Chemotherapy With Mitoxantrone Plus Prednisone or
`Prednisone Alone for Symptomatic Hormone-Resistant
`Prostate Cancer: A Canadian Randomized Trial With
`Palliative End Points
`
`By Ian F. Tannock, David Osoba, Martin R. Stockier, D. Scott Ernst, Alan J. Neville, Malcolm J. Moore,
`George R. Armitage, Jonathan 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-
`cer using relevant end points of palliation in a randomized
`controlled trial.
`Patients and Methods: We randomized 161 hormone-
`refractory patients with pain to receive mitoxantrone plus
`prednisone or prednisone alone (10 mg daily). Nonre-
`sponding patients on prednisone could receive mitoxan-
`trone subsequently. The primary end point was a palliative
`response defined as a 2-point decrease in pain as assessed
`by a 6-point pain scale completed by patients (or complete
`loss of pain if initially I +) without an increase in analgesic
`medication and maintained for two consecutive evaluations
`at least 3 weeks apart. Secondary end points were a de-
`crease of ý 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 [PROSQOLI]),
`the core questionnaire of the European Organization for
`Research and Treatment of Cancer (EORTC), and a disease-
`specific module.
`
`P ROSTATE CANCER metastasizes most often to pel-
`
`vic lymph nodes and to bone, and the dominant symp-
`tom is usually pain. Initial treatment of metastatic disease by
`orchidectomy or by drugs that decrease androgen stimulation
`relieves symptoms in approximately 75% of patients, but all
`patients progress eventually to hormone-resistant disease. The
`role of chemotherapy in providing palliation has been contro-
`versial.
`Many types of chemotherapy are tolerated poorly by pa-
`tients with prostate cancer, who are often elderly men with
`concurrent medical problems and limited bone marrow re-
`
`From the Department of Medicine, Princess Margaret Hospital;
`Department of Medicine, University of Toronto; Humber Memorial
`Hospital, Toronto; British Columbia Cancer Agency; University of
`British Columbia, Vancouver; Tom Baker Cancer Centre; University
`of Calgary, Calgary; Hamilton Regional Cancer Centre; Saskatoon
`Cancer Centre; and Cross Cancer Institute, Edmonton, Canada.
`Submitted October 13, 1995; accepted January 16, 1996.
`Supported by Lederle Laboratories, Division of Cyanamid Can-
`ada, Inc.
`Address reprint requests to lan F. Tannock, MD, PhD, Depart-
`ment of Medicine, Princess Margaret Hospital, 610 University Ave,
`Suite 4-405, Toronto, M5G 2M9 Canada; Email ian_tannock@pmh.
`toronto.on.ca.
`C 1996 by American Society of Clinical Oncology.
`0732-183X/96/1406-0002$3.00/0
`
`Results: Palliative response was observed in 23 of 80
`patients (29%; 95% confidence interval, 19% to 40%) who
`received mitoxantrone plus prednisone, and in 10 of 81
`patients (12%; 95% confidence interval, 6% to 22%) who
`received prednisone alone (P = .01). An additional seven
`patients in each group reduced analgesic medication _
`50% without an increase in pain. The duration of palliation
`was longer in patients who received chemotherapy (me-
`dian, 43 and 18 weeks; P < .0001, log-rank). Eleven of 50
`patients randomized to prednisone treatment responded
`after addition of mitoxantrone. There was no difference in
`overall survival. Treatment was well tolerated, except for
`five episodes of possible cardiac toxicity in 130 patients
`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 and
`prednisone provides palliation for some patients with
`symptomatic hormone-resistant prostate cancer.
`J Clin Oncol 14:1756-1764. © 1996 by American So-
`ciety of Clinical Oncology.
`
`serve. Although the goal of treatment is palliation, few studies
`have assessed outcome with validated scales for pain or qual-
`ity of life that are completed by patients. Some anticancer
`drugs have biologic activity as assessed by a decrease in the
`prostate-specific antigen (PSA) level,1-6 but these agents are
`often given with corticosteroids, which provide palliation to
`some patients when used alone.' All anticancer drugs cause
`toxicity, so they have potential to cause some symptoms
`while relieving others.
