Colon A rKtum

94,030 UlBnnc caipu* «,160 Mon Hodgkin tymphonin M,990 Mnlnnonin tfo» *Kkl £9,640 Thyroid Î7.2ÛÛ Ovary 21JH0 Kitfnty S r*nil p*fm ÎÎ.3M Lauk#mia 1»,t» Ahl ailu-s ÎU.MlO


Luns A bronc hui Prestad» 27, ÏM Colon A r*cHim 25.2M r—n im ia,MO

liw S ¡rítr»hípjil¡i bur- (liîîi lï.0» Enoph.^qirn 11,«0 Urinjiry hL"ictrif>r io. iw

Nan-Hodçkin lyrrpha-mn 3,830


Lung & Jjionehui 70.490 Biflíít 40.1ÍH CoJsn t rectum 3!S.6B0 Pncnn 17,210 Ov&ty

Non . ladgki n tyjnphomn 9,670 LH^rin* ÏÇipus TJW

Non . ladgki n tyjnphomn 9,670 LH^rin* ÏÇipus TJW

Livcr & inHnhcpnlic 6.070 AU xHas nun

Jl bils duel

'Excèdes basa) and sqiramous. oe* skin canœ-rs in silti carcinoma except urinary Wadder,

FIGURE 88-1. Cancer incidences (left) and deaths (right) in the United States for males and females estimated for 2009. (Reprinted with permission from American Cancer Society. Cancer facts and figures—2009. Atlanta: American Cancer Society; 2009.)

Cancer Prevention

Because most cancers are not curable in advanced stages, cancer prevention is an important avenue of exploration. Both lifestyle modifications and chemoprevention agents ultimately may reduce the risk of developing cancer.


Tobacco smoking increases the risk of developing not only lung cancer but also many other types of cancer, including cancer of the bladder, mouth, pharynx, larynx, and esophagus. While the immediate benefit of smoking cessation is minimal for lung cancer, documented benefit has been observed 6 or more years after stopping.

Sun Exposure

Ultraviolet light and increased skin exposure may increase the risk of skin malignancies, especially in individuals who are fair-skinned. Practitioners can counsel patients to minimize skin exposure to the sun and to use strong sunscreens on exposed areas.


The exact cause of cancer remains unknown and probably is very diverse given the vast array of diseases called cancer. It is thought that cancer develops from a single cell in which the normal mechanisms for control of growth and proliferation are altered. Initiation occurs when a carcinogenic substance encounters a normal cell to produce genetic damage, or a mutated cell. Environmental or other factors that favor the growth of the mutated cell refer to promotion. Transformation occurs when the mutated cell becomes malignant, and progression occurs when cell proliferation takes over and the tumor spreads or develops metastases. Depending upon the type of cancer, many years may go by between the carcinogenic phases and the development of a clinically detectable tumor.

Carcinogenic agents include chemicals in the environment, such as aniline and benzene, which are associated with the development of bladder cancer and leukemia, respectively. Environmental factors, such as excessive sun exposure, also may result in cancer. Viruses, including the human papilloma virus and hepatitis B, may be associated with the development of cancer. Some of the chemotherapy agents cause secondary cancers after therapy has been completed. Numerous factors may contribute to the development of cancer. In addition to the carcinogenic agents mentioned, factors such as the patient's age, gender, diet, and chronic irritation or inflammation may be considered to be promoters of carcinogenesis.

Cancer Genetics

Because the human genome has been sequenced, and with the great improvements in genetic technology, there is an ever-increasing body of knowledge regarding the genetic changes of cancer. Currently, there are two major classes of genes involved in cancer: oncogenes and tumor-suppressor genes. Protooncogenes are normal genes that, through some genetic alteration caused by carcinogens, change into oncogenes. Protooncogenes are present in all normal cells and regulate cell function and replication. Genetic damage of the protooncogene may occur through point mutation, chromosomal rearrangement, or an increase in gene function, resulting in the oncogene. The oncogene produces abnormal or excessive gene product that disrupts normal cell growth and proliferation. This may cause the cell to have a distinct growth advantage, increasing its likelihood of becoming cancerous. Table 88-1 provides examples of oncogenes.

Tumor-suppressor genes inhibit inappropriate cellular growth and proliferation by gene loss or mutation. This results in loss of control over normal cell growth. The p53 gene is one of the most common tumor-suppressor genes, and mutations of p53 may occur in up to 50% of all malignancies. This gene stops the cell cycle to enable "repairs" of the cell. If p53 is inactivated, then the cell allows the mutations to occur. While mutations of the p53 gene are found in many tumors, such as breast, colon, and lung cancer, it is also associated with drug resistance of cancer cells. DNA-re-pair genes fix errors in DNA that occur because of environmental factors or errors in replication and sometimes are referred to as tumor-suppressor genes. Mutations in DNA-repair genes have been reported in hereditary nonpolyposis colon cancer and in some breast cancer syndromes.

'©' Numerous cellular changes occur in the genetic material of the cancer cell so that programmed cell death, or apoptosis, does not occur. Proliferation of cancer cells goes unregulated. If mutations persist and cells aren't repaired or suppressed, cancer may develop. Apoptosis, or programmed cell death, may prevent the mutated cell from becoming cancerous. Loss of p53 and overexpression of bcl-2 are two examples of changes within the cell that occur to result in enhanced cell survival. Cellular senescence refers to cell death that occurs after a preset number of cell doublings. Telomeres are DNA segments at the ends of chromosomes that shorten with each replication to the point where senescence is triggered.

Table 88-1 Examples of Oncogenes and Tumor-Suppressor Genes

FUrttlifth fts iDiiated Human Canitr angenH

fa' grortih iatiats ofihtlt Hcepiofi iett ur fwi-er cod« for eck H€R-2/wuor Codesfor a giowth Factoi leceptor EHff-S?

RET Codesfor a giowth fac Id< receptor

Gcnei fcrcyjoptamic rctoyi ifun'muftirory fignoHng petbnVYf

XfMi Codes for guanine nucleotide proleins v<»tf» GTfase activity


Genes for rrflrocn'ptrw? foclwj £fipf activate growth'prorrfclirggenei f-MHC


Generft/tyiapfoimic fcr.«is.i

J?C1-ABL Codes a iwnreotptor lynMinc kinase fienei far orJM/ mofeiiiiei

JVlO ClSilM C|V a qjllSliirt that ISltSikS /ifr. )(jli imi

JJCMof PWO.i Codes tacyclinDI. 3 cell cycle clods stimuli MIMJ ftuteln antagonist oipSJUimoi suppress« protein t>i(\is| com ■-. '."|"i !irsc:i?* CW inym,i ftnftist, salivary gland, prostate, bladder and ovarkm cancers Thyioid cancer

Lung, oi'ariar^ oolorv pancreatic binding cancers NemobiSitoma, acute l> 'iiki 'nv.i

Lei*iinii anO Iwessr, eckXLiliStrlc, -iftd Kiriq careers Ni-uioblastorria. sinjlkoll king cancer, jnd qlioblasturna

Clutiiit myi.'tigciiijus kut^mk)

Indolent El fill JyiTCiphCHYLAS liiuust. head, and iwdt cancers

Tumor Suppressor Gçhîs

ûenci foi ¿MMfi'rif m rhe cyiefilmm

^PC 54CTJ iiqrtdlirxj pathway

HF-1 tjod« for a protein lhat inhixlï Ihe iliriKil»1ary ftn protein

Nf-7 CotÎiS ter » pfcnein irai inhiffli ihi1 i Sdi i'h^'j[h■',:■.

