Eur] Cancer Clin Oncol, Vol. ?4, No. [0, pp. l367-1572, 1988.
`Printed in Great Britain
`
`U277-3379/K3$3.(l() + 0.00
`© 1988 Pergamon Press plc
`
`The Definition of the ‘No Change’ Category in
`Patients Treated with Endocrine Therapy and
`Chemotherapy for Advanced Carcinoma of the
`Breast
`
`A. HOWELL,* J. MACKINTOSH,* MARY ]ONES,T JUDITH REDFORD,i J. W/\GSTAFF* and R.A.
`SELLWOOD:
`
`*CRC Department of [Medical Oncology and TDepartment of Statistics, Christie Hospital and Holt Radium Institute, Wilmslaw
`Road, Manchester and iDepartment of Surgery, Withington Hospital, Nell Lane, Withington, Manchester M20 9BX, U.K .
`
`Abstract—In the criteria usedfor assessment of response to treatment for advanced breast cancer
`the definition of no change (NC) is clear; however,
`there is no indication of the duration of
`stabilization required for patients to qualify for this categoyr of response. We have made the
`assumption that NC is a worthwhile category Qf response
`the overall
`time to progression
`(TTP) and survival of this group is not significantly different from patients with partial
`remissions (PR). Two hundred and sixty—three evaluable patients treated with endocrine therapy
`and 302 evaluable chemotherapy—treated patients were studied and the TTP and survival curves
`for PR and periods ty” NC from 1
`to 6 months compared. For the endocrine—treated patients the
`TTP and survival curves for NC became non-significantly diffirent from the PR curves after 4
`and 5 months respectively. For chemotherapy-treated patients the TTP curves became non-
`significantly different from PR at 4 months and for survival the period was 3 months. In order
`to define NC as a useful category of response and to eliminate the possibility that NC taken for
`a shorter period could simply represent a slowly progressive tumour, we suggest that the minimum
`period of disease stabilization be taken as 5 months for both endocrine— and chemotherapy—treated
`patients.
`
`INTRODUCTION
`
`osseous metastases and 2 or 3 months for osseous
`
`THE CRITERIA for evaluating the response to treat-
`ment in patients with advanced cancer of the breast
`are well established and generally acceptable. This
`standardization has made the comparison ofresults
`from centre to centre and between different treat-
`ments more reliable.
`
`The no change (NC) category of response is
`defined in all international criteria as the mainten-
`ance of a <50°/o decrease or a <25”/o increase in
`
`In the most widely
`size of measurable lesions.
`utilized criteria for cancer of the breast published
`for the International Union Against Cancer (UICC)
`by Hayward et al. [1] there is no mention of the
`duration of stabilization required for patients to
`qualify for the NC category;
`in other published
`criteria the period is taken as 1 month for non-
`
`Accepted 16 February l988.
`Address for correspondence: Dr A. Howell, Senior Lecturer
`and Consultant, Department of Medical Oncology, Christie
`Hospital, Manchester, U.K.
`
`metastases [2, 3].
`Advanced breast cancer patients achieving a par-
`tial remission (PR) with either endocrine therapy
`or chemotherapy usually survive longer than those
`with progressive disease. We recognize that this
`may not be related to the treatment or indeed to a
`direct effect of response on survival but rather that
`response may identify a group of patients with
`pretreatment characteristics favouring longer sur-
`vival. The problems ofanalysing survival by tumour
`response have recently been reviewed [4]. Given
`these limitations, a comparison of survival curves
`by response category may still be clinically useful
`in predicting the subsequent course of a patient’s
`disease, PR being associated with longer survival
`[5—l 7]. There is less certainty concerning the value
`of NC.
`In some reports patients with NC have
`similar durations of response and survival as pat-
`ients with PR [5—ll, I8, 19];
`in others the NC
`group fare less well [l2—l7]. This may be due to
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`1553
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`A. Howell et al.
`
`the variability of response criteria, in particular the
`minimum required duration of NC. Tonkin et al.
`[20] have shown how even subtle differences in
`‘standard’
`response criteria may cause marked
`variability in reported response rates.
