Cancer Chemotherapy Update Rituximab plus cyclophosphamide by tgv36994


									                Hospital Pharmacy
       Volume 37, Number 2, pp 119–123, 196
           2002 Facts and Comparisons

                      Cancer Chemotherapy Update

          Rituximab plus Cyclophosphamide,
          Hydroxydaunomycin (Doxorubicin),
         Oncovin (Vincristine), and Prednisone
                (R-CHOP) Regimen for
              Non-Hodgkin’s Lymphomas
     J. Aubrey Waddell, PharmD, BCOP and Dominic A. Solimando, Jr., MA, FAPhA, FASHP, BCOP

                                                                         can deplete malignant B-cells through complement-depen-
  The increasing complexity of cancer chemotherapy
                                                                         dent cell cytotoxicity, antibody-dependent cell-mediated cyto-
  makes it mandatory that pharmacists be familiar with
                                                                         toxicity, and apoptotic mechanisms. The rationale for the
  these highly toxic agents. This column reviews various
                                                                         combination of CHOP, a standard regimen for the treatment
  issues related to the preparation, dispensing, and admin-
                                                                         of non-Hodgkin’s lymphoma, with rituximab includes single-
  istration of cancer chemotherapy, both commercially
                                                                         agent efficacy of rituximab, non-cross-resistant mechanisms
  available and investigational. Questions or suggestions
                                                                         of action, nonoverlapping toxicities, and in vitro synergy of rit-
  should be addressed to: Dominic A. Solimando, Jr., Pres-
                                                                         uximab with certain cytotoxic drugs, including doxorubicin.1
  ident, Oncology Pharmacy Services, Inc., 4201 Wilson
  Boulevard, #110-545, Arlington, VA 22203 or J. Aubrey
                                                                         DRUG PREPARATION
  Waddell, Pharmacy Consultant, HHC, U.S. Army 18th
                                                                         A. Cyclophosphamide
  MEDCOM (Unit 15281), Box 711, APO AP 96205-0017
                                                                            1. Follow institutional policies for preparation of haz-
  (Seoul,      Korea).     E-mail:;
                                                                               ardous medications when preparing cyclophos-
  The opinions or assertions contained herein are the private views         2. Reconstitute cyclophosphamide according to the pack-
  of the authors and are not to be construed as official or reflecting         age insert.
  the views of the U.S. Department of the Army or Department of             3. Dilute with 100 to 250 mL 0.9% sodium chloride injec-
  Defense.                                                                     tion or 5% dextrose injection, or dispense in a syringe.
                                                                         B. Doxorubicin
                                                                            1. Follow institutional policies for preparation of haz-
                                                                               ardous medications when preparing doxorubicin.
                                                                            2. Use doxorubicin injection (2 mg/mL), or reconstitute
Regimen: R-CHOP                                                                doxorubicin according to the package insert.
Origin of Name: Acronym for rituximab plus the four                         3. Dispense in a syringe for IV bolus administration. The
drugs in the CHOP regimen: cyclophosphamide, hydroxy-                          volume should not exceed 80% of the syringe capaci-
daunomycin (doxorubicin), Oncovin                                              ty. If necessary, the dose may be divided and dis-
(vincristine), and prednisone.                                                 pensed in two syringes.
                                                                         C. Vincristine
                                                                            1. Follow institutional policies for preparation of haz-
INDICATIONS                                                                    ardous medications when preparing vincristine.
   R-CHOP is used to treat low-grade or aggressive non-                     2. Use vincristine sulfate available as a ready-to-use solu-
Hodgkin’s lymphomas of B-cell origin.1–3                                       tion in a 1 mg/mL concentration.
                                                                            3. Withdraw the calculated volume needed to administer
COMMENTS                                                                       the entire dose; dispense in a syringe. The syringe
     The majority of non-Hodgkin’s lymphomas are of B-cell                     must have the following warning attached to it: “Fatal if
origin, with > 90% of patients expressing the CD20 antigen.                    given intrathecally. For IV use only.” Additionally, the
Rituximab is a chimeric monoclonal anti-CD20 antibody that                     syringe must be enclosed in an overwrap bearing the

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Cancer Chemotherapy Update

                                                           TABLE 1

 Drug                         Dose                    Route of                    Administered                  Total Dose/
                                                    Administration                 on Day(s)                       Cycle