`We have undertaken previous single-arm studies of predni-
`sone alone7 and mitoxantrone plus prednisone for treatment
`of hormone-resistant prostate cancer. Mitoxantrone has low
`toxicity, and studies have suggested some palliative benefit
`for patients with metastatic prostate cancer.8"(cid:127) 0 Our studies
`were also used to develop and evaluate methods for assessing
`pain and quality of life.7,s In the present randomized trial, we
`address the hypothesis that chemotherapy with mitoxantrone
`plus prednisone provides better palliation than prednisone
`alone.
`
`Patients
`
`PATIENTS AND METHODS
`
`From August 1990 to April 1994, 161 patients in 11 Canadian
`institutions were randomized to receive mitoxantrone plus predni-
`sone (80 patients) or prednisone alone (81 patients). All patients
`had metastatic adenocarcinoma of the prostate with symptoms that
`
`1756
`
`Journal of Clinical Oncology, Vol 14, No 6 (June), 1996: pp 1756-1764
`
`Downloaded from jco.ascopubs.org on July 25, 2013. For personal use only. No other uses without permission.
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 1
`
`

`
`CHEMOTHERAPY FOR PROSTATE CANCER
`
`included pain, and had disease progression despite standard hor-
`monal therapy. All patients provided written informed consent to
`participate in the study.
`Patients had an Eastern Cooperative Oncology Group (ECOG)
`performance status of - 3 (ie, they were capable of at least limited
`self-care) and were stratified by ECOG score (0,1 v 2,3). They had
`a life expectancy Ž 3 months and were capable of completing pain
`and quality-of-life scales. Exclusion criteria were as follows: (1)
`prior malignancy, except for nonmelanotic skin cancer; (2) prior
`chemotherapy or treatment of cancer with glucocorticoids; (3) treat-
`ment with radiotherapy in the last month or strontium 89 in the last
`2 months; (4) contraindications to the use of prednisone such as
`active peptic ulcer; and (5) uncontrolled cardiac failure or active
`infection. Eligible patients had serum concentrations of WBCs
`greater than 3.0 x 109/L, polymorphonuclear granulocytes greater
`than 1.5 x 109/L, platelets greater than 150 x 109/L, bilirubin less
`than 54 gmol/L, and testosterone less than 3.5 nmol/L.
`Patients had initial adjustment and stabilization of analgesic medi-
`cation. They were assessed by the following: (1) physical examina-
`tion; (2) completion of pain- and health-related quality-of-life ques-
`tionnaires; (3) standard blood tests of hematologic and biochemical
`parameters plus serum testosterone, prostatic acid phosphatase, and
`PSA (not available in all centers at initiation of the study); (4)
`radionuclide bone scan and radiographs of the chest, pelvis, and
`painful bone sites; and (5) computed tomographic scan or ultrasound
`scan of the abdomen and pelvis if there was abnormal liver function
`or other evidence of soft tissue disease in these sites.
`
`Treatment
`
`Patients continued their primary androgen ablation therapy (orchi-
`dectomy, luteinizing hormone-releasing hormone agonist, estrogen,
`or cyproterone acetate); flutamide alone was not regarded as provid-
`ing adequate androgen suppression. Most patients had discontinued
`additional antiandrogen treatment. Midway through this study, with-
`drawal responses to flutamide were recognized,(cid:127)'12 and patients were
`then evaluated for at least 4 weeks after stopping flutamide before
`entry onto the study.
`Patients continued to take analgesic medication and adjusted the
`dosage to provide optimal control of pain. Following randomization,
`all patients took oral prednisone 5 mg twice daily. Those randomized
`to receive mitoxantrone received initially 12 mg/m2 body-surface
`area by intravenous injection. Prochlorperazine was recommended
`as antiemetic medication; dexamethasone or other steroids were not
`used. Chemotherapy was repeated at 3-week intervals if serum con-
`centrations of WBCs were greater than 3 x 109'L, granulocytes
`greater than 1.5 x 109/L, and platelets greater than 100 x 10'/L; if
`not, chemotherapy was delayed until these values were exceeded.
