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ASCO 1999: Critical Commentaries |
Massachusetts General Hospital, Boston, Massachusetts, USA
Correspondence: Irene Kuter, M.D., D.Phil., Massachusetts General Hospital Cancer Center, Hematology-Oncology Department, 100 Blossom Street, Cox 640, Boston, Massachusetts 02114-2617, USA. Telephone: 617-726-8743; Fax: 617-724-3166; e-mail: Kuter.Irene{at}MGH.Harvard.edu
Although there was no major breakthrough reported at this year's meeting to compare with the report last year on the efficacy of Herceptin, there were a number of quality presentations that will contribute substantially to clinical practice. The plenary session, in which substantial information was presented regarding the efficacy (or lack thereof) of high-dose chemotherapy for patients with metastatic breast cancer or high-risk primary disease, attracted the highest attendance. In the session on systemic therapy, the emphasis was on improving chemotherapy regimens either with regard to efficacy or with regard to toxicity. The session on local-regional therapy focused on the use of hormonal therapies in the adjuvant setting for premenopausal women. Finally, there was a brief update on the prevention trials.
Role of High-Dose Chemotherapy/Stem Cell Transplantation in Breast Cancer
The plenary session included four abstracts addressing the role of high-dose chemotherapy/stem cell transplantation for the treatment of breast cancer. One of these involved women with metastatic disease. The other three were in the setting of high-risk primary disease.
Phase III Randomized Trial of High-Dose Chemotherapy (HDC) and
Stem Cell Support (SCT) Shows No Difference in Overall Survival or
Severe Toxicity Compared to Maintenance Chemotherapy with
Cyclophosphamide, Methotrexate and 5-Fluorouracil (CMF) for Women with
Metastatic Breast Cancer Who Are Responding to Conventional Induction
Chemotherapy: The "Philadelphia" Intergroup Study
(PBT-1).
EA Stadtmauer, A O'Neill, LJ Goldstein, P
Crilley, KF Mangan, JN Ingle, HM Lazarus, J Erban, C Sickles, JH
Glick. Southwest Oncology Group (SWOG) and Eastern Cooperative
Oncology Group (ECOG). (Abstract 1)
Study Design and Results
The first plenary presentation was by Dr. Stadtmauer, who
reported on the "Philadelphia" Intergroup Study
(PBT-1). This trial looked at the role of high-dose chemotherapy with
STAMP V (cyclophosphamide 1,500 mg/m2, thiotepa 125
mg/m2, carboplatin 200 mg/m2 for four days,
followed by stem cell transplantation) compared with
"maintenance CMF" (given for up to two years, with a
median of eight cycles) as consolidation treatment after induction
chemotherapy with either CMF or CAF
(cyclophosphamide/Adriamycin/fluorouracil) for four to six cycles in
women with stage IV breast cancer. Five hundred fifty-three women were
enrolled. There was no significant difference in response rates to
induction CMF or CAF (57% overall response, with 11% complete response
[CR]). Of the 296 responders, 67% were randomized to bone marrow
transplantation versus CMF. With a 37-month follow-up, median survival
is 24 months in the transplant group and 26 months in the CMF group
( Table 1), with no
difference in the subsets who were randomized in CR or partial
response (PR). There was no difference in time to progression (9.6
months in the transplant group, 9.0 months in the CMF group) with no
benefit to bone marrow transplantation in any subset analyzed. There
was no major difference in lethal toxicity (one death in the
transplant group, none in the CMF group) but a substantial increase in
grade 3 toxicities in the transplant group. The authors concluded that
there is no demonstrable benefit for STAMP V consolidation with bone
marrow transplantation over maintenance CMF in patients with
metastatic breast cancer responding to standard chemotherapy, and its
failure could not be ascribed to excess toxic deaths in the transplant
arm.
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Study Design and Results
The second plenary presentation was from Dr. Peters, who reported the long-awaited results of the trial run by CALGB/SWOG/NCIC (CALGB 9082) to examine the possible benefit of high-dose consolidation in the adjuvant setting for women with primary breast cancer (stage II or IIIA) with 
10 involved axillary lymph nodes. This trial was written in 1990 after a pilot protocol (CALBG 8782) had yielded promising results [1]. Patient accrual began in 1991 and ended in 1998. In this trial 884 women were given adjuvant CAF for four cycles and then via randomization 785 were subsequently assigned to either high-dose (HD) CPB (cyclophosphamide 5,625 mg/m2, cisplatin 165 mg/m2, BCNU 600 mg/m2) and bone marrow transplantation or lower (intermediate dose [ID], nontransplant) doses of the same drugs (cyclophosphamide 900 mg/m2, cisplatin 90 mg/m2, BCNU 90 mg/m2). The primary endpoint was event-free survival. The median number of axillary lymph nodes was 14 (range 10-52). At 42 months of follow-up, there is a trend (but no significant difference) in event-free survival favoring the high-dose arm (78% in HD arm, 68% in ID arm; Table 1). Furthermore, there was a surprisingly high mortality of 7.4% in the HD arm (3% in the first 100 days, the rest later in the first year). There was no significant difference in overall survival in the two arms (78% in HD arm, 80% in ID arm at 37 months). Despite the negative results, Peters maintained an optimistic attitude toward future trials. He conceded that the mortality rate in the HD group was excessive, and maintained that the lower relapse rate in the HD group held promise that a less toxic regimen might still yield improved results compared with standard therapy in the adjuvant setting.
