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Challenges and Controversies |
US Oncology, Inc., Dallas Texas, USA
Correspondence: Joyce O'Shaughnessy, M.D., Co-Director Breast Cancer Research, Director, Chemoprevention Research, US Oncology, Inc., 3535 Worth Street, Collins 5, Dallas, Texas 75246, USA. Telephone: 214-820-2021; Fax: 214-820-4713; e-mail: Joyce.O'Shaughnessy{at}usoncology.com
Over the last 17 years, the question of whether increasing the dose intensity of chemotherapy can improve breast cancer patients' survival and cure rates has been the focus of intensive study. As with most scientific hypotheses, a single study does not tell the whole story, and answering this question is like assembling a puzzle, with pieces of data becoming available year by year. As practicing oncologists, we are used to this process. The recommendations we make for our patients are often based on early and incomplete data, some of which have been presented only at national meetings but have not yet been peer reviewed and published. Thankfully, breast oncology is anything but a static field. Over the past decade, nearly every year has brought important new data from large randomized trials that have changed the practice of breast oncology. Particularly in the adjuvant setting, the impact that promising new data can have on women's disease-free and overall survival is great and oncologists have generally been quick to incorporate important new findings into their practice patterns. Recent examples of this include: the survival advantage to be had by administering four cycles of paclitaxel following four cycles of doxorubicin and cyclophosphamide (AC) in node positive breast cancer patients [1]; the improvement in disease-free survival achieved by adding goserelin to tamoxifen in hormone receptor positive, node positive, premenopausal breast cancer patients whose ovaries are still functioning following standard chemotherapy [2]; and the reduction in local breast cancer recurrences and new contralateral breast cancers obtained by treating women who have undergone lumpectomy and radiation therapy for ductal carcinoma in situ with five years of tamoxifen [3]. Two of these three pivotal trials have not yet been published, but the presented data have been persuasive enough to change the standard of care.
High dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) has been directed towards a group of breast cancer patients for whom new approaches and improved survival are sorely needed; those with 10 or more positive nodes and those with metastatic disease. Early single institution data in both of these patient populations appeared promising compared to historical controls and, as a result, oncologists around the world became enthusiastic about offering this potentially beneficial therapy to their poor prognosis patients. Interest in this treatment grew steadily from the mid-1980's to the mid-1990's and, paradoxically, hampered accrual to the definitive phase III trials. However, by the mid-1990's, enthusiasm for HDC/ASCR began to wane as it became clear that some subsets of metastatic patients did not appear to benefit, e.g., those who had only a partial response to induction chemotherapy [4], and with the finding that metastatic breast cancer patients who were transplanted immediately after achieving a complete response had inferior overall survival compared to those who were transplanted when their disease progressed [5]. Then, in 1999, the results of five pivotal phase III studies definitively answered some questions, e.g., cyclophosphamide thiotepa carboplatin (STAMP V) with ASCR does not improve the overall survival of metastatic breast cancer patients compared with standard CMF [6] but, like all influential trials, the results also raised additional questions.
What questions remain for women with 10 or more positive nodes? The Scandinavian study which compared dose-intensive 5-fluorouracil epirubicin cyclophosphamide to high dose STAMP V with ASCR showed equivalent disease-free and overall survival for the two treatments at 2 years of median follow-up [7], while the Cancer and Leukemia Group B (CALGB) study left open the possibility that the relapse rate from breast cancer with high-dose cyclophosphamide BCNU cisplatin (STAMP I) might become significantly superior statistically compared to intermediate-dose STAMP I with longer follow-up [8]. However, even should this positive result emerge over time, the fact that few transplant centers are experienced in administering STAMP I and that 7% of patients had treatment-related mortality (up to 13% in less experienced centers) will significantly limit the application of these results to standard practice. Another important consideration for practitioners is the ever-changing standard of care—we now know that the addition of four cycles of paclitaxel to four cycles of AC significantly improves the overall survival of high-risk node positive breast cancer patients [1]. There are no data that suggest that adding STAMP I/ASCR to what has become the new standard of adjuvant chemotherapy will result in further patient benefit.
Another issue that bears close watching, which to date has been inadequately addressed, is the question of whether HDC/ASCR may benefit premenopausal high risk women by causing permanent ovarian ablation. The recent demonstration of improved disease-free survival with the addition of goserelin to tamoxifen following cyclophosphamide doxorubicin 5-fluorouracil (CAF) chemotherapy in premenopausal, node positive, hormone receptor positive breast cancer patients [2] has again focused attention on the potential benefits of ovarian ablation. A recent study that tracked the rates of chemotherapy-related amenorrhea (CRA) illustrates the potential importance of this variable in influencing efficacy results in chemotherapy trials. In node positive, premenopausal women who were treated with chemotherapy alone, without tamoxifen, the rates of CRA following cyclophosphamide epirubicin 5-fluorouracil (CEF) were greater than with cyclophosphamide methotrexate 5-fluorouracil (CMF), raising the question of whether the improved survival associated with CEF was partially due to an indirect endocrine effect [9]. As the results of the CALGB and other phase III studies of HDC/ASCR in high risk women mature, it will be important to assess the CRA rates on both study arms, since it is likely that HDC leads to permanent amenorrhea in a greater proportion of women than does standard-dose chemotherapy.
