Reprintedfrom
`
`Volume 7, Number 5
`
`May 1, 1989
`
`JOURNAL OF
`CLINICAL
`ONCOLOGY
`
`Treatment of metastatic prostatic cancer with low—dose prednisone:
`evaluation of pain and quality of life as pragmatic indices of response.
`
`I Tarmock, M Gospodarowicz, W Meakin, TPanzarella, L Stewart, W Rider
`
`Disclaimer
`The ideas and opinions expressed in the Joumal of Clinical Oncology (ICO) do not neceswily reflect those of the American Society
`of Clinical Oncology (ASCO). The mention of any product. service. or therapy in any JCO article should not be construed as an
`endorsement of the products mentioned.
`
`It is the responsibility of the treating physician or other health care provider. relying on independent experience and knowledge of the
`patient. to determine drug dosages and the best treatment for the patient. Readers are advised to check the appropriate medical
`literature and the product information currently provided by the manufadurer of each dmg to be administered to verify the dosage.
`method. and duration of administration. or contraindications. Readers are also encouraged to contact the manufacturer with questions
`about the features or limitations of any products. ASCO assumes no responsibility for any injury or damage to persons or property
`arising out of or related to any use ofthe material contained in JCO or to any errors or omissions.
`
`ASCQE
`
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`
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`ARGENTUM EX1031
`ARGENTUM EX1031
`Page 1
`
`Page 1
`
`

`
`.2.-."ss_t
`
`Treatment of Metastatic Prostatic Cancer With Low-Dose
`Prednisone: Evaluation of Pain and Quality of Life
`as Pragmatic Indices of Response
`
`By Ian Tannock, Mary Gospodarowicz, William Meakin, Tony Panzarella, Lesley Stewart, and Walter Rider
`
`Thirty-seven men with symptomatic bone metastases
`from prostate cancer that had progressed following
`earlier treatment with estrogens and/or orchidectomy
`were treated with low-dose prednisone (7.5 to I0 mg
`daily). The rationale for this treatment was that some
`patients might still have hormone-sensitive disease
`that was stimulated by weak androgens of adrenal
`origin, and that these androgens could be suppressed
`by prednisone through its negative feedback on
`secretion of adrenocorticotrophic hormone (ACTH).
`Response to treatment was assessed by requirement
`for analgesics, by the McGill-Melzaclc pain question-
`naire, and by a series of 17 linear analog self-
`assessment
`(LASA) scales relating to pain and to
`various aspects of quality of life. Fourteen patients
`(38%) had improvement in indices used to assess pain
`at
`I month after starting prednisone, and seven
`patients (19%) maintained this improvement for 3 to
`30 months (median, 4 months). Reduction in pain was
`
`BOUT 75% of patients with symptomatic
`prostate cancer will report relief of symp-
`toms (primarily boric pain) following orchidecto-
`my, or after initial treatment with estrogens, or
`luteinizing hormone-releasing hormone
`(LHRH) analogs. These measures reduce serum
`testosterone to castrate levels, thus removing the
`major source of androgen stimulation. The dura-
`tion of response to primary androgen ablation is
`variable, with median values of about 1 year.”
`When symptoms recur,
`this might be due to
`selection of prostatic cancer cells that are hor-
`mane-independent, or to the growth of cells that
`are stimulated by weak androgens of adrenal
`origin.’ Thus, secondary responses are sometimes
`observed with anti-androgens such as flutamide
`or cyproterone acetate,‘ following adrenalecto-
`my,5 or
`following adrenal
`suppression with
`
`
`From the Princesss Margaret Hospital; the University of
`Toronto; and the Ontario Cancer Treatment and Research
`Foundation, Toronto.
`_
`Submitted July 11, 1988; accepted December 22, 1988.
`Address reprint requests to Ian Tannock, MD, Princess
`Margaret Hospital, and University of Toronto, 500 Sher-
`bourne St, Toronto, Ontario, Canada M4X 1K9.
`© 1989 by American Society of Clinical Oncology.
`0732-l83X/89/0705-001433.00/0
`
`associated with improvement in other dimensions of
`quality of life, and in the scale for overall well-being.
