Abstract

Background:

The efficacy of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation for breast cancer (BC) has been an area of intense controversy among the medical oncology community. Over the last decade, due to the presentation of negative results from early randomized studies, this approach has not longer been considered an option by the vast majority of medical oncologists. This article is aimed to clarify what happened and where we are now in this not exhausted field.

Methods:

We critically revised the published literature regarding HDC in the setting of high-risk BC, including a recent meta-analysis using individual patient data from 15 randomized studies.

Results:

A significant benefit by HDC in recurrence-free survival has been clearly documented in unselected patient populations. In HER2-negative population, particularly in the triple-negative disease, a positive effect of intensified therapy in overall survival is biologically plausible and supported by clinical evidence. Over the years HDC with support of adequate number of stem cells has become a safe treatment modality.

Conclusions:

The administration of higher doses of chemotherapy with stem cell support may still represent a therapeutic option (and not a recommendation) in selected BC patients. This approach should be investigated further.

Breast cancer (BC) is the most common malignant tumor occurring in women and is a leading cause of cancer death worldwide (1). In 2013, it is estimated that there will be about 90000 and 40000 BC-related deaths among women in Europe (2) and in the United States (3), respectively. Survival rates have improved over the last decades due to both early diagnosis and the advance of systemic treatments, including cytotoxic chemotherapy (CT), endocrine therapy, and targeted therapy or combinations of these modalities, with selection mainly based on patient and tumor characteristics (4).

Adjuvant CT was introduced in the seventies demonstrating the efficacy on preventing relapse in patients with high-risk (HR) early-stage/locally advanced BC (4). The clinical correlation between dose intensity of CT, that can be achieved by either increasing the single dose per cycle (ie, higher dose) or by reducing the intervals between cycles (ie, dose density) (5), and outcome in HRBC has been subsequently described (6,7). Based on this evidence, nonrandomized studies conducted in the eighties and early nineties demonstrated apparent improvements for patients with HRBC receiving high-dose chemotherapy (HDC) (8,9). This led to the premature acceptance of HDC as a treatment option in the adjuvant setting (and for metastatic disease), also favored by a significant reduction of the morbidity and mortality of the procedure (10), and the number of transplants performed worldwide consistently increased during the 1990s (11). At the turn of the century, preliminary reports of randomized trials did not show a significant overall survival (OS) benefit of HDC (12), the scene was prematurely set for the demise of HDC in BC.

It is worth noting that positive phase I/II studies that provided the impetus for large prospective randomized trials in BC were all conducted in young, premenopausal, hormone receptor–negative women, whereas the large randomized trials included older, and both endocrine-responsive and endocrine-resistant women which may have significantly influenced the power of the studies.

In recent years the number of transplants has diminished and in fact this procedure is no longer an option for the vast majority of medical oncologists. In the era of great expectations for molecular therapies and novel treatment modalities, data from randomized studies demonstrating an OS benefit by HDC for HRBC (13,14) has gone almost unnoticed in the oncology community.

Recently, the first meta-analysis using individual patient data from 15 randomized trials comparing HDC with hematopoietic stem cell transplantation (HSCT) versus conventional CT (CCT) in HRBC has been published (15) showing, in the whole population, a significant benefit of HDC in recurrence-free survival (RFS) but not in OS. The authors conclude that HDC with HSCT for HRBC, as it was studied in these trials, does not produce sufficient benefit to be worthwhile. However, based on the data of subgroup analyses and on previous reports some authors believe that the clear-cut view of the meta-analysis is somehow questionable as HDC might be of potential benefit in selected patients, also considering the present limited toxicity of the procedure (16–19). It is important to underline the fact that HDC studies have been conducted in the absence of biological information therefore including many patients (ie, with HER2-positive tumor) for which we now know that the impact of CT is limited. Moreover, studies have consistently demonstrated, also recently, a survival benefit of dose-dense and dose-intense regimens not requiring hematopoietic support over conventional dosing schedule, thus becoming one of the standards of adjuvant CT for HRBC (20–22).

