Health-Related Quality of Life in Women With Metastatic
`Breast Cancer Treated With Trastuzumab (Herceptin)
`David Osoba and Michael Burchmore
`
`The measurement of health-related quality of life
`(HRQL) was an important component ofclinical trials
`of trastuzumab (Herceptin; Genentech, San Francisco,
`CA) In women with progressive HER2-overexpressing
`metastatic breast cancer who may or may not have had
`prior chemotherapy. Health-related quality oflife was
`measured at baseline and specified intervals during
`therapy using the European Organization for Research
`and Treatment of Cancer core Quality of Life Ques-
`tionnaire (QLQ-C30, version 1.0). Five domains were
`chosen a priori for analysis: global quality oflife, phys-
`ical, role and socia! functioning, and fatigue. In the
`phase II study, in which trastuzumab was given alone,
`there was no changein on-treatment QLQ-C30 scores
`compared with baseline, These results suggest that
`trastuzumab does not adversely affect HRQL during
`therapy. In the phaseIII study, the effects of trastu-
`zumab plus chemotherapy were compared with those
`of chemotherapy alone. A comparison of QLQ-C30
`scores during treatment did not show statistically sig-
`nificant differences between the two groupsat the pre-
`set level of P = .0], However, comparison of on-treat-
`ment
`scores with baseline
`In patients
`receiving
`chemotherapy alone indicated mild worsening of phys-
`ical and role functioning and of fatigue throughout the
`duration of treatment, whereas a similar comparison
`of those receiving chemotherapy with trastuzumab re-
`vealed mild worsening of role functioning at weeks 8
`and 20 and of fatigue only at week 8. These results
`suggest that trastuzumab may be associated with an
`amelioration of the deleterious effects of chemother-
`apy alone. In summary, in the doses and schedules used
`in these studies, trastuzumab is not associated with
`worsening of HRQL.
`Semin Oncol 26 (suppl 12):84-88. Copyright © 1999 by
`W.B. Saunders Company.
`
`HE TESTING of any new treatments for
`their efficacy in women with metastatic
`breast cancer should include a concomitantassess-
`ment of health-related quality of life (HRQL).
`Without such assessments, the benefits of treat-
`ment and effect of adverse events on patients’
`well-being will be only partially understood.If the
`
`From the Department of Medicine, University of British Colum-
`bia, Quality of Life Consulting, Vancouver, BC; and Genentech,
`Inc, South San Francisco, CA.
`Dr Osoba has received consulting fees from Genentech, Inc.
`Address reprint requests to David Osoba, MD, QOL Consult-
`ing, 4939 Edendale Court, Vancouver, BC, Canada V7W 3H7.
`Copyright @ 1999 by W.B. Saunders Company
`0093-7754/99/2604-1207$10.00/0
`
`84
`
`risks and benefits to HRQL posed by treatmentare
`unknown,health care professionals are hampered
`in their ability to fully explain them to patients
`who mayreceive similar treatment in the future.
`In the work reported here, HRQL was measured
`as a secondary outcome in twoclinical trials of
`women whoreceived trastuzumab (Herceptin; Ge-
`nentech, San Francisco, CA) for treatment of
`metastatic breast cancer in which HER2is over-
`expressed. As the results of these clinicaltrials are
`reported in detail elsewhere in this supplement,!
`this report is limited to an overview of the results
`of the HRQL assessment.
`
`PATIENTS AND METHODS
`
`Women with progressive HER2-overexpressing metastatic
`breast cancer who either had been previously treated with
`chemotherapy (phase II study) or who had not received previ-
`ous cytotoxic chemotherapy (phaseII] study) were treated with
`trastuzumab, as described elsewhere.! In the phase II study,
`HRQLassessments were scheduled far week [ (at baseline,ic,
`before the initiation of trastuzumab), weeks 12, 24, 36, and 48,
`and every 12 weeks thereafter, as well as on withdrawal from
`study or study termination.! In the phase III study, the assess-
`ments were performed at weeks 1, 8, 20, and 32, and every 12
`weeks thereafter.! All assessments were to be completed in the
`clinic before the administration of trastuzumab and/or chemo-
`therapy.
`Health-related quality oflife was assessed by the self-admin-
`istered European Organization for Research and Treatment of
`Cancer (EORTC)core Quality of Life Questionnaire (QLQ-
`C30, version 1.0).2 This questionnaire contains 30 Items,
`grouped into a global quality oflife (QL)scale, five functioning
`scales (physical, role, emotional, social, and cognitive), three
`symptom scales (fatigue, pain, and nausea/vomiting), and six
`single items dealing with common symptoms/problems that
`patients with cancer may experience. Additional modules con-
`sisting of study-specific icems were also used, buc analysis of
`these data is still incomplete and will not be reported here.
`The QLQ-C30 responses were scored and analyzed using
`algorithms in the scoring manual supplied by the EORTC
`Study Group on Quality of Life.3 All raw scores were trans-
`formed to a scale ranging from 0 to 100. Over time, higher
`scores in the functioning scales indicate an improvement,
`whereas in the symptomscales and items, higherscores indicate
`a worsening of symptoms.
`In the phaseII study, the purpose of the HRQLassessments
`was to determine whether treatment with crastuzumab was
`associated with a decline in HRQL. To determine changes in
`HRQLscores, the values obtained at various time paints while
`on treatment and at disease progression were subtracted from
`the baseline scores. The purpose of the analysis in the phaseII]
`study was to test the null hypothesis of no difference in the
`
`Seminars in Oncology, Val 26, No 4, Supp! 12 (August), 1999: pp 84-88
`
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`

