Several standardized toxicity grading scales are available to assess toxicity

associated with chemotherapy. However, the National Cancer Institute Common

Toxicity Criteria for Adverse Events is the most commonly used.

31,58 Toxic effects of

systemic therapy will be further discussed in Chapter 94, Adverse Effects of

Chemotherapy and Targeted Agents.

Because toxicities associated with systemic therapy are potentially severe, it is

important to evaluate the risks and benefits. The benefits of a treatment regimen

should outweigh the negative effects it has on the physical, mental, and social wellbeing of the patient. To monitor a patient’s quality of life, several comprehensive

assessment tools have been developed.

59

In addition, other clinical benefits (e.g.,

reduced pain, decreased use of analgesics, weight gain, improved performance

status) have been recognized by the US Food and Drug Administration as acceptable

criteria for measuring quality of life. These criteria are also considered when

evaluating new agents for approval.

G.K. should continue to receive the same therapy as long as her tumor is

responding and she does not experience intolerable or life-threatening treatmentrelated toxicities. For some cancers, continued therapy after a certain number of

cycles is not associated with further benefit because toxicity becomes an overriding

issue.

Tumor Markers

Tumor markers are substances found in tumor tissue or released from tumor into the

blood or other body fluids (e.g., urine).

34 However, not all cancers have relevant

tumor markers. The ideal tumor marker should be produced and released primarily

by cancer cells (or by other tissues in response to tumor) at levels proportional to the

tumor mass. Surgical removal of the tumor, radiation therapy, or therapeutic response

to systemic therapy should result in a reduction in the level of the marker. In addition,

the ideal tumor marker should be measurable at very low levels, allowing for

detection of tumor at lower volumes than conventional diagnostic imaging permits.

60

Tumor markers may therefore be used to monitor patients in remission and to detect

recurrent disease. Unfortunately, few tumor markers fulfill these criteria sufficiently

to be clinically useful as the sole screening or diagnostic test. Most tumor markers

lack specificity for tumor and may be elevated due to other causes. Table 93-15 lists

some of the common tumor markers used in practice.

p. 1962

p. 1963

Table 93-11

Other Targeted and Miscellaneous Agents

Class

Agent

(Trade

Name) Mechanism of Action

Route of

Administration Notable Toxicities

HDAC inhibitors Inhibits HDAC resulting in

accumulation of acetyl

groups, cell cycle arrest,

Nausea, vomiting; fatigue;

myelosuppression; fever;

peripheral edema; EKG

and apoptosis changes

Belinostat

(Beleodaq)

IV

Panobinostat

(Farydak)

PO Also: diarrhea; electrolyte

abnormalities; increased

creatinine; fever

Romidepsin

(Istodax)

IV Also: anorexia, dysgeusia;

pruritis, dermatitis; infection

Vorinostat

(Zolinza)

PO Also: diarrhea, anorexia, weight

loss, dysgeusia; proteinuria;

pruritis, alopecia

Proteasome inhibitor Inhibits proteasomes,

enzymes that regulate

protein homeostasis within

cells

Nausea, diarrhea, constipation;

peripheral neuropathy;

headache, fatigue, fever;

myelosuppression; herpes

zoster reactivation

Bortezomib

(Velcade)

IV and SC

Carfilzomib

(Kyprolis)

IV Also: edema, dyspnea; cardiac

toxicity; hypersensitivity

reactions

mTOR inhibitors Inhibits mTOR kinase,

VEGFR

Fatigue, nausea, anorexia;

dermatologic toxicity;

hyperlipidemia, hyperglycemia,

electrolyte abnormalities;

stomatitis; myelosuppression,

infection; pneumonitis

Everolimus

(Afinitor)

PO

Temsirolimus

(Torisel)

IV Also: gastrointestinal

perforation

Immunomodulating Agents Immunomodulatory and

angiogenic effects

Fatigue; teratogenic potential;

thromboembolism; arthralgias

Lenalidomide

(Revlimid)

