Chemotherapy With Mitoxantrone Plus Prednisone or
`Pred nisone Alone for Symptomatic Hormone-Resistant
`Prostate Cancer: A Canadian Randomized Trial With
`Palliative End Points
`
`By ion F. Tonnock, David Osobo, Marti n R. Stockier, D. Scott Ernst, Alan J. Neville, Malcolm J. Moore,
`George R. Armitage, Jona thon J. Wilson , Peter M. Venner, Christopher M.l. Coppin, and Kevin C. Murphy
`
`Purpose: To investigate the benefit of chemotherapy in
`patients with symptomatic hormone-resistant prostate can(cid:173)
`cer using relevant end points of palliation in a randomized
`controlled trial.
`Patients and Methods: We randomized 161 hormone(cid:173)
`refractory patients with pain to receive mitoxantrone plus
`prednisone or prednisone alone (10 mg daily). Nonre(cid:173)
`spanding patients on prednisone could receive mitoxan(cid:173)
`trone subsequentfy. The primary end paint was a palliative
`response defined as a 2-point decrease in pain a s assessed
`by a 6-point pain scale completed by patients (or complete
`loss of pain if initially 1 + J without an increase in analgesic
`medication and maintained for twa consecutive evaluations
`at least 3 weeks apart. Secondary end points were a de(cid:173)
`crease of 2: 50% in use of analgesic medication without an
`increase in pain, duration of response, and survival.
`Health-related quality of life was evaluated with a series of
`linear analog self-assessment scales (LASA and the Prostate
`Cancer- Specific Quality·of·life Instrument (PROSQOU]),
`the core questionnaire of the European Organization for
`Research and Treatment of Cancer (EORTC), and a disease(cid:173)
`specific module.
`
`PROST ATE CANCER metastasi.zcs most ofte n to peJ(cid:173)
`
`vic lymph nodes ami to bone, and Lhe domillanl. symp(cid:173)
`tom i~ usually pain. Initial treaunent of metastatic disease by
`orchidectomy or by drugs that decrea.<:e androgen stimulation
`relieves symptoms in approximately 75% of patients. but all
`patients pmgress eventually to hormone-resistant disease. The
`role of chemotherapy in pmviding palliation hm; been contro(cid:173)
`versial.
`Many types of chemotherapy are toler .. tted poorly by pa(cid:173)
`tients wit.h prostate cancer. who are often elderly men \o\~ th
`concum:nt medical problems and l i mjt~d bone mruTOw re-
`
`Fmm rlrt Depurrmem of Medicine. Prim;esl MarJ.:arel flo.rpiiCII:
`Department of Medicine. Unil•ersity of Toromo: N11mber Ml'mnn'u/
`Hu.fpilal. Tammo: Briti.1h Colwnhia Cwrcer Agen(:~·: Uni1•ersity of
`Britilh Columbic1. Vtmco11ver: Tom Baku (cmctr Centrl!; Uni1•usiry
`ofCal~:al)'. Co/gal)': Hamilton Reginnal Can('er CMire; Sa.d:aroon
`Comer Centre; cmd Cross Cancer ltlllilllft', Edmomon. Canada.
`S111Jmitted Octahu 13. 1995: uccepftld Jwman• 16. 1996.
`SttfJpnned IJv /..Pdrrle Laborawries. DiviJirm of Cyanamid Can·
`alia. Inc.
`A dd reJs repri111 rl!qul.!stf to fan F. Tamwck. MD. Ph D. Ot'parr·
`men/ o( Mudid ne, Prince.u Margaret HOlflilal. filO University Ave.
`S11ite 4-405. Torm11u, M5G 1M9 Canada: Entail ian 1<1/l/hiCI..@ptllh.
`/(J/'()/l/(1,(1/1,('(/,
`c.: 1!196 by Amnit•w1 Society of Clinical Onc11/ogy.
`0732-IIJ3,YJQ6/1406-0002$3.00/0
`
`Results: Palliative response was observed in 23 of 80
`patients (29%; 95% confidence interval, 19% to 40%) w ho
`received mitoxantrone plus prednisone, and in 10 of 81
`patients (12%; 95% c.onfidence interval, 6% to 22%) who
`received prednisone alone (P = .01). An additional seven
`patients in each group reduced analgesic medication ?:.
`SO% without an increase in pain. The duration of palliation
`was longer in patients who received chemotherapy (me(cid:173)
`dian, 43 and 18 weeks; P < .0001, log-rank). Eleven of 50
`patients randomized to prednisone treatment responded
`after add~ion of mitoxantrone. There was no difference in
`overall survival. Treatment was well tolerated, except for
`five episodes of possible cardiac toxicity in 130 patientll
`who received mitoxantrone. Most responding patients had
`an improvement in quality·of-life scales and a decrease in
`serum prostate-specific antigen (PSA) level.
