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The Status of High-Dose Chemotherapy in Breast Cancer

Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Correspondence: S. Rodenhuis, M.D., Ph.D., The Netherlands Cancer Institute, Department of Medical Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Telephone: 31-20-512-2870; Fax: 31-20-512-2572; e-mail: sroden{at}nki.nl

	ABSTRACT

Top Abstract Introduction High-Dose Chemotherapy and the... The Toxicity of High-Dose... The Ability of High-Dose... High-Dose Chemotherapy in High... Developments in High-Dose... The Selection of High-Dose... Prospects References

 
High-dose chemotherapy in breast cancer is a subject of considerable controversy. Preliminary results from several randomized trials have shown that it is certainly not the breakthrough hoped for in the early 1990s. The available data are, however, compatible with a modest but potentially important effect on relapse-free survival in the adjuvant treatment of high-risk breast cancer. To prove such an effect, several more years of maturation are required for a number of randomized studies. At this point in time, there is no justification for the use of high-dose chemotherapy in breast cancer outside clinical studies.

Key Words. Breast cancer • High-dose chemotherapy • Adjuvant chemotherapy • Cyclophosphamide • Thiotepa • Carboplatin • Carmustine (BCNU) • Stem cell transplantation • Bone marrow transplantation

	INTRODUCTION

Top Abstract Introduction High-Dose Chemotherapy and the... The Toxicity of High-Dose... The Ability of High-Dose... High-Dose Chemotherapy in High... Developments in High-Dose... The Selection of High-Dose... Prospects References

 
High-dose chemotherapy in breast cancer continues to be a controversial subject. Following an era in which this treatment modality was considered by many to represent a standard of care for patients with high-risk primary breast cancer, many physicians and most of the public now believe that high-dose chemotherapy is both excessively toxic and ineffective. This precipitous shift of opinion has been caused by the publication of a small number of randomized studies that did not show benefit for the high-dose approach. In addition, a scientific misconduct investigation has revealed that the author of the only two randomized studies of high-dose therapy [1, 2] that showed a significant benefit falsified data [3]. This sequence of events is highly unfortunate since both the earlier uncritical belief in the efficacy of high-dose chemotherapy and the more recent rejection of this modality are equally unreasonable and scientifically unsound.

The rationale of high-dose chemotherapy in breast cancer, the early studies and an analysis of the few available data from randomized studies have recently been reviewed by Peters et al. [4] in this journal. Rather than present a similar comprehensive overview, this paper will offer an interpretation of the available data from a slightly different perspective. In addition, the revelation that Dr. Bezwoda has falsified his results forces us to reevaluate the available information. The elimination of the randomized study of Bezwoda from our knowledge base actually simplifies this task, since it suggested a degree of (recurrence-free) survival benefit for high-dose therapy that was difficult to explain against the background of other randomized studies.

	HIGH-DOSE CHEMOTHERAPY AND THE CURE OF BREAST CANCER

Top Abstract Introduction High-Dose Chemotherapy and the... The Toxicity of High-Dose... The Ability of High-Dose... High-Dose Chemotherapy in High... Developments in High-Dose... The Selection of High-Dose... Prospects References

 
High-dose chemotherapy with bone marrow or peripheral blood progenitor cell (PBPC) transplantation is undeniably an expensive and toxic treatment modality. The quality of life during treatment and in the first few months following it is clearly worse than that of patients who receive conventional chemotherapy [5, 6]. Consequently, lengthening survival by a few months is insufficient to justify its use. The objective of high-dose chemotherapy should be cure or rather "long-term disease-free survival." Since breast cancer may recur up to 15 to 20 years following treatment, "cure" is not a practical endpoint for clinical studies. Long-term disease-free survival, operationally defined as three or more years following the end of treatment without the requirement of additional therapy or evidence of disease, is more useful for patients with stage IV disease. In practice, very few stage IV breast cancer patients achieve long-term disease-free survival according to this definition.

In high-risk primary breast cancer, recurrence-free survival is a reasonable but intermediate endpoint for randomized studies. As with any other form of adjuvant therapy, the objective is cure, but up to 20 years of follow-up would be required to ascertain that this goal has been achieved. Fortunately, long-term survival gain tends to accompany recurrence-free survival improvement in primary breast cancer [7].

