The determination of optimal dosing and scheduling has been an important
objective during the development of the taxanes. This issue pertains to
both paclitaxel (Taxol) and docetaxel (Taxotere). The clinical development
of docetaxel has largely involved a single administration schedule (1-hour
infusion) and a narrow dosing range (60 to 100 mg/m², with most studies
using 100 mg/m² over 1 hour every 3 weeks). The range of paclitaxel
doses and schedules, on the other hand, has been broad (ranging from 135
to 250 mg/m² over 1 to 96 hours every 3 weeks).
Impressive antitumor activity has been reported recently for paclitaxel
on disparate administration schedules, which leads to the question of whether
an optimal dosing schedule truly exists for the taxanes. Fortunately, the
results of several prospective randomized studies, in addition to retrospective
analyses, may shed light on these questions. This review summarizes pertinent
preclinical, pharmacologic, and antitumor results pertaining to optimal
taxane dosing and scheduling in clinical practice.
The results of in vitro studies designed to evaluate taxane dose-response
relationships and optimal taxane scheduling have been reviewed previously.[1,2]
Many relevant biologic effects in vitro, such as cytotoxicity, formation
of microtubule bundles and mitotic asters, increase in tubulin polymer
mass, stabilization of microtubules against depolymerization, apoptosis,
radiosensitization, antiangiogenesis, and inhibition of chemotaxis and
motility, appear to be directly related to the concentration of the taxanes.[3-14]
The taxanes may induce different intracellular effects, depending on
the drug concentration. They inhibit proliferation of cells by inducing
a sustained mitotic block at the metaphase/anaphase boundary at concentrations
much lower than those required to increase microtubule mass and microtubule
bundle formation. Half-maximal inhibition of HeLa cell proliferation
and 50% blockade of mitotic metaphase occur at 8 nM of paclitaxel, whereas
microtubule mass increases half-maximally at 80 nM of paclitaxel, with
maximal effect at 300 nM. At high concentrations, the unique effects
of paclitaxel in increasing microtubule mass and microtubule bundles have
been associated with growth inhibition.[12,15]
Because these effects have not been noted at the lowest effective concentrations,
they could not have accounted for the antiproliferative effects observed
at low concentrations. Instead, growth inhibition has been associated with
the formation of an incomplete metaphase plate of chromosomes and an arrangement
of spindle microtubules resembling the abnormal organization that occurs
at low concentrations of the Vinca alkaloids.
Plateau and Threshold Concentrations
As paclitaxel concentrations progressively increase, a plateauing of
dose-response effects has been observed in various cell lines.[12,17-22]
In other words, a situation of diminishing returns occurs as paclitaxel
and docetaxel concentrations are increased above specific plateau concentrations,
the magnitude of which appears to vary between cell lines. The broad clinical
implication of these results is that there may be a critical plateau concentration,
ie, a dose above which toxicity, but not efficacy, increases.
The cumulative results of in vitro studies suggest that the precise
concentrations at which plateauing occurs depends on the specific treatment
schedule and varies according to tumor type. In addition, there appear
to be precise threshold concentrations below which drug effects do not
usually occur. Like plateau concentrations, the precise level at which
threshold effects take place also varies among cell lines. Threshold concentrations
typically are inversely related to the duration of treatment. In essence,
these preclinical observations resemble clinical observations to date.
For both paclitaxel and docetaxel, treatment duration appears to be
the most critical determinant of in vitro effect. Prolonging the duration
of exposure in vitro generally produces much greater cytotoxicity than
increasing drug concentration.[1,2,9,12,14,17,18, 20,23-25] For example,
an 11-fold increase in the duration of paclitaxel exposure was more effective
in increasing the cytotoxic effect of paclitaxel in an LC8A lymphoma cell
line than was a 100-fold increase in paclitaxel concentration. Interestingly,
this effect appears to be much more pronounced in taxane-resistant cell
lines.[24,26-29] The taxane concentrations at which cell survival curves
plateau tend to decrease as the treatment durations are prolonged.
For paclitaxel, and probably docetaxel, the effects of increasing microtubule
mass are maximal at drug concentrations that are equimolar with tubulin
or when the stoichiometry approaches 1 M of paclitaxel per 1 M of polymerized
tubulin dimer.[4,30-33] The binding of paclitaxel to polymerized tubulin
is reversible with a binding constant of approximately 0.9 µM. Docetaxel,
which most likely shares the same tubulin binding site as paclitaxel, has
a 1.9-fold higher effective affinity for the site. The assembly of guanosine
diphosphate- or guanosine triphosphate-tubulin induced by docetaxel also
proceeds with a critical protein concentration that is 2.1-fold lower than
that of paclitaxel. In addition, comparative in vitro cellular pharmacologic
studies have demonstrated that higher intracellular levels of docetaxel
in P388 murine leukemia cells may also be attributed, in part, to its threefold
slower efflux rate.
