module 14 - pharmacotherapy for onocologic disorders

7/31/2019 Module 14 - Pharmacotherapy for Onocologic Disorders

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GeriatricPharmacyReview

Module14:

PharmacotherapyforOncologicDisorders


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Copyright 2011 American Society of Consultant Pharmacists

Accreditation Information

ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuingpharmacy education.

This home study web activity has been assigned 3.5 credit hours.

ACPE UPN: 0203-0000-10-041-H-01-P

Release Date: 3/15/2010

Expiration Date: 3/15/2013

To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the on-line assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment,you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements ofcredit online.

Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.


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Content Experts

Trinh Pham, PharmD, BCOP

Assistant Clinical Professor

University of Connecticut School of Pharmacy

Yale New Haven Hospital

Disclosure:

Trinh Pham has no relevant financial relationships to disclose.


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Aging and Cancer

Learning Objectives:

By the end of this Review Concept you should be able to:

Describe the incidence and mortality trends associated with oncological disorders among the elderlyDescribe the process of malignant transformation and the development of a clinically significant tumorCite some of the current theories regarding the relationship between age and the incidence of cancerDescribe primary strategies for the prevention and treatment of cancer

Explain the importance of early cancer screening and reasons why early detection is difficultUnderstand the importance of a comprehensive geriatric assessment and its role in determining the appropriate therapy forthe elderly cancer patient

List the patient and disease related factors that influence the choice of cancer treatmentDescribe the complications that can occur as a result of cancer treatment and how they are managed


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Cancer in the Elderly: Incidence and Mortality

Cancer is the second leading cause of death in the United States and it is a major problem for the elderly. The mostcommon cancers include breast, lung, colon, and prostate.

The incidence of cancer increases with age and it is estimated that by the year 2030 approximately 20% of the UnitedStates population will be 65 years of age or older, compared to 12.4% at the present time. Since over 60% of all newlydiagnosed cancers and 71% of all cancer deaths occur in persons over the age of 65, it may be expected that the burden ofcancer care will rise dramatically in the United States in the future.This shift in the population demographics is due to the

aging of the baby boomers and has created an increased interest in developing programs and fostering research focusingon the optimal care of geriatric cancer patients.This module will focus on the management of cancer in the geriatric patientpopulation and the following specific areas will be addressed:the biology of cancer in the older person; the goals of cancerprevention in the elderly; the determination of the fitness of the elderly patient using the comprehensive geriatricassessment; the pharmacologic, pharmacodynamic and pharmacokinetic changes involved with the process of aging, theirimpact on therapy selection and consequences on toxicity outcomes; the evidence based guidelines for the treatment ofcancer; and, lastly, the evidence based guidelines for the management of toxicities related to the treatment of cancer.

Incidence(%)inpersons>65years Mortality(%)inpersons>65years

LungCancer ~70 ~70

Colon&Rectum ~70 -

ProstateCancer 68 91.8

BreastCancer 48 58.6


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The Process of Malignant Transformation and Tumor Proliferation

Genetic alterationFailure of normal control mechanismsProliferation and metastases

Malignant transformation or carcinogenesis involves a number of different genetic alterations that occur sequentially in acell. These alterations include deletion of tumor suppressor genes, the mutation of proto-oncogenes, and otherchromosomal aberrations. These genetic changes may be caused by exposure to carcinogens, viruses or occur as a resultof hereditary predisposition.

The result is the generation of cells that lack the specific appearance and function of the normal cells. Under normalconditions, hormones and growth factors tightly control the proliferation of cells; however, these control mechanisms havefailed in the process of carcinogenesis and the result is an uncontrolled proliferation of malignant cells that eventually mayinvade and metastasize to other tissues in the body.


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Theories Associating Aging and Cancer

Longer duration of carcinogenic exposureIncreased susceptibility of cells to carcinogensDecreased ability to repair DNAActivation of oncogene/loss of tumor suppression geneDecreased immune surveillanceEffect of Aging on Neoplastic Behavior

Rate of tumor growth

Logarithmic growth of some tumors with ageCarcinogen Exposure

Older individuals are at greater risk of developing cancer compared to younger individuals when exposed to thesame carcinogen

Tissue Aging

Molecular alterations in the aged tissue is similar to those that occur in carcinogenesis

Proliferative SenescenceLoss of ability of cell to proliferate with agingInvolves molecular changes that predispose to increased risk of malignant changesSenescent cells are resistant to apoptosis


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Biology of Cancer and Aging

Changes intrinsic to the neoplastic cell (seed effect)i.e., expression of multi drug resistance (MDR) gene in AML

Changes in tumor host (soil effect)i.e. increased circulating level of interleukin-6 (IL- 6) in NHL which increases proliferation rate

More Aggressive Cancers in Older Adults

Non-Hodgkins LymphomaAcute Myelogenous LeukemiaMalignant MelanomaThyroid Cancer

Less Aggressive Cancers in Older Adults

Lung CancerBreast CancerColon CancerProstate CancerRenal Cancer

As a person ages, the potential for malignant transformation of cells increases.Why is there this increased risk with age?Several theories have been proposed to explain the increased susceptibility of cells to neoplastic alteration in older adults.

First, older persons have less resistance and longer exposure to carcinogens. They also have a decline in their immunefunction, changes in defense mechanisms against tumors, and furthermore, they have defects in tumor suppressor genesand a decreased ability to repair DNA.


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Second, the epidemiology of squamous cell carcinoma of the skin in humans have documented that there is a logarithmicgrowth of the tumor with age.Studies of lung cancer have also demonstrated that when older and younger individuals were

exposed to the same carcinogen, the incidence of lung cancer was higher among the aged as compared to the young.

And lastly, a new and promising theory for the correlation between cancer and aging is based upon the concept ofproliferative senescence. This theory hypothesizes that molecular changes that occur in aging organisms to slow downcellular proliferation rate may actually render the cells more susceptible to environmental carcinogens.

In summary, the process in which aging affects the development of cancer is dependent on many factors. Furthermore, theclinical course of the cancer is also dependent upon the biologic behavior of the neoplasm in addition to the age of theperson. The prognosis of the cancer may be either worse or better depending on the biology of the tumor cells, the seed,

and changes in the ability of the older tumor host to sustain and stimulate tumor growth, the soil effect.

For most cancers, there is no consistent difference in clinical presentation for different age groups. While the five-yearsurvival rate for many cancers is lower in the elderly, there are some cancers that behave less aggressively in older adultsand sorting out the biologic factors that differentially affect neoplastic behavior in elderly patients is complex.


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Strategies for the Prevention of Cancer: Primary Prevention

Environmental Carcinogens

Eliminate tobacco useLimit exposure to UV light

Use sunscreenWear protective clothing (hat, long sleeves, tightly woven materials)Avoid sunlight between 10:00 am and 2:00 pm

Watch Dietary IntakeReduce fat in the dietAlcohol in moderation

Chemoprevention

SelectedPosiAveCancerPrevenAonTrials

ChemoprevenAongents PrevenAonType

BreastCancer Tamoxifen Primary1,Ter:ary

ColorectalCancer SulindacCelecoxib

Secondary2

ColorectalCancer AspirinCalciumCarbonate Ter:ary3

LungCancer Anetholedithiolethione Secondary


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SelectedPosiAveCancerPrevenAonTrials

ChemoprevenAongents PrevenAonType

LungCancer Re:nylpalmitate Ter:ary

ProstateCancer Finasteride Primary

ProstateCancer DoxazosinFinasteride Secondary

Head&NeckCancer Isotre:noinVitaminABetaCaroteneInterferon-a

Secondary

Isotre:noin

Interferon-a

Ter:ary

1-Prevent de novo malignancies in otherwise healthy person2- Prevent the progression of pre-malignant lesions to cancers3- Preventing second primary tumor in patients cured of initial cancer


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Ongoing Chemoprevention Trials

Breast CancerTamoxifen, Raloxifene

Lung Cancer

COX-2 Inhibitors

Selenium

Gefitinib

An encouraging area of research in oncology is in the field of cancer prevention. This is an enticing concept because theproactive approach of cancer prevention may eliminate or decrease the chance of being diagnosed with cancer, preservelife, and avert the complications associated with a malignancy or its treatment.

However, when cancer prevention is being considered in the elderly, it is essential to consider that due to the limited lifeexpectancy of this population, the benefit of survival gain may be reduced. Thus, the value of chemoprevention should be

assessed in terms of its potential in averting cancer-related morbidity and preserving quality of life in addition to the outcomeof possible gain in survival time.

