The NEW ENGLAND IOURNAI. JMEDICINE
`
`ORIGINAL ARTICLE
`
`Docetaxel plus Prednisone or Mitoxantrone
`plus Prednisone for Advanced Prostate Cancer
`
`Ian F. Tannock, M.D., Ph.D., Ronald de Wit, M.D., William R. Berry, M.D.,
`JozsefHorti, M.D.,Anna Pluzanska, M.D., Kim N. Chi, M.D.,
`Stephane Oudard, M.D., Christine Théodore, M.D.,
`Nicholas D.James, M.D., Ph.D., lngela Turesson, M.D., Ph.D.,
`Mark A. Rosenthal, M.D., Ph.D., and Mario A. Eisenberger, M.D.,
`for the TAX 327 Investigators
`
`ABSTRACT
`
`BA C K G I! O U N D
`
`Mitoxantrone plus prednisone reduces pain and improves the quality of life in men
`with advanced, hormone-refiactory prostate cancer, but it does not improve survival.
`We compared such treatment with docetaxel plus prednisone in men with this disease.
`M ET H O D S
`
`From March 2000 through June 2002, 1006 men with metastatic hormone-refiactory
`prostate cancer received 5 mg ofprednisone twice daily and were randomly assigned to
`receive 12 mg ofmitoxantrone per square meter ofbody-surface area every three weeks,
`75 mg ofdocaaxel per square meter every threeweeks, or 30 mg ofdocetaxel per square
`meter weekly for five of every six weeks. The primary end point was overall survival.
`Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality
`oflife. All statistical comparisons were against mitoxantrone.
`R E S U LTS
`
`As compared with the men in the mitoxantrone group, men in the group given doce-
`taxel every three weeks had a hazard ratio for death of0.76 (95 percent confidence in-
`terval, 0.62 to 0.94; P=0.009 by the stratified log—rank test) and those given weekly
`docetaxel had a hazard ratio for dmth of0.91 (95 percent confidence interval, 0.75 to
`1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9
`months in the group given docetaxel every3 weeks, and 17.4 months in the group givu
`en weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent
`ofmen, respectively, had at leasta 50 percent decrease in the serum PSA level (P<0.001
`for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31
`percent (P= 0.08) had predefined reductions in pain; and 13 percent, 22 percent
`(P=0.009), and 23 percent (P=0.005) had improvements in the quality oflife. Adverse
`events were also more common in the groups that received docetaxel.
`C O N C L U S I O N S
`
`When given with prednisone, treatment with docetaxel every threewedts led to superi-
`or survival and improved rates ofresponse in terms ofpain, serum PSA level, and qual-
`ity oflife, as compared with mitoxantrone plus prednisone.
`
`From the Department of Medial Oncology
`and Hematology. Princess Margaret Hos-
`pital and University of Toronto. Toronto
`(I.F.T.); the Department ofMedical Oncol-
`ogy. Erasmus University Medical Centre,
`Rotterdam. the Netherlands (R.W.); Raleigh
`Hematology Oncology Associates. Cary,
`N.C. (W.R.B.); the Department of Cherno-
`theran and Clinical Pharmacology, Nation-
`al Institute ofOncology, Budapest. Hunga-
`ry (].H.); the Department ofChemotherapy,
`Medical University. Lodz. Poland (A.P.);
`BC Cancer Agency, Vancouver, B.C.. (‘ana-
`da (K.N.C); Hopital Européen Georges
`Pompidou. Paris (S.O.); Institut Gustav
`Roussy, Wllejuif. France (C.T.); Cancer Re-
`search UK Institute for Cancer Studies, Bir-
`mingham. United Kingdom (N.DJ.); the
`Section of Oncology. Uppsala University
`Hospital. Uppsala. Sweden (l.T.); Cancer
`Trials Australia. Victoria. Australia (M.A.R.);
`and the Sydney Kimmel Comprehensive
`Cancer Center; johns Hopkins University,
`Baltimore (MAE). Address reprint
`re-
`quests to Dr. Tannoclt at the Department
`of Medical Oncology and Hematology.
`Princess Margaret Hospital, 610 Universi-
`ty Ave.. Toronto. ON MSG 2M9, Canada.
`or at ian.tannock@uhn.on.ca.
`
`N Engl] Med 2004;35l:l502—l2.
