Dr. Pritchard has received honoraria and served as a member of the advisory board for Aegera, AstraZeneca, Hoffmann-LaRoche, Novartis, Ortho-Biotech (advisory board only), Pfizer, Sanofi-Aventis, and YM Biosciences. She has also served as a consultant for AstraZeneca, Biomira, Hoffmann-LaRoche, Novartis, Ortho-Biotech, Pfizer, Sanofi-Aventis, and YM Biosciences and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, the National Cancer Institute of Canada, Novartis, Ortho-Biotech, Pfizer, Sanofi-Aventis, and YM Biosciences. Dr. Pritchard also has provided expert testimony for AstraZeneca and Sanofi-Aventis.
Combining endocrine agents with chemotherapy: Which patients and what sequence?†
Version of Record online: 10 DEC 2007
Copyright © 2007 American Cancer Society
Volume 112, Issue S3, pages 718–722, 1 February 2008
How to Cite
Pritchard, K. I. (2008), Combining endocrine agents with chemotherapy: Which patients and what sequence?. Cancer, 112: 718–722. doi: 10.1002/cncr.23189
Presented at Endocrine and Targeted Manipulation of Breast Cancer: Proceedings of the Sixth Cambridge Conference, Cambridge, Massachusetts, April 30-May 1, 2007.
- Issue online: 18 JAN 2008
- Version of Record online: 10 DEC 2007
- Manuscript Accepted: 11 OCT 2007
- Manuscript Revised: 4 OCT 2007
- Manuscript Received: 30 JUL 2007
- breast cancer;
- endocrine therapy;
- hormone therapy;
- aromatase inhibitors
In metastatic breast cancer, attempts to improve response to therapy by combining hormones and chemotherapy began in the 1970s. Since then, several randomized trials comparing single-agent hormone therapy or chemotherapy versus sequential combinations of these agents have been performed. In the majority of those studies, an increased response rate or an increased time to progression was observed when chemotherapy was added to hormone therapy or when hormone therapy was added to chemotherapy. However, in few of those trials was the increased response rate statistically significant or the response duration significantly prolonged, and no studies reported an improvement in overall survival. Furthermore, the studies did not make the correct comparisons of 1) hormone therapy alone followed by chemotherapy alone versus hormone therapy and chemotherapy given concurrently or 2) chemotherapy alone followed by hormone therapy versus concurrent chemotherapy and hormone therapy. To truly be advantageous, concurrent treatment should provide an increased response rate and response duration compared with the added or overall response rate and response duration of the same agents used sequentially. In the adjuvant setting, the timing and sequencing of hormone therapy and chemotherapy also has not been studied well. However, it has been accepted widely that adjuvant chemotherapy should be completed before beginning tamoxifen. No trials examining concurrent versus sequential treatment have been performed with hormone therapy and chemotherapy in the premenopausal setting or with aromatase inhibitors and chemotherapy in postmenopausal women. Considering the demonstrated importance of the timing of chemotherapy and tamoxifen in the postmenopausal setting, these questions should be explored further. Cancer 2008. © 2007 American Cancer Society.
It is believed that endocrine therapy acts by a cytostatic mechanism, which prevents cells from dividing. Other cells in the tumor die in the normal process of events; this, together with the cytostatic effect of endocrine agents, can produce shrinkage in tumor volume. Conversely, many chemotherapeutic agents work better in patients who have cells that are cycling at a more rapid rate or in whom higher proportions of cells are cycling actively. Thus, theoretically, it is quite likely that chemotherapy and hormones used together may act in an antagonistic fashion. Unfortunately, this hypothesis has not been explored well in either the metastatic or adjuvant setting.
Cytotoxics and hormones used concurrently may have effects that are additive, synergistic, or antagonistic. It is known that cytotoxics have certain endocrine effects, particularly in premenopausal women, in whom decreased estrogen levels and a subsequent increase in gonadotropin levels are observed. In vitro, tamoxifen acts synergistically with the antimetabolites methotrexate1 and 5-fluorouracil2 and with cyclophosphamide,3 but it acts antagonistically with melphalan.4 Progestins, androgens, and corticosteroids may cause leukocytosis and, thereby, may enable the administration of higher doses of cytotoxics,5 but there are now more specific methods to achieve this objective.