Randomized Phase III Trials and the Meta-Analysis of HDC in HRBC

The premature acceptance by the oncology community of HDC as a treatment option for BC led to a sort of “rush to transplantation” with up to nearly 2000 patients per year in the mid-1990s in Europe alone (Figure 1). Unfortunately, the vast majority of patients were treated outside prospective randomized studies so credible evidence for years remained at a low level, as it was based on phase II studies (8,9,23).

Figure 1.

Trend of HDC for breast cancer in Europe: 1992–2012; data from the registry of the European group for blood and marrow transplantation (EBMT). For 2012 data are incomplete.

Figure 1.

Trend of HDC for breast cancer in Europe: 1992–2012; data from the registry of the European group for blood and marrow transplantation (EBMT). For 2012 data are incomplete.

Since the early 1990s, a total of 15 randomized trials of HDC with HSCT in HRBC (13,14,24–36) (Table 1) have been conducted, 11 being published in peer-reviewed journals. These showed an advantage in RFS, which is often regarded as the primary endpoint for studies in medical oncology, while an OS benefit was observed in two modern European trials (13,14). In particular, the WSG AM 01 study (13) randomly assigned patients with greater than nine involved lymph nodes to receive either dose-dense CCT (ie, four·epirubicin/cyclophosphamide followed by three·cyclophosphamide, methotrexate, 5-fluorouracil q2w) or a rapidly cycled tandem high-dose regimen (ie, two·epirubicin/cyclophosphamide q2w followed by two·E90/C3000/Thiotepa400 q3w). Other than demonstrating an advantage in OS overall in the whole study population, younger patients with triple-negative (TN) BC and/or G3 tumors derived greater benefit from the rapidly cycled tandem approach than from the dose-dense conventional regimen. The high-dose approach lead to 5-year RFS rates as high as 71% in patients with TNBC compared with only 26% in TNBC patients treated by conventional dose-dense CT (37).

Table 1.

Randomized studies of high-dose chemotherapy in high-risk primary breast cancer; adapted from Martino et al. (19)*