`In this study of patients with advanced breast
`cancer we compared the TTP and survival of partial
`responders and patients with NC. We have made
`the assumption that NC is of‘value’ if these patients
`fare as well as those with a PR. We have therefore
`
`taken various time periods for the definition of NC
`(1, 2, 3, 4, 5 and 6 months) and compared the
`overall time to progression (TTP) and survival so
`produced with those in patients who have a definite
`PR. The data suggest that periods of NC from 4 to
`5 months indicate subsequent response duration
`and survival times equivalent to those for advanced
`patients with PR.
`
`MATERIALS AND METHODS
`
`Patients: endocrine therapy
`Two hundred and sixty-three patients treated
`with tamoxifen
`(post-menopausal) or ovarian
`ablation (pre-menopausal) were studied. One had
`previous systemic treatment for advanced disease
`although 34 were treated with adjuvant chemo-
`therapy. All patients had progressive disease at the
`time of entry to the study and were evaluable for
`response according to UICC criteria
`
`Chemotherapy
`Three hundred and two patients were treated
`with several regimens ofcombination chemotherapy
`most of which have been previously described:
`CMFP [2l]; AC [22]; vincristine, adriamycin,
`cyclophosphamide and prednisolone (VAP cyelo)
`[23]; dibromodulcitol, mitomycin C and vinblastine
`(DMV) [24], and an oral regimen ofCMF (CMFO)
`consisting ofcyelophosphamide 250 mg/m2, metho-
`trcxate 16 mg/m2 and fluorouracil 500 mg given
`on the 1st, 3rd and 5th days of each week respect-
`ively. The majority of patients were treated as part
`ofa randomized trial comparing CMFP (n = 100)
`and AC (n = 105), 20 were treated with VAPcyclo,
`six with DMV and 45 with CMFo. A further seven
`
`patients were given CMFP and 19 AC, but these
`patients were not in the trial.
`
`Methods
`
`Criteria for tumour response were as defined by
`Hayward et at. for the UICC [1]. In particular,
`survival was dated from the time of first treatment
`
`to death; duration of response was dated from the
`start oftreatment to the date oftumour progression.
`Chemotherapy-treated patients were assessed at
`3-4 week intervals and endocrine-treated patients
`at 4-8 week intervals. TTP and survival were
`
`calculated according to the method of Kaplan and
`Meier [25] and compared using the log—rank test
`[26]. The chi-squared test was used to compare
`tumour response categories and pretreatment pat-
`ient characteristics. Mann—Whitney comparisons
`[27] of Karnofsky performance status were also
`made. Curves were plotted for durations of NC of
`1, 2, 3, 4, 5 and 6 months. TTP and survival curves
`for patients with each period of NC were compared
`with the appropriate curves of patients with PR in
`order to determine the least period of stabilization
`where there was no statistical difference between NC
`
`and PR. Estrogen (ER) and progesterone receptor
`(PR) status was measured as previously described
`[28, 29].
`
`RESULTS
`
`Patient characteristics
`
`Response according to the regimen used in pat-
`ients treated with endocrine therapy and Chemo-
`therapy is shown in Table 1. For this analysis a
`minimum off) months of disease stabilization was
`
`taken for the definition of NC, as discussed below.
`
`For patients treated with endocrine therapy there
`were no significant differences in response to ovarian
`ablation (30 oophorectomy and two radiation-
`induced menopause) compared with tamoxifen
`(P = 0.48). For patients treated with chemotherapy
`there were no significant differences in response
`rates between regimens (P = 0.72).
`The TTP for the tamoxifen-treated patients was
`significantly longer than for
`those treated with
`ovarian ablation (Fig. IA) but there was no differ-
`ence in survival between the two groups (Fig. 1B).
`There were no significant differences in either the
`TTP or the survival for any of the chemotherapy
`regimens (Fig. 1C and 1D). For the purposes of
`this analysis it was felt justifiable to combine all
`chemotherapy-treated patients into one group and
`all endocrine-treated patients into another group.
`The characteristics of the patients in these two
`groups is shown in Table 2.