`Copyrigli Q 2004 Moaachusdts Maical Sodety.
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`1502
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`N ENGLJ MED 351:1; WW\nI.NEjM.ORG ocronea 7, 2oo4
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`
`DOCETAXEL VERSUS MITOXANTRONE FOR PROSTATE CANCER
`
`ROSTATE CANCER IS THE MOST COM-
`
`I
`
`moncanceramongmen,withapproximate-
`
`ly 220,000 cases and 29,000 deaths annu-
`ally in the United States.‘ About 10 to 20 percentof
`men with prostate cancer present with metastatic
`disease, and in many others, metastases develop
`despite treatment with surgery or radiotherapy.
`Treatment ofmetastatic prostate cancer is pal-
`liative. In about 80 percent ofmen, primary andro-
`gen ablation leads to symptomatic improvement
`and a reduction in serum levels ofprostate-specific
`antigen (PSA), but in all patients the disease even-
`tually becomes refractory to hormone treatment.
`The options then include symptomatic care with
`narcotic analgesics, radiotherapy to dominant sites
`ofbone pain, treatmentwith bone-seeking isotopes
`such as strontium-89, and cytotoxic chemothera-
`py. Bisphosphonates may reduce skeletal compli-
`cations,’ 4 and low-dose prednisone or hydrocor-
`u'sone may be palliative in some patients.”
`Chemotherapy can reduce serum PSA levels in
`patients with hormone-refractory prostate cancer
`and relieves pain in some patients, but tolerability
`is of concern, particularly since most patients are
`elderly and many have other medical problems.’
`A randomized trial showed that mitoxantrone plus
`low-dose prednisone relieved pain and improved
`the quality of life more frequently than did pred-
`nisone alone.” Consistent benefits ofmitoxantro-
`
`ne plus a corticosteroid were observed in other ran-
`domized trials, but none found that this approach
`improved survival.‘° 1’ These trials established mi-
`toxantrone plus a corticosteroid as the treatmentof
`reference for hormone-refractory prostate cancer.
`Phase 2 studies ofthe taxane docetaxel have re-
`
`ported PSA responses (defined as a reduction in
`serum PSA levels ofatleast 50 percent) in up to 50
`percent ofpatients.“ 1° Studies ofdocetaxel plus
`either estramustine or calcitriol have shown PSA
`
`responses in up (1380 percent ofpatients." 19 How-
`ever, outcomes ofsingle-group studies are subject
`to bias.”
`
`We conducted a phase 3 study, the TAX 327
`Study, comparing docetaxel (given either every three
`weeks orweekly) plus daily prednisone with mito-
`xantrone plus prednisone. The docetaxel regimens
`were selected on the basis oftheir dose equivalence
`(a dose intensity of25 mg per square meter ofbody-
`surface area per week and a maximal cumulative
`dose of750 mg per square meter) and their activi-
`ty and tolerability in phase 2 studies. The primary
`hypothesis was that treatment with docetaxel plus
`
`prednisone would improve overall survival as com-
`pared with mitoxantrone plus prednisone.
`
`METHODS
`
`PATI E N TS
`
`This randomized, nonblinded, phase 3 study in-
`volved centers in 24 countries. Eligible patients had
`histologically or cytologically confirmed adeno-
`carcinoma ofthe prostate with clinical or radiolog-
`ic evidence of metastatic disease, had had disease
`progression during hormonal therapy, and were re-
`ceivingprimary androgen-ablation therapyas main-
`tenance therapy. At least four weeks had to have
`elapsed between the withdrawal ofantiandrogens
`(six weeks in the case ofbicalutamide) and enroll-
`
`ment, so as to avoid the possibility ofconfounding
`as a result of the response to antiandrogen with-
`drawal.‘1»” Another req uirementwas disease pro-
`gression, as indicated by increasing serum levels of
`PSA on three consecutive measurements obtained
`
`at least one week apart or findings on physical ex-
`amination or imaging studies.