L-inti for proriinf in rue nuïteuu

AiHJ cod« (t" pw pwflfa • cnJirnJepmdetu iuiust»ih(ji(yi fiSJ Codei for the pflff pialein, j ™s1er txjhif et lhe oeil cycle pSi

Cad« for the pSl pcrtein. whkh car. hal; œil division and iftduWipoplöSft

Cotii jnd giiitrk eafiffli

Npiüo'ihfonu, leukemia, and phecKhomocytoina hVflif<iP»iH,»pendyiTtorTii, .:rd vchiY-irunxiis

IrtYOlvCd ni ¿widr ijrttic yi tJrKCi > PAli'Kjblastonia. tHfficsaramna, bladdi'Mnull tell luflii-OOtliK. ¿nd fcfWSTiiïVSri Involved in a wide rangs of cancers

Centi far^rorei'n uhese ittlaht tatetiün injixieaf


MSrtlMiHI, PMif. fiWS?r AfiHS

f^îÀ i^ijir. Vjnsr.'¡¡iliynjl PPQ<jlolH.J[*l

RNA repair fa.tJuUKJT Of p*0Htl1 SUbilKy DNA mismaicîi repair enrymei fttwM and ovdrijn cintaJ Bies-bt cancel

Rerakdl tantfi

NeiedHary rcnpdypcisji coloeecfal cancer

Fnirn ISPhij I r. r.ilhrit RL Yii'ii, l'I .il. (ji^O Ptuin-ii;<illv.Tjp^ A Pjllïi|)hyu<>lixjii Aj Tïo-lc h, M NrwYtifli: Uî(tIîw Hili JfJCy IttUc 1M ?,

Cancer genetics may be done on the tumor itself to determine if a particular drug will be effective, or if the patient will suffer toxicity. Table 88-2 presents the genetic tests currently recommended for either tumor or patient.

Principles of Tumor Growth

It takes about 109 cancer cells to be clinically detectable by palpation. Figure 88-2 demonstrates the classic Gompertzian kinetics tumor-growth cycle. From the diagram, one can see that malignant cell growth occurs many times before a mass may be palpated. The number of malignant cells may plummet drastically because of surgery or in decreasing steps by each administration of chemotherapy. One dosing round, or cycle, of chemotherapy does not eliminate all malignant cells, and therefore, repeated cycles of chemotherapy are administered to eliminate tumor-cell burden. The cell kill hypothesis states that a fixed percentage of tumor cells will be killed with each cycle of chemotherapy. According to this hypothesis, the number of tumor cells will never reach zero. There are three assumptions to this theory: all cancers are equally responsive and drug resistance and metastases do not occur.

Table 88-2 RECIST Criteria




Disappearance of all targeted lesions

response {CR)


At least a 30% decrease in the sum of ihe

response {PR)

longest diameter of target lésions from



At least a 20% increase in the sum of the

disease (PD)

longest diameter of target lesions from

baseline, including new lesions discovered

during treatment


Neither sufficient shrinkage to qualify for

disease (SD)

PR nor sufficient increase to qualify for PD


A metastasis is a growth of the same cancer found at some distance from the primary tumor site.3 The metastasis may be large, or it may be just a few cells that may be detected through polymerase chain reaction (PCR); however, the presence of metastasis at staging usually is associated with a poorer prognosis than the patient with no known metastatic disease. As the technology to find malignant cells evolves, the dilemma exists on how to treat patients based on current guidelines that were not based on cellular detection technology.

Cancers spread usually by two pathways: hematogenous (through the bloodstream) or through the lymphatics (drainage through adjacent lymph nodes). The malignant cells that split from the primary tumor find a suitable environment for growth. It is believed that malignant cells secrete mediators that stimulate the formation of blood vessels for growth and oxygen, the process of angiogenesis.

DiMflM Symplon^ ScccnMi irt«piKi(aiirg

O-agnu&s. pgHlM jlirrlsyinploiiish

Cimcjil/ UrKjCKWIOlWfr twnof

FIGURE 88-2. The Gompertzian growth curve demonstrating symptoms and treatments versus tumor volume. (From Buick RN. Cellular basis of chemotherapy. In: Dorr RT, Von Hoff DD, eds. Cancer Chemotherapy Handbook. 2nd ed. New York: Elsevier; 1994: 3-14.)

The usual metastatic sites for solid tumors are the brain, the bone, the lung, and the liver. It is important to realize and educate patients that breast cancer cells may metastasize to the brain, so the individual does not have brain and breast cancer but breast cancer with metastases to the brain.

pathophysiology Tumor Characteristics

Tumors are either benign or malignant.4 Benign tumors often are encapsulated, localized, and indolent; they seldom metastasize; and they recur rarely once removed. Histologically, the cells resemble the cells from which they developed. Malignant tumors are invasive and spread to other locations, even if the primary tumor is removed. The cells no longer perform their usual functions, and their cellular architecture changes. This loss of structure and function is called anaplasia. Despite improvements in screening procedures, many patients have metastatic disease at the time of diagnosis. Usually, once distant metastases have occurred, the cancer is deemed to be incurable.

O-agnu&s. pgHlM jlirrlsyinploiiish

FIGURE 88-2. The Gompertzian growth curve demonstrating symptoms and treatments versus tumor volume. (From Buick RN. Cellular basis of chemotherapy. In: Dorr RT, Von Hoff DD, eds. Cancer Chemotherapy Handbook. 2nd ed. New York: Elsevier; 1994: 3-14.)

Tumor Origin

Tumors may arise from epithelial, connective (i.e., muscle, bone, and cartilage), lymphoid, or nerve tissue. The suffix -oma is added to the name of the cell type if the tumor cells are benign. A lipoma is a benign growth that resembles fat tissue.

Precancerous cells have cellular changes that are abnormal but not yet malignant and may be described as hyperplastic or dysplastic. Hyperplasia occurs when a stimulus is introduced and reverses when the stimulus is removed. Dysplasia is an abnormal change in the size, shape, or organization of cells or tissues.

Malignant cells are divided into categories based on the cells of origin. Carcinomas arise from epithelial cells, whereas sarcomas arise from muscle or connective tissue. Adenocarcinomas arise from glandular tissue. Carcinoma in situ refers to cells limited to epithelial origin that have not yet invaded the basement membrane. Malignancies of the bone marrow or lymphoid tissue, such as leukemias or lymphomas, are named differently.

diagnosis of cancer

Cancer can present as a number of different signs and symptoms as well as pain and loss of appetite. Unfortunately, many people fear a diagnosis of cancer, and may not seek medical attention at the first warning signs, when the disease is at its most treatable stage. After the initial visit with the physician, a variety of tests will be performed, which are somewhat dependent on the initial differential diagnosis. Appropriate blood work, radiologic scans, and tissue sample are necessary. The sample of tissue may be obtained by a biopsy, fine-needle aspiration, or exfoliative cytology. No treatment of cancer should be initiated without a pathologic diagnosis of cancer. During the pathologic workup, cytogenetics may be done. Depending on the type of cancer, the cytogenetics can provide the additional information on prognosis of the malignancy, and whether certain therapies may be appropriate.