Cancer prevention may be either primary or secondary. Primary prevention involves the elimination of exposure tocarcinogens and environmental factors that are associated with the growth of some cancers.Chemoprevention, defined asthe administration of natural, synthetic, or biologic chemical agents to suppress, reverse, or prevent the development ofcancer, is also considered to be primary prevention.

ColorectalCancerCOX-2Inhibitors

ProstateCancerSeleniumVitamin E


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Examples of agents that have demonstrated in clinical trials to be effective in reducing the risk of developing newlydiagnosed cancers, the occurrence of second cancers, or the progression of premalignant cancer to overt cancer include

the selective estrogen receptor modulators, examples of which are tamoxifen and raloxifene, the 5-alpha reductase inhibitorand example of which is finasteride, the non-steroidal anti-inflammatory agents, and vitamin A derivatives. The tablesprovide summary data on agents that are effective for the prevention of specific cancers and ongoing trials that areevaluating the efficacy other agents.

The critical questions that have not been answered in the use of these chemoprevention agents and need to be addressedin the future are: At what age should these agents be administered and for how long?Will the elderly, who have presumedpre-cancer, benefit from chemoprevention? Does chemoprevention reduce the number of cancer deaths? What are the sideeffects associated with these chemopreventive agents and what is the acceptable risk versus benefit ratio? Do thesechemopreventive agents improve quality of life? And lastly, what are the costs associated with the administration of theseagents?


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Strategies for the Prevention of Cancer: Secondary Prevention

Screening Recommendations

BreastCancer

MammographyACS- Annually after age 40USPSTF Every 1 to 2 years ages 50-69AMA Every 1-2 years 40-49, annually at age 50

Clinical Breast ExaminationACS- Every 3 years 20-39, yearly after 40, monthly self breast examination starting at 20 years.USPSTF Insufficient data to recommend for or against

CervicalCancer

Pap TestACS-Annually at 18 years or when sexually active, after 2-3 negative tests continue at discretion of physicianUSPSTF- every 3 years if ever had sexual intercourse, discontinue after 65 years of age with consistently negativeresultsAGS- Every 3 years until 70

ColorectalCancer

ACS- after 50, yearly FOBT PLUS flexible sigmoidoscopy and DRE every 5 years or colonoscopy and DRE every 10 yearsor double contrast enema and DRE every 5 to 10 years

AMA- Annual FOBT & DRE starting at age 50 and flexible sigmoidoscopy every 3 to 5 years


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Prostate Cancer

ACS and AUA- Offer annual DRE and PSA starting at age 50 to men with at least 10 -year life expectancy and to youngermen at high risk

Skin Cancer

ACS- Skin examination every 3 years between 20-40 years, every year at age 40 and older

ACS-American Cancer Society, USPSTF-U.S. Preventive Services Task Force, AMA-American Medical Association, AGS-

American Geriatrics Society, AUA-American Urologic Society. DRE- Digital Rectal Exam, FOBT-Fecal Occult Blood Test,PSA-Prostate Specific Antigen

Secondary prevention involves diagnosing cancer at an earlier stage by screening individuals at high risk of developingcancer.The assumptions are that the cancer may be diagnosed during the pre-clinical phase and that early diagnosis isassociated with increased curability due to early treatment initiation.The effectiveness of secondary prevention is measuredby the reduction in cancer-related deaths.

Presently, guidelines are available for the early screening of cancers from medical organizations such as the United States

Preventive Services Task Force, the American Cancer Society, the American Geriatric Society, the American UrologicalAssociation, and the American Medical Association.Unfortunately, the recommendations from these organizationssometimes conflict with each other and the primary care physician and health care providers working in the field of oncologymust synthesize the data and determine the best course of action for his patient.


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In general, a clinical breast examination and mammography is recommended every 1 to 2 years for women between 50 to70 years of age for breast cancer screening. Most organizations recommend a PAP smear and pelvic examination at least

every 3 years for women between 20 and 65 years of age for cervical cancer screening.

For colorectal cancer screening, the standard recommendation is an annual fecal occult blood test and flexiblesigmoidoscopy every 5 to 10 years starting at age 50.The recommendation for prostate cancer screening is controversial.Some organizations recommend an annual digital rectal exam and serum prostate specific antigen test starting at 50 yearsof age and some organizations such as the U.S. Preventive Services Task forces have no recommendations for prostatecancer screening citing insufficient evidence to support such practice.

Cancer screening guidelines in the elderly patient is uncertain. The recommendations for this population should not bebased exclusively on age-specific guidelines but rather accompanying factors such as life expectancy, the risk of cancerrelated deaths, the potential for harm due to psychological stress, the possibility of false positives, and the possibility oftreating clinically insignificant cancers should be taken into consideration.


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Cancer Symptoms in the Elderly

Signs/Symptoms PossibleMalignancy Confusedwith

IncreasedSkinPigment Melanoma

AgeSpots SquamousCellCarcinoma

RectalBleeding

Cons:pa:on

Colorectal

Rectal

Hemorrhoids,Aging

Dyspnea Lung Aging,OutofShape

DecreasedUrinaryStream Prostate Dribbling,BPH

BreastChange Breast NormalAtrophy

Fa:gue Metasta:corHematologic

Cancer

Aging,OutofShape

BonePain Metasta:cCancer,Mul:ple

Myeloma

Arthri:s,Aging


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Cancer Symptoms in the Elderly

Cancer screening and routine follow up visits with a primary care physician is beneficial for the early identification of cancersin the elderly patient population. Most types of cancer can only be cured if they are diagnosed before they metastasize. As is

well known, a delay in the diagnosis of cancer results in more advanced stage presentation which portends a poorerprognosis overall. Therefore early detection of cancer increases an individuals chance of survival.

This is especially imperative in light of the fact that the early symptoms of cancer in the elderly are sometimes more difficultto recognize compared to younger, healthier patients. Despite well publicized warning signs, elderly individuals often do notpresent for early detection. The explanation for this is due to the tendency to confuse specific cancer symptoms with normalchanges of the aging process.

For example, early symptoms such as pain may be confused with exacerbation of preexisting chronic pain and may be

ignored by the patient, or the coexistence of other diseases such as anemia can mask the early symptoms of cancers.There is no easy solution to this dilemma other than educating the elderly on the importance of routine physician check upvisits and emphasizing to physicians the need of being more attuned to their patient population and the possibility of cancerin their work up differential.


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Assessment of Aging

Categoryofging geRange ClassificaAon

Young-Old 70-75years Beginningofsenescence

Old-Old 76-84years

Oldest-Old >85years Beginningoffrailty

ComprehensiveGeriatricssessment(CG)

Domain Instrument

Health Numberofcomorbidcondi:onsCharlsonsComorbidityScaleChronicIllnessRa:ngScale-Geriatric

(CIRS-G)FuncAon PerformanceStatusInstrumentalAc:vi:esofDailyLiving(IDL)-(shopping,useoftransporta:on,cooking,cleaning,managingmoney,takingmedica:ons)

Ac:vi:esofDailyofLiving(DL)-(bathing,grooming,toile:ng,dressing,feeding,appropriatebehavior)


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Assessment of Aging

ComprehensiveGeriatricssessment(CG)

Domain Instrument

CogniAon FolsteinMiniMentalStatus (MMS)Demen:aRa:ngScale(DRS)

EmoAons GeriatricDepressionScale(GDS)

Social Livingcondi:ons,maritaladjustment,caregiveradequacy,caregiverstress,income,transporta:on

NutriAon MiniNutri:onalAssessment(MN)

Pharmacy Druglistandinterac:on

Defining the Frail Elderly

Age > 85Dependence in 1 or more activities of daily living (ADLs)3 or more comorbid conditions1 or more geriatric syndromes


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Assessment of Aging

Originating from Medicare and Social Security regulations, the arbitrary definition of geriatric or elderly is a person who is65 years of age or older. This population, however, is heterogeneous and the definition does not reflect the underlying health

status of the individuals in this group.

Although aging is associated with a progressive decline in a persons functional reserve, this is an individualized processand different people develop disease, functional restrictions and physiologic limitations at varying rates that are not reflectiveof chronologic age. It is significant, however, to note that starting at the age of 70 years, the incidence of age relatedchanges increases steeply and starting at the age of 85 years the functional reserve is almost exhausted and an individualmay be categorized as frail elderly.