`Eligible patients had a Kamofsky performance-
`status score ofat least60 percent, no prior treat-
`ment with cytotoxic agents (except estramustine)
`or radioisompes, no history ofanother cancer with-
`in the preceding five years (except basal or squa-
`mous-cell skin cancer), no brain or leptomeningeal
`metastases, no symptomatic peripheral neurop-
`athy of grade 2 or higher, and no other serious
`medical condition. At least four weeks had to have
`
`elapsed between prior surgery or radiotherapy (lim-
`ited to no more than 25 percent of the bone mar-
`row) and enrollment. Prior treatmentwith cortico-
`steroids was allowed. Normal cardiac function was
`
`required. Laboratory criteria for eligibility included
`a neutrophil count ofat least 1500 per cubic milli-
`meter, a hemoglobin level ofat least 10.0 g per deci-
`liter, a platelet count of at least 100,000 per cubic
`millimeter, a total bilirubin level below the upper
`limit of the normal range for each institution, and
`serum alanine aminotransferase, aspartate amino-
`transferase, and creatinine levels thatwere no more
`
`than 1.5 times the upper limit ofthe normal range.
`A clinical history was obtained, and a physical
`examination, with radiographic imaging, comput-
`ed tomography, and bone scanning, was performed
`within 14 days before randomization. Blood tests
`including measurementofserum PSA, electrocar-
`diography, and an evaluation of the left ventricu-
`lar ejection fraction by means of a multiple gated
`
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`The new england journal of medicine
`
`acquisition scan or echocardiography were per-
`formed. Pain, analgesic intake, and the quality of
`life were assessed at baseline. Pain was assessed by
`means of the Present Pain Intensity (PPI) scale from
`the McGill–Melzack questionnaire, which uses ver-
`bal descriptors; scores can range from 0 to 5, with
`higher scores indicating greater pain.23 Patients
`recorded their daily PPI score and analgesic use in
`a diary. A daily analgesic score was calculated by
`assigning a score of 4 for a standard dose of a nar-
`cotic analgesic (e.g., 10 mg of morphine) and a score
`of 1 for a standard dose of a nonnarcotic analgesic.
`Patients were required to have stable levels of pain
`for at least seven days before randomization, de-
`fined by a daily variation of no more than 1 in the
`PPI score or of no more than 25 percent in the anal-
`gesic score. The quality of life was assessed with
`the Functional Assessment of Cancer Therapy–Pros-
`tate (FACT-P) questionnaire; scores on this self-
`administered questionnaire can range from 0 to
`156, with higher scores indicating a better quality
`of life.24,25
`All patients provided written informed consent,
`and the study was approved by all institutional re-
`view boards in accordance with the international
`standards of good clinical practice. An independent
`data and safety monitoring committee was estab-
`lished.
`
`randomization and treatment
`Randomization was centralized with the use of a
`stratified, permuted-block allocation scheme ac-
`cording to the baseline pain level (pain was classi-
`fied as present, as defined by a median PPI score of
`at least 2 or a mean analgesic score of at least 10,
`or as absent, as defined by a median PPI score of
`less than 2 and a mean analgesic score of less than
`10) and the baseline Karnofsky performance-status
`score (70 percent or less vs. 80 percent or more).
`Patients who were randomly assigned to the doc-
`etaxel groups received either 75 mg of docetaxel
`(Taxotere, Aventis) per square meter as a 1-hour in-
`travenous infusion on day 1 every 21 days or 30 mg
`of docetaxel per square meter as a 30-minute in-
`travenous infusion on days 1, 8, 15, 22, and 29 of a
`6-week cycle. Patients who were randomly assigned
`to the standard-therapy group received 12 mg of
`mitoxantrone (Novantrone, Immunex and Wyeth–
`Ayerst) per square meter as a 30-minute infusion
`on day 1 every 21 days. All patients received 5 mg
`of prednisone (or prednisolone, if prednisone was
`not available) orally twice daily starting on day 1. Pre-
`
`medication with dexamethasone was required in
`the docetaxel groups (8 mg given 12 hours, 3 hours,
`and 1 hour before the docetaxel infusion in the
`group treated every three weeks and 8 mg given
`1 hour before docetaxel in the group treated week-
`ly). Antiemetic medication was prescribed accord-
`ing to local practice.