`Prednisone treatment led to a decrease in the concen-
`tration of serum testosterone in seven of nine patients
`where it was not initially suppressed below 2 nmol/l,
`and caused a decrease in serum levels of androstene-
`dione and dehydroepiandrosterone sulfate in more
`than 50% of patients. Symptomatic response was
`associated with a decrease in serum concentration of
`
`adrenal androgens. We conclude that (1) low-dose
`prednisone may cause useful relief of pain in some
`patients with advanced prostatic cancer; (2) relief of
`pain was associated with suppression of adrenal
`androgens; and (3) measures of pain and quality of
`life can be used to assess possible benefits of systemic
`therapy in patients with metastatic prostate cancer.
`J Clin Oncol 7:590-597. © I 989 byAn1erican Society of
`Clinical Oncology.
`
`aminoglutethimide and hydrocortisone.° An al-
`ternative approach is to prescribe low-dose corti-
`costeroids” with the aim of producing negative
`feedback on the pituitary gland to inhibit
`secretion of adrenocorticotrophic hormone
`(ACTH). This might in turn lead to inhibition of
`the synthesis of the androgens androstenedione
`and dehydroepiandrosterone (DHEA) and its
`sulfate (DHEAS), which is thought to be stimu-
`lated by ACTH. These relatively weak andro-
`gens can undergo metabolism to produce small
`amounts of testosterone."‘° Adrenal sources of
`
`androgens may account for up to 20% of activity
`associated with the normal testis.’
`
`Assessment of response to systemic therapy of
`patients with prostatic cancer has been both
`difficult and unreliable."'” Most patients do not
`have measurable soft
`tissue metastases, and
`serum markers such as acid and alkaline phos-
`phatasc are not consistent
`indices of disease
`activity. Many patients may report dramatic
`improvement in symptoms after initial hormone
`therapy without improvement in x-rays or bone
`scan. When the aim of treatment is palliation,
`effectiveness should be assessed optimally by
`reproducible indices of symptom control.
`In the current study we first reviewed the
`
`590
`
`Journal of Clinical Oncology, Vol 7, No 5 (May), 1989: pp 590-597
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus Artic|eWorks.on November 30, 2015 from 65.
`Copyright © 1989 American Society of Clinical Oncology. All rights reserved.
`
`6.76.
`
`Page 2
`
`

`
`QUALITY OF LIFE AND PROSTATE CANCER
`
`591
`
`charts of all patients with symptomatic meta-
`static prostate cancer who had received predni-
`sone treatment between 1976 and 1980.
`
`Although this retrospective review revealed that
`some patients had major improvement in pain,
`there was no objective assessment of pain control
`(other than requirement for analgesics), and
`serum levels of androgens were not measured
`routinely. We therefore designed a prospective
`study with the following aims: (1) to develop
`methods for assessment of pain and other symp-
`toms in patients with metastatic prostate cancer;
`(2) to document
`the probability of subjective
`relief of symptoms in patients receiving predni-
`sone following progression after primary an-
`drogen ablation; and (3) to determine whether
`response to prednisone was correlate with a
`decrease in the serum levels of androgens.
`
`METHODS
`
`Patients
`
`The retrospective chart review revealed that 28 patients
`who had undergone prior orchidectomy, or who had pro-
`gressed on estrogens, were started on prednisone as treatment
`for symptomatic bone metastases. The charts of
`these
`patients were reviewed initially for evidence of response.
`Thirty-seven patients were then entered into the prospec-
`tive study. All patients had biopsy-proven prostate cancer
`and progressive symptomatic bone metastases despite
`estrogen treatment or previous orchidectomy. Patients were
`ineligible if they had received systemic therapy other than
`estrogens, or if they had life-threatening complications such
`as cord compression or hypercalcemia. They had to under-
`stand English (in order to complete pain and quality-of-life
`questionnaires). Patients with a history of diabetes or peptic
`ulcer disease, and those who had received corticosteroids
`since diagnosis of prostate cancer were excluded.
`
`Therapy
`Most patients in the retrospective series, and in the early
`part of the prospective study, received prednisone in a dose of
`5 mg in the morning and 2.5 mg in the evening; subsequently,
`patients received 5 mg twice daily. Those patients who were
`receiving estrogen therapy continued this medication at the
`same dose, usually diethylstilbestrol (DES) 1 mg three times
`daily.