Results from a Randomized Adjuvant Breast Cancer Study with
High-Dose Chemotherapy with CTC, Supported by Autologous Bone Marrow
Stem Cells Versus Dose Escalated and Tailored FEC Therapy
The Scandinavian Breast Cancer Study Group 9401. (Abstract 3)
Study Design and Results
The second report of a study of high-dose chemotherapy in the adjuvant setting was by the Scandinavian Breast Cancer Study Group. The SBG 9401 study accepted women with primary breast cancer who were under 60 years old and satisfied the requirement that they had a 70% relapse risk within five years using standard adjuvant therapy. Women with eight or more positive axillary lymph nodes constituted the majority of the eligible women. Patients were all treated with FEC initially, and half were randomized to high-dose consolidation with bone marrow transplantation, but in the nontransplant group the cycles were dose-adjusted by preset guidelines based on leukocyte and platelet counts during treatment to achieve a standard degree of hematological toxicity. Standard FEC was defined as 5-FU 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 given i.v. every three weeks. In the nontransplant arm, nine cycles of "tailored" FEC were given (with G-CSF and prophylactic ciprofloxacin). Delivered doses per cycle ranged from 300-600 mg/m2 of F, 38-120 mg/m2 of E, and 450-1,800 mg/m2 of C. In the transplant arm, two cycles of standard FEC were given, but in the third cycle the dose of cyclophosphamide was doubled (to 1,200 mg/m2) to mobilize stem cells. Patients were then given high-dose CTCb chemotherapy (cyclophosphamide 6 g/m2, thiotepa 0.5 g/m2, and carboplatin 0.8 g/m2) with stem cell support. Five hundred twenty-five patients were accrued. At follow-up after two years there is no difference in relapse-free survival in the two arms of the study, with 35% relapse in the transplant arm and 25% relapse in the tailored FEC arm. Overall survival was also similar, with 21% deaths in the transplant arm and 18% in the tailored FEC arm. The authors concluded that there is no evidence to support the hypothesis that transplantation improves outcome in these high-risk women. Curiously, in this trial the total dose intensity of the FEC drugs in the "standard" arm of FEC for nine cycles was higher than that in the transplant arm. This is reflected in the high rate of myelodysplastic syndrome (MDS) (three cases) and acute myelogenous leukemia (AML) (five cases) in this arm compared with none after bone marrow transplantation.
Randomized, Controlled Trial of High Dose Chemotherapy
(HD-CNVp) versus Standard Dose (CAF) Chemotherapy for High Risk,
Surgically Treated, Primary Breast Cancer
WR Bezwoda. (Abstract 4)
Study Design and Results
In the final plenary presentation, Dr. Bezwoda presented the South African trial of high-dose chemotherapy compared with standard dose chemotherapy in the adjuvant setting for high-risk primary breast cancer. Women with 10 positive axillary lymph nodes were eligible, as were women with seven to nine positive lymph nodes and T3 tumors with at least one other poor prognostic factor (estrogen receptor [ER] negative tumors or two or more affected first-degree relatives). The standard dose chemotherapy in this trial was six cycles of CAF (cyclophosphamide 600 mg/m2, doxorubicin 50 mg/m2 [or 4' epiadriamycin, 70 mg/m2] and 5-FU 600 mg/m2) given every 21 days for six cycles. In this trial the transplantation arm was unusual in three ways: first of all, nonconventional drugs were used (cyclophosphamide 4.4 gm/m2, mitoxantrone 45 mg/m2, and VP-16 1.5 gm/m2). Secondly, the high-dose treatment was given twice (six weeks apart), each preceded by a single, high-volume peripheral stem cell collection. Thirdly, no standard induction therapy was given prior to the high-dose chemotherapy. One hundred fifty-four patients were entered into the study and the results are reported at a median follow-up of more than five years (277 weeks). To date there have been 76 relapses, 21 (27%) in the high-dose arm, and 55 (71%) in the standard arm ( Table 1). This is a statistically significant result showing a benefit to the transplantation arm. There is also a statistically significant difference in overall survival favoring the high-dose chemotherapy group (figures not given).