`Up to 10 cycles of treatment were planned for
`the group given docetaxel every three weeks and
`the mitoxantrone group and up to 5 cycles (of six
`weeks each) in the weekly-docetaxel group. Treat-
`ment delays of up to two weeks and up to two dose
`reductions were allowed. Dose reductions were
`specified for patients who had had grade 4 neutro-
`penia for at least seven days, an infection, or grade
`3 or 4 neutropenia with an oral temperature of at
`least 38.5°C. A dose reduction or treatment delay
`was also stipulated for patients who had an abso-
`lute neutrophil count of less than 1500 per cubic
`millimeter (for those on three-week schedules) or
`less than 1000 per cubic millimeter (for those re-
`ceiving weekly docetaxel) on a treatment day and
`for those with grade 3 or 4 thrombocytopenia. Treat-
`ment with granulocyte colony-stimulating factor
`was allowed for patients with febrile neutropenia.
`Systemic corticosteroids (other than dexametha-
`sone and prednisone) and bisphosphonates were
`not permitted.
`
`follow-up and outcomes
`Physical examinations and baseline blood tests
`were repeated at three-week intervals. Imaging
`studies to determine the extent of disease were per-
`formed at intervals of six to nine weeks and repeat-
`ed after four weeks to identify those with a response.
`The primary end point was overall survival. Sec-
`ondary end points were predefined reductions in
`pain, an improvement in the quality of life, a reduc-
`tion in serum PSA levels of at least 50 percent, and
`objective tumor responses.
`Patients with a PPI score of at least 2, an analgesic
`score of at least 10, or both (averaged over the pre-
`vious week) at baseline were assessed for the pain
`response at three-week intervals. A pain response
`was defined as a two-point reduction in the PPI
`score from baseline without an increase in the an-
`algesic score or as a reduction of at least 50 percent
`in the analgesic score without an increase in the
`PPI score, either of which was maintained for at
`least three weeks. Pain progression was defined as
`an increase in the PPI score of at least one point
`from the nadir, an increase from baseline of at least
`
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` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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`
`docetaxel versus mitoxantrone for prostate cancer
`
`25 percent in the analgesic score, or a requirement
`for palliative radiotherapy.
`Serum PSA was measured every three weeks,
`and a response (for patients with a baseline PSA
`level of at least 20 ng per milliliter) was defined as a
`reduction from baseline of at least 50 percent that
`was maintained for at least three weeks, whereas
`PSA progression was defined as an increase from
`the nadir of either at least 25 percent for men with
`no PSA response or at least 50 percent for all oth-
`ers. The duration of the PSA response and the pain
`response was defined as the time between the first
`and last evaluations at which the response criteria
`were met. For patients with at least one bidimen-
`sionally measurable lesion, tumor response was
`evaluated with the use of World Health Organiza-
`tion criteria.26
`The quality of life was assessed with the FACT-P
`questionnaire at baseline, every three weeks dur-
`ing therapy, and every month after the completion
`of therapy. All patients who answered the question-
`naire at baseline were included in the evaluation,
`and the FACT-P score was compared with the base-
`line value for each of these patients. Patients were
`defined as having a quality-of-life response if they
`had a 16-point improvement in their FACT-P score,
`as compared with baseline, on two measurements
`obtained at least three weeks apart.
`Adverse events were classified according to the
`Common Toxicity Criteria of the National Cancer
`Institute (version 2). Serious adverse events were
`fatal or life-threatening, required or prolonged hos-
`pitalization, resulted in persistent or substantial
`disability or incapacity, or were considered im-
`portant medical events. Treatment was stopped
`for any of the following reasons: completion of
`planned treatment, progression of disease, severe
`adverse events, or withdrawal of consent.
`
`statistical analysis
`There were three comparisons of interest between
`the docetaxel and mitoxantrone groups: docetaxel
`given every three weeks was compared with mito-
`xantrone, weekly docetaxel was compared with mi-
`toxantrone, and the combined docetaxel groups
`were compared with mitoxantrone. The study was
`designed to detect with 90 percent power a hazard
`ratio of 0.75 for death in the docetaxel groups as
`compared with the mitoxantrone group, with a
`two-sided type I error of 0.05 and with the data
`analyzed according to the intention to treat. The
`sample size was established as 1002 patients, and
`
`analysis was planned after 535 deaths had occurred.
`To allow for multiple comparisons, a P value of
`0.04 was considered to indicate statistical signif-
`icance for the comparison of the combined doce-
`taxel groups with the mitoxantrone group, and a
`P value of 0.0175 was considered to indicate sta-
`tistical significance for the comparison of each
`docetaxel group with the mitoxantrone group (all
`P values were two-sided), thus ensuring an overall
`significance level of 0.05.