Once the pathology of cancer is established, then the staging of the disease is done before treatment is initiated. Each cancer disease chapter will discuss the specifics of staging of the disease. Cancer staging will be done according to the primary tumor size, extent of lymph node involvement, and the presence, or absence of metastases, or sometimes referred to the tumor, nodes, metastases (TNM) system (Table 88-3). The stage of the disease is a compilation of the primary tumor size, the nodal involvement, and metastases, and is usually referred to as stages I through IV. Not all cancers can be staged according to this system, but many of the solid tumors are classified this way.

Why are tumors staged? First, the stage of the disease is an important part of determining prognosis of the cancer. Second, staging of the cancers allows comparison of patient groups when examining data from clinical trials; staging reflects the extent of disease. Third, the clinician uses it as a guide to treatment, and may use restaging after treatment to guide further treatment.

Some cancers produce substances that are detected by a blood test, that may be useful in following response to therapy or detecting a recurrence; these are referred to as tumor markers. Unfortunately, some tumor markers are nonspecific and may be elevated from nonmalignant causes. Some tumors may express a marker in some patients, and not in others. The full role of tumor markers has not been fully elucidated.

treatment Desired Outcome

While at the time of surgery the surgeon may be able to remove all macroscopic disease, microscopic cells may be present near the surgical site or may have traveled to other parts of the body. When malignant cells have traveled to other parts of the body and become established there and are able to grow in this new environment, they are called metastatic cancer cells. Thus, for chemotherapy-sensitive diseases, systemic therapies may be administered after surgery to destroy these microscopic malignant cells; this is called adjuvant therapy. The goals of adjuvant therapy are to decrease recurrence of the cancer and to prolong survival. Chemotherapy may also be given prior to surgical resection of the tumor; this is referred to as neoadjuvant therapy. Chemotherapy given prior to surgery should decrease the tumor burden to be removed (which may result in a shorter surgical procedure) and make the surgery easier to perform because the tumor has shrunk away from vital organs or vessels. Neoadjuvant chemotherapy also gives the clinician an idea of the responsiveness of the tumor to that particular chemotherapy.

Chemotherapy may be given to cure cancers that are curable, or it may be given to help control the symptoms of an incurable cancer, which is referred to as palliative therapy.

Table 88-3 TNM Staging Classification System for Colorectal Cancer

Primary lumur (7J

I Primary tumor cannot be assessed T tto evidence of pittraiy luirwr

I t .irr.ittifri rn jit« inn^epiitwL'iI qt ¡nv^jtori nf l.nrtnij pr(>p<ia T Tumor invades Kjbmucosa I Tumor Invades mutcularis propria

T Tl«nc* iiv.'jif?hmiir|h I In* nnu^culiikmui rilr> llx% vub\rio\.* 01 ink] riimjuvi'iirv.i >■:I fini oik c* |in¥iv1<3l Cr'.MJTV

T, Tumor ixi forafles the viit-eial peritoneum, andl/bi directly invades other organs or structures Huyibnal lymph nodei IN) N lyniph Aides ianrWI be jsit'sied

N Sio regional lymph- node metastases

N. MetasTail; in(ine K>ihrw per^iilk; (w peristal lynrfih rnjde; N, Metastasis in four or more pericolic or perteclal lymph nodes Din ¿m meiastasls iM)

W raTWflCS Of [Ir.l.inC inb^'t.i -.!->■ '.iv CMflflrt I .1 .■.■■■.^iii tto d alani metastasis rihianr metutisis

Stage_Cropping_Onkti_Modified AilltrCallitt

Siege 0



Stage 1










Stage ll A






»^r HE






Söge MA.






Sljrjc HIP






Stage BC





Si^ge iv


Any N




Horn DiPiif JT. Tjlbwl RL. VccGC, ct jl PharmaarthirJpy; A Palhonhyuolugit Aptro^h. OL-h od. Nrw Vcrk Möj(i»irHi1t ¿005 Tab)? 114-T.

Clinical Presentation and Diagnosis Cancer Chemotherapy and Treatment Signs and Symptoms

The seven warning signs of cancer are:

• Change in bowel or bladder habits

• Unusual bleeding or discharge

• Thickening or lump in breast or elsewhere

• Indigestion or difficulty in swallowing

• Obvious change in wart or mole

• Nagging cough or hoarseness

The eight warning signs of cancer in children are:

• Continued, unexplained weight loss

• Headaches with vomiting in the morning

• Increased swelling or persistent pain in bones or joints

• Lump or mass in abdomen, neck, or elsewhere

• Development of a whitish appearance in the pupil of the eye

• Recurrent fevers not caused by infections

• Excessive bruising or bleeding

• Noticeable paleness or prolonged tiredness Diagnostic Procedures

• Laboratory tests: CBC, lactate dehydrogenase (LDH), renal function, and liver function tests

• Radiologic scans: x-rays, CT scans, MRI, position-emission tomography (PET)

• Biopsy of tissue or bone marrow with pathologic evaluation

• Cytogenetics

• Tumor markers

• Staging determination of the primary tumor size, extent of lymph node involvement, and the presence or absence of metastases, or sometimes referred to the TNM

system (Table 88-2). Many tumors are staged according to the TNM system. Metastases are cancer cells that have spread to sites distant from the primary tumor site and have started to grow. The mostfrequently-occurring sites of metastasis are the brain, bone, liver, and lungs.


The responses to chemotherapy may be referred to as complete response (CR), partial response (PR), stable disease (SD), or disease progression. A cure in oncology implies that the cancer is completely gone, and the patient will have the same life expectancy as a patient without cancer. The World Health Organization response criteria were updated in 2000. The Response Evaluation Criteria in Solid Tumors (RECIST) is considered to be the standard criteria to evaluate a response to therapy (see Table 88-2). A CR refers to complete disappearance of all cancer for 1 month after treatment. A PR is defined as a 30% or greater decrease in tumor diameter along with no new disease for 1 month. The term overall objective response rate refers to the combination of PR and CR. SD occurs in a patient whose tumor size neither grows nor shrinks by the above criteria. Disease progression refers to tumor that has spread or the primary tumor that has increased in size by 20% while receiving treatment. Some cancers, such as leukemia, cannot be measured by size, so biopsy of the bone marrow provides a cellular indication of absence or presence of disease.

Cancer chemotherapy and the treatment of cancers are analogous to anti-infectives and the treatment of infections. Cancer cells may be sensitive to certain chemotherapy agents, but then with repeated exposure, the cells become resistant to treatment. The resistant cells then may grow and multiply. While tumors may be tested for chemotherapy sensitivity, this area is still developing. Today, tumor sensitivity can demonstrate tumor resistance so that needless exposure to an inadequate therapy and its toxicity can be avoided.

