BRITISH MEDICAL jOURNAL VOLUME 286
`
`1
`
`jANUARY 1983
`
`5
`
`CLINICAL RESEARCH
`
`
`
`Concurrent or sequential use of cytotoxic chemotherapy
`and hormone treatment in advanced breast cancer:
`report of the Swiss Group for Clinical Cancer Research
`
`F CAVALLI, M BEER, G MARTZ, W F JUNGI, P ALBERTO,
`K W BRUNNER
`
`J P OBRECHT, B MERMILLOD,
`
`Abstract
`
`In a trial of combined hormone treatment and cytotoxic
`chemotherapy 464 patients with advanced breast cancer
`were randomly allocated to either concurrent or sequen-
`tial treatment. Cytotoxic drugs were given only if the
`antitumour activity of the hormone treatment was
`inadequate. Hormone treatment consisted of oophorec-
`tomy for premenopausal and tamoxifen administration
`for postmenopausal patients. Length of survival was
`better,
`though not
`significantly,
`in premenopausal
`patients (p :0-29)-treated concurrently and in post-
`menopausal women (p=0-l7) treated sequentially; the
`difference was highly significant (p:0-003) only for
`postmenopausal women in the low-risk category. The
`
`
`
`Ospedale San Giovanni, 6500 Bellinzona, Switzerland
`F CAVALLI, MD, head of the division of oncology
`M BEER, MD, senior registrar, division of oncology
`
`University Hospital, 8091 Zurich, Switzerland
`G MARTZ, MD, professor, division of oncology
`
`Kantonsspital, 9007 St Gallen, Switzerland
`W'F JUNGI, MD, consultant, division of oncology
`
`Hopital Cantonal, 1205 Geneva, Switzerland
`P ALBERTO, MD, senior lecturer, division of oncology
`
`Kantonsspital, 4004 Basle, Switzerland
`J P OBRECI-IT, MD, professor, division of oncology
`
`Operations Office, Schweizerische Arbeitsgruppe fiir Klinische
`Krebsforschung, 1205 Geneva, Switzerland
`B MERMILLOD, PHD, senior statistician
`
`lnselspital, 3010 Berne, Switzerland
`K W BRUNNER, MD, professor, Institute for Medical Oncology
`
`that postmenopausal women with
`suggest
`findings
`metastatic breast cancer should probably be treated
`primarily by carefully monitored hormone treatment.
`
`Introduction
`
`Breast cancer tissue is thought to be composed of at least two
`different cellular types, one which is responsive to hormone
`treatment and one which is sensitive to cytotoxic drugs.1 A
`combination of both treatments should therefore improve the
`results of treatment of advanced breast cancer, particularly as
`no appreciable progress seems to occur when only one of the
`currently available treatments is used. The firSt trials of the
`efficacy of combining hormone and cytotoxic drug treatment
`yielded conflicting results?—4| Nevertheless there is a widespread
`tendency to treat many patients with a combination of both
`treatments
`simultaneously.
`In our
`randomised study we
`compared this approach with more conservative management,
`in which chemotherapy was given only if the antitumour
`activity of hormone treatment was insufficient.
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`
`Patients and methods
`SELECTION
`
`Between September 1975 and December 1980, 464 patients with a
`measurable advanced breast cancer who had not previously received
`chemotherapy or hormone treatment were entered into the trial.
`Patients with brain metastases and impaired renal or hepatic function
`were excluded. Osteoblastic boney metastases and malignant effusions
`were not accepted as measurable lesions. Fifty-eight patients had to
`be excluded from the present analysis, because in seven tumour size
`was difficult to evaluate, in 42 there was a major protocol violation,
`and in nine death occurred within four weeks of starting treatment.
`The patients were stratified according to menopausal status and risk
`category, based on retrospective analysis of two of our previous
`studies?
`Low-risk category—This was based on the following features: (a)
`
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`

`BRITISH MEDICAL JOURNAL VOLUME 286
`
`1 JANUARY 1983
`
`which did not reach the limits of a partial remission. The disease was
`considered to be progressive if new lesions appeared or the size of the
`measurable lesions increased by more than 25“...
