Phase II Trial of Single-Agent Weekly Docetaxel in Hormone- Refractory, Symptomatic, Metastatic Carcinoma of the Prostate

William Berry, Shaker Dakhil, Mary A. Gregurich, and Lina Asmar

The purpose of this study was to assess the efficacy of

weekly administration of docetaxel as a single agent in

patients with hormone-refractory, symptomatic, met-

astatic prostate cancer with respect to symptom palli-

ation, tumor response, time to progression, and sur-

vival. Sixty men with progressive metastatic prostate

cancer that had progressed on at least one hormonal

regimen were enrolled in this multicenter phase II

study. Twenty-one percent of patients had received

prior palliative radiotherapy, and 25% had received

prior chemotherapy for hormone-refractory disease.

Patients were scheduled to receive three 8-week cycles

of docetaxel(36 mg/m’ on days I, 8, I5,22,29, and 36)

with 2-week intervals between cycles. The docetaxel

dose could be decreased in the event of toxicity, but no

dose escalation was permitted. A 250% decrease in

serum prostate-specific antigen (PSA) levels from

baseline with stabilization or improvement of perfor-

mance status lasting 2 months or longer occurred in 24

(4 I %) patients, of whom I6 (27%) had a 280% decrease

for 2 months or more. The median time to progression

for all patients was 5.1 months (range, 0.9 to 18.2

months). The estimated median time to progression

for patients who had and those who did not have a

250% reduction in serum PSA level with stable or

improved performance status was 6.65 and 4.3 months,

respectively. The median overall survival was 9.4

months (range, I .6 to 18.2 months). Treatment toxic-

ity was considered acceptable. Single-agent docetaxel

at 36 mg/m’ weekly was associated with a PSA re-

sponse rate of 4 I %, increased time to progression and

survival, and minimal myelosuppression in patients

with hormone-refractory metastatic prostate cancer.

Semin Oncol28 (suppl /5):8-15. Copyright 0 2001 by MB.

Sounders Company.

I

N THE UNITED STATES, prostate cancer is now the most commonly diagnosed cancer in

men, accounting for 29% of new cancer cases. It was expected that 180,400 new cases of prostate

cancer would be diagnosed in the year 2000. At least 3 1,900 deaths each year are estimated to be

From US Oncology Inc, Houston, TX. Supported by Aventis Pharmaceuticals Inc. Dr Berry has given lectures on prostate cancer that were spon-

sored by Aventis, Immunex, and Bristol-Myers Squibb. Address reprint requests to Lina Asmar, PhD, LJS Oncology Inc,

16825 Northchase Dr, Suite 1300, Houston, TX 77060. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2804-l 503$35.00/O doi:JO.1053/sonc.200J .26893

8

caused by the disease. l Nearly all of these deaths

occur after disease progression in patients receiv- ing standard hormonal therapy. The optimum

treatment strategy for these patients has yet to be established; however, for patients whose disease

progresses on combined androgen blockade, anti-

androgen therapy withdrawal is mandatory, and further hormonal maneuvers may be useful in

asymptomatic patients.2 In patients with symptom-

atic hormone-refractory prostate cancer (HRPC), the therapeutic options are radiotherapy, chemo-

therapy, and experimental therapy.

Interest in the use of cytotoxic drugs for HRPC is increasing.),4 Durable palliative responses to a

regimen of mitoxantrone, an anthracycline deriv- ative, plus prednisone have been reported.5 The

taxanes, which lack the cardiotoxicity of the an- thracyclines, have also demonstrated efficacy in

this setting. Response rates exceeding 60% have

been achieved with regimens containing pacli- taxel using a decrease of at least 50% from the

pretreatment baseline prostate-specific antigen (ISA) level as the measure of response.6~s Similar

response rates have also been reported in phase I

studies using docetaxel in combination with estra- mustine.9JO In one of these studies, in which more

than one third of patients had previously under* gone chemotherapy, median survival from study

onset was 22.8 months,10 compared with the usual

expected survival time of 8 to 12 months. These results suggest that further studies of the taxanes

are warranted. Toxicity is an important consideration when

chemotherapy is used in a palliative situation.