`Conclusion: Chemotherapy with mitoxantrone a nd
`prednisone provides palliation for some patients wit!,
`symptomatic hormone-resistant prostate cancer.
`J Clin Oncol 14: 1756- 1764. :0 1996 by American So
`ciety of Clinical Oncology.
`
`serve. Although the goal oftrerurnenl is palliation. few studic~
`have assessed outcome with validated scales for pain or qual
`ity of life thnt ru-e completed by patients. Some anticancer
`drug have biologic activity as asse~d by a tlecrea...e in t.he
`.{> but these agents are
`prostate-specific antigen {PSA) level. 1
`often given with corticosteroids. which provide palliation to
`some patients when used :llone.7 AJl anticancer drugs ca~
`toxicity, o tJ1cy have potential to cau~ some symptoms
`while reLieving others.
`We have unde1taken previous single-arm studies of predni
`sone alone7 and mitoxm1trone plus prednisone8 for ~-eatment
`of hum1one-resistant prostate ceu1cer. Mitoxantrone has IO\o\·
`toxiciLy, and studies have suggested some palliative benefi1
`for patient with metastatic prostate cancer.ts-w Our studies
`wen! also used to develop and evaluate methods for asses in!:
`pain and quality of life.7 6 ln rhe present randomized trial, we
`address the hypothesis tJ1at chemotherapy with mitoxantrone
`plus predni.,one provides better paJliat.ion than prednisonl
`alone.
`
`PATIENTS AND METHODS
`
`Patie11ts
`From i\ugu't 19CJO 10 A,prll 1994. 161 p<~liem~ in II Canadiuu
`institu t ion~ wore mndorni1.ed to receive miLo,~an lrone plus predni(cid:173)
`souc (SO paricnL,) or prednisone alone (8 1 patient~). All parielll•
`bad meta~tatic :tdenO<.·arcinoma uf 1he prostate wi1h symptoms that
`
`1756
`
`Journal of Clinical Oncology, Vol 14 , No 6 (June), 1996: pp 17 56-17 64
`
`WCK1010
`Page 1
`
`

`
`1757
`
`dose of 140 mg/mz mitoxantrone continue trea tment wnh prednisone
`alone.
`
`Assessmem of Owcome
`Patients were examined at intervals of J weeks. At these visits,
`they underwent blond tests and completed questionnaires related to
`pain and quality of life. Bone scans and mc;liographs lo define diseuse
`were performed ar 3-month intervals. Toxic side effects of chemo(cid:173)
`therapy were assessed by World Health Org1tniz.1tion (WHO) cri(cid:173)
`teria.'1
`We cho~e pain rdief as the primary indicatOr of palliation, bec.ause
`pain is the dominant symptom in this population. 1l1e primary end
`poim of respon~e was a 2-point reduction in the 6-point presem
`pain intenMty ~cale of the McGili-Melzack Pain Questionnnire7
`•
`
`(or complete lo~l> of pain if initially I+ ). This criterion had to be
`maintained on two consecutive evaluations at least 3 weeks apnrt
`without an increase iu analgesic score. The paiu scale has verbal
`descriptors (0 = no pain. I = mild pain, 2 = discomforting pain, 3
`= distressing pain, 4 = horrible pain, and 5 = excruciating pain},
`:~nd patient~ were asked to classify the average pain level during the
`previous 24 hours.
`Patients kept a diru-y in which they recorded ull medications. and
`at each visit the average daily quantities taken during the previous
`week were calculmed. A numeric scale was u~ed to compute a daily
`analgesic score: l unit was IISed for standard dose~ of nonnarcotic
`mcdicmion (aspirin 325 mg, acetaminophen 325 mg, indomethacin
`25 mg, etc.) and 2 units for standard dose~ of narcotic medication
`(morphine 10 mg, hydromorphone 2 mg. codeine 60 mg, etc.}. These
`units may not be equivalent in analgesic potency. but patients usually
`adjusted the dose of the baseline medication(s) mther than switch
`to a different medicntion of similar type. A secondary criterion of
`response was 11 50% decrease in analgesic score without an increase
`in pain maintained fur two consecutive evaluations at least 3 weeks
`apan. All patients were consiJered as~es~ablc for response.
`Other end points of the study were duration of palliative response
`(as defined by the primary end point} and survival. The l>t:art and
`end of response were defined. respectively, as the date of initial
`treatment and of the lost assessment for which rel>ponse criteria were
`satisfied.
`Progrcs.\lon wns defined as either an increase 111 the prescm pain
`inronsiry scale of 2:: I point compared with the nadir. or an increase
`in analgesic s.:ore of greater than 25% t:omparcd with baseline, each
`maintained on two consecutive visiiS. Unequivocal evideoce of new
`lesinns or of' mdiologic progression or a requirement for radiation
`therapy also constituted d isease progrcsoion.
