Cancer Chemotherapy Update Estramustine and vinblastine (EV) regimen

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					               Hospital Pharmacy
        Volume 37, Number 7, pp 714–720
          2002 Facts and Comparisons

                     Cancer Chemotherapy Update

          Estramustine and Vinblastine (EV)
               Regimen for Advanced
         Hormone-Refractory Prostate Cancer
         J. Aubrey Waddell, PharmD, BCOP and Dominic A. Solimando, Jr., MA, FAPhA, FASHP, BCOP

 The increasing complexity of cancer chemotherapy
 makes it mandatory that pharmacists be familiar with
 these highly toxic agents. This column reviews various
                                                                             EV is used as palliative therapy for advanced hormone-
 issues related to the preparation, dispensing, and admin-
                                                                        refractory prostate cancer;1,2 however, estramustine/taxane
 istration of cancer chemotherapy, both commercially
                                                                        regimens, with their superior PSA reductions, are increas-
 available and investigational. Questions or suggestions
                                                                        ingly employed in this setting.3
 should be addressed to: Dominic A. Solimando, Jr., Pres-
 ident, Oncology Pharmacy Services, Inc., 4201 Wilson
                                                                        DRUG PREPARATION
 Boulevard, #110-545, Arlington, VA 22203 or J. Aubrey
                                                                        A. Estramustine
 Waddell, Department of Pharmacy, Walter Reed Army
                                                                           1. Follow institutional policies for preparation of haz-
 Medical Center, Washington, DC 20307-5001. E-mail:
                                                                              ardous medications when dispensing estramustine
 The opinions or assertions contained herein are the private views         2. Dispense 140 mg capsules.
 of the authors and are not to be construed as official or reflecting   B. Vinblastine
 the views of the U.S. Department of the Army or Department of             1. Follow institutional policies for preparation of haz-
                                                                              ardous medications when preparing vinblastine.
                                                                           2. Vinblastine is available from several sources as a ster-
                                                                              ile powder and a 1 mg/mL ready-to-use solution. When
                                                                              preparing the powder, reconstitute with 0.9% sodium
                                                                              chloride or bacteriostatic 0.9% sodium chloride to
Regimen: EV (see Table 1).
                                                                              achieve a final concentration of 1 mg/mL.
Origin of Name: acronym for the two drugs in the regi-
                                                                           3. Vinblastine doses must have the following warning
men: estramustine and vinblastine
                                                                              attached to the syringe: “Fatal if given intrathecally. For
                                                                              IV use only.” Additionally, the syringe must be enclosed
COMMENTS                                                                      in an overwrap bearing the following warning: “Do not
     When hormone manipulations cease to be effective in                      remove covering until moment of injection. Fatal if
the treatment of advanced prostate cancer, there is a pallia-                 given intrathecally. For IV use only.”
tive role for combination chemotherapy.1,2,3 This was not                  4. The dose is usually dispensed in a syringe for IV bolus
always standard practice, mainly due to low objective                         administration.
response rates with single chemotherapy agents in trials
conducted before the routine use of serum prostate specific             DRUG ADMINISTRATION
antigen (PSA) as an effective tumor marker for prostate can-            A. Estramustine: This agent is usually given as two or three
cer. In the PSA era, some chemotherapy regimens have                       divided doses per day. The drug should be taken at least
caused declines in PSA in up to 70% to 75% of patients, and                1 hour before or 2 hours after meals and should be swal-
clear symptomatic relief has been documented. Therefore,                   lowed whole with a glass of water. Milk, milk products, and
combination chemotherapy regimens continue to be studied                   calcium-rich foods or drugs must not be taken at the same
for tumor response, survival, and quality of life outcomes.                time as estramustine.
Combination chemotherapy regimens are routinely used for                B. Vinblastine: Administer as an IV bolus over 3 to 10 min-
palliative care of advanced, hormone-refractory prostate                   utes through the side-arm of a free-flowing IV saline or

714      Volume 37, July 2002
                                                                                   Cancer Chemotherapy Update

                                                          TABLE 1

                                                        EV Regimen4,5
 Drug                           Dose                   Route of                 Administered                Total Dose/
                                                     Administration              on Day(s)                     Cycle