 Rituximab                 375 mg/m2                      IV                             1                      375 mg/m2
 Cyclophosphamide          750 mg/m                       IV                             3                      750 mg/m2
 Doxorubicin                50 mg/m2                      IV                             3                       50 mg/m2
 Vincristine               1.4 mg/m                       IV                             3                      2 mg (max)
                        (2 mg maximum)
 Prednisone                  100 mg                       PO                           3–7                        500 mg
 Cycle repeats: every 21 days for 6 cycles
 1.Czuczman et al used the regimen above for cycles 1, 3, and 5, but also gave a rituximab dose 6 days prior to cycle 1,
 3 weeks after cycle 6, and 4 weeks after cycle 6.1
 2.Coiffier et al administered all five drugs on day 1 of each cycle and continued therapy for eight cycles.3

      following warning: “Do not remove covering until                  after a meal.
      moment of injection. Fatal if given intrathecally. For IV      E. Rituximab
      use only.”                                                        1. First Infusion: The rituximab solution for infusion should
   4. Vincristine can be diluted in 25 or 50 mL of 0.9% sodi-              be administered intravenously at an initial rate of
      um chloride injection in polyvinyl chloride bags or in 20            50 mg/hr. If hypersensitivity or infusion reactions do not
      mL of 0.9% sodium chloride injection in 30 mL                        occur, escalate the infusion rate in 50 mg/hr increments
      polypropylene syringes. Dispensing vincristine in larger             every 30 minutes to a maximum of 400 mg/hr. If a
      volumes in minibags, rather than undiluted in syringes,              hypersensitivity or an infusion reaction develops, the
      has been recommended as a safety precaution to pre-                  infusion should be temporarily slowed or interrupted.
      vent inadvertent intrathecal injection.4                             The infusion can continue at one-half the previous rate
D. Rituximab                                                               upon improvement of patient symptoms.
   1. Use rituximab available as a ready-to-use solution in a           2. Subsequent Infusions: If the patient tolerates the first
      10 mg/mL concentration.                                              infusion well, subsequent rituximab infusions can be
   2. Using appropriate aseptic technique, draw up the vol-                administered at an initial rate of 100 mg/hr and
      ume of rituximab and dilute to a final concentration of 1            increased by 100 mg/hr increments at 30-minute inter-
      to 4 mg/mL into an infusion bag containing 0.9% Sodi-                vals to a maximum of 400 mg/hr as tolerated. If the
      um Chloride, USP or 5% Dextrose in Water, USP.                       patient does not tolerate the first infusion well, follow
                                                                           the guidelines under First Infusion.
A. Cyclophosphamide: Usually given as a short (15- to 60-            SUPPORTIVE CARE
   minute) infusion. Some institutions allow doses < 1000            A. Acute Emesis Prophylaxis:5–8 Rituximab does not cause
   mg to be administered as a slow (3 to 10 minute) IV push.            significant nausea or vomiting, but the CHOP portion of
B. Doxorubicin: Administer as an IV bolus over 3 to 10 min-             the regimen is predicted to cause acute emesis in > 90%
   utes through the tubing of a free-flowing IV of saline or            of patients. Appropriate acute emesis prophylaxis should
   dextrose. Doxorubicin is a potent vesicant. Extravasation            include a serotonin antagonist. One of the following regi-
   precautions should be followed.                                      mens is suggested:
C. Vincristine: Administer as a slow (1 to 2 minute) direct IV          1. Ondansetron 24 mg PO given 30 minutes prior to
   push, or through the tubing of a rapidly flowing saline or              CHOP, with the day 1 dose of prednisone given with
   dextrose infusion. Vincristine is a moderate vesicant;                  the ondansetron.
   extravasation precautions should be followed.                        2. Granisetron 2 mg PO given 30 minutes prior to CHOP,
D. Prednisone: Usually given as a single daily dose. To avoid              with the day 1 dose of prednisone given with the
   gastric irritation, the drug should be taken with food or               granisetron.