`Blood cell counts were repeated on days 10 and 14 of the first cycle,
`and at one point within days 10 to 14 in subsequent cycles. If nadir
`blood cell counts showed granulocytes less than 0.5 x 109/L or
`platelets less than 50 x 109/L, the dose of mitoxantrone was reduced
`by 2 mg/m 2 on subsequent cycles. If nadir blood cell counts showed
`granulocytes greater than 1.0 x 109/L and platelets greater than
`100 x 109/L with minimal nonhematologic toxicity, the dose of
`mitoxantrone was increased by 2 mg/m 2 on subsequent cycles.
`Nonresponding patients or those with progressive symptoms after
`treatment with prednisone alone for > 6 weeks were to receive
`mitoxantrone in addition.
`To minimize the probability of cardiac toxicity, it was recom-
`mended that patients who were still responding after a cumulative
`
`1757
`
`dose of 140 mg/m2 mitoxantrone continue treatment with prednisone
`alone.
`
`Assessment of Outcome
`
`Patients were examined at intervals of 3 weeks. At these visits,
`they underwent blood tests and completed questionnaires related to
`pain and quality of life. Bone scans and radiographs to define disease
`were performed at 3-month intervals. Toxic side effects of chemo-
`therapy were assessed by World Health Organization (WHO) cri-
`teria. 3
`We chose pain relief as the primary indicator of palliation, because
`pain is the dominant symptom in this population. The primary end
`point of response was a 2-point reduction in the 6-point present
`pain intensity scale of the McGill-Melzack Pain Questionnaire 714
`(or complete loss of pain if initially 1+). This criterion had to be
`maintained on two consecutive evaluations at least 3 weeks apart
`without an increase in analgesic score. The pain scale has verbal
`descriptors (0 = no pain, 1 = mild pain, 2 = discomforting pain, 3
`= distressing pain, 4 = horrible pain, and 5 = excruciating pain),
`and patients were asked to classify the average pain level during the
`previous 24 hours.
`Patients kept a diary in which they recorded all medications, and
`at each visit the average daily quantities taken during the previous
`week were calculated. A numeric scale was used to compute a daily
`analgesic score: 1 unit was used for standard doses of nonnarcotic
`medication (aspirin 325 mg, acetaminophen 325 mg, indomethacin
`25 mg, etc.) and 2 units for standard doses 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 medications)
`rather than switch
`to a different medication of similar type. A secondary criterion of
`response was a 50% decrease in analgesic score without an increase
`in pain maintained for two consecutive evaluations at least 3 weeks
`apart. All patients were considered assessable for response.
`Other end points of the study were duration of palliative response
`(as defined by the primary end point) and survival. The start and
`end of response were defined, respectively, as the date of initial
`treatment and of the last assessment for which response criteria were
`satisfied.
`Progression was defined as either an increase in the present pain
`intensity scale of - 1 point compared with the nadir, or an increase
`in analgesic score of greater than 25% compared with baseline, each
`maintained on two consecutive visits. Unequivocal evidence of new
`lesions or of radiologic progression or a requirement for radiation
`therapy also constituted disease progression.
`To assess the effects of disease and treatment on health-related
`quality of life, we used three different patient-based multidimen-
`sional instruments that addressed functions, symptoms, and global
`perceptions, as follows: (1) the Prostate Cancer-Specific Quality-
`of-Life Instrument (PROSQOLI), which includes nine linear analog
`self-assessment (LASA) scales that relate to pain, physical activity,
`fatigue, appetite, constipation, passing urine, family/marriage rela-
`tionships, mood, and overall well-being, as well as Present Pain
`Intensity and analgesic score7 ; (2) the European Organization for
`Research and Treatment of Cancer (EORTC) core questionnaire
`(EORTC/QLQ-C30), with 30 ordinal scale items that included multi-
`item domains for physical function, emotional function, social func-
`tion, pain, and global quality of life, and single items that included
`fatigue, appetite, and constipation(cid:127),6; and (3) a specific module for
`prostate cancer developed according to EORTC guidelines that will
`be reported elsewhere.
`
`Downloaded from jco.ascopubs.org on July 25, 2013. For personal use only. No other uses without permission.