Commentary
Although it would be hard to leave the plenary session and remain optimistic about the role of high-dose chemotherapy in breast cancer either in the metastatic or adjuvant setting, it may be instructive to scrutinize more carefully the South African study, which was the only one to show a benefit to the high-dose arm. This was a small trial and, although the result may be aberrant and certainly would need to be corroborated by other groups before being accepted, it is interesting to note that the control arm delivered a more standard regimen than the other two studies. Patients in this control arm actually behaved as might have been predicted by historical controls, while patients in the high-dose arm relapsed at a similar rate as those in the high-dose arm in the Peters study. There is a possibility that the intermediate dose alkylating agent treatment in the Peters study and the dose escalation of FEC in the Scandinavian trial improved outcome in the control arm of both of these studies to the extent that the addition of high-dose chemotherapy made no additional impact. In other words, the nontransplant arm in these two studies did much better than expected. If Peters is right, longer-term follow-up of the CALGB trial may show a superiority emerge favoring the transplant arm, since mortality in the transplant arm early on was exaggerated by the toxicity of the regimen, but it challenges credibility to expect that the arms will separate to a significant degree. It will be difficult to justify future trials comparing STAMP style regimens to standard therapy after induction chemotherapy in either the metastatic or adjuvant setting. The Bezwoda trial needs to be corroborated. If this can be done, it may tell us something exciting about how to use high-dose chemotherapy in the treatment of breast cancer. It may be that induction therapy, which may be simply giving prolonged suboptimal cell kill, is neither necessary nor desirable prior to high-dose therapy and that the selection of resistant cells that occurs during induction negates its value in decreasing the tumor burden prior to high-dose consolidation.
Advances in Treatment of Metastatic Breast Cancer
The oral presentations on systemic treatment for advanced disease began with several papers on Herceptin (trastuzumab, a chimeric monoclonal antibody against the HER-2 receptor).
Overall Survival (OS) Advantage to Simultaneous Chemotherapy
(CRx) Plus the Humanized Anti-HER2 Monoclonal Antibody Herceptin (H)
in HER2-Overexpressing (HER2+) Metastatic Breast Cancer (MBC)
L Norton, D Slamon, B Leyland-Jones, J Wolter, T Fleming, W
Eirmann, J Baselga, J Mendelsohn, A Bajamonde, M Ash, S
Shak. Multinational Herceptin Investigator Group. (Abstract
483)
Study Design and Results
At ASCO in 1998, the results of a phase III trial for patients with newly diagnosed metastatic breast cancer overexpressing HER-2 had been presented [2]. In this trial women were randomized to AC (doxorubicin and cyclophosphamide) chemotherapy or AC plus Herceptin (H), or, if they had received prior anthracycline in the adjuvant setting, to Taxol (T) or T plus Herceptin. The study showed a clear advantage to combination treatment with Herceptin and chemotherapy over herceptin alone, both in time to progression, response rates, and percent of patients who had not progressed at one year. The benefit of adding Herceptin to chemotherapy had been most pronounced in the Taxol subset, where response to Taxol had been increased from 16% to 42% with the addition of Herceptin. These results had been presented to the Food and Drug Administration (FDA), resulting in the approval last year of Herceptin to treat metastatic breast cancer. This year, Dr. Norton from Memorial Sloan-Kettering presented the survival data from this phase III trial. Despite a crossover design that allowed patients initially assigned to chemotherapy alone to receive subsequent Herceptin when they progressed, a survival advantage was seen favoring the women who were randomized to chemotherapy and Herceptin over those initially receiving chemotherapy alone. At 25 months of follow-up median overall survival is 25.4 months in the chemotherapy plus Herceptin group compared with 20.9 months in the chemotherapy alone group, with a relative risk of death of 0.77 in the chemotherapy plus Herceptin group. The overall survival advantage of adding Herceptin was seen both in the AC group (33.4 months with AC plus H, 24.5 months with AC alone) and in the Taxol group (22.1 months versus 18.4 months, respectively). Cardiac dysfunction was seen more commonly with AC plus H (19%) than with Taxol plus H (4%), but overall the benefit/risk ratio favors adding Herceptin to chemotherapy for HER-2 positive metastatic breast cancer. This is one of the few studies that show a survival advantage for a regimen that adds more drugs to the initial treatment compared with using the same drugs in sequence, suggesting the possibility of more than additive effects.