120      Volume 37, February 2002
                                                                                    Cancer Chemotherapy Update

   3. Dolasetron 100 mg PO given 30 minutes prior to             D. Hypersensitivity Precautions:10
      CHOP, with the day 1 dose of prednisone given with            1. Cyclophosphamide has rarely caused hypersensitivity
      the dolasetron.                                                  reactions. Reported symptoms range from urticaria to
   In some patients, nausea or vomiting may not begin for 12           anaphylaxis with shock or bronchospasm. No specific
   to 24 hours after cytotoxic drug administration. Prophy-            precautions are required.
   lactic therapy to prevent this late onset emesis should          2. Doxorubicin can induce acute hypersensitivity reac-
   continue for 2 to 3 days. One suggested regimen is:                 tions. However, such reactions are rare and require no
   Ondansetron 8 mg PO BID for 3 days, starting the day                specific precautions. Doxorubicin may cause a “flare
   after CHOP. Another option is to add a dopamine antago-             reaction,” manifested by erythema, pruritus, and
   nist (eg, metoclopramide 20 mg PO, thiethylperazine 10              urticaria localized to or adjacent to the drug injection
   mg PO, or prochlorperazine 10 mg PO) PRN after treat-               site. Although sometimes confused as an extravasation
   ment.                                                               or a serious allergic reaction, it does not progress in
B. Breakthrough Antiemetics:7,8 Patients should receive an             most cases. Additional drug doses can be administered
   antiemetic prescription to treat breakthrough nausea.               without concern for more serious problems.
   These regimens are often sufficient for patients who have        3. Rituximab has been associated with hypersensitivity
   only mild-to-moderate nausea. The following regimens                reactions that may respond to adjustments in the infu-
   are suggested:                                                      sion rate and in medical management. Hypotension,
   1. Metoclopramide 20 to 40 mg PO every 4 to 6 hours as              bronchospasm, and angioedema have occurred in
      needed, ± diphenhydramine 25 to 50 mg PO every 4 to              association with rituximab infusion. Treatment of these
      6 hours.                                                         symptoms with diphenhydramine and acetaminophen
   2. Prochlorperazine 10 mg PO every 4 to 6 hours as                  is recommended; additional treatment with bron-
      needed, or prochlorperazine 15 mg (extended release              chodilators or IV saline may be indicated. In most
      capsule) every 8 to 12 hours as needed, or prochlor-             cases, patients who have experienced non-life-threat-
      perazine 25 mg rectally every 6 hours as needed.                 ening hypersensitivity reactions have been able to
   3. Thiethylperazine 10 mg PO every 4 to 6 hours as                  complete the full course of therapy.11
       needed.                                                      Deaths within 24 hours of rituximab infusion have been
C. Hydration:9 Patients must be adequately hydrated to              reported. These fatal reactions followed an infusion reac-
   reduce the risk of hemorrhagic cystitis secondary to             tion complex that included hypoxia, pulmonary infiltrates,
   cyclophosphamide. Patients should be encouraged to               acute respiratory distress syndrome, myocardial infarc-
   void their bladders frequently. This can be accomplished         tion, ventricular fibrillation, or cardiogenic shock. Approxi-
   by encouraging liberal fluid consumption (3 to 4 L/day)          mately 80% of fatal infusion reactions occurred in associ-
   during each day of treatment with cyclophosphamide and           ation with the first infusion.11
   for at least 24 hours after the last cyclophosphamide         E. Hematopoietic Growth .actors: Accepted practice guide-
   dose. No hemorrhagic cystitis was reported in the studies        lines and pharmacoeconomic analyses suggest that a
   reviewed; however, Stillwell reports it could occur follow-      chemotherapy regimen have a greater than 20% to 40%
   ing a single IV dose. The risk of hemorrhagic cystitis           (depending upon institutional cost differences) incidence
   increases with higher total doses of cyclophosphamide            of febrile neutropenia before prophylactic use of colony-
   and the incidence increases when cyclophosphamide and            stimulating factors (filgrastim, sargramostim) is warrant-
   radiation are given, especially when they are adminis-           ed.12–14 In the studies reviewed, a 20% incidence of febrile
   tered concurrently.                                              neutropenia1 and up to 58% incidence of grade 4 neu-
                                                                    tropenia1,2 were reported. Economic studies support the
                                                                    routine use of hematopoietic growth factors in patients
                                                                    with non-Hodgkin’s lymphomas, especially among the
                                                                 .. Extravasation17,18
                                                                    1. Doxorubicin is a potent vesicant. Extra care should be
                                                                       taken to avoid extravasation. If extravasation does
                                                                       occur, stop the infusion immediately and aspirate as
                                                                       much of the extravasated solution as possible before
                                                                       withdrawing the needle. The limb should be elevated
                                                                       and cooled intermittently (ice packs for 15 to 20 min-
                                                                       utes four times daily for 3 days).
                                                                    2. Vincristine a moderately potent vesicant and extrava-