`To ;Jsses~ the effects of dise~se and treatment on health-related
`qua lity of life. we used three different patient-based multidimen(cid:173)
`sional instruments that addressed functions, symptoms, and global
`perceptions, us follows: (1) the Prostate Cancer- Specilic Quality(cid:173)
`of-Life Instrument (PROSQOLJ}, which includes nine linear analog
`self-al.ses~ment (LASA) scales that relate to pain, physical activity,
`fatigue. appetite. constipation. passing urine, fanilly/maniage rela(cid:173)
`tionships, mood, and overall well-being. as well us Pre&ent Pnin
`lntensity and analgesic score7
`; (2) the European Organization for
`Research and Treatment of Cancer (EORTC) core questionnaire
`(E0RTC/QLQ-C30), with 30 ordinal scale items that included multi(cid:173)
`item domains for pbysicalli.tnction, emotional function. sociul fum:(cid:173)
`tion, pnin, nnd g lobul quality of life, and single items that included
`fatigue , appetite, and con~tipation 1~·'6: and (3) u specific module for
`prostate cancer developed according to EORTC guadelines that will
`be reponed elsewhere.
`
`1•
`
`..:HEMOTHERAPY FOR PROSTATE CANCER
`
`.ncluded pain, and had disease progression despite standatd hor(cid:173)
`·•onal therapy. All patients provided written informed consent 10
`panicipare in the ~tudy.
`Patients had an Eu>tem Coopemtive Oncolog )' Group (ECOG)
`performance s tatus or ~ 3 1 ie, they were capable of at least limited
`lf-cnre) nnd were ~Lratified by ECOG score (0.1 v 2.3). They had
`11 life expectancy ~ 3 months and were capable of completing pnin
`<11d quulity-of-life scules. Exclusion c ri teria were as follows: ( I)
`prior malignancy, except for oonmelnnotic skin cancer; (2) prior
`, hemothcrapy or treatment of cancer wi th glucocortkoid&: (3} treat(cid:173)
`ment with rndiotherapy in the last month or ~•rorttium 89 in the lust
`_ months; (4) contraindications to the use of prednisone such as
`, cli ve peptic ulcer; and (5) unco01rolled cardiac failure or active
`aulection. Eligible patients had serum concentrations of \VBCs
`erca1er than J .O x I<Y'IL. polymorphonuclear granulocytes greater
`th•tn 1.5 X 10~/L, plateleiS greater than 150 X 10•/L. bilirubin less
`than 54 pmol/L, and testosterone less than 3.5 nmoi!L.
`Patients had initial adjustment and stabilization of <lll:IJgesic mec;li-
`l tion. They were assessed by U1e fol.lowing: ( I) physical examina(cid:173)
`uon; (2) completion of pnin- and health-related CJU!IIity-of-llfe que~­
`'"'nnrtircs; (J) standard blood tests of hematologic and biochemical
`p~tramcters plu~ serum testosterone, pro~tatic ac id pllnsph<~tase, and
`PSA (not available in ttll centers at initiation of the study): (4}
`radionudidt- bone scan and radiographs of the chest. pelvis. and
`l'o~lnful bone sites; and (5) computed tomographic scan or ultra$ound
`r.can or the :•bdom~ :lnd pelvis if there \VOS abnormal Liver fun\' ion
`"' other e vidence of son tissue disease in these ~ate~.
`
`Treatment
`
`Patients continued their primary androgeq nbl!llion therapy (orchi(cid:173)
`tl.:ctomy. luteinizing hormone- releasing hormone agonist, estrogen,
`or cyproterone :•cetate): tlutamide alone wn!> not regarded as provid(cid:173)
`i·•g adeCJllate W)drogen suppression. Most patients had discontinued
`additional :~ntiandrogen treat.:meot. Midway through tJ)iS study, with(cid:173)
`llro~wul respon~es to Autnmide were recognized,' 1·' 2 and patients were
`then evaluated for at least 4 weeks after stopping nutamide before
`entry nntn the '>tudy.
`Potient~ continued to take nnalgesic medication and adjus1ed the
`dosage to provide optimal control of pain. Following randomization,
`all pntients rook orul prednisone 5 mg twice daily. Tho~c randomized
`to receive mitoxanLrone received inirially 12 mg/m2 bQdy-surface
`~rea by intravenous injecrion. Prnchlorperaz.inc was recommended
`a~ antiemetic rm:dicutJon: dexamethasone or other steroids were not
`u•cd. Chemotherapy was repeated at 3-weck intervals if senul1 con(cid:173)
`centrations of WBCs were greater than 3 X 1 0~/L. granulocytes
`g1cater than 1.5 X I OY/L, and platelets greater than I 00 X I 0"/L: if
`not, chemotherapy was delayed until these values were exceeded.
