Paclitaxel and Carboplatin for Advanced Breast Cancer
`
`Edith A. Perez and Lynn C. Hartmann
`
`This report evaluates the activity of paclitaxel alone
`(Taxol; Bristol-Mye rs Squibb Company, Princeton, NJ),
`carboplatin alone, and their combination in the treat(cid:173)
`m ent of patients with advanced breast cancer. The pre(cid:173)
`liminary safety information of this c~mbination in other
`~umor types also is discussed. Finally, the overall ratio(cid:173)
`nale for ongoing study of the efficacy of paclitaxel and
`carboplatin, along with appropriate translational stud(cid:173)
`ies, as first-line che motherapy in patients with meta(cid:173)
`static. breast cancer is examined. Both paclltaxel and
`c~boplatin have w ell-established single-agent activity
`in the treatment of women with breast cancer. The
`tolerability of this combination, using the sequence
`paclitaxel followed by carboplatin infusion, already has
`been established In patients with lung cancer and ovar(cid:173)
`ian cancer. In addition, this therapy has the novel attri·
`bute of a relative platelet-sparing effect. A phase II trial
`evaluating the efficacy of the paclltaxelfcarboplatin
`combination, along with an evaluation of thrombopoie(cid:173)
`t in levels and quality of life, has been initiated recently
`through the North Central Cancer Treatment Group.
`In this trial, intrave nous paclitaxel 200 mg/m1 infused
`over 3 hours is followed by c.arboplatin at a calculated
`area under the concentration-time curve dose of 6,
`with cycles repeated every 21 days. Results from this
`trial will help document the role of the paclitaxel/car(cid:173)
`boplatin combination in the treatment of women with
`breast cancer.
`Copyright © 1996 by W.B. Saunden Company
`
`M ET AST A TIC breast cancer is rarely curable
`
`with standard chemotherapy. Standard
`chemotherapy combinations like cyclophospha(cid:173)
`mide/doxorubicin or cyclophosphamide/metho(cid:173)
`trexate/5-fluorouracil result in objective responses
`in approximately 30% to 50% of such patients. 1
`Since a significant portion of patients with opera(cid:173)
`ble breast cancer are candidates for adjuvant che(cid:173)
`motherapy with cyclophosphamide/methotrexate/
`5-fluorouracil or cyclophosphamide/doxorubicin/
`5-fluorouracil (or similar regimens), many patients .
`with advanced breast cancer will already have been
`exposed to the drugs most commonly used to treat
`advanced d.isease, rendering them less likely to re(cid:173)
`spond to such treatment a second time. 1 The iden(cid:173)
`tification of active new drugs or drug combina(cid:173)
`tions, therefore, is urgently needed.
`
`PACLITAXEL IN ADVANCED
`BREAST CANCER
`
`Paclitaxel (Taxol; Bristol-Myers Squibb Com(cid:173)
`pany, Princeton, NJ) is a promising new agent in
`
`the treatment of women with advanced breast can(cid:173)
`cer. Its use Leads to objective responses in approxi(cid:173)
`mately 50% to 60% of such patients when used as
`initial therapy. 2
`•3 Paclitaxel also produces objective
`responses in approximately 20% to 25% of patients
`with advanced disease who are resistant to other
`chemotherapy.Ho Clinical trials have investigated
`the administration of paclicaxel every 3 weeks at
`,varying doses (135 to 250 mg/m2
`) and schedules
`( 1- to 96-hour infusions). Weekly administration
`of paclitaxel is also being investigated, as is pro(cid:173)
`longed continuous infusion. Paclitaxel's optimal
`dose and administration schedule, whether used as
`a single agent or in a combination regimen, are a
`matter of extensive ongoing research. The dose(cid:173)
`limiting toxicity of paclitaxel, a deep but brief neu(cid:173)
`tropenia, is both dose and schedule dependent. A
`variety of combination chemotherapy trials with
`paclitaxel and other agents have been reported
`recently, demonstrating the potentially important
`role of this agent in combination treatment. Phase
`l/ll studies by Gianni and colleagues1
`2 and Gehl
`1.1
`et al 13 evaluated paclitaxel and doxorubicin in pa(cid:173)
`tients with metastatic breast cancer. Preliminary
`data are consistent with previous trials and show
`overall response rates greater than 85% and com(cid:173)
`plete response rates between 30% and 40%; how(cid:173)
`ever, further follow-up will be necessary to evalu(cid:173)
`ate the impact of this combination on median
`length of survival. The concurrent use of these rwo
`agents is associated with a somewhat greater than
`expected degree of cardiac toxicity, thereby lim(cid:173)
`iting the total cumulative dose of doxorubicin to
`no greater than 360 mg/m2
`• Recent phase II studies
`evaluating paclitaxel 200 mg/m1 plus doxorubicin
`60 mg/m1 intravenously (IV) every 3 weeks, with
`and without hematopoietic growth factors, have
`·been initiated through the Eastern Cooperative
`Oncology Group and the Southwest Oncology
`Group.