These differences may explain the varying cytotoxic potencies of the
taxanes, with median inhibitory concentrations generally much lower for
docetaxel.[4,21,22,33-36] The relative potencies may not necessarily translate
into a greater therapeutic index for docetaxel, since greater potency may
also result in more severe toxicity at identical drug concentrations in
vitro. In addition, the taxanes may
not be completely cross-resistant, although differences in potency may
confound the interpretation of both preclinical and clinical studies regarding
These schedule-dependent effects have also been documented in studies
designed to determine the
in vitro interactions of the taxanes with ionizing radiation. In most
studies, the radiopotentiating effects of the taxanes have been directly
related to the duration of taxane exposure prior to radiation. In one
series of studies involving lung cancer cells, a radiosensitizing effect
could not be demonstrated for treatment durations of less than 6 hours
at any concentration of paclitaxel.
In early studies performed by the National Cancer Institute, paclitaxel
was administered as a suspension and antitumor evaluations were limited
to studies using intraperitoneally (IP) implanted tumors treated with IP
drug administration or human tumor xenografts implanted in the subrenal
capsule and treated subcutaneously. In mice-bearing IP-implanted P388
leukemia, paclitaxel administered every 3 hours for three doses (pharmacologically
simulating a 24-hour infusion schedule) was more effective than other schedules,
including those with multiple-drug treatments on days 1, 5, and 9, or daily
treatment for 9 consecutive days. However, these studies were constrained
due to the limited solubility of paclitaxel in the formulation vehicles
used at that time, thereby precluding the design of proper comparative
studies of prolonged schedules and single-dosing schedules.
Lung Cancer Model
When studies designed to evaluate different schedules were later performed
by Bristol-Myers Squibb in the M109 lung cancer model using polyoxyethylated
castor oil (Cremophor EL) or polysorbate 80 formulations, no schedule-dependent
differences were observed. However, neither the optimal schedule demonstrated
in the P388 leukemia studies (every 3 hours × 8 doses) nor prolonged
(eg, 3 24-hour) infusion schedules were evaluated.
The schedule-finding studies in the M109 model indicated that both daily
× 5 and daily × 7 schedules were superior to multiple daily
dosing for longer intervals (2 or 3 days between injections). Significantly,
maximal antitumor activity was achieved at doses that were substantially
lower than the maximum tolerated dose (MTD). This was particularly true
for the daily × 7-day schedule, in which dosing at the MTD did not
result in any therapeutic advantage over an equally effective, but less
toxic, lower dose. These results are consistent with the plateau effects
noted in the dose-response curves from a variety of cell lines.
Nevertheless, dose-response effects have been observed in many other
preclinical in vitro models. Progressive reductions in vertebral metastases
were noted in combined immunodeficient mice inoculated with PC-3 ML prostate
cancer cells that were previously incubated with increasing paclitaxel
concentrations from 0.1 to 1.0 µM  and in mice bearing bladder
Dose-toxicity relationships have been especially profound. Substantially
greater toxicity in both rapidly proliferating (lymphoid, myeloid, gastrointestinal)
and nonproliferating (peripheral nerve) tissues has been observed on almost
all schedules in mice, rats, and dogs.[43-45] The schedule's effects are
more profound in that lower total doses are typically required to induce
equivalent toxic effects in animals treated with more intermittent dosing
schedules or treatment over more prolonged durations.[38,43]
It is difficult to compare paclitaxel and docetaxel with respect to
dose and schedule dependency in preclinical studies in animals due to differences
in tumor models, dosing schedules, and the proximity of treatment doses
to the MTD. Nevertheless, results of limited studies with docetaxel have
indicated clear dose-response relationships, particularly with short- and
single-dosing schedules. Although one may conclude that the type of administration
schedule appears to have minimal impact on docetaxel's antitumor activity,
it should be noted that only limited studies with prolonged schedules have
1. Arbuck SG, Canetta R, Onetto N, et al: Current dosage and scheduling
issues in the development of paclitaxel (TAXOL). Semin Oncol 4(suppl 3):31-39,
2. Arbuck SA, Blaylock B: Dose and Schedule Issues, in McGuire WP, Rowinsky
EK (eds): Paclitaxel in Cancer Treatment, pp 151-173. Marcel Dekker, New
3. Schiff PB, Horwitz SB: Taxol stabilizes microtubules in mouse fibroblast
cells. Proc Natl Acad Sci USA 77:1561-1565, 1970.