Conventionally, taxanes have been administered every 3 to 4 weeks, resulting in substantial myelo-

suppressioni However, weekly dosing schedules of paclitaxel have been studied with the aim of

achieving an increased dose intensity with accept- able toxicity.i2J3 Peripheral neuropathy, which re-

mains a dose-limiting toxicity with paclitaxel,l‘+ occurs infrequently with docetaxel. In a phase I study in patients with metastatic breast cancer,

docetaxel given as a single agent weekly at doses up to 43 mg/m2 for 6 weeks followed by 2 weeks without treatment produced minimal myelosup-

Seminars in Oncology, Vol 28, No 4, Suppl I5 (August). 200 I : pp 8- I5

PHASE II TRIAL OF WEEKLY DOCETAXEL IN METASTATIC PROSTATE CANCER 9

pression. Furthermore, efficacy was not compro- mised; at doses of 35 to 40 mg/m’, the response rate was 50%. Similarly promising results in pa- tients with breast cancer have been reported by other groups,14 and weekly docetaxel regimens are now being evaluated in phase II studies in patients with a variety of solid tumors.

A study of weekly administration of docetaxel as a single agent in patients with symptomatic, met- astatic HRPC was undertaken. The objectives of this multicenter, phase II study were to assess the efficacy of docetaxel with respect to symptom pal- liation, tumor response, time to progression, and survival.

MATERIALS AND METHODS

Study Design

This open-label phase II trial was conducted at 26 centers

across 15 states in the United States. Study recruitment took

place from April to October 1998. Surviving patients were

followed up through January 2000. The protocol was approved

by a central Institutional Review Board with jurisdiction over

specific sites that registered patients into the study, and all

patients were required to sign an informed consent form before

they were admitted into the study.

Patients

Sixty patients with metastatic adenocarcinoma of the pros-

tate that had progressed on at least one hormonal regimen,

which included orchiectomy, a luteinizing hormone-releasing

hormone analogue, or diethylstilbestrol, were enrolled into this

study. Progression could be documented either biochemically

(twofold or greater elevation in the PSA on two determina-

tions at least 2 weeks apart) or objectively (an increase of

~25% in the sum of the perpendicular diameters of all mea-

surable disease or an increase of ~25% in the number of bone

lesions). However, all patients had to have measurable or

evaluable metastatic disease; patients whose only sign of disease

was increasing PSA were not eligible. All patients had an

Eastern Cooperative Oncology Group performance status of 0

to 2.

Patients were eligible if at least 4 weeks had elapsed since

radiation therapy (with full recovery), they had undergone

antiandrogen withdrawal (with no subsequent decrease in

PSA), they were no longer receiving systemic corticosteroid

therapy (unless as a maintenance dosage for adrenal insuffi-

ciency), or at least 3 weeks had elapsed since major surgery.

Patients were required to have an absolute neutrophil count

(ANC) of ?1,50O/~L, a platelet count of ?lOO,OOO/~L, a

hemoglobin concentration of 29 g/dL, a serum bilirubin level

below the upper limit of normal (ULN), and aspartate amino-

transferase (AST) and alanine aminotransferase (ALT) levels

~2.5 times the ULN.

Patients were excluded from the study if they had an AST or

ALT level > 1.5 times the ULN with a concomitant serum

alkaline phosphatase level ~2.5 times the ULN, a history of

other malignancy within the last 5 years, parenchymal brain

metastases, or prior immunotherapy. Further exclusion criteria

were prior treatment with more than one cytotoxic agent

(combination chemotherapy regimen) and treatment with tax-

ane as a single agent or in combination.