`
`From the Division of Hematology/Oncology Mayo Clinic and
`Mayo Foundation, Jacksonville, FL; and <he Mayo Clinic Roches(cid:173)
`ter, MN.
`Address reprint requests tO Edich A. Peret, MD, Division of
`Hemacology/Onco!ogy, Mayo Clinic Jacksonville, 4500 San Pablo
`Rd, Jacksonville, FL 32224.
`Copyright It> l996 lry W .B. Saunders Company
`@3-7754/96/2305-l I 10$05.0010
`
`Semina11 in Oncology, Vol 23. No S. Suppl 1 I (October). 1996: pp 4 1--45
`
`41
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`1 of 5
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`<42
`
`PEREZ AND HARTMANN
`
`The combination of paclitaxel/cisplatin has
`been studied by several groups using biweekly
`schedules for the treatment of breast cancer. Re(cid:173)
`sponse rates are reported to be between 44% and
`18
`94%, depending on the extent of prior therapy.14•
`Cumulative neurotoxicity appears co be signifi(cid:173)
`cant, with 9.1 % of patients ·in one study presenting
`with some degree of neuropathy by the fifth course
`of treatment and 50% of patients in another study
`19
`· having co be withdrawn from treatment.14
`•
`Data from trials of paclitaxel combined with
`other agents, including ifosfamide, also have been
`reported recently. Murad et al, for example, evalu(cid:173)
`ated paclitaxel 175 mg/m2 IV over 3 hours on day
`1, plus ifosfamide at a dose of 1.8 g/m2 on days 2
`to 4, along with mesna in 22 patients receiving
`third- or fourth-line chemotherapy for metastatic
`breast cancer, with cycles repeated every 21 days.20
`Preliminary data are consistent with a response
`rate of 50% and only moderate toxicity, with one
`case of grade 3 neuropathy and three cases of tran(cid:173)
`sient grade 4 neutropenia. Further combination
`trials of paclitaxel and other chemotherapy agents
`are warranted.
`
`Carboplatin in Advanced Breast Cancer
`Like paclitaxel, carboplatin also has substantial
`activity when used as a single agent in the treat(cid:173)
`ment of advanced breast cancer, yielding objective
`responses in approximately 25% to 37% of patients
`who have not received chemotherapy for advanced
`disease. zo.22 Carboplatin is a less reactive derivative
`of cisplatin, but both drugs are activated co the
`same aquated metabolites. The major difference
`between carboplatin and cisplatin is that car(cid:173)
`boplatin has a lower toxicity profile. The renal,
`neurologic, ototoxic, and emetic toxicities of car(cid:173)
`boplatin are reduced substantially compared with
`those seen with cisplatin, making carboplatin a
`better-tolerated form of the parent compound. Fur(cid:173)
`thermore, carboplatin can be administered on an
`outpatient basis. The most prominent toxic effect
`of carboplatin is myelosuppression with prominent
`thrombocytopenia. Several published formulas,
`such as the Calvert formula,23 can now successfully
`predict for a particular level of carboplatin-induced
`thrombocytopenia. This is based on dosage indi(cid:173)
`vidualization based on the glomerular filtration
`rate (GFR) and target arf!a under the concentra·
`tion-time curve (AUC), with die total dose of
`carboplatin (mg) = AUC X (GFR + 25).
`
`Paclicaxel Plus Carboplatin
`
`To our knowledge, the combination of pacli(cid:173)
`taxel/carbopl.atin has not been studied in the treat(cid:173)
`ment of patients with metastatic breast cancer.
