma multiforme) Multiple myeloma (carmustine) Lymphomas Pancreatic neuroendocrine tumors (streptozocin)
	Alkyl sulfonate	Busulfan		Myeloablation prior to hematopoietic stem cell transplant
	Hydrazines	Procarbazine		Hodgkin lymphoma Brain tumors (e.g., gliomas)
	Platinum-based agents	Cisplatin Carboplatin Oxaliplatin		Bladder cancer Testicular cancer Ovarian cancer Cervical cancer Colorectal cancer Lung cancer Osteosarcoma
Topoisomerase inhibitors	Topoisomerase I inhibitors	Irinotecan	S and G2 phase	Colorectal cancer
	Topoisomerase I inhibitors	Topotecan		Cervical cancer Ovarian cancer Small-cell lung cancer (SCLC)
	Topoisomerase II inhibitors	Etoposide		Testicular cancer SCLC Leukemias Lymphomas
	Topoisomerase II inhibitors	Teniposide		Leukemias (e.g., acute lymphocytic leukemia)
Mitotic inhibitors	Vinca alkaloids	Vincristine	S and M phase	Solid tumors Neuroblastoma Rhabdomyosarcoma Nephroblastoma Others Acute lymphoblastic leukemia (ALL) Hodgkin lymphomas and NHL
		Vinblastine		Solid tumors Kaposi sarcoma Langerhans cell histiocytosis Testicular cancer Others: Hodgkin lymphomas and NHL
		Vinorelbine		NSCLC Breast cancer
	Taxanes	Docetaxel Paclitaxel	M phase Late G2 mitotic phase	Breast cancer Ovarian cancer Prostate cancer Gastric cancer Kaposi sarcoma NSCLC
	Nontaxane microtubule inhibitors	Eribulin	G2/M phase	Breast cancer Liposarcoma
	Nontaxane microtubule inhibitors	Ixabepilone Epothilone	M phase	Breast cancer
Antibiotics	Bleomycin		G2 phase M phase	Squamous cell carcinomas of the head and neck Testicular cancer Hodgkin lymphoma Malignant pleural effusion
	Actinomycin D		Nonspecific	Childhood tumors Nephroblastoma Ewing sarcoma Rhabdomyosarcoma Gestational trophoblastic neoplasia
	Anthracyclines Doxorubicin Daunorubicin Idarubicin		Nonspecific	Solid tumors Leukemias Lymphomas (Hodgkin and non-hodgkin lymphomas)
	Mitomycin		Nonspecific	Palliative chemotherapy of gastric and pancreatic cancer Bladder cancer
Protein kinase inhibitors (e.g., tyrosine kinase inhibitors)	BCR-ABL tyrosine kinase inhibitors and c-KIT tyrosine kinase inhibitors	Imatinib Dasatinib Nilotinib	Variable	Chronic myeloid leukemia (CML) (BCR-ABL) ALL Gastrointestinal stromal tumor (c-KIT) Aggressive systemic mastocytosis Dermatofibrosarcoma protuberans Chronic eosinophilic leukemia
		Imatinib Dasatinib Nilotinib	G0/G1 phase
	EGFR tyrosine kinase inhibitors	Erlotinib Gefitinib Afatinib Osimertinib		NSCLC Pancreatic cancer
	ALK tyrosine kinase inhibitors
		Alectinib Crizotinib		NSCLC
			G0 and G1 phase
			G0/G1 phase
	V600E mutated-BRAF oncogene inhibitor	Dabrafenib Vemurafenib Encorafenib	G0/G1 phase	Metastatic melanoma NSCLC Thyroid cancer Erdheim-Chester disease
	MEK inhibitors	Trametinib	G0/G1 phase	Melanoma NSCLC
	Bruton tyrosine kinase inhibitors	Ibrutinib Acalabrutinib	G1 phase	Neoplastic conditions CLL Mantle cell lymphoma Waldenstrom macroglobulinemia Nonneoplastic conditions: Graft-versus-host disease
	Janus kinase inhibitors	Ruxolitinib	G1 phase	Polycythemia vera Myelofibrosis
	CDK inhibitors	Palbociclib	G1/S phase	Metastatic breast cancer
Other	Enzymes	L-asparaginase	G1 phase	ALL
	Proteasome inhibitors	Bortezomib Carfilzomib Ixazomib	G2/M phase	Mantle cell lymphoma (bortezomib) Multiple myeloma
	PARP inhibitors	Olaparib	G2 and S phase	Breast cancer Ovarian cancer Prostate cancer Pancreatic cancer
Monoclonal antibodies	See “Biological agents used in immunotherapy” in “Immunosuppressants.”