Given this diversity of functional status in the elderly population, the process of assessing the fitness of these individuals is

challenging. The comprehensive geriatric assessment is a multidisciplinary tool, which assesses the domains of health,functional status, nutrition, cognition, socio-economic aspects, and emotional aspects that are likely to change with aging.This multidimensional, interdisciplinary patient evaluation instrument is effective in identifying unsuspected comorbidconditions, physical or emotional dysfunction, and incompetence in daily functional activities. These factors have beenshown to be independent predictors of survival and are vital in determining the ability of the patient to undergo andwithstand surgery, cytotoxic therapy or other types of treatment.

The National Comprehensive Cancer Network (NCCN) has developed guidelines for the treatment of older patients withcancer to ensure that therapy is adequate, toxicities are avoided, and quality of life is maintained. Performing acomprehensive geriatric assessment is one of their recommendations for the initial evaluation of elderly patients diagnosedwith cancer.


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Factors to Consider in Deciding Cancer Treatment for the Elderly

Age of patientAge-related organ function statusPresence of comorbid disesase or other medical conditionsTherapeutic goals based on the probability of survival, quality of life, etc.Potential for durg interactions and / or toxicityQuestions to Ask Prior to Designing a Therapeutic Management Plan for an Elderly Person Diagnosed with Cancer

What is the life expectancy of the person without cancer?What is the natural course of this cancer?Will the cancer compromise the quality of life of the person?What are the therapeutic complications associated with treatment?What are the possibilities of a favorable outcome with treatment?What is the patients preference?The elderly patient with newly diagnosed cancer requires special consideration when the appropriate management of themalignancy is being deliberated. The comprehensive geriatric assessment is the first step in the process of evaluating othercomorbid conditions and overall capability of the patient to endure treatment.

The answers to the following questions will also influence the subsequent decisions regarding therapy selection for thepatient: What is the natural course of the cancer, the life expectancy of the patient and will the patient most likely die OFcancer or WITH cancer? Does the patient have the functional reserve to tolerate the possible complications of aggressivelife-prolonging treatment or will the patient have compromised function and decreased quality of life as a consequence ofthe therapy? Conversely, will the patient suffer pain and disability due to the cancer and will the benefit of treatmentoutweigh the complications of the side effects of therapy? And most importantly, what are the chances of a favorableoutcome with therapy and what is the patients preference with regards to the pursuit of eradicating or controlling thecancer? The risks and benefits of therapeutic intervention for cancer in a newly diagnosed elderly patient must be carefullyweighed. The biological, psychological and social impact of the therapy on the patient must be thoroughly considered.


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Cancer Treatment Options

SurgeryChemotherapy and Hormonal TherapyRadiation Therapy

Aggressive surgery, radiation therapy, and standard chemotherapy are viable treatment options for the elderly patientdiagnosed with cancer.Elective cancer surgery and standard doses of radiation therapy is tolerated well by patients even intheir 80s.Therefore, the arbitrary implementation of less aggressive therapy for cancer patients based upon chronologic ageis not acceptable as there are no data to support this practice.


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Pharmacokinetics in the Elderly Patient & Considerations for Chemotherapy Drug Administration

Absorption

Decreased gastrointestinal motilityDecreased splanchnic blood flowDecreased secretion of digestive enzymesMucosal atrophyDistribution

Increased body fatDecreased intracellular water contentDecreased plasma albuminDecreased red blood cell concentrationMetabolsim

Decreased liver size and liver blood flowDecreased Phase I metabolism

CYP450 1A2:20 30% decrease in clearanceExcretion

Decreased renal massDecline in renal function and glomerular filtration rate (GFR)


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Pharmacokinetics in the Elderly Patient & Considerations for Chemotherapy Drug Administration

Dose Modification with Renal Impairment

Dose Modification with Hepatic Impairment, Elevated Bilirubin

BleomycinAnthracyclines

Daunorubicin

Doxorubicin

Epirubicin

Idarubicin

Busulfan

Etoposide

CarboplatinFluorouracil

Capecitabine

Imatinib

Carmustine

Taxanes

Paclitaxel

DocetaxelCisplatin

Vinca Alkaloids

Vincristine

Vinorelbine

Vinblastine

Cytarabine

Dacarbazine (DTIC)

Etoposide

Hydroxyurea

Ifosfamide

Melphalan

Methotrexate

Topotecan


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Considerations in the Use of Oral Chemotherapy Agents

CostPatient preferenceQuality of lifeCompliancePolypharmacyComplementary / Alternative medicineDrug interactions

CommonlyPrescribedOralChemotherapygents CommonCancerType

Capecitabine Breast,Colorectal

GefiAnib Lung

ImaAnibChronicMyelogenousLeukemia,

Gastrointes:nalStromalTumor

Temozolomide Anaplas:cAstrocytoma,Melanoma

Etoposide Lung

ChlorambucilChronicLymphocy:cLeukemia,Lymphomas


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In the last 20 years the availability of oral chemotherapy agents for the treatment of various malignancies has increased.Factors such as patient preference, improved quality of life, and cost of therapy have been influential in the development ofthese agents. On the other hand, the issue of compliance can be a major obstacle in the implementation of an oralchemotherapy regimen.

Some factors associated with higher rates of noncompliance include lower socioeconomic status, treatment in a communitybased setting, female gender, poor recall of the medication regimen, and the complexity of the medication regimen. Theimplication is that the effectiveness of the medication will be diminished and the chance of disease free survival is affected ifthe patient is not taking their medication as directed.

CommonlyPrescribedOralChemotherapygents CommonCancerType

Melphalan Lymphoma,Mul:pleMyeloma

Cyclophosphamide Breast,Leukemia,Lymphoma

CarmusAne

(CCNU)

BrainTumor

Thalidomide Mul:pleMyeloma


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Another facet to consider in the use of oral chemotherapy is the issue of polypharmacy and drug interactions.On average,the older patient takes at least four medications and self-medication with alternative herbal therapies is increasing. Theconsequence is an increase in the probability of drug interactions and toxicities.

The dilemmas that may limit the use of oral chemotherapy agents can be minimized by prescribing simple dosage regimens,suggesting the use of devices that helps with compliance, and educating patients on the importance of adhering to thedosing schedule and the necessity of consulting with a pharmacist or other health care providers prior to self initiation ofalternative therapies.

On the whole, the expanding role of oral chemotherapy in the treatment of malignancies is a positive step forward inproviding cancer patients with more options, convenience, and control in the management of their disease.


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Managing the Complications of Cancer Therapy: Neutropenia

Consequences of Neutropenia

Increased risk of infectionFebrile neutropeniaHospital admissionAntibiotic administration

Consequences of Older Age and Chemotherapy AdministrationIncreased neutropenic complicationsIncreased risk of febrile neutropenia (FN)Increased risk of death from FNReduced dose intensity of chemotherapyIncreased risk of 1st cycle hematologic toxicity

Role of Colony Stimulating Factors in Elderly Patients:

Should be administered in patients older than 70 years of age receiving moderately toxicchemotherapy:

i.e., CHOP (Cyclophosphamide, doxorubicin, vincristine, prednisone)Or regimens with toxicity level of CHOP

Consider adding colony stimulating factor early in the course of treatment i.e. 1st or2nd cycle ofchemotherapy


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Managing the Complications of Cancer Therapy: Neutropenia

Colony Stimulating Factor 1

Dosing RecommendationG-CSF (Granulocyte colony stimulating factor, filgrastim, Neupogen )

5 mcg/kg/day SC/IV once dailyGM-CSF (Granulocyte macrophage colony stimulating factor, Sargramostim, Leukine)

250 mcg/kg/day SC/IV once dailyPeg-Filgrastim (Neulasta)

6 mg SC once per cycle of chemotherapy

1- The colony stimulating factor should be initiated 24 hours after the end of chemotherapy.

One of the most common dose-limiting side effects of chemotherapy is myelosuppression.The spectrum ofmyelosuppression includes neutropenia, anemia, and thrombocytopenia, which leads to the clinical manifestations ofincreased infection risk, fatigue, and bleeding episodes.

It is observed that the concentration of pluripotent hematopoietic stem cells decline with age yet normal basal hematopoiesisis maintained and preserved. It is only under stress conditions that the blunted response of the hematopoetic stem cells isevident. A review of clinical trials involving breast cancer and non-hodgkins lymphoma patients older than 65 years

demonstrate that the incidence of myelosuppression and the risk of complications from neutropenia and mortality fromfebrile neutropenia increase with increasing age.The use ofcolony stimulating factors (CSF) such as granulocyte-CSF (G-CSF) or granulocyte-macrophage CSF(GM-CSF) have been proven to shorten the duration of neutropenia and the risk ofhospitalization for neutropenic fever after induction chemotherapy administration.