Treatment

Patients were scheduled to receive three H-week cycles of

treatment, although the number of cycles could be extended at

the discretion of the investigator. Each cycle comprised an

infusion of docetaxel (Taxotere; Aventis, Bridgewater, NJ) on

days 1,8, 15,22, 29, and 36, with no treatment on days 43 and

50. Docetaxel was diluted in either 0.9% sodium chloride or

5% dextrose to a final concentration of 0.3 to 0.9 mg/mL and

administered by intravenous infusion over 30 to 60 minutes.

All patients received premeditation with oral dexamethasone

(three 8-mg doses at 12-hour intervals starting 12 hours before

each docetaxel infusion).

The initial dose of docetaxel was 36 mg/m’, and no escala-

tion of this dose was permitted. Dose reductions were made in

the presence of toxicity based on the body system showing the

greatest degree of toxicity. The dose was temporarily reduced by

25% on the day of the planned therapy if the ANC was 500 to

1,5OO/pL, the platelet count was 50,000 to 99,OOO/pL, or

transaminase levels were >2.5 but 55.0 times the ULN. Do-

cetaxel was withheld if the ANC was <5OO/pL, the platelet

count was <5O,OOO/pL, or the transaminase or bilirubin level

was >5 times the ULN. In patients in whom the ANC was

<5OO/pL for 7 days or longer, the docetaxel dose was reduced

by 25% in all subsequent cycles.

Docetaxel was discontinued in patients with grade 3 periph-

eral neuropathy or grade 4 hypersensitivity (anaphylaxis). For

patients with moderate or severe hypersensitivity reactions, the

infusion was temporarily discontinued, and treatment with

diphenhydramine with or without dexamethasone and/or epi-

nephrine was administered. The infusion was resumed at a

slower rate after recovery, if appropriate. In subsequent cycles,

antihistamine premeditation could be given and the infusion

rate adjusted. In patients with mild hypersensitivity (localized

cutaneous symptoms only), the infusion rate was reduced until

symptoms resolved. In general, for other grade 3 or 4 toxicities,

docetaxel was withheld until resolution to grade 2 or below,

then treatment was reinstituted, if medically appropriate, with

a 25% dose reduction. A maximum of two 25% dose reductions

were permitted, and the maximum delay in treatment was 2

weeks.

Patients continued with androgen ablation therapy (orchi-

ectomy, luteinizing hormone-releasing hormone analogue, or

diethylstilbestrol) throughout the study. No other treatment for

prostate cancer was permitted, but supportive care, such as

antiemetics, blood products, and hematopoietic growth factors,

was provided as appropriate.

Patients could be withdrawn from the study at any time for

unacceptable toxicity, intercurrent illness, progressive disease,

protocol violation, or patient request.

Assessments

Patients underwent a full prestudy evaluation within 2 weeks

of entering the study, including a physical examination, a

complete blood count (with platelets and differential), liver

function tests (bilirubin, AST, ALT, alkaline phosphatase),

IO BERRY ET AL

and PSA measurement. Additionally, each patient’s disease was assessed clinically. Objective assessments of indicator le- sions (computed tomography scans, magnetic resonance imag- ing, bone scan, liver scan, ultrasound, and/or x-rays) had to be performed within 6 weeks of study entry. Functional Assess- ment of Cancer Therapy (Prostate) [FACT-P] quality-of-life (QOL) questionnaires were scheduled at baseline, at the end of each cycle, and at the end of therapy.

With the exception of the bone scan, which was performed after three treatment cycles, all assessments were repeated before each treatment cycle and after the final treatment cycle. A complete blood count was also obtained before each dose of docetaxel was administered. Patients who completed treatment were followed up for progression and for survival. However, patients who progressed or withdrew from the study were fol- lowed up only for survival.

Any worsening of a pre-existing condition after exposure to the trial medication was considered an adverse event. A serious adverse event was defined as any event that was life threaten- ing, produced permanent disability, or required hospitalization. The severity of the adverse events was scored according to the National Cancer Institute (NCI) Toxicity Criteria, Version 2 (http://ctep.info.nih.gov/ctc3/ctc.htm). In this study, the term “toxicity” referred to grade 3 and 4 adverse effects that occurred after exposure to the study drug.

