Potential strategies for improving the results of high-dose chemotherapy in patients with metastatic breast cancer

Annals of Oncology 6 (Suppl. 4): S21-S26, 1995. O 1995 Kluwer Academic Publishers. Printed in the Netherlands.

Symposium article Potential strategies for improving the results of high-dose chemotherapy in patients with metastatic breast cancer J. Crown1 & L. Norton2 l

St. Vincent's Hospital, Dublin, Ireland; 2Memorial Sloan-Kettering Cancer Center, New York, U.S.A.

Summary

Current status of high-dose chemotherapy in metastatic breast cancer

Key words: high-dose chemotherapy, breast cancer, G-CSF, peripheral blood progenitor cells

with those who receive conventionally-dosed therapy [15]. A major difference however is that in most series, 10%-15% of patients who have undergone HDC have achieved remissions which were durable beyond five years [6, 7]. This outcome is very rare following conventional chemotherapy [16-18]. While the reality of these sustained remissions from HDC has prompted speculation that these regimens might have curative potential in this condition, confirmatory survival data from randomised comparisons are still awaited. A second major area of investigation concerns patients with stage II breast cancer who have metastases involving 10 or more axillary lymph nodes. Without adjuvant therapy, up to 90% of these patients will ultimately develop fatal dissemination of cancer [19]. Conventional adjuvant chemotherapy has had a modestly beneficial impact in this setting [20]. Yet, Peters and

Considerable controversy surrounds the use of highdose chemotherapy (HDC) with autologous bone marrow or peripheral blood progenitor support as a treatment for patients with breast cancer [1-3]. Nevertheless, several facts concerning this modality can be regarded as fairly well established. The first is that in terms of its ability to induce complete remissions, HDC is clearly the most active systemic therapy currently available for metastatic breast cancer. In a retrospective analysis, Eddy compared the reported results of trials of HDC and of more conventionally-dosed therapy [4]. He found that complete remission (CR) was achieved more than four times more frequently with the highdose approach. In the more modern studies which include only patients with cancer not refractory to prior chemotherapy, CR rates in excess of 50% are common [5-13] (Table 1). The only randomised comparison of Table 1. Activity of HDC in metastatic breast cancer. high- versus low-dose therapy for which response data Strategy Complete are available, demonstrated CR rates of 50% and 10%, response (%) respectively [14]. 25% It is also established that most of these CRs end in Salvage chemotherapy Initial chemotherapy for metastases 50% relapse. Hence, the median survival of patients treated Consolidation of prior response 60%-70% with HDC is not conclusively prolonged compared

Reference [23] [5, 6, 14) [7-10]

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High-dose chemotherapy (HDC) is the most effective approach for inducing complete remissions in patients with metastatic breast cancer, and although most patients will relapse, a small percentage (10%-15%) achieve durable remissions beyond five years. Additionally, HDC has produced five-year relapse-free survival rates in excess of 70% in patients with stage II breast cancer with > 10 nodes. The use of HDC in breast cancer remains controversial and randomised trials are required to assess the survival impact of this approach. The introduction of haematopoietic growth factors (HGF) and peripheral blood progenitor cells (PBPC) has advanced the use of HDC by reducing treatment-related mortality (from 20% to 5%) and by allowing the development of multiple cycles of intensive therapy. Based on tumour kinetic models we have hypothesised that multiple, rapidly cycled

courses of high-dose therapy may improve the rate of durable remission in metastatic breast cancer. The feasibility of this approach has been shown in a series of pilot studies in which one or more courses of high-dose cyclophosphamide and recombinant granulocyte colony-stimulating factor (G-CSF) (filgrastim) were given to obtain PBPC which were then used to support one or more courses of HDC. In successive studies the HDC component consisted of: a single course of carboplatin, etoposide and cyclophosphamide; four courses of carboplatin; tandem courses of thiotepa; or a sequence of melphalan and thiotepa. Promising response rates have been produced in advanced breast and ovarian cancer with the later generation of regimens. These results justify the conduct of prospective randomised trials.