`
`Assessment of Patients
`In the retrospective series patients were classified as
`responding to prednisone if all of the following conditions
`were satisfied for a minimum period of 2 months: (1) the
`clinical record gave clear indication of improvement in pain:
`(2) there was reduced intake of analgesics; and (3) no
`additional therapy was required (other than continuation of
`estrogens).
`All patients entered in the prospective study were assessed
`
`initially with a complete history and physical examination,
`bone scan and radiographs of painful areas. A complete blood
`count (CBC), and serum levelsof acid and alkaline phospha-
`tase, calciutn,
`testosterone, androstenedione, and DHEAS
`were to be measured monthly. Hormone levels were mea-
`sured by radioimmunoassay.
`Three methods were used to assess pain prior to initiation
`of prednisone therapy’ and at monthly intervals thereafter.
`First, the patients were asked about their average daily intake
`of analgesics during the week before their clinic visit. This
`information was used to generate an analgesic score, repre-
`senting the total daily analgesic intake. Doses of morphine (5
`mg), codeine (30 mg), hydromorphone (2 mg), anileridine
`(25 mg), or mixed formulations containing codeine (30 mg)
`or oxycodone (15 mg) were assigned two points. Nonnarcotic
`analgesics such as aspirin (325 mg) or acetaminophen (325
`mg) were assigned 1 point. The above doses may not accu-
`rately represent analgesic potency. but this does not introduce
`error in the present study since patients did not change
`medication, but merely increased or decreased the dosage.
`Secondly. patients were asked to complete the McGill-
`Melzack pain questionnairem‘ under the direction of the
`study nurse. This questionnaire presents 20 groups of verbal
`descriptors relating to sensory, affective, evaluative, and
`miscellaneous aspects of pain (Fig la). Within each group
`the patient was asked to select one word (if any) that best
`described the pain that he had been experiencing during the
`prior week. These words were ranked in each group, and the
`rank values of the words selected were summed to provide the
`“pain rating index.” A simpler assessment of pain “the
`present pain intensity” was selected from a 6-point verbal
`scale (0 = no pain,
`1 = mild, 2 = discomforting, 3 =
`distressing, 4 = horrible, 5 = excruciating).
`The third method for assessing pain was part of a series of
`17 linear analog self-assessment (LASA) scales"‘” (Fig lb).
`For each scale the patient was presented with a l0-cm line
`that is anchored at its left end by the worst possible scenario
`(eg, extremely severe pain) and at its right end by the best
`possible scenario (eg, no pain at all). The patient was then
`asked to place a vertical mark on the line that represented his
`state (in relation to the end descriptors) during the preceding
`24 hours. The current series of LASAs were adapted from
`scales that were developed and validated for use in patients
`with breast cancer.” They included scales related to general
`health and to symptoms of disease. We also included a global
`scale relating to overall well-being, which was anchored by
`the descriptors “extremely ill” and “I feel well.” Each scale
`was measured in centimeters (to the nearest 0.5 cm) from its
`left end, so that higher scores represent less symptoms.
`
`RESULTS
`
`Characteristics of Patients
`
`Characteristics of patients who were started
`on prednisone therapy are summarized in Table
`1. Most of the patients had received extensive
`prior treatment, including a median of two hor-
`monal treatments (orchidectomy and /or a vari-
`ety of estrogens). Many patients had also
`
`Information downloaded from jeo.ascopubs.org and provided by at Cadmus Artic|eWorks on November 30, 2015 from 65.196 76.99
`Copyright © 1989 American Society of Clinical Oncology. All rights reserved.
`
`Page 3
`
`Page 3
`
`

`
`592
`
`TANNOC K ET Al.
`
`1. sggmont at
`
`the MeGilI-Moluek Pain Quolllonnaira
`
` lffltlblliflflll
`
`Igcnrotln l
`flllllflhll
`
`5
`pinching
`p!OIlllIq
`gnawing
`
`crimping
`cruoltln
`
`
` drawing
`
`
`
`b. Example: oi Llnur Analog Salt Auournlnt Sealu
`Please place I mark on the line below to
`indlcoto your status durlnq the past 24 noun.
`
`3.
`
`Fatigue
`
`extremely
`tired
`
`tired
`e not
`at all
`
`9.
`
`Social Life, Meeting and Dealing with People Outside the Family
`
`l
`i
`:1: sr:tT:.- y
`taetory
`
`Illustration of (a) the McGil|-Molzaelr pain
`Fig I.