`In the primary analysis, overall survival was an-
`alyzed by means of the Kaplan–Meier method,
`with log-rank comparisons stratified according to
`the level of pain and the Karnofsky performance-
`status score. Pain, PSA, tumor, and quality-of-life
`responses were compared by means of the Coch-
`ran–Mantel–Haenszel test. All randomized patients
`were included in the analysis of survival, and all
`treated patients were included in the evaluation of
`adverse effects.
`Hazard ratios for death were calculated after
`adjustment for any chance imbalance in potential
`prognostic factors between the groups. The follow-
`ing factors were entered into a full stratified Cox
`proportional-hazards model and a backward selec-
`tion model in which nonsignificant factors were
`eliminated sequentially at a P level of 0.10: age (less
`than 65 years vs. 65 years or older); visceral involve-
`ment (yes vs. no); liver involvement (yes vs. no);
`number of prior hormonal therapies (two or fewer
`vs. more than two); prior estramustine (yes vs. no);
`presence of rising serum PSA levels alone, as com-
`pared with the presence of other indications of pro-
`gression; baseline hemoglobin level; and baseline
`serum level of alkaline phosphatase. One planned
`interim analysis of safety was conducted after the
`recruitment of 120 patients. No interim analysis
`for efficacy was performed.
`The study was designed by Dr. Tannock in col-
`laboration with Aventis personnel, and the proto-
`col was finalized after being reviewed by the other
`study cochairs, Drs. de Wit and Eisenberger. The
`data were collected and maintained by Aventis, but
`the cochairs handled all questions regarding the
`management of the study. Only the data and safety
`monitoring committee saw the results of the inter-
`im safety analysis; no analysis was undertaken nor
`were the results seen by Aventis, the study cochairs,
`or any other investigator until the predefined num-
`ber of events had occurred. The protocol contained
`a plan for analysis and publication at that time. All
`data were provided to the cochairs at the comple-
`
`n engl j med 351;15 www.nejm.org october 7, 2004
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`

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`The NEW ENGLAND JOURNAL IJMEDICINE
`
`lion ofthe study. Aventis personnel undertook the
`statistical analysis. The article was drafted by Dr.
`Tannock and modified after being reviewed by the CHARACTERISTICS or TH E PATIENTS
`cochairs and othercoauthors. Aventis reviewed the AND rnenu em’
`
`RESULTS
`
`manuscript, but its final oontentwas entirely detu'- A total of 1006 patients underwent randomiza-
`mined by the investigators.
`tion from March 2000 through June 2002. The da-
`
`Tabb 1. BaselineChIacleristi¢s oftlle PItients.*
`
`Doeetaxel Every 3 Wk Weekly Docetlxd Mitoxantrone Every 3 Wk
`335
`334
`337
`
`12
`
`68
`
`2o
`
`42
`
`31
`
`26
`
`19
`
`S2
`19
`
`12
`
`69
`
`21
`
`40
`
`31
`
`29
`
`24
`
`44
`
`12
`
`68
`
`43-86
`
`2o
`
`42
`
`28
`
`30
`
`21
`
`S1
`20
`
`Characteristic
`No. randomized
`
`Ineligible (96)
`Age
`
`Median (yr)
`
`Range (yr)
`
`275 Yr (96)
`
`Gleason score (96)
`57
`
`8-10
`
`Not available
`
`Prior treatment (96)
`Prostatectomy
`
`Radiotherapy
`Estramustine
`
`Hormonal manipulations (96)1-
`
`l 2 >
`
`2
`
`Karnofsky performancestatus score s70% (96)
`Pain (96):
`Serum PSA
`
`Median (ng/ml)
`
`220 ng/ml (96)
`
`Extent ofdisease (96)
`Bone metastases
`
`Visceral disease
`
`Measurable lesions
`
`Evidence of progression at entry (96)§
`Bone scan
`
`Increase in measurable lesions
`
`Increase in nonrneasurable lesions
`
`Increased PSA
`
`* All patients were included in the intention-to—treat analysis. Because of rounding. not all percentages total 100.
`1‘ Hormonal manipulation was defined as bilateral orchiectomy or hormone therapy.
`1: Pain was defined by a score of2 or more on the Present Pain Intensity scale or an analgesic score ofat least 10.
`§ Patients may have more than one indication for progression ofdisease.