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 2
`
`

`
`TANNOCK ET AL
`
`Table 1. Characteristics of Patients at Entry Onto the Study According
`to Randomized Group
`
`Prednisone
`(n = 81)
`
`Mitoxantrone + Prednisone
`(n - 80)
`
`Variable
`
`No.
`
`%
`
`No.
`
`%
`
`69
`63-75
`
`98
`22
`
`4 9
`
`78
`18
`
`3 7
`
`67
`64-74
`
`77
`15
`3
`8
`
`95
`19
`4
`10
`
`57
`9
`19
`25
`30
`
`6
`57
`26
`10
`
`1 1
`
`38
`38
`19
`5
`
`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
`
`18
`10-30
`
`5.9
`4.7-8.1
`
`46
`33-58
`
`46
`7
`15
`20
`24
`
`5
`45
`21
`
`8 1 1
`
`30
`30
`15
`4
`
`158
`42-548
`
`3.7
`1.1-18.8
`
`2.4
`1.6-5.0
`
`0.8
`0.7-0.9
`
`2.9
`1.5-4.6
`
`58
`14
`10
`21
`11
`
`4
`59
`28
`10
`
`1 1
`
`28
`46
`19
`6
`
`47
`11
`8
`17
`
`9 3
`
`47
`22
`
`8 1 1
`
`23
`37
`15
`5
`
`14
`6-24
`
`6.5
`4.8-8.0
`
`50
`33-58
`
`Age
`Median
`Interquartile range
`Sites of metastasis
`Bone
`Lymph nodes
`Visceral
`Other
`Serum concentration*
`PSA (Ag/L)
`Median
`Interquartile range
`Prostatic acid phosphatase
`Median
`Interquartile range
`Alkaline phosphatase
`Median
`Interquartile range
`Creatinine
`Median
`Interquartile range
`Time from diagnosis, years
`Median
`Interquortile range
`Hormonal therapy (current)t
`Orchidectomy
`Estrogen
`LHRH agonist
`Cyproterone acetate
`Flutamide
`ECOG performance status
`
`0123U
`
`nknown
`Present pain intensity
`
`01234
`
`Analgesic score
`Median
`Interquartile range
`Overall quality of life+
`By LASA scale
`Median
`Interquartile range
`By EORTC QLQ-C30
`Median
`Interquartile range
`
`*PSA was available for only 134 patients. Serum concentrations of other
`parameters are expressed as a fraction of the upper limit of normal values.
`"tSome patients continued on dual therapy.
`tLASA: 0 = extremely ill; 10 = I feel well. EORTC: 0 = very poor; 100
`= excellent.
`
`1758
`
`Statistical Considerations
`
`The planned sample size of 150 patients was based on detection
`or exclusion of a doubling of palliative response rate due to predni-
`sone alone, which was then (ie, before availability of antiandrogen
`drugs) anticipated to be approximately 20% with an a of .05 and
`1- 3 of .80. A few additional patients were entered to allow for
`incomplete data.
`One planned interim analysis was undertaken by an independent
`statistical consultant after entry of 80 patients. None of the investiga-
`tors were aware of any results before study completion and the
`current analysis.
`Statistical comparisons of the primary end point of response were
`made by Fisher's exact test. Distributions of survival time and dura-
`tion of palliative response were compared by the log-rank test. We
`used nonparametric descriptive statistics to assess the quality-of-life
`data. Each patient's profile of scores for each domain of health-
`related quality of life was summarized by the median and best scores.
`These were converted to median and best-change scores by sub-
`tracting the appropriate baseline score. Differences in these summary
`scores between the two treatment groups were assessed with the
`Wilcoxon rank-sum test. The change from baseline in the group of
`responding patients was tested with the Wilcoxon signed-rank-sum
`test. All statistical tests were two-sided. Corrections were not applied
`for multiple significance testing; thus, apart from the end points
`defined a priori in the protocol, apparent correlations should be
`regarded as hypothesis-generating rather than definitive.