Overview of important antimetabolites
Subgroup	Agent	Mechanism of action	Indications	Adverse effects
Antifolates	Methotrexate	Competitive inhibition of dihydrofolate reductase via displacement of dihydrofolate → ↓ formation of pyrimidine nucleotides (↓ dTMP) and purine nucleotides → ↓ DNA synthesis Inhibition of AICAR transformylase → inhibition of adenosine deaminase → ↑ intracellular concentration of adenosine and adenine nucleotides	Neoplastic conditions Leukemias (especially ALL) Lymphomas (e.g., cutaneous T-cell lymphoma, non-Hodgkin lymphomas) Sarcomas Choriocarcinoma Breast cancer Head and neck cancers (e.g., squamous cell carcinoma) Lung cancer Nonneoplastic conditions Hydatidiform moles Ectopic pregnancy Medical abortion (in combination with misoprostol) Immunosuppression for autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, psoriasis, vasculitides)	Myelosuppression, anemia Hepatotoxicity, hepatic fibrosis Pulmonary fibrosis, pneumonitis Nephrotoxicity Mucositis (e.g., oral ulcerations) Megaloblastic anemia Birth defects (due to folate deficiency), e.g., neural tube defects Neurotoxicity (e.g., seizures)
Antifolates	Pemetrexed	Multitargeted antifolate Inhibition of thymidylate synthase → ↓ synthesis of deoxythymidine monophosphate (dTMP) → ↓ DNA and RNA synthesis	Pleural mesothelioma NSCLC Ovarian cancer	Alopecia Erythematous, pruritic rash (pemetrexed) Desquamation Anemia Pharyngitis GI symptoms (e.g, diarrhea)
Pyrimidine antagonists	Cytarabine	Incorporation of pyrimidine analog into DNA→ ↓ DNA synthesis (via termination of DNA chain) Inhibits DNA polymerase at higher doses	Leukemias (especially AML) Lymphomas	Myelosuppression (pancytopenia) Megaloblastic anemia Hepatotoxicity Pancreatitis Sudden respiratory distress syndrome Neurotoxicity (e.g., seizures, cerebellar toxicity)
	5-Fluorouracil (5-FU) Capecitabine (prodrug for 5-FU)	Activation of 5-fluorouracil to 5-FdUMP Complex formation with thymidylate synthase and folic acid → inhibition of thymidylate synthase → ↓ dTMP production → ↓ DNA synthesis Incorporation of pyrimidine analog into DNA and RNA → ↓ DNA and RNA synthesis Leucovorin enhances antineoplastic efficacy of 5-fluorouracil	Systemic treatment Breast cancer Gastric cancer Colorectal cancer Pancreatic cancer Topical treatment Actinic keratosis Basal cell carcinoma	Myelosuppression Palmar-plantar erythrodysesthesia (hand-foot syndrome) Cardiotoxicity GI symptoms (e.g., nausea, diarrhea, mucosal ulcerations) Higher toxicity in patients with dihydropyrimidine dehydrogenase deficiency Hepatotoxicity Hyperammonemic encephalopathy