`
`STATISTICAL ANALYSIS
`
`The survival period and the time to progression of the disease were
`calculated from entry into the study. Actuarial curves were based on
`the method described by Kaplan and Meier.T The statistical compari-
`son among actuarial curves was carried out using the log-rank test,
`the Mantel—Cox test, and the generalised Wilcoxon test.8 In the case
`of differences among the statistical tests the least significant result was
`recorded.
`
`Results
`
`Of the 406 evaluable patients, 207 were allocated to group A and
`199 to group B. The response rate is summarised in table II. For
`group B the best results with either hormone treatment or cytotoxic
`drugs were recorded. Patients achieving a partial remission with both
`treatments were counted only once. Among the premenopausal
`patients 46“,, had a partial remission in group A and 43% in group B.
`Among the postmenopausal women 409;, had a partial remission in
`group A and 33% in group B. A minor response was seen more often
`in group B than in group A (26% compared with 259;.
`in the pre—
`menopausal and 28% compared with 22% in the postmenopausal
`women).
`
`TABLE II—O-oerall response rate to concurrent (group A) or sequential (group B)
`hormone treatment and cytotoxic chemotherapy in premenopausal and post-
`menopausal women
`
`Treatment
`
`Partial
`Minimal
`Menopausal
`No of
`remission
`response
`Total
`
`status
`patients
`(m)
`("0)
`(‘70
`Premenopause
`55
`25 (46)
`14 (25)
`39 (71)
`Concurrent
`54
`23 (43)
`14 (26)
`37 (69)
`Sequential
`Postmenopause
`152
`60 (40)
`33 (22)
`93 (61)
`Concurrent
`
`
`145 48 (33) 41 (28)Sequential 89 (61)
`
`
`
`The therapeutic results of hormone treatment alone were evaluable
`only among the patients who received delayed chemotherapy (group
`B). After oophorectomy 12 of 54 (22%) premenopausal patients had
`a partial remission. In a further eight (159-5) cases a minor response
`was seen. Among the 145 postmenopausal patients, treatment with
`tamoxifen produced a partial response in 25 (17%) women but a
`minor response in 21 (14%). The median time to disease progression
`after a partial remission or a minor response was 125 months in
`premenopausal women after oophorectomy and 10-7 months in
`postmenopausal women treated with tamoxifen. Forty—two per cent
`of those patients in group B who responded to hormone treatment
`had a second cytotoxic drug—induced tumour regression whereas 52%
`of the patients who did not respond to hormone treatment showed a
`remission with chemotherapy. The median time to disease progression
`again after a second cytotoxic drug-induced tumour regression was
`12-5 months for patients responding to hormone treatment and 7-5
`months for those showing disease progression with hormone treatment
`(p=0-006). The median time to disease progression was similar for
`all three cytotoxic drug regimens: 19-6 months after a partial remission
`for patients receiving concurrent hormone treatment and chemotherapy
`(group A) and 125 months, from the start of chemotherapy, for the
`same result to be achieved with delayed chemotherapy (group B)..
`Figures 1 and 2 represent the survival curves for the premenopausal
`and postmenopausal patients in both groups. Among premenopausal
`patients the median survival time was 253 months for group A and
`210 months for group B (p=0-29). Among postmenopausal patients
`the median survival time was 23-7 months for group A and 275
`months for group B (p=O-17). Figure 3 represents survival correlated
`with the overall therapeutic result; the median survival
`time was
`longer than 41 months for patients with a partial remission, less than
`seven months for those with progressive disease, and 23 and 21 months
`respectively for patients with a minor response and no change (partial
`remission vs minor response +no change 115 progressive disease:
`p < 00001).
`
`6 c
`
`ontralateral nodal metastases only, with a free interval between
`mastectomy and diagnosis of the first metastasis of at least two years;
`(b) boney metastases only, irrespective of the free interval; and (c)
`no more than two of the following: (i) lung or liver metastases (not
`both) with a free interval of at least four years; (ii) an isolated boney
`metastasis with a free interval of at least two years; (iii) skin metastases
`or an ipsilateral malignant pleural effusion with a free interval of at
`least two years or both; and (iv) ipsilateral nodal metastases and a
`free interval of at least two years.