From evidence-based data, the American Society of Clinical Oncology and the National Comprehensive Cancer Networkrecommend primary prophylactic administration of colony stimulating factors in patients aged 70 and older receivingmoderately toxic chemotherapy such as CHOP or CHOP-like regimens.


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Managing the Complications of Cancer Therapy: Anemia

Potential Causes of Anemia

Iron DeficiencyVitamin B12 DeficiencyRenal InsufficiencyAnemia of Chronic DiseaseAnemia of Unknown CausesChemotherapy or Radiation Therapy

Consequences of AnemiaDecline in energy level, fatigueDecline in quality of lifeLoss of independence

Increased risk of heart failure, myocardial infarctionDecreased cognitionEnhanced toxicity of chemotherapyReduced survival

nemiaToxicityScale

Grade Severity NCI1Scale

(Hemoglobining/dl)

WHO2scale

(Hemoglobining/dl)

1 Mild 10-normal* 9.510

2 Moderate 810 89.4

3 Severe 6.57.9 6.5-7.9

4 Life-Threatening


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National Cancer Institute Definition of Anemia

Male: Normal Hemoglobin =14 - 18 g/dl Female: Normal Hemoglobin =12-16 g/dl

World Health Organization Definition of Anemia

Male: Hemoglobin < 13 g/dl Female: Hemoglobin < 12 g/dl

Risk Factors for Developing Symptomatic AnemiaTransfusion in past 6 monthsHistory of prior myelosuppressive therapyHistory of radiation therapy to > 20% of skeletonMyelosuppression potential of current therapyAgeHemoglobin level

Anemia is one of the most common symptoms experienced by patients diagnosed with cancer.The causes may be theunderlying cancer disease, nutritional deficiencies, anemia of chronic disease, the toxic effect of therapy such aschemotherapy or radiation, or a combination of these factors.

According to the World Health Organization, the definition of anemia is a hemoglobin level less than 13 g/dl in males andless than 12 g/dl in female.There is a minor discrepancy in the definition for mild and moderate anemia between theNational Cancer Institute and the World Health Organization; however, they are identical in their classification of moresevere anemia.


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As a person ages the risk of anemia is high due to concomitant comorbid factors. The prevalence and incidence of anemiastarts to increase at the age of 65 years and the increase is even steeper after age 80.Patients with anemia experience

fatigue, decreased quality of life, increased risk for cardiovascular complications, decreased cognition, increased toxicitywith chemotherapy agents, increased need for blood transfusions, and lastly decreased survival.

In general the treatment of anemia should be individualized and based upon the underlying cause. There should becorrection of nutritional deficiencies and treatment of the infection or inflammatory processes, hemolytic diseases and occultblood loss.

Red blood cell transfusions or crystalloid replacement should be administered to symptomatic patients with transientanemia.


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Managing the Complications of Cancer Therapy: Anemia (cont.)

Indications for Erythropoietin

Asymptomatic with risk factors of developing anemiaSymptomatic - Consider when Hgb = 10 11 g/dl

Strongly consider when Hgb < 10 g/dlPackage Insert Recommendation

Epoetin alfa

150 units/kg or 10,000 units;

administered SC 3x a week dose to 300 units/kg or 20,000 units;

administered SC 3x a week

Darbepoetin

2.25 mcg/kg/week SC

up to 4.5 mcg/kg/week SC

Common Clinically Used Regimens

Epoetin alfa40,000 units weekly SC

dose to 60,000 units weekly SC

Darbepoetin3 mcg/kg every 2 weeks SC

to 5 mcg/kg every 2 weeks SC

Darbepoetin

200 mcg every 2 weeks SC up to 300 mcg fixed dose every 2 weeks SC

Reduce dose by 25% if Hgb by > 1 g/dl in 2 weekperiod

Hold Therapy if Hgb > 12 g/dl, reinitiate 75% of dosewhen Hgb < 12 g/dl

* All patients should have iron panel studies with serum iron, total iron binding capacity, and serumferritin and add iron supplementation if ferritin is < 100 and transferrin saturation is < 20%


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Managing the Complications of Cancer Therapy: Anemia (cont.)

The hematologic growth factor erythropoietin regulates proliferation, maturation, and differentiation of red blood cells. It isindicated in patients who have symptomatic anemia or who are asymptomatic but have risk factors for development of

anemia after other treatable causes of anemia have been ruled out.

The initial dosing recommendations, dose adjustments and monitoring parameters for the administration of the differenterythropoietin formulations are provided in the accompanying table.

It is important to ensure that patients have adequate iron stores and that iron supplementation is provided as needed. Thepatient should be reassessed 4 weeks after initiation of therapy to ensure adequate response. If the patient is notresponding, the dose should be increased as recommended. If there is still no response after the dose increase 4 weekslater, then the therapy should be discontinued to prevent the administration of an expensive drug without clinical benefit. If

the patient has responded as indicated by a hemoglobin increase of at least 1 g/dl, then the therapy may be continued untilit is deemed that the patients hematopoeitic system has recovered completely.


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Managing the Complications of Cancer Therapy: Nausea & Vomiting

Types of Nausea and Vomiting

Acute Nausea/vomiting occurring 0 to 24 hours after chemotherapy administration and usually resolves within the first 24hoursDelayed Nausea/vomiting occurring > 24 hours after chemotherapy administrationBreakthrough Nausea/vomiting occurring despite prophylactic antiemeticsAnticipatory Nausea/vomiting occurring before receiving chemotherapy

Usually occurs in patients who had poor control of acute or delayed emesis with prior chemotherapyPrinciples of Antiemetic Therapy

The goal is to PREVENT nausea and vomitingThe emetogenicity potential of the chemotherapy regimen should be determined to facilitate the appropriate choice ofantiemetic regimen

Patient should receive antiemetic therapy throughout the full period of emesis risk.For moderately and highly emetogenic chemotherapy regimens, the risk of emesis is at least 4 days.For chemothepray regimens with a high potential of causing delayed emesis, patient should have around the clockantiemetic to cover the delayed emesis phase.

A benzodiaepine should be considered for patients who are at risk for anticipatory emesisThe lowest, efficacious dose should be usedOral and IV antiemetic formulations are equally effectiveConsider the toxicity of the antiemetics based upon patient specific characteristics such as age


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Managing the Complications of Cancer Therapy: Nausea & Vomiting

Management of Breakthrough Emesis

Administer multiple concurrent antiemetics from different classesRectal or intravenous may be routes of administration of choiceAdminister antiemetics around the clock with alternating schedules or routes with the different classes of antiemeticsNon Pharmacologic Measures

Hydration, electrolyte replacementMultiple small meals. Bland, non-spicy, non-oily foodsNausea and vomiting is a frequent complication of chemotherapy. It is classified as acute onset, delayed, breakthrough, and

anticipatory. The principles for controlling emesis and the types of antiemetic agents used for each of these phases ofnausea vomiting may differ slightly.

Prevention of nausea and vomiting is the primary goal in the management of chemotherapy induced emesis. The first stepin the management of chemotherapy induced emesis is to assess the emetogenic potential of the chemotherapy becausethe choice of antiemetic regimen is based upon this classification. The patient should receive antiemetics around the clockto control both acute and delayed emesis. For patients who are at risk for anticipatory emesis, a benzodiazepine such aslorazepam should also be prescribed. There is no difference in efficacy between the oral or intravenous route ofadministration of the antiemetics; however, if the patient has ongoing emesis, the intravenous or rectal route is preferable.The side effect profile of the different classes of antiemetics is also an important factor to consider. Elderly patients are

especially susceptible to the side effects of some antiemetic drugs, for example, the phenothiazines, butyrophenones, andhigh dose metoclopramide may cause excessive sedation, hypertension, and extrapyramidal reactions. The steroids maycause hyperglycemia, agitation, insomnia, and irritability. On the other hand, the serotonin antagonists are not associatedwith significant side effects.

The non-pharmacologic measures used to treat chemotherapy induced emesis include hydration and electrolyte repletion asneeded. Patients should be advised to eat multiple small meals consisting of bland foods that are not spicy or oily.


