Fourth Edition
`rrent
`CANCER
`Therapeutics
`
`John M. Kirkwood, MD
`
`Professor and Chief, Division of Medical Oncology, University of Pittsburgh School of Medicine;
`■ Chief, Melanoma Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
`
`Michael T. Lofze, MD
`
`Vice President and Director, Departments of Inflammation, Tissue Repair, and Oncology,
`SmithKIine Beecham Pharmoceuticals, King of Prussia, Pennsylvania
`
`Joyce M. Yasko, PhD
`
`Professor, School of Nursing, University of Pittsburgh;
`Associate Director, Clinical and Network Programs, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
`
`With 69 contributors
`
`CMCURRENTS
`
`MEDICINE
`
`Developed by Current Medicme, hu., Philadelphia
`
`I
`
`Vermont Technical Coifege
`Randolph Center. VT 05061
`
`IPR2018-01714
`Celgene Ex. 2012, Page 1
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`

`

`CURRENT MEDICINE, INC.
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`ISBN: 1-57340-176-5
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`Printed in the United States of America by Port City Press.
`5 4 3 2 1
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`
`IPR2018-01714
`Celgene Ex. 2012, Page 2
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`

`

`301
`
`310
`
`323
`
`334
`
`.340
`
`.349
`
`,367
`
`,374
`
`382
`
`392
`
`CONTENTS
`
`iS
`
`__
`PARTI: AGENTS
`1. ALKYLATING AND PLATINATING AGENTS,
`Stanton L. Gerson
`2. ANTIMETABOLIC AGENTS......................
`Judy Chiao, Julie Beitz, Robert J. DeLap
`3. BIOLOGIC AGENTS............................
`Ulrich Kielholz, Michael T. Lotze
`4. HORMONAL AGENTS..........................
`Douglas Yee, David T Kiang
`5. TUBULIN-TARGETING DRUGS
`Johann Sebastian de Bono, Anthony W. Tolcher,
`Eric K. Rowinsky
`PART 2: SPECIFIC NEOPLASMS AND
`THERAPEUTIC PROTOCOLS
`6. BREAST CANCER........................
`Minetta C. Liu, Marc E. Lippman
`7. UPPER GASTROINTESTINAL CANCER
`Kevin F. Staveley-0’Carroll, Herbert J. 7,eh,
`Margaret A. Tempera
`8. LOWER GASTROINTESTINAL CANCER
`Jean L. Grem
`9. HEAD AND NECK CANCER...........
`Roger Stupp, Everett E. Yokes
`10. LUNG CANCER
`Carlos William de Araujo, Paul A. Bunn, Jr
`IT. MELANOMA AND OTHER TUMORS OF THE SKIN
`Michael T. Lotze, John M. Kirkwood
`12. SARCOMAS....................................................
`Ronald H. Blum, Herbert J. Teh, David L. Bartlett
`13. GENITOURINARY CANCER....................................
`Marc S. Ernstoff, Christopher Tretter, John A. Heaney
`14. GYNECOLOGIC MALIGNANCIES...............................
`Scott Wadler
`IS.MAIIGNANTGLIOMU
`Michael Prados
`'■ ENDOCRINE CANCER..............................
`Jennifer Lowney, GerardM. Doherty
`’7. LEUKEMIA..................
`Edward D. Ball, Edwin Alyea, Jerome Ritz
`
`JJl
`
`,55
`
`76
`
`,95
`
`109
`
`130
`
`150
`
`163
`
`177
`
`.205
`
`.217
`
`,230
`
`.250
`
`.266
`
`.275
`
`,287
`
`Vii
`
`18. HODGKIN'S DISEASE
`Alan R. Yuen, Sandra J. Horning
`19. NON-HODGKIN’S LYMPHOMA....
`Dorothy Pan, Carol S. Portlock
`20. MYELOMA
`James R. Berenson
`21. MALIGNANT EFFUSIONS IN THE CHEST,
`John C. Ruckdeschel, DavidJablons
`22. CARCINOMA OF UNKNOWN PRIMARY,
`Mela^iie B. Thomas, James L. Ahbruzzese
`23. AIDS-RELATED MALIGNANCIES.....