Weekly (W) Herceptin (H) + 1 Hour Taxol (T): Phase II Study
in HER2 Overexpressing (H2+) and Non-Overexpressing (H2-) Metastatic
Breast Cancer (MBC)
M Fornier, AD Seidman, FJ Esteva, M Theodoulou, M Moynahan, V
Currie, M Moasser, N Sklarin, T Gilewski, A Surbone, C Denton, D
Bacotti, J Wiley. (Abstract 482)
Study Design and Results
The other Herceptin presentation from Memorial Sloan-Kettering and
M.D. Anderson Cancer Centers reported a study of Herceptin (which is
given weekly) given together with weekly Taxol. Seidman et
al. had previously reported weekly Taxol to be very active and
well tolerated in metastatic breast cancer [3]. Given the synergy between Taxol (given
every three weeks in the seminal phase III study) and Herceptin, it
was natural to look at the weekly administration of both agents
together. In this trial 42 patients with metastatic breast cancer were
given weekly Taxol (90 mg/m2) over 1 h, followed by
Herceptin (2 mg/kg over 30 min), both intravenously (loading dose of
Herceptin of 4 mg/kg was given over 90 min on week 1). The majority of
patients had had at least one prior chemotherapy regimen. Twenty-three
out of 36 evaluable patients have responded (64%). Of patients with
HER-2 positive tumors, 20 out of 28 (71%) have responded. Of patients
with HER-2 negative tumors, 3 out of 8 (38%) have responded. There is
no reason to believe, on the basis of preclinical trials, that HER-2
negative tumors will be affected by Herceptin and most likely this
response rate represents the effect of Taxol alone. Peripheral
neuropathy was the major dose-limiting toxicity. There was no
significant change in left ventricular ejection fraction after 8 or 16
cycles. Weekly Herceptin with Taxol therefore seems both active and
safe in the treatment of metastatic breast cancer with low
morbidity.
A Phase III Trial Comparing Doxorubicin (A) and Docetaxel (T)
(AT) to Doxorubicin and Cyclophosphamide (AC) as First Line
Chemotherapy for MBC
JM Nabholtz, G Falkson, D Campos, J Szanto, M Martin, S Chan, T
Pienkowski, WR Bezwoda, J Zaluski, T Pinter, M Krzakowski, D Vorobiof,
R Leonard, I Kennedy, N Azli, M Murawski, A Riva, P
Pouillart. International TAX306 Study Group. (Abstract 485)
Study Design and Results
Dr. Nabholtz presented the results of a phase III trial for first-line treatment of metastatic breast cancer. Four hundred twenty-nine patients were accrued to a study in which patients were randomly assigned to treatment with doxorubicin and Taxotere (AT, 50/75 mg/m2) or doxorubicin and cyclophosphamide (AC, 60/600 mg/m2) given once every three weeks without prophylactic G-CSF or antibiotics, for a maximum of eight cycles. Over half the patients had a cumulative doxorubicin exposure of >360 mg/m2. The response rate was 54% (7% CR, 47% PR) in the AC group, and 71% (11% CR, 60% PR) in the AT group. There was a statistically significant improvement in time to progression on the AT arm. In the AC arm more patients had a drop in left ventricular ejection fraction (LVEF) of >20% (10% AC, 5% AT), >30% (6% AC, 1% AT) or clinical congestive heart failure (CHF) (4% AC, 3% AT). There were more instances of fever and neutropenia (33%) in the AT arm compared with the AC arm (10%) and more grade IV infections (7% AC, 1% AT) but no infectious deaths. The AT regimen may therefore be superior to AC in terms of response rate and time to disease progression with less cardiac morbidity. However, since the two groups were not well balanced for febrile neutropenia it is possible that adjustment of the dose intensity might negate this advantage. Nevertheless the safety of the AT combination merits its testing in the adjuvant setting.