`.
`.
`:3 questionnaire" and (b) LASA scales that were used to
`anus pain and quality of life.
`
`received one or more courses of radiation to bony
`metastases.
`
`Symptomatic Response to Prednisone
`
`Tolerance of Prednisone Therapy
`
`One patient discontinued prednisone because
`he claimed that it caused nausea, and a second
`patient experienced gastrointestinal pain. There
`was no observable toxicity in the remaining
`patients. In particular there was no gastrointesti-
`nal bleeding, and patients did not become
`Cushingoid with the low doses that were used.
`
`Of the 28 patients who were reviewed retro-
`spectively, seven had improvement in pain with a
`reduced requirement for analgesics for a median
`duration of 5 months (range, 2 to ll months).
`Pretreatment values of the four indices used to
`
`assess pain in patients treated prospectively were
`as follows (mean 1 SEM): daily analgesic score,
`10.2 : 2.2; linear analog scale, 4.3 : 0.5; pain
`rating index, 21 : 2; present pain intensity, 2.0 «.-
`
`Talslo ‘I. Characteristics of 37 Patients Treated Prospoctivoly
`Median age (range)
`62 (46-76) yr
`Previous therapy to primary
`Radical prostatectomy
`Radiation to primary
`Median no. of prior endocrine maneuvers’ (range)
`Median no. of irradiated metastatic sites (range)
`Median interval from diagnosis (range)
`Median interval from initial endocrine therapy‘ (range)
`Subjective response to initial endocrine therapy
`Yes
`No
`Not assessablet
`Initial serum concentration (range) of:
`Acid phosphatase
`Alkaline phosphatase
`*IncIudes orchidectomy and different estrogens.
`Tsame patients had endocrine therapy when they were asymptomatic.
`¢Nonnal values for serum concentration of acid and alkaline phosphatase are < 0.8 and 120 IU/L, respectively.
`
`0
`"I2
`2 (1-4)
`1 (0-4)
`27 (6-1 l9) mo
`18 (4-1 17) mo
`
`25
`4
`8
`
`2.7 (0.3-89.6) IU/ L
`313 (751,000) lu/L
`
`lnformation downloaded from jco.ascopubs.org and provided by at Cadmus Artic|eWorks on November 30, 2015 from 65.196.76.99
`Copyright © 1989 American Society of Clinical Oncology. All rights reserved.
`Page 4
`
`Page 4
`
`

`
`QUALITY OF LIFE AND PROSTATE CANCER
`
`593
`
`0.2. Thus, most of the patients were symptomatic
`from pain. Of 37 patients who received predni-
`sone in the prospective study, 14 (38%) had
`improvement in each of the three scales that were
`used to assess pain, and a decreased or stable
`requirement for analgesics for a minimum of 1
`month. Five patients became free of pain and
`required no analgesics.
`In seven patients
`improvement
`in each of the pain indices and
`decreased analgesic requirement persisted for 3
`to 30 months (median, 4 months). Of 14 patients
`with initial relief of pain on prednisone, ten had
`responded subjectively to their initial hormonal
`treatment with estrogens and/or orchidectomy,
`one had not responded, and three could not be
`assessed for response.
`The overall elfect of prednisone on pain expe-
`rienced by the entire patient population was
`assessed by comparing pain indices after one
`month of treatment with prednisone, with those
`recorded at the start of treatment. Statistical
`
`evaluation using the two—tailed paired t—test
`showed significant improvement in the median
`values of pain rating index and present pain
`intensity (P = .009 and .011, respectively) and
`nonsignificant
`trends toward improvements in
`analgesic score or LASA evaluation of pain
`(P = .24 and .12, respectively). The alternative
`statistical method of using the nonparametric
`sign test to compare pre— and posttreatment pain
`indices gave similar conclusions.