`
`Comparison of no change andpartiai response
`Duration of NC was taken to be 1, 2, 3, 4, 5 and
`
`6 months and a comparison of TTP and survival
`curves so produced made with those for patients
`with PR. Representative curves are shown in Figs. 2
`and 3. Patients who progressed within the particular
`time periods taken for NC were placed in the
`progressive disease category. Clearly, as the period
`of NC was increased,
`less patients qualified for
`this category and more for the progressive disease
`category.
`For endocrine-treated patients TTP and survival
`duration for NC were not significantly different
`from PR at 4 and 5 months respectively (Figs. 2
`and
`For chemotherapy-treated patients these
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`The ‘No Change’ Category in Breast Cancer
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`1569
`
`Table 1. Response according to the type of endocrine therapy and regimen of chemotherapy given
`
`Number
`
`Complete response
`Partial response
`No change
`Progressive disease
`
`Number
`
`Complete response
`Partial response
`No change
`Progressive disease
`
`Endocrine therapy
`Ovx*
`(%) TAM (°/o)
`
`32
`
`1
`9
`7
`15
`
`(3)
`(28)
`(22)
`(47)
`
`CMFP‘i
`
`107
`
`12
`38
`17
`40
`
`(1 1)
`(36)
`(16)
`(37)
`
`231
`
`22
`48
`55
`106
`
`124
`
`ll
`54
`18
`41
`
`(10)
`(21)
`(24)
`(46)
`
`Chemotherapy regimen
`VAPC
`DNIV
`
`AC
`
`(jM1“o
`
`20
`
`2
`10
`2
`6
`
`(10)
`(50)
`(10)
`(30)
`
`6
`
`0
`3
`2
`1
`
`(9)
`(43)
`(15)
`(33)
`
`1')
`
`3
`12
`8
`20
`
`(11)
`(27)
`(18)
`(44)
`
`(0)
`(50)
`(33)
`(17)
`
`*()vx = ovarian ablation; TAM = tamoxifen.
`‘.lSee text for details of chemotherapy regimens.
`
`1.00
`
`Endocrine therapy
`
`
`
`Alive
`
`%
`
`60
`
`40%Remission
`
`20
`
`NC was defined as 1, 2, 3 or 4 months in patients
`treated with endocrine therapy the NC category
`clearly included some patients destined to relapse
`and die early, and the TTP and survival curves were
`intermediate between those of PR and progressive
`disease. However, when the minimum period ofNC
`was taken as 5 months, durations of response and
`survival were equivalent to PR.
`For chemotherapy-treated patients both TTP
`and survival curves became supcrimposable when
`NC was taken at 4 months, suggesting that a
`shorter period of stabilization is of some prognostic
`significance. However, we believe a minimum per-
`iod of5 months free from disease progression should
`be taken as standard for all categories oftreatment,
`particularly with the widespread use of combined
`chemo—endocrine regimes. This period has the
`advantage that it should exclude from NC those
`patients with very slowly progressive disease who
`are unresponsive to systemic treatment.
`The chemotherapy group had a much poorer
`prognosis than the endocrine therapy group with
`median survivals from the start of treatment of 13
`
`and 27 months respectively. More ol‘ the chemo-
`therapy patients had rcceived previous systemic
`therapy and they formed a more advanced group
`as reflected by their poorer pretreatment Karnofsky
`performance status (Table 2). Paradoxically they
`did not have more sites 01' tumour involvement but
`
`a tendency to have more sites ol‘ visceral disease
`than the endocrine therapy group (Table 2). It is
`possible that the NC category fared well because
`this group had particularly favourable prognostic
`features. However, when the clinical features of the
`
`%Alive
`
`%Remission
`
`Fig. 1. Time; to progresxion (TTP) and surzrizral by treatment. (A) TTP
`and (B) iurzvizral durationg/or tamoxzfen—treatea' /zatientr (--—) and there
`treated with ovarian ablation (~—). (C) TTP and (D) rurzrizval tluralimz
`fin‘ rhemothera/gr treateeljmtientr (---1).\'I\’.
`CMFP. ...RC,
`(}\l Po).
`
`periods were 4 and 3 months respectively (Figs. 2
`and 3).
`
`DISCUSSION
`
`The aim of the study was to find a period of NC
`which defined a group of patients with the same
`prognosis as those with PR. When this period of
`
`equivalent NC and PR patients were compared
`there were only minor differences for both the
`endocrine and chcmothcrapy~treated patients.