`the remaining patients.
`High-risk category—This included all
`Hormone receptors were not considered, since their determination
`was generally possible only towards the end of the accrual period.
`
`RANDOMISATION
`
`After stratification patients were randomised to treatment groups
`A (concurrent hormone treatment and chemotherapy) or B (sequential
`hormone treatment and chemotherapy). Premenopausal women
`underwent oophorectomy and postmenopausal patients received 20
`mg tamoxifen daily. In group A the patients received chemotherapy
`concurrently; in group B cytotoxic drugs were given only after 6-8
`weeks of hormone treatment except in cases of confirmed tumour
`regression, in which chemotherapy was begun later and only after
`the tumour had been reassessed. At the time of randomisation to the
`two treatment groups, patients were also randomly allocated to three
`different regimens representing minimal, conventional, and intensive
`cytotoxic treatment. The details of these three regimens and the
`results of the comparison among the three groups, showing significant
`differences in response rates but similar survival curves, have been
`published elsewhere.6 The two randomisation procedures yielded an
`equal number of patients in groups A and B receiving each of the
`different cytotoxic regimens.
`
`EVALUATION OF TREATMENT RESPONSE
`
`The distribution of the major prognostic factors among patients
`treated with concurrent (group A) or sequential (group B) drug and
`hormone treatments is shown in table I. The non-evaluable cases (30
`
`TABLE I—Major prognostic factors in patients receiving
`hormone treatment and cytotoxic drugs either concurrently
`(group A) or sequentially (group B)
`
`.
`.
`Characteristics
`
`Treatment group
`A
`B
`
`575
`26-5
`27
`73
`25
`75
`2‘13
`
`58-5
`23-5
`27
`73
`24
`76
`215
`
`Median age (years)
`Median free interval (months)
`Premenopausal (9..) (n = 109)
`Postmenopausal (“0) (n = 297)
`High-risk category (",0) (n = 306)
`Low-risk category (°;,) (n = 100)
`Mean No of metastatic lesions
`Site of metastases (70‘:
`9
`8
`(a) Local
`18
`17
`Skeletal
`2
`3
`Local + pleura
`20
`15
`Local + skeletal
`9
`12
`Visceral + local
`31
`33
`Visceral + skeletal
`11
`12
`Visceral only
`12
`18
`(b) Liver
`40
`41
`Lung
`9
`6
`Local + soft tissue
`39
`31
`Bone
`
`
`3Others l
`
`.
`
`‘All patients are accounted for in both groups (a) and (b).
`
`in group A, 28 in group B) and the reasons for their exclusion from
`the analysis were evenly distributed. For the evaluation of the
`therapeutic result the following categories were used : partial remission,
`minor response, no change, and progressive disease. A partial remission
`corresponded to a decrease of more than 50% in the sum of the
`products of the two largest diameters of all measurable lesions. In the
`case of osteolytic metastases either a complete recalcification or a
`partial recalcification indicated by a decrease in size were required.
`A partial remission had to last at least two months. No change meant
`that tumour size remained unchanged or the variation was less than
`25%. A minor response was defined as clear cut tumour shrinkage,
`
`

`

`BRITISH MEDICAL JOURNAL
`
`VOLUME 286
`
`1 JANUARY 1983
`
`The risk category, the free interval, and the localisation and number
`of metastatic sites had a statistically significant effect on survival. A
`multifactorial analysis correlating these prognostic factors with the
`two different
`therapeutic approaches failed to show statistically
`significant differences in most instances. The survival period tended to
`be consistently longer with concurrent chemotherapy in patients with
`a more aggressive disease (that is, a shorter free interval and less
`favourable pattern of metastatic lesions). Patients with a less aggressive
`disease, however (that is, longer free interval and more favourable
`metastatic sites) showed a similar not statistically significant tendency
`to live longer with sequential chemotherapy. Only in two subgroups
`was there a statistically significant difference in survival. Patients in
`the age group 40-45 years had a median survival time of 43-1 months
`in group A and 18 months in group B (p < 005). Among the 80 post—
`
`10
`
`08
`
`0-6
`
`0'4
`
`Probability of
`survtval
`
`0'2
`
`p:0 294
`
`36
`Months
`FIG l—Survival curve for premenopausal patients receiving concurrent
`( - "
`) or sequential chemotherapy (.— 0) after oophorectomy.