Inhibits secretion of

proinflammatory

cytokines; induces cell

cycle arrest and apoptosis

in myeloma cells

PO Also: thrombocytopenia,

neutropenia, pruritus; rash;

diarrhea, pyrexia; dizziness

Pomalidomide

(Pomalyst)

Induces cell cycle arrest

and apoptosis in myeloma

cells; enhances T-celland NK-cell-mediated

cytotoxicity

PO Also: rash; peripheral edema;

constipation, nausea, diarrhea;

myelosuppression; muscle

spasms; dyspnea, renal

dysfunction

Thalidomide

(Thalomid)

PO Also: bradycardia; dizziness;

somnolence; neutropenia,

peripheral neuropathy

BRAF inhibitor Blocks cellular

proliferation of mutated

BRAF

Dermatologic toxicity; nausea,

diarrhea; edema; headache;

hepatic dysfunction; fever,

chills; secondary skin cancer

Dabrafenib

(Tafinlar)

PO Also: electrolyte abnormalities,

hyperglycemia;

myelosuppression

Vemurafenib

(Zelboraf)

PO Also: fatigue; arthralgias;

anorexia

Other

CDK inhibitor Palbociclib

(Ibrance)

Reversibly inhibits CDK PO Myelosuppression, infection,

fatigue; nausea, vomiting,

diarrhea; stomatitis, alopecia;

thrombosis

Hedgehog

inhibitor

Vismodegib

(Erivedge)

Selectively binds and

inhibits the

transmembrane protein in

Hedgehog signal

transduction pathway;

inhibits unrestricted

proliferation of skin basal

cells

PO Fatigue; alopecia; anorexia,

nausea, diarrhea, constipation;

muscle spasms; arthralgias

p. 1963

p. 1964

IL-2 receptor

inhibitor

Denileukin

diftitox (Ontak)

Fusion protein containing

diphtheria toxin and IL-2

segments; directs cytocidal

action of diphtheria toxin

to IL-2 receptorexpressing cells leading to

inhibition of protein

synthesis, cell death

IV Hypersensitivity reaction;

nausea, vomiting, diarrhea;

fatigue; rash; fever, rigors,

capillary leak syndrome;

peripheral edema

PARP inhibitor Olaparib

(Lynparza)

Inhibits the PARP

enzyme, inducing synthetic

lethiality in BRCA

deficient cells

PO Nausea, vomiting, fatigue;

myelosuppression;

musculoskeletal pain;

thrombosis; upper respiratory

infection; interstitial lung

disease; secondary malignancy

VEGF inhibitor Ziv-Aflibercept

(Zaltrap)

Fusion protein comprised

of VEGF receptor binding

domains, acting as a decoy

receptor for VEGF,

inhibiting angiogenesis

IV Fatigue, diarrhea, stomatitis;

myelosuppression; hypertension,

proteinuria; bleeding, impaired

wound healing; thrombosis;

gastrointestinal perforation

IV, intravenous; PO, oral; SC, subcutaneous; HDAC, histone deacetylase; mTOR, mammalian target of

rapamycin; VEGF, vascular endothelial growth factor; NK, natural killer; BRAF, proto-oncogene b-Raf; CDK,

cyclin-dependent kinase; IL-2, interleukin 2; PARP, poly ADP-ribose polymerase.

Table 93-12

Endocrine Therapies

Class Agent Mechanism of Action

Route of

Administration Notable Toxicities

Androgens Synthetic derivative of

testosterone; suppresses

GnRH, LH, FSH by a

negative feedback system

Deepening voice,

alopecia, hirsutism, facial

or truncal acne, fluid

retention, menstrual

irregularities, cholestatic

jaundice

Fluoxymesterone

(Androxy)

PO

Antiandrogens Hot flashes; breast

tenderness; hepatic

dysfunction, diarrhea;

fatigue; edema;

hypertension; arthralgia

Abiraterone (Zytiga) Inhibits formation of

testosterone precursors

(DHEA,

androstenedione);

selectively inhibits CYP17

PO Also:

hypertriglyceridemia;

electrolyte abnormalities

Bicalutamide

(Casodex)