	Gemcitabine	Incorporation of pyrimidine analog into DNA → ↓ DNA synthesis	Breast cancer NSCLC Ovarian cancer Pancreatic cancer	Myelosuppression Capillary leak syndrome Hemolytic uremic syndrome Pulmonary toxicity Hepatotoxicity
Purine antagonists	6-Mercaptopurine (6-MP) Azathioprine (prodrug for 6-MP)	6-Mercaptopurine is converted into the active metabolite by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) → ↓ de novo synthesis of purines Incorporation of purine analog (thiol analog) into DNA → ↓ DNA synthesis	Acute lymphoblastic leukemia Non-neoplastic conditions: immunosuppression Prevention of organ transplant rejection Treatment of autoimmune diseases For example, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis Used in patients with steroid-resistance or to reduce steroid dose	Myelosuppression GI symptoms (e.g., CINV, diarrhea) Hepatotoxicity Secondary malignancy [4] Metabolized by xanthine oxidase; therefore, toxicity increases with concurrent use of allopurinol and/or febuxostat
	Fludarabine	Incorporation of purine analog into DNA → ↓ DNA and RNA synthesis	CLL Low-grade lymphomas (e.g., follicular B-cell lymphoma) Myeloablation prior to hematopoietic stem cell transplant	Autoimmune effects (e.g., autoimmune hemolytic anemia, idiopathic thrombocytopenia) Myelosuppression Neurotoxicity
	Cladribine	Incorporation of purine analog into DNA → breakage of DNA strand → ↓ DNA synthesis Inhibits DNA polymerase Selectively toxic to lymphocytes and monocytes that have a high deoxycytidine kinase and a low deoxynucleotidase content. Deoxycytidine kinase phosphorylates cladribine Monophosphorylated cladribine is resistant to adenosine deaminase and accumulates within the cells. [5]	Hairy cell leukemia CLL Low-grade lymphomas Nonneoplastic conditions: multiple sclerosis	Myelosuppression Headache Nephrotoxicity Neurotoxicity Cardiotoxicity Hepatotoxicity
Ribonucleotide reductase inhibitors	Hydroxyurea (hydroxycarbamide)	Inhibition of ribonucleotide reductase → ↓ DNA replication (S phase) → massive cytoreduction	Myeloproliferative disorders Chronic myeloid leukemia Polycythemia vera Essential thrombocythemia Leukostasis syndrome Head and neck cancer	Myelosuppression Macrocytosis, macrocytic anemia Secondary malignancy Birth defects Pulmonary toxicity
Ribonucleotide reductase inhibitors	Hydroxyurea (hydroxycarbamide)	Increases production of hemoglobin F (HbF)	Sickle cell crisis prophylaxis