4. Diaz JF, Andreu JM: Assembly of purified GDP-tubulin into microtubules
induced by Taxol and Taxotere. Biochemistry 32:2747-2755, 1993.
5. Bissery M-C, Nohynek, Sanderlink G-J, et al: Docetaxel (Taxotere):
a review of preclinical and clinical experience: Part I: preclinical experience.
Anti-Cancer Drugs 6:339-355, 1995.
6. Ringel I, Horwitz SB: Studies with RP56976 (Taxotere): A semisynthetic
analogue of Taxol.
J Natl Cancer Inst 83:288-291, 1991.
7. Jordon MA, Wendell K, Gardiner S, et al: Mitotic block induced in
HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal
mitotic exit and apoptotic cell death. Cancer Res 56:816-825, 1996.
8. Haldar S, Chintapalli J, Croce CM: Taxol induces bcl-2 phosphorylation
and death of prostate cancer cells. Cancer Res 56:1253-1255, 1996.
9. Schiff PB, Gubits R, Kashimawo, et al: Paclitaxel with ionizing radiation,
in WG McGuire, Rowinsky EK (eds): Paclitaxel in Cancer Treatment, pp 81-90.
Marcel Dekker, New York, 1995.
10. Belotti D, Rieppi M, Nicoletti MI, et al: Paclitaxel inhibits motility
of paclitaxel resistant human ovarian cancer cell. Clin Cancer Res 2:1725-1730,
11. Belotti D, Vergani V, Drudis T, et al: The microtubule-affecting
drug paclitaxel has antiangiogenic activity. Clin Cancer Res 2:1843-1849,
12. Rowinsky EK, Donehower RC, Jones RJ, et al: Microtubule changes
and cytotoxicity in leukemic cell lines treated with Taxol. Cancer Res
13. Horwitz SB, Cohen D, Rao S, et al: Taxol: Mechanisms of action and
resistance. Monogr Natl Cancer Inst 15:63-67, 1993.
14. Bhalla K, Ibrado AM, Tourkina E, et al: Taxol induces intranucleosomal
DNA fragmentation associated with programmed cell death in human myeloid
leukemia cells. Leukemia 7:563-568, 1993.
15. Jordan MA, Toso RJ, Thrower D, et al: Mechanism of mitotic block
and inhibition of cell proliferation by Taxol at low concentrations. Proc
Natl Acad Sci 90:9552-9556, 1993.
16. Jordan MA, Thrower D, Wilson L: Mechanism of inhibition of cell
proliferation by Vinca alkaloids. Cancer Res 51:2212, 1991.
17. Lopes NM, Adams EG, Pitts TW, et al: Cell kill kinetics and cell
cycle effects of Taxol on human and hamster ovarian cell lines. Cancer
Chemother Pharmacol 32:235-242, 1993.
18. Helson L, Helson C, Malik S, et al: A saturation threshold for Taxol
cytotoxicity in human glial and neuroblastoma cells. Anti-Cancer Drugs
19. Riccardi R, Servidei T, Spiridigliozzi A, et al: Cytotoxicity of
Taxol in neuroblastoma SH-SY5Y and medulloblastoma TE-671 cell lines in
vitro. 8th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam,
195, March 15-18, 1994.
20. Liebmann JE, Cook JA, Lipschultz C, et al: Cytotoxic studies of
paclitaxel (Taxol) in human tumour cell lines. Br J Cancer 68:1104-1109,
21. Rhiou JF, Naudin A, Lavelle F: Effects of Taxotere on murine and
human tumor cell lines. Biochem Biophys Res Commun 187:164-170, 1992.
22. Hill BT, Whelan RHD, Shellard SA, et al: Differential cytotoxic
effects of docetaxel in a range of mammalian tumour cell lines and certain
drug resistant cell lines in vitro. Invest New Drugs 12:169-182, 1994.
23. Rowinsky EK, Donehower RC, Tucker RW: Microtubule changes and cytotoxicity
produced by Taxol in human ovarian cell lines. Proc Am Assoc Cancer Res
24. Georgiadis MS, Russell E, Johnson BE: Prolonging the exposure of
human lung cancer cell lines to paclitaxel increases the cytotoxicity.