`Phase I and 11 dose escalation studies of this combi(cid:173)
`nation, however, have sought an effective, well(cid:173)
`tolerated dose for the treatment of patients with
`non-small cell lung cancer.24
`29 Cumulative severe
`'
`neurotoxicity was not found to be a significant
`problem when paclitaxel was infused over 3 hours
`and then followed by carboplatin. In a recent dose
`escalation study of paclitaxel and carboplatin in
`previously untreated patients with non-small cell
`lung cancer, the investigators established that the
`maximum tolerated dose was paclitaxel 250 mg/
`m2 with carboplatin at an AUC of 6 given every
`3 weeks. 24 The dose-limiting toxicity consisted pri(cid:173)
`marily of grade 3 osteo/arthralgias or sensory neu(cid:173)
`ropathy. Paclitaxel 225 mg/m2 given over 3 hours
`and followed immediately by carboplatin at an
`AUC of 6 was established as the optimal dose.
`Grade 3 or 4 thrombocycopenia was not seen, but
`10% of patients demonstrated grade 3 sensory neu(cid:173)
`ropachy after the third treatment cycle. Prelimi(cid:173)
`nary data of chis combination for advanced non(cid:173)
`small ceLJ lung cancer are consistent with response
`rates between 50% and 65% and median lengths
`of survival in excess of 1 year.
`Based on this background information, we initi·
`ated through the North Central Cancer T reatmem
`Group a phase !I study of patients receiving first·
`line chemotherapy for advanced or metastatic
`breast cancer. Paclitaxel 200 mg/m2, IV was admin(cid:173)
`istered over 3 hours followed by carboplatin at an
`AUC of 6, based on the Calvert formula, with
`cycles repeated every 21 days. In addition to evalu(cid:173)
`ating the efficacy and toxicity of this combination,
`this trial includes two corollary studies, one to de(cid:173)
`termine its effec.t on thrombopoietin (TPO) levels
`and the ocher to evaluate effect of treatment on
`quality of life using the Functional Assessment of
`Cancer Therapy-Breast (FACf-B) scale.30
`Our primary objective is to determine the re(cid:173)
`sponse rate achieved by paclitaxel/carboplatin in
`the treatment of women with advanced breast can(cid:173)
`cer; the secondary objectives are to determine its
`time-to-progression and toxicity and to evaluate
`its effect on patients' quality of life and serum TPO
`levels. The study is being conducted in women
`who are at least 18 years of age who have histologi·
`
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`are not altered by concurrent use of paclitaxel. The
`pathophysiology of this interaction has not been
`elucidated, but potencial inhibition of platelet mi(cid:173)
`crotubules, modulation of cytokines such as TPO,
`or interference with megakaryocyte ploidy/bleb(cid:173)
`bing are hypotheses worthy of exploration.
`Platelets are released from long pseudopods ex(cid:173)
`tending from megakaryocytes, either directly or
`from proplacelets, which are fragments of pseudo(cid:173)
`pods containing multiple platelet domain. Intra(cid:173)
`cellular cytoskeletal proteins, such as tubulin, par(cid:173)
`ticipate in pseudopod formation.31 Paclitaxel binds
`to tubulin subunits and thus may alter platelet re(cid:173)
`lease processes. 35
`The primary hormone-regulating platelet pro(cid:173)
`6.37 Thrombopoietin, also re(cid:173)
`duction is TP0.34
`ferred to as c-Mpl ligand or megakaryocyte growth
`and development factor, is a mature polypeptide
`of 332 amino acids. Recombinant TPO stimulates
`the proliferation and maturation of megakaryo(cid:173)
`cytic stem cells and megakaryocytes in vitro.34 ·It
`also infiuences characteristics of megakaryocytic
`maturation, such as cell size, ploidy, and the ten(cid:173)
`dency to form pseudopods. Thrombopoietin can
`enhance che recognition of multilineage colonies
`that have a megakaryocytic component and thus
`may stimulate multipotential cells to some extent.
`Thrombopoietin blood levels change reciprocally
`to the circulating platelet count in both animals
`and hurnan.5,34•38 but the effect of chemotherapeu(cid:173)
`tic drugs on circulating TPO levels or the relation(cid:173)
`ship of TPO levels to platelet nadirs seen after
`the administration of chemotherapy have not been
`explored.
`Jn this ongoing North Central Cancer Treat(cid:173)
`ment Group study we propose to test the hypothe(cid:173)
`sis that TPO blood levels are higher during periods
`of thrombocytopenia when paclitaxel is given just ·
`prior to carboplatin, compared with what would
`be expected with similar levels of chrombocyto(cid:173)
`penia in patients with primary bone marrow disor(cid:173)
`ders.