`Blood cell count~ were repeated on days 10 and 14 oftJ1c first cycle,
`and at one point within days 10 to 14 in subsequent cycles. [f nadir
`blood cell counts showed granulocytes Jess than 0.5 X 109/L or
`pl:uclcls less than 50 x 1 09/L. the dose of mitoxantrone was reduced
`b} 2 mg/m1 on subsequent cycles. Jf Mdir blood cell counts showed
`granu locytes greater 1han 1.0 X 10"/L and platelet~ greater than
`100 X 10°/L with minimal nonhematologic toxicity. the dose of
`tnrtoxan trone was increased by 2 mg/m2 on subsequent cycles.
`Nonresponding patients or those with progressive symptoms after
`tl\':.ttntent wilh prednisone alone for 2: 6 weeh were to receive
`ntitox.anii'One in addition.
`To minimi1.e the probability of cardiac toxicity. it wru. recom(cid:173)
`mended thna patients who were still r~ponding after a cumulative
`
`WCK1010
`Page 2
`
`

`
`1758
`
`Statistical Cmtsideratinns
`The plannrd ~ample site of 150 patients was ba.~ed on detection
`or exclu~inn nr a dnullling nf palliative rc;.pon~c mtc due to predni(cid:173)
`sone alone. which was then (ie. before availabilit) of antiandrogen
`drug:.) anticipated to be appro~irnately 2011} with an a of .OS and
`1-/3 of .80. A few additional pmicnL\ were entered to allow for
`incomplete data.
`One planned interim analysi~ was undenaken by an independent
`stmbtical consultant after entry of 80 pmiems. None of the inve~tiga­
`tors "e~ aware of any results before study completion and the
`current analysis.
`Statj~tical compari-.<•n' M the primary end point of response were
`made by Fi;.her's exact te\t. OiMributions of .urvivnl time and dura(cid:173)
`tion of palliative rc~pon~e wen! compun:t.l by lhr log-rank test. W e
`used nonparamctric dc~criptive statistics to aS$CSs the quality-of-life
`dattt. Each patient's profile of scorcN for each domain of health"
`related quality of life was summarized by ihe median and best scor.:~.
`Th.:se were converted to mcdiun and hest -change scores by sub(cid:173)
`tracting the appropriate baseline score. DitTcrcnces in the$e summw-y
`scores between the two treatment groups were II$Sessell with lhe
`WilcoXlil1 rank-~um test. The change frolll baseline in the group of
`re~pnnding patient~ was te~ted with the Wilcoxon signed-rank-sum
`test. All statistical test~ were twu·~>idcd. CoJTcctions were not applied
`for multiple sigJ1ifkance testing: thu~. apart from tJ1c en{! poin~
`defined a priori in the prCHI1CO], apparent correlations should he
`regarded as hypothe~i~·genor:lli ng rmher than definitive.
`Associution~ between baseline characteriMi;.;s and survival dura(cid:173)
`tion were as•es~ed with the log-rank test. Factor$ that appeared
`importunt (P :s: .05) in univ:trinblc anal}$iS were II 'J>~sed For inde(cid:173)
`pendent contribution~ with ccn,orcd linear regression afh:r a suitabk
`tr.msfonnation of ~un ivai time.11 Th1s model was chosen in prefer(cid:173)
`ence to Cox·' rnodt:l. becau~e J...ey \'ariable~ \ iolated the pruponional
`hazard~ assumption. Separate analyse~ were performed for the two
`ultema.ll\e measure.' ofheahh-rclatcd quality of life. For each analy(cid:173)
`sis. the "bel>t" subset of vatiable, wa~ chmen from an exhaustive
`sear.:h u~ing Mallow~· Cp as the criterion.'"
`
`External l?eview
`An im.lependent external consultant (provided by lhe National
`Cancer Institute of Canada) reviewed the records of <111 respondi ng
`patients and or u rund(•mly ~elected series of additional patien1s.
`
`RESULTS
`
`Baseline Cllaratlerislics
`
`Characteristics of lhc patients at entry onto the study
`are listed in Table I. The patients are well balanced for
`prognostic factors. although there is a trend for patients
`randomiL.eu to receive mitoxantrone plus prednisone to
`have a higher analgesic !>core and to be treated with ftu(cid:173)
`tamide. Two patients had pain score!'> o f zero after optimi(cid:173)
`zation of analgesic medication: both showed evidence of
`symptomatic progression.