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Causes of treatment failure in metastatic breast cancer

Historically, the principal causes of treatment failure following HDC in patients with metastatic breast cancer have been treatment-related death and either relapse from, or failure to achieve, a CR. In early studies, treatment-related mortality rates were as high as 20%. Most fatalities occurred during the prolonged phase of profound neutropenia which was an inevitable accompaniment of this therapy. Organ toxicities, especially pneumonitis and venoocclusive disease of the liver, were also leading causes of death [23]. The introduction of the haematopoietic colony-stimulating factors (CSFs) resulted in a substantial acceleration of neutrophil recovery following autografting [24]. In addition, haematopoietic progenitor cells, normally present at very low levels in the peripheral blood, are mobilised from the marrow into the blood stream during the haematopoietic rebound which occurs following growth factor-supported myelosuppressive chemotherapy [25]. These cells can be harvested by leukapheresis, and their reinfusion as a supplement or alternative to autologous bone marrow can produce accelerated haematologic recovery. As a consequence of these advances, mortality rates have been reduced to less than 5% [26, 27]. This reduction in mortality may itself translate into somewhat improved overall long-term DFS, in that patients who might otherwise have died from toxicity of therapy might now realise their small chance of achieving sustained remission. A leading cause of treatment failure following HDC [6, 7, 13] is relapse from CR, which occurs in approximately 75% of patients who achieve remission. Another cause is failure to achieve CR. A tenable possibility is that most patients who fail to achieve a CR harbour cancer cells sufficiently drug-resistant that they cannot be eradicated by any clinically achievable doses of currently available agents. Hence, substantial

improvements in the treatment of these patients may require wholly novel approaches. For the majority of patients who do attain CR however, failure to eradicate sensitive cells is a major issue. Some of these relapses may be due to reinfusion of cancer cells with the stem cell product. The focus of attempts to eradicate contaminating tumour cells in the cellular product has recently switched from classic purging experiments [28], to the use of new technologies which can positively select populations of haematopoietic progenitor cells from bone marrow or leukapheresis collections. Preliminary clinical data indicate that this approach does not result in delayed haematopoietic recovery, and that it might substantially reduce the degree of cancer contamination of marrow or peripheral blood [29]. Most relapses, however, occur in areas of prior bulk disease, which strongly suggests that persistence of cancer in vivo, rather than in vitro, is the predominant mechanism of failure. If one assumes that this reflects the survival of resistant cancer cells among the heterogeneous clones in the original tumour, clinical advances would require additional non-cross-resistant treatment. Several groups are investigating such strategies using either novel chemotherapy combinations [30] or immunological manipulations [31]. It might be useful to consider an alternative explanation however, based both on tumour kinetic models, and on the history of curative chemotherapy for several malignancies. The cure of Hodgkin's disease [32], malignant lymphoma [33] and germ-cell cancer has been based on two principles. One is the development of active regimens; the second is the administration of a sufficient number of courses of those regimens to eradicate the cancer. Thus, in the original MOPP (mustine, vincristine, procarbazine, prednisone) series from the United States National Cancer Institute, in which patients with Hodgkin's disease achieved a CR after an average of three cycles of therapy, two cycles beyond CR, or a minimum of six cycles, was fundamental to cure. In germ-cell tumours of the testes, three courses of cisplatin-etoposide therapy appear to be inferior to four courses [34, 35]. The importance of a minimum number of active courses has also been demonstrated in the adjuvant chemotherapy of stage II breast cancer, where a single perioperative cycle of CMF has been demonstrated to be inferior to a more conventional, multi-cycle regimen [36]. Thus, classical curative chemotherapy consists of multiple cycles of treatment with an effective regimen, rather than the single cycles administered for high-dose regimens. Rationale for HDC as consolidation following lower dose induction therapy.