Phase III Study of Liposome-Encapsulated Doxorubicin (TLC
D-99) Versus Doxorubicin (DOX) in Combination with Cyclophosphamide
(CPA) in Patients (PTS) with Metastatic Breast Cancer (MBC)
G Batist, SC Rao, G Ramakrishnan, J Gutheil, T Guthrie, L
Welles, Y Park, and the TLC D-99 Study Group. (Abstract 486)
Study Design and Results
Another phase III study looked at the comparison of liposome-encapsulated doxorubicin (TLC D-99) compared with doxorubicin in combination with cyclophosphamide as first-line therapy for patients with metastatic breast cancer. Both groups received cyclophosphamide at 600 mg/m2 and either doxorubicin, 60 mg/m2, or the liposome-encapsulated doxorubicin, TLC D-99, 60 mg/m2. Patients could be enrolled after prior doxorubicin therapy in the adjuvant setting as long as they had received less than 300 mg/m2 of doxorubicin. There were no differences in the disease response rates (43% in each arm) or in the overall survival. However, there was a significant difference in cardiac toxicity. Cardiac dysfunction was defined as a drop in LVEF of 20 points to a value 50%, or a 10 point drop in ejection fraction to a value <50%, or clinical congestive heart failure. In the doxorubicin arm 32% of patients experienced a cardiac adverse event, whereas only 9% did in the TLC D-99 arm. Five percent of patients in the doxorubicin group developed congestive heart failure and none in the TLC D-99 group. There was also a trend to less neutropenia, less mucositis, and less diarrhea in the TLC D-99 group compared with the doxorubicin group. The TLC D-99/cyclophosphamide combination thus seems to be as effective as doxorubicin/cyclophosphamide with significantly less cardiotoxicity and less myelosuppression.
Commentary
Since the first results of the phase III trial of chemotherapy with or without Herceptin for first-line treatment of HER-2 positive breast cancer were announced at ASCO last year [2], there has been an enormous interest in the use of Herceptin, and adjuvant trials are now in progress. The cost is substantial (drug cost alone for one weekly treatment of a 65 kg patient is at least $600), the need for weekly infusions inconvenient, and the duration of therapy undefined. There has been a bias among oncologists that since increasing response rates with the use of more aggressive treatments has not led to increased survival benefits, it makes sense to use the available treatment options in sequence rather than in combination. Where to put Herceptin in the sequence has just been made a little easier by the report from Dr. Norton (Abstract 483) that despite the crossover design allowing later use of Herceptin in the phase III trial, patients given Herceptin "up front" with their first chemotherapy have a clear survival advantage. This is likely to establish the use of Herceptin as part of first-line therapy as the standard of care for patients with HER-2 overexpressing breast cancers.
Given the cardiac toxicity debate surrounding the concomitant administration of doxorubicin with Herceptin, the increased efficacy and lowered toxicity of weekly Taxol versus Taxol given every three weeks, and the 71% response rate reported here by Dr. Seidman (Abstract 482) for women with HER-2 overexpressing breast cancer, weekly Taxol plus Herceptin seems likely to become a strong favorite for first-line treatment of newly diagnosed metastatic disease for this group of women (especially those who have already been treated with doxorubicin in the adjuvant setting). The low toxicity profile (mild neuropathy and partial alopecia in most women are the most common side effects) and safety (so far no significant cardiac toxicity seen) make it an especially appealing regimen.
While the addition of Herceptin to Taxol is moving into adjuvant trials, so are the doxorubicin/taxane combinations. The data presented in Abstract 485, while not totally convincing for improved efficacy of doxorubicin/Taxotere (AT) over doxorubicin/cyclophosphamide (AC) because of higher rate of fever and neutropenia in the AT arm, at least establishes its excellent efficacy in the metastatic setting (similar to that of doxorubicin/Taxol), thus justifying its testing in the adjuvant setting in trials already underway. It is notable that even with more fever and neutropenia in the AT arm, cardiac toxicity was less than in the AC arm. With the results last year [4] from the CALGB showing AC followed by Taxol is more effective than AC alone in the adjuvant setting, the race is on to find the optimal way of sequencing cyclophosphamide, doxorubicin, and the taxanes in the adjuvant setting.
That TLC D-99 with cyclophosphamide is equally efficacious as doxorubicin and cyclophosphamide with less cardiac, bone marrow, and gastrointestinal toxicity makes this liposomal doxorubicin a winner when the focus is on patients' quality of life. If TLC D-99 is approved by the FDA this year, as appears likely, it remains to be seen whether its cost will prevent its widespread use in place of doxorubicin. Studies are now ongoing combining TLC D-99 with other drugs such as paclitaxel, docetaxel, and Herceptin.
Studies on the Role of Adjuvant Hormonal Therapy in Premenopausal Breast Cancer
There were a number of abstracts dealing with adjuvant hormonal therapy in premenopausal women with breast cancer. Two of these trials (Abstracts 248 and 250) compared hormonal treatment with CMF chemotherapy in ER+ breast cancer patients. A third paper (Abstract 249) looked at the addition of two different hormone treatments to CAF and yet another (Abstract 251) looked at tamoxifen versus Zoladex versus the combination compared with a control group.