`LASA scores for 13 of the 14 patients who had
`
`improvement in all indices of pain are summa-
`rized in Table 2. Initial scores were not available
`
`testing
`for one patient, but his subsequent
`showed normal or near normal scores (2 9) for
`all dimensions of quality of life. At the time of
`maximum improvement
`in pain, 46% of the
`scales had improved, 11% had deteriorated, and
`43% were unchanged. Most of the unchanged
`scores reflected a normal state (before and after
`treatment) for some of the quality-of-life dimen-
`sions that were assessed. Large improvements
`were seen in the LASA scale, which reflected
`overall well-being by asking patients “How do
`you feel?” (Table 2), and all but two patients
`with improved pain indices had improvement in
`this scale. Overall, the panel of indices that were
`used to assess pain and quality of life provide
`consistent evidence for at least transient relief of
`
`symptoms in 12 of the 37 patients (32%) who
`received prednisone prospectively.
`
`Biochemical Response to Prednisone
`
`Values of alkaline and acid phosphatase were
`elevated initially in 31 and 22 of the 37 patients,
`respectively. Decreases of > 10 IU/mL in alka-
`line phosphatase were seen in 16 patients during
`prednisone therapy, but only eight of these had
`consistent improvement in pain. Nine patients
`had a decrease of > 1 IU/mL in acid phospha-
`tase, and only four of these patients had improve-
`ment in pain. Thus there is little evidence for
`
`Table 2. Changes in I6 LASA Scales Reflecting Different Dimensions of Quality of Life for Patients
`who Had Improvement in lndices of Pain
`
`Patient
`l
`2
`3
`4
`5
`6
`7
`3
`9
`IO
`ll
`12
`l3
`Total
`
`Improved
`l l
`l l
`l l
`10
`9
`9
`9
`6
`5
`4
`3
`3
`0
`91
`
`Change in Score for Overall
`Well-Being
`Unchanged
`+3.5
`5
`+4.0
`3
`+ 1.0
`3
`+5.5
`5
`+3.5
`5
`+ 2.0
`5
`+ 4.0
`5
`+2.0
`5
`—- 'l.5
`4
`+6.5
`10
`+1.0
`l2
`— l.0
`9
`+4.0
`l3
`84
`
`Dederiorated
`0
`0
`l
`‘I
`l
`l
`2
`4
`7
`0
`0
`3
`l
`21
`
`*For dimensions, see Table 4. some dimensions (eg, employment) were not relevant to some individuals and were not scored. Initial LASA
`scores were not available for one patient who had complete resolution of pain at 1 month.
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus Articleworks on November 30, 2015 from 65.196.76.99
`Copyright © 1989 American Society of Clinical Oncology. All rights reserved.
`
`Page 5
`
`Page 5
`
`

`
`594
`
`TA NNOCK ET AL
`
`correlation between relief of symptoms and these
`biochemical markers.
`
`Only five patients with pain relief had reas-
`sessment with skeletal x—rays and/or bone scan.
`Two showed improvement (one after initial dete-
`rioration), one was unchanged, and two had
`deterioration. All three of the patients without
`symptomatic improvement who had reassess-
`ment showed deterioration in bone scan and /or
`skeletal x-rays.
`
`Changes in Hormone Levels
`
`Initial serum concentration of the androgens
`testosterone, androstenedione, and DHEAS, and
`their changes in response to prednisone are sum-
`marized in Table 3. There were no difierences in
`the initial
`levels of these hormones between
`
`patients who did or did not have subsequent
`improvement in symptoms on prednisone.
`Nine patients had serum concentration of tes-
`tosterone > 2 nmol/ L which has been regarded
`as an upper limit for castrate men; eight of these
`men had previous orchidectomy and one patient
`was receiving DES. Seven of these patients had a
`decrease in serum testosterone concentration
`
`after initiation of prednisone. Three of these
`patients, and one whose testosterone level
`remained unchanged, experienced relief of pain;
`all four responding patients also experienced a
`decrease in serum concentration of androstene-
`
`dione and DHEAS, whereas those who had ele-
`
`vated testosterone initially and did not respond
`
`symptomatically experienced no decrease in
`adrenal androgens.
`Symptomatic relief on prednisone was asso-
`ciated with suppression of serum levels of andro-
`stenedione and/ or DHEAS (Table 3). Serial
`assessment of one or both of these hormones was
`
`13 patients who experienced
`available for
`improvement in pain; ten of these had a decrease
`in one or both hormones, and in two others they
`were initially present in low concentration. This
`contrasts with a decrease in one or both hormone
`
`levels in only six of 16 patients without pain relief
`who had serial assessment of hormone reduction
`
`(P = .06, for hormone reduction; P = .006 for
`hormone reduction or initial suppression, Fish-
`er’s exact test, two—sided).