First author (ref.) No. randomized patients Patient characteristics TRM, (%) Median FU, y Control arm HDC arm Outcome Control HDC P Comment 
Hortobagyi et al. (24) 78 > 9 LN+ 6.5 FEC × 8 FAC × 8 + CEC × 1/2 3 y RFS 62% 48% .35 Few pts, pts receiving adjuvant and primary CT included; some pts in HDC arm receiving SD and vice versa 
> 4 LN+ (after primary CT) OS 77% 58% .23 
Rodenhuis et al. (25) 97 infraclavicular LN+ FEC × 3, surgery, FEC × 1 FEC × 3, surgery, CTCb 4 y RFS 54%  ND No difference in survival, few pts, primary CT 
OS 75%  
Tokuda et al. (31) 97 > 9 LN+ FAC × 6 FAC × 6 + HD TC 4 y RFS 48% 60% ND Few pts 
OS 66% 67% 
Bergh et al. (32) 525 > 7 LN+ 0.7 Tailored FEC FEC × 3 + CTCb 3 y RFS 72% 63% .04 Higher dose intensity in the SD arm 
> 4 LN+, HR− OS 83% 77% .12 
Leonard et al. (34) 605 > 4 LN+ 1.6 D × 4 D × 4 + TC 5 y RFS 54% 57% .73 26 pts in HDC arm never treated. Weak control arm 
OS 64% 62% .38 
Zander et al. (29) 304 > 9 LN+ 2.4 3.8 EC × 4 EC × 4+ CTM 4 y RFS 42% 52% .09 Trend favors HDC in RFS (estimated RR = 0.75); short follow-up 
CMF × 3 OS 62% 70% .33 
Coombes et al. (30) 281 > 4 LN+ 2.3 5.7 FEC × 6 FEC × 3 + CTCb 5 y RFS 59% 57% .76 No subgroup analysis 
OS 67% 66% .4 
Tallman et al. (26) 540 > 9 LN+ 3.5 FAC × 6 FAC × 6 + TC 6 y RFS 47% 49% .55 Weak HDC arm, high TRM. RFS advantage in pts fulfilling eligible criteria (P = .045) 
OS 62% 58% .32 
Peters et al. (27) 785 > 9 LN+ 7.4 5.1 FAC × 4 + ID CPB FAC × 4 + HD CPB 5 y RFS 61% 58% .24 RFS advantage of HDC in pts <50 y (P = .02). High TRM; nonconventional control arm 
OS 71% 71% .75 
Roche et al. (33) 314 > 7 LN + 0.5 5.1 FEC × 4 FEC × 4 + CMA 5 y RFS 40% 59% .001 Mitoxantrone-containing HD regimen 
OS 68% 74% .17 
Gianni et al. (28) 382 > 3 LN + 0.5 4.3 E × 3 HDS 5 y RFS 62% 65% ND RFS advantage in younger pts and in pts with 4–9 LN+; abstract only 
CMF × 6 OS 77% 76% 
Basser et al. (35) 344 > 9 LN+ 0.5 5.8 EC × 4 + CMF × 3 HD EC × 3 5 y RFS 43% 52% .7 Survival advantage of HDC in pts with ER+ tumors (P = .02 and .05) 
> 5 LN+, ER− OS 61% 70% .12 
Rodenhuis et al. (14) 885 > 3 LN+ FEC × 5 FEC × 4 + CTCb 5 y RFS (Her2−) 59% 72% .006 Largest study so far. Overall RFS advantage of HDC in pts with > 10 LN+ 
OS (Her2−) 71% 78% .02 
Nitz et al. (13) 403 > 9 LN+ DD EC × 4 + CMF × 3 EC × 4 + ECT × 2 4 y RFS 44% 60% .0007 Very low toxicity in the HD arm. Greater advantage of HD in the triple-negative population (37) 
OS 70% 75% .02 
Moore et al. (36) 536 > 4 LN+ 1.1 5.8 DD A-T-C AC × 4 + CTCb or CPB 5 y RFS 80% 75% .32 Not conventional control arm 
OS 88% 84% .34 Two HDC regimens used 
First author (ref.) No. randomized patients Patient characteristics TRM, (%) Median FU, y Control arm HDC arm Outcome Control HDC P Comment 
Hortobagyi et al. (24) 78 > 9 LN+ 6.5 FEC × 8 FAC × 8 + CEC × 1/2 3 y RFS 62% 48% .35 Few pts, pts receiving adjuvant and primary CT included; some pts in HDC arm receiving SD and vice versa 
> 4 LN+ (after primary CT) OS 77% 58% .23 
Rodenhuis et al. (25) 97 infraclavicular LN+ FEC × 3, surgery, FEC × 1 FEC × 3, surgery, CTCb 4 y RFS 54%  ND No difference in survival, few pts, primary CT 
OS 75%  
Tokuda et al. (31) 97 > 9 LN+ FAC × 6 FAC × 6 + HD TC 4 y RFS 48% 60% ND Few pts 
OS 66% 67% 
Bergh et al. (32) 525 > 7 LN+ 0.7 Tailored FEC FEC × 3 + CTCb 3 y RFS 72% 63% .04 Higher dose intensity in the SD arm 
> 4 LN+, HR− OS 83% 77% .12 
Leonard et al. (34) 605 > 4 LN+ 1.6 D × 4 D × 4 + TC 5 y RFS 54% 57% .73 26 pts in HDC arm never treated. Weak control arm 
OS 64% 62% .38 
Zander et al. (29) 304 > 9 LN+ 2.4 3.8 EC × 4 EC × 4+ CTM 4 y RFS 42% 52% .09 Trend favors HDC in RFS (estimated RR = 0.75); short follow-up 
CMF × 3 OS 62% 70% .33 
Coombes et al. (30) 281 > 4 LN+ 2.3 5.7 FEC × 6 FEC × 3 + CTCb 5 y RFS 59% 57% .76 No subgroup analysis 
OS 67% 66% .4 
Tallman et al. (26) 540 > 9 LN+ 3.5 FAC × 6 FAC × 6 + TC 6 y RFS 47% 49% .55 Weak HDC arm, high TRM. RFS advantage in pts fulfilling eligible criteria (P = .045) 
OS 62% 58% .32 
Peters et al. (27) 785 > 9 LN+ 7.4 5.1 FAC × 4 + ID CPB FAC × 4 + HD CPB 5 y RFS 61% 58% .24 RFS advantage of HDC in pts <50 y (P = .02). High TRM; nonconventional control arm 
OS 71% 71% .75 
Roche et al. (33) 314 > 7 LN + 0.5 5.1 FEC × 4 FEC × 4 + CMA 5 y RFS 40% 59% .001 Mitoxantrone-containing HD regimen 
OS 68% 74% .17 
Gianni et al. (28) 382 > 3 LN + 0.5 4.3 E × 3 HDS 5 y RFS 62% 65% ND RFS advantage in younger pts and in pts with 4–9 LN+; abstract only 
CMF × 6 OS 77% 76% 
Basser et al. (35) 344 > 9 LN+ 0.5 5.8 EC × 4 + CMF × 3 HD EC × 3 5 y RFS 43% 52% .7 Survival advantage of HDC in pts with ER+ tumors (P = .02 and .05) 
> 5 LN+, ER− OS 61% 70% .12 
Rodenhuis et al. (14) 885 > 3 LN+ FEC × 5 FEC × 4 + CTCb 5 y RFS (Her2−) 59% 72% .006 Largest study so far. Overall RFS advantage of HDC in pts with > 10 LN+ 
OS (Her2−) 71% 78% .02 
Nitz et al. (13) 403 > 9 LN+ DD EC × 4 + CMF × 3 EC × 4 + ECT × 2 4 y RFS 44% 60% .0007 Very low toxicity in the HD arm. Greater advantage of HD in the triple-negative population (37) 
OS 70% 75% .02 
Moore et al. (36) 536 > 4 LN+ 1.1 5.8 DD A-T-C AC × 4 + CTCb or CPB 5 y RFS 80% 75% .32 Not conventional control arm 
OS 88% 84% .34 Two HDC regimens used 