Tumor cells may become resistant when genetic changes occur during cell proliferation. Resistant cancer cells with the mdr-1 gene may possess a membrane-associated protein, p-glycoprotein, that facilitates efflux of chemotherapy agents out of the cells. Numerous attempts at blocking this efflux pump have been unsuccessful.

Nonpharmacologic Therapy

The three primary treatment modalities of cancer are surgery, radiation, and pharma-cologic therapy. Surgery is useful to gain tissue for diagnosis of cancer and for treatment, especially those cancers with limited disease. Radiation plays a key role not only in the treatment and possible cure of cancer but also in palliative therapy. Together, surgery and radiation therapy may provide local control of symptoms of the disease. However, when cancer is widespread, surgery may play little or no role, whereas radiation therapy localized to specific areas may palliate symptoms.

Pharmacologic Therapy

Chemotherapy of cancer started in the early 1940s when nitrogen mustard was administered to patients with lymphoma. Since then, numerous agents have been developed for the treatment of different cancers.

Dosing of Chemotherapy

Chemotherapeutic agents typically have a narrow therapeutic index. Many chemotherapy agents have significant organ toxicities that preclude using larger and larger doses to treat the cancer. The doses of chemotherapy must be spaced out to allow the patient to recover from the toxicity of the chemotherapy; each period of chemotherapy dosing is referred to as a cycle. Each cycle of chemotherapy may have the same dosages, or the dosages may be modified based on toxicity, or a chemotherapy regimen may alternate from one set of drugs given during the first, third, and fifth cycles to another set of different drugs given during the second, fourth, and sixth cycles. Dose density of chemotherapy refers to shortening of the period between doses of chemotherapy. This can accomplish two things: First, the tumor has less time between doses of chemotherapy to grow, and second, patients receive chemotherapy over a shorter period of time and hopefully can get back to a normal life sooner. Usually dose-dense chemotherapy regimens require colony-stimulating factors to be administered to shorten the time of neutropenia. The chemotherapy regimens that are dose-dense tend to be adjuvant regimens, where the tumor burden is not measurable, and the cancer outcome is a cure. When a chemotherapy regimen is used as palliative therapy (to control symptoms), the dosages of chemotherapy should be decreased based on toxicity, or the interval between dosages should be lengthened to maintain quality of life.

Patient and tumor biology also affect how cancer therapy is dosed. Patients with a uridine diphosphate-glucuronosyltransferease 1A1 enzyme deficiency can have life-threatening diarrhea and complications from irinotecan. The patient may have a blood test prior to therapy to determine if there is a genetic problem prior to receiving iri-notecan (see Table 88-4). In the case of the some of the monoclonal antibodies, flow cytometry results will reveal whether the tumor has the receptor where the drug will bind and exert the pharmacologic effect.

Another consideration of chemotherapy administration is the patient. Factors that affect chemotherapy selection and dosing are age, concurrent disease states, and performance status. Performance status can be assessed through either the Eastern Cooperative Oncology Group Scale or the Karnofsky Scale (Table 88-5). The patient is evaluated on whether he or she is active to bedridden most of the day; performance status is a very important prognostic factor for many types of cancer. If a patient has kidney dysfunction, and the chemotherapy is eliminated primarily by the kidney, dosing adjustments will need to be made. If a patient has had a myocardial infarction recently, the clinician will weigh the risks of anthracycline therapy against the benefit of the treatment of the cancer.

Another important consideration for treatment of cancers is reimbursement by third-party payors for off-label use of chemotherapy agents because of the high expense. The American Association of Cancer Centers (www. accc-cancer. org) provides a drug compendium quarterly to which clinicians may refer to verify coverage by Medicare based on ICD-9 codes. The drugs used according to FDA-approved indications are almost always reimbursed. If sufficient literature exists, an insurer may pay for an off-label use.

Table 88-4 Oncology Drugs With Valid Genomic Biomarkers


Approved Label Conlrnr

Biomarkers for selection of therapv f.iif IrlLllirtii]

Gnomoíome i delel on Len AJomtJe fGW iwunession

HFH 1/ntti Trd^uEumati Lapjfriib

Ph¡|j(i;l|J-.u ckfcrnosomc Buyjffjri. Djutinib

FML/PAH fusion yew

Slomarkersfor preventing loxldiy

TFMT AialhiTtvirie.

Mvcsph pwfne


ÜfD deficiency tflnoiMWI

lnylliililj Ls ¡«IkvUhcJ Ioi rlit■ iHMlmt'iir f.l |mI«t¡1\ wilhlffi (tClll/ltXKniut1

unresectable andtor metastatic ni kjn.nnt ÍJiT tenalidtnmick» p indicated í» ihe tie¡jtm<?nc oí paiirnts with asrishnion dependent anemü Jue to Low a niefmecLHe ! ink 11 iyuLidyf dJ^ík syndrcflnes asoüaned wubsiklctiuíi c/logorwiic diinoiiTkjIity wth w wlhctfl uddmcnjl t,>tog(.Ti(;tc flbroflflBlltlis Erioflnlb i'íííieKijfejsion wj-j iíeíeifnir^íci usiryj the í(j)R uKjinno kit. IncwiUitt to the I oit-off specified In tlvphirmOiklt instruciions. a positive FtJR e*pfe«ion stjtui wat dclriud di hi,ivnyj ji loiil IOHj of rtllí ilüiTiing tof EGíR. rheplyrmchüit has ryu bien vílidíiíO for tv* if! (Mncr^cic onta. Art appareínlly lager effect, Hiiwe/Fr. waiohimwi In (wo siihwK putlenfiwit+i ECffl[»4i[ivr tumultAHR 0.5S1 ifd UJlt'nts-whoiKivtr iiixJd.'d (HP0.4ÍI. Getudrob fiokxt amref)

f'atienls ervoUed in the clinical studies weip leqwed to hake immuncilvstci-íhemiCiii i'vidifflte ci pwirivc EGFft eip* w>¡on *j5¡ní] IT* [Jjkníytomíiion EGfR plunnDx test kit Celedón oF ftffl-í pioiein oveiexpreHlCn ü netcswiy íor seletlian of pjii?n(s apfnoprute foí ti^mumb and lapjunib theiapy fr»ulFan >i cfcsirly tas effective .íi pjlients with cfnonit myelogenous Icuk'irij who Iwk PhllíWp'i'^ (PhlKhr(ifrtosíiine Dasatinib« indicated '01 the lieatmíjnt of adults with PhildUelptiia cluomosamo ptftifiw ^utií lymphcíjljttk: Ituternl Cht ALL) wilh itiMjr>u.L a> Intokiance to pfiOÍ lh*>r,i¡ly

Mution cH Ihtfípy wtfh ireSfidin truy bt1 tídstdon llK.Linua(jfiokjgídl diagnosis of «cute prooiyelocvií kvtmiii iAíi}.Ooiiflni»tionijf die diagnosis of should be sotflht ^detection üf (he 1fí) genetk nwiloef by cytogenetic tbudk"). II thc-ic jif rf-tKilrvL-, WlV RW ^llpl^) íuiiun thuuld Ix1 nwqfit u^iny nnolecuLjr íiisgriíMiii; T«hnidUi'5. Ihe i«fxvi5e rjie of otliei AML íufcHylM (0 helinom hm nc< heen dernonUraled: therefore, patienh who Isct the genetic ninlíiv íhíxikl IVí-^^nvirld'iíJ k>i ^ICim^rii-e iN^riíiírtl