Response Criteria

The primary study endpoint was the percentage of patients who achieved an objective tumor response, defined as patients whose PSA levels decreased by ~50% from baseline and per- sisted for 4 weeks or longer based on two consecutive measure- mentsl’ with stable or improved performance status. For pa- tients with measurable bidimensional disease (masses 2 2 X 2 cm), tumor response was defined as a decrease of 50% or more in tumor measurements. An objective tumor response for mea- surable disease was defined using standard criteria: complete response (CR) and partial response (PR). A CR required the disappearance of all disease for ~4 weeks, with normalization of PSA. A PR required a ~50% decrease in the sum of the products of the perpendicular diameters of all measurable masses lasting 4 weeks or longer, with no new masses or progression at other sites.

Further endpoints were the time to progression (TTP) of disease, duration of response, survival, and symptom palliation. Disease progression was defined as a ~25% increase in the sum of the products of the perpendicular diameters of all measurable masses or the appearance of new lesions. In addition, patients whose PSA increased by ~50% over nadir or whose perfor- mance status worsened were considered progressors. TTP was computed from the start of treatment to the first sign of pro- gressive disease or to death.

Objective symptomatic response was defined as a two-point reduction in the six-point McGill pain intensity scale or com- plete loss of pain if it was initially 1+ at baseline and a decrease in PSA of at least 25% with no increase in analgesics main- tained for at least 8 weeks. Survival was computed from the date of the start of treatment until the date of last follow-up for living patients or until death. Patients lost to follow-up were censored at the last available date.

Statistical Analysis

This phase II study was conducted to determine whether the true response rate (p) was less than or equal to an uninteresting level (H, = p 5 p0 = 0.10) against the alternate hypothesis that the true response rate is equal to or greater than a desirable level (H, = p 2 p1 = 0.30). Entry of 60 evaluable patients in a single-stage design with a statistical significance level of m = 0.05 (one-sided test) assures nearly 99% power for detecting the improved level of response.

The analysis was done on an intent-to-treat basis. All pa- tients were included in the efficacy analysis, and all patients who received at least one dose of study drug were analyzed for safety. The survival curves were generated using the Kaplan- Meier ( 1958)16 method, and the log-rank test17 was used to measure differences between the curves. Statistica (1999 edi- tion; Statsoft, Inc, Tulsa, OK) software was used to run the analysis.

RESULTS

Patient Demography

A total of 60 men with metastatic HRPC were

enrolled in this trial; their pretreatment character- istics are shown in Table 1. Most patients (80%) were older than 65 years, and the majority (83%) were white. The median time since diagnosis was

4.7 years, and the median PSA level at study entry was 91.6 ng/mL. Osseous metastases were present in 57 patients (95%). Regarding previous treat- ment, 16 patients (27%) had received mitox-

antrone, 26 (43%) had undergone orchiectomy, 58 (97%) had received secondary hormonal ther- apy, and 39 (65%) had received two or more

hormonal treatments. Most patients (70%) had received palliative radiotherapy to the bone, pros- tate, and/or nodes.

Sixteen patients received only one treatment cycle or discontinued treatment before completing the second cycle. Seven patients (12%) were con- sidered not evaluable for response: four had severe

toxicity, two had early death (one of congestive heart failure and pneumonia and one of cerebro- vascular accident and gastrointestinal bleeding), and one refused to continue treatment. Nine pa- tients had early progressive disease. Nearly half of the patients received three cycles of treatment,

and seven patients underwent four or more treat- ment cycles.