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Pharmacologic Agents for Control of Chemotherapy-Induced Nausea & Vomiting

Serotonin (5-HT3) Antagonists ondansetron, granisetron, dolasetron, palonosetronNK-1 Antagonist aprepitantSteroids dexamethasone, prednisonePhenothiazines prochlorperazine, promethazine, chlorpromazineButyrophenones haloperidol, droperidolBenzamides metoclopramide, trimethobenzamideBenzodiazepines lorazepam, alprazolamCannabinoids dronabinolAnticholinergic scopolamineAntihistamine diphenhydramine, dimenhydrinate, meclizine, cyclizine

EmetogenecityoftheChemotherapyRegimen

(RiskofEmesis) RecommendednAemeAcRegimenforcuteEmesis

High(>90%)

5HT3Antagonist+Cor:costeroid+/-NK-1antagonist

Moderate(30-90%) 5HT3Antagonist+Cor:costeroid

Low(10-30%)Singleagentcor:costeroidordopamineantagonistorphenothiazinesor

butyrophenones

Minimal(


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Emetogenicity

Options for Delayed Emesis

High

Dexamethasone Plus 5-HT3 antagonist ormetoclopramideModerate

DexamethasoneOR Dexamethasone + 5HT3 OR5HT3OR metoclopramide + 5HT3 ORmetocopramide

Low / Minimal

NONE

There are many pharmacologic options for the treatment of chemotherapy induced nausea and vomiting and theyinclude the serotonin antagonists, corticosteroids, phenothiazines, anticholinergics, and the newly approved

neurokinin antagonists.

The administration of the serotonin antagonist in conjuntion with a corticosteroid has been proven to be effective inthe management of acute-onset nausea and vomiting and should be considered as first line therapy for highly tomoderately emetogenic chemotherapy regimens. The NK-1 antagonist, aprepitant, should be added for multi-daychemotherapy regimens that are highly emetogenic and is associated with significant risk for delayed nausea andvomiting.


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For patients receiving low emetogenicity chemotherapy regimens, single agent antiemetic is effective in preventing nauseaand vomiting and the options include a corticosteroid, phenothiazine, or butyrophenone.

For anticipatory nausea and vomiting, a benzodiazepine such as lorazepam is effective.

In general, all 5-HT3 antagonists are considered to be equally efficacious and the oral route is as effective as theintravenous route. The distinguishing characteristic is that palonosetron has a 100-fold higher binding affinity for the 5-HT3receptor and a longer half life compared to the other serotonin antagonists. Palonosetron has equivalent efficacy for controlof acute emesis as compared to the other 5HT3 antagonists. However, for delayed emesis palonosetron may be better.Palonosetrons role in the treatment of chemotherapy induce emesis is not well defined yet at this point, but as we havemore data available, it may the agent of choice for highly emetogenic chemotherapy regimens that have a high potential ofcausing delayed nausea and vomiting.


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Minimizing Chemotherapy-Associated Toxicities

Recommendations for Minimizing Toxicities Associated with Chemotherapy

Initial patient evaluation with the comprehensive geriatric assessmentExclude frail patients from aggressive treatmentInstitute nutrition support, social supportControl underlying diseases and disabilitiesAdjust chemotherapy doses according to patients creatinine clearance, liver function, and bilirubin levelMaintain hemoglobin levels above 12 g/dlAdminister granulocyte hemopoietic growth factors prophylactically in patients > 70 years of age receiving CHOP or similar

regimens

For patients > 60 years administer granulocyte hemopoietic growth factors prophylactically for induction or consolidationtherapy for acute myelogenous leukemia

Provide aggressive fluid resuscitation for mucositis and diarrheaConsider less toxic alternatives to doxorubicin where there is data demonstrating equal effectiveness in patients > 70 yearsProvide antiemetics to prevent nausea and vomitingCounsel patient to take laxative and stimulant agents to prevent constipation associated chemotherapy agents that causes

autonomic neuropathy


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Minimizing Chemotherapy-Associated Toxicities

There are many factors to consider in the treatment of the elderly patient diagnosed with cancer.A comprehensive geriatricassessment is an essential first step to determine the patients overall health, functional status and support network.Thedecision to treat the patient should not be from preconceived perceptions that elderly patients are automatically not able totolerate chemotherapy, surgery, or radiation therapy.Instead, therapy should be individualized based upon the patientsspecific organ status function, performance status, comorbid conditions, predicted life expectancy, and desire outcome oftreatment.

If chemotherapy is deemed appropriate for the patient, aggressive measures should be taken prevent toxicities.Appropriateadjustment of chemotherapy dose based upon kidney, heart, lung, or liver function should be explored.The administrationsof colony stimulating factors to facilitate hematopoetic recovery should be considered.Close patient monitoring for sideeffects such as mucositis, diarrhea or constipation should be performed in order to institute appropriate supportive care assoon as possible.

As our population ages and the number of elderly people is predicted to almost double by the year 2030, it is crucial thatclinicians become familiar with the common health issues faced by this patient population.Therapy should not be withhelddue to discrimination based on age and lack of understanding of the physiologic status of this group of patients.Systematicevaluation of each patient and individualized therapy is the key to ensuring appropriate therapeutic outcome and treatmentof the elderly patient population diagnosed with cancer.


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References

For additional information, see:

Balducci L. Anemia, Cancer, Aging. Cancer Control 2003 Nov/Dec; 10(6); 478-484.

Balducci L. Evidence-based management of cancer in the elderly. Cancer Control 2000 Jul/Aug; 7(4); 368-374.

Balducci L, Beghe C. Prevention of cancer in the older person. Clin Geriatr Med 2002 Aug; 18(3); 505-528.

Balducci L, Beghe C. Cancer and age in the USA. Crit Rev Oncol Hematol 2001;37;137-145.

Balducci L, Beghe C. The application of the principles of geriatrics to the management of the older person with cancer. CritRev Oncol Hematol 2000;35;147-154.

Balducci L, Extermann M. Cancer and aging. An evolving panorama. Hematol Oncol Clin North Am 2000 Feb;14(1);1-16.

Balducci L, Hardy CL, Lyman GH. Hemopoietic reserce in the older cancer patient: clinical and economic considerations.Cancer Control 2000 Nov/Dec; 7(6); 539-546.

Balducci L, Lyman G, Ozer H. Patients aged > 70 are at high risk for neutropenic infection and should receive hemopoietic

growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2000; 19; 1583-1585.

Balmer C., Valley A. W.(1996).Basic Principles of cancer treatment and cancer chemotherapy. In: Dipiro JT, Talbert RL, YeeGC, et al. (Eds). Pharmacotherapy: A Pathophysiologic Approach. Samford: Appleton and Lange, 2403-2466.

Carbone PP. Advances in the systemic treatment of cancers in the elderly. Crit Rev Oncol Hematol 2000;35;201-218.


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References

Cohen, H. J.(1994).Oncology and aging:Generaly principles of cancer in the elderly.In Hazzard, W. R., Bierman, E.L., Blass,J. P., Ettinger, W. H. & Halter, J. B. (Eds.). Geriatric Medicine and Gerontology, 3rd ed.New York:McGraw-Hill: 77-90.

Ettinger, D. S. (1995).Preventing chemotherapy-induced nausea and vomiting: An update and a review of emesis. SeminOncol; 22(4) Suppl 10:6-18.

Groopman JE, Itri L. Chemotherapy-Induced Anemia in Adults: Incidence and Treatment. J Natl Cancer Inst 1999 Oct; 9(19);1616-1634.

Grunberg,S. M., HeskethP. J. (1993). Control of chemotherapy-induced emesis. N Engl J Med; 329(24):1790-97.

Jacox, A. K., Carr, D. B, Payne, R, et al. (1994). Management of cancer pain. Clinical practice guideline no. 9. Rockville,MD: Agency for Health Care Policy and Research (AHCPR publication no. 94-0592).

Kennedy BJ. Aging and cancer. Oncology (Huntingt)2000 December; 14(12);1731-1740.

Levy, M. H. (1996). Pharmacologic treatment of cancer pain. N Engl J Med; 335(15):1124-32.

Lichtman, SM. Chemotherapy in the elderly. Semin Oncol 2004 April; 31(2);160-174.

Lichtman, SM. Guidelines for the treatment of elderly cancer patients. Cancer Control 2003 Nov/Dec; 10(6); 445-452.

Lichtman, S. M. (1995). Physiological aspects of aging Implications for the treatment of cancer. Drugs-Aging;7(3):212-21.


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References

National Cancer Institute http://www.nci.nih.gov/

National Comprehensive Cancer Network. Practice Guidelines in Oncology. Version.1.2004. Antiemesis

National Comprehensive Cancer Network. Practice Guidelines in Oncology. Version.2.2004. Cancer and Treatment RelatedAnemia.

Pharmaceutical Information Network: Cancer Information Center http://pharminfo.com/disease/cancer_db.html

Pizzo, P. A. (1993). Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med; 328(18):1323-1332.

Portenoy, R. K. (1993). Cancer pain management. Semin Oncol;20(2) Suppl 1:19-35.