                                                                                                    Hospital Pharmacy        121
Cancer Chemotherapy Update

      sation should also be avoided. If extravasation does             (grade 3 or 4) 3%, pharyngitis (grade 1 or 2) 18% to 25%,
      occur, stop the infusion immediately and aspirate as             rhinitis (grade 1 or 2) 9% to 25%, sepsis (grade 3 or 4)
      much of the extravasated solution as possible before             6%, sialadenitis (grade 3 or 4) 3%, sinusitis (grade 1 or 2)
      withdrawing the needle. Although Larson reported                 15%.
      using cold for vinca alkaloid extravasations,18 other         H. Neurologic:1 anxiety (grade 1 or 2) 28%, arthralgias
      reports recommend the application of heat to the area            (grade 1 or 2) 18%, arthralgias (grade 3 or 4) 2.5%, asthe-
      if vincristine is extravasated.19 This literature also rec-      nia (grade 1 or 2) 38%, asthenia (grade 3 or 4) 2.5%,
      ommends the administration of hyaluronidase (150                 dizziness (grade 1 or 2) 13%, headache (grade 1 or 2)
      units) as five 0.2 mL injections into the extravasation          33%, hypertonia (grade 1 or 2) 13%, insomnia (grade 1 or
      site.19                                                          2) 20%, myalgia (grade 1 or 2) 23%, pain (grade 1 or 2)
   In the majority of cases, this conservative approach                25%, paresthesias (grade 1 or 2) 13%.
   allows spontaneous resolution and requires no further            I. Pulmonary:1 dyspnea (grade 1 or 2) 18%, dyspnea (grade
   treatment. Patients experiencing continuing pain or loss of         3 or 4) 2.5%.
   function should be referred to a plastic surgeon for possi-      J. Rituximab Infusion-Related Events:1,2 fever (grade 1 or 2)
   ble graft repair.                                                   30% to 33%, chills (grade 1 or 2) 23% to 30%, pruritus
                                                                       (grade 1 or 2) 15%.
MAJOR TOXICITIES                                                    K. Other:1,2 abdominal pain (grade 1 or 2) 10%, abdominal
      Most of the toxicities listed below are presented accord-        pain (grade 3 or 4) 2.5%, cerebral vascular accident 3%,
ing to their degree of severity. Higher grades represent more          cholecystitis 3%, dehydration 3%, cough (grade 1 or 2)
severe toxicities. Although there are several grading systems          22%, death due to reactivation of hepatitis with subse-
for cancer chemotherapy toxicities, all are similar. One of the        quent liver failure 3%, hyperglycemia (grade 1 or 2) 8%,
frequently used systems is the National Cancer Institute               hyperglycemia (grade 3 or 4) 5%, intestinal perforation
(NCI)              Common              Toxicity         Criteria       3%, obstruction intestine 3%, right heart failure 3%,
