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. Tonnock, David Osoba, Martin R. Stockler, D. Scott Ernst, Alan J. Neville, Malcolm J. Moore,
`George R. Armilage, Jonathan J. Wilson, Peter M. Venner, Christopher M.L. Coppin, and Kevin C. Murphy
`
`fl: To investigate the benefit of chemotherapy in
`patients with symptomatic hormone-resistant prostate can-
`cer using relevant and points of palliation in a randomized
`controlled trial.
`Patients and Methods: We randomized I61 hormone-
`
`relroctory patients will; pain to receive mitoxantrone plus
`prednisone or prednisone alone (I 0 mg daily). Nonre-
`spending 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 it 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 .>_ 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 IPROSGOLII),
`the core questionnaire of the European Organization for
`Research and Treatment of Cancer (EORTC), and a disease-
`specilic module.
`
`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 l'10l'm0n€‘-I‘CSlS[2ifll 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 bonc manow re-
`
`From the Department of Medicine, Princess Margaret Hospital."
`Department of Medicine. Urtiirersitv of ’l‘oronto: Humber Memorial
`Hospital, Toronto; British Culumbitt Canter Agent‘_v; Universitv of
`British Columbia, Vancouver; Tom Baker Cancer Centre.‘ Unit-'ersit)'
`of Calgary, Calgary,' Hamilton Regional Cancer Centre; Saskatoon
`Cancer Ccntre: and Crass Cancer Institute, Edmonton, Canada.
`Submitted October I3, 1995; (l(‘(‘t’[7f(*(l January 16. 1996.
`Supported by Lederle Laboratories. Division of Cyanamid Can-
`ada. Inc.
`Address reprint reque.rt.\- to Ian F. Tannock, MD. PhD. Depart-
`ment of Medicine. Prirtress Margaret Hospital. 610 University Ave,
`Suite 4-405, Toronto, M50 2M9 Canada; Email ian_Iannock@pmh.
`Ioromo.on.Ca.
`
`© 1996 by American Society of Clinical Oircology.
`0732- I83X/96/I406-000233.00/(J
`
`Results: Palliative response was observed in 23 of 80
`patients (29%; 95% confidence interval, 19% to 40%) who
`received mitoxontrone plus prednisone, and in I0 of 81
`patients (12%; 95% confidence interval, 6% to 22%) who
`received prednisone alone (P = .0l). An additional seven
`patients in each group reduced analgesic medication 2
`50% without an increase in pain. The duration of palliation
`was longer in patients who received chemotherapy (me-
`dian, 43 and I8 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
`live episodes of possible cardiac toxicity in I30 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
`prcgnisone provides palliation for some patients with
`symptomatic hormone-resistant prostate cancer.
`J Clin Oncol 14:! 756- 1764. @~ I 996 by American So-
`ciety af 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,“ 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 prednisones for treatment
`of hormone-resistant prostate cancer. Mitoxantrone has low
`toxicity, and studies have suggested some palliative benefit
`for patients with metastatic prostate cancer.’““ Our studies
`were also used to develop and evaluate methods for assessing
`pain and quality of life.” 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 I990 to April I994, 16] patients in 11 Canadian
`institutions were randomized to receive mitoxantrone plus predni—
`sonc (80 patients) or prednisone alone (81 patients). All patients
`had metastatic adenocarcinoma of the prostate with symptoms that
`
`l 756
`
`Journal ol Clinical Oncology, Vol I4, No 6 (June), 1996: pp 1756-1764
`
`personal use only. No other uses without permission.
`Downloaded from jco.ascopubs.org on July 25, 2013. For
`Copyright 9 1996 American Society of Clinil Oncology. All rights reserved.
`
`ARGENTUM EX1006
`ARGENTUM EX1006
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`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.
`
`Page 2
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`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
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`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
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`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
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`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
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`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`Page 7
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`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
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`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.
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