The positive data from the small South African phase III study in patients with 10 or more positive nodes raised the intriguing question of whether two tandem cycles of HDC/ASCR, without preceding induction chemotherapy, could improve patients' overall survival [10]. Unfortunately, the recent admission of data falsification and subsequent discreditation of these data by the University of Witwaterstrand in South Africa has invalidated this study. It is now unclear whether there is adequate scientific rationale to pursue large phase III studies of tandem transplants, with or without induction chemotherapy, in the adjuvant setting.
What questions remain for women with metastatic breast cancer? The phase III Philadelphia trial conclusively showed that HDC/ASCR and maintenance CMF have equivalent overall survival as well as three-year progression-free survivorship [6]. The number of complete responders following induction chemotherapy who subsequently underwent randomization to HDC/ASCR versus CMF was too small to draw any definitive conclusions about the effectiveness of transplant in these patients. However, the 1996 Peters' randomized study, described above, of immediate versus delayed transplant in complete responders did not provide evidence that these patients benefit from HDC/ASCR [5]. The survival benefit observed in the South African randomized trial of tandem transplants without induction chemotherapy compared to cyclophosphamide, mitoxantrone, and vincristine in metastatic breast cancer patients is open to question not only because of the recent discreditation of the adjuvant study by the same group, but also because only patients who responded to chemotherapy were subsequently treated with tamoxifen [10]. While 95% of patients on the tandem transplant arm achieved at least a partial response, only 53% did so on the standard arm, resulting in a potentially important imbalance in the use of tamoxifen. In addition, the women entered in this study were all under age 50 with a median age of 37, and half of them had not received adjuvant chemotherapy. Although rates of CRA are not reported in this study, it is possible that ovarian ablation caused by the endocrine effects of tandem transplants may have contributed to the reported therapeutic superiority.
Peters et al. have suggested that even though there was no progression-free or overall survival benefit associated with STAMP V/ASCR [11], metastatic patients may prefer a single dose of HDC/ASCR to two years of maintenance CMF. However, the median progression-free survival was the same on both arms of the study at nine months, and the median number of CMF cycles administered was eight before a change in therapy was required. Therefore, it does not seem likely that treatment with STAMP V resulted in a clinically meaningful freedom-from-chemotherapy interval, especially given the three to six month period required to recover from the toxicities of transplant.
Seventeen years into the study of high dose chemotherapy in breast cancer, we clearly see the perils of concluding too much from phase II metastatic or single arm adjuvant studies that are compared to historical controls because of patient selection that occurs with more aggressive staging [12, 13]. The preponderance of data from randomized dose intensity trials is consistent with the concept that there is a threshold dose of chemotherapy that confers maximal benefit [1, 14, 15]. There is as yet no convincing evidence that administering drug doses that require hematopoietic growth factor and/or stem cell support enhance breast cancer patient benefit due to direct antitumor effects.
The notion that tumor cytoreduction is a prerequisite for extending breast cancer patients' survival is also being rethought in view of the rather surprising findings that single agent paclitaxel is associated with superior survival compared to combination CMF [16], and that anastrozole improves survival compared to megestrol acetate [17], in spite of similar objective response rates in these two studies, and that the addition of trastuzumab to paclitaxel improves survival compared to paclitaxel alone, in spite of trastuzumab's rather modest single agent activity [18, 19]. While oncologists will continue to monitor the objective response rates of new therapies for metastatic disease, it will not be surprising to see survival advantages emerging for both metastatic and high risk patients with the administration of more targeted agents that can subdue and control disease, without marked cytoreduction.
The high dose chemotherapy pendulum, having swung to one extreme by the mid-1990's, has now swung close to the other extreme. There is growing agreement that, at present, breast cancer patients should be offered treatment with HDC/ASCR only as part of hypothesis-driven clinical trials, and not as standard care. However, the final story has not been written; additional pieces of the puzzle are still to come, and practice patterns may again evolve. Yet still questions remain. Will the ECOG phase III trial of STAMP V/ASCR versus no transplant following CAF in patients with 10 or more nodes be a positive study? Does foregoing induction chemotherapy lead to less drug resistance thereby enhancing the efficacy of HDC/ASCR? If STAMP I reduces breast cancer recurrence rates, can we administer this regimen more safely? Oncologists and informed patients will continue to follow this story closely but will expect mature results from large randomized studies that account for and balance all known prognostic and treatment variables.
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