`Associations between baseline characteristics and survival dura-
`tion were assessed with the log-rank test. Factors that appeared
`important (P - .05) in univariable analysis were assessed for inde-
`pendent contributions with censored linear regression after a suitable
`transformation of survival time." This model was chosen in prefer-
`ence to Cox's model, because key variables violated the proportional
`hazards assumption. Separate analyses were performed for the two
`alternative measures of health-related quality of life. For each analy-
`sis, the "best" subset of variables was chosen from an exhaustive
`search using Mallows' Cp as the criterion.' 8
`
`External Review
`An independent external consultant (provided by the National
`Cancer Institute of Canada) reviewed the records of all responding
`patients and of a randomly selected series of additional patients.
`
`RESULTS
`
`Baseline Characteristics
`
`Characteristics of the patients at entry onto the study
`are listed in Table 1. The patients are well balanced for
`prognostic factors, although there is a trend for patients
`randomized to receive mitoxantrone plus prednisone to
`have a higher analgesic score and to be treated with flu-
`tamide. Two patients had pain scores of zero after optimi-
`zation of analgesic medication; both showed evidence of
`symptomatic progression.
`
`Response to Therapy
`
`The primary criterion of palliative response was met
`in 23 of 80 patients randomized to receive mitoxantrone
`
`Downloaded from jco.ascopubs.org on July 25, 2013. For personal use only. No other uses without permission.
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 3
`
`

`
`CHEMOTHERAPY FOR PROSTATE CANCER
`
`1759
`
`100
`
`80
`
`60
`g 60
`
`S40
`
`20
`
`20
`
`Sone alone
`ntrone +Prednisone
`
`0
`
`5
`
`10
`Time (months)
`
`15
`
`20
`
`Fig 1. Duration of primary response in patients randomized to
`receive prednisone (n = 10) or mitoxantrone plus prednisone (n =
`23).
`
`plus prednisone and in 10 of 81 patients who received
`prednisone alone. Response rates were thus 29% (95%
`confidence interval, 19% to 40%) and 12% (95% confi-
`dence interval, 6% to 22%), respectively (P = .01). The
`duration of palliative response is shown in Fig 1. Re-
`sponse duration was longer for treatment with mitoxan-
`trone plus prednisone than for prednisone alone (median,
`43 v 18 weeks, P < .0001). Most of the patients who
`satisfied the primary criterion of response reduced their
`analgesic medication.
`An additional seven patients in each arm satisfied the
`secondary criterion of palliative response, a decrease of
`> 50% in analgesic score without an increase in pain.
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`v
`
`c,
`
`a,
`n
`
`Time (months)
`
`Fig 2. Actuarial survival curves for patients randomized initially
`to receive prednisone (n = 81) or mitoxantrone plus prednisone (n =
`80).
`
`Table 2. Patients With a Reduction in Serum PSA Level
`According to Treatment
`
`Decrease in Serum PSA
`a 25%
`- 50%
`ý 75%
`
`Prednisone
`In = 54)
`
`Mitoxantrone +
`Prednisone
`(n = 57)
`
`No.
`
`25
`12
`5
`
`%
`
`46
`22
`9
`
`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 treatments.
`The proportion of patients with ý 25% decrease in PSA level includes those
`- 50% or - 75% decrease; the proportion with >- 50% decrease in
`with
`PSA level includes those with - 75% decrease. The difference between the
`2 randomized groups is not significant (P = . 11, Wilcoxon rank-sum test).
`
`Twelve of these 14 patients had some reduction in pain.
`The mean duration of secondary response was 33 weeks
`(mitoxantrone + prednisone) and 24 weeks (prednisone
`alone). If both primary and secondary criteria of response
`are included to indicate palliative benefit from treatment,
`this was achieved in 30 of 80 (38%) of patients random-
`ized to mitoxantrone plus prednisone and 17 of 81 (21%)
`of patients randomized to prednisone (P = .025).
`Only two responding patients had discontinued fluta-
`mide within 4 weeks before study entry; both of these
`patients received mitoxantrone. There is no influence of
`prior therapy with flutamide on the primary end point (P
`= .022, stratified for flutamide).
`Fifty patients randomized to receive prednisone were
`crossed-over subsequently to receive added mitoxantrone.
`Eleven patients (22%) responded on crossover for a me-
`dian duration of 18 weeks (range, 9 to 69).