`Ashfin Dowlati, Scot C. Remick
`PART 3: SUPPORTIVE CARE
`24. PALLIATIVE CARE...................
`Robert M. Arnold, Linda King
`25. MYELOSUPPRESSION
`Michael S. Gordoft
`26. GASTROINTESTINAL TOXICITIES
`John Hohneker, Tom Lampkin, Paul Wissel
`27. RENAL AND METABOLIC COMPLICATIONS....................
`Janet A. Amico,Jean L. Holley, Sai Subhodhini Reddy
`28. PULMONARY AND CARDIOVASCULAR COMPLICATIONS
`OF CANCER THERAPY.........................................
`Matthew Volm, Howard Hochster
`29. NEUROTOXICITIES.......................................
`TjeerdJ. Postma
`30. EVALUATION OF QUALITY OF LIFE IN CANCER
`CLINICAL TRIALS........................................
`Bernard F. Cole, Richard D. Gelber, Shari Gelber
`31. SYSTEMIC MANIFESTATIONS OF CANCER AND MANAGEMENT
`,427
`OF SYSTEMIC PARANEOPLASTIC SYNDROMES................
`Jayesh Idesai, Michelle Gold, Sonia Fullerton, Jonathan Cebon
`,442
`32. MALNUTRITION..............................................
`Yuman Fong, Stephen F. Lowry
`PART 4: CLINICAL TRIAL DATA COLLEaiON
`33. CLINICAL TRIALS; MONITORING AND REPORTING OF
`TOXICITIES, AND EVALUATING TUMOR RESPONSE....
`Linda Barry Robertson
`34. SYNOPTIC PATHOLOGY REPORTS
`MichaelJ. Becich
`INDEX,
`
`,406
`
`,414
`
`,421
`
`.455
`
`,459
`
`,481
`
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`

`

`CHAPTER 25: MYEIOSUPPRESSION
`Michael S. Gordon
`
`Patients receiving chemotherapy or radiation therapy experience
`certain side effects. Some {eg, acute nausea and vomiting) occur
`acutely and are managed with medications or intravenous fluids
`designed to counteract these effects. Other side-effects {eg, alope­
`cia), although uncomfortable and perhaps damaging in terms of
`patient self-image, are not dangerous and do resolve at the conclu­
`sion of therapy. Among all side effects seen, those associated with
`the effects of anticancer therapy on the bone marrow (BM) repre­
`sent a potentially dangerous and even life-threatening circumstance
`[1]. Because most anticancer treatments affect rapidly dividing cells
`preferentially, BM is an ideal target for these effects. This is the
`primary reason that myelosuppression is among the complications
`most frequently seen.
`Temporary damage to BM can result in decreases in all three
`major strains of peripheral blood, although effects on leukocytes and
`especially the myeloid series tend to dominate, given that they have
`the shortest survival of all BM-derived cells (Table 25-1). This
`results in a drop in the infection-fighting neutrophil series, with an
`associated increased risk of infection. Although these patients are at
`increased risk for both bacterial and fungal forms of infection, the
`former tends to be more commonly seen. Generally, only patients
`with long-term severely low (absolute neutrophil count < 250
`cells/pL) for lengthy periods experience mycotic infections. Bodey et
`al. [2] reviewed the experience at the National Institutes of Health
`leukemia service, which defined that both the depth and duration of
`neutropenia play roles in the risk of developing systemic infectious
`complications. Because in most cases, neutropenia is of a short dura­
`tion, the average risk of infection with standard chemotherapy is
`relatively low. Among the remaining lineages, anemia is most often
`cumulative in nature. A current controversy disputes which level ot
`anemia represents a sufficiently significant drop to warrant interven­
`tion with medical therapy even though transfusion therapy continues
`to be a mainstay of management of this side effect. This complica­
`tion most often lowers patients’ quality of life by fatiguing them.
`Finally, a small percentage of patients develops clinically significant
`thrombocytopenia from cancer therapy. The risk of clinically severe
`bleeding in patients with thrombocytopenia is low and occurs
`primarily when the platelet count falls to dangerously low levels.