Cytarabine causes myelosuppression with pancytopenia.

Overview of important alkylating agents
Subgroup	Agent	Mechanism of action	Indications	Adverse effects
Oxazaphosphorines	Cyclophosphamide	Alkylation of DNA/RNA →cross-linksDNA at guanine N–7 →↓ DNA replication Cyclophosphamide and ifosfamide require activation in the liver.	Malignancies [6] Solid tumors (e.g., breast cancer, ovarian cancer, small cell lung cancer) Leukemias Lymphomas Multiple myeloma Nonneoplastic conditions Autoimmune diseases (e.g., systemic lupus erythematosus, granulomatosis with polyangiitis) Nephrotic syndrome	Bladder toxicity: metabolism of oxazaphosphorines produces the urotoxic substance acrolein Hemorrhagic cystitis: inflammation of the bladder, damaging to the epithelium and blood vessels Bladder carcinoma Myelosuppression Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Pulmonary toxicity Cardiac toxicity Infertility Fanconi syndrome (ifosfamide) Neurotoxicity (ifosfamide)
Oxazaphosphorines	Ifosfamide		Solid tumors (e.g., testicular germ-cell cancer, osteosarcoma) [7]
Nitrogen mustards	Chlorambucil		Chronic lymphocytic leukemia Hodgkin lymphoma Non-Hodgkin lymphoma	Myelosuppression Oral ulcerations GI symptoms (e.g., CINV) Pulmonary fibrosis Infertility
Nitrogen mustards	Melphalan		Multiple myeloma Ovarian cancer Amyloidosis	Myelosuppression Pulmonary toxicity Hypokalemia Peripheral edema Secondary leukemia
Imidazotetrazines	Temozolomide		Glioblastoma Anaplastic astrocytoma	Myelosuppression Neurotoxicity Pneumocystis pneumonia
Nitrosoureas	Carmustine Lomustine Streptozocin	Alkylation of DNA/RNA →cross-links between DNA →↓ DNA synthesis Require bioactivation Due to their high lipophilicity, carmustine and lomustine can cross the blood-brain barrier and act in the CNS.	Brain tumors (e.g., glioblastoma multiforme) Multiple myeloma (carmustine, lomustine) Hodgkin lymphoma Pancreatic neuroendocrine tumors (streptozocin)	Neurotoxicity (e.g., convulsions, dizziness, ataxia) Myelosuppression Pulmonary toxicity Secondary leukemia
Alkyl sulfonate	Busulfan	Cross-links between DNAstrands →↓ DNA replication	Myeloablation prior to hematopoietic stem cell transplantation CML	Severe myelosuppression (expected effect) Pulmonary fibrosis Hyperpigmentation Electrolyte imbalance Cardiotoxicity Hepatotoxicity Neurotoxicity (e.g., convulsions)
Hydrazines	Procarbazine	Mechanism of action is not fully understood Inhibition of transmethylation of methionine into transfer RNA → ↓ DNA, RNA, and protein synthesis Also acts as a weak MAO inhibitor	Hodgkin lymphoma Brain tumors (e.g., gliomas) [8]	Myelosuppression Pulmonary toxicity Secondary leukemia Disulfiram-like reaction Tyramine crisis Gonadal damage
Platinum-based agents	Cisplatin Carboplatin Oxaliplatin	Cross-links between DNAstrands →↓ DNA replication	Lymphomas Solid tumors Bladder cancer (cisplatin) Testicular cancer (cisplatin) Ovarian cancer (cisplatin, carboplatin) Colorectal cancer (oxaliplatin) Lung cancer (cisplatin, carboplatin) Cervical cancer (cisplatin) Osteosarcoma (cisplatin)	Myelosuppression Nephrotoxicity (may manifest as Fanconi syndrome) Neurotoxicity (including peripheral neuropathies) Ototoxicity CINV

Cyclophosphamide can cause hemorrhagic cystitis.

Busulfan and Bleomycin Block your Breath: busulfan and bleomycin cause pulmonary fibrosis.

Overview of important topoisomerase inhibitors
Subgroup	Agent	Mechanism of action	Indications	Adverse effects
Topoisomerase I inhibitors	Irinotecan	Inhibition of topoisomerase I →↓ DNAunwinding →↓ DNA replication and DNA degradation (because of ssDNA breaks)	Colorectal cancer Small-cell lung cancer Pancreatic cancer	Myelosuppression GI symptoms (e.g., diarrhea) Cholinergic syndrome Alopecia Pulmonary toxicity (irinotecan)
Topoisomerase I inhibitors	Topotecan		Cervical cancer Ovarian cancer Small-cell lung cancer
Topoisomerase II inhibitors	Etoposide	Inhibition of topoisomerase II →↑ DNA degradation (dsDNA breaks) and ↓ DNA replication (cell cycle arrest in S and G2 phase)	Solid tumors Testicular cancer Small-cell lung cancer Leukemias Lymphomas	Myelosuppression Alopecia Hypotension Mucositis (teniposide)