In assessing the combination of hormones with chemotherapy, as in assessing hormone combinations, it is important to recognize that an increased response rate is not necessarily the most important endpoint. To be truly advantageous, the combination should provide an increased response rate and response duration compared with the additive or overall response rate and response duration provided by the same agents used sequentially. Better yet, an overall survival advantage favoring the combination over the sequential use of the same agents would establish a real benefit. In addition, it must be recognized that the combination of 2 therapies, in particular, the addition of chemotherapy to hormone therapy, almost certainly will increase toxicity. Thus, careful assessments of quality of life should be performed before recommending a combination, particularly in situations in which no overall survival benefit has been demonstrated.
Attempts to improve response to therapy by combining hormones and chemotherapy began in the 1970s.6 Since that time, several randomized trials comparing hormone therapy alone with the same hormone agent plus chemotherapy7–15 have been performed. In the majority of those studies, an increased response rate was observed when chemotherapy was added to hormone therapy, but in only 2 studies was this increase statistically significant.8, 11 In another of those trials, response duration was prolonged significantly.15 In that study, patients were randomized after they had an initial response to oophorectomy to either receive or not to receive additional therapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Response duration was prolonged from 6 months to 17.5 months in the patients who received additional CMF (P = .05). In yet another study, overall survival was prolonged significantly. In that trial of diethylstilbestrol (DES) alone versus DES plus cyclophosphamide and 5-fluorouracil, the median survival of patients who received the combination was increased from 29 months to 72 months (P = .05).13
In addition, a large number of randomized trials in which chemotherapy alone was compared with the same chemotherapy plus hormone therapy have been reported.16–25 In 4 of those trials, the combination produced a significantly higher response rate than chemotherapy alone.16, 17, 22, 24 Careful examinations of additive sequential overall response rates to chemotherapy followed by the same hormone were not made in most of those trials. Consequently, appropriate comparisons between the reported response rates cannot be made. There was no trial noted in which the combination produced a statistically significant improvement in overall survival, although 1 trial produced a prolonged median survival that came close to significance (19 months vs 24 months; P = .07) when tamoxifen was added to CMF.22
One large Australian trial randomized women with metastatic breast cancer to receive either 1) tamoxifen, or 2) cyclophosphamide and doxorubicin (adriamycin) (CA), or 3) tamoxifen and CA concurrently. The initial response rate to tamoxifen alone (22%) was significantly lower than either CA (45%; P > .001) or tamoxifen plus CA (51%; P > .001). Patients receiving tamoxifen were treated with combined CA and 5-fluorouracil (CAF) at the time of disease progression, however, and additive response rates and overall survival on all study regimens were similar.8
Until chemotherapy and hormones used concurrently produce clear prolongation of survival or increased response rates and prolonged response durations accompanied by improved quality of life compared with the additive response rates and duration observed with the 2 modalities used sequentially, it appears prudent to use hormone therapy first, in appropriate patients, followed by chemotherapy when the tumor becomes resistant to sequential endocrine therapy.