`A total of 140 patients died (as of April 1995). The
`distributions of survival duration for the two groups of
`
`Table 3. Patients With a Reduction in Serum PSA Level According to
`Criteria of Palliative Response
`
`Primary Response
`
`Primary and/or Secondary
`Response
`
`Yes
`(n = 27)
`%
`No.
`
`No
`(n = 84)
`%
`No.
`
`Yes
`(n = 38)
`%
`
`No.
`
`Decrease in
`Serum PSA
`S25%
`r 50%
`S75%
`
`20
`13
`9
`
`33
`74
`18
`48
`9
`33
`P = .001 *
`
`39
`21
`11
`
`26
`17
`12
`
`27
`68
`14
`45
`6
`32
`P = .0001 *
`
`No
`(n = 73)
`
`No.
`
`%
`
`37
`19
`8
`
`NOTE. Data 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 comparison of distributions of the decrease
`in PSA levels in patients who did and did not meet criteria for palliative
`response.
`
`Downloaded from jco.ascopubs.org on July 25, 2013. For personal use only. No other uses without permission.
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 4
`
`

`
`1760
`
`TANNOCK ET AL
`
`patients are shown in Fig 2. There was no significant
`difference in overall survival (P = .27, favoring mitoxan-
`trone plus prednisone).
`Assessment of serum 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, but this was not significant statis-
`tically (Table 2). The distribution of change in serum PSA
`differed among patients who did and did not meet criteria
`for palliative response (Table 3), but change in serum
`PSA did not provide useful discrimination between these
`groups of patients.
`
`Changes in Health-Related Quality of Life During
`Treatment
`
`Compliance with completion of quality-of-life scales
`was high. Completed present pain intensity scales were
`obtained for 92% of clinic visits during initially allocated
`treatment, with no difference between the arms. LASA
`scales for pain were completed on 89% of visits, with
`similar values for other scales.
`Median changes in LASA scores and in domains of the
`EORTC questionnaire during initially assigned treatment
`and maximum improvements as compared with baseline
`are shown in Fig 3 for all patients in the randomized
`
`LASA
`SCALES
`Pain
`
`Physical activity
`
`Fatigue
`
`Appetite
`
`Constipation
`
`Passing urine
`
`Relationships
`
`Mood
`
`Overall well-being
`
`L
`-4
`
`I
`-2
`
`C
`
`EORTC
`DOMAINS
`Pain
`
`Physical function
`
`Fatigue
`
`Appetite
`
`Constipation
`
`Urinary symptoms
`
`Social function
`
`Emotional function
`
`Global QL
`
`I
`-40
`
`I
`-20
`
`Worse
`Worse
`
`I
`
`-U~-----
`
`F-
`
`-I
`-4
`
`I
`
`-I-
`
`I=
`
`0
`
`I
`2
`
`I-
`
`---
`
`m
`
`0
`
`A changes
`Median
`
`-4
`
`m
`
`B
`
`Best
`changes
`
`I
`2
`
`I
`4
`
`LL(cid:2)
`-4
`
`D
`
`U
`
`U-
`I-
`
`-(cid:3)--
`
`1
`
`-e
`
`U
`
`I
`
`e
`
`I
`
`4
`
`-4--
`
`-4---
`
`~---U--
`
`4---
`
`--
`
`-U--
`
`-U-
`-4-
`
`-U-e
`
`Fig 3. Comparisons during
`treatment for all patients who
`had
`- 2 assessments (n = 154).
`Median changes (A and C) and
`best changes (B and D) compared
`with baseline LASA scales (A and
`B) and EORTC domains (C and D)
`that indicate attributes of health-
`related quality of life. Median
`and maximum values for each
`scale were determined for all pa-
`tients throughout the period that
`they continued on the therapy to
`which they were randomized ini-
`tially. Medians and interquartile
`ranges are shown for patients
`randomized to mitoxantrone +
`prednisone (n = 78, E) or pred-
`nisone alone (n = 76, 0). Dif-
`ferences between groups were
`(by
`significant
`the Wilcoxon
`test) for the dimen-
`rank-sum
`sions of pain (P = .01 for A and
`B; P < .05 for C and D) and con-
`stipation (P < .05 for A, B, and
`D), and borderline for mood (A,
`P= .06; B, P = .02).