`
`Response lo Therapy
`
`The primary criterion of palliative respo nse was met
`i n 23 of SO patients randomized to receive mitoxantrone
`
`Table 1. Characteristics of Patients at Entry On to the Study Accordins
`to Random ize d Group
`
`TANNOCK ET AL
`
`Vmioble
`
`Age
`Median
`lnlerquortile range
`Sites of metastasis
`Bone
`lymph nodes
`Visceral
`Other
`Serum concenlrotion·
`PSA (llg/l)
`Median
`lnlerquadile range
`Praslotic acid pho~photose
`Median
`lnterquorlile range
`Alkaline phosphatase
`Median
`lnterquartile Jange
`Creatinine
`Median
`tnterquortile range
`Time from diagnosis, years
`Median
`lnterquartile range
`Hormonal therapy lcurront)t
`Orchidectomy
`Estrogen
`LHRH agonist
`C yprolerone acetate
`Flutamide
`ECOG performance status
`0
`1
`2
`3
`Unknow.n
`Presen1 pain intensity
`0
`1
`2
`3
`4
`Analgesic score
`Median
`lnterquortile range
`Overall quality of lif&-1'
`By LASA scole
`Median
`lnterquortile range
`By EORTC QlQ·CJO
`Median
`tnterquortile range
`
`Prodni"""e
`In - 811
`No
`
`"
`
`67
`64·74
`
`77
`15
`3
`8
`
`95
`19
`4
`10
`
`MitoAontrone - Prednisoslot!;
`In = SO)
`
`No
`
`~
`
`69
`63·75
`
`78
`18
`3
`7
`
`98
`22
`<I
`9
`
`158
`42-548
`
`3.7
`I 1· 18.8
`
`2.4
`1.6·5.0
`
`0.8
`07·0,9
`
`2.9
`1.5·4.6
`
`47
`11
`8
`17
`9
`
`3
`47
`22
`8
`
`1
`23
`37
`15
`5
`
`58
`14
`10
`21
`11
`
`4
`59
`28
`10
`
`1
`28
`46
`19
`6
`
`14
`6·24
`
`6 .5
`4.8·8.0
`
`50
`33·58
`
`209
`66·678
`
`5,3
`1.2-16.5
`
`2.0
`1 0·5.3
`
`0.8
`0.7·0.9
`
`3.0
`1.6-5.1
`
`46
`7
`15
`20
`24
`
`5
`45
`21
`8
`
`1
`30
`30
`15
`4
`
`57
`9
`19
`25
`30
`
`6
`57
`26
`10
`
`38
`38
`19
`5
`
`18
`10·30
`
`5.9
`4.7-8.1
`
`46
`33·58
`
`•pSA was available Far only 134 patients. Serum concentrations al otht'·
`parameters are expressed as o fraction of the upper limit of J>ormal values
`tSome palients continued on dual therapy.
`tLASA: 0 = extremely ill, 10 - I feel well. EORTC: 0 =very poor; 100
`= excellen l
`
`WCK1010
`Page 3
`
`

`
`CHEMOTHERAPY FOR PROSTATE CANCER
`
`1759
`
`100
`
`80
`
`e e
`-.;
`c: c c. 60
`"' ~ c 40
`
`C!l
`~
`<r
`(i..
`
`P< 0.0001 (log rank)
`
`: .. l
`:
`\. ......... . '"l
`i,
`L:
`......... :
`._, __ :
`
`-- Predmsone alone
`· ·· · · · · Mitoxantrone +Prednisone
`
`20
`
`~,
`t,
`i
`
`0
`
`5
`
`10
`Time (months)
`
`15
`
`20
`
`' ig 1. Duration of primary response in patients randomized to
`receive prednis one (n • 1 Ol or mitoxantrone plus prednis9ne (n =
`231.
`
`plus prednisone and in l 0 of 8 1 patients who recei ved
`pt-ednisone alone. Response rmcs were thus 29% (95%
`confidence interval, 19% to 40%) and 12% (95% confi(cid:173)
`dence inrerval. 6% to 22%). respectively ( P = .01 ). The
`doJration of palliative response is shown in Fig I . Re(cid:173)
`sponse duration was longer for treatment with mitoxan(cid:173)
`trone plus prednisone than for prednisone alone (median,
`4} I' 18 weeks, p < .000 I). Most or the patients who
`satisfied the primary criterion of respon e reduced their
`analgesic medication.
`An additional . even patients in each arm satisfied the
`secondary criterion of palliative respon e. a decrease of
`:=::: 50% in analgesic :.core without an increase in pain.
`
`100
`
`80
`
`til
`>
`·~ 60
`:l
`Q
`c
`0..
`~ 40
`Q)
`0.
`
`20
`
`0
`
`0
`
`~ ~
`:..~.
`1..,
`
`Prednisone
`Mitoxantrone +Prednisone
`
`p = 0.27 (log rank)
`
`...
`
`...... ., =t __ _
`
`10
`
`30
`20
`Time (months)
`
`40
`
`50
`
`Fig 2. Actuarial surviva l curves for patients random ized initially
`to receive prednisone (n = 81 ) or mitoxantrone plus predni,sone (n =
`80).
`
`Table 2. Patients With a Reduction in Sorum PSA level
`According to Treatment
`
`Decrease in Serum PSA
`
`~ 2St
`2: 50%
`~ 75');
`
`No
`
`25
`12
`5
`
`Prodm1011o
`(n
`5.41
`
`'
`
`46
`22
`9
`
`M1toxontrone -t
`P,.edni&OI1o
`(n = 57)
`
`No
`
`28
`19
`13
`
`%
`49
`33
`23
`
`NOTE. Data represent the maximum observed decrease in PSA level
`compared with baseline while receiving the randomly assigned rreotrnents.