Repetto L, Biganzoli L, Koehne CH, Luebe AS, Soubeyran P, Tjan-Heijnen VCG, Aapro MS. EORTC Cancer in the elderlytsk force guidelines for the use of colony-stimulating factors in elderly patients with cancer. Eur J Cancer 2003; 39;2264-2272.

Repetto L, Balducci L. A case for geriatric oncology. Lancet Oncol May 2002; 3; 289-297.

Repetto Lazzaro, Comandini D. Cancer in the elderly: assessing patients for fitness. Crit Rev Oncol Hematol2000;35;155-160.

Rosti G, Kopf B, Cariello A, Monti M, Dazzi C, Papiani G, et al. Prevention and therapy of neutropenia in elderly patients.Crit Rev Oncol Hematol 2003; 46; 247-253.


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References

Schwartz R. N. (1995). Cancer in the Elderly. In: Delafuente J. C., Stewart,R. B., (Eds.) Therapeutics in the elderly.Cincinnati: Harvey Whitney Books, 500-12.

Tsao AS, Kim ES, Hong WK. Chemoprevention ofCancer. CA Cancer J Clin 2004 May/June; 54; 150-180.

University of Pennsylvania Cancer Center: OncoLink

http://cancer.med.upenn.edu/

Yancik R, Ries L Aging and cancer in America. Demographic and epidemiologic perspectives. Hematol Oncol Clin North Am2000 Feb;14(1);17-23

Yancik R, Ries L.Cancer in older persons: An international issue in an aging world. Semin Oncol 2004 Apr;31(2):128-136

Zagonel V, Fratino L, Sacco C, et al. (1996). Reducing chemotherapy-associated toxicity in elderly cancer patients. CancerTreat Rev; 22:223-244.

Zoorob R, Anderson R, Cefalu C, Sidani M. Cancer screening guidelines. Am Fam Physicians 2001; 63: 1101-1112.

Zulian GB. Health care delivery in the older person with cancer. Crit Rev Oncol Hematol 2000;35;227-232.


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Cancer of the Breast, Lung, and Brain

Learning Objectives:

By the end of this review concept, you should be able to:

Cite the epidemiologic trends associated with lung, breast and brain cancers.

Differentiate the signs and symptoms of presentation and diagnosis of lung, breast and brain tumors.

Analyze the various treatment regimens and related effects for lung, breast and brain cancers.

List common sites for metastases for lung, breast and brain cancers.


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Lung Cancer

Incidence

Estimated 219,440 new cases in 2009Male: 116,090 casesFemale: 103,350 cases

Mortality

Estimated 159,390 deaths in 2009Male: 88,900 deathsFemale: 70,490 deaths

Overall 5 year survival rate is 15%88% mortality rateMore than 2/3 of patients are over 65 years of age

Epidemiology in Elderly Patients

Median age at diagnosis is 69 yearsMore than 50% are over 65 years of ageMore 30% are over 70 years of age

Lung cancer is the most common cause of cancer-related death in both men and women in the United States. It accountsfor 15% of all cancer diagnosis and 29% of all cancer related deaths. The risk of developing lung cancer rises with age.During the last decade, the incidence and mortality from lung cancer has decreased among individuals who are 50 years ofage or younger; on the other hand, the incidence has increased among those 70 years of age and older. In consideringgender, the incidence rate of lung cancer declined significantly in men and the death rate declined at 2% per year from 1994to 2004. In women, there was a sharp rise in lung cancer incidence in the 1960s and since 1987, more women have diedfrom lung cancer than breast cancer. After increasing for many decades in women, the lung cancer death rates are finallyapproaching a plateau


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Classification of Lung Cancers

Lung cancer is divided into 2 major histologic types: non-small cell lung cancer and small cell lung cancer. Non-small celllung cancer is the more common subtype and accounts for more than 85% of all lung cancer cases. Small cell lung canceraccounts for only 15% of all lung cancer cases. Non- small cell lung cancer is often diagnosed in the advanced stage of thedisease and is generally considered to be chemotherapy resistant. Small cell lung cancer is rarely cured and it ischaracterized by a rapid doubling time, high growth fraction, and early development of metastasis.

Non-small cell lung cancer is further classified as adenocarcinoma, squamous cell carcinoma and large cell carcinoma.Adenocarcinoma is the most common subtype and is most frequently observed in patients who never smoked, women, andis rising in incidence in younger adults. Adenocarcinoma may also metastasize rapidly to other sites such as liver, bones,brain, and adrenal glands. Squamous cell carcinoma is the second most common subtype of non-small cell lung cancer andtends to be more indolent.

Subtypes

NonSmallCellLungCancer (85%)

denocarcinoma(40%)

Women

Non-Smokers

SquamousCellCarcinoma (20%)

LargeCellCarcinoma (5%)

SmallCellLungCancer (15%) SmallCellorOatCell


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Risk Factors for Developing Lung Cancer

Tobacco

20 fold increase in lung cancer riskcause of 90% of lung cancers in mencause of 75-85% of lung cancers in womenExposed non-smokers (second-hand smoke)

25-35% increased risk compared to non-smokers

Genetic predisposition

Family historyGerm-line mutation in:

DNA repair genesEpidermal growth factor receptor genep53 tumor suppressor gene

Occupational and chemical exposure

Radon, ionizing radiationAsbestosArsenicChromiumNickel

Cigarette smoking is the most important risk factor for lung

cancer. Smoking causes all types of lung cancer but it ismost strongly linked with small cell lung cancer andsquamous cell lung cancer. There is a dose-responserelationship in the development of lung cancer where therisk increases with increased duration of smoking and thenumber of cigarettes smoked per day. The risk ofdeveloping lung cancer decreases after smoking cessationand quitting smoking can benefit at any age no matter howlong a person has smoked. The decrease in risk, however,will not be equal to that of a non-smoker.

Reports of familial clustering of lung cancer suggest thatthere is a hereditary basis to the development of lungcancer. Lung cancer susceptibility and risks are increasedin germ line mutations p53 tumor suppressor genes,epidermal growth factor receptor genes or DNA repairgenes.

Other less common causes of lung cancer include

exposure to radon gas, asbestos, and carcinogenicchemicals such as organic arsenic compounds, nickel, andchromium.


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Screening and Diagnosis for Lung Cancer

Screening

No recommendation for routine screening for early detection of lung cancerNational Lung Cancer Screening TrialCompares low dose CT vs. chest x-ray for early detection of lung cancer

Enrolled current and former smokersDesigned to detect improvement in mortality with CT screeningResults are pending and expected to be available around 2012

Work-Up and Diagnosis of Lung Cancer

History and Physical ExamBiopsy and pathological review for classification of lung cancer histologyChest X-Ray

Chest, liver CT scansMRI or CT scan of head for small cell lung cancerBone ScanBaseline CBC, serum chemistries, liver function tests, LDH

At the present time, there are no standard screening recommendations for the early diagnosis of lung cancer. This isbecause neither chest x-ray nor sputum cytology has been shown to reduce mortality. Ongoing clinical trials are evaluating

the efficacy of different screening and early detection methods for lung cancer and its role in possibly decreasing mortality.The National Comprehensive Cancer Network encourages high-risk individuals to participate in these trials.

For the diagnostic work up of lung cancer, a biopsy and an analysis of the tumor by a pathologist is necessary for adefinitive diagnosis. Other additional tests include a chest x-ray and CT scan of the chest, liver, and brain, and a bone scanfor evaluation of metastasis. Baseline complete blood count, serum chemistries and liver function tests are also essential toevaluate potential toxicity from chemotherapy.


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Clinical Manifestations of Lung Cancer

Clinical Manifestations of Lung Cancer

Persistent coughSputum streaked with bloodChest painVoice changeRecurrent pneumonia or bronchitisPleural effusionSuperior vena caval obstructionBone PainNeurologic symptomsSpinal cord compression

A new or changing cough that is sometimes associated with blood is the most common presenting symptom of lung cancer.Frequently, patients may also manifest dyspnea, hoarseness, anorexia, weight loss and fatigue. Patients with metastaticdisease to the brain can present with neurologic symptoms such as severe headaches and double vision. Otherextrapulmonary symptoms include bone pain or pathologic fractures secondary to bone metastasis or liver dysfunction dueto spread of the cancer to the liver. Compression of the superior vena cava by the lung cancer may cause patients to

develop shortness of breath and swelling of the face and arms because blood is not able to return to the heart.