Proc Int Assoc Study Lung Cancer 11:95, 1994.
25. Figg WD, Thibault A, McCall NA, et al: The in vitro activity of
Taxol on three hormone refractory prostate cancer cell lines, PC3, DU145,
and PC3M. Proc Am Assoc Cancer Res 35:431, 1994.
26. Zhan Z, Kang Y-K, Regis J, et al: Taxol resistance: In vitro and
in vitro studies in breast cancer and lymphoma. Proc Am Assoc Cancer Res
27. Lai GM, Chen YN, Mickley LA, et al: P-glycoprotein expression and
schedule dependence of Adriamycin cytotoxicity in human colon carcinoma
cell lines. Int J Cancer 49:696-703, 1991.
28. Cahan MA, Walter KA, Colvin OM, et al: Cytotoxicity of Taxol in
vitro against human and rat malignant brain tumors. Cancer Chemother Pharmacol
29. Kelland LR, Abel G: Comparative in vitro cytotoxicity of Taxol and
Taxotere against cisplatin-sensitive and -resistant human ovarian carcinoma
cell lines. Cancer Chemother Pharmacol 30:444-450, 1992.
30. Wilson L, Miller HP, Farrell KW, et al: Taxol stabilization of microtubules
in vitro. Biochemistry 24:5254-5262, 1985.
31. Parness J, Horwitz SB: Taxol binds to polymerized microtubules in
vitro. J Cell Biol 91:479-487, 1981.
32. Collins CA, Vallee RB: Temperature-dependent reversible assembly
of Taxol-treated microtubules. J Cell Biol 105:2847-2854, 1987.
33. Lavelle F, Fizames C, Gueritte-Voegelein F, et al: Experimental
properties of RP 56976, a Taxol derivative. Proc Am Assoc Cancer Res 30:2254,
34. Kelland LR, Abel G: Comparative in vitro cytotoxicity of Taxol and
Taxotere against cisplatin-sensitive and resistant human ovarian carcinoma
cell lines. Cancer Chemother Pharmacol 30:444-450, 1992.
35. Braakhuis BMJ, Hill BT, Dietel M, et al:
In vitro antiproliferative activity of docetaxel (Taxotere), paclitaxel
(Taxol), and cisplatin against human tumours and normal bone marrow cells.
Anticancer Res 14:205-208, 1994.
36. Garcia P, Braguer D, Carles G, et al: Comparative effects of Taxol
and Taxotere on different human carcinoma cell lines. Cancer Chemother.
Pharmacol 34:335-343, 1994.
37. Young DH, Michelotti EL, Swindell CS, et al: Antifungal properties
of Taxol and various analogues. Experientia 4:882-885, 1992.
38. National Cancer Institute Clinical Brochure: Taxol (NSC 125973).
Division of Cancer Treatment, NCI, Bethesda, MD, 1993.
39. Rose WC: Taxol: A review of its preclinical in vitro antitumor activity.
Anticancer Drugs 3:311-321, 1992.
40. Rose, WC: Taxol-based combination chemotherapy and other in vitro
preclinical antitumor studies. Monogr Natl Cancer Inst 15:47-53, 1993.
41. Stearns ME, Wang M: Taxol blocks processes essential for prostate
tumor cell (PC-3ML) invasion and metastases. Cancer Res 52:3776-3681, 1992.
42. Medalia O, Aronson M, Ringel I, et al: Inhibition of mouse bladder
by intravesicular installation of Taxol. Proc Am Assoc Cancer Res 35:325,
43. Rowinsky EK, Cazenave LA, Donehower RC: Taxol: A novel investigational
anticancer agent. J Natl Cancer Inst 82:1247-1259, 1990.
44. Apfel SC, Lipton RB, Arezzo JC, et al: Nerve growth factor prevents
toxic neuropathy in mice. Ann Neurol 29:87-90, 1991.
45. Roytta M, Horwitz SB, Raine CS: Taxol-induced neuropathy: Short-term
effects of local injection. J Neurocytol 13:685-671, 1984.
46. Bissery MC, Guenard D, Gueritte-Voegelein F, et al: Experimental
antitumour activity of Taxotere (RP 57976, NSC 628503), a Taxol analog.
Cancer Res 51:4845-4852, 1991.