`The proportion ol patients with ,.... 25% decrease in PSA level includes those
`with :;, 50% or 2: 75% decrease; the proportion with <: 50% decrease in
`PSA level includes those with .., 75% decrease. The difference between the
`2 randomized groups is not signi~cont (P .,. .11 , Wilcoxon ronk·sum lest!.
`
`Twel ve of these 14 patients had some reduction in pain.
`The mean duration of , econdary response was 33 weeks
`(mitoxantrone + prednisone) and 24 weeks (prednisone
`alone). If both primary and secondary criteria of response
`are included to iodicale pull intivc benefi t from treatment,
`thi was achieved in 30 or 80 (38%) or patients random(cid:173)
`ized to mitoxantrone plus prednisone and 17 of 81 (21 %)
`of patients randomized to prednisone ( P = .025).
`Only two responding patients had discontinued fluta(cid:173)
`mide within 4 weeh before ~ tudy entry: both of these
`patients received mitoxantrone. There is no influence of
`prior therapy with fiutamide on the primary end point (P
`= .022. stratified for Hutamide).
`Fifty patients randomized to receive prednisone were
`crossed-over s ub~equently to receive added mitoxantrone.
`Eleven patients (22%) re~po nded on crossover for a me(cid:173)
`dian duration of 18 week~ (range. 9 to 69).
`A total of 140 patients died (as of Apri l 1995). The
`distTibutions of survi val duration for the two groups of
`
`Table 3. Patients With o Reduction in Serum PSA level According to
`Criteria of Polliotive Response
`
`Decreo1e •n
`Serum PSA
`
`Primary Ro1ponao
`
`Ye•
`In - 271
`
`No
`84)
`
`in
`
`Prirnary ond/or Secondary
`RMpon5e
`
`v ..
`38)
`
`In
`
`No
`In % 731
`
`No
`
`20
`13
`9
`
`'-
`
`74
`48
`33
`p
`
`No
`33
`18
`9
`.001 '
`
`"'
`39
`21
`t1
`
`No
`
`26
`17
`12
`
`'\,
`
`No,
`
`68
`27
`14
`45
`32
`6
`P = .0001'
`
`%
`
`37
`19
`8
`
`NOTE. Dolo represent the maximum decrease in PSA level compared
`with baseline while receiving the randomly assigned treatment. Each row
`includes patients who satisfy more stringent conditions, as in Table 2.
`'Wilcoxon rank-sum test for companson ol d istributions of the decrease
`in PSA levels ln patlents who did and did not meet criteria for palliative
`response.
`
`WCK1010
`Page 4
`
`

`
`1760
`
`TANNOCK ET AL
`
`patients are shown in Fig 2. There was no significant
`difference in overall survival (P = .27, favoring mitoxan(cid:173)
`trone plus p rednisone).
`Assessment of senun PSA at baseline and at least one
`subsequent visit was obtained on 111 patients. There was
`a higher probability of reduction in PSA for patients who
`received chemotherapy, bur this was not significant statis(cid:173)
`tically (Table 2). T he distribution of change in serum PSA
`differed among patients who did and d id not meet criteria
`for palliative response (Table 3), but change in serum
`PSA did not provide useful discrimination between tl1ese
`groups of patients.
`
`Changes in Healrh-Rt•lated Qutllily of Life During
`Treatment
`Compliance with completion of qual ity-of-life scales
`was high. Completed present pain intensity scales were
`obtained for 92% of clinic visits during initially allocatt',L
`treatment. with no difference between the anns. LASA
`scales for pain were completed on 89% of visits. wilh
`similar values for other scales.
`Meruan cbanges in LASA scores and in domains of the
`EORTC questionnaire during initially assigned treatm e ,t
`and maximum improvements as compared with baseline
`are shown in Fig 3 for all patients in tlle randomized
`
`A Median
`changes
`
`B
`
`Best
`changes
`
`I
`
`-
`
`- t-.
`:::
`":' f.+-
`
`I
`-2
`
`c
`
`i
`2
`
`I
`4
`
`0
`
`I
`-2
`
`I
`-4
`D
`
`-
`
`I \
`
`F:==
`~
`
`~
`
`I
`2
`
`I
`4
`
`0
`
`•
`
`Fig 3. Comparisons du ring
`treatment for all patients w ho
`hod 2: 2 assessments (n = 154).
`Median changes (A and C) ord
`best changes (Band D) compa red
`w ith baseline LASA scales (A dnd
`B) a nd EORTC domains (C and D)
`that indicate attributes of health·
`related qua lity of life. Median
`a nd maximum values for each
`scale were determined for all po·
`tients throughout the period thc11
`they continued on the thera py to
`wh ich they were randomized ini·
`tioll y. Medians and interquartile
`ranges ore shown lor patients
`randomized to mitoxa ntrone .,.