Overview of important mitotic inhibitors
Subgroup	Agent	Mechanism of action	Indications	Adverse effects
Vinca alkaloids	Vincristine	Binding of β-tubulin → inhibition of β-tubulin polymerization into microtubules→ prevention of mitotic spindleformation →mitotic arrest of the cell in metaphase (M-phase)	Solid tumors Neuroblastoma Rhabdomyosarcoma Nephroblastoma Other Acute lymphocytic leukemia Hodgkin lymphoma NHL	Neurotoxicity (e.g., areflexia, peripheral neuropathy) Paralytic ileus, constipation Extravasation can cause significant irritation and/or ulceration of local tissue Acute bronchospasm Uric acid nephropathy
	Vinblastine		Solid tumors Kaposi sarcoma Langerhans cell histiocytosis Testicular cancer Other Hodgkin lymphoma NHL	Myelosuppression Extravasation can cause significant irritation of local tissue Pulmonary toxicity
	Vinorelbine		NSCLC Breast cancer	Myelosuppression Hypersensitivity reactions
Taxanes	Docetaxel Paclitaxel	Hyperstabilization of polymerized microtubules →↓ mitotic spindles breakdown →mitotic arrest in metaphase (not proceeding to anaphase)	Breast cancer Ovarian cancer Prostate cancer Gastric cancer Kaposi sarcoma NSCLC	Myelosuppression Neuropathy Hepatotoxicity Hypersensitivity reactions Fluid retention Nail changes (e.g., nail bed purpura, onycholysis, nail pigmentation, splinter hemorrhage, subungual abscess)
Nontaxane microtubule inhibitors	Eribulin	Inhibition of mitotic spindle formation → mitotic blockage → cell cycle arrest at the G2/M phase	Breast cancer Liposarcoma	Myelosuppression Peripheral neuropathy QT prolongation
Nontaxane microtubule inhibitors	Ixabepilone Epothilone	Binding to β-tubulin → hyperstabilization of the microtubules → ↓ breakdown of mitotic spindles breakdown → mitotic arrest in metaphase	Breast cancer	Hypersensitivity Myelosuppression Peripheral neuropathy

The tax rates are stable: taxanes stabilize microtubules.

Assemblies are not permitted in the vineyard: vinca alkaloids prevent microtubule assembly.

Vincristinecrisps the nerves and vinblastine blasts the bone marrow.

Overview of important cytotoxic antibiotics
Agent	Mechanism of action	Indications	Side effects
Bleomycin	Induces formation of free radicals → breakage of DNAstrand →cell cycle arrest at G₂ phase and M phase	Squamous cell carcinomas of the head and neck Testicular cancer Hodgkin lymphoma Malignant pleural effusion	Bleomycin-induced lung injury Pulmonary fibrosis Bronchiolitis obliterans Acute pneumonitis ARDS Flagellate hyperpigmentation of the skin Minimal myelosuppression Mucositis Alopecia Idiosyncratic reaction
Actinomycin D (dactinomycin)	DNA intercalation → interference with DNA transcription → ↓ RNA synthesis	Childhood tumors Nephroblastoma Ewing sarcoma Rhabdomyosarcoma Gestational trophoblastic neoplasia	Myelosuppression Mucocutaneous toxicity Nephrotoxicity Hepatotoxicity
Anthracyclines (doxorubicin, daunorubicin, idarubicin)	Inhibition of topoisomerase II →↑ DNA degradation (dsDNA breaks) and ↓ DNA replication Formation of free radicals → breakage of DNA strands DNA intercalation → breakage of DNA strands and ↓ DNA replication	Breast cancer (doxorubicin) Metastatic solid tumors (doxorubicin) Lymphomas (doxorubicin) Kaposi sarcoma (doxorubicin) Leukemias (daunorubicin, idarubicin) Osteosarcoma	Anthracycline-induced cardiotoxicity Dilated cardiomyopathy with systolic CHF Dose-dependent [9] Myelosuppression Alopecia Urine discoloration Extravasation Infertility
Mitomycin	Cross-linking between DNA strands → ↓ DNA and RNA synthesis	Palliative chemotherapy of gastric and pancreatic cancer Bladder cancer	Myelosuppression Hemolytic uremic syndrome Heart failure Thrombotic thrombocytopenic purpura Bladder fibrosis (with intravesical administration) ARDS

Busulfan and bleomycin block your breath: Busulfan and bleomycin cause pulmonary fibrosis.