`
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`
`DOCETAXEI. VERSUS MITOXANTRONE FOR PROSTATE CANCER
`
`tabase was locked on August 6, 2003, after the req-
`uisite number ofdeaths, specified in the statistical
`Plan» had0eel1ffed-
`The basdine charactaistics ofthe patients were
`well balanced among the three treatment groups
`(Table 1). The median age was 68 years; about 20
`percent ofthe patients were at least 75 years old.
`About 45 percent had pain, and about 40 percent
`had measurable soft-tissue lesions. The most com-
`
`mon indicators ofdisease progression before study
`entry were an increasing serum PSA level and evi-
`dence of an increase in bone metastases on bone
`
`scanning.
`Only nine patients (1 percent) did not receive
`chemotherapy and prednisone (Table 2). Patients
`tended to receive more cycles of the regimen in
`which docetaxel was given every three wedcs than
`of the regimen in which mitoxantrone was given
`arery three wedcs. Most patients received the pre-
`scribed doses on schedule, with 8 to 12 percent
`requiring a dose reduction and 21 to 34 percent
`requiring at least one chemotherapy infiision to be
`delayed. Twenty percent of the patients who were
`randomly assigned to receive mitoxantrone sub-
`sequently received docetaxel, and 27 percent of
`those in the group given docetaxel every three
`weeks received subsequent mitoxantrone, as did
`24 percent ofthose in the weekly-docetaxel group.
`
`E r r I ca cv
`
`Variable
`No randomized
`'
`"°- “eated with C"e'"°“‘e'3PY
`No. treated with prednisone
`
`Weekly Mitoxantrone
`noeetuel
`Every 3 WI: Docetaxel
`Every 3 wk
`335
`334
`337
`
`332
`332
`
`33°
`330
`
`335
`335
`
`No. ofcycles
`Median
`
`Range
`
`21 Infusion delayed (96)
`Dose reduction (96)
`Major protocol violation (96)
`
`Re-95°05 f°' St°PPi"8 treatment (95)
`compneted neatmem
`
`Progression ofdisease
`Adverse event
`
`Wthdrawal ofconsenl
`Death
`Other
`
`C'°55°”°' ‘° °‘l'°' d"‘3 (96)
`
`" Percentages relate to the number ofpatients treated in each group. Because of
`rounding, not all percentages total 100.
`
`r—I
`
`
`
`
`
`
`
`
`
`The median duration of follow-up was similar
`among the three groups: 20.8 months in the group
`given docetaxel every 3 weeks and 20.7 months in
`the other two groups. There were 166 deaths (50
`percent; hazard ratio for death, 0.76; 95 percent
`confidence interval, 0.62 to 0.94) in the group giv-
`en docetaxel every three weeks and 190 deaths (57
`percent; hazard ratio, 0.91; 95 percent confidence
`interval, 0.75 to 1.11) in the group given weeldy
`docemxel, as compared with 201 deaths (60 per-
`cent) in the mitoxantrone group. When the two
`docetaxel groups wue combined and compared
`with the mitnxantrone group, the hazard ratio for
`death was 0.83 (95 percent confidence interval, 0.70
`to 0.99; 1>=o.o4). As compared with the survival N” M
`rate lll tllfl II1ltOX3Ilt'1'0IlC group, the SllIVlV3l rate
`Doceg;xe|eVe;y
`was significantly higher (P=0'009) in the group
`\Ne3el:k docetaxel
`8iVett doeemxel Wet)’ three Weeks but not in the
`Mitoxintrone
`group given weeldy docetaxel (P=0.36). The medi-
`Figure 1. ItapIan—Meier Estirnats ofthe Probability ofovenll Survival
`an duration of survival was 18.9 months (95 p&-
`in the "Wee 5'°"PS-
`cent confidence interval, 17.0 to 21.2) in the group
`given docetaxel every 3 weeks, 17.4 months (95 per-
`
`
`
`Mitatantrone
`
`
`
`ProbabilityofoverallSurvival(96)
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`13
`
`21
`
`24
`
`27
`
`30
`
`33
`
`335
`334
`337
`
`296
`297
`297
`
`"M"
`104
`105
`95
`
`217
`200
`192
`
`37
`29
`29
`
`5
`4
`3
`
`
`
`
`
`N ENGL] ME!) 35135 www.N:pa.onc ocronzn 7, 2004