Nonsteroidal androgen

receptor inhibitor

PO Also: gynecomastia; back

pain; constipation;

infection

Enzalutamide

(Xtandi)

Inhibits androgen receptor

translocation, leading to

cellular apoptosis

PO Also: constipation;

neutropenia

Flutamide (Eulexin) Inhibits androgen uptake

and binding in tissue;

nonsteroidal

PO Also: galactorrhea;

decreased libido;

impotence; rectal

hemorrhage

Nilutamide

(Nilandron)

Nonsteroidal androgen

receptor inhibitor

PO Also: insomnia; headache;

constipation; flu-like

syndrome; decreased

libido

Antiestrogens Competitive binding of

estrogen receptors

produces downregulation

of estrogen receptors

Liver enzyme elevation;

hot flashes; myalgia,

arthralgia; nausea,

vomiting;

thromboembolism

Fulvestrant

(Faslodex)

IM

Tamoxifen

(Nolvadex,

Soltamox)

PO Also: nausea, vomiting;

edema, endometrial

cancer

p. 1964

p. 1965

Aromatase inhibitors Inhibits aromatase

preventing androgen

conversion to estrogen

Hot flashes; nausea;

fatigue, insomnia;

increased risk of bone

fractures, arthralgia

Anastrozole

(Arimidex)

PO

Exemestane

(Aromasin)

PO

Letrozole (Femara) PO Also:

hypercholesterolemia

Estrogens Suppresses androgen

synthesis, as well as

secretions of

gonadotropins, FSH and

LH via negative feedback

system

Nausea, vomiting, fluid

retention, hot flashes,

anorexia,

thromboembolism, hepatic

dysfunction

Ethinyl estradiol

(Estradiol)

PO

Conjugated estrogens

(Premarin)

PO Also: headache

GnRH analogs (LHRH agonists) Downregulates GnRH

receptor on the pituitary

gland, decreasing

secretion of FSH and LH

Amenorrhea, hot flashes,

sexual dysfunction;

nausea, edema; tumor

flare; injection-site

reaction; osteoporosis

Goserelin (Zoladex) SC Also: headache, emotional

lability, cystitis, vaginitis

Histrelin (Vantas) SC

Leuprolide (Lupron,

Eligard)

IM, SC Also: vaginitis

Triptorelin (Trelstar) IM

GnRH antagonists Binds to GHRH receptors

on the pituitary gland,

blocking secretion of FSH

and LH

Hot flashes; hepatic

toxicity; injection-site

reaction

Degarelix (Firmagon) SC

Progestins Promotes differentiation

and maintenance of

endometrial tissue

Weight gain, edema; hot

flashes, vaginal bleeding;

thrombosis

Medroxyprogesterone

(Provera)

PO Also: emotional lability

Megestrol acetate

(Megace)

Also: may suppress LH

and enhance estrogen

metabolism

PO

CYP, cytochrome; DHEA, dehydroepianderosterone; FSH, follicle-stimulating hormone; GnRH, gonadotropinreleasing hormone; IM, intramuscular; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone;

PO, oral; SC, subcutaneous.

Table 93-13

Regional or Local Routes of Chemotherapy Administration

Route of Administration Cancer Managed With Alternative Route

Intrathecal or intraventricular Leukemia, lymphoma

Intravesicular Bladder

Intraperitoneal Ovarian

Intrapleural Malignant pleural effusions

Intra-arterial Melanoma, sarcoma

Hepatic artery Liver metastases

Chemoembolization (intra-arterial or intravenous) Colon, rectal, carcinoid, liver metastases

p. 1965

p. 1966

Table 93-14

Response Criteria for Evaluating Effects of Chemotherapy of Target Lesion

(RECIST version 1.1)

Complete Response

Disappearance of all target lesions. Any pathologic lymph nodes (whether target or nontarget) must have

reduction in short axis to <10 mm

Partial Response

At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum

diameters

Progressive Disease

At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study

(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the

sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is

also considered progression

Stable Disease

Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive

disease, taking as reference the smallest sum diameters while on study

HANDLING OF CYTOTOXIC DRUGS

Impact on the Pharmacy

CASE 93-11

QUESTION 1: The administrator of an outpatient care clinic recently announced that two medical oncologists

will be joining the staff. Previously, patients were referred to outside oncologists and no cytotoxic drugs were

prepared or administered at this clinic. What implications will the addition of these physicians have on the

pharmacy department?