Except for bleomycin, all antitumor antibiotics are cell cycle nonspecific agents. Bleomycin is effective against cells in the G2 and M phase.

Overview of important protein kinase inhibitors
Subgroup	Agent	Mechanism of action	Indications	Side effects
BCR-ABL and c-KIT tyrosine kinase inhibitors	Imatinib	Inhibition of autophosphorylation and activation of multiple proteins by tyrosine kinases (e.g.,BCR-ABL, c-KIT)	Chronic myeloid leukemia BCR-ABL positive ALL Kit (CD117)-positive gastrointestinal stromal tumors Aggressive systemic mastocytosis (imatinib) Dermatofibrosarcoma protuberans (imatinib) Hypereosinophilic syndrome (imatinib) Chronic eosinophilic leukemia (imatinib) Myelodysplastic/Myeloproliferative diseases (imatinib)	General Fluid retention and edema Myelosuppression Hepatotoxicity (e.g., ↑ LFTs) Myalgia For imatinib Neurotoxicity Bullous dermatologic reactions Hemorrhage Nephrotoxicity For dasatinib: Cardiotoxicity Skin rash Hemorrhage Pulmonary arterial hypertension QT prolongation
	Dasatinib
	Nilotinib
EGFR tyrosine kinase inhibitors	Erlotinib Gefitinib Afatinib Osimertinib	Inhibition of HER1/EGFR tyrosine kinase → blockage of intracellular phosphorylation → cell death	NSCLC Pancreatic cancer	Dermatologic toxicity (e.g., rash, bullous, blistering, and exfoliating skin conditions) Fatigue GI toxicity (e.g., diarrhea) Hepatotoxicity Ocular toxicity Nephrotoxicity
VEGFR tyrosine kinase inhibitors [10][11]	Cabozantinib Pazopanib Sunitinib Sorafenib Tivozanib Axitinib Lenvatinib Regorafinib Vandetanib	Inhibition of VEGF tyrosine kinase → multimodal change to tumor microenvironment via antiangiogenic effect, effects on vessel function, and immune modulation [12]	Renal cell carcinoma (e.g., sorafenib) HCC (e.g., sorafenib) Thyroid cancer (e.g., sorafenib) Pancreatic neuroendocrine tumor (e.g., sunitinib) GIST (e.g., sunitinib, regorafinib)	GI toxicity (e.g., diarrhea) Dermatologic toxicity (e.g., rash, hand-foot syndrome) Cardiac toxicity (e.g., HTN) Fatigue Thyroid toxicity
ALK tyrosine kinase inhibitors	Alectinib Crizotinib	Inhibition of the anaplastic lymphoma kinase	NSCLC	GI toxicity (e.g., diarrhea) Fluid retention and edema Dermatologic toxicity (e.g., rash) Ocular toxicity Neurotoxicity Hepatotoxicity
V600E mutated-BRAF oncogene inhibitors	Dabrafenib Encorafenib	Selective inhibition of BRAF oncogene with V600E mutation → inhibition of cancer cell growth Often administered with MEK inhibitors (e.g., trametinib)	Metastatic melanoma NSCLC Thyroid cancer	General Dermatologic toxicity (e.g., rash) GI toxicity (e.g., nausea, diarrhea) Fatigue QT prolongation For dabrafenib and encorafenib Cardiomyopathy Febrile reactions Hyperglycemia Venous thromboembolism For vemurafenib Dupuytren contracture and plantar fascial fibromatosis Pancreatitis
V600E mutated-BRAF oncogene inhibitors	Vemurafenib		Metastatic melanoma Erdheim-Chester disease
MEK inhibitors	Trametinib	Inhibition of MAP kinase signaling pathway → inhibition of cancer cell growth and induction of apoptosis	Melanoma NSCLC	Hepatotoxicity Dermatologic toxicity GI toxicity
Bruton kinase inhibitors	Ibrutinib	Inhibition of Bruton tyrosine kinase (BTK) → growth inhibition of malignant B cells	Chronic lymphocytic leukemia (CLL) Mantle cell lymphoma Waldenstrom macroglobulinemia Graft-versus-host disease	GI toxicity Cardiotoxicity (e.g., atrial fibrillation) Hepatotoxicity
Janus kinase inhibitors	Ruxolitinib	Inhibition of JAK1 and JAK2 kinase → reduced activation of hematopoietic progenitor cells	Polycythemia vera Myelofibrosis	Hepatotoxicity (e.g., ↑ LFTs) Hematologic toxicity (e.g., thrombocytopenia, anemia)
CDK inhibitors	Palbociclib	Inhibition of cyclin-dependent kinase 4 and 6 → inhibition of cancer cell growth and induction of apoptosis	Metastatic breast cancer	Myelosuppression Pulmonary toxicity (e.g., pneumonitis)