Thiopunnc i-ne!hyfirani.1cf3sflctefkicn;); m Icwer xtivily di» lt> mutation íl Irvirwsed risk oí rnyelduxiciiy. T^lTiHirinq Iq ncorvñtnded ,tkJ co<uld«¿tlVi be giveíi to eithw gcnolypü 01 phenot/pc pstic«1s toi TPMÍT fcídivkfwl^ wl>y jir.1 Mr:nKV>v>:nr* íc:f 11k* I IvtTI A*,13 ..iUHr' jíí1 ,tl irn n neuticpenia following iniliatíon of "irYJiecan trealment. A reduced miiul dtMO ihouW tjeíonsííitreO fei iMtení hftsivn w be lioirKjzpjoiíS kx ihí ugtia"26 allele. KeierWVÍ)™4 fM™'nl'' nruyhe ¿i inrrftr.ef1 iKk al neutrcfienií; however clinical results have been rouble thai patients have been shown to to leíate nturiwl ?ijiTiíi{]

Rarely unenpectedi larfcrty (e.g^stünwHilidlafrhea, neutropenia and npwOtt»»: it^) jtwxi.Hfd /ii(Fi !> fkiofcuir.K il h.i\ ariribtned If a rfcFk. ¡ltr y flfdihydrflpviifl\í ™> deí^J^i1™^1 ififfit aerial/, A I:-1- heriVPertdft-jí^eíJ levels oí DH> and increased, polencidlfy fabl to»c effects of i-fluoiouracJ ttwtfoit cjniVl IK i.isluikil

During the time of chemotherapy, patients will experience toxicity from it. The National Cancer Institute (NCI) has provided a standardized system for evaluating and grading the toxicity from chemotherapy to provide uniform grading of toxicity and evaluation of new agents and new regimens (see Table 88-6).

Combination Chemotherapy

Again, the analogy to antibiotic therapy can be made when deciding on monotherapy versus combination therapy for the treatment of cancer. The underlying principles of using combination therapy are to use (a) agents with different pharmacologic actions, (b) drugs with different organ toxicities, (c) agents that are active against the tumor and ideally synergistic when used together, and (d) agents that do not result in significant drug interactions (although these can be studied carefully and the interactions addressed). When two or more agents are used together, the development of resistance may be slowed, but increased toxicity may result. Each category of chemotherapy drugs has similar side effects. Anthracyclines cause cardiac toxicity, which is related to the cumulative dose. Tubulin-interactive agents are associated with neuropathy and ileus. Alkylating agents are associated with secondary malignancies.

Table 88-5 Performance Status Scales

KarnAffliy Zubred

Nu LortiOlainti; no wklenie of distubL1 Ahle to cairy on norrv>al x.tirtiy; minor signs or symptoms of disease Klormal Ir.lty with ff fori. some siijfn t*

symptoms of disease Cjr.'l fur i.L'11; uivrMr.' lotjriyyn i**rrijl activity or lodo activi work texjuhei oitJüaM iHsüiiiTjf ixn n able to taie for most personal needs Requires considerable assntanceand fniH^nr medial car« Disabled: requires special care and assistance

ICO 0 Fully JitiirtrabtolotirryondllCfrfisiik.'ii[ivily

Aesiricifd in siifouftn acuity liui Jirtiulaiory .iryl able tocarry-our work, of a ligtitor sedentaiy nature

CW & bed mtHe tlun 50*6 of tiir< jriifculjKiiy Jiid (diMör.-of (ílf-círe, buHinalíie ro «rry out jr^ work scTr.-nies

In bed more than 5(Bt of time; capable of onfy limited setf-csne ieveiely disabled, haspitalrralion indicated, although dtMlh not rnmincnt

Very-in k, Tíjrfjii.ili.'.íiinr rwessary, require; activo ajpfxs Lrvo [i<Wlnw!n(

Hrtdrlditen; cannot carry m>t aity self-care; coivfilelely ¡tobisd

Moribund; faral processes progressing iapidly Dead

10 0


Table 88-6 Selected NCI Common Toxicity Criteria

Toxicity_find? 1

Grade 2

Grade 3

tirade 4

Gride 5

(Jiiierdl hJe^lrofienia







Lowest baseline: y^DnVJitm' (75 X IOVL) hreasiof l«S than 4 stools per djyimM Uwnne or mild increase in ostomy output

AiymptunVltir paiho logic, ladkjgiaphic, c.'i endoscopic findingsonly l«4 oi iHWtitt without allerjtlon in raring Iwbils

1 episode in 24 hours


Lesslhan I.SdO-ljtKXVmiiV il .5—1 X KM)

Lesslhsn 75,(300 jWUVmrr' <Ji-5d* 10ft]

Intieaseof %ioci5 per day ove* baselne, IV 1lu>ds liMJkilit) leiilhjn 24- hours moderat? increase in womy output convarcd with bJSilirie, noi "TIKi firing lyith ADl iyiiVlflHWtiC iltflrid fjtinriy swjliin ng iVfaiids irviicaied lesslhan 24 hours intake dix issfti.d w lixy.Jl significant woohL loss, dehydration yi nulnutrition: IV fluids indicaiMi Ii^s 24 hours Z-5 eiiisodes in ¡A hours; IV ftuds indicated less Ihan 24 hours

Life-threinenint) death I ess than 5«l'mml {5 K ICT/L)


Less than IjiMo-SAVhirin1 (1 -Cti xKVLl

Less than SCuCOO-JSiWKVmm' (»-¡fjx I0VLI

irkrrwse cf greater than o< to 7 stools |soi day oner baseline, intoiiiifieiKe, IV fluids -g^ter than or «quail» 24 houri hospitalization: severe incnMse in Wtorriy Culput tortlpsred to baseline: InlerfernKi with AlX

VwoiTiiHk jnd y/wieiy aflmed LfrttiiMWfiin^

eating/s^allcuiiftigi IV fluid!, conse^uerves tube feedings, or TPN .ideated 1A houis or insoie less than 25U0OO mm'li^-y l(ryy

Lile-thrfrjivnintj con sequences ■ffj^H htmu-

dimsmfc: collar^)



!: i-i: ■■ :\.i|. ■ CakxiC i:r intake; IV fluids tube feedings, or TPH indicated grralier lixjn M hoi*s

L ift-1 f i rtil t.T) i rKj consequences

$ epriOifes 01 more in IA hours; IV Lile-threatening fluids or TPN indicant greater consequences (furiiH WXif Ifl 24 hows




NCL Mslfcusal CirtcGi Institute Fiomi JH!p>Ji OtyMOMl'.^OK

Currently, anticancer agents are categorized by the mechanism of action. As depicted in Figure 88-3, different agents work in different parts of the cell.



Inditas pynmxJmo biosynthesis

IrWxts aóenosno deaminase

Purine synthesis

Pynrwdine synthesis

6-Mercaptopurino 6-Thioguanine


Inhibí punne ring biosynthesis

Inhibit nocleolxto interconversions.