`
`12
`
`24
`
`48
`
`60
`
`Probability of
`survival
`
`10
`
`0-8
`
`0'4
`
`0 2
`
`p: 0168
`
`12
`
`24
`
`36
`
`48
`
`60
`
`Months
`
`FIG 2—Survival curve for postmenopausal patients receiving tamoxifen and
`either concurrent ( If
`I‘) or sequential chemotherapy (O— Q).
`
`TABLE III—Median survival (in months) according to risk category and con—
`current (group A) or sequential (group 8) treatment with hormone and cytotoxic
`chemotherapy
`
`Treatment group
`Risk category
`Statistical
`
`A
`B
`significance
`Premenopausal women
`Low-risk
`High-risk
`Postmenopausal women
`Low-risk
`High«risk
`
`20
`209
`40
`227
`
`NS
`NS
`p = 00034
`NS
`
`26-6
`24-2
`21 -8
`23-7
`
`NS , not significant
`
`Probability of survival
`
`12
`
`24
`
`36
`Months
`
`48
`
`60
`
`
`FIG 3—Survival curve of all patients in relation to therapeutic result: partial
`remission (Q—Q), minor response (C— 0), no change (A
`A),
`progressive disease (A— A).
`
`Probability of
`survival
`
`0-8
`
`06
`
`0-2
`
`04
`
`12
`
`24
`
`36
`Months
`FIG 4—Survival curve for postmenopausal
`low—risk patients receiving
`
`tamoxifen and either concurrent (0—0) or sequential chemotherapy
`(<'
`“l
`
`48
`
`60
`
`menopausal patients in the low-risk category, those receiving delayed
`chemotherapy had a median survival of 40 months and those receiving
`simultaneously tamoxifen and chemotherapy 21 8 months (p = 00034).
`These survival curves are represented in fig 4. The median survivals
`according to menopausal status within the risk categories of the other
`subgroups of patients are summarised in table 111.
`
`Discussion
`
`The best therapeutic approach to patients with metastatic
`breast cancer remains a matter of debate. It is well known that
`all effective hormone treatments will produce tumour regression
`in about one-third of patients. The response rate can only be
`increased if patients are selected according to one or more of
`the following criteria: content of hormone receptors of the
`tumour, well—defined
`favourable prognostic
`factors,
`and
`observed tumour regression due to previous hormone treatment.
`On the other hand the best regimens of cytotoxic drugs achieve
`tumour regression in 50-70% of patients, but only in-lO—15%
`will all measurable lesions completely disappear; remissions are
`here generally more short—lived than with hormone treatment.”
`The combined use of cytotoxic drugs and hormone treatment,
`the possibility of consolidating the achieved remission with
`radiotherapy (as in malignant lymphomas), and different very
`
`

`

`BRITISH MEDICAL JOURNAL VOLUME 286
`
`1 JANUARY 1983
`
`received the four-drug combination after primary or secondary
`failure of the combination without tamoxifen.17 Even if initial
`treatment with the four-drug combination produced a signifi—
`cantly higher response rate, survival was longer for patients
`treated initially with the three-drug combination and later by
`the same regimen supplemented with tamoxifen. This empha—
`sises again the poor correlation between differences in the
`response rate to primary treatment and eventual survival of
`patients with breast cancer and supports, as do our present
`findings, a sequential
`therapeutic approach as superior
`in
`postmenopausal patients. Since subsequent
`remissions are
`possible with later hormone and cytotoxic regimens, more
`detailed clinical studies are necessary to define the most appro-
`priate sequence of the various treatments available for post—
`menopausal patients with advanced breast cancer.