47. Bruno R, Sanderink GJ: Pharmacokinetics of Taxotere. Cancer Surveys
48. Rowinsky EK, Donehower RC: Antimicrotubule Agents, in Chabner BA,
Longo DL (eds): Cancer Chemotherapy, pp 263-296. Lippincott-Raven, Philadelphia,
49. Rowinsky EK, Wright M, Monsarrat B, et al: Taxol: Pharmacology,
metabolism, and clinical implications. Cancer Surveys 17:283-304, 1993.
50. Kearns CM, Gianni L, Egorin MJ: Paclitaxel pharmacokinetics and
pharmacodynamics. Semin Oncol 22(suppl 6):16-23, 1995.
51. van Oosterom AT, Schrijvers D: Docetaxel (Taxotere), a review of
preclinical and clinical experience. Part II: Clinical experience. Anticancer
Drugs 6:356-358, 1995.
52. Lesser G, Grossman SA, Eller S, et al: The neural and extaneural
distribution of systemically-administered [3H]paclitaxel in rats. Cancer
Chemother Pharmacol, 1997 (in press).
53. Eiseman JL, Eddington ND, Leslie J, et al: Plasma pharmacokinetics
and tissue distribution of paclitaxel in CD2F1 mice. Cancer Chemother Pharmacol
54. Marland M, Gaillard C, Sanderink G, et al: Kinetics, distribution,
metabolism, and excretion or radiolabelled Taxotere (14C-RP 56976) in mice
and dogs. Proc Am Assoc Cancer Res 34:393, 1993.
55. De Valeriola D, Brassine C, Gaillard C, et al: Study of excretion
balance, metabolism, and protein binding of 14C-radiolabelled Taxotere
(RP56976, NSC628503) in cancer patients. Proc Am Assoc Cancer Res 34:373,
56. Monsarrat B, Alvinerie P, Wright M, et al: Hepatic metabolism and
biliary excretion of Taxol in rats and humans. Monogr J Natl Can Inst 15:39-46,
57. Walle T, Walle UK, Kumar GN, et al: Taxol metabolism and disposition
in cancer patients. Drug Met Disp 23:506-512, 1995.
58. Gaver RC, Deeb G, Willey T, et al: The disposition of paclitaxel
(Taxol) in the rat. Proc Am Assoc Cancer Res 34:390, 1993.
59. Eisenhauer E, ten Bokkel Huinink W, Swenerton KD, et al: European-Canadian
randomized trial of Taxol in relapsed ovarian cancer: High vs low dose
and long vs short infusion. J Clin Oncol 12:2654-2666, 1994.
60. Wilson WH, Berg SL, Bryant G, et al: Paclitaxel in doxorubicin-refractory
or mitoxantrone-refractory breast cancer: A phase I/II trial of 96 hour
infusion. J Clin Oncol 12:1621-1629, 1994.
61. Seidman AD, Hochhauser D, Gollub M, et al: Ninety-six hour paclitaxel
infusion after progression during short taxane exposure: A phase II pharmacokinetic
and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 14:1877-1884,
62. Hainsworth JD, Thompson DS, Greco FA: Paclitaxel by 1-hour infusion:
an active drug in metastatic non-small cell lung cancer. J Clin Oncol 13:1609-14,
63. Rowinsky EK, Onetto N, Canetta RM, et al: Taxol: the prototypic
taxane, an important new class of antitumor agents. Semin Oncol 19:646-662,
64. Rowinsky EK, Donehower RC: Drug therapy: Paclitaxel (Taxol). N Engl
J Med 332:1004-1114, 1995.
65. Cortex JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643-2655, 1995.
66. Sarosy G, Kohn E, Stone DA, et al: Phase I study of Taxol and granulocyte
colony-stimulating factor in patients with refractory ovarian cancer. J
Clin Oncol 10:1165-70, 1992.
67. Kohn EC, Sarosy G, Bicher A, et al: Dose-intense Taxol: High response
rate in patients with platinum-resistant recurrent ovarian cancer. J Natl
Clin Inst 86:18-24, 1994.
68. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic
agent with significant activity in advanced ovarian epithelial neoplasms.
Ann Intern Med 111:273-279, 1989.
69. Thigpen T, Blessing J, Ball H, et al: Phase II trial of paclitaxel
in patients with progressive ovarian carcinoma after platinum-based chemotherapy:
A Gynecological Oncology Group study. J Clin Oncol 12:1748-1753, 1994.
70. Einzig AI, Wiernik P, Sasloff J, et al: Phase II study and long-term
follow up of patients treated with Taxol for advanced ovarian adenocarcinoma.