Capecitabine 5-Fluorooracil

InhibtdTMP synthesis


OooxynbooucieoOdes ■

Inhibits ponne ring biosynthesis

Cytarabine Flwdarabine Cta drib« no Gemcitabine

Intatts dTMP synthesis

Inhibit DNA synOws

Etoposide. Tenipos«de Irinotecan. Topotecan


Damage DNA and prevent repair

Alkylating agents Mitomycin Cisplatin, Carboplatin Oacarbazine Procarbazine

Cross-Irk DNA

Dactinomycin Anthracyclmes Mitoxantrooe ntfifcaiaie with ONA

(T ransfer-messerger-nbosomal i

Inhita RNA synthesis

Vinca alkaloids Taxanes


Inhita function of rr»crotub<Aes

Dearn nales asparagme

Inhitas proton

FIGURE 88-3. The mechanisms of action of antineoplastic agents. (From Chabner BA, Ryan DP, Paz-Ares L, et al. Antineoplastic agents. In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman's The Pharmacologic Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001: 1381.)

Antimetabolites Fluorouracil

5-Fluorouracil, commonly referred to as 5-FU, is an analog of the pyrimidine uracil. It is metabolized by dihydropyrimi-dine dehydrogenase. 5-FU ultimately is metabolized to fluorodeoxyuridine monophosphate (FdUMP), which interferes with the function of thymidylate synthase, which is required for synthesis of thymidine. The triphosphate metabolite of 5-FU is incorporated into RNA to produce the second cytotoxic effect of 5-FU. It appears that inhibition of thymidylate synthesis occurs with the continuous infusion regimens, whereas the triphosphate form is associated with bolus administration. Patients with low activity of dihydropyrimidine dehydrogenase appear to be at risk for life-threatening toxicities.5 Folates appear to increase the stability of the FdUMP-thymidylate synthase inhibition, which enhances the activity of the drug in certain cancers. 5-FU has shown to be useful in the treatment of cancers of the colon, rectum, gastric, head and neck, and breast. 5-FU is metabolized extensively by the liver, whereas up to 15% of a dose may be found unchanged in the urine. The

22 clearance of 5-FU ranges from 155 L/m /h (range 56-466 L/m /h) in women to 179

22 L/m/h (range 29-739 L/m/hr) in men. Age does not appear to alter the pharmacokin-

etics of 5-FU. 5-FU has shown clinical activity in the treatment of colorectal, breast, esophageal, pancreas, stomach, anal, and head and neck cancers. Side effects of 5-FU include stomatitis, diarrhea, cardiac abnormalities, and rarely reported cerebellar toxicities. Esophagitis and gastric ulcerations also may occur. Some alopecia may occur, but hair regrowth may occur with subsequent doses. A recent study demonstrated that if the patient uses ice chips in the mouth for 30 minutes while receiving bolus 5-FU, mucositis may be decreased significantly. Neurotoxicity may consist of headaches, visual disturbances and cerebellar ataxia. Cardiac toxicity may consist of ST-segment elevation, which appears to be more common in patients with a prior history of coronary artery disease.


Capecitabine is the prodrug of 5-FU and comes as oral tablets that are administered with food twice a day. Capecitabine has shown to be active in tumors of the colon, rectum, and breast. The toxicity profile of capecitabine is similar to that of 5-FU

and includes diarrhea, mucositis, palmar-plantar erythrodyesthesia, nausea, and myel-osuppression. Palmar-plantar erythrodyesthesia refers to redness, itching, and blistering of the palms of the hands and soles of the feet. Patients should be educated to notify the prescriber when palmar-plantar erythrodyesthesia occurs. Significant increases in International Normalization Ratio (INR) and prothrombin time may occur within several days when capecitabine is started in patients who are on warfarin, and the INR should be monitored closely, or the patient may be switched to a low-molecular weight heparin. Phenytoin levels may become elevated related to possible CYP2C9 inhibition by capecitabine. Patients should be instructed to take capecitabine within 30 minutes of a meal.


Cytarabine, often referred to as Ara-C, is an analog of cytosine and is phosphorylated intracellularly to the active triphosphate form, which inhibits DNA polymerase. The triphosphate form also may be incorporated into DNA to result in chain termination to prevent DNA elongation. The drug may be administered as a low-dose continuous infusion, high-dose intermittent infusion, and into the subdural space via intrathecal or intraventricular administration. There is also a liposomal formulation available for less-frequent administration into the CNS. Cytarabine pharmacokinetics are best described by a two-compartment model, with an a-half-life of 15 minutes and a ft-half-life of 2 hours. Cytarabine is eliminated by the kidney with a renal clearance of 90 mL/min. Cytarabine has shown efficacy in the treatment of acute leukemias and some lymphomas. The toxicities of cytarabine in high doses include myelosuppres-sion, cerebellar syndrome (i.e., nystagmus, dysarthria, and ataxia), and eye irritation that requires round-the-clock steroid eye drop administration. The risk of CNS toxicity is increased with the high-dose cytarabine regimen with renal dysfunction; dosage modification is necessary with the high-dose regimen with renal dysfunction.


Gemcitabine is a deoxycytidine analog that is structurally related to cytarabine. Gem-citabine inhibits DNA polymerase activity and ribonucleotide reductase to result in DNA chain elongation. The pharmacokinetics of gemcitabine are best described by a two-compartment model, with a terminal half-life of 6 to 20 minutes. Approximately 5% of the dose is excreted unchanged by the kidney.6 Gemcitabine has shown activity in cancers of the pancreas, breast, lung, ovary, and lung (nonsmall cell), along with some lymphomas. The toxicities include myelosuppression, flu-like syndrome with fevers during the first 24 hours after administration, rash that appears 48 to 72 hours after administration, and hemolytic uremic syndrome. While hemolytic uremic syndrome is uncommon, it is a life-threatening side effect. Patients should be counseled about using acetaminophen to treat the fevers during the first 24 hours; however, fevers occurring 7 to 10 days after gemcitabine are likely to be febrile neutropenias and need prompt treatment with broad-spectrum antibiotics.


Azacitidine, a cytidine analog, causes hypomethylation of DNA, which normalizes the function of genes that control cell differentiation to promote normal-cell maturation. The suspension is administered as a subcutaneous injection daily for 7 days for the treatment of myelodysplastic syndrome, a preleukemia disease. The pharmacokinetics of azacitidine are best described by a two-compartment model, with a terminal halflife of 3.4 to 6.2 hours, whereas peak concentrations are achieved 30 minutes after

a subcutaneous injection. Azacitidine has been shown to be clinically active in the treatment of myelodysplastic syndromes. The side effects include myelosuppression, renal tubular acidosis, renal dysfunction, and injection-site reactions.


Decitabine, approved by the FDA in 2006 for the treatment of myelodysplastic syndrome, is incorporated into DNA and directly inhibits DNA methyltransferase which causes hypomethylation of DNA. The pharmacokinetics of decitabine are best described by a two-compartment model, with a terminal half-life of 0.5 hours. Side effects include myelosuppression, constipation, edema, headache, and nausea.