Addition of cancer treatment to institutional services will affect three areas of the

pharmacy department: budget, policies and procedures for safe drug handling and

disposal, and the staff education program. The pharmacy department will need to

increase its budget to accommodate additional personnel and purchase new

equipment, supplies, supportive care medicines, and chemotherapy agents. To

estimate the projected budget increase, pharmacy leadership should meet with the

oncologists to discuss anticipated volume of chemotherapy orders including systemic

therapy and supportive care medicines (e.g., antiemetic therapy, analgesics, growth

factors) likely to be prescribed. All new systemic therapy agents and supportive care

medicines should be added to the institutional formulary. In addition, projected use of

investigational agents, clinical pharmacy services needed, and any plans to develop

an ambulatory infusion program should be determined. Institutional policies and

procedures to ensure safe handling of chemotherapy agents must be created. These

should be conveyed to all personnel affected through a staff education program

because safe handling of chemotherapy agents is critical in decreasing the risk of

medication errors and injuries.

Medication Errors

Several chemotherapy-related medication errors resulting in death or permanent

disability have been highly publicized. These devastating events have brought

significant attention to the entire drug use process in oncology and have identified

several factors that appear to contribute to the risk. Use of abbreviations, verbal

orders, multiple-day regimens, incorrect references and protocols, and illegible

medication orders has contributed to medication errors. Increasing use of

computerized prescriber order entry and standardized preprinted orders have helped

eliminate many errors. Several groups have responded to the problem by issuing

policy recommendations to minimize such errors.

61–66

Table 93-15

Clinically Useful Tumor Markers

Tumor Markers

Cancers Commonly Associated With Increased

Markers

CA-19-9 Pancreatic

CA-15-3, CA-27-29 Breast

α-Fetoprotein (AFP) Liver, testicular, ovarian

CA-125 Ovarian

Carcinoembryonic antigen (CEA) Colon, lung

Human chorionic gonadotropin (hCG) Trophoblastic, testicular

β2

-Microglobulin Multiple myeloma

Prostate-specific antigen (PSA) Prostate

Risks

CASE 93-11, QUESTION 2: What are the potential risks of handling cytotoxic drugs? What resources are

available to assist the pharmacy director and the pharmacy staff in the development of policies and procedures?

Many of these agents are carcinogenic, teratogenic, or mutagenic in animal models

and in humans at therapeutic doses.

66 Danger to healthcare personnel handling such

agents results from inherent toxicities of the agents and the extent (i.e., amount and

length of time) to which the workers are exposed during drug handling.

66 Various

studies have attempted to assess the effect of occupational exposure to hazardous

drugs on healthcare workers. These studies measured urine mutagenicity,

chromosomal damage, blood concentrations, and the level of contamination that

occurs in the work areas used for drug preparation and administration.

66–68 These

studies indicate urine mutagenicity and chromosomal damage in workers may be a

direct result of cytotoxic exposure. Other reports have correlated reproductive risks

(e.g., infertility or increased risk of miscarriage) and birth defects in pregnant

workers handling cytotoxic drugs.

67,69 Findings from these reports together with the

toxicities observed in patients receiving therapeutic doses led the American Society

of Health-System Pharmacists to conclude that healthcare workers exposed to

hazardous drugs may be absorbing or inhaling these drugs and may be at risk for

adverse outcomes.

66

In response to concerns regarding occupational exposure to hazardous drugs,

several groups have published guidelines for the safe handling of these agents in the

workplace (i.e., storage, preparation, administration, and disposal).