Comparable Effect of Ovarian Ablation (OA) and CMF
Chemotherapy in Premenopausal Hormone Receptor Positive Breast Cancer
Patients (PRP)
B Ejlertsen, P Dombernowsky, HT Mouridsen, C Kamby, M Kjaer, C
Rose, KW Andersen, MB Jensen, NO Bengtsson, J Bergh. (Abstract
248)
Study Design and Results
Dr. Ejlertsen reported on the results of a Swedish trial
(DBCG 89B) in which premenopausal women with primary breast cancer
(node positive or primary tumor >5 cm; ER+ or PR+) were treated
with either adjuvant CMF (600/40/600 i.v. every three weeks for nine
cycles) or ovarian ablation (OA; either surgical oophorectomy or
pelvic radiation). Seven hundred thirty-two patients were entered, and
at a median follow-up of 68 months there is no difference between the
groups in terms of disease-free survival (DFS) (67% OA, 66% CMF) or
overall survival (78% OA, 82% CMF; Table 2). There was no difference between the treatment
arms for women under or over the age of 45. Sixty-nine percent of the
patients who were given CMF developed amenorrhea for more than three
months compared with 98% of women treated with OA (one patient refused
OA). Subset analysis has not yet been done to see if patients who did
not achieve amenorrhea benefited equally from CMF.
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Study Design and Results
Dr. Jakesz presented the results of Trial 5 of the
Austrian Breast Cancer Study Group of adjuvant treatment of
premenopausal women with stage I/II breast cancer. Patients with ER+
and or PR+ tumors were randomized to treatment with either CMF
(600/40/600 i.v. on days 1 and 8 for six cycles) or combination
endocrine therapy (tamoxifen 20 mg daily for five years plus goserelin
3.6 mg s.c. every 28 days for three years). One thousand forty-five
patients (24% of the eligible patients in Austria during the accrual
period) were entered on the study. Fifty-one percent of the patients
had a T1 lesion and 46% had negative lymph nodes. At a median
follow-up of four years, there was a statistically significant
decrease in recurrence in the tamoxifen plus goserelin group compared
with CMF (14% versus 18%) and also in local recurrence (3.1% versus
7.1%; Table 2). There
was a trend to lower death rate in the tamoxifen plus goserelin arm
compared with the CMF arm (5.6% versus 7.4%), and to a decrease in the
incidence of contralateral breast cancer (four cases versus nine
cases) but these differences were not statistically significant. At
this early follow-up, the combination of five years of tamoxifen and
three years of goserelin seems to be more effective than CMF as well
as less toxic.
Effect of Chemohormonal Therapy in Premenopausal, Node (+),
Receptor (+) Breast Cancer: An Eastern Cooperative Oncology Group
Phase III Intergroup Trial (E5 188, INT-0101).
N Davidson, A O'Neill, A Vukov, CK Osborne, S Martino, D
White, MD Abeloff for ECOG, SWOG, and CALGB. (Abstract 249)
Study Design and Results
Dr. Davidson (Abstract 249) next reported the results of
an ECOG phase III trial (Int 0101), which also looked at adjuvant
treatment of premenopausal women with ER+ breast cancer. There were
1,537 patients registered and assigned to either CAF alone
(cyclophosphamide 100 mg/m2 po daily for 14 days,
doxorubicin 30 mg/m2 and 5-FU 500 mg/m2 i.v. on
days 1 and 8 for six 28-day cycles) or CAF followed by five years of
goserelin (CAFZ) or CAF followed by both goserelin and tamoxifen for
five years (CAFZT). With six years of median follow-up, the
disease-free survivals for the CAF, CAFZ, and CAFZT groups are 67%,
70%, and 78%, respectively, and overall survival is 85%, 86%, and 86%,
respectively ( Table
2). The benefits of the hormonal therapies were most
marked in the <40-year-old subgroup: in these younger women both
the addition of Z to CAF, and the addition of T to CAFZ were found to
be helpful (five-year DFS: CAF 54%, CAFZ 65%, CAFZT 72%) whereas in
the >40-year-old subgroup the addition of Z to CAF was not
beneficial but the addition of T to CAFZ was (five-year DFS: CAF 72%,
CAFZ 73%, CAFZT 79%).