Nelarabine is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma, whose disease has been already treated with at least two other chemotherapy regimens. Nelarabine is a prodrug, which accumulates as the active 5'-triphosphate form in leukemic blasts to result in inhibition of DNA synthesis and cell death. The plasma half-life of nelarabine is approximately 30 minutes. Nelarabine is primarily metabolized by demethylation, with only 5% to 10% excreted unchanged by the kidney.

Purines and Purine Antimetabolites


6-Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine £-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitaliz-ations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediat-ric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP.


6-Thioguanine (6-TG) is another oral purine analog that works similarly to 6-MP, and because of this, cross-resistance is observed. While little is known about the pharma-cokinetics of thioguanine, it appears that absorption is incomplete and approximates 30% of the dose. Thioguanine may be used in the treatment of acute and chronic myelogenous leukemia. Side effects include myelosuppression, mild nausea, cholestasis, and rarely, veno-occlusive disease.


Fludarabine is an analog of the purine adenine. It interferes with DNA polymerase to cause chain termination and inhibits transcription by its incorporation into RNA. Fludarabine is dephosphorylated rapidly and converted to 2-fluoro-Ara-AMP (2-FLAA), which enters the cells and is phosphorylated to 2-fluoro-Ara-ATP, which is cytotoxic. Fludarabine is converted rapidly to 2-FLAA. The pharmacokinetics of 2-FLAA are best described by a two-compartment model, with an a-half-life of 0.6 hours and a terminal half-life of 9.3 hours.8 Fludarabine is used in the treatment of chronic lymphocytic leukemia, some lymphomas, and refractory acute myelogenous leukemia. This drug is given IV usually daily for 5 days every 4 weeks. Significant myelosuppression may occur, along with immunosuppression, so patients are susceptible to opportunistic infections. Mild nausea and vomiting and diarrhea have been observed. Rarely, interstitial pneumonitis has occurred.


Cladribine (2-chlorodeoxyadenosine, or 2-CDA) is a purine nucleoside that once it is in the triphosphate form is incorporated into DNA, which results in inhibition of DNA synthesis and chain termination. The pharmacokinetics of cladribine are best described by a two-compartment model, with an a-half-life of 35 minutes and a terminal half-life of 6.7 hours.9 It may be administered as a continuous 7-day IV infusion or as a 2-hour infusion daily for 5 days; both regimens deliver the same total dose of drug. Cladribine is used to treat hairy cell leukemia and, therefore, is myelosuppress-ive. Unfortunately, one of the other side effects of the drug is fever, so the clinician struggles with the dilemma of whether the fever is due to the drug or an infection. Rash occurs in approximately 50% of patients with hairy cell leukemia. Cladribine also may be used to treat chronic lymphocytic leukemia, refractory low-grade non-Hodgkin's lymphoma, and Waldenstrom's macroglobulinemia.


Clofarabine was developed based on the structures of fludarabine and cladribine, with the hope it would be resistant to deamination by adenosine deaminase. Clofarabine

has shown activity in myeloid leukemia and myelodysplastic syndrome. The pharmacokinetics are best described by a two-compartment model with a terminal half-life of approximately 5.2 hours. Clofarabine is 47% bound to plasma proteins, primarily albumin. In children, 49% to 60% of the dose is excreted unchanged in the urine. No dosing adjustments are available for renal dysfunction. Side effects include bone marrow suppression, severe but transient liver dysfunction in 15% to 25% of patients, skin rashes, and hand-foot syndrome.


Pentostatin is an inhibitor of adenosine deaminase, an enzyme important in purine base metabolism. Pentostatin irreversibly inhibits adenosine deaminase, which ultimately is believed to block DNA synthesis through inhibition of RNA ribonucleotide reductase. The pharmacokinetics of pentostatin are best described by a two-compartment model with a half-life of 2.6 to 6 hours. While the drug is primarily eliminated unchanged by the kidney, preliminary data suggest no dosage adjustments are necessary for renal dysfunction. Side effects include bone marrow suppression, myalgias, conjunctivitis, and rash.


Folates carry one-carbon groups in transfer reactions required for purine and thymidylic acid synthesis. Dihydrofolate reductase is the enzyme responsible for supplying reduced folates intracellularly for thymidylate and purine synthesis.


Methotrexate inhibits dihydrofolate reductase of both malignant and nonmalignant cells. When high doses of methotrexate are given, leucovorin, a reduced folate, is administered to bypass the methotrexate inhibition of dihydrofolate reductase of normal cells and is usually initiated 24 hours after methotrexate administration. For safety purposes, the term folinic acid, another term used for leucovorin, should not be used because of medication errors where folic acid was given instead. Methotrexate concentrations should be monitored to determine when to stop leucovorin administration. Generally, leucovorin administration may be stopped when methotrexate concentrations decrease to 5 x 10-8 M, although this may vary by the chemotherapy regimen. High dosages of methotrexate may cause methotrexate to crystallize out in the kidney, which may result in renal dysfunction and decreased methotrexate clearance. IV hydration with sodium bicarbonate to maintain urinary pH greater than or equal to

7 helps to prevent methotrexate-induced renal dysfunction. The pharmacokinetics of methotrexate are best described by either a two- or three-compartment model. The a-half-life is less than 1 hour, whereas the P-half-life is 3 to 4 hours, and the y-half-life is

8 to 10 hours or longer with impaired kidney function. Approximately 60% to 100% of methotrexate is eliminated primarily as unchanged drug by the kidney. Since me-thotrexate is eliminated by tubular secretion, concomitant drugs that may inhibit or compete for tubular secretion should be avoided. Methotrexate doses must be adjusted for renal dysfunction. A recommended dosing adjustment is to divide the creatinine clearance of the patient by 70 mL/minute, which is the average creatinine clearance of patients who received methotrexate during clinical trials, and then to multiple this fraction by the dosage recommended for that disease state. Again, close monitoring of methotrexate concentrations in patients with renal impairment is advised. Methotrex-ate has shown activity in lymphoma, gastric, esophageal, bladder, and breast cancer and acute lymphocytic leukemia. Side effects of methotrexate include myelosuppres-sion, nausea and vomiting, and mucositis. Methotrexate also may be administered via the intrathecal route in very low doses as small as 12 mg to doses of 20 g IV, so it is crucial for the clinician to know the correct dose by the correct route in order to avoid substantial toxicity. Methotrexate is also administered as an intrathecal injection in to the cerebrospinal fluid or directly into the ventricle via an Ommaya reservoir. The methotrexate used for intrathecal and intraventricular injection must be preservative free. Drugs that may block the tubular secretion of methotrexate include probenecid, salicylates, penicillin G, and ketoprofen.