`
`We are grateful to Professor W H Hartmann, LICR Berne Branch,
`for his critical review, and to O Kraitrova, for her careful preparation
`of the manuscript.
`Correspondence should be addressed to Dr Franco Cavalli, Division
`of Oncology, Ospedale San Giovanni, 6500 Bellinzona, Switzerland.
`
`References
`
`‘ Henderson IC, Canellos GP. Cancer of the breast. The past decade._N
`Engl] Med 1980 ;302:17—30,78-90.
`3 Brunner KW, Sonntag RW, Alberto P, et al. Combined chemo- and
`hormonal therapy in advanced breast cancer. Cancer 1977;39:2923-33.
`3 Carter SK. The interpretation of trials: combined hormonal therapy and
`chemotherapy in disseminated breast cancer. Breast Cancer Research and
`Treatment l981;1:43—52.
`‘ Tormey DC, Falkson G, Crowley I, Falkson HC, Voelkel J, Davis TE.
`Dibromodulcitol and adriamycin itamoxifen in advanced breast cancer.
`Am}v Clin Oncol 1982;5233-9.
`5 Fey MF, Brunner KW, Sonntag RW. Prognostic factors in metastatic
`breast cancer. Am] Clin Oncol 1981 ,4:237—48.
`“Cavalli F, Beer M, Martz G, et al. Gleichzeitige oder sequentielle
`HormonOs’Chemotherapie sowie Vergleich verschiedener Polychemo-
`therapien in der Behandlung des metastasierenden Mammakarzinoms.
`Schweiz [Med Wochenschr l982;112:774~83.
`7 Kaplan EL, Meier P. Nonparametric estimation from incomplete
`observations. 7 Am Stat Assoc 1958;53:457—81.
`“ Peto R, Pike MC, Armitage P, el al. Design and analysis of randomized
`clinical
`trials requiring prolonged observation of each patient.
`II
`Analysis and examples. Br] Cancer 1977;35:1-39.
`" Legha S, Buzdar AU, Smith TL, et al. Complete remissions in metastatic
`breast cancer treated with combination drug therapy. Ann Intern Med
`1979,91 1847—52.
`'0 Buzdar A, Blumenschein G, Montague E, Powell K, Hortobagyi G, Yap
`H. Regional consolidative therapy following systemic chemotherapy in
`metastatic breast cancer. Proc Am Soc Clin Oncol 1982;] :74.
`" Tormey DC, Kline J, Davis TE, et al. Short
`term intensive chemo—
`hormonotherapy in metastatic breast cancer. Proceedings of the American
`Association for Cancer Research and the American Society of Clinical
`Oncology 1981;22:445.
`'3 Vogel C, Lefante J, East D, et al. Cyclophosphamide, adriamycin and
`5-fluorouracil alternating with a cycle-active regimen in metastatic
`breast cancer. A randomized Southeastern Cancer Study Group trial.
`Proceedings of the American Association for Cancer Research and the
`American Society of Clinical Oncology 1981;22:439.
`'3 Powles T], Coombes RC, Smith IE, et al. Failure of chemotherapy to
`prolong survival in a group of patients with metastatic breast cancer.
`Lancet l980;i:580-l.
`'4 Paterson AHG, Szafran O, Cornish F, Lees AW, Hanson J. Effect of
`chemotherapy on survival in metastatic breast cancer. Breast Cancer
`Research and Treatment 1981;]:357-63.
`'1" Ahmann DL, O’Connell JO, Haan RG, et al. An evaluation of early or
`delayed adiuvant chemotherapy in premenopausal patients with
`advanced breast cancer undergoing oophorectomy. N Eng! 3' Med
`1977 ,297 :356-60.
`"‘ Falkson G, Falkson HC, Glidewell O, Weinberg V, Leone L, Holland JF.