`HEALTH-RELATED QUALITY OFLIFE
`
`85
`
`change of HRQL scores from baseline between treatment
`groups at a significance level of P = .O1. In both studies, five
`QLQ-C30 scales were prospectively identified as the primary
`variables of interest, ie, global QL, physical, role and social
`functioning, and fatigue. Only the results obtained for these
`variables will be presented here.
`Time windows were created for each predetermined mea-
`surementtime. All questionnaires completed within 4 weeks of
`the specified times were accepted for scoring and analysis. In
`cases of missing data, the following imputations were assigned:
`patient death was assigned a value of “O"; if the patient was
`alive but data missing, the last observation was carried forward.
`Missing data at week 8 or 10 were not included in the data
`analysis. No analyses were attempted after week 32 in the phase
`II study and week 36 in the phase III study due to attrition of
`data.
`Analyses were performed using a SAS program (SASInsti-
`tute, Cary, NC). For primary HRQLanalysis, a repeated-
`measures ANOVAwas used. In the phase III study, standard F
`statistics were used to assess the between-subjectfactors and a
`Huynh-Feldt epsilon adjustment was used for the time-interac-
`tion terms.
`
`RESULTS
`
`Phase II Study
`QLQ-C30 completion rates. Baseline QLQ-
`C30 scores were collected for 207 of the 222
`patients entered into the study (93%). At subse-
`quent times the percentages of patients for whom
`QLQ-C30 scores were available or analyzed were
`90% at week 12, 97% at week 24, and 94% at
`week 36. These high rates of available scores are
`attributable in part
`to the imputation methods
`used for assigning scores to missing values. The
`ratios of completed questionnaires to those ex-
`pected from patients who werealive andstill on
`study were as follows: 110 of 122 (92%) patients at
`week 12, 83 of 86 (97%) patients at week 24, and
`31 of 33 (94%) patients at week 36. One hundred
`fifty-four patients (74%) had complete scores,
`
`which included measurements at baseline and at
`week 12, and at progression before 12 weeks.
`Health-related quality of life results. Overall,
`there was no apparent worsening of QLQ-C30
`scores in the five predeterminedscales (global QL,
`physical, role and social functioning, andfatigue;
`Table 1). Individual patient scores for all
`five
`scales were calculated for each time point and
`baseline scores were subtracted from values at
`weeks 12, 24, and 36 to determine the change in
`each. For patients with missing data after week 12,
`the mean changes in scores are likely to underes-
`timate the true changes, since after week 12 the
`last available observation was carried forward.
`Theseresults indicate that patients who were able
`to continue therapy with trastuzumab did not ex-
`perience deleterious effects in their HRQL. How-
`ever, attrition rates over time were high, and these
`results must be interpreted with some caution
`since surviving patients remaining on treatment
`are more likely to report better HRQL than those
`who must discontinue treatment because of disease
`progression.
`
`Phase IH Study
`Atbaseline, 431 of
`QLQ-C30 completion rates.
`469 (92%) patients completed the questionnaire.
`At subsequent time points, the numbers of regu-
`larly scheduled questionnaires completed were 369
`of 390 (95%) at week 8, 282 of 320 (88%) at week
`20, and 160 of 181 (88%) at week 32.
`Health-related quality of life results. Analysis of
`the five predetermined scales did not show any
`statistically significant differences between those
`receiving trastuzumab with chemotherapy and
`those receiving chemotherapy only, at the preset
`
`Table I. Mean Change in QLQ-C30 Scores From Baseline to Week 36 (Phase tl Study)
`
`A negative numberindicates worsening for global QL, physical, role and social functioning, and improvement forfatigue.
`
`Global QL.
`Physical function
`Social function
`Role function
`Fatigue
`
`Baseline Score
`
`62.2 + 21.0
`75.7 + 24.6
`70,4 + 29.5
`67,7 + 38.1
`33.9 + 23.4
`
`Week 12
`
`4.3 + 20.!
`0+228
`65 + 24.8
`1.0 + 32.8
`—0.| + 23.3
`
`Mean Change From Baseline*
`Week 24
`
`1.1213
`—0.3 + 24.4
`4.8 + 26.0
`0+ 33.7
`0.4 * 23.0
`
`Week 36
`—O5 + 21.7
`—2.2 + 24.4
`1.9 + 25.3
`144325
`2.0 + 232
`
`* Mean change from baseline (mean + SD)forall patients who completed baseline and week |2 assessments; Includes disease progression.
`
`