( Oncologists gen-          weight loss (grade 1 or 2) 13%.
erally do not adjust doses or change therapy for grade 1 or 2
toxicities but make, or consider, dosage reductions or thera-       PRETREATMENT LABORATORY STUDIES
py changes for grade 3 or 4 toxicities.                             NEEDED
A. Allergy:2 (grade 3 or 4, rituximab-related) 3%, anaphylax-       A. Baseline
    is (grade 3 or 4, rituximab-related) 3%.                           1. AST/ALT*
B. Dermatologic:1 alopecia (grade 1 or 2) 58%, alopecia                2. Total bilirubin*
    (grade 3 or 4) 2.5%.                                               3. Serum creatinine*
C. .ebrile Neutropenia:1 20%.                                          4. CBC with differential or WBC
D. .ever:1,2 (all grades) 6%, (grade 3 or 4) 5%.                    *Some clinicians prefer to obtain these studies prior to each
E. Gastrointestinal:1 constipation (grade 1 or 2) 28%, diar-        treatment cycle.
    rhea (grade 1 or 2) 15%, dyspepsia (grade 1 or 2) 23%,
    esophagitis (grade 1 or 2) 13%, esophagitis (grade 3 or 4)      DOSAGE MODIFICATIONS
    2.5%, nausea (grade 1 or 2) 65%, nausea (grade 3 or 4)          A. Renal function:20 None are recommended.
    2.5%, vomiting (grade 1 or 2) 35%, vomiting (grade 3 or         B. Hepatic function:21
    4) 2.5%, stomatitis (grade 1 or 2) 20%, stomatitis (grade          1. Cyclophosphamide
    3 or 4) 2.5%.                                                         a. Reduce dose by 25% for total bilirubin 3.1 to 5 mg/dL
.. Hematologic:1,2 anemia (grade 1 or 2) 35%, anemia (grade                  or AST > 180 IU/L.
    3 or 4) 5% to 12%, leukopenia (all grades) 33% to 48%,                b. Omit dose for total bilirubin > 5 mg/dL.
    leukopenia (grade 1 or 2) 23%, leukopenia (grade 3 or 4)           2. Doxorubicin
    25%, neutropenia (all grades) 73% to 78%, neutropenia                 a. Reduce dose by 50% for total bilirubin 1.5 to 3 mg/dL
    (grade 1 or 2) 18%, neutropenia (grade 3 or 4) 58% to                    or AST 60 to 180 IU/L.
    60%, patients requiring blood transfusion 15%, patients               b. Reduce dose by 75% for total bilirubin 3.1 to 5 mg/dL
    requiring platelet transfusion 0%, patients requiring at                 or AST > 180 IU/L.
    least one course of granulocyte colony-stimulating factor             c. Omit dose for total bilirubin > 5 mg/dL.
    55%, thrombocytopenia (grade 1 or 2) 10%, thrombocy-               3. Vincristine
    topenia (grade 3 or 4) 3% to 10%.                                     a. Reduce dose by 50% for total bilirubin 1.5 to 3 mg/dL
G. Infection1,2 any (grade 1 or 2) 33%, any (grade 3 or 4)                   or AST 60 to 180 IU/L.
    2.5%, cellulitis (grade 3 or 4) 3%, neutropenia plus infec-           b. Omit dose for total bilirubin > 3.1 mg/dL or AST >
    tion 2.5%, oral thrush (grade 1 or 2) 9%, oral thrush                    180 IU/L.