	THE TOXICITY OF HIGH-DOSE CHEMOTHERAPY IN BREAST CANCER

Top Abstract Introduction High-Dose Chemotherapy and the... The Toxicity of High-Dose... The Ability of High-Dose... High-Dose Chemotherapy in High... Developments in High-Dose... The Selection of High-Dose... Prospects References

 
All high-dose chemotherapy regimens used to treat solid tumors have significant toxicity in addition to their myeloablative properties [8]. Because of this, patients undergoing high-dose therapy are subjected to prolonged hospitalization or long stays in hostel facilities.

Acute toxicities commonly include nausea, vomiting, hair loss, mucositis, diarrhea, fatigue, and skin abnormalities. Severe organ toxicity is less frequent but may be life-threatening. In the randomized American Intergroup Study reported by Peters et al. [9], 7.4% of all transplanted patients died from toxicity. A major problem was a BCNU-induced pneumonitis that is absent in regimens not incorporating this drug. We have described a high frequency of veno-occlusive disease when multiple courses of a high-dose alkylating chemotherapy regimen are given [10]. The administration of oxazaphorines (cyclophosphamide or ifosfamide) as part of a high-dose regimen is associated with hemorrhagic cystitis, despite concomitant administration of mesna. Long-lasting or irreversible toxicity to sensory nerves and ototoxicity are characteristic for cisplatin and carboplatin-based regimens. Other chronic toxicities include infertility, premature menopause, chronic fatigue syndrome, and renal function impairment. We have recently reported that patients who received high-dose chemotherapy have significant neuropsychological sequelae, which may be irreversible [11]. Although these neuropsychological abnormalities are readily detectable by standard neuropsychological tests, their significance for the quality of life of patients and their ability to return to their prior work and lifestyle are uncertain at this point. Finally, high-dose therapy is associated with an increase in second malignancies, including myelodysplastic syndromes and leukemias [12], but probably also solid tumors.

	THE ABILITY OF HIGH-DOSE CHEMOTHERAPY TO INDUCE LONG-TERM SURVIVAL IN ADVANCED BREAST CANCER

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The hope that high-dose chemotherapy is able to induce long-term disease-free survival in a subgroup of patients with advanced breast cancer is not unreasonable. It is based on a large number of phase II studies reviewed by Peters [4], and on extensive data from both the American and European bone marrow registries [13, 14]. All these data show that a small proportion of patients, typically 10%-20%, achieve long-term disease-free survival after transplant. Clearly, it may be argued that the same patients could have achieved a similar survival following conventional-dose chemotherapy; in fact, we know that a small percentage of patients do [15]. The fact that the percentage of patients achieving this in high-dose chemotherapy studies is relatively high could, in theory, be a result of patient selection bias.

It is also quite obvious that the majority of patients undergoing high-dose therapy relapses and dies from disease. Several authors have reported on prognostic factors predicting survival after high-dose therapy [16, 17]. Most studies agree that the patients who are most likely to benefit from intensive chemotherapy are those with limited metastatic disease who are in good clinical condition and have tumors responsive to conventional-dose chemotherapy. This finding is remarkably consistent. For example, data from the European bone marrow registry indicate that patients who are transplanted in first complete remission from advanced breast cancer have a 35% disease-free survival for 3+ years [14]. A prospective, but unrandomized study performed by the Dutch Working Group on Autologous Transplantation in Solid Tumors indicated that patients in first complete remission following conventional-dose chemotherapy had a long-term disease-free survival of 43% [18]. These and many other reports essentially confirm the early study of Peters that showed that a single course of high-dose chemotherapy without any other treatment could achieve long-term disease-free survival in 3 of 22 patients with advanced breast cancer [19].

Based on all this evidence, there can be no doubt that high-dose chemotherapy induces long-term survival in a subgroup of patients. But the question remains if this subgroup is larger than that which achieves long-term disease-free survival after conventional-dose chemotherapy. The only randomized study addressing this is the recently reported study of Stadtmauer et al., frequently called the "Philadelphia study" [20]. Disappointingly, this study does not show a difference in disease-free survival between the patients randomized to the standard-dose arm and those randomized to high-dose arm. Also, the long-term disease-free survivals were identical: these were lower than 10%, for both the high-dose and conventional-dose groups. This is an important and discouraging result, and it strongly argues against the previously common practice of administering CTCb chemotherapy routinely several months after a response to conventional-dose chemotherapy. The results should, however, not be overinterpreted. The study had a number of important limitations:

• The number of randomized patients (199) was relatively small. In addition, there was a substantial number of treatment refusals and arm crossovers, all diminishing the power of the study to detect a beneficial effect.
  