`

`86
`
`OSOBA AND BURCHMORE
`
`level of P = .01 (Table 2). As in the phase II
`breast cancer while on treatment with trastu-
`study, the changes in scoresare likely to be under-
`zumab. The results indicate that HRQL, as mea-
`estimates of the true values due to use of the
`sured byselected scales of the QLQ-C30 question-
`catry-forwatd method to impute scores after the
`naire, did not change appreciably over 36 weeks of
`week 8 assessment.
`,
`treatment. However, since the numberof patients
`We have developed another approachto inter-
`remaining on ‘treatment decreased rapidly over
`time (only 33 patients at 36 weeks), those surviv-
`preting the significance of changes, in which the
`degree of change in QLQ-C30 scores perceived by
`ing and completing HRQL questionnaires would
`patients is categorized as “ little,” “moderate,” or
`be expected to report higher HRQL scores than
`“very much."4 In this method, changes between 5
`those in whom treatment was stopped dueto dis-
`and 10 in QLQ-C30 scores would indicate “little”
`ease progression. The results at week 12 are of
`change,
`11 to 20 would indicate “moderate”
`interest because at this time there werestill 83 of
`change, and more than 20 would indicate “very
`207 patients on treatment with HRQL data, some
`much” change. Using this interpretation, the tras-
`of whom had progressive disease, yet the HRQL
`tuzumab plus chemotherapy group would be
`scores had not changed appreciably from baseline
`judged to have experiencedalittle worsening in
`(other than a little worsening in social function-
`social and role functioning andin fatigue scores at
`ing). A comparison of the scores in patients with
`week 8, in only role functioning at week 20, and
`complete and partial disease responses with those
`no change from baseline at week 32. The chemo-
`for patients with progressive disease would help to
`therapy-only group experiencedalittle worsening
`clarify the true picture. However, in the phase II
`in physical and role functioning and in fatigue,
`study the numberof patients remaining on studyat
`which persisted throughout the entire 32 weeks of
`week 38 is probably too small for a meaningful
`observation.
`comparison.
`The HRQL component was included in the
`phaseIII study to determine whether the addition
`of trastuzumab to chemotherapy with doxorubicin
`and cyclophosphamideorpaclitaxel was associated
`with a worsening of HRQL compared withtreat-
`ment with chemotherapy alone. In this study,
`
`The objective for inclusion of the HRQL com-
`ponent in the open-label phase II study was to
`describe changes in HRQLfor previously treated
`women with HER2-overexpressing metastatic
`
`DISCUSSION
`
`Table 2, Change in QLQ-C30 Scores From Baseline to Week 32 (Phase III Study)
`
`Mean Change From Baseline*
`Week 20
`
`improvementforfatigue.
`
`Trastuzumab plus chemotherapy
`Global QL
`Physical function
`Social function
`Role function
`Fatigue
`
`Chemotherapy alone
`Global QL
`Physical function
`Social function
`Role function
`Fatigue
`
`Baseline Score
`
`N = 207
`59.3 + 1.8
`TAS + 19
`68.0 + 2.1
`64.6 + 25
`37.6419
`
`N= 194
`58.4 + 18
`70.6 + 2.1
`68.5422
`66.2427
`36.9 +20
`
`N=199
`3.7 + 1.9%
`25 +18
`-74+21
`—B6 + 2.6
`BO+ 20
`
`N= 188
`“42419
`54419
`3.2420
`=5.9 £27
`87+2.1
`
`* Changes represent mean + SE. A negative number Indicates a worsening for global QL, physical, role, and social functioning, and
`
`