`
`I
`20
`
`I
`40
`
`Better
`Better
`
`I
`I
`-40
`-20
`WorseWorse
`
`I
`20
`
`I
`40
`
`0
`
`Better
`
`Downloaded from jco.ascopubs.org on July 25, 2013. For personal use only. No other uses without permission.
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 5
`
`

`
`CHEMOTHERAPY FOR PROSTATE CANCER
`
`groups that had > two assessments (n = 154). These
`distributions favored treatment with mitoxantrone plus
`prednisone for domains related to pain, physical activity
`or function, constipation, 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). These patients had improvements in most domains of
`quality of life, which included highly significant improve-
`ments in overall well-being.
`
`Delivery of Therapy and Toxicity
`
`Minimal toxicity was attributed to prednisone: only
`one diabetic patient discontinued the drug because of
`toxicity. Patients randomized to mitoxantrone received a
`median of six (range, one to 16) cycles. The median dose
`of mitoxantrone per cycle was 12 mg/m2 body-surface
`area (range, 3 to 18). The dose was increased above 12
`mg/m2 in 36 of 80 patients randomized to receive mito-
`xantrone, and decreased to less than this level in 20 pa-
`tients. Almost all patients received chemotherapy on
`scheduled 3-week cycles.
`Nausea and vomiting were assessed for 654 cycles of
`mitoxantrone in 120 patients (including crossover). There
`was no nausea or vomiting after 71% of cycles, and severe
`nausea and vomiting (WHO grades 3 or 4) after only
`three cycles (0.5%). Ninety (76%) of these patients 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 to
`4) among 130 patients (including crossover) who received
`796 courses of mitoxantrone chemotherapy. All of these
`infections resolved following antibiotic therapy. Throm-
`bocytopenia was rare.
`Thirty-four patients had a cumulative dose of mitoxan-
`trone greater than 100 mg/m2 body-surface area, and four
`patients had a cumulative dose greater than 140 mg/m 2.
`Five patients who received cumulative doses of 116 to
`214 mg/m 2 developed cardiac abnormalities (Table 5).
`Two of these patients were symptomatic with congestive
`heart failure, but no patient died of cardiac causes.
`
`Prognostic Factors and Survival
`
`Table 6 lists the relationships between baseline factors
`and survival. In univariable analyses, all of the patient-
`based measures except urinary symptoms and emotional
`function were associated with duration of survival,
`whereas serum levels of PSA, acid phosphatase, and cre-
`atinine and analgesic score were not. Multivariable analy-
`ses identified performance status, present pain intensity,
`
`1761
`
`LASA
`SCALES
`Pain
`
`A
`
`Physical activity
`
`.--.-
`
`Fatigue
`
`Appetite
`
`Constipation
`
`Passing urine
`
`Relationships
`
`Mood
`
`Overall well-being
`
`0
`
`-0-
`--------
`-0----
`
`-13
`
`0
`
`-13--
`-0-
`
`-4
`
`-0-
`
`-0-
`
`-
`
`-2
`
`0
`
`2
`
`4
`
`6
`
`EORTC
`DOMAINS
`Pain
`
`B
`
`0
`
`Physical function
`
`Fatigue
`
`Appetite
`
`Constipation
`
`Urinary symptoms
`
`Social function
`
`Emotional function
`
`Global QL
`
`00-
`
`-0--
`---
`
`--
`
`-0
`
`-0--
`
`------
`
`-0
`
`---
`
`0--
`
`-0--
`
`20
`
`i
`
`60
`
`40
`
`-20
`
`0
`
`Worse
`
`Better
`
`Fig 4. Comparisons for 33 patients who met the criterion of pri-
`mary response on either arm of the study. Median (0) and best-
`change (0) scores for LASA scales (A) and EORTC QLQ-C30 domains
`(B) that indicate attributes of health-related quality of life. Medians
`and interquartile ranges are shown. Differences from baseline were
`significant (by the Wilcoxon signed-rank-sum test for zero mean) for
`median changes in LASA scales for pain, physical activity, fatigue,
`appetite, constipation, and overall well-being (P < 10 3) and for
`median changes in EORTC domains for pain, fatigue, social function,
`global quality of life (P < 10-3), physical function, appetite, constipa-
`tion, and emotional function (Ps 10-2). All best-change scores were
`) except for scales that pertain to passing
`highly significant (Ps 10
`urine (P < 10-2).