J Clin Oncol 10:1748-1753, 1992.
71. Reed E, Bitton R, Sarosy G, et al: Paclitaxel dose intensity. J
Infus Chemother 6:59-63, 1996.
72. Rowinsky EK, Mackey MK, Goodman SN: Meta analysis of paclitaxel
dose-response and dose-intensity in recurrent or refractory ovarian cancer.
Proc Am Soc Clin Oncol 15:284, 1996.
73. Omura GA, Brady MF, Delmore JE, et al: A randomized trial of paclitaxel
at 2 dose levels and Filgastrim (G; G-CSF) at 2 dose levels in platinum
pretreated epithelial ovarian cancer (OVCA): A Gynecologic Oncology Group,
SWOG, NCTTG and ECOG study. Proc Am Soc Clin Oncol 15:280, 1996.
74. Nabholtz J-M, Gelmon K, Bontenbal M, et al: Multicenter, randomized
comparative study of two doses of paclitaxel in patients with metastatic
breast cancer. J Clin Oncol 14:1858-1867, 1996.
75. Ravdin P, Burris HA, Cook G, et al: Phase II trial of docetaxel
in advanced anthracycline-resistant or anthracenedione-resistant breast
cancer. J Clin Oncol 13:2879-2885, 1995.
76. Valero V, Holmes FA, Walters RS, et al: Phase II trial of docetaxel:
a new, highly effective antineoplastic agent in the management of patients
with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13:2886-2894,
77. Rhone-Poulenc Rorer: Data on file.
78. Hudis CA, Seidman AD, Crown JPA, et al: Phase II and pharmacologic
study of docetaxel as initial chemotherapy for metastatic breast cancer.
J Clin Oncol 14:58-65, 1996.
79. Chevallier B, Fumoleau P, Kerbrat P, et al: Docetaxel is a major
cytotoxic drug for the treatment of advanced breast cancer: A phase II
trial of the Clinical Screening Cooperative Group of the European Organization
for Research and Treatment of Cancer. J Clin Oncol 13:314-322, 1995.
80. Trudeau ME, Eisenhauer EA, Higgins BP, et al: Docetaxel in patients
with metastatic breast cancer: A phase II study of the National Cancer
Institute of Canada-Clinical Trials Group. J Clin Oncol 4:422-428, 1996.
81. Dieras V, Chevalier B, Kerbrat P, et al: A multicentre phase II
study of docetaxel 75 mg/m2 as first-line chemotherapy for patients with
advanced breast cancer: Report of the Clinical Screening Group of the EORTC.
Br J Cancer 74:650-656, 1996.
82. Peretz T, Sulkes A, Chollet P, et al: A multicenter randomized study
of two schedules of paclitaxel in patients with advanced breast cancer.
Eur J Cancer 31A (suppl 5):S75, 1995.
83. Bristol-Myers Squibb: Data on file.
84. Velero V, Burris HA, Jones SE, et al: Multicenter pilot study of
Taxotere in Taxol-resistant metastatic breast cancer. Proc Am Soc Clin
Oncol 15:95, 1996.
85. Kunitoh H, Watanabe K, Onoshi T, et al: Phase II trial of docetaxel
in previously untreated advanced non-small cell lung cancer. J Clin
Oncol 14:1649-1655, 1996.
86. Bonomi P, Kim K, Chang A, et al: Phase III trial comparing etoposide-cisplatin
versus Taxol with cisplatin-granulocyte-colony-stimulating factor versus
Taxol-cisplatin in advanced non-small cell lung cancer: An Eastern Cooperative
Oncology Group trial. Proc Am Soc Clin Oncol 15:382, 1996.
87. Rowinsky EK, Bonomi P, Jiroutek M, et al: Pharmacodynamic studies
of paclitaxel in ECOG 5592: A phase III trial comparing etoposide plus
cisplatin vs low-dose paclitaxel plus cisplatin vs high-dose paclitaxel
plus cisplatin plus G-CSF in advanced non-small cell lung cancer. Proc
Am Soc Clin Oncol, 1997 (in press).
88. Forastiere AA, Leong T, Murphy B, et al: A phase III trial of high
dose paclitaxel + cisplatin + G-CSF versus low dose paclitaxel + cisplatin
in patients with advanced squamous cell carcinoma of the head and neck:
An Eastern Cooperative Oncology Group trial. Proc Am Soc Clin Oncol, 1997