66,68 These

guidelines will be helpful to the pharmacy department when developing policies and

procedures.

Policies and Procedures

CASE 93-11, QUESTION 3: What specific policies and procedures are necessary? What other departments

should be consulted during the development and implementation of the handling guidelines?

p. 1966

p. 1967

Policies must be developed that address the entire scope of potential occupational

exposures within the workplace. These policies should include (a) a worker’s “right

to know” regarding potential hazards; (b) education and training for workers

involved with hazardous drug handling; (c) quality assurance to monitor adherence to

safe handling procedures; and (d) guidelines for workers who are attempting to

conceive a child, become pregnant, or are nursing.

Specific procedures that outline appropriate handling of hazardous agents during

all aspects of institutional storage, use, and disposal should be developed. These

procedures should address appropriate (a) storage in the receiving and storeroom

areas, (b) preparation and administration of parenteral formulations, (c) manipulation

and dispensing of oral and topical formulations, (d) cleanup of spills, (e)

management of acute exposures, and (f) disposal of hazardous agents and supplies

used to prepare and dispense chemotherapy. If the oncology program includes

ambulatory infusion or home-care components, procedures should also be developed

for appropriate handling and disposal of these products in the home. Handling of oral

chemotherapy and biotherapy must also be specifically addressed. Policies should

include processes for cleaning of tools and nondisposable items used to dispense

oral cytotoxic agents to minimize contamination with other drugs.

70

Other departments may be affected by these guidelines including medical staff,

nursing, environmental services staff (in the cleanup of spills and equipment),

maintenance (upkeep of equipment), and the receiving area (where cytotoxic drugs

may be received from suppliers). The institutional safety office and legal staff also

should be consulted to help devise the policies and procedures.

Necessary Equipment and Supplies

CASE 93-11, QUESTION 4: What equipment and supplies are necessary for handling hazardous drugs?

Proper equipment and supplies can minimize occupational exposure in the

healthcare workplace by protecting both the worker and the environment. All

handling guidelines recommend that manipulations (e.g., reconstitution, admixing) of

hazardous drugs be done in a class II biologic safety cabinet (BSC) to provide

maximal protection for the worker and the work environment. Workers also should

wear gloves (one or two pairs), protective boot covers, hair cover, mask, and a

disposable gown of lint-free, low-permeability fabric with long sleeves, knit cuffs,

and back closure. In addition, only syringes and intravenous sets with threaded Luer

lock connections should be used. Final products (e.g., syringes, intravenous bags or

bottles) should be placed in sealable containers such as zipper-closure plastic bags

to prevent accidental spillage and clearly labeled as a hazardous drug. The United

States Pharmacopeia dictates guidelines for compounding sterile products including

appropriate facilities for preparation.

71

Disposal of hazardous waste requires specific receptacles, which should be

placed in all areas where workers handle these drugs. Disposal of these agents

should follow institutional, state, and local regulations. Materials for the cleanup of

spills (e.g., absorbent material, plastic bags or containers, protective garments) also

must be available in all areas where hazardous drugs are stored, prepared, or

administered.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

DeVita VT, Jr et al, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 9th ed.

Philadelphia, PA: Lippincott Williams & Wilkins; 2011.

Siegel RL et al. Cancer statistics, 2015. CA Cancer J Clin. 2015:65(1):5–29.

Key Websites

American Cancer Society. http://www.cancer.org.

American Society of Health-Systems Pharmacists. The ASHP Discussion Guide on USP Chapter for

Compounding Sterile Preparations. Summary of Revisions to USP Chapter. https://www.ashp.org/-

/media/assets/policy-guidelines/docs/guidelines-compounding-sterile-preparations.ashx. (78)

American Society of Health-Systems Pharmacist. ASHP Guidelines on Handling Hazardous Drugs.

https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines-handling-hazardousdrugs.ashx.

National Cancer Institute. http://www.cancer.gov.

National Cancer Institute. Surveillance, Epidemiology and End Results. http://seer.cancer.gov.

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