`
`•3
`
`CONCLUSION
`
`Both paclitaxel and carboplatin have significant
`single-agent activity in the treatment of breast
`cancer. The combination appears to be tolerable,
`with less hematopoietic toxicity tha.n was expected
`based on the potential additive toxicities of each
`agent. The antitumor activity of this combination
`is being established in a variety of tumor types.
`
`PACLITAXEL/CARBOPlATIN FOR ADVANCED BREAST CANCER
`
`cally confirmed adenocarcinoma of the breast with
`manifestations of metastatic cancer and · measur(cid:173)
`able disease. All women have an Eastern Coopera(cid:173)
`tive Oncology Group performance status of 0, 1,
`or 2, a life expectancy of 2:3 months, and adequate
`hematologic, renal, and hepatic functions.
`· Premedication for paclitaxel is required and
`consists of dexamethasone 20 mg orally 6 and 12
`hours before paclitaxel plus dexamerhasone 20 mg
`IV in combination with diphenhydramine 50 mg
`and cimetidine 300 mg IV administered 30 to 60
`minutes before paclitaxel. (Omitting the oral dexa(cid:173)
`methasone premedication at 6 and 12 hours prior
`to paclitaxel infusion is permitted.) Paclitaxel is
`then administered as a 3-hour infusion in 500 mL
`of D5W. Carboplatin is infused immediately after
`paclitaxel, over 30 minutes in 250 mL of DSW.
`The dose of carboplatin administered is calculated
`by the Calvert formula: carboplatin dose (mg) =
`target AUC X (GFR + 25). The treatment cycles
`are repeated every 21 days. Preliminary results from
`this trial should be available in the next several
`months.
`
`Paclitaxel, Carboplatin, and Platelets
`In addition to the above tolerability and re(cid:173)
`sponse data, Keams et al have observed that pacli(cid:173)
`taxel has a modulating effect on the thrombocyto(cid:173)
`penia caused by carboplatin.31 This effect was
`measured in two other separate studies as well.
`Each study demonstrated that platelet nadirs in(cid:173)
`creased as the doses of paclitaxel increased.3032
`Bolis et al29 reported that as the dose of pacli(cid:173)
`taxel increased, while the dose of carboplatin re(cid:173)
`mained at 300 mg/m2, both the median platelet
`nadir. and the median white blood cell nadir in(cid:173)
`creased. This finding suggests a modulatory effect
`· of paclitaxel on carboplatin-induced myelosup(cid:173)
`pression. In addition, significant dose-limiting
`nonhernatologlc toxicity was not observed using
`the combination of paclitaxel 150 to 250 mg/m2
`administered over 3 hours and carboplatin at 300
`mg/m2 in this study.
`A study by Siddiqui et al33 demonstrated that
`the incidence of thrombocytopenia decreased as
`the dose of paclitaxel increased from 150 to 175
`mg/m2 administered over 3 hours in combination
`with carboplatin. The investigators concluded that
`paclitaxel has a protective effect on the· thrombo(cid:173)
`cytopenia caused by carboplatin. They further con(cid:173)
`cluded that the pharmacokinetics of carboplatin
`
`3 of 5
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`-,
`
`I
`·~
`
`Our ongoing trial of paclitaxel 200 mg IV over 3
`hours followed by ·carboplatin AUC = 6 will help .
`answer the question of the potentiai role of this
`combination in the treatment of advanced breast
`cancer.
`
`REFERENCES
`I. Honig SF: Treatmenc of metastatic disease: Honnonal
`therapy and chemotherapy, in Harris JR, Lippman MC, Morrow
`M, et al (eds): Diseases of the Breast. Philadelphia, PA, Lippin(cid:173)
`cott, 1996 pp 669-734
`2. Holmes FA, Walrers RS, Theriault RL, et al: Phase II
`trial of T axol: An active drug in the treatment of metastatic
`breast cancer. J Natl Cancer Inst 83:1797-1805, 1991
`3. Reichman BS, Seidman AD, Crown JPA, et al: Taxol
`and recombinant human granulocyce colony-stimulating faccor
`as initial chemotherapy for metastatic breast cancer. J Clin
`Oncol 11:1943-1951, 1993
`4. Seidman A, Reichman BS, Crown JP, et al: Paclitaxel as
`second and subsequent therapy for metastatic breast cancer:
`Activity independenc of prior anchracycline response. J Clin
`Oncol 3:1152- 1159, 1995
`5. Holmes FA, Valero V, Walters), et al: The M.D. Ander(cid:173)
`son Cancer Cencer experience with T axol and metastatic breast
`cancer. MonogT Nae! Cancer Inst 15:161- 169, 1993
`6. Geyer CE, Green SJ, Moinpour C, et al: A phase II trial
`of paclita.xel in patients with metastatic refractory carcinoma
`of the breast; A Southwest Oncology Group (SWOG) study.