• Patients in the conventional chemotherapy group received a substantially higher cumulative dose of chemotherapy than those randomized to the "high-dose" group. A median of eight additional courses of CMF were given to patients randomized to the conventional arm of the study. This amounts to 11.2 grams per m² cyclophosphamide, which is almost twice as much cyclophosphamide as in the CTCb regimen.
  
• The high-dose chemotherapy regimen employed, CTCb, may not be a true high-dose regimen. While the thiotepa dose is significantly elevated over its standard single-agent dose (approximately eight times), the carboplatin dose is less than twice the single-agent dose. In addition, the cyclophosphamide and thiotepa are both given as continuous i.v. infusions. The continual presence of thiotepa inhibits the activation route of cyclophosphamide and may thus significantly decrease the peak plasma level and/or area under the curve of the active metabolites (mainly of 4-hydroxycyclophosphamide) [21, 22].
  
• Patients were randomized at a maximum of eight weeks after the last dose of conventional chemotherapy. Following these eight weeks, a bone marrow harvest and/or stem cell mobilization and harvest took place and patients were scheduled for high-dose therapy. As a result, patients could have had up to three months delay between their last conventional chemotherapy and the actual start of the high-dose therapy. This could have allowed tumor regrowth during the chemotherapy-free interval, thus impacting on the results of high-dose therapy. If the available mathematical models of tumor growth [23, 24] are of any value in describing the true biology of breast cancer (which is of course debatable), substantial regrowth of tumor could have taken place, eliminating all benefit of the induction chemotherapy.
  

These points of criticism certainly do not invalidate the findings of the Philadelphia study [20]. It is, however, conceivable that any benefit of high-dose therapy, even given as late intensification, could have been missed as a result of the study design.

Two other randomized studies of high-dose chemotherapy have been reported in stage IV breast cancer. The first was a study by Peters et al. [25]. This study indicated a relapse-free survival advantage for patients receiving high-dose therapy, but it compared early transplant to late transplant and therefore it does not directly provide information regarding the comparison between high-dose and conventional-dose therapy. Moreover, the overall survival was superior in the group that received delayed high-dose therapy. The second is a small French study, presented at the American Society of Clinical Oncology (ASCO) meeting in 1999 [26]. Sixty-one patients with stage IV breast cancer responding to conventional-dose chemotherapy were randomized to either receive two to four additional courses of conventional-dose chemotherapy, or to undergo high-dose chemotherapy with a regimen containing mitoxantrone 45 mg/m², cyclophosphamide 120 mg/kg, and melphalan 140 mg/m² (CMA). The study showed an insignificant trend for improved overall survival (p = 0.08) for the high-dose arm with an overall median survival of 36.1 versus 15.7 months.

In summary, the evidence from randomized studies is compatible with a modest gain in disease-free survival for high-dose chemotherapy, but this effect is far from proven. Because of this, randomized studies of high-dose chemotherapy in advanced breast cancer remain very important and several are in progress in North America and Europe. Unfortunately, it is quite likely that the recent negative publicity regarding high-dose therapy may adversely affect patient recruitment in these studies and many investigators may have lost interest.

	HIGH-DOSE CHEMOTHERAPY IN HIGH-RISK PRIMARY BREAST CANCER

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Adjuvant chemotherapy has a well-established role in high-risk breast cancer and it is reasonable to hope that a more effective approach in the adjuvant setting can be derived from improvements in the chemotherapy for advanced disease. A recent example of this mechanism is the demonstration that the addition of paclitaxel improves the outcome of adjuvant chemotherapy in breast cancer [27].

Unfortunately, it is uncertain at this point whether high-dose chemotherapy can add significantly to survival in advanced breast cancer, and the only information to go on in the adjuvant setting are the largely preliminary results of a few randomized studies. Only two trials with mature results are available. Both are negative, but both were small and had little statistical power [28, 29]. A number of large studies have been completed but all are still in the process of maturing.