`Overall, development of myelosuppression as a complication of
`cancer therapy can be related to a range of variables (Table 25-2); the
`development of other complications such as disseminated intravascu­
`lar coagulopathy or other underlying illness can complicate this issue.
`
`stem cell factors) and the lineage-specific colony-stimulating
`ctoill
`(eg, granulocyte colony-stimulating factors [G-CSF], granulo(_
`cytei
`macrophage colony-stimulating factors [GM-CSF], and erythro-
`pot
`etin). These biologic agents control the proliferation, differentiatio
`and maturation of multipotential precursor cells that can be directed*
`to various lineages based on the relative expression of specific factoif
`in a BM microeimronment. Hematologic lineages are regulated by |
`series of feedback loop such as that of the renal tubules that control
`erythropoietin expression in response to hematocrit.
`Blood cell production begins with the multipotential stem cell
`which has the ability to self replicate and thereby ensure thli:
`adequate precursor cells are always available. The exhaustion of this
`stem cell supply, although theoretical, could lead to severe BM apla­
`sia and hyiaoproduction of all blood cells. Although BM aplasia
`as a
`result of cancer therapy is rare, it generally only happens with the
`most intensive chemotherapy regimens.
`In general, the environment in which the stem cells exist needs to;
`be conducive to their growth and development. Severe fibrosis froiji
`diseases, such as the myeloproliferative disorders or chronic changes
`as a result of radiation therapy, tends to make BM space inhospitable
`to blood cell production. This therefore can contribute significantly
`to the development of myelosuppression.
`Kinetically, the myelosuppressive effects of cancer therapy tend tO:
`be related to what stage of development is damaged by the agent in
`question. Neutrophils, which usually survive 7 hours in circulation,
`are most sensitive to treatment effects. Similarly, platelets that last 7
`to 10 days are more commonly affected than erythrocytes, which last
`120 days in circulation. The progression of hematopoietic develop­
`ment is similar for all lineages taking approximately 7 days to
`progress from stem cell to committed progenitor and another 7 to 10
`days to progress from committed progenitor to mature cell, ready for
`release into the circulation. It is this latter 7- to 10-day period that
`can be compressed by the available CSFs to accelerate blood cell
`production rapidly.
`
`CAUSES
`The principal forms of cancer therapy that cause myelosuppression
`are chemotherapy and radiation therapy. In the case of radiation, the
`damaging effect is not limited to the hematopoietic compartment,
`but to the marrow microenvironment itself Not uncommonly, it can
`take up to several years for recovery of a previously irradiated area. In
`
`PATHOPHYSIOLOGY
`Production of blood cells by BM is an orderly process controlled by
`both positive and negative regulators termed hematopoietic growth
`factors (HGFs) and cytokines (Table 25-3) [2]. These include both
`early-acting stem cell factors (primarily interleukins 1, 3, 6, as well as
`
`Table 25-1. Categories of Cytopenias
`
`Lineage
`
`Megakaryocyte
`
`Approximate Survival
`(in Circulation)______ Deficiency
`7h
`Neutropenia
`Anemia
`120
`7-1 Od
`Thrombocytopenia
`
`Table 25-2. Factors Associated With
`Myelosuppression
`
`Therapy
`Choice of chemotherapy agents ond dose-intensity
`Radiation therapy including total dose and volume radiated
`Bone marrorv reserve
`Patient's age and nutritional status
`Prior therapy
`Bone marrow involvement with malignancy or other process
`Bone marrow involvement with cancer or other process
`Comorbid conditions such as autoimmune processes
`Drug-related effects (nonchemotherapy)
`Infection-related complications (is, disseminated intravascular coagulation)
`
`P
`
`i
`
`H
`
`the intofmotion here is provideci qs guidance only. Prescribers should! otways consult tKe mcmufacttirer's curretit pfescribing infgfjmgtion
`374
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`MYEIOSUPPRESSION
`
` :
`
`contrast to these two therapies, biologic therapy {eg, immunotherapy)
`jtiay cause myelosuppression by inducing a peripheral consumptive
`'state related to hypersplenism or some similar mechanism. This
`former effect most commonly resolves quickly following discontinua-
`dibn of these agents. In some cases of antibody-directed irradiation
`ifusing a monoclonal antibody to target radiation particles), the
`UKipact can be more significant.