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`1570
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`A. Howell et al.
`
`Table 2. Patient characteristics at the ttart oftreatment
`
`Endocrine therapy
`
`(%)
`
`Chemotherapy
`
`(%)
`
`Number of patients
`Mean age
`<50
`50+
`Premenopausal
`Perimenopausal
`Postmenopausal
`Not known
`Previous systemic treatment
`Endocrine:
`
`adjuvant
`advanced
`Chemotherapy:
`adjuvant
`Median RFI (months)
`Median time from 1st relapse to
`systemic treatment (months)
`Dominant site
`
`Soft tissue
`Bone
`Lung
`Liver
`Number of sites of disease
`
`1
`2
`3+
`Karnofsky performance status
`90
`80
`70
`$60
`Not known
`
`263
`63
`
`12
`
`I
`
`(19)
`(81)
`(16)
`(5)
`(73)
`(6)
`
`——
`——
`
`(13)
`
`(32)
`(29)
`(22)
`(6)
`
`(43)
`(32)
`(25)
`
`(52)
`(26)
`(I6)
`(6)
`—
`
`93
`209
`30
`80
`190
`2
`
`36
`183
`
`—
`
`86
`62
`100
`34-
`
`133
`95
`74
`
`41
`74
`52
`59
`76
`
`302
`55
`
`15
`
`6
`
`(31)
`(69)
`(10)
`(26)
`(63)
`(1)
`
`(12)
`(61)
`
`—
`
`(28)
`(21)
`(33)
`(1 1)
`
`(44-)
`(31)
`(25)
`
`(18)
`(33)
`(23)
`(26)
`——
`
`50
`213
`43
`2
`192
`16
`
`—
`—
`
`34
`
`84-
`77
`58
`17
`
`1 14
`83
`66
`
`123
`61
`39
`14
`26
`
`no
`
`1 flnth
`
`Endocrine therapy
`
`XRemission
`
`3s
`
`XRemission
`
`Chemotherapy
`2 months
`_
`
`3 months
`
`Fig. 2. Comparixon Qf the timer to progression between patient; with a partial rexponse (PR), no change (NC) between 1 and 4
`montlu, andprogrenive diseaxe (PD). P valuer refer to zlzflrerenees between PR and NC only (...PR, --—NC,
`P
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`The ‘No Change’ Category in Breast Cancer
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`1571
`
`Endocrine therapy
`
`3 months
`
`
`20
`
`
`Chemotherapy
`100
`-.
`3 months
`
`B0
`
`50
`
`40
`
`%Alive
`
`
`20
`
`goo
`
`5 months
`
`50
`
`60
`
`I0
`
`Fig. 3. Comparison of survival duration between patients with a partial rerponse (PR), no change (NC) between 1 and 5 months.
`PD)
`and progressive disease (PD). P values refer to differences between PR and NC only (..,PR, ---NC,
`
`In phase three studies which compare different
`chemotherapy regimens, it is rare for one to have a
`significant survival advantage over the other even if
`the response rates of the two regimens are markedly
`different. For example, in the study of Nemoto et al.
`[5], four chemotherapy regimens were evaluated in
`patients with advanced breast cancer and whereas
`the
`response
`rates
`ranged from 18
`to 63%
`(CR + PR) there were no differences in survival
`between any of the regimens. When NC (duration
`not defined) was added, the ‘response’ rates had a
`narrow range between 71 and 85°/o. The least
`effective regimen in conventional
`terms had the
`highest NC category;
`this may have contributed
`to the equivalent survival. Failure to define NC
`
`appropriately may lead to erroneous conclusions
`concerning the effectiveness of chemotherapy regi-
`mens and a more rigorous definition of this group
`of patients is required for this supposition to be
`tested.
`We consider that in advanced breast cancer the
`
`NC category is valid provided a minimum duration
`of 5 months is taken. This will allow more meaning-
`ful comparisons of response rates between published
`clinical trials. In addition this NC category gives
`useful prognostic information and indicates that
`a treatment regimen should not be prematurely
`discontinued even if there is no objective tumour
`regression.
`
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