`
`Evaluation ofMelhods
`for Assessing Symptoms
`
`Consistency of the four methods that were
`used to evaluate pain was assessed by calculating
`correlation coeflicients between the two McGill—
`
`the analgesic score, and the
`Melzack scales,
`LASA scale for the entire data set. These corre-
`
`lation coefficients were in the range of 0.44 to
`0.68 indicating significant correlation between
`them (P < .01 for all comparisons, Spearman’s
`rank correlation coefficient).
`The 16 LASA scores representing various
`dimensions of quality of life were also compared
`with each of the four measures of pain. There
`
`Table 3. Initial Scrum Concentration of Hormones, and Changes After Receiving Prodnisono
`Patients With
`Patients Vtlitttout
`Entire Series
`Improvement of Pain (N : 23)
`(N = 37)‘
`Improvement of Pain (N -1 14)
`
`Testostoronef
`Median (range)
`Decrease (by > 1 nmal/l)
`Increase or no change
`Initial value < 2 nmol/l.
`Androstenedionef
`Median (range)
`Decrease (by 2 l nmol/ L)
`Increase or no change
`Initial value < l nmol/l
`DHEAST
`Median (range)
`Decrease (by 2 lumol/l)
`Increase or no change
`Initial value < I umo|/ L
`
`1.2 (0-5.6)
`7
`2
`27
`
`3.9 (0.1-8.0)
`I4
`I2
`3
`
`2.3 (0.3-8.7)
`‘l3
`8
`4
`
`,
`
`1.3 (o-4.5)
`3
`1
`1o
`
`3.9 (0.1-e.o)
`3
`3
`2
`
`2.3 (0.5-3.2)
`s
`1
`3
`
`1.1 (05.6)
`4
`1
`17
`
`37 (03.7.7)
`6
`9
`1
`
`2.2 (0.331)
`5
`7
`1
`
`*Hormone levels were available at follow-up visits for 36 patients (testosterone), 29 patients (anclrostenedione), end 25 patients (DHEAS).
`1*Normal values: testosterone, 12 to 31 nmol/l. (castrate, < 2 nmol/ L); androstenedione, 2.0 to 8.7 nmol/ L; DHEAS, 2.7 to 10.9 umol/ L.
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus Articleworks on November 30, 2015 from 65.196.76.99
`Copyright © 1989 American Society of Clinical Oncology. All rights reserved.
`Page 6
`
`Page 6
`
`

`
`QUALITY OF LIFE AND PROSTATE CANCER
`
`595
`
`was a significant correlation for 29 of these 64
`comparisons (P < .05, Spearman’s rank correla-
`tion coefficient, corrected for multiple compari-
`sons by the Bonferroni method). The correlation
`coefficient averaged over the four pain scores is
`shown in Table 4. Note that the correlation is
`
`particularly strong for the overall scale indicat-
`ing sense of well-being.
`Few patients reported abnormalities in the
`categories of self-care, speaking or writing, or
`mental function, so that scores were clustered
`
`close to 10, ie, at the end of the scale representing
`normal status (Table 4). Therefore, these scales
`give little useful information, and the clustering
`of scores leads to a weaker association with
`
`indices of pain control. A high proportion of
`patients were retired, but the LASA scale relat-
`ing to employment was completed by 46% of
`patients; this scale also showed a poorer correla-
`tion with indices of pain.
`In an attempt to reduce the number of LASA
`scales without losing information, we examined
`correlations between scales where similar factors
`
`might influence the ability to function. Spear-
`man rank correlation coelficients (r,) > 0.45
`were recorded for all associations within the
`
`(1) mobility, physicial activity, recre-
`groups:
`ation, social life, and housework, (2) fatigue and
`sleeping (rs = 0.53), and (3) mood and anxiety
`(r, = 0.61). Thus, in future trials a single LASA
`
`scale might be used to represent each of these
`groupings.
`
`DISCUSSION
`
`Response to Prednisone
`
`We have demonstrated that about 30% of
`
`in symptoms
`patients may have improvement
`after treatment with low-dose prednisone, when
`they are no longer
`responding to primary
`androgen ablation with orchidectomy and/or
`estrogens. Although this response is usually tran-
`sient the treatment is nontoxic and inexpensive,
`and a few patients have prolonged relief of pain.