The American Intergroup study has been reported in preliminary form by Peters [9]. A total of 783 patients who had received four courses of CAF as adjuvant chemotherapy for high-risk breast cancer were randomized to either receive the high-dose CPB regimen with PBPC transplantation or an intermediate dose of CPB that did not require PBPC transplantation. All patients subsequently received radiotherapy and tamoxifen if the primary tumor was positive for the estrogen receptor. At the median follow-up of 37 months, the event-free survival and overall survival comparisons between the high-dose and the intermediate-dose CPB patients were inconclusive (68% versus 64%, p = 0.7; and 78% versus 80%, respectively). There were, however, significantly fewer relapses in the high-dose group. Unfortunately, this benefit was offset by a high mortality in the high-dose group (7.4% of all patients transplanted). This high toxic death rate was mainly attributable to pulmonary toxicity of the CPB regimen, which contains 600 mg/m² of carmustine.

The randomized study in high-risk breast cancer with the largest number of randomized patients is the study of the Dutch Working Group on Autotransplantation in Solid Tumors. This study, which closed in July of 1999, randomized a total of 885 patients. Roughly one-third of these patients had 10 or more tumor-positive axillary lymph nodes, the remainder of patients had four to nine positive axillary lymph nodes. Following definitive surgery, patients were randomized to receive either five courses of fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by radiation therapy and tamoxifen, or to the same sequence in which the fifth course of FEC was replaced by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin. This high-dose regimen is similar to the CTCb (STAMP V) regimen, but it contains a double dose of carboplatin and the three alkylating agents are infused as short i.v. infusions rather than as continuous infusions [30]. This may lead to less inhibition of the activation route of cyclophosphamide than the continous infusion employed in the CTCb regimen [21, 22].

Preliminary survival results of this study have been reported at the ASCO meeting in 2000 [31]. At a median follow-up of 35 months, the three-year recurrence-free survival for the high-dose group was 72% versus 65% for the conventional-dose group (p = 0.057). A planned subgroup analysis of the first 284 patients in the study, who had a median follow-up of 53 months and a lead follow-up of almost seven years, showed recurrence-free and overall survival benefits that were both statistically significant. Clearly, these encouraging survival results of the Dutch study need further maturation, and a first meaningful statistical analysis is anticipated for the year 2002. At this point, however, it is also clear that the treatment mortality was only 1% in the high-dose arm compared to 7.4% in the American Intergroup study. The Dutch study was conducted in only 10 centers and probably included over 50% of the eligible patients in all of the Netherlands. It therefore approaches a population-based study. In addition, there was no crossover from the conventional-dose arm to the high-dose arm and there were fewer than 10% treatment refusals among patients randomized to the high-dose arm. Consequently, this study does not include a possible patient selection bias, and its results should answer the question whether late intensification is beneficial in the adjuvant treatment of high-risk breast cancer.

A number of other randomized studies are either ongoing or have recently been closed (Table 1) from which no preliminary data have been released. Together with the studies described above, these should be able to provide a reliable answer by 2005.

	DEVELOPMENTS IN HIGH-DOSE CHEMOTHERAPY REGIMENS

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There are investigators who, based on data from uncontrolled studies and/or on conjectures and mathematical models, prefer certain approaches over others. Up front high-dose chemotherapy has been strongly advocated by some. Most of these investigators were encouraged by the apparently positive data of Bezwoda in both the adjuvant and advanced disease setting [1, 2], but now that these reports appear to be untrue, little empirical evidence for this approach remains.

Late intensification (high-dose therapy following conventional-dose induction therapy) continues to be a reasonable standard. The proof of concept that late intensification may improve treatment results has been delivered in other tumors, such as non-Hodgkin's lymphoma [32, 33]. In addition, conventional chemotherapy offers the additional benefit that it helps to identify a patient population that is more likely to derive long-term benefit from the high-dose part of chemotherapy [18].

Another matter of debate is whether repeated high-dose chemotherapy can best be given as high-dose alternating chemotherapy in which several different agents are used sequentially at their maximum dose [34, 35], or if repeated administration of the same high-dose regimen in a narrow time frame is preferable. We have advocated the latter approach, mainly because alternating chemotherapy has not been shown to have any clinical advantage in the conventional-dose setting [36, 37]. This line of reasoning appears to be justified, since it is difficult to see why different laws would govern the administration of high-dose versus conventional-dose chemotherapy.