`
`and serum alkaline phosphatase level as powerful inde-
`pendent predictors of survival duration with an additional
`significant contribution from one other patient-based mea-
`sure of health-related quality of life.
`
`Downloaded from jco.ascopubs.org on July 25, 2013. For personal use only. No other uses without permission.
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 6
`
`

`
`1762
`
`TANNOCK ET AL
`
`Table 4. Hematologic Toxicity in 130 Patients (including crossover)
`Who Received 796 Cycles of Mitoxantrone
`
`Parameter
`
`No. of Courses
`
`% Toxicity*
`
`Table 6. Association of Baseline Factors With Duration of Survival
`
`Univariable Analyses*
`
`Multivariable
`Analysest
`
`171
`69
`9
`
`Granulocyte nadir (x 109/L)
`0.5-1.0
`< 0.5
`Neutropenia (< 1.0 x 10 9/L) with sepsis
`Platelet nadir (x 109/L)
`4.2
`22
`50-100
`< 50
`3
`0.6
`"*Based on the number of courses for which midcycle blood cell counts
`are available (n = 520), except for sepsis, which is based on total number
`of courses of mitoxantrone.
`
`32
`13
`1.1
`
`DISCUSSION
`
`The present results indicate a higher probability of pal-
`liation for patients with symptomatic hormone-resistant
`prostate cancer with the use of mitoxantrone plus predni-
`sone versus prednisone alone. Responses were more dura-
`ble and were accompanied by improvements in several
`dimensions of quality of life.
`Two reviews published in 1985 concluded that there
`was little evidence for benefit from chemotherapy for
`patients with prostatic cancer.'19 20 A variety of response
`criteria had been used that did not reflect either the vol-
`ume of tumor or the benefit to patients. More recent trials
`of chemotherapy have assessed changes in serum PSA as
`an index of response that may reflect changes in tumor
`volume,' 6 and some studies have reported improvement
`in pain as assessed by physicians. 121 However, physicians
`tend to underestimate subjective morbidity, and chemo-
`therapy does not necessarily improve quality of life when
`assessed by patients. 22 In the present study, palliative re-
`sponse correlated 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 the duration and quality of survival.
`The present study emphasized palliative end points de-
`veloped in two previous studies,7 '8 and used randomiza-
`tion to compare benefits that might be obtained from the
`
`Factor
`
`A
`
`B
`
`A
`
`<
`<
`
`.0001
`.0001
`.2
`
`< .0001
`.005
`
`B
`
`.002
`.04
`
`ECOG performance status
`Present pain intensity
`Analgesic score
`Measures of health-related
`quality-of-life LASA
`scales/EORTC
`domains
`Physical activity/function
`Appetite
`Overall well-being/
`global
`Mood/emotional
`function
`Fatigue
`Relationships/social
`function
`Pain
`Constipation
`Urinary symptoms
`Hemoglobin
`Alkaline phosphatase
`Acid phosphatase
`PSA
`Creatinine
`Aget
`Time from diagnosis
`
`< .0001
`< .0001
`
`< .0001
`<.0001
`
`.02
`
`.001
`
`.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 test.
`tVariables assessed together (with censored linear regression) and in-
`cluded either LASA scores (A) or EORTC domains (B) for health-related
`quality of life. Each Pvalue reflects the statistical significance of that vari-
`able in a model that includes (and therefore adjusts for) each of the vari-
`ables identified by a P value in that column.
`tYounger living longer than older.
`
`use of corticosteroids alone, adjustment of analgesics, and
`other aspects of supportive care. In an ideal trial, both
`patients and physicians would be blinded as to treatment
`received, but this presents logistic and perhaps ethical
`problems when comparing chemotherapy and nonchemo-
`therapy arms. Our results