`Chemotherapy
`■Chemotherapy affects hematologic cells in much the same way it
`does cancer cells. Chemotherapy drugs can be classified into cate-
`: |ories based on mechanism of action. Alkylating agents typically
`'bind to nucleotide bases of DNA and thereby inhibit protein synthe­
`sis and replication. This effect is similar to that of the antitumor
`Antibiotics such as doxorubicin or daunorubicin that intercalate into
`iDNA strands, thus preventing DNA synthesis. Vinca alkaloids
`' (vincristine or vinblastine) and the taxanes (paclit'axel and docetaxel)
`‘Inhibit microtubular synthesis that inhibits spindle formation
`‘preventing cells from actively undergoing mitosis. Finally,
`Antimetabolltes frequently substitute themselves for purine or pyrimi­
`dine nucleotides, thereby blocking DNA or RNA synthesis. These
`latter agents may also block specific enzymes required for nucleotide
`Synthesis. BM cells take up these chemotherapy drugs in much the
`‘Same way as cancer cells. Flence, BM, because of its rapidly prolifer­
`ating state, often tends to be more sensitive to the effects of
`chemotherapy because unlike cancer cells, these progenitors often
`ilack mechanisms of resistance to the chemotherapy. An outline of
`'cancer chemotherapeutic agents and their relative effects on different
`dines is shown in Table 25-4. Several agents such as vincristine, low-
`sdose methotrexate, L-asparaginase, and oral cyclophosphamide
`‘generally do not cause significant myelosuppression. Conversely,
`Agents such as the nitrosureas and mitomycin-C frequently induce
`jdelayed and prolonged myelosuppression because of their relative
`effects on the stem cell population.
`(Immunotherapy
`‘Biologic agents
`can be divided into two specific groups with regard to
`Iteir effects
`on the hematologic system. The first group, which
`includes the interferons (alfa, beta, and gamma), can exert a direct
`fnppressive effect on BM and although not specifically myelotoxic.
`
`certainly is not myelosuppressive. This impact on blood counts is typi-
`c'ally relatively rapidly reversible after the drug has been discontinued.
`In contrast, lymphopenia and neutropenia associated with interleukin-
`2 (IL-2) appear to be predominantly related to peripheral consumption
`by immunostimulated cells or by vascular margination of pools of cells.
`Both these side effects are rapidly reversible, appear to be dose related,
`and generally are not associated with infectious complications. In addi­
`tion to the IL-2-mediated neutropenia, this agent has the ability to
`induce neutrophil dysfunction, which lasts longer than quantitative
`neutropenia and may be associated with increased infectious risk.
`Radiafion Therapy
`Radiation therapy induces cell death by causing lethal double-
`stranded DNA breaks. These DNA breaks result in cell death and
`apoptosis when the cell enters the cell cycle. For this reason, it is cells
`in Gq that tend to be more sensitive to DNA damage than those in
`Gj or S-phase, which tend to be more resistant due to their ability to
`correct damage enzymatically. Hence, myelosuppression associated
`with radiation therapy is often related to the volume of BM irradi­
`ated, the total radiation dose, and the patient’s overall BM reseive
`(which may be compromised by either prior therapy or BM involve­
`ment with cancer).
`
`DIAGNOSIS
`The first evidence of myelosuppression is often a defined drop in the
`number of peripherally circulating blood cells. Because of the kinetics
`and life span of blood cells as previously noted, leukopenia and
`neutropenia are typically the first deficiencies noted. This drop,
`which may be mild, is frequently found 7 to 10' days following the
`completion of therapy, although more intensive treatments may
`accelerate the process. In the case of moderately to severely intensive
`regimens, thrombocytopenia may be noted at or around the same
`time. Anemia, as a side-effect of therapy, is more commonly cumula­
`tive and develops over time or a series of cycles.
`In typical situations, response to the development of cytopenias is
`an increase in BM production of blood cells. This generally corrects
`mild leukopenia or thrombocytopenia in a short time (7 to 14 days).