Eficacy

PSA measurements were available for 59 pa- tients (Table 2). According to the intent-to-treat analysis, an objective tumor response (a ~50% decrease in serum PSA from baseline lasting 4

PHASE II TRIAL OF WEEKLY DOCETAXEL IN METASTATIC PROSTATE CANCER I I

Table I. Baseline Demographics and Cancer Status of

60 Evaluable Patients in a Phase II Trial of Weeldy

Docetaxel in Patients With Hormone-Refractory

Metastatic Prostate Cancer

Evaluable Patients 60 ( 100%)

Race

White 50 (83%)

Black 8(13%)

Hispanic I (2%)

Other I (2%)

Median age, yr (range) 72 (4 I-86)

Age distribution, yr

<so 2 (3%)

50-65 lO(l7%)

>65 48 (80%)

Median time since diagnosis, yr (range) 4.7 (0.5- 19.0)

Median baseline PSA, ng/mL (range) 9 I .6 (O-2,737)

Site of metastases

B0lle 46 (77%)

Bone + nodes 4 (7%)

Bone + visceral 4 (7%)

Bone + nodes + visceral 3 (5%)

Nodes I (2%)

Visceral I (2%)

Nodes + visceral I (2%)

Performance status (ECOG)

0 (full activity) I5 (25%)

I (ambulatory) 35 (58%)

2 (in bed 550% of time) lO(l7%)

Previous chemotherapy I6 (27%)

Previous palliative radiotherapy

Total 42 (70%)

BOllt? I5 (25%)

Prostate I2 (20%)

Prostate + nodes I I(l8%)

Strontium 3 (5%)

Unknown I (2%)

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

weeks or longer with a stable or improved perfor- mance status) occurred in 24 patients (41%), of whom 16 (27%) had a decrease of ~80% for 4 weeks or longer. The median duration of the PSA response was 4.5 months for the patients with ~50% serum PSA reduction and 5.0 months for the patients with 280% serum PSA reduction. The PSA response to docetaxel was not influenced by previous use of mitoxantrone. Of the 16 pa- tients who had been exposed to mitoxantrone, PSA decreased in six (38%), compared with 18 (41%) of the remaining 44 patients.

Nine patients were progression-free 18 months or longer after the study opened. Overall, the

estimated median TTP from the start of treatment was 5.1 months. The percentage of patients who were progression-free at 3, 6, 9, and 12 months after the start of treatment was 80%, 41%, 33%, and 29%, respectively. The estimated median TTP for patients with a 150% PSA reduction was 6.6 months (Fig 1). In contrast, the estimated median TTP for patients who did not have a ~50% PSA reduction was 4.3 months (I’ < .Ol; Table 2).

Of the 60 patients enrolled in the study, 37 (62%) died within 18 months. The estimated me- dian survival time from the start of treatment for the study population as a whole was 9.4 months. At 3, 6, 9, and 12 months, 95%, 70%, 52%, and 38% of patients, respectively, were still alive. The estimated median duration of survival for patients with a ~50% PSA decrease has not been reached (Fig 2), whereas for patients who did not have a ~50% PSA decrease, the estimated median sur- vival time was 8.1 months (Table 2).

Only six patients had measurable soft tissue disease. Of these, two had objective tumor re- sponses, one of which was a CR. This patient had a PSA level of 0 at baseline because of the undif- ferentiated nature of his tumor. The other patient had a PSA response in parallel with the decrease in soft tissue lesions and stable performance status.

Thirty-seven (70%) of 53 evaluable patients completed the McGill pain assessment form and were evaluated for symptomatic response. Of these, three (8%) had PRs and 34 (92%) had stable disease.

Among the patients who completed three cycles of chemotherapy, 84% completed the QOL ques- tionnaire. The FACT-P and general scores in- creased over baseline during the trial, indicating improvement in targeted physical and emotional factors. There were no quantitative data for QOL.