Overview of chemotherapeutic agents from other groups
Subgroup	Agent	Mechanism of action	Indications	Side effects
Enzymes	L-asparaginase	Cleavage of the amino acid L-asparagine by L-asparaginase → ↓ asparagine source for leukemic cells → cytotoxicity specific to leukemic cells	Acute lymphoblastic leukemia	Hepatotoxicity Pancreatitis Hypofibrinogenemia and bleeding Thrombosis Hyperglycemia Allergic reactions
Proteasome inhibitors	Bortezomib Carfilzomib Ixazomib	Inhibition of ubiquitinated apoptoticprotein degradation (e.g., of p53) → arrest in G2/M → programmed cell death (apoptosis)	Mantle cell lymphoma (bortezomib) Multiple myeloma	Peripheral neuropathy Herpes zoster reactivation Hepatotoxicity Thrombocytopenia Neutropenia Pulmonary toxicity Heart failure
PARP Inhibitors	Olaparib	Inhibition of poly (ADP-ribose) polymerase → ↓ repair of single-strand DNA breaks	Breast cancer Ovarian cancer Prostate cancer Pancreatic cancer	Myelosuppression Fluid retention and edema GI toxicity (e.g., diarrhea)
Monoclonal antibodies	See “Biological agents used in immunotherapy.”

VemuRAFenib and daBRAFenib are BRAF inhibitors.

Detoxifying agents for antineoplastic treatment

The toxicity of certain chemotherapeutic agents can be prevented by the administration of particular detoxifying agents.

Overview of important detoxifying agents for antineoplastic treatment
Subgroup	Agent	Preventable adverse effect	Detoxifying agent
Antifolates	Methotrexate	Numerous adverse effects, the most important of which include: Myelosuppression Mucositis Hepatotoxicity Pulmonary fibrosis	Leucovorin (folinic acid) Precursor of tetrahydrofolate Application 24 h after the administration of antifolates Increases the therapeutic efficacy of thymidylate synthase inhibitors (e.g., 5–FU)
Oxazaphosphorines	Cyclophosphamide Ifosfamide	Bladder toxicity Hemorrhagic cystitis Bladder carcinoma	Mesna (2-MErcaptoethaneSulfonate Na) and fluids The sulfate group of mesna binds toxic metabolites
Platinum-based agents	Cisplatin Carboplatin Oxaliplatin	Nephrotoxicity (may manifest as Fanconi syndrome)	Amifostine: free radical scavenger IV saline: induces chloride diuresis → ↑ urine chloride concentration → ↓ cisplatin reactivity
Anthracyclines	Doxorubicin Daunorubicin Idarubicin	Cardiotoxicity	Dexrazoxane: iron chelating agent [2]

Management of complications

See “Oncologic emergencies” and “Complications of cancer therapy.”