`As with other systemic therapies for prostate
`cancer, there was little evidence that prednisone
`caused a consistent improvement in serum levels
`of acid and alkaline phosphatase, or in x—rays or
`bone scans. These indices have sometimes been
`
`referred to as objective, in contrast to subjective
`improvement in symptoms. We believe that the
`words “objective” and “subjective” are used here
`inappropriately. The aim of treatment is pallia-
`tion, which can be defined as improvement in
`either the duration or quality of survival. There is
`no convincing evidence that systemic therapy
`improves the survival of patients with metastatic
`prostate cancer,” and measures of symptom con-
`trol should therefore be used to assess palliation.
`Whereas radiologic or biochemical assessment of
`
`Table 4. LASA Scales Used to Evaluate Different Features of Quality of life‘
`
`
`Absolute Average
`Correlation
`Coellcient
`No.
`Moon
`Median
`With 4 Pain
`
`Dimension
`Completed
`Score
`Score
`Range
`Indices
`Mobility
`123
`7.4
`8
`1-10
`0.36
`Employment
`56
`6.1
`8
`0-10
`0.19
`Self-care
`123
`9.4
`10
`2-10
`0.21
`Physical activity
`123
`8.2
`8.5
`1-10
`0.36
`Recreation
`116
`5.8
`7
`0-10
`0.31
`Social life
`123
`7.5
`9
`0-10
`0.28
`Family relationships
`123
`8.5
`10
`0-10
`0.30
`Housework
`92
`7.0
`10
`0-10
`0.31
`Speaking/writing
`123
`9.8
`10
`6-10
`0.20
`Fatigue
`123
`5.7
`5
`0-10
`0.29
`Appetite
`123
`7.6
`9
`0-10
`0.28
`Sleep
`123
`7.6
`8.5
`1-10
`0.26
`Mental lunction
`123
`9.7
`10
`6-10
`0.15
`Mood
`123
`7.0
`7.5
`0-10
`0.18
`Anxiety
`123
`6.5
`7
`0-10
`0.24
`
`123 6.1 6 0-10Sense of well-being 0.52
`
`
`
`
`*A score of 0 corresponds to the worst possible state and a score of 10 indicates a normal state.
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus ArlicleWorks_on November 30, 2015 from 65.196.76.99
`Copyright © 1989 American Society of Clinical Oncology. All rights reserved.
`
`Page 7
`
`Page 7
`
`

`
`596
`
`TA NNOCK ET AL
`
`patients is known to be poorly correlated with
`clinical well-being of the patient, our study has
`shown that various methods of assessing pain and
`quality of life can be consistent. Thus assessment
`of symptoms is not only the most relevant end
`point, but also may be the most objective method
`for assessing response to systemic therapy in
`prostatic cancer.
`Comparison of nonrandomized series of
`patients is fraught with difficulty because of
`variability in selection factors (eg, extent of prior
`treatment) and in criteria for judging response.
`However,
`the probability of improvement
`in
`symptoms after secondary treatment with pred-
`nisone appears to be within the same range as
`when patients progressing after orchidectomy or
`estrogens are treated with anti-androgens (cy-
`proterone acetate or flutamide) or with amino-
`glutethimide and hydrocortisone.
`Indeed,
`the
`observations of Plowman et al8 and Dowsett et al°
`
`that adrenal androgens were suppressed less with
`aminoglutethimide plus hydrocortisone than
`with hydrocortisone alone, suggests that hydro-
`cortisone rather than aminoglutethimide may be
`the active drug when this combination produces
`subjective response. Moreover, corticosteroids
`such as dexamethasone are used frequently as
`antiemetics in patients
`receiving cytotoxic
`chemotherapy, and may contribute to any
`improvement in symptoms that is observed in
`such patients.
`In the absence of randomized
`trials demonstrating superiority of other drugs, a
`trial of low-dose prednisone can be recommended
`for most patients with progressive symptomatic
`prostate cancer who have undergone orchidecto-
`my, or who are receiving estrogens or LHRH
`agonists.