122      Volume 37, February 2002
                                                                                            Cancer Chemotherapy Update

C. Myelosuppression22                                                       the last cytotoxic dose. The suspected mechanism for this
      In clinical practive, a pretreatment ANC of 1000                      effect is a reversible alteration in the intestinal mucosa
cells/mcL and a platelet count of 75,000 cells/mcL are usual-               that decreases the amount of digoxin absorbed. Clinical
ly considered acceptable for full-dose therapy with R-CHOP.                 management includes the monitoring of digoxin trough
Examples of dosage modifications from CHOP studies are                      plasma concentrations before, during, and after cytotoxic
as follows:                                                                 therapy. Alternatively, an equivalent IV dose could be
    1. Delayed for 1 week if the absolute neutrophil count                  given during the course of cytotoxic therapy. This permits
        (ANC) is < 1500 cells/mcL or the platelet count is <                continuation of therapy with fewer digoxin trough mea-
        100,000 cells/mcL.                                                  surements.
    2. No dose reductions for leukocyte counts 4 x 109
        cells/L and platelet counts 100 x 109 cells/L.                   REFERENCES
    3. Twenty-five percent reduction of cyclophosphamide                 1. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treat-
        and doxorubicin if the leukocyte count is 3 x 109                ment of patients with low-grade B-cell lymphoma with the
        cells/L and 4 x 109 cells/L or the platelet count is             combination of chimeric anti-CD20 monoclonal antibody and
                                                                         CHOP chemotherapy. J Clin Oncol. 1999;17:268–76.
        75 x 109 cells/L and 100 x 109 cells/L.
                                                                         2. Vose JM, Link BK, Grossbard ML, et al. Phase II study of
    4. Fifty percent reduction of cyclophosphamide and dox-              rituximab in combination with CHOP chemotherapy in
        orubicin if the leukocyte count is 2 x 109 cells/L and           patients with previously untreated, aggressive non-Hodgkin’s
          3 x 109 cells/L or the platelet count is 50 x 109              lymphoma. J Clin Oncol. 2001;19:389–97.
        cells/L and 75 x 109 cells/L.                                    3. Coiffier B, Lepage E, Gaulard P, et al. Prognostic factors
    5. Fifty percent dose reduction of cyclophosphamide and              affecting the efficacy of rituximab plus CHOP (R-CHOP) ther-
                                                                         apy in elderly patients with diffuse large B-cell lymphoma
        doxorubicin if the neutrophil count is 0.8 x 109 cells/L to      (DLCL): Results of a randomized GELA trial. Proc Am Soc
        1.5 x 109 cells/L or if the platelet count is 75 x 109 cells/L   Clin Oncol [CD ROM version 2001]. Alexandria, VA: Ameri-
        to 124 x 109 cells/L on the day of treatment. All therapy,       can Society of Clinical Oncology; 2001. Abstract 1131.
        including vincristine and prednisone, are held if the            4. Trissel L, Zhang Y, Cohen M. The stability of diluted vin-
        neutrophil count is < 0.8 x 109 cells/L or the platelet          cristine sulfate used as a deterrent to inadvertent intrathecal
                                                                         injection. Hosp Pharm. 2001;36:740–5.
        count is < 75 x 109 cells/L.
                                                                         5. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for
    6. Twenty percent reduction of doxorubicin and                       classifying the acute emetogenicity of cancer chemotherapy.
        cyclophosphamide if the WBC is < 1500 cells/mm3 or               J Clin Oncol. 1997;15:103–9.
        the platelet count is < 50,000 cells/mm3.                        6. American Society of Health-System Pharmacists. ASHP
D. Neurologic:23,24 The vincristine dose should be reduced by            therapeutic guidelines on the pharmacologic management of
    50% if a patient is unable to walk on the heel, has severe           nausea and vomiting in adult and pediatric patients receiving
                                                                         chemotherapy or radiation therapy or undergoing surgery.
    obstipation, or exhibits grade II neurotoxicity (excluding           Am J Health Syst Pharm. 1999;56:729–64.
    reflex changes). Vincristine should be discontinued if the
                                                                         7. National Comprehensive Cancer Network. NCCN
    patient has difficulty walking or if grade III or IV neurotox-       antiemesis practice guidelines. The Complete Library of
    icity is observed.                                                   NCCN Oncology Practice Guidelines [CD-ROM, version
                                                                         2000]. Rockledge, PA: National Comprehensive Cancer Net-
                                                                         work; 2000.
                                                                         8. Gralla RJ, Osoba D, Kris MG, et al. Recommendations for
1. Verapamil appears to alter the distribution of doxorubicin            the use of antiemetics: evidence-based, clinical practice
   in neoplastic cells. Various authors have described                   guidelines. J Clin Oncol. 1999;17:2971–94.
   increases in doxorubicin toxicity and alteration of mul-              9. Stillwell TJ, Benson RC. Cyclophosphamide-induced
   tidrug resistance following verapamil administration. The             hemorrhagic cystitis: A review of 100 patients. Cancer.
   mechanism for this phenomenon is unknown. This sug-                   1988;61:451–7.
   gests the need for closer monitoring of cardiac function in           10.Weiss RB. Hypersensitivity reactions. Semin Oncol.
   patients on these agents. Verapamil appears to be the
   only calcium channel-blocking drug to exert this effect.
2. Coadministration of doxorubicin, bleomycin, cyclophos-
   phamide, or vincristine with digoxin can cause a 20% to
   30% reduction in the area under the plasma concentra-
   tion–time curve (AUC) of digoxin and subsequent cardiac
   decompensation in some patients. This change in
   bioavailability can occur as soon as 24 hours after the first
   dose of cytotoxic agent and may persist up to 7 days after                                               continued on page 196

                                                                                                           Hospital Pharmacy       123
Cancer Chemotherapy Update

Continued from page 123
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Lyman GH, Balducci L. Update of the economic analyses of
the use of the colony-stimulating factors. Curr Opin Hematol.
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18.Larson DL. What is the appropriate management of tis-
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196      Volume 37, February 2002

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