`In some cases, in which more severe or prolonged myelosuppression
`occurs, further investigation may be necessary.
`
`Table 25-3. Hematopoietic Growth Factors and Cytokines
`
`Atony-stimulating factors
`
`Name
`C-CSF
`GM-CSF
`EPO
`TPO
`M-CSF
`
`Interleukin-3
`
`Lineage
`m
`m, mo
`e
`P
`mo
`
`P
`m, e, p
`
`Approval Stotus
`Approved
`Approved
`Approved
`Investigotionol
`No longer under study
`
`No longer under study
`No longer under study
`No longer under study
`
`Pm
`
`, e, p
`^—eryihfoiil; 6-CSf—granulocyte colony-slinwhtiiig factor; GM-CSf— granulocyte-rnacroplmge colony-stimulating factor; UPO—etYlhropoielln; m—myeloid; mo—monocytic; M-CSF—macrophage colony-stimulating
`factor; p—platelet; IPO—llirombopoietk
`
`■imi? '"formation here is provided as guidance only. Prescribers should always tonsult the manufacturer's current prescribing information.
`375
`
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`

`MYEIOSUPPRiSSIOfl
`
`M
`
`:
`
`such as that of a leukoeiythroblastic picture (elevated numbg^^ ^
`Peripheral Blood
`early leukocytes and nucleated erythrocytes) consistent with*;gw
`Evaluation of a peripheral blood (PB) smear is the easiest form of
`involvement with tumor or fibrosis. Both these situations ma
`can
`“tissue biopsy” available. Comprehensive review of a PB smear
`increase the risk of more severe myelosuppression.
`V
`nrovide sifiiificant insiitht both before and after chemotherapy as to
`i . . j • r i
`the risk and complications of chemotherapy administration. In addi- After therapy has been administered, a review of the PB
`tion to being able to evaluate leukocytes, erythrocytes, and platelets will allow a differentid count to
`leukocytes
`quantitatively, a PB smear allows qualitative evaluation. and a ca culation of the absolute neutrophil count (ANC), winch ^
`Prechemotherlpy evaluation may demonstrate important findings the total number of leukocytes multiplied by the percentage of
`
`§
`
`Table 25-4. Drug-Induced Wlyelosuppression
`
`Route of
`administration
`
`Degree of suppression*
`
`Time to nadir (wk)* Time to recovery (wk)*
`
`Affected cell type
`
`Alkylating agents
`
`Cyclophosphamide
`
`Antibiotics
`Bleomycin
`Daunorubicin
`Doxorubicin ■
`
`Mitoxantrone
`Mitomycin
`Antimetabolites
`2-Chlorodeoxyadenosine
`Cytosine orabinoside
`
`Fluorouracil
`Gemcitabine
`Mercoptopurine
`Methotrexate
`Vinca alkaloids/
`
`Etoposide
`Teniposide
`Vinblastine
`Vincristine
`
`PO
`PO
`
`PO
`
`IV
`
`IV
`
`PO
`
`IV,PO
`IV
`
`IV
`
`Miscellaneous
`L-asparaginase
`Cisplatin
`Carboplatin
`Dacarbazine
`Docetaxel
`Hydroxurea
`
`PO
`IV
`PO
`Procarbazine
`*flepende;)f on dose, administration, and scUuling.
`[—erythrocytes; I—leukocytes: P—platelets.
