Chemotherapeutic Agents

Fig. 31.1
Four phases of cell division (Source: Brunton et al. [3]. Copyright © McGraw Hill Companies, Inc)

Antimetabolites (S-Phase)

Antimetabolite drugs are also referred to as nucleic acid synthesis inhibitors [10]. They include folate analogs, pyrimidine analogs, and purine analogs. Their particular usefulness is in destroying cells during the S-phase (synthesis phase) of the cell cycle.

Folate Analogs: Methotrexate and Pemetrexed


Methotrexate is transferred into cells via a reduced folate carrier, and it inhibits dihydrofolate reductase (DHFR) which is the enzyme that uses reduced folate as a methyl donor in the synthesis of both purines and pyrimidines. The disruption of DHFR interferes with the synthesis of tetrahydrofolate, causing an intracellular folate deficiency. The end result of this folate deficiency is that the 1-carbon transfer reactions necessary for the synthesis of DNA, RNA, and key cellular proteins cease. Methotrexate can be administered intravenously, intrathecally, and by oral route, but oral bioavailability is erratic at doses greater than 25 mg/m2. It is eliminated mainly through renal excretion which is a reflection of glomerular filtration and tubular secretion. Elimination may be impaired in renal insufficiency. Around 50 % of the drug is found unchanged in the urine, suggesting that significant metabolism of methotrexate does not occur. Leucovorin (5-formyltetrahydrofolate) is used as rescue therapy for normal cells subjected to undue toxicity from methotrexate. Methotrexate is widely used in combination with other drugs in treatment of malignant disorders and also in some nonmalignant diseases. It is used in the treatment of acute lymphoblastic leukemia in children but not adults and is effective as the sole agent in choriocarcinoma [10]. Psoriasis and rheumatoid arthritis are nonmalignant disease processes that also show benefit with treatment by methotrexate.


Like methotrexate, pemetrexed works to inhibit the S-phase of the cell cycle, and it is transported into cells via a folate carrier. Its main target is to inhibit thymidylate synthase, but it also targets DHFR and other enzymes involved in de novo purine nucleotide biosynthesis [7, 10]. Supplementation with folate and vitamin B12 appears to reduce the toxicity of pemetrexed without altering its clinical efficacy. In combination with cisplatin, it is used for the treatment of non-small cell lung cancer and also mesothelioma.

Pyrimidine Analogs: Fluorouracil, Capecitabine, Cytarabine, and Gemcitabine

Pyrimidine analogs prevent the biosynthesis of pyrimidine nucleotides (cytosine, thymine, uracil), or they mimic these nucleotides to the extent that they interfere with vital cellular activities such as synthesis and nucleic acid function.


5-Fluorouracil (5-FU) requires activation via several enzymatic reactions in which it ultimately prevents the de novo synthesis of thymidylate preventing DNA synthesis. It is also converted into another form which gets inserted into RNA and interferes with mRNA translation and RNA processing. Therefore, 5-FU’s cytotoxic effect works by means of both DNA and RNA inhibitory effects. 5-FU is the mainstay agent in the treatment of colorectal cancer, as both adjuvant therapy and therapy for advanced disease. It is also effective against a variety of other solid tumors. Its half-life is only 10–15 min, and therefore it is often administered as a continuous infusion over bolus dose schedules. Eighty to 85 % of the drug is metabolized by dihydropyrimidine dehydrogenase (DPD), which of note roughly 5 % of cancer patients are deficient in this enzyme [10]. DPD-deficient patients manifest severe toxic effects of myelosuppression, nausea and vomiting, diarrhea, and neurotoxicity.


This fluoropyrimidine carbamate drug has 70–80 % oral bioavailability, and it functions as a prodrug. After extensive metabolism in the liver, it is eventually hydrolyzed by thymidine phosphorylase to 5-FU directly within the tumor [10]. Thymidine phosphorylase expression is found to be significantly higher in the tissue cells of tumors when compared to normal tissue. Capecitabine is used in the treatment of metastatic breast cancer as well as metastatic colorectal cancer. In certain regimens (as illustrated by the Table 31.1 in the following section), it replaces 5-FU therapy as an oral agent.

Table 31.1
An overview of malignancies categorized by organ system affected [9]

Site and/or type of malignancy

Treatment modalities

Chemotherapy agents used

Perioperative clinical considerations

Head and neck cancer


Primary en bloc surgical resection when possible. Radiation and chemotherapy as adjunct or primary treatment if resection not possible or contraindicated


Cisplatin alone

Cisplatin +5FU

Postradiation and surgical changes to head and neck anatomy in relation to airway management


Advanced disease (incurable)

Cisplatin or carboplatin +5FU + cetuximab (non-nasopharyngeal)

Cisplatin or carboplatin + paclitaxel or docetaxel

Neurotoxic and peripheral neuropathy occurring with taxanes and platinum agents and perioperative pain management

Nasopharynx oral cavity larynx

Ethmoid sinus Maxillary sinus

Ethmoid sinus Maxillary sinus

Salivary gland

Breast cancer

Invasive or noninvasive

Surgical treatment ranging from lumpectomy to radical mastectomy

AC (doxorubicin/Adriamycin + cyclophosphamide) + paclitaxel weekly or biweekly

Doxorubicin- and daunorubicin-associated cardiomyopathy; a preoperative assessment of cardiac function is prudent

Ductal or lobular

Radiation and chemotherapy as adjunct therapy depending on staging

TC (docetaxel + cyclophosphamide)


Phyllodes (soft tissue sarcoma)

Hematologic malignancies

Acute lymphoblastic leukemia (ALL)

Leukemias typically are treated by chemotherapy alone classified as regimens (induction, maintenance, etc.)