Patients with small cell lung cancer may present with a paraneoplastic syndrome, which are a collection of symptoms thatresult from the production of biologically active substances by the tumor. These signs and symptoms occur remotely fromthe primary tumor site or the metastatic site and may be endocrine, neuromuscular or musculoskeletal in nature. EatonLambert myasthenic syndrome presenting with proximal leg weakness is an example of a neurologic manifestation. SIADHdue to the production of vasopressin or Cushings syndrome due to the production of adrenocorticotropic hormone by thecancer cells is a another common manifestation of the paraneoplastic syndrome.

Paraneoplastic SyndromeWeight loss/cachexiaSyndrome of Inappropriate Anti-Diuretic Hormone (SIADH)Cushings SyndromeHypercalcemiaEaton Lambert myasthenic syndrome


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Staging of Lung Cancer

Non Small Cell Lung Cancer

TNM Staging SystemTumor size; Lymph node involvement; Metastasis

Stage I - confined to the lung without lymphatic spread

Stage II - large tumor with lymph node involvement in the same side of the chest where the tumor originated.

Stage III- includes lymph node and other regional involvement near the lung

Stage IV - includes any tumor with distant metastasis to sites such as the liver, bone or brain

Small Cell Lung Cancer

Limited Disease - tumor is confined to the side of the chest where it originated (ipsilateral hemithorax): the mediastinumand the supraclavicular lymph nodes. Can be safely encompassed within a tolerable radiation field.

Extensive Disease disease beyond ipsilateral hemithorax. Metastasis to liver, bone, brain or may include malignantpleural or pericardial effusion or hematogenous metastasis

Non-Small Cell Lung cancer is classified by the TNM staging system according to the American Joint Commission on

Cancer. T is for tumor size, N evaluates the presence of lymph node involvement and M assesses for metastasis. Thesestaging procedures are useful in determining if the tumor is surgically resectable and the prognosis for the patient.

Small cell lung cancer is usually advanced at the time of diagnosis; therefore; it is classified as either Limited Disease orExtensive Disease.


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Lung Cancer Prognosis

Non-SmallCellLungCancer

Stage Incidence 5-yearsurvivalrate

StageI 10% 57-67%

StageII 20% 40-55%

StageIIIA 15% 23-25%

StageIIIB 15% 3-7%

StageIV 40% 1%

SmallCellLungCancer

Stage 2yearsurvivalrate Medianoverallsurvival

LimitedDisease 40% 14-20months

ExtensiveDisease Lessthan5% 9-11months


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14.02.07 Lung Cancer Prognosis

Good Prognostic Factors

Early stage of the disease at diagnosisGood performance statusWeight loss not more than 5%Female genderPoor Prognostic Factors

Mutation of p53 tumor suppressor geneActivation of k-ras oncogenesElevated LDHEndocrine paraneoplastic syndromePoor performance status

Factors that predict good prognosis include early stage at diagnosis, good performance status, weight loss of less than 5%,and female gender. Unfortunately, only about 30% of non-small cell lung cancer patients are diagnosed with stage I or II of

the disease, the remaining 70% are diagnosed with advanced stage III or IV. For small cell lung cancer, about one-third ofpatients present with limited disease and two thirds present with extensive disease.

As can be seen from the table, 5-year survival rate is highest for patients diagnosed with stage I or II non small cell lungcancer. Survival is poorest in patients diagnosed with extensive stage small cell lung cancer where the 2-year survival rateis less than 5%.


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Non-Small Cell Lung Cancer Treatment Options

Surgery

Localized diseasePotentially curative for stage I and II

Lobectomy is the standard surgical procedureRarely indicated for stage IV except for:Solitary lesion brain metastasis

Radiotherapy

Unresectable cancers (stage I through IIIB)Radiation alone or in combination with chemotherapyAdjuvant radiation therapy with chemotherapy after surgeryStage IIISurgical resection is the cornerstone of therapy for patients with stage I through IIIA non-small cell lung cancer. For stage Iand II disease, it is the best option for cure if the cancer can be completely resected and the patient is able to tolerate thesurgical procedure.

Radiation with curative intent is a viable alternative for patients who are not able to tolerate surgery because of othercomorbid conditions. It also indicated for non-resectable stage IIIB non-small cell lung cancer. For these situations, radiationis usually administered in combination with chemotherapy to optimize outcome.

Radiation in combination with chemotherapy is also indicated as adjuvant therapy after surgical resection in patients withstage IIIA disease.


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Chemotherapy

Resectable stage I through IIIAdjuvant therapy after surgery

Cisplatin based chemotherapy offers survival advantageCarboplatin + paclitaxel if patient is not able to tolerate cisplatin

Unresectable stage IIIA and IIIB

Concurrent chemotherapy with radiationCisplatin based therapy in combination with:

Etoposide or vinblastine or gemcitabine or paclitaxel or vinorelbineCarboplatin + Paclitaxel if patient is not able to tolerate cisplatin

Metastatic or recurrent disease

First-line therapy

2 drug regimens (doublet) preferredPlatinum (cisplatin or carboplatin) based with any of the following:

DocetaxelPaclitaxelGemcitabineVinorelbine


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Second line therapy

Disease progression during or after 1st line therapyMay use single agent:Docetaxel (Taxotere) or

Pemetrexed (Alimta)Targeted Therapy

Bevacizumab (Avastin ) inhibits angiogenesisNon-squamous cell carcinomaNo history of hemoptysisNo untreated CNS metastasis

Erlotinib (Tarceva )

First-line therapy with or without chemotherapyAdvanced or metastatic diseaseNever smokedActive epidermal growth factor receptor (EGFR) mutation

Second line therapyDisease progression during or after 1st line chemotherapy

Third line therapy


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Administering adjuvant chemotherapy after surgical resection of stage I, II or III non-small cell lung cancer has been shownto improve survival.

In patients with unresectable disease, concurrent chemotherapy with radiation is the treatment of choice. Median survival forpatients is about 16 to 17 months.

Chemotherapy is primarily palliative for patients with metastatic lung cancer. It has been shown that combinationchemotherapy with 2 agents produce 30-40% one-year survival rate and is superior to single agent as first line therapy.

If chemotherapy is used, a platinum-based combination chemotherapy regimen is the preferred choice. The platinum isusually cisplatin. Combination chemotherapy prolongs survival, improves symptoms and quality of life. All the different

platinum-based doublets are considered equally efficacious and the response rate and survival did not differ between theregimens.

If a patient fails first line therapy, single agent chemotherapy with activity against non-small cell lung cancer is the next step.Docetaxel, pemetrexed and erlotinib are indicated as single agent second line therapy. Pemetrexed is a multi-targetedantifolate agent.

Bevacizumab is a monoclonal antibody that blocks vascular endothelial growth factors and inhibits angiogenesis. In 2006, itreceived FDA approval for unresectable, locally advanced, recurrent or metastatic non-small cell lung cancer. It is

administered in conjunction with the carboplatin plus paclitaxel chemotherapy regimen. To be eligible for this therapy thepatient has to be diagnosed with adenocarcinoma or large cell carcinoma. Patients with squamous cell subtype, hemoptysisat baseline or brain metastasis are not eligible because it was found that they are at higher risk of bleeding in phase IIstudies.

Erlotinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and inhibits cell proliferation. Itwas approved by the FDA in 2004 for locally advanced or metastatic non-small cell lung cancer after failure of at least oneprior chemotherapy regimen. It may be given as first line therapy for patients who have known active epidermal growthfactor receptor mutation and never smoked. Diarrhea and acne like rash are the dose limiting toxicities for this therapy.


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Small Cell Lung Cancer Treatment Options

Surgery

Limited role in small cell lung cancerIndicated for early stage, limited disease

Radiation

Combination with chemotherapy in limited stage diseaseLocal failure reduced by 25-30%2 year survival improved by 5-7%

Chemotherapy

Limited stageConcurrent chemotherapy and radiationCisplatin + Etoposide x 4-6 cycles

Extensive stage

Cisplatin + etoposideCarboplatin + irinotecan

Extensive stage with brain metastasis

Chemotherapy before or after whole brain radiation therapy


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Lung Cancer and Older Patients

NON-SMALL CELL LUNG CANCER

Stage IB IIRestrospective Study: Surgery followed by combination cisplatin + vinorelbine vs.

surgery followed by observation

Patients 65 years or older receive less chemotherapy than younger counterpartsElderly patients receiving chemotherapy have improved survival with tolerable toxicity

Locally Advanced Disease (Stage III)Selected fit elderly patients may receive combined chemotherapy and radiation; preferably in a clinical trial

Advanced Disease

Single agent third-line chemotherapy such as vinorelbine is recommended as standard of care instead of bestsupportive care alone

Select fit elderly patients may be eligible for cisplatin based doublet therapyProspective trials with attenuated cisplatin dose in combination with gemcitabine or vinorelbine show activity

against the cancer with good toxicity profile in elderly patients

Need large clinical trials specifically designed for elderly patients to confirm these results.Bevacizumab is not well tolerated in elderly patients in combination with chemotherapy and is not recommended

SMALL CELL LUNG CANCER

Limited Stage DiseaseConcurrent chemotherapy and radiation

similar response rate as younger patients with potential for curesignificantly more toxicity compared to younger patients


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Lung Cancer and Older Patients

Extensive Stage Disease

Elderly patients experience more toxicity compared to younger patientsShould not a priori exclude chemotherapy in the elderly since small cell lung cancer is very responsive tochemotherapy

Elderly cancer patients often present with multiple comorbidities and physiological limitations such as decreased organfunction that makes it challenging to select optimal treatment options for them. Furthermore, in lung cancer, if the patientunderwent surgical resection, they may also be at higher risk for experiencing chemotherapy induced toxicity.