`
`Moderate-i
`Moderate
`Mild-moderate
`Moderate
`Moderate
`Moderate-
`
`0-mil
`
`Moderate-marked
`
`Moderate
`
`Moderate
`Moderate-marked
`Mild-moderate
`Mild-moderate
`Moderate-marked
`Moderate
`Moderate-marked
`
`Mild-moderate
`Moderate-marked
`Moderate
`
`Moderate-marked
`
`0-mild
`Moderate
`Moderate
`
`Moderate—marked
`Moderate—marked
`Moderate
`Moderate
`
`2-4
`2-3
`
`1-2
`2-3
`2-3
`
`1-2
`2
`2
`1-2
`2
`1-2
`Up to 8
`
`2
`2-3
`1-2
`1-2
`
`1-2
`
`1-2
`1-2
`
`1-2
`2-3
`2-3
`2-3
`1-2
`1
`1-2
`3-4
`
`6-8
`
`2-4
`2-4
`4-7
`4-6
`
`2-3
`3-4
`3-4
`2-3
`3-4
`3
`Up to 10
`
`3-4
`3
`3-5
`2-3
`2-3
`3-4
`2-3
`
`3
`2-3
`2-3
`2
`3-4
`
`4-6
`4-6
`4-5
`2-3
`2-3
`2-3
`4-6
`
`L,P
`L
`L
`L,P
`L,P
`P,L
`PA
`L,P
`IP
`L,E
`
`L,P
`L,P
`
`1,P
`L,P
`U
`L,P
`L,E,P
`L,P
`l,P
`
`L
`L
`L
`
`L
`G,P,E
`G,P,E
`G,P
`L,E
`G,P
`u
`P,G
`
`,,
`
`...
`The information here is mm
`
`m.
`
`1
`376
`
`m
`
`informatigL
`
`ing
`
`pi
`
`iI I
`
`I
`
`ft
`
`||
`
`ft
`
`i
`
`11
`
`II
`
`IPR2018-01714
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`

`

`MYELOSUPPRESSION
`
`It
`
`M
`
`i M
`
`segmented neutrophils plus band forms. The ANC is a critical calcu­
`lation on which treatment of patients with fever during leukopenia is
`based. Early BM recovery is typically heralded by a PB monocytosis.
`Monocytes, a more primitive type of anti-infectious cell, tend to
`increase in number transiently before granulocytosis.
`In addition to quantitative evaluation of blood cells, qualitative
`analysis of the PB smear is critical. Complications such as infection
`with disseminated intravascular coagulation (DIG) may be identified
`the smear based on the features of fragmented erythrocytes and
`on
`deficient platelets. Furthermore, patients with prolonged leukopenia,
`who are at risk for secondary malignancies following chemotherapy
`with or without radiation, may demonstrate signs of an underlying
`myelodysplastic syndrome. Evidence in support of this diagnosis may
`include pseudo Pelger-Huet neutrophils (unilobed or bilobed
`segmented neutrophils), hypogranularity of the myeloid series, or
`long-standing PB monocytosis with erythrocyte macrocytosis.
`
`Bone Marrow
`In some settings, BM evaluation may be necessaiy to explore etiologies
`for relative or absolute cytopenias. Examples of such diagnoses include
`the superimposed autoimmune cytopenias. This is conducted through
`BM aspiration and biopsy, typically on the posterior iliac spine unless
`the pelvis has been previously irradiated. In that case, a sternal BM
`aspirate alone is appropriate. A sternal BM aspirate is performed in the
`region approximately 2 to 3 cm below the sternomanubrial joint in the
`midline. The key feature of a successful BM aspirate is the presence of
`spicules, which represent small bony particles around which
`hematopoietic precursors develop. Occasionally, it may be impossible
`to attain an adequate aspirate due to the lack of spicules (as may be the
`case in severely aplastic marrows) or because of a “dry tap,” which may
`occur due to scarring or fibrosis in the BM space. In these situations, a
`BM biopsy is critical to adequately evaluate the BM pathophysiology.
`Magnetic resonance imaging (MRI) to investigate BM cellularity
`using the difference in water content between hypoceUular BM (high
`fat content) and hypercellular BM is being investigated. Abnormal
`signal in the BM may also be seen on MRI, which may indicate
`involvement of the BM space with malignant tumor.
`
`HIMATOLOGK TOXtCiTY
`Neutropenia
`As noted previously, neutropenia is one of the first findings consis­
`tent with myelosuppression. It is of potential value in terms of moni­
`toring the effect of orally administered chemotherapy in which
`variable absorption may play a role in activity of the drug. Such is the
`case for oral melphalan in the setting of multiple myeloma in which
`torial blood counts demonstrating development of mild-to-moderate
`neutropenia is indicative of adequate drug absorption.