 Estramustine                 600 mg/m2                    PO                       1–42                  25,200 mg/m2
                           in two or three
                            divided doses
 Vinblastine                   4 mg/m2                     IV                1, 8, 15, 22, 29, 36            24 mg/m2
 Cycle repeats: Every 8 weeks until not tolerated or disease progression.
 1.Estramustine 10 mg/kg in three divided doses per day has been used in the regimen above.6–8
 2.Estramustine 420 mg in three divided doses per day plus vinblastine 5 mg/m2 or 6 mg/m2 IV once each week, continu-
   ously with no rest period, has been used.9,10

   dextrose infusion.                                            G. Extravasation:22–24 Vinblastine is a moderate vesicant and
                                                                    extravasation should be avoided. If extravasation occurs,
SUPPORTIVE CARE                                                     stop the infusion immediately and aspirate as much of the
A. Acute Emesis Prophylaxis:4–6,9,10–14 EV causes emesis in         extravasated solution as possible before withdrawing the
   fewer than 10% of patients; however, nausea from EV has          needle. The limb should be elevated and cooled intermit-
   been reported in up to 66.7% of patients. Acute emesis           tently (ice packs for 15 to 20 minutes four times daily for
   prophylaxis is not generally prescribed. Because most of         3 days). Although Larson reported using cold for vinca
   EV’s emetogenicity and nausea is contributed by the daily        alkaloid extravasations, most other reports recommend
   estramustine, patients should receive an antiemetic pre-         the application of heat to the area if vinblastine is
   scription to treat breakthrough nausea/vomiting. Since the       extravasated.
   efficacy of the serotonin antagonists is reported to dimin-
   ish with repeated dosing over multiple days,15 the routine    MAJOR TOXICITIES
   use of these agents to manage estramustine-induced                 Most of the toxicities listed below are presented accord-
   nausea or vomiting is not recommended. The following          ing to their degree of severity. Higher grades represent more
   regimens are suggested:                                       severe toxicities. Although there are several grading systems
   1. Metoclopramide 20 to 40 mg PO every 4 to 6 hours as        for cancer chemotherapy toxicities, all are similar. One of the
       needed; diphenhydramine 25 to 50 mg PO every 4 to         frequently used systems is the National Cancer Institute
       6 hours as needed for restlessness or agitation.          (NCI)            Common               Toxicity         Criteria
   2. Prochlorperazine 10 mg PO every 4 to 6 hours as            ( Oncologists gen-
       needed, or 15 mg (extended-release capsule) every 8       erally do not adjust doses or change therapy for grade 1 or 2
       to 12 hours as needed, or 25 mg rectally every 6 hours    toxicities; but make or consider dosage reductions or thera-
       as needed.                                                py changes for grade 3 or 4 toxicities.
   3. Thiethylperazine 10 mg PO every 4 to 6 hours as            A. Cardiovascular:4,5 atrial fibrillation (grade 1) 1.1%, con-
       needed.                                                      gestive heart failure (grade 3or 4) 3.2%, deep vein throm-
D. Hydration: No special precautions are required.                  bosis (grade 2, 3, or 4) 3.2%, edema (grade 1 or 2)
E. Hypersensitivity Precautions:16 No special precautions           28.9%, edema (grade 3 or 4) 2.6%, hypotension (grade 1)
   are required.                                                    1.1%, leg edema (grade 2, 3, or 4) 11.6%, myocardial
F. Hematopoietic Growth Factors:4–10,17–21 Accepted prac-           infarction 2.6%, palpitations (grade 1) 1.1%, transient
   tice guidelines and pharmacoeconomic analysis suggest            ischemic neurologic event 2.6%.
   that a chemotherapy regimen have a greater than 20% to        B. Febrile Neutropenia:4,9,10 0%.
   40% (depending on institutional cost differences) inci-       C. Gastrointestinal:4–6,9,10 anorexia (grade 1 or 2) 10.5% to
   dence of febrile neutropenia before prophylactic use of          60%, anorexia (grade 3 or 4) 0% to 6.7%, indigestion
   colony-stimulating factors is warranted. Since febrile neu-      (grade 1 or 2) 10.5%, nausea (grade 1 or 2) 50%, nausea
   tropenia with EV is rarely reported, prophylactic use of         (grade 3 or 4) 2.6%, nausea (grade 2, 3, or 4) 28.4%, nau-
   colony-stimulating factors is not recommended.                   sea (mild) 20%, nausea/vomiting (grade 1 or 2) 66.7%,