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`1507
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`The New Englandloumal ofMedidne
`Downloaded fiomnejm.o1gonIu.ly 22, 2015. Forpcrsonalusconly. Nootheruseswithout permission
`Copyright 0 2oo4 Massachusetts Medical Society. All rights reserved
`
`P
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`age
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`Page 6
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`

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`The new england journal of medicine
`
`Table 3. Response to Treatment, as Measured by Decreases in Pain, PSA Level,
`and Tumor Burden and Improvements in the Quality of Life.*
`
`Variable
`
`Pain†
`
`Docetaxel
`Every 3 Wk
`
`Weekly
`Docetaxel
`
`Mitoxantrone
`Every 3 Wk
`
`No. who could be evaluated
`
`153
`
`154
`
`157
`
`Response (%)
`
`Rate
`
`95% CI
`
`P value
`
`Duration (mo)‡
`
`Median
`
`95% CI
`
`35
`
`27–43
`
`0.01
`
`31
`
`24–39
`
`0.08
`
`22
`
`16–29
`
`3.5
`
`5.6
`
`4.8
`
`2.4–8.1
`
`2.8–6.8
`
`4.4–indeter-
`minate
`
`≥50% Reduction in serum PSA
`
`No. who could be evaluated
`
`291
`
`282
`
`300
`
`Response (%)
`
`Rate
`
`95% CI
`
`P value
`
`Duration (mo)‡
`
`Median
`
`95% CI
`
`Tumor response
`
`45
`
`40–51
`
`<0.001
`
`48
`
`42–54
`
`<0.001
`
`32
`
`26–37
`
`7.7
`
`8.2
`
`7.8
`
`7.1–8.6
`
`6.3–11.5
`
`5.4–10.5
`
`No. who could be evaluated
`
`141
`
`Response (%)
`
`Rate
`
`95% CI
`
`P value
`
`Quality of life
`
`12
`
`7–19
`
`0.11
`
`No. who could be evaluated
`
`278
`
`Response (%)§
`
`Rate
`
`95% CI
`
`P value
`
`22
`
`17–27
`
`0.009
`
`134
`
`8
`
`4–14
`
`0.59
`
`270
`
`23
`
`18–28
`
`0.005
`
`137
`
`7
`
`3–12
`
`267
`
`13
`
`9–18
`
`* P values are for comparisons with the mitoxantrone group. CI denotes confi-
`dence interval.
`† A pain response was defined as a two-point reduction in the Present Pain In-
`tensity (PPI) score without an increase in the analgesic score or a reduction of
`at least 50 percent in the analgesic score without an increase in the PPI score,
`which was maintained for at least three weeks.
`‡ Data on 54 percent and 63 percent of patients were censored in the Kaplan–
`Meier analysis of the median duration of pain and PSA response, respectively.
`The chief reason for data censoring was further antitumor therapy after pro-
`gression of disease as defined by other criteria.
`§ A response was defined by a 16-point improvement from baseline in the Func-
`tional Assessment of Cancer Therapy–Prostate (FACT-P) score on two mea-
`surements obtained at least three weeks apart.
`
`cent confidence interval, 15.7 to 19.0) in the group
`given weekly docetaxel, and 16.5 months (95 per-
`cent confidence interval, 14.4 to 18.6) in the mito-
`xantrone group. Kaplan–Meier survival curves for
`the three groups are shown in Figure 1.
`The result of the sensitivity analysis, in which
`survival was adjusted for possible imbalances in
`potential prognostic factors, was consistent with
`the primary result. The hazard ratio for death in the
`group given docetaxel every three weeks, as com-
`pared with the mitoxantrone group, was 0.76 with-
`out adjustment and 0.74 and 0.75 after adjustment
`in the full stratified and backward Cox propor-
`tional-hazards models, respectively. As expected,
`visceral involvement, a high baseline alkaline phos-
`phatase level, and a low hemoglobin level were
`negative prognostic factors in the multivariate mod-
`els, whereas a rising serum PSA as the sole indica-
`tor of progression was a favorable factor. Post hoc
`analysis indicated that a high Gleason score (8, 9, or
`10) was an adverse prognostic factor for survival.