For many years tamoxifen, in the adjuvant setting, was given concurrently with chemotherapy by many investigators and in the study protocols of several large breast cancer research groups.26 In addition, however, it was given sequentially with chemotherapy given first in other trial groups.27 Theoretical considerations took investigators and clinicians in 2 directions. It was believed that, if patients had tumors that were highly responsive to endocrine therapy, such as tumors with very high levels of estrogen receptors (ERs) and/or progesterone receptors (PgRs), that starting endocrine therapy sooner after surgery would be more efficacious. Conversely, because endocrine therapy is cytostatic and many chemotherapeutic agents work better in the cells that are dividing, giving hormones and chemotherapy simultaneously could be disadvantageous. Early data by Sertoli et al.28 suggested that, in postmenopausal women with positive ER status, giving tamoxifen concurrently was better; whereas, in women with low or no ER, giving chemotherapy first followed by tamoxifen was better. However, because of the small sample size of that trial, the results were not significant, only suggestive; and long-term follow-up did not confirm this finding.29 An additional study by Pico et al.30, 31 also suggested additional benefit for the sequential use of epirubicin and tamoxifen, but the benefit was not significant. On the basis of these theoretical considerations and tantalizing clinical hints, Albain et al. from the North American Intergroup designed a study in the late 1980s in the adjuvant setting that randomized 1477 postmenopausal women with ER-positive and/or PgR-positive breast cancer to receive 1) tamoxifen alone, 2) tamoxifen plus concurrent CAF, or 3) CAF followed by tamoxifen. Data from that trial indicated not only that CAF added to tamoxifen overall32, 33 but that giving CAF first followed by tamoxifen resulted in a nearly 50% fewer recurrences and deaths from breast cancer and concurrent therapy.34
Subsequent to that study, although there are few little additional data, most clinicians have adopted the approach of giving chemotherapy followed by tamoxifen. A few studies that were included in a meta-analysis in the Oxford Overview, however, suggested that there is no difference between the use of tamoxifen given concurrently with chemotherapy and given sequentially after chemotherapy, but the data are few; and, to date, detailed, formal comparisons between the trial designs have not been made?38 No such trials examining concurrent versus sequential treatment have been performed with the aromatase inhibitors (AIs) and chemotherapy in postmenopausal women, or with tamoxifen and chemotherapy, or with ovarian ablation or chemotherapy in the premenopausal setting.
In conclusion, considering the demonstrated importance of the timing of adjuvant chemotherapy and tamoxifen in the postmenopausal setting, it is clear that these questions should be explored further in the near future. It also may be possible that trials in which patients are treated simultaneously or sequentially with hormones and chemotherapy in the neoadjuvant setting may be helpful, particularly if surrogate endpoints could be used, such as measures of proliferation like Ki-67 or other surrogate markers.
The questions and discussion below follow from the oral presentation given at the Sixth Cambridge Conference on Endocrine and Targeted Manipulation of Breast Cancer and do not correspond directly to the written article, which is a more general review.
Dr. Paul Goss. Am I right to say that all of the National Surgical Adjuvant Breast and Bowel Project (NSABP) trials gave endocrine and chemotherapy concurrently?
Dr. Kathleen Pritchard. Until recently, all of the NASBP trials gave it concurrently, but they now give it sequentially. So, this is really an unexplored area. There is a proposal with the Intergroup to study this, and there is a big assumption that all the AIs are the same in relation to chemotherapy as tamoxifen, but there is no big randomized study looking at that. From what I have seen in looking at combining chemotherapy with endocrine therapy, there are no trials in premenopausal women and no studies with the AIs in adjuvant therapy. We also haven't addressed it in the metastatic or neoadjuvant setting in a long, long time. There isn't much that is recent on this whole subject. I think that, in metastatic disease, most of us would sequentially use chemotherapy drugs but first use endocrine therapy as long as we can, because it gives a better quality of life. In the adjuvant setting, I think we have accepted that chemotherapy followed by tamoxifen is the drill, but with very limited data, and we don't know about the AIs. I think this would be an area to look at.
Dr. Goss. In the premenopausal setting with the Tamoxifen and Exemestane Trial clinical trial design, one blockades the ovaries and gives the chemotherapy along with it. It's hard to imagine that the ovarian blockade is important though, because the chemotherapy is predominantly shutting down ovulation in any case. It's probably hard to argue that leaving women to ovulate normally at the outset of chemotherapy is likely a helpful strategy, because most if not all women have a substantial hit to their ovarian function while receiving chemotherapy.
Dr. Pritchard. They probably get a hit, but they may not get it until part way through the chemotherapy. And whether that's important or not important, we don't really know.
Dr. Goss. These 2 issues are not irrelevant. The concurrent endocrine therapy with radiation and chemotherapy is a really a very important discussion. You're giving therapy with significant toxicity and with long-term toxicity with long-term hope that, over 10 years, there will be a beneficial effect.
Dr. Pritchard. I think the Cancer Therapy Evaluation Program was very interested in this question of the timing of systemic endocrine therapy in combination with chemotherapy and with radiation. I personally think that the AI timing concurrent with chemotherapy and also concurrent with radiation are very important.