`Neutropenia is a deficiency of the number of circulating
`neutrophilic granulocytes. As the primary bacterial infection-fighting
`nell of the body, it is responsible for preventing overwhelming
`Pyogenic infections. A pool of neutrophils exists in a marginated
`state and some patients, particularly those of African descent, have a
`relative neutropenia that responds to the administration of low doses
`of
`- epinephrine, which redistributes the marginated pool. This is
`toore of a pseudoneutropenia and is not associated with an increased
`r*sk of infection.
`Absolute neutrophil count (ANC) levels below 1000 cells/pL are
`(*ssociated with increased risk of infection. This is common in
`ces in which patients are receiving combination chemotherapy.
`tostan
`
`Incidence of infection is directly related to the depth of the neutrope­
`nia as well as its absolute duration (how low and for how long) [3].
`As has been noted previously, recovery of ANC to normal levels may
`take approximately 2 weeks following administration of standard
`dose chemotherapy. During the period when patients are effectively
`neutropenic, close monitoring for signs or symptoms of infection
`must take place. Any clinically significant fever must be met with a
`thorough investigation of potential sources of infection including risk
`of infection related to indwelling central venous catheters.
`After a patient with neutropenia has been determined to have a
`fever (temperature at or above 38.5°C), appropriate antibiotic coverage
`with a third-generation cephalosporin is indicated. This monotherapy
`is appropriate for all patients with culture-negative febrile neutropenia
`with an adjustment of the antibiotic coverage for positive blood
`cultures. Patients with indwelling central venous catheters are candi­
`dates for the addition of vancomycin either at the initiation of antibi­
`otic coverage or within 48 to 72 hours if fever continues (if a source is
`not found). Antibiotics should be continued until the ANC exceeds
`500 cells/pL and the patient is afebrile. Patients with positive blood
`cultures and an indwelling central catheter require treatment based on
`culture and symptom. It is rare in the setting of short-lasting neutrope­
`nia for patients to develop fungal infections. In a case in which
`systemic fungal infection develops, intravenous therapy with ampho­
`tericin B is appropriate; duration of this therapy is defined by the
`severity of the infection and the fungal isolate.
`The two hematopoietic colony-stimulating factors (G-CSF,
`GM-CSF) entered into clinical use in the early 1980s. Approved
`several years later, G-CSF has demonstrated the ability to reduce
`the depth and duration of chemotherapy-induced neutropenia asso­
`ciated with combination chemotherapy [4J. As a'result of this effect,
`it also significantly decreases incidence of febrile neutropenia.
`Although GM-CSF has similar biologic activities, its benefits are
`seen in the setting of BM transplantation in which it accelerates
`recovery of neutrophils and hastens the ability to discharge the
`patient from the hospital [5]. Anecdotal use of these agents in the
`setting of drug-induced neutropenia also suggests a benefit. The
`value of CSF use for the treatment of radiation-induced neutropenia
`remains unclear; at least one study in non-small cell lung cancer
`demonstrates that concomitant GM-CSF and radiation therapy
`results in poorer survival compared with radiation alone. Of signifi­
`cance, no study has demonstrated a survival advantage to the use of
`CSFs in conjunction with cancer therapy. Hence they remain as
`supportive care and their use is based on a physician’s perception of
`the individual risk-benefit ratio.
`Anemia
`The past several years have seen more and more attention focused on
`the impact of anemia on patient tolerance of chemotherapy and their
`overall quality of life. Anemia is defined as a drop in the hemoglobin
`or hematocrit to a level below the lower limit of normal. In most
`Institutions, this is represented by a fall below 12 g/dL or a hemat­
`ocrit of 36%. Although most patients at this level are minimally
`symptomatic in terms of fatigue, new studies suggest that mild
`anemia may contribute to slowing of the mental processes with deci­
`sion making. This so-called “executive function” is a critical new
`endpoint in anemia research. Evaluation for contributing factors such
`as nutritional deficiencies (folic acid or vitamin Bj2) or a destructive
`process must be completed.
`Declines in hematocrit levels tend to be cumulative in that
`patients progressively develop more symptoms, which include
`
`L The information here is provided os guidance only. Prescribers should always consult the manufatturer's current prescribing intormation.