`Proc Am Soc Clin Oncol 15: 107, 1996 (abscr)
`7. Bishop JF, Dewar J, Tattersall MH: A randomited phase
`111 study of T a.xol (paclita.xel) vs CMFP in uncreated patients
`with metastatic breast cancer. Proc Am Soc Clin Oncol 15: 110,
`1996 (abstr)
`8. Mamounas E, Brown A, Fisher B. et al: Three-hour, high.
`dose Ta.xol infusion in advanced breast cancer (ABC): An
`NSABP phase II srudy. Proc Am Soc Clin Oncol 15:127, 1995
`(abscr)
`9. Abrams JS, Vena D, Baltz J, et al: Paclicaxel acti viry in
`heavily precreaced breast cancer: A National Cancer lnscicute
`treatment referral cencer trial. J Clio Oncol 13:2056-2065, 1995
`10. Swain S, Honig S, Walton L, et al: Phase II trial of pacli(cid:173)
`caxel (Taxol) as first-line chemotherapy for metastatic breast can(cid:173)
`cer (MBC). Proc Am Soc Clio Oncol 14:132, 1995 (abscr)
`11. Gianni L, Munzone E, Capri G, et al: Paclicaxel by 3-
`hour infusion in combination with bolus doxorubicin in women
`with untreated metastatic breast cancer: High ancitumor effi(cid:173)
`cacy and cardiac effects in a dose-finding and sequence-finding
`scudy. J Clin Oncol 13:2688-2699, 1995
`12. Gianni L, Capri G, Tarenzi F, et a l: Efficacy and cardiac
`effects of 3-H paclitaxel (P) plus bolus doxorubicin (DOX) in
`women with uncreated metastatic breast carcinoma. Proc Am
`Soc Clin Oncol 15:116, 1996 (abstr)
`13. Gehl J, Boesgaard M, Paaske T, et a l: Efficacy and toxic(cid:173)
`ity of combined doxorubicin (D) and paclica.xel (P) given as
`3 -hour infusion in metastatic breast cancer. Sixth Internacional
`Congress on Anti-Cancer Treacme~t. Paris, France, February
`6-9, 1996, p 148
`14. Gelmon KA. O'Reilly S, Plenderleich IH, et al: Biweekly
`paclitaxcl and cisplacin in the treatment of metastatic breast
`cancer. Proc Am Soc C lin Oncol 13:71, 1994 (abstr)
`
`PEREZ AND HARTMANN
`
`15. Alter R, Speyer j, Hochscer H, ec al: Phase II trial of
`paclicaxel and cisplatin (COOP) in women with metastatic
`breast cancer. Proc Arn Soc Clin Oncol 13:100, 1994 (abstr)
`16. Berry), Ezzat A, El-Warith A, et al: Sequential Ta.xol/
`platinum: Pilot study in mecaseatic breast cancer. Proc Am Soc
`Clin Oncol 14:136, 1995 (abstr)
`17. Browne M, Kennedy T , Cummings F, ec al: Phase II
`study of sequential Taxol and cisplatin for the treatment of
`metastatic breast cancer. Proc Am Soc Clin Oncol 14:136,
`1995 (abstr)
`18. McCaskill-Stevens W, Ansari R, Fisher W, ec al: Phase
`II study of biweekly cisplatin (C) and paclica.xel (P) in the
`treatment of metastatic breast cancer. Proc Am Soc Clin Oncol
`15:120, 1996 (abstr)
`19. Wasserheit H , Frazein A, Oracz R, et al: Phase II trial
`of paclitaxel and cisplacin in women with advanced breast
`cancer: An active regimen with limiting neurocoxicicy. J Clin
`Oncol 14:1993-1999, 1996
`20. Murad AM, Tinoco LA, Schwartsmann G : Phase II trial
`of che use ofTa.xol (T) and ifosfamide (!)in heavily pre-treated
`patients with metastatic breast cancer. Proc Am Soc Clin On(cid:173)
`col 15:97, 1996 (abstr)
`21. O'Brien MD, Talbot DC, Smith IE: Carboplatin in the
`treatment of advanced breast cancer: A phase II study using a
`pham1acokinetically guided dose schedule. J Clin Oncol
`11:2112-2117, 1993
`22. Marcin M, Diaz-Rubio E, Casado A, et al: Carboplacin:
`An active drug in metastatic breast cancer. j Clin Oncol
`10:433-437, 1992
`23. Calvert AH, Newell DR, Gumbrell LA, ec al: Cat·
`boplatin dosage prospective evaluation of a simple formula
`based on renal function. j Clin Oncol 7:1748-1756, 1989
`24. Yafai D, Israel V, Zaretsky S, et al: Phase I/II crial of
`combination carboplacin and Taxol in non- small cell lung
`cancer. Proc Am Soc C lin Oncol 14:352, 1995 (abstr)
`25. Israel VK, Zaretsky S, Natale RB: Phase 1/11 trial of
`combination carboplacin and Taxol in advanced non- small
`cell lung cancer. Proc Am Soc Clin Oncol 13:351. 1994 (abm)
`26. Belani CP, Hiponia D, Engsrrom C, er al: Phase l srudy of
`paclicaxel and carboplacio in advanced and metastatic non-small
`cell lung cancer. Proc Am Soc Clin Oncol 14:174, 1995 (absrr)
`27. Paul D, Devore RD, Hande K, ec al: Phase II trial of
`carboplacin plus paclicaxel in advanced non-small cell lung
`cancer. Proc Am Soc Clin Oncol 14:361, 1995 (abscr)
`28. Langer CJ, Leighton j, Comis R, et al: Paclita.xel and
`carboplatin combination in the treatment of advanced non(cid:173)
`small cell lung cancer: A phase 111 toxicity, response, and sur(cid:173)
`vival analysis. J Clin Oncol 13:1860-1870, 1995
`29. Bolis G, Scarfone G, Maggi R, et· al: A dose-finding
`srudy with fixed dose of carboplatin and escalating paclitaxel
`in advanced ovarian cancer. Proc Am Soc Clin Oncol 14:270,
`1995 (abstr)
`30. Cella DF: F.A.C.T . Manual. Chicago, IL, Rush-Presby(cid:173)
`terian Sc Luke's Medical Cencer, 1994
`31. Keams CM, Belani CP, Erkman K, et al: Reduced
`placelet toxicity wich combination carboplacin and pacli(cid:173)
`ta.xe l: Pharmacodynamic modulation of carboplatin associ(cid:173)
`aced thrombocytopenia. Proc Am Soc Clin Oncol 14: 170,
`1995 (abm)
`32. Bishop JF, Dewar J, Tattersall MH, et a l: A randomited
`phase Ill study of Taxol (paclicaxel) vs CMFP in uncreated
`
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`PACLITAXEUCARBOPLATIN FOR. ADVANCED BR.EAST CANCER
`
`45
`
`patients with metastatic breast cancer. Proc Am Soc Clin On(cid:173)
`col 15:1 10, 1996 (abstr)
`.
`33. Siddiqui N, Bailey. N, Memon M, et al: A phase I phar(cid:173)
`macokineric study of escalating paclir:axel (P) in ~ombinalion
`wich carboplatin {C) dosed al a fixed area under the curve
`(AUC) in epithelial ovarian cancer. Proc Am Soc Clin Oncol
`14:271, 1995 (abstr)
`34. Kaushansky K: Thrombopoietin: The primary regulator
`of platelet producrion. Blood 86:419-431, 1995
`35. Derry WB, Wilson L, Jordan MA: Substoichiomccric
`binding ofTaxol suppresses microtubule dynamics. Biochemis(cid:173)
`try 34:2203-2211, 1995
`
`36. deSauvage FJ, Hass PE, Spencer SD, et al: Stimulation of
`megakaryocycopoiesis and thrombopoiesis by the c-mpl ligand.
`Narure 369:533-538, 1994
`37. Fielder PJ, Burney AL, Stefanich E., et al: Regulation of
`thrombopoietin levels by c-mpl-mediaced binding co platelets.
`Blood 87:2154-2161, 1996
`38. Sawyer BM, Westwood NB. Pearson NC: Circulating
`megakaryocytic progenitor cells in patients with primary throm·
`bocythemia and reactive thrombocytosis: Results using serum·
`deprived culcure assay and a positive detection technique. Eur
`J Haemacol 53:108-113, 1994
`
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