`Improved remission rates and remission duration in young women with
`metastatic breast cancer following combined oophorectomy and chemo—
`therapy. A study by Cancer and Leukemia Group B. Cancer 1979,43:
`2215-22.
`'7 Cocconi G, De Lisi V, Boni C, Mori P. CMF vs CMF plus tamoxifen (T)
`in postmenopausal metastatic breast cancer. A prospective randomized
`study. Proc Am Soc Clin Oncol 1982;] :75.
`
`(Accepted 29 September 1982)
`
`8 a
`
`ggressive chemotherapeutic regimens are presently being
`explored to improve these results.“”” At
`the same time,
`however, the overall impact of the use of multiple cytotoxic
`agents on the survival of most patients with advanced breast
`cancer has been questioned.” 1‘
`’
`Our results may partially support this assumption. In the
`analysis of the effect of cytotoxic drugs in our trial the statistically
`significant differences in the response rate with various cytotoxic
`regimens could only be marginally translated to the different
`survival curves.6 Differences in survival according to therapeutic
`result (fig 3) are of limited value in assessing the effect of
`treatment on survival. In fact some of the patients who responded
`might have survived almost as long without treatment, whereas
`in some patients who did not respond the treatment may have
`actually shortened their survival. At present probably only some
`subgroups of patients with advanced breast cancer will have
`their life significantly prolonged by chemotherapy.
`Our trial is the third to assess the effects of simultaneous
`
`compared with sequential use of combined hormone treatment
`and chemotherapy in premenopausal patients with metastatic
`breast cancer. To our knowledge, however, such a study has so
`far not been carried out in postmenopausal women. Our results
`for premenopausal women confirm the findings of the two
`previous reports.” ‘6 Overall, patients receiving cytotoxic drugs
`immediately after oophorectomy tended to live longer than
`patients for whom the onset of cytotoxic treatment was delayed;
`the difference, however, was not statistically significant. In all
`three trials a clear definition of the subgroups of premenopausal
`patients who would benefit from the concurrent use of both
`treatments has possibly been hampered by the difficulty in
`finding a sufficient number of suitable patients. Furthermore,
`the very similar survival data in our study for low-risk and high-
`risk cases brings into question the usefulness of this stratification
`in premenopausal women. Whereas in the two previous studies
`chemotherapy was given in cases in which the tumour had
`progressed after hormone treatment, in our trial cytotoxic drugs
`were also given to patients who showed no change with hormone
`treatment. The possibility that with a less prudent study design
`our differences in survival would have been more pronounced
`cannot be dismissed.
`Among the postmenopausal patients women receiving
`cytotoxic drugs only after treatment with tamoxifen had failed
`to produce or maintain measurable tumour regression survived
`consistently longer, even if not statistically significantly, than
`those receving tamoxifen and cytotoxic drugs simultaneously.
`For patients with a less aggressive tumour, the low-risk group,
`the difference was highly significant (fig 3). Interestingly, the
`median survival was very similar with both treatments among
`postmenopausal patients in the high-risk category (table III).
`In the analysis of the different subgroups of postmenopausal
`patients according to their prognostic factors (that
`is,
`free
`interval and number and localisation of metastatic sites) we
`were unable to define a group which could have benefited from
`concurrent treatment with tamoxifen and cytotoxic drugs. Our
`data suggest that postmenopausal women with metastatic breast
`cancer should probably be primarily treated by a carefully
`monitored trial of hormone treatment and not initially with
`cytotoxic drugs, which in older patients can have unpleasant
`side effects. It is, perhaps, noteworthy that among the post-
`menopausal women the longest median survival was recorded
`for patients treated sequentially with the least intensive regimen
`of cytotoxic drugs.6
`In our previous trial only a subgroup of patients receiving
`simultaneously cytotoxic drugs and oestrogens lived longer than
`patients treated with cytotoxic drugs alone.2 In a more recent
`and careful study of simultaneous treatment with cytoxan,
`methotrexate, fluorouracil, and tamoxifen in postmenopausal
`women compared with cytoxan, methotrexate, and fluorouracil
`alone, patients treated with the three drugs alone subsequently
`
`