`predn isone (n = 78, • J or pred·
`nisone alone (n = 76, e ). Dit(cid:173)
`ferences betwee n groups were
`significant
`(by
`the Wilcoxon
`ronk ·sum test) for the dimen(cid:173)
`sions of pain (P = .01 lor A a n.J
`8; P < .05 lor C a nd D) and con·
`stipotion (P < .05 lor A, 8, and
`D), and borde rline for mood (A,
`P = .06; B, P = .02).
`
`LASA
`SCALES
`
`Pain
`
`Physical activity
`
`Fatigue
`
`Appetite
`
`Constipation
`
`Passing urine
`
`Relationships
`
`Mood
`
`Overall well-being
`I
`-4
`
`EORTC
`DOMAINS
`Pain
`
`Physical function
`
`Fatigue
`
`Appetite
`
`Constipation
`
`Urinary symptoms
`
`Social function
`
`Emotional function
`
`GlobaiQL
`
`-
`
`0
`
`20
`
`-20
`
`40
`
`...
`
`Better
`
`-40
`
`...
`
`Worse
`
`-20
`
`0
`
`20
`
`40
`
`-40
`
`...
`
`Worse
`
`...
`
`Better
`
`WCK1010
`Page 5
`
`

`
`CHEMOTHERAPY FOR PROSTATE CANCER
`
`groups that had c: two assessments (n = 154). These
`dist 1butions favored treatment with mitoxantrone plus
`preJni!'one for doma,in!' related to pain. phy ical activity
`or func tion, con tipation. and mood. The median and best
`changes in scores were determined also for 33 patients
`who met the primary criterion for palliative response (Fig
`4). 1 he e patients had improvements in most domains of
`quu11ty of life, whjcb included highly signi ficant improve(cid:173)
`ments in overall weU-bcing.
`
`Deli ·el)' of Therapy and To.riciry
`
`Minimal toxicity was attributed to predn i~one: only
`one diabetic patient discontinued the drug because of
`toxtcity. Patients randomized to mitoxantrone re<jeived a
`median of six (range, one to 16) cycles. The median dose
`of mjtoxantrone per cyc.:le wus 12 mg/m2 body.,surface
`are:J (range, 3 to 18). T he dose was increased above 12
`mg/m2 in 36 of 80 patients randomized to receive mito(cid:173)
`xantrone, and decreased to less than this level in 20 pa(cid:173)
`tiel <S. Almost al l patients received chemotherapy on
`scheduled 3-week cycle~.
`Nausea and vomjting were nsscssed for 654 cycles of
`mit •xantrone in 120 patients (including crossover). There
`wa' no nausea or vomiting after 71% of cycles. and severe
`oau!')ea and vornitmg (WHO grades 3 or 4) after only
`thn::-.! cycles (0.5%). Ninety (76%) of these patient:. had
`no alopecia. and the remainder had minimal or patchy
`loss of hair.
`Hematologic toxicity is listed in Table 4. There were
`nine instances of fever with neutropenia (WHO grade 3 10
`4) among 130 patients (including crossover) who received
`796 courses of mitoxantrone chemotherapy. All of these
`infections resolved fo llowing antibiotic therap y. Throm(cid:173)
`bot.ytopenia was rare.
`Thirty-four patients had a cumulative dose of mitoxan(cid:173)
`trone greater than I 00 mg/m2 body-sur face area, and four
`paltents had a cumu lnti ve dose gTeater than 140 mg/m2
`.
`flive patients w ho received cumulative doses of 11 6 to
`214 mg/m2 developed card iac abnormalities (T able 5).
`T\\ o of these patients were symptomatic with congestive
`beilrt fa ilure. but no patient died of card iac cnuses.
`
`Prognoslic Factor~ and Survival
`Table 6 lists the relationships between baseline factors
`and survival. In univariable analyses, all of the palient(cid:173)
`b[l!')ed mea ures except UJinary symptoms and emotional
`fun-:tion were <tSSOciated with duration of survival,
`wherea'> serum levels of PSA. acid phosphatase, and cre(cid:173)
`atinine and analgesic score were not. Multivariable analy(cid:173)
`se~ identified performance starus, present pain intensity.
`
`1761
`
`LASA
`SCALES
`Pain
`
`A
`
`Physical activity
`
`Fatigue
`
`Appetite
`
`Constipation
`
`Passing urine
`
`Relationships
`
`Mood
`
`Overall well-being
`
`-(J>--- - -
`
`-2
`
`0
`
`2
`
`4
`
`EORTC
`DOMAINS
`Pain
`
`8
`
`Physical function
`
`Fatigue
`
`Appetite
`
`Constipation
`
`-o -
`--o
`
`- o -
`
`Urinary symptoms
`
`~
`
`Social function
`
`Emotional function
`
`Global QL
`
`--o---
`--o-
`20 _...