`377
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`MYELOSUPPRESSION
`
`fatigue, exercise intolerance, tachycardia, dyspnea on exertion and, in
`extreme cases, exacerbation of preexisting cardiopulmonary disease.
`Most of these symptoms can be alleviated by the transfusion of
`packed erythrocytes, although transfusions are expensive and not
`without risks {eg, viral Infections). As an alternative to transfusions,
`of recombinant human erythropoietin has been explored [6,7].
`use
`Proven as beneficial to decrease the need to eiythrocyte transfusions,
`it is widely perceived as a therapy that also improves quality of life for
`patients receiving chemotherapy, although this has not been widely
`randomized trial. Optimal timing of the initiation of
`confirmed in a r
`erythropoietin use is before patients require transfusions. Current
`initial dose is a once weekly, subcutaneously administered, treatment
`at a dose of 40,000 units per week.
`
`Thrombocytopenia
`Thrombocytopenia represents a deficiency in the number of circulat­
`ing platelets, which normally circulate at levels between ISO and
`400,000/pL. Levels of 50,000/pL and higher are generally adequate
`for hemostasis to allow minor or major surgical procedures. The
`degree to which patients develop thrombocytopenia is directly related
`minor
`the incidence of bleeding complications. Spontaneous
`to
`bleeding episodes increase in frequency when the platelet count falls
`below 20,000/(L. Major bleeding complications occur in the setting
`of more severe thrombocytopenia (platelet counts below 10,000/L)-
`With the use of more intensive regimens, newer drugs, and patients’
`receiving overall more chemotherapy, thrombocytopenia is becoming
`more common.
`Increased risk of bleeding can be seen in patients with coagulation
`disorders contributing to their thrombocytopenia. In these cases,
`processes such as DIG, which can be associated with metastatic
`infection, can increase risk of bleeding. In addition,
`cancer as well as
`this risk can also be affected by drugs that either affect platelet func
`
`REFERENCES
`1. De Vita V, Jr: Principles of cancer management: chemotherapy. In
`Cancer: Principles and Practice of Oncology. Edited by De Vita V, Jr,
`Heilman, Rosenberg. Philadelphia: Lippincott-Raven; 1997:333-348.
`2. Bodey G, Buckley M, Sathe Y, et ale Qiiantitative relationships
`between circulating leukocytes and infection in patients with acute
`leukemia. Ann Intern Med 1966, 64:328-340.
`3. Bagby G, Jr, Segal G: Growth factors and the control of
`hematopoiesis. In Hecnatology: Basic Principles and Practice. Edited by
`Hoffman B, Jr, Shattil et al. New York: Churchill Livingstone;
`1995:207-241.
`4. Crawford J, Ozer H, Stoller R, et ale Reduction by granulocyte
`lony-stimulating factor of fever and neutropenia by chemotherapy in
`CO
`patients with small-cell lung cancer. N Engl J Med 1991, 325:164-170.
`5. Nemunaitis J, Rabinowe S, Singer J, et ale Recombinant granulocyte-
`e marrow
`macrophage colony-stimulating factor after autologous bon
`transplantation for lymphoid cancer. NEngl]Med 1991,
`324:1773-1778.
`
`tion {eg, aspirin or other nonsteroidal anti-inf].ammatory agents)
`or
`coagulation function {eg, heparins or coumadin).
`Recent studies have validated an acceptable threshold of 10,000/|flj
`for transfusion of platelets and have recognized single donor or pooled
`random donor platelets as reasonable options for transfusion. This
`lower threshold has the potential not only to liitilt viral infection expo­
`sure and potentially reduce the development of alloimmunization, but
`also to reduce costs related to transfusion support.
`Advances in the field of hematopoietic growth factors have
`resulted in the approval of interleuldn-11 (Neumega [oprelvekin;
`Genetics Institute, Cambridge, MA]) for prevention of severe
`chemotherapy-induced thrombocytopenia [8]. These data support its
`which the risk of severe thrombocytopenia and the;
`use in settings in
`likelihood of the need for transfusion are high.
`
`4
`
`Omm INTERVENTIONS: PROGENITOR CELL INFUSIONS
`Use of PB progenitor or stem cells (PBPC or PBSC) has become
`increasingly widespread although the overall v