`

`HEALTH-RELATED QUALITY OF LIFE
`
`87
`
`changes in QLQ-C30 scores were notstatistically
`significantly different at the preset level of P = .01
`between the two arms of the study. However, in
`the trastuzumab plus chemotherapy group, base-
`line QLQ-C30 scores for global QL as well as role
`and social functioning worsened by 8 wecks, then
`returned to baseline by 20 and 32 weeks of the
`study. In contrast, they remained worse than base-
`line for global QL and physical and role function-
`ing in the chemotherapy-alone arm forthe entire
`32 weeks. As in the phaseII study, the comparison
`of HRQLscores at various on-treatment
`times
`with baseline scores includes patients with varying
`disease responsestatus. Further analysis comparing
`scores of patients with complete and partialre-
`sponses to those with progressive disease may be
`helpful. There appears to be sufficient patients
`remaining at each time point to make such a
`comparison meaningful.
`In previous studies of chemotherapy in breast
`cancer, it has been shown that HRQLscores de-
`teriorate while patients are receiving treatment.>§
`In the phase II trial reported here, no significant
`deterioration in HRQL scores was observed in
`patients treated with trastuzumab.In the phase III
`study, deterioration in HRQL scores appeared to
`be shorter in duration in patients treated with
`trastuzumab alone compared with those treated
`with trastuzumab and chemotherapy. These results
`suggest that not only is there is no additional
`deterioration of HRQL associated with trastu-
`zumab therapy, but trastuzumab therapy also may
`be associated with an ameliorative effect on
`HRQL. This possibility remains to be explored
`further in future studies.
`Onedifficulty with the interpretation of these
`results from both studies is that calculation of
`scoresfor patients with missing data (due to factors
`other than death) is problematic. In this study we
`used a “last available observation carried forward”
`approach. However, in patients with progressive
`disease, this approach tends to overestimate the
`results at the missing time points, since the scores
`from the completions atearlier time points in the
`study, before disease progression, are likely to be
`better (ie, higher functioning scores and lower
`symptom scores) than those fromlater time points
`at which data are morelikely to be missing. This
`“better” score, if carried forward for two or more
`time points, will skew the score in favor of a better
`score for the later time points. If missing data are
`
`associated with worsening disease just preceding
`death or removalof the patient from study (non-
`random missing data), then the direction of the
`incorrect estimate can be known with certainty.
`However,
`if the true score of the missing data
`(were it known) from a later time pointis actually
`better than from a previous time point, and the
`data are missing at random(ie, there are additional
`scores after the missing score), then the carry-
`forward score will be an underestimate of the truc
`score. If the missing data are random but
`the
`disease status cannot be assessed or the effects of
`toxicity on HRQLareuncertain,it is impossible to
`determine whetherthe last available observation
`is an overestimate or an underestimate of the true
`score,
`
`A method that may circumvent some of the
`difficulties associated with imputation of datais to
`determine the mean duration of change (improve-
`mentor deterioration) by a time-to-eventanalysis
`in the intent-to-treat population(s).? In this ap-
`proach, the event needs to be well defined (eg, a
`score improvementofat least 10 points [on a scale
`of 0 to 100] compared with baseline, lasting for a
`defined pcriod of time, followed by a detcrioration
`of at least 10 points). To obtain the mean duration
`of improvement for the group,
`the duration of
`improvement for each subject is calculated, and
`the individual durations are summed and divided
`by the numberof patients in the intent-to-treat
`population. In phase HI studies, the mean duration
`of improvement in each HRQL domain score can
`then be compared in two or more arms of the
`study.
`Furthermore,
`duration-of-improvement
`curves can be plotted for various HRQLscalesfor
`those patients who experienced improvement. If
`the pattern in HRQL scores in a given study
`indicates an initial deterioration in HRQLscores,
`then a similar method could be used to first cal-
`culate the mean duration of deterioration followed
`by a calculation of the mean duration of improve-
`ment.
`
`Despite the limitations in the analysis method
`used in the studies reported here, it can be concluded
`that trastuzumab does not appearto adversely affect
`HRQLas measured by the QLQ-C30, Furtheranal-
`ysis of the data, using an intent-to-treat approach,
`and the continued measurement of HRQL in pa-
`tients treated with trastuzumab are warranted.
`
`

`

`88
`
`OSOBA AND BURCHMORE
`
`ACKNOWLEDGMENT
`
`The authors thank Genentech, Inc, for supporting these
`studies and Jill Vardy for assistance with preparation of the
`manuscript.
`
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