`Better
`
`40
`
`0
`
`..___.
`·20
`Worse
`
`60
`
`Fig 4 . Comparisons for 33 patients who met th e criterion of pri·
`mary response on either orm of the study. Median IO ) and best(cid:173)
`change (0 ) stores for lASA scales (A) and EORTC QlQ· C30 domains
`IBl that indicate attributes of health· reloted quality of life. Medians
`and interquartile ranges are shown. Differences from baseline were
`significant (by the Wilcoxon signed· rank·sum test far zero mean) for
`median changes in LASA scale~ for pain, physical activity, fatigue,
`appetite, constipation, and overall well· being (P < 10 'l and for
`median changes in EORTC domains for pain, fatigue, social function,
`global quality of life (P < lo-a), physical function, appetite, constipa·
`lion, ond emotional function (P s 1 o-'). All best-change scores were
`highly significant (P s 10-3) except for scales that pertain to passing
`urine (P < 10- '1.
`
`and serum alkaline phosphatase level as powerful inde(cid:173)
`pendent predictors of survival duration with an additional
`significant contribution from one other patient-based mea(cid:173)
`sure of health-related quality of life.
`
`WCK1010
`Page 6
`
`

`
`1762
`
`Table 4. Hematologic Toxicity in 130 Patients (including crossover}
`Who Received 796 Cycles of Mitoxantrone
`
`Poromator
`Granulocyte nadir (X 109 / L)
`0.5· 1.0
`< 0.5
`Neutropenia ( < 1.0 X 1 o• /L) with sepsis
`Platelet nodlr (x 109 /L)
`50·100
`< 50
`
`No. of Counes
`
`% Toxidty'
`
`171
`69
`9
`
`22
`3
`
`32
`13
`L1
`
`4.2
`0 ,6
`
`'Based on the number of courses For which midcycle blood cell counts
`are ova liable (n =c 520). except for sepsis, which is based on total number
`of courses of mito)\ontrone.
`
`DISCUSSION
`
`The present results indicate a higher probability of pal(cid:173)
`liation for patients with syrnptomt\tic hormone-resistant
`prostate cancer with the use of mitoxantrone plus predni(cid:173)
`one versus prednisone alone. Responses were more dw·a(cid:173)
`ble and were accompanied by improvements in several
`dimension~ of quality of life.
`Two reviews published in 1985 concluded that there
`was little evidence for benefit from chemotherapy for
`20 A valiety or response
`patients wilh prostatic C:lncer.t9·
`criteria had been used that did not reflect either the vol(cid:173)
`ume of tumor or the benefit to patients. More recent trials
`of chemotherapy have assessed changes in serum PSA as
`tm index of response that may reflect chaoges in tumor
`volume,t·6 and some studies have reported improvement
`in pain as assessed by physicians. ul However, physicians
`tend to underestimate subjective morbidity, and chemo(cid:173)
`therapy does not necessarily improve quaJity or life when
`assessed by patients.:ll l11 the present study, palliative re(cid:173)
`sponse con·elated with a decrease in serum PSA level,
`but the decrease was a poor discriminant between patients
`who did and did not achieve a palliative response. When
`the aim of treatment is palliation, it seems appropriate to
`assess directly tbe duration and quaJity of survival.
`The present study emphasized palliative end points de(cid:173)
`veloped in two previous studies.7·~ and used randomiza(cid:173)
`tion to compare benefits that might be obtained from t.he
`
`Table 6. Association of Baseline Factors With Duration of Survival
`
`TANNOCK ET 1\L
`
`Factor
`
`A
`
`Multlvorlobto
`Anotysest
`
`A
`
`< .0001
`.005
`
`.002
`.04
`
`< .0001
`< .0001
`.2
`
`ECOG performance status
`Present pain intensity
`Analgesic score
`Measures of heolth·reloted
`quolity·of-life LASA
`scales/EORTC
`domoi11s
`Physical activity /function
`Appetite
`Overall well·being/
`global
`Mood/ emotional
`function
`Fatigue
`Relationships/ social
`function
`Pain
`Cons~pation
`Urinary symptocns
`Hemoglobrn
`Alkaline phosphatase
`Acid phosphatase
`PSA
`Creatinine
`Age'!'
`Time from diagnosis
`
`< ,0001
`< .0001
`
`< .0001
`<.0001
`
`.02
`
`.00 1
`
`.002
`
`.0003
`
`.003
`.004
`
`.006
`.01
`.03
`.9
`
`.16
`.002
`
`.007
`.008
`.003
`.8
`
`.001
`.003
`.4
`.6
`.9
`.05
`.2
`
`.008
`
`.004
`
`•variables assessed separately using the log-rank lest.
`tVoriables assessed togeJher (with censored linear regression} and in·
`eluded either LASA scores (A) or EORTC domains (B) for heolth·relatM
`quali ty of life, Each P value reflects the statistical significance of that vari·
`able \n o model that includ