                                                                                                    Hospital Pharmacy      717
Cancer Chemotherapy Update

   stomatitis (grade 1 or 2) 13.3%, stomatitis (grade 2) 5.3%,         or platelets below 75,000 cells/mcL.5–7
   vomiting (grade 1 or 2) 7.8%.                                    2. Amato et al held the weekly vinblastine dose for
D. Hematologic:4–6,9 anemia (grade 1 or 2) 31.6% to 73.3%,             absolute granulocyte counts (AGCs) less than 900
   anemia (grade 3 or 4) 0% to 23.3%, granulocytopenia                 cells/mcL or platelets less than 50,000 cells/mcL and
   (grade 1 or 2) 10%, granulocytopenia (grade 2) 7.4%,                did not restart weekly vinblastine doses until the AGC
   granulocytopenia (grade 3 or 4) 8.4% to 66.7%, leukope-             recovered to 1500 cells/mcL and platelets recovered to
   nia (grade 1 or 2) 31.6%, leukopenia (grade 2) 8%,                  100,000 cells/mcL.9
   leukopenia (grade 3 or 4) 7.9%, leukopenia (grade 4) 4%,         3. In clinical practice, a pretreatment absolute neutrophil
   thrombocytopenia (grade 1 or 2) 0% to 16.7%, thrombo-               count (ANC) of 1000 cells/mcL and platelets of 75,000
   cytopenia (grade 2, 3, or 4) 1.1%, thrombocytopenia                 cells/mcL are usually considered acceptable for full-
   (grade 3 or 4) 3.3%.                                                dose combination chemotherapy.
E. Infection:5,9 (grade 1 or 2) 43.3%, (grade 2 or 3) 7.4%.      D. Other: Hudes et al reduced the estramustine dose by two
F. Neurologic:4,6,9,10 constipation (grade 1 or 2) 7.9% to          capsules (280 mg) per day for nausea or vomiting unre-
   23.3%, constipation (grade 2, 3, or 4) 3.2%, constipation        sponsive to oral antiemetics, held estramustine and vin-
   (grade 3 or 4) 0% to 2.6%, ileus 2.6% to 3.3%, leg cramps        blastine for any grade 3 or 4 nonhematologic toxicity, and
   (grade 1 or 2) 13.2%, paresthesias (grade 1 or 2) 13.2%          resumed both drugs at 50% of the starting dose after
   to 33.3%, peripheral neuropathy (grade 1 or 2) 10.5% to          recovery from toxicity.5
G. Other:4–6,9 breast tenderness (grade 1 or 2) 26.3%, fatigue   REFERENCES
   (grade 1 or 2) 28.9% to 70%, fatigue (grade 2, 3, or 4)       1. National Comprehensive Cancer Network. NCCN Prac-
   15.8%, fatigue (grade 3 or 4) 2.6% to 3.3%, painful           tice Guidelines in Oncology: Prostate cancer (The Complete
   gynecomastia 8%.                                              Library of Practice Guidelines in Oncology [CD-ROM]).
                                                                 Rockledge, PA: National Comprehensive Cancer Network;
H. Treatment-Related Death:8 cardiovascular-related 4.3%.        2001.
                                                                 2. Culine S, Droz JP. Chemotherapy in advanced androgen-
PRETREATMENT LABORATORY STUDIES                                  independent prostate cancer 1990-1999: A decade of
NEEDED                                                           progress? Ann Oncol. 2000;11:1523–30.
A. Baseline                                                      3. Harris KA, Reese DM. Treatment options in hormone-
   1. AST/ALT*                                                   refractory prostate cancer—current and future approaches.
                                                                 Drugs. 2001;61:2177–92.
   2. Total bilirubin*
   3. Serum creatinine                                           4. Hudes GR, Greenberg R, Krigal RL, et al. Phase II study
                                                                 of estramustine and vinblastine, two microtubule inhibitors, in
   4. CBC with differential                                      hormone-refractory prostate cancer. J Clin Oncol.
*Some clinicians prefer to obtain these studies before each      1992;10:1754–61.
treatment cycle.                                                 5. Hudes G, Einhorn L, Ross E, et al. Vinblastine versus vin-
B. Prior to each treatment: CBC with differential.               blastine plus oral estramustine phosphate for patients with
                                                                 hormone-refractory prostate cancer: A Hoosier Oncology
                                                                 Group and Fox Chase Network phase III trial. J Clin Oncol.
DOSAGE MODIFICATIONS                                             1999;17:3160–6.
A. Renal function:25 None necessary.                             6. Seidman AD, Scher HI, Petrylak D, et al. Estramustine
B. Hepatic function:26                                           and vinblastine: Use of prostate specific antigen as a clinical
   1. Vinblastine                                                trial end point for hormone refractory prostatic cancer. J Urol.
      a. Reduce dose by 50% for total bilirubin 1.5 to 3
          mg/dL or AST 60 to 180 IU/L.                           7. Attivissimo LA, Fetten JV, Kreis W. Symptomatic improve-
                                                                 ment associated with combined estramustine and vinblastine
      b. Omit dose for total bilirubin levels greater than 3.1   chemotherapy for metastatic prostate cancer. Am J Clin
          mg/dL or AST values greater than 180 IU/L.             Oncol (CCT). 1996;19:581–3.
C. Hematologic                                                   8. Albrecht W, Horenblas S, Marechal, JM, et al. Random-
   1. Hudes et al, Seidman et al, and Attivissimo et al gave     ized phase II trial assessing estramustine and vinblastine
                                                                 combination chemotherapy vs estramustine alone in patients
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      counts greater than or equal to 3000 cells/mcL and         cer [abstract]. Proc Am Soc Clin Oncol. 1998;17:101a.
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      75,000 to 99,000 cells/mcL, and omitted the weekly         10.Sella A, Flex D, Konichezky M, et al. Combination
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                                                                 independent prostate cancer. Eur Urol. 2000;38:255–8.

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Cancer Chemotherapy Update

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