There are few prospective studies evaluating the tolerability of chemotherapy in elderly patients with lung cancer. Availabledata are usually from retrospective analysis and is not ideal for basing treatment decisions. More clinical trials that arespecific for the elderly patient population are needed in order to better define optimal therapy for elderly patients.

For many stages of lung cancer, cisplatin based chemotherapy with or without radiation is the standard of care. Someelderly patients may be able to tolerate the toxicity of these regimens and derive survival benefit; therefore, dose reductionof chemotherapy or withholding chemotherapy should not be a priori planned strategy for elderly patients diagnosed withlung cancer. There are phase III trials that support the use of single agent chemotherapy in place of best supportive care for

patients with metastatic disease who are not able to tolerate combination chemotherapy. Patients with good performancestatus, adequate organ function and minimal comorbid conditions should be carefully selected for chemotherapy orcombination therapy with radiation. If the data is available, the decision should be supported by data from clinical trials thatare specifically designed to evaluate the effect of therapy in elderly patients.


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Symptom Management in Lung Cancer

Symptom Recommendations

SIADH Fluid restriction, saline for symptomaticpatients, demeclocycline, treat the cancer

Cushings Syndrome Consider ketoconazole

CoughCough suppressants: opioid and non-opioid (e.g. dextromethorphan). Considersteroid therapy if coughing is secondary toradiation pneumonitis

DyspneaShort acting opioids, oxygen, relieveanxiety (benzodiazepine), relaxationtechniques, cool air or fan

Hypercalcemia Hydration, furosemide, bisphosphonateSuperior Vena Caval (SVC) Obstruction Radiation to shrink tumor and relievesymptoms of SVC obstruction


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Symptom Recommendations Side effects from bevacizumab Wound healing complications Do notadminister bevacizumab within 28 days of

any major surgery

Nephrotic syndrome- monitor proteinuriaby dipstick urinalysis. If urine dipstick is 2+or greater, obtain 24 hour urine collection.

Adminster bevacizumab only if proteinuriais less than 2gm/24 hours

Hypertension- monitor blood pressureevery 2 to 3 weeks during treatment withbevacizumab. Initiate appropriate antihypertensive medication if hypertensiondevelops

Hemorrhage- do not administer to patientswith serious hemorrhage or recenthemoptysis. If bleeding occurs discontinuebevacizumab

GI perforation discontinue bevacizumabif this occurs


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Surveillance After Lung Cancer TreatmentAfter recovery

from primary therapy Non-Small Cell Lung Cancer Small Cell Lung CancerHistory and Physical ExamCT scan

History and Physical ExamChest imagingBlood work as necessary

Year One

Every 4 to 6 monthsEvery 2-3 months

Year TwoEvery 3 to 4 months

Year Three

Annually

Year FourEvery 4 to 6 months

Year FiveYear 6 and beyond Annually


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Breast Cancer

60 years of age and older70% of breast cancer patients70 years of age and older46% of breast cancer patients

Breast cancer incidence is 6-fold higher in elderly womenBreast cancer mortality rate is 8-fold higher in elderly women

New Cases (Invasive Breast Cancer) NewCases(in situ)

Deaths

Total 194,280 62,280 40,610Female 192,370 40,170Male 1,910 440


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Breast Cancer

Breast cancer is the most commonly diagnosed cancer in American women and accounts for thirty two percent of allmalignancies. It is the second leading cause of cancer death among women, trailing only after lung cancer. From 2001 to2004, the incidence of breast cancer started to decline by 3.5% per year, after continuously increasing in incidence for more

than 2 decades. This is attributed to the reduced use of hormone replacement therapy after publication of results that linkedhormone replacement therapy use to increased risk of heart disease and breast cancer from the Womens Health Initiativestudy in 2002. The National Health Interview survey showed that the rate of mammography screening in women 40 years ofage and older dropped from 70% in 2000 to 66% in 2005 and this maybe another contributing factor to the decline of breastcancer incidence rates.

Breast cancer mortality has steadily decreased since 1990, with larger decreases in women younger than 50 years of agecompared to women who are 50 years of age or older. The reason may be due to breast cancer screening, which detectsthe disease earlier, and the availability of improved treatment options.

Breast cancer is a disease of aging and more than 50% of breast cancer cases occur in women 60 years and older. As theelderly population in the United States is increasing due to the aging of the baby boomers, the number of older patientsdiagnosed with cancer will also increase accordingly. By the year 2030 an estimated 70.2 million people will be over the ageof 65 and the number of women diagnosed with breast cancer will increase by 72%.This escalating number of elderlywomen who will be diagnosed with breast cancer stresses the need for more research focusing in this patient population forthe best evidence to prevent and treat the disease.


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Risk Factors for Developing Breast Cancer

Age:

Lifetime risk is 1 in 7 based on life expectancy of 85 yearsFamily history (1st degree relative)

Previous breast cancer diagnosisDiagnosis of lobular carcinoma in situ or benign breastdisease

High breast tissue densityIrradiation of the breastGenetic mutations in the BRCA1 and BRCA2 genesEstrogen Exposure History

Early age at menarche (14 years of age or younger)Late onset of menopause (55 years of age or older)Age of birth of first child (>30 years)NulliparityModifiable risk factors

ObesityPost menopausal obesityPost menopausal hormone replacement therapyPhysical inactivityAlcohol consumption

Estimated Risk ofDeveloping Breast Cancer

Age(years)

1 in 14 60-791 in 24 40-59

1 in 228 < 39


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Modified Gail Model of Breast Cancer Risk Assessment:

A model to determine the relative risk of developing breast cancerAnalyzes the combination of the following factors:

History of ductal or lobular carcinoma in situAge (> 35 years)First degree relatives with breast cancerPrior breast biopsies and presence of atypical ductal hyperplasiaAge at menarcheAge at first live birthEthnicity

Many risk factors are associated with the development of breast cancer; however, it should be noted that 60% of womenwith breast cancer have no identifiable major risk factors, emphasizing that the actual cause of breast cancer is largelyunknown. Aside from being female, age is the most significant risk factor for the development of breast cancer. A positivefamily history of breast cancer, a previous diagnosis of breast cancer or benign breast disease such as hyperplasia, or highdose radiation to the chest are additional risk factors.

Mutations of the breast cancer 1 or 2 gene, otherwise known as BRCA1 or BRCA2 gene, predisposes the woman to an 80%lifetime risk of developing breast cancer. BRCA1 or BRCA2 gene mutation accounts for 5 to 10% of all breast cancer cases

and only 1% of the general population has a mutation in either of these genes.


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Evaluation of reproductive factors that increase breast cancer risk include obtaining the patients menstrual history, where ahistory of early menarche defined as 14 years of age or younger and late menopause defined as 55 years of age or older,increases the risk. Never having children or having children after age 30 also increases the risk of developing breast cancer.

The risk of a woman developing breast cancer may be predicted mathematically by various models. The modified GailModel is one such tool. Seven different factors are analyzed in this model and the composite score of relative risk for eachfactor is utilized to calculate the overall risk of developing breast cancer. The instrument does have its limitations and it isonly one of many models that predict the risk of developing breast cancer.

Accurate assessment of a womans risk of developing breast cancer is important and may have ramifications for therapydecisions. A woman should undergo counseling and thorough discussion with her physician prior to initiating the riskassessment process.


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Prevention of Breast Cancer

Intervention Benefits Indications Side Effects

Tamoxifen

~ 50% risk ofdeveloping breastcancer

* Limited data forwomen with BRCA1/2 mutation

module 14 - pharmacotherapy for onocologic disorders

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