A drawback of repeating the same type of high-dose chemotherapy, however, is the threat of severe end-organ toxicity. We have previously shown that three closely spaced cycles of high-dose cyclophosphamide, thiotepa, and carboplatin (CTC) lead to a high incidence of veno-occlusive disease, hemolytic uremic syndrome, and hemorrhagic cystitis [10]. More recently, we were able to demonstrate that three subsequent cycles of a somewhat lower dose of CTC are not associated with this excess toxicity [38, 39].

	THE SELECTION OF HIGH-DOSE CHEMOTHERAPY REGIMENS FOR BREAST CANCER

Top Abstract Introduction High-Dose Chemotherapy and the... The Toxicity of High-Dose... The Ability of High-Dose... High-Dose Chemotherapy in High... Developments in High-Dose... The Selection of High-Dose... Prospects References

 
It is possible or even likely that all the confusion about the relative efficacy of different chemotherapy regimens (conventional or high-dose) in breast cancer stems from our lack of understanding the perplexing heterogeneity of this disease. Every medical oncologist knows that some patients have rapidly progressive disease that is refractory to any therapeutic measure. Other tumors, even when locally advanced or metastasized, prove to be indolent or respond to every new line of chemotherapy. We have spent the past decades accumulating statistics that relate clinical features to response and survival rates, but we have failed miserably in predicting the behavior and therapy-responsiveness of individual tumors. As a result, patient selection is a more important determinant of survival in clinical studies than the type of chemotherapy given. In addition, when we find that two chemotherapeutic regimens are equivalent to each other in terms of survival, we may well miss the point that for an individual patient (and for an individual tumor), one of these regimens may be much better than the other.

It is reasonable to assume that high-dose chemotherapy should be added to effective conventional-dose therapy rather than substitute for it. For the cure of some breast cancers, dose-intensive therapy may be required. The eradication of other tumors may demand a high cumulative dose or, possibly, chemotherapy that is given over a very long period of time. Of course, any combination of these requirements may also be present in some tumors, and for other tumors none of these strategies may be effective. If this tumor characteristic is unknown, as is usually the case, the addition of high-dose therapy to conventional therapy (rather than the replacement of the former with the latter) affords the patient exposure to two strategies, either of which may be more beneficial for that individual's tumor. This could explain in part why both the Scandinavian study in high-risk breast cancer [40] and the Philadelphia study [20] in advanced breast cancer are negative. Both compare brief high-dose chemotherapy with prolonged and relatively dose-intensive conventional therapy. If certain tumors require either a high cumulative dose of chemotherapy or a long period of treatment, then these tumors will do better in the conventional arms. Only the tumors that are curable by a single exposure to very high concentrations of alkylating agents would be eradicated in the high-dose arms of these two studies. Such tumors appear to exist [19] but must be relatively infrequent.

The fact that we cannot classify breast cancer with similar characteristics and perform the studies in more homogenous patient categories leads to insensitive clinical trials and possibly to misleading interpretations. This situation may change dramatically in the next few years. Using micro-array mRNA expression profiling [41], we may for the first time be able to work out a sophisticated genetic classification of breast cancers, and this may help to design better clinical studies for sets of patients with well-characterized tumors [42].

	PROSPECTS

Top Abstract Introduction High-Dose Chemotherapy and the... The Toxicity of High-Dose... The Ability of High-Dose... High-Dose Chemotherapy in High... Developments in High-Dose... The Selection of High-Dose... Prospects References

 
It is clear that high-dose chemotherapy in advanced breast cancer is associated with a very high complete remission rate, almost certainly higher than that which can be achieved with conventional-dose therapy. Only a minority of these complete remissions can be maintained for many years. Most patients in complete remission after high-dose therapy have thus entered a state of minimal residual disease. Many new treatment options are emerging that raise hope that minimal residual disease can be converted to cure. Obviously, immunologic strategies could contribute, such as vaccinations against HER2-neu or other molecules that control various aspects of growth, differentiation, and survival. Some of the many new anti-angiogenesis factors entering clinical trials could be ideal to prevent the growth of micrometastases into clinically detectable lesions. For these and other treatment strategies, the ability to achieve cytoreduction by high-dose therapy may prove to be an essential component of a multistep approach to find one of the holy grails of medical oncology: the cure for high-risk and advanced breast cancer.

	References

Top Abstract Introduction High-Dose Chemotherapy and the... The Toxicity of High-Dose... The Ability of High-Dose... High-Dose Chemotherapy in High... Developments in High-Dose... The Selection of High-Dose... Prospects References

 

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