HDC as a treatment for metastatic breast cancer has evolved along somewhat non-classical lines, in response to two considerations. The first is the toxicity of

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colleagues have reported that 70% of such patients who were treated with HDC and an autograft, following four cycles of conventional doxorubicin-based 'induction' therapy, remained relapse-free at five years [21]. Similar results were reported by Gianni et al. using sequential high-dose single agents with haematopoietic support [22]. These results are clearly sufficiently promising to justify the conduct of confirmatory randomised trials, several of which have already started. Randomised trials will also be necessary to assess the survival impact of this approach in patients with metastatic disease. However, since currently available regimens have produced only modest long-term disease-free survival rates (DFS), there is considerable need for further research and development. It is critical that such studies proceed in concert with the randomised trials of other high-dose regimens that are now in progress.

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multiple courses of HDC initially. It is thus reasonable to expect that as more effective, multi-cycle treatments are developed, they might profitably be applied to patients without prior conventional treatment. Greatly increasing the effectiveness and acceptability of this approach would be a better means of predicting on the basis of biological examination of their tumours which patients have a sufficiently high chance of being cured to justify the use of HDC. Inter-treatment interval

In addition to the use of multiple cycles, the interval between courses of treatment may be another important determinant of outcome. According to the NortonSimon model, populations of sub-clinical cancer cells might undergo accelerated, but still clinically inapparent, regrowth following a phase of massive but noneradicative cell-kill [37]. Thus, the shorter the delay after a high-dose treatment course, the higher the probability that the subsequent high-dose course would be eradicative.

The design of improved treatments

Based on the above concepts we have hypothesised that multiple, rapidly cycled courses of high-dose therapy might improve the rate of durable remission in patients with metastatic breast cancer. Several other groups have studied the use of multicycle HDC supported by autologous bone marrow. However, in the era before the introduction of the haematopoietic growth factors, the toxicity of highdose therapy tended to result in relatively prolonged inter-treatment intervals [38], and in some cases in unacceptable morbidity [39]. With the advent of modern haematopoietic support technology, truly 'dose-dense' therapy may be possible. High doses of cyclophosphamide [40, 41] and of some other agents and regimens [42-44], can be administered using CSFs as sole support. For some of the more myelosuppressive drugs [45-47], which are important components of autologous marrow transplantation regimens, CSFs alone do not provide adequate rescue [48, 49], because they accelerate leucocyte reTable 2. Conventionally-dosed induction chemotherapy prior to covery only and because of cumulative myelosuppresHDC. sion [24]. For this reason, the Milan group, and our group have devised multi-course HDC regimens in Cytoreduction Arguments for: which patients are treated initially with one or more Determine chemosensitivity cycles of high-dose cyclophosphamide supported by Arguments against Minimal cytoreductive impact in most cases CSFs. This is used both as anti-cancer therapy and to ? Lengthy induction phase may allow expansion of populations which are only par- mobilise haematopoietic progenitors into the periphtially sensitive to the high-dose treatment, eral blood stream. The collection and reinfusion of thus compromising its ability to eradicate these cells are then used to support a subsequent them course of such agents as melphalan [50], or of carbo? Responsiveness to a prior high-dose platin-based combination chemotherapy [51]. course might be more relevant CSF-mobilised peripheral blood progenitors (PBP)