`
`Mechanism of Action of Prednisone
`
`The antiinflammatory properties of predni-
`sone might lead nonspecifically to improvement
`in pain and other symptoms. However,
`this
`mechanism seems unlikely to explain the magni-
`tude of responses seen in the present study, since
`the low dose of prednisone used was comparable
`to the physiological production of corticosteroids
`by the adrenal gland. It seems probable that most
`of the benefit was mediated through hormonal
`efl'ects on the adrenal gland.
`3H-labeled androstenedione or DHEAS has
`been shown to be incorporated into dihydrotes-
`
`the major intranuclear androgen in
`tosterone,
`prostatic cells.” Although incorporation of
`androstenedione and DHEAS was much less
`
`than testosterone, these weak androgens proba-
`bly can stimulate prostatic tissue. Prednisone
`treatment suppressed the serum concentration of
`androstenedione and DHEAS in more than 50%
`
`of patients with initial levels above 1 nmol / L and
`1 nmol/L, respectively, as previously reported
`for smaller series of patients.” All but one of the
`patients who responded symptomatically either
`had suppression of adrenal androgens, or had
`initial low levels of these hormones, suggesting
`that this may have been a mechanism leading to
`response.
`
`Two mechanisms may be expected to lead to
`progression of prostatic cancer in patients who
`have previously undergone orchidectomy or are
`taking estrogens:
`(1) cells that are no longer
`responsive to hormones may have been selected
`from a heterogeneous initial population, or (2)
`some of the cells may remain androgen-respon-
`sive and are stimulated by adrenal androgens or
`their derivatives. For the latter patients, therapy
`with prednisone (or other measures to suppress
`or counter adrenal androgens) may be effective
`palliation. Unfortunately, all patients ultimately
`progress to a state of hormone nonresponsive-
`ness.
`
`Evaluation of Symptoms in Prostatic Cancer
`
`We have used the present study to evaluate
`methods for assessment of pain and quality of
`life. The methods used for assessment of pain
`were well correlated, and the use of multiple
`indices decreases
`the probability of
`falsely
`assessing response. Three of these indices, the
`LASA scale, the analgesic score, and the simpler
`6-point verbal scale of
`the McGill—Melzack
`method (present pain intensity) could be applied
`rapidly and were easily understood by all
`patients. The more complex pain rating index of
`the McGill—Melzack questionnaire required con-
`siderable linguistic ability and was particularly
`difficult for patients whose first language was not
`English.
`Several studies have demonstrated that qual-
`ity of life is multifactorial, and our study used 17
`LASA scales (including that for pain) to assess
`various dimensions of health. These scales were
`adapted from a series that had been used to
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus Arlic|eWorks on November 30, 2015 from 65.196.76.99
`Copyright © 1989 American Society of Clinical Oncology. All rights reserved.
`Page 8
`
`Page 8
`
`

`
`QUALITY OF LIFE AND PROSTATE CANCER
`
`597
`
`Table 5. Simplified Instrument for Assessing Symptoms
`in Patients With Metastatic Prostate Cancer
`Analgesic Scare‘
`[ASA Scales for:
`
`Pain
`Present pain intensity scale of
`Physical activity
`McGil|-Melzack method, ie,
`Fatigue
`0 - no pain
`Appetite
`1 — mild
`Bowel function
`2 — discomforting
`Family relationships
`3 — distressing
`Mood
`4 a horrible
`5 — excruciating Overall well-being
`
`
`
`assess quality of life in patients with metastatic
`breast cancer where they were shown to be
`reproducible and valid.“ Some of the scales
`assessed related functions, and scores for these
`dimensions were highly correlated; others tested
`function that was only rarely abnormal, and gave
`little useful information; an additional scale to
`assess bowel function is suggested by the fre-
`quent side effect of constipation in patients who
`are taking narcotic analgesics. Based on this
`experience we suggest that adequate information
`could be obtained by using a smaller series of
`
`eight LASA scales that would assess pain, physi-
`cal activity, fatigue, appetite, bowel function,
`family relationships, mood, and well-being. The
`combination of the analgesic score, the present
`pain intensity, and eight LASA scales (Table 5)
`could provide a simple and useful instrument for
`assessing response to all types of systemic ther-
`apy in metastatic prostate cancer, but will
`require testing for validity and reproducibility in
`a larger series of patients.
`In conclusion, we have documented that some
`patients with symptomatic prostatic cancer may
`respond to prednisone as second-line hormonal
`treatmen