Safety

Details of toxicities occurring at any time during treatment are presented in Table 3. The toxicity of the study regimen was considered similar to other studies of weekly docetaxel,lsai9 and no grade 3 or 4 event occurred in more than 10% of the pa- tients. In particular, the incidence of grade 3 or 4 myelosuppression was very low. Ten patients (17%) had treatment withheld because of toxici- ties (asthenia, diarrhea, neuropathy, hyperglyce- mia, sepsis, and renal insufficiency), and 25 pa- tients (42%) required dose adjustments. There was

12 BERRY ET AL

No. of Patients

Response or Median

Time

PSA response

~50% decrease, %

>80% decrease,* % -

<50% decrease or increase, %

Time to progression

All patients, mo (range)

~50% PSA decrease, mo (range)

<50% PSA decrease or increase, mo (range)

Survival time

250% PSA decrease, mo (range)

<SO% PSA decrease or increase, mo (range)

*Out of 24 patients with 250% decrease in PSA.

59

24 41

16 27

35 59

60 5. I (0.9- 18.2)

24 6.6 (3.2- 18.2)

36 4.3 (0.9- 17.2)

60 9.4 (I .6- 18.2)

24 Not reached (3.2- 18.2)

36 8. I (I .9- 17.2)

one treatment-related death caused by adult respi- ratory distress syndrome, possibly related to the

study drug.

DISCUSSION

lenged by the findings of several recent studies,334 and results from the present clinical trial support the view that meaningful responses can be achieved using palliative chemotherapy in this

setting.

Historically, HRPC has been regarded as resis- A ~50% decrease in serum PSA levels from

tant to chemotherapy. This view has been chal- baseline with stable or improved performance sta-

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

. “ “ “ - ,

150% PSA Decrease I,,,,,,,,,,,,,---

TTP All Patients I . .

-r , , I I_ 1 ’ ‘.

,,.,#I. -l,,,,,,,,,,,,,lll,,,,III.IIIIIIIII

~50% PSA Decrease or Increase

0 2 4 6 8 10 12 14 16 18 20

Months

Fig I. Estimated time to progression (TTP) grouped by serum PSA reduction and T T P for all patients.

PHASE II TRIAL OF WEEKLY DOCETAXEL IN METASTATIC PROSTATE CANCER 13

1.0

0.9

0.8

0.7

p .- 2

0.6

z tz 0.5

E .- r g

0.4

2 a 0.3

0.2

0.1

0.0 0

w m - -

I

~50% PSA Decrease L--------m-----..

Overall Survival

I I I I I I I I I . I s I , I I I , , , , ,

~50% PSA Decrease or increase

2 4 6 8 10 12 14 16 18 20

Months

Fig 2. Estimated survival grouped by serum PSA reduction and overall survival for all patients.

tus is generally regarded as evidence of a response because few patients have measurable disease.2OJi In our study, weekly docetaxel administration de- creased PSA by ~50% from baseline for at least 4

Event* No. of Patients (%)

Asthenia 6(10) Diarrhea 6(10) Anemia 4 (7)

Neuropathy 3 (5) Sepsis 2 (3) Hyperglycemia 2 (3) NFlUSSi 2 (3) Neutropenia 2 (3)

Stomatitis 2 (3) Coronary artery disease 1 (2) Renal insufficiency ’ (74 Thrombocytopenia ’ (2)

*Some patients experienced more than one event. One

patient had grade 4 respiratory failure, and one patient had

grade 4 thrombocytopenia.

weeks in 41% of men with metastatic HRPC. Of these patients, 27% had a ~80% decrease in PSA of the same duration. These results were not in- fluenced by previous exposure to mitoxantrone. Importantly, a docetaxel-induced ~50% decrease in PSA was associated with prolongation in both median time to symptom progression and median duration of survival.

Few patients in our study had measurable soft tissue disease. However, among the six who could be assessed for tumor response, one had a PR and one had a CR, including the disappearance of liver metastases. A decrease in PSA was seen in parallel with the objective tumor response in one of these patients, while the other had a PSA level of 0 at baseline.