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the approach, which has mitigated against the use of multiple cycles. The second is the perception that patients must first prove their suitability for HDC by virtue of responding to preliminary lower dose therapy. Most HDC programmes thus consist of a phase of conventionally-dosed induction therapy followed by one, or occasionally two, courses of high-dose treatment for those patients who had first achieved an objective response (CR or partial remission [PR]). A rationale has been that the preliminary induction produces a degree of cytoreduction prior to the administration of the high-dose therapy. While this strategy may be valid, it could be challenged on several particulars (Table 2). For example, the cytoreductive component of the conventional chemotherapy may be relatively minor in many cases. PR, a traditional entry point for eligibility to high-dose trials, likely represents no more than several logarithms (to the base 10) of cell kill (i.e. from 1011 to 109 cells), which would constitute a relatively small step towards the eradication of the tumour. In addition, it could be argued that a lengthy phase of induction chemotherapy might allow the gradual expansion of clinically inapparent pre-existing subclones of cells which are resistant to the induction therapy, hidden by the simultaneous regression of numerically dominant sensitive clones. While the highdose therapy would be applied at a time of maximum clinical response, the actual burden of cells which could be eradicated only by this treatment might be somewhat greater than it would have been had such therapy been applied at the outset. The latter arguments are moot, and can be resolved only by prospective research. Another justification for low-dose induction chemotherapy, however, is largely ethical. If induction chemotherapy acts as an in vivo bioassay it may enable patients with highly resistant disease to be spared from undergoing what is likely to be ineffective high-dose therapy. This view derives from the oft-replicated poor results in patients who undergo HDC for metastatic breast cancers that were refractory to prior conventional therapy [23]. In contrast, it can be argued that about half of such 'refractory1 patients do respond to highdose therapy, and up to a quarter achieve temporary CRs. It is possible that some of these patients might have been more successfully treated had they received

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Table 3. Memorial Sloan-Kettering Cancer Center studies of accelerated multi-cycle HDC in metastatic breast cancer. Reg

Cycle 1

Cycle 2

Cycle 3

Cycle 4

1)

Cy 3000

Cy 3000

—

2) 3)

Cy 3000 Cy 5000

Cy 3000 L-PAM 180

Car 1500/ Cy 5000/ VP1200 Thio 700 Thio 700

Thio 700 Thio 700

All doses in mg/m2. Cy — cyclophosphamide; Car — carboplatin; VP — etoposide; L-PAM - melphalan; Thio - thiotepa.

Conclusion The results which have been obtained with HDC in patients with high-risk primary breast cancer are already sufficiently encouraging to justify the conduct of pro-

spective randomised trials. Simultaneously, development efforts, such as have been outlined here, should continue to obtain a high priority in the setting of metastatic disease. The prospect of achieving very high CR rates and the enticing possibility of converting these responses into durable 'cures' should provide powerful motivation for clinical research in this exciting field of inquiry. Acknowledgements

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have also been used to support multiple chemotherapy courses. Using this approach, Shea and colleagues administered three cycles of high-dose carboplatin at 4-5 week intervals [52]. Investigators at Dana-Farber administered four cycles of carboplatin and cyclophosphamide (each at 600 mg/m2) at four-week intervals [53]. The same group demonstrated the feasibility of a similar PBP-supported tandem transplant with a treatment interval of 3.5 weeks [54]. Our group has conducted a series of studies in which the new haematopoietic technologies are used to support multiple, accelerated cycles of HDC. In these trials, one or more courses of high-dose cyclophosphamide supported by filgrastim were administered, PBPs were obtained, and these were then used to support one or more courses of high-dose myelosuppressive chemotherapy. In successive studies, the PBP-supported high-dose component consisted of a single course of carboplatin, etoposide and cyclophosphamide [51], four courses of carboplatin [55, 56], tandem courses of thiotepa [57] or a sequence of melphalan and thiotepa [58] (Table 3). These trials demonstrated the feasibility of administering very large doses of chemotherapy at approximately 14-15-day intervals. The later generation studies have produced promising response rates in both advanced breast and ovarian cancer [59J. Highly promising results have also been reported to a high-dose multi-cycle regimen consisting of sequential doxorubicin, paclitaxel and cyclophosphamide in patients with node-positive breast cancer [60]. The integration of biological treatments with HDC may offer the prospect of further advances. Baselga and colleagues treated patients with breast cancer which expressed the her-2-neu protein with an antibody against this antigen, and reported clinical responses. The co-administration of such an antibody with HDC might inhibit interval regrowth of tumour, and also produce synergistic cytotoxicity [61].

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