Zoladex® and Tamoxifen as Adjuvant Therapy in Premenopausal Breast Cancer: A Randomised Trial by the Cancer Research Campaign (CRC.) Breast Cancer Trials Group, the Stockholm Breast Cancer Study Group, the South-East Sweden Breast Cancer Group and the Gruppo Interdisciplinare Valutazione Interventi in Oncologia (GIVIO)
LE Rutqvist. (Abstract 251)
Study Design and Results
Finally, Dr. Rutqvist reported the results of a trial
conducted by the Cancer Research Campaign Breast Cancer Trials Group,
the Stockholm Breast Cancer Study Group, the South-East Sweden Breast
Cancer Group and the Gruppo Interdisciplinare Valutazione Interventi
in Oncologia. Premenopausal women with breast cancer were randomly
assigned after surgery to two years of tamoxifen (20 or 40 mg per
day), Zoladex (goserelin) 3.6 mg s.c. monthly for two years, both
tamoxifen and Zoladex, or neither. To maximize accrual, individual
centers were allowed to modify eligibility and treatment in a number
of ways (such as inclusion of only women with ER+ tumors or all women
regardless of ER status, or permitting the use of chemotherapy). There
were 2,631 patients entered. Forty-three percent received adjuvant
chemotherapy. Only the Zoladex data were presented. At a median
follow-up of almost five years there were 31% recurrences in the
control group and only 25% in the Zoladex group (relative risk (RR)
0.77; statistically significant), although survival was not
statistically different in the two groups (84% in the control group,
86% in the Zoladex group). A benefit from Zoladex was seen
irrespective of the use of concurrent adjuvant tamoxifen or adjuvant
chemotherapy. In addition, Zoladex decreased the rate of contralateral
breast cancer (4.4% in the control group, 2.4% in the Zoladex
group).
Commentary
These long-awaited results on hormonal therapies other than
tamoxifen in the adjuvant setting for premenopausal women with breast
cancer will no doubt change our approach to premenopausal breast
cancer. The meta-analysis of adjuvant trials published by the EBCTCG
in 1992 [5] had raised
the question of whether adjuvant oophorectomy might be as efficacious
as adjuvant chemotherapy for premenopausal breast cancer patients. A
randomized prospective Scottish trial published in 1993 [6] had shown that indeed
oophorectomy seemed equivalent to adjuvant CMF overall, and that in
the ER+ subgroup it appeared superior to CMF (though inferior in the
ER– subgroup). The larger Swedish trial presented here (Abstract
248) shows equal efficacy for ovarian ablation and adjuvant CMF for
premenopausal women with hormone receptor positive breast cancer. The
Austrian trial (Abstract 250) demonstrates that tamoxifen plus
goserelin is actually superior to CMF for hormone receptor positive
breast cancer. An added benefit was a decrease in contralateral breast
cancer and a decrease in local recurrence risk. However, since it is
accepted that at least part of the efficacy of chemotherapy in
premenopausal women is due to its toxic effect on the ovaries, an even
more important question is whether combinations of hormonal therapy
and chemotherapy are better than either alone. The meta-analysis
update [7] has already
answered the question in part: five years of tamoxifen is known to
benefit premenopausal women whose tumors are ER+, whether or not they
have had chemotherapy. The ECOG study (Abstract 249) verifies the
benefit of tamoxifen added to CAF (for recurrence but not for overall
survival) but, in addition, looked at whether ovarian ablation with
goserelin also improved outcome. Whereas the addition of Zoladex did
not increase benefit over CAF alone in women over 40 (these women are
commonly precipitated into menopause by adjuvant CMF), the addition of
Zoladex to CAF was beneficial in women under 40 (who are less commonly
rendered menopausal with CAF). The likely inference is that ovarian
ablation is desirable in women less than 40 years old, however the
ECOG study does not test whether CAFZT is better than CAFT, that is,
whether Zoladex adds any benefit in addition to tamoxifen. The study
reported by Rutqvist (Abstract 251) does attempt to answer
the question of whether Zoladex independently adds benefit. This is a
complex trial with different entry criteria depending on treatment
center. However, the data presented suggests that the use of Zoladex
for two years was of benefit, even in women who also had adjuvant
chemotherapy or adjuvant tamoxifen. Again, Zoladex was noted to
decrease the rate of contralateral breast cancer. It remains to be
seen, with more detailed follow-up, what is the additional benefit
over tamoxifen alone of two years of Zoladex (average cost of GnRH
agonist is $450 to $600 a month in the United States), and whether the
addition of Zoladex affects survival. Other intriguing questions
relate to whether patients under 40 who develop amenorrhea from
chemotherapy still benefit from Zoladex, and the duration of
amenorrhea required for optimal benefit (Transient? Two years? Five
years? Lifetime?). Finally, which premenopausal women could be safely
treated with Zoladex and tamoxifen alone in the adjuvant setting
(avoiding the toxic effects of chemotherapy) is a key question. A
study of (Zoladex plus tamoxifen) ± chemotherapy would be
ideal, but would be challenging to complete in the adjuvant setting
since the majority of premenopausal women are given chemotherapy at
this time.
Update on Prevention Trials
The final breast cancer session at the conference focused on the breast cancer prevention trials.