Our results must be considered in the context of the multi-institutional community-based nature of this study and against the clinical background of the patients, who had a long duration of disease and were heavily pretreated. All patients had met- astatic disease that had progressed on standard hormonal treatment. Most patients (58; 97%) had undergone secondary hormonal maneuvers, of whom 20 (34%) progressed during this study. The

14 BERRY ET AL

majority (70%) h d 1 a a so received palliative radio- therapy, and 27% had received mitoxantrone che-

motherapy. The 41% PSA response rate with single- agent docetaxel observed in this study compares favorably with the 33% response rate reported for

mitoxantrone and prednisone in patients with no prior exposure to chemotherapy.5 Higher PSA re- sponse rates (63% to 82%) were obtained in two phase I studies of docetaxel in patients with

HRPC,aJa both of which used a combination reg imen with estramustine. Thus, it may be possible

to achieve even higher responses with combina- tion of weekly regimens of docetaxel, although these benefits would have to be balanced against any increased toxicity.

The toxicity of the weekly docetaxel regimen reported here was considered acceptable in the context of palliative treatment for HRPC in el-

derly (median age, 72 years) men. In accordance with the results of studies of weekly docetaxel in patients with different solid tumors,ilJ2 the inci- dence of grade 3 or 4 myelosuppression in our patients was low. Four patients (7%) developed

grade 3 or 4 anemia, two (3%) developed grade 3 or 4 neutropenia, and one (2%) developed grade 3 or 4 thrombocytopenia. Furthermore, no grade 3

or 4 toxicity occurred in more than 10% of pa- tients, and there was only one treatment-related death. Although a total of 25 patients (42%) re- quired a dose reduction during treatment, only 10

(17%) of the study population withdrew from treatment because of toxicity, mainly asthenia,

diarrhea, anemia, and neuropathy.

CONCLUSIONS

Weekly administration of docetaxel, 36 mg/m’, as a single agent was associated with a PSA re- sponse of 41% and minimal myelosuppression in this sample of mainly elderly patients with meta-

static HRPC who had received extensive prior therapy. Both TTP and survival time were pro- longed in patients with a PSA response. Based on these preliminary data, phase III studies of this weekly docetaxel schedule, alone and in combina- tion regimens, are warranted.

ACKNOWLEDGMENT

The authors thank the patients who shared their experiences

and all US Oncology physicians (see Appendix), coordinators,

project managers, and data reviewers who participated in this

study. They thank Dr Barry Flannelly for helping to write the

manuscript and Dr Elvira De Mejia for providing editorial

support.

APPENDIX

Members of the US Oncology Study Group: A. Kales, J.

Miller, Annandale/Fairfax, VA; D. Jackson, Asheville, NC; D.

Tweedy, Austin, TX; J. Fleagle, Boulder, CO; M. Willen,

Clifton Park (Albany/Latham/Rexford), NY; N. DiBella, D.

Faragher, K. Fink, D. Paul, Denver (Midtown), CO; M.

Elkordy, Durham, NC; R. Brooker, M. O’Rourke, Greenville,

SC, R. Pluenneke, Independence, KS; A. Greenspan, D.

Loesch, Indianapolis (East), IN; Y. Abubakar, Jacksonville

(M&J), FL; L. Adler, J. Stone, Jacksonville (Stone), FL; R.

Belt, J. Davis, Kansas City (Westwood), KS; J. Kessler, S.

Kruger, J. Mattern, J. Schulz, Newport News/Hampton, VA; E.

George, Norfolk, VA; A. Kritz, R. Kubica, C. Reitz, R. Staab,

J. Young, Oklahoma City, OK; T. Crandall, P. Ellis, S. Marks,

D. Spadaro, Pittsburgh, PA; D. Gruenberg, R. Weinstein, Port-

land (PNOA)/Vancouver, OR; A. Chang, Rochester, NY; E.

McAloon, G. Robbins, Tampa, FL; R. Tolley, Thornton, CO;

M. Modiano, R. Rosenberg, Tucson (Tucson Medical), AZ; M.

Slatkoff, Winston-Salem (Triad), NC; and J. Medellin, San

Antonio, TX.

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