Dr. Jo Anne Zujewski. I do agree, and the only way this will get done is by an international collaboration. It would be a huge and challenging study. And no drug company would pay for it. I don't think we can do both concurrently; so, ideally, we would prioritize the questions and consider adding them, perhaps in a factorial design to other large studies.
Dr. Goss. Of the 2 questions, I think the concurrent chemotherapy with AI is more important versus the radiation. With extended endocrine therapy, local recurrence is going down. To power a study over 12 years, to really make this question clinically relevant, would be incredibly difficult.
Dr. Zujewski. It's true that we don't know the answer to it. But how would you design this? Would you hypothesize that sequential would be some percent better? Why don't you just give it sequentially?
Dr. Goss: There isn't a lot of rationale for giving it concurrently. There's no modeling, no data
Dr. Pritchard. There were logical reasons both for giving endocrine and chemotherapy concurrently: Those who are receptor positive would get their endocrine therapies 6 months or so sooner, which might be more helpful. And arguments for giving it sequentially are that the drugs may interfere with each other. I think there's no logical way to interpret this without doing a trial.
- 1Effects of estrogen and tamoxifen on dihydrofolate reductase in gene-amplified methotrexate resistant human breast cancer cells. Proc Am Assoc Cancer Res. 1983; 24: 173., , , .
- 2RNA and estrogen receptor effects associated with tamoxifen-fluorouracil synergy in breast cancer. Proc Am Assoc Cancer Res. 1983; 24: 173., , .
- 3Treatment of rat mammary cancer by combinations of tamoxifen and cyclophosphamide. Proc Am Assoc Cancer Res. 1980; 21: 293., , , et al.
- 4The effect of diethylstilbestrol and tamoxifen on the cytocidal activity and uptake of melphalan (M) in human breast cancer cells in vitro [abstract]. Proc Am Soc Clin Oncol. 1983; 2: 22..
- 8Australian and New Zealand Breast Cancer Trials Group. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol. 1986; 4: 186–193.
- 14Sequential versus concomitant chemo-hormonal therapy in breast cancer. Breast. 1982; 8: 2–7., , , et al.
- 18Chemotherapy (CT) vs chemohormonal therapy (CT+HT) for postmenopausal patients (PT) with advanced breast cancer. Proc Am Assoc Cancer Res. 1988; 29: 197., , , et al.
- 20Response to chemotherapy or chemoendocrine therapy in patients with advanced breast cancer previously treated with adjuvant chemotherapy. Breast Cancer Res Treat. 1985; 6: 185., , , et al.
- 27Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group. J Clin Oncol. 1997; 15: 2302–2301., , , et al.
- 28A randomized study of concurrent versus sequential chemotherapy and tamoxifen in stage II breast cancer [abstract]. Proc Am Soc Clin Oncol. 1991; 10: 14a., , , et al.
- 29A randomized study of concurrent versus sequential adjuvant chemotherapy and tamoxifen in stage II breast cancer [abstract]. Proc Am Soc Clin Oncol. 2002; 21: 46a., , , et al.
- 30Epirubicin-cyclophosphamide chemotherapy plus tamoxifen administered concurrent versus sequential: randomized phase III trial in postmenopausal node-positive breast cancer patients. GEICAM 9401 study [abstract]. Proc Am Soc Clin Oncol. 2002: 21: 37a., , .
- 32Overall survival after cyclophosphamide, Adriamycin, 5-FU, and tamoxifen (CAFT) is superior to T alone in postmenopausal receptor (+), node (+) breast cancer: new findings from phase III Southwest Oncology Group Intergroup Trial S8814 (INT-0100) [abstract]. Proc Am Soc Clin Oncol. 2001; 20: 94a., , , et al.
- 33Tamoxifen (T) versus cyclophosphamide, Adriamycin and 5-FU plus either concurrent or sequential T in postmenopausal receptor (+), or node (+) breast cancer: a Southwest Oncology Group phase III Intergroup trial (SWOG-8814, INT-0100) [abstract]. Proc Am Soc Clin Oncol. 1997; 16: 128a., , , et al.
- 34Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from Intergroup trial 0100 (SWOG-8814) [abstract]. Proc Am Soc Clin Oncol. 2002; 21: 37a., , , et al.