Average Annual Rates of Invasive and Noninvasive Breast
Cancer by History of LCIS and Atypical Hyperplasia for Participants in
the BCPT
DL Wickerham, J Costantino, B Fisher, M Kavanah, N
Wolmark. (Abstract 327)
Study Design and Results
Dr. Wickerham presented data from the NSABP P-1 trial
regarding the benefit of tamoxifen in reducing the risk of breast
cancer in women who entered the trial (comparing tamoxifen with
placebo) with a diagnosis of either atypical ductal hyperplasia (AH)
or lobular carcinoma in situ (LCIS). Overall, approximately 15% of the
women in the P-1 trial had either LCIS (6%) or AH (9%). Of note,
although 24% of all the women in the trial had no first degree
relative with breast cancer, this applied to 78% of the women with
LCIS and 56% of those with AH. The cumulative incidence of invasive
breast cancer in women with LCIS was 68.5/1,000 in the placebo group
and 25.4/1,000 in the tamoxifen group, a 56% reduction in breast
cancer incidence from tamoxifen. For women with AH the results were
even more striking: the cumulative rate of invasive breast cancer was
50.3/1,000 in the placebo group and only 5.1/1,000 in the tamoxifen
group, an 88% reduction in the incidence of breast cancer from taking
tamoxifen. These data suggest that tamoxifen substantially benefits
women with AH and LCIS: their benefit from tamoxifen was substantially
greater than the 49% reduction in the incidence of invasive breast
cancer seen for the entire tamoxifen group ( Table 3).
|
Study Design and Results
The other presentation addressing prevention was by Dr. Cauley on behalf of the MORE (multiple outcomes of raloxifene) study. In this study, 7,705 postmenopausal women aged <80 years with osteoporosis (previous vertebral fracture or T score 
2.5) were randomly assigned to raloxifene 60 mg daily, raloxifene 120 mg daily, or placebo. Mammograms were optional at one year and were accepted by 46% of the women. They were required at two and three years and were accepted by 88%. At a median follow-up of 40 months, there were 32 cases of breast cancer in the placebo group (five DCIS, 27 invasive cancers) and 22 in the raloxifene group (seven DCIS, 13 invasive cancers, and two awaiting review). Since there were twice as many women in the raloxifene groups as in the placebo group, this gives an RR of 0.35 of breast cancer in women given raloxifene. As in the NSABP P-1 study, the reduction was seen only in the ER+ invasive cancers (20 versus 4) and not in the ER– invasive cancers (four versus seven). As with tamoxifen, raloxifene significantly increased the risk of deep vein thrombosis (DVT) (38 versus 5 cases) and PE (17 versus 3 cases), however, no increased rate of endometrial cancer was seen in the raloxifene group compared to the control (0.5/1,000 compared with 0.7/1,000).
Commentary
We have been looking forward for a long time to the day when we will be able to prevent breast cancer. This last year with the release of the NSABP P-1 trial result [8] the first step was taken toward making prevention a reality. In the exciting update of the P-1 trial presented by Dr. Wickherham, a group of women is identified who have an even greater benefit from tamoxifen than the 49% reduction in breast cancer incidence seen in the group of high-risk women as a whole. It is well known that the diagnoses of atypical ductal hyperplasia (AH) and LCIS confer a high risk of future breast cancer. Fifteen percent of the women in the P-1 trial had either LCIS or AH. That there is such a profound benefit from tamoxifen in these two groups of women is very gratifying and is a powerful reason to prescribe tamoxifen for these women but also raises the question of whether there is a group of women (perhaps those with a family susceptibility) who do not benefit from the preventive action of tamoxifen. Only further trials and subset analysis will tell. As with the high-risk women in general, risk-benefit ratio will have to be assessed individually, but for most women with AH or LCIS the benefit is likely to outweigh the risk substantially.
The update in the MORE study continues to afford promise that raloxifene, like tamoxifen, may substantially decrease breast cancer risk. Furthermore, although raloxifene shares many of the other side effects of tamoxifen (hot flashes, thromboembolic complications) it is hoped that it will not increase the risk of endometrial cancer. A few cautionary notes need to be added, however. Women entering the MORE study were not assessed for, nor stratified by, breast cancer risk and so it cannot be assessed whether the control and raloxifene groups were equivalent with respect to breast cancer risk. It should also be borne in mind that these data, published recently [9], are preliminary and should not lead immediately to the recommendation that raloxifene be used currently to treat or prevent breast cancer. The current recommendations for clinicians with regard to the use of tamoxifen and raloxifene in the prevention of breast cancer are best summarized by the recently published ASCO guidelines [10]. These guidelines state:
Acknowledgments
We gratefully acknowledge the cooperation of Kirin Pharmaceuticals and Excerpta Medica, Japan.
References
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