Pemetrexed inhibits at least three pathways in thymidine and purine synthesis. Pemetrexed is excreted primarily as unchanged drug by the kidney, with 70% to 90% of a dose recovered in 24 hours as unchanged drug in the urine. Patients with normal kidney function have a half-life of 3.5 hours.11 Pemetrexed has shown activity in the treatment of mesothelioma and nonsmall cell lung cancer. Side effects include myelosuppression, rash, diarrhea, and nausea and vomiting. Patients should receive fo-lic acid and cyanocobalamin to reduce bone marrow toxicity and diarrhea. Doses of folic acid of at least 400 mcg/day starting 5 days before treatment and continuing throughout therapy, as well as for 21 days after the last pemetrexed dose, have been used. Cyanocobalamin 1,000 mcg is given intramuscularly the week prior to pemetrexed and then every three cycles thereafter. Dexamethasone 4 mg twice daily the day before, the day of, and the day after pemetrexed administration helps to decrease the incidence and severity of rash.

Tubulin Active Agents

The periwinkle, or vinca plant, served as a source for the drugs vincristine and vin-blastine, which are commonly referred to as the vinca alkaloids. The vinca alkaloids inhibit the assembly of microtubules, which interferes in the formation of the mitotic spindle. Care must be taken not to confuse the names and doses of vincristine and vin-blastine.


Vincristine causes mitotic inhibition to arrest cells in metaphase. The pharmacokinet-

ics of vincristine have been described by a three-compartment model, with an a-half-

life of 0.8 minutes, a ^-half-life of 7 minutes, and an a-half-life of 164 minutes. Biliary excretion accounts for a significant portion of elimination of vincristine and its metabolites, so doses need to be adjusted for obstructive liver disease. Vincristine has been useful in the treatment of sarcomas, Wilms' tumor, many kinds of lymphoma, multiple myeloma, and acute lymphocytic leukemia. Vincristine is a vesicant that may cause significant neuropathy. Patients should be counseled regarding prevention of constipation and ileus caused by vincristine. Many clinicians cap IV vincristine doses at 2 mg to prevent severe neuropathic side effects, however, if the intent of chemotherapy is curative, the vincristine dose is often not capped at 2 mg. Several patients have died as a result of vincristine being administered intrathecally; it should only be administered IV and appropriate labeling should be placed on all doses. Itraconazole has been reported to cause severe neurotoxicity when administered to patients receiving vincristine. Patients have been reported to experience paralytic ileus, neurogenic bladder, absence of deep reflexes, and severe paralysis of the lower extremeties within 10 days of starting itraconazole. Clinicians need to be aware of the potential interactions of the newer azoles with vincristine and the agents should only be used in combination when the benefit clearly outweighs the risk In most cases, alternative antifungals can be administered.


Vinblastine is another vesicant vinca alkaloid that causes myelosuppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a-half-life of 25 minutes, a B-half-life of 53

minutes, and a terminal half-life of 19 to 25 hours. Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis.


The vesicant vinorelbine is structurally similar to vincristine and may cause many of the same side effects as vincristine. Vinorelbine is administered IV over 6 to 10 minutes, and patients should be counseled about neuropathy, ileus, and myelosuppres-sion. The pharmacokinetics of vinorelbine are best described by a three-compartment model, with an a-half-life of 2 to 6 minutes, a B-half-life of 1.9 hours, and a y-half-life of 40 hours. Vinorelbine has shown efficacy in the treatment of breast cancer and non-small cell lung cancer. Additional side effects include myelosuppression, paresthesias, and mild nausea and vomiting.


Paclitaxel, a taxane, binds to tubulin to promote microtubule assembly and to prevent microtubule disassembly. The pharmacokinetics of paclitaxel can be described by a two-compartment model, with an a-half-life of 30 to 45 minutes and a B-half-life of 4 to 8 hours. Hepatic metabolism and biliary excretion account for the majority of pac-

litaxel's elimination. Paclitaxel has demonstrated activity in ovarian, breast, nonsmall cell lung, prostate, esophageal, gastric, and head and neck cancers. Considerable variability exists in paclitaxel dosing, from weekly 1-hour infusions to 24-hour infusions administered every 3 weeks. The diluent for paclitaxel, Cremophor EL, is composed of ethanol and castor oil. Infusions must be prepared and administered in non-PVC-containing bags and tubings, and solutions must be filtered. Patients receive dexa-methasone, diphenhydramine, and an H2 blocker to prevent hypersensitivity reactions from paclitaxel/Cremophor EL. Patients also may have asymptomatic bradycardia (i.e., heart rates around 45 bpm) during the infusion. Approximately 3 to 5 days after administration, patients may complain of myalgias and arthralgias that may last several days. Myelosuppression, flushing, neuropathy, ileus, and total-body alopecia are other common side effects. Because paclitaxel is a substrate for CYP 3A4, steady-state concentrations of paclitaxel were 30% lower in patients receiving phenytoin than in patients not receiving phenytoin. Paclitaxel clearance was decreased by 33% when it was administered following cisplatin, so paclitaxel is administered before cisplatin.

Recently, a nanoparticle albumin-bound paclitaxel product became available commercially for the treatment of metastatic breast cancer. This product does not have the serious allergic reactions encountered with paclitaxel in Cremophor EL, so premed-ication with Hi and H2 blockers and steroids is not necessary. The dose is infused over 30 minutes and does not require a special IV bag, tubing, or filter. The dosing of this product is different from that of the original paclitaxel, so practitioners need to be aware of which product is being prescribed. The pharmacokinetics of the albumin-bound paclitaxel display a higher clearance and larger volume of distribution than paclitaxel. The drug is eliminated primarily via fecal excretion.14 The side effects of bone marrow suppression, neuropathy, ileus, arthralgias, and myalgias still occur.


Docetaxel, a semi-synthetic taxane, binds to tubulin to promote microtubule assembly. The pharmacokinetics of docetaxel are best described by a three-compartment model, with an a-half-life of 0.08 hours, a ^-half-life of 1.6 to 1.8 hours, and a terminal halflife of 65 to 73 hours.15 Docetaxel has activity in the treatment of breast, nonsmall cell lung, prostate, bladder, esophageal, stomach, ovarian, and head and neck cancers. Dexamethasone, 8 mg twice daily for 3 days starting the day before treatment, is used to prevent the fluid-retention syndrome associated with docetaxel and possible hypersensitivity reactions. The fluid-retention syndrome is characterized by edema and weight gain that is unresponsive to diuretic therapy and is associated with cumulative doses greater than 800 mg/m . Myelosuppression, alopecia, and neuropathy are other side effects associated with docetaxel treatment.


Estramustine, an oral drug, also inhibits microtubule assembly and has weak estrogenic activity at the estradiol hormone receptors of the cell. Approximately 75% of a dose of estramustine is absorbed.16 The terminal half-life ranges between 20 and 24 hours, with nonrenal excretion as the major route of elimination. This drug is used primarily for the treatment of prostate cancer, but its use is limited by the side effects, which include nausea and vomiting, diarrhea, thromboembolic events, and gynecomastia.


Ixabepilone, an epothilone analog, bind to ^-tubulin sub-units on microtubules which leads to suppression of microtubule dynamics. Ixabepilone is primarily eliminated by the liver by oxidation through the CYP3A4 system, with a terminal half-life of 52 hours. Approximately 5% of the drug is excreted unchanged by the kidney. Ixabepilone is indicated for the treatment of metastatic or locally advanced breast cancer after failures of anthracyclines and ataxane. Side effects include hypersensitivity reactions, myelosuppression, and peripheral neuropathy. To minimize the occurrence of hyper

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