`The survival benefit of docetaxel given every three
`weeks was consistent across subgroups defined ac-
`cording to the presence or absence of pain at base-
`line, the Karnofsky performance-status score (70
`percent or less vs. 80 percent or more), and age
`(younger than 65 years vs. 65 years or older) (data
`not shown).
`A reduction in pain was more frequent among
`patients receiving docetaxel every three weeks than
`among those treated with mitoxantrone (35 per-
`cent vs. 22 percent, P=0.01) (Table 3), but the per-
`centage of patients with reduced pain in the weekly
`docetaxel group (31 percent) did not differ signifi-
`cantly from that of the mitoxantrone group. The
`median duration of reduced pain was 3.5 to 5.6
`months and did not differ significantly among the
`groups.
`Rates of PSA response were significantly higher
`in the docetaxel groups (45 percent in the group
`given docetaxel every three weeks and 48 percent in
`the group given weekly docetaxel, P<0.001 for both
`comparisons) than in the mitoxantrone group (32
`percent) (Table 3). The median duration of the PSA
`response ranged from 7.7 to 8.2 months and did
`not differ significantly among the three groups.
`Although patients with measurable soft-tissue
`lesions who received docetaxel every three weeks
`had a somewhat higher rate of tumor response than
`such patients who received mitoxantrone every
`three weeks (12 percent vs. 7 percent, P=0.11), this
`difference was not significant (Table 3).
`
`1508
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`n engl j med 351;15 www.nejm.org october 7, 2004
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`The New England Journal of Medicine
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`Downloaded from nejm.org on July 22, 2015. For personal use only. No other uses without permission.
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` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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`Page 7
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`

`
`DOCETAXEI. VERSUS MITOXANTRONE FOR PROSTATE CANCER
`
`ADVERSE EVENTS
`
`The incidence of grade 3 and 4 neutropenia was
`relatively low, and febrile neutropenia was rare (Ta-
`ble 4). Two patients died from sepsis during treat-
`ment, one in the docetaxel group and one in the
`mitoxantrone group. There was a higher incidence
`ofcardiac events among patients who received mi-
`toxantrone (fable 4). Most other types of advase
`events were more frequent among patients receiv-
`ing docetaxel, and thue was no trend toward a low-
`er frequency with weddy docetaxel than with doce-
`taxel given every three weeks. Low-grade advase
`events that occurred in at least 15 percent of pa-
`tients in one ofthe groups included fatigue, nausea
`or vomiting or both, alopecia, diarrhea, nail clung-
`es, sensory neuropathy, anorexia, changes in taste,
`stomatitis, dyspnea, tearing, puipheral edema, and
`epistaxis (Table 4). More patients in the docetaxel
`groups than in the mitoxantrone group had at least
`one serious adverse event, with rates of26 percent
`among those in the group given docetaxel every
`three weeks, 29 percent among those given weeldy
`docetaxel, and 20 percent among those given mito-
`xantrone. Five deaths were probably related to treat-
`ment, three ofthem in the mitoxantrone group.
`More patients in the mitoxantrone group stopped
`treatment because ofdisease progression than was
`the case in the docetaxel groups, and more stopped
`treatment because of completion of treatment or
`adverse events in the docetaxel groups (Table 2).
`Adverse events that led to the discontinuation of
`
`treatment included fiitigue, musculoskeletal or nail
`changes, sensory neuropathy, and infection in the
`docemxel groups and cardiac dysfiinction in the
`mitoxantrone group.
`
`QUALITY or ur:
`
`The quality oflife was evaluated in 815 patients,
`a group that made up the intention-to-treat popu-
`lation from countries in which a local translation of
`
`the FACT-P was available (fable 3). The percenmge
`ofpatients who had an improvement in the quali-
`ty of life was similar in the two docetaxel groups
`(22 percent in the group given docetaxel every three
`weeks and 23 percent in the group given weeldy
`docemxel) and significantly higher than that in
`the mitoxantrone group (13 percent; P=0.009 and
`P: 0.005, respectively). Figure 2 shows the greatest
`changes in the scores and the median changes in
`the scores for individual domains of the FACT-P
`
`during treatment. The greatest bendit in the doc-
`etaxel groups was in the subscale representing
`
`Table4.Adverse EventsofAnyGrade.,orofGrade3or4,That0ea.Irred
`orworserledduringfieatment.
`
`Docelaxelwedtly
`Every3Wlr
`Doce