ALL induction therapy

TKI (tyrosine kinase inhibitor) + hyper-CVAD (imatinib or dasatinib + cyclophosphamide, vincristine, doxorubicin/adriamycin, and dexamethasone)

Consider long-term consequences of induction chemotherapy agents when caring for surgical patients – i.e., cardiomyopathy

Acute myeloid leukemia (AML)

Lymphomas often require tissue diagnosis (this can be a surgical procedure) and then are treated with chemotherapy +/− radiation therapy

Maintenance therapy

Methotrexate, 6mercaptopurine

Pediatric patients requiring anesthesia for maintenance therapy (often intrathecal chemotherapy) may have increased requirements for agents primarily cleared or metabolized in the liver due to induction of the P450 enzyme system

Chronic myelogenous leukemia (CML)

AML induction therapy

ATRA (all trans retinoic acid) + daunorubicin + cytarabine

In patients with the diagnosis of lymphoma, it is imperative to know the details of patients’ disease process, for these patients can present with sizeable mediastinal masses which can cause hemodynamic compromise and airway compression that is positional in nature. Induction of general anesthesia in these patients can result in devastating outcomes if appropriate preoperative risk assessment is not performed

Hodgkin’s lymphoma

CML treatment

TKI (imatinib)

Non-Hodgkin’s lymphoma

Hodgkin’s lymphoma

ABVD (adriamycin + bleomycin + vinblastine + dexamethasone)

Non-Hodgkin’s lymphoma

CHOP (cyclophosphamide + hydroxydaunorubicin + vincristine/“Oncovin” = trade name + prednisone)

Gastrointestinal cancers

Colon cancer

In disease that is not metastatic, surgical resection occurs for most gastrointestinal cancers. Patients receive adjuvant or neoadjuvant chemotherapy and/or radiation therapy

Colorectal cancer

FOLFOX (folinic acid/leucovorin + 5-FU + oxaliplatin) or FOLFIRI (folinic acid/leucovorin + 5-FU + irinotecan) or CapeOX (capecitabine + oxaliplatin)

Neurotoxic and peripheral neuropathy occurring with taxanes and platinum agents and perioperative pain management

Rectal cancer

Gastric cancer

Paclitaxel + carboplatin or cisplatin + 5FU or capecitabine

Many of these patients may have undergone chemotherapy and radiation treatment prior to oncologic surgery

Gastric cancer

Esophageal cancer

Paclitaxel + carboplatin or cisplatin +5FU or capecitabine

Esophageal cancer

Lung cancers

Non-small cell lung cancers (NSCLC)

In appropriate candidates, surgical resection in combination with radiation therapy a typical treatment of NSCLC. Neoadjuvant and adjuvant chemotherapies are also used, according to staging


Cisplatin + gemcitabine or in combination with another agent of the following: etoposide, paclitaxel, docetaxel, vinorelbine

Paraneoplastic syndromes can occur with small cell lung cancers including but not limited to Eaton-Lambert syndrome, carcinoid syndrome, syndrome of inappropriate antidiuretic hormone production, superior vena cava syndrome, and/or mediastinal lymphadenopathy that can cause similar hemodynamic or respiratory changes to mediastinal masses found with lymphoma [6]

Small cell lung cancers (SCLC)


Cisplatin + etoposide or cisplatin + irinotecan

Genitourinary cancers

Prostate cancer

Depending on staging, surgical resection of primary tumor +/− with radiation chemotherapy depending on cancer type and staging

Prostate cancer

 Antiandrogen therapy + paclitaxel or docetaxel

Considerations are to be taken for patients exposed to agents that cause pulmonary toxicity such as bleomycin, where administration of high inspired oxygen fraction can worsen pulmonary disease and function [5]

Testicular cancer

Testicular cancer

BEP (bleomycin + etoposide + cisplatin) or VIP (etoposide + ifosfamide + cisplatin)

Neurotoxicity and peripheral neuropathy occurring with taxanes and platinum agents and perioperative pain management

Ovarian cancer

Ovarian cancer

Paclitaxel + carboplatin or docetaxel + carboplatin

Uterine cancer

Uterine cancer

Cisplatin + doxorubicin + paclitaxel

Cervical cancer

Cervical cancer

Cisplatin/carboplatin + paclitaxel or cisplatin + topotecan

Renal cancer

Renal cancer

 Clinical trial recommended or temsirolimus

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Sep 18, 2016 | Posted by in ANESTHESIA | Comments Off on Chemotherapeutic Agents
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