*A-T-C = doxorubicin, placlitaxel, cyclophosphamide; AC = doxorubicin cyclophosphamide; CEC = cyclophosphamide, etoposide, cisplatin; CMA = cyclophosphamide, mithoxanthrone, alkeran; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CPB = cyclophosphamide, cisplatin, BCNU; CT = chemotherapy; CTCb = cyclophosphamide, thiotepa, carboplatin; CTM = cyclophosphamide, thiotepa, mitoxantrone; D = docetaxel; DD = dose dense, E = epirubicin; EC = epirubicin, cyclophosphamide; ECT = epirubicin, cyclophosphamide, thiotepa; ER = estrogen receptor; FAC = 5-fluorouracil, adriamycin, cyclophosphamide; FEC = 5-fluorouracil, epirubicin, cyclophosphamide; FU = follow-up; HD = high dose; HDC = high-dose chemotherapy; HDS = high-dose sequential; HR = hormone receptor; ID = intermediate dose; LN = lymph nodes; ND = no difference; OS = overall survival; pts = patients; RFS = relapse-free survival; RR = relapse rate; SD = standard dose; T = paclitaxel; TC = thiotepa, cyclophosphamide; TRM = transplant-related mortality.

Many studies showing only RFS advantage should be reanalyzed as they were published long before adequate follow-up for OS.

It is important to note that all HDC adjuvant studies included only patients with gross involvement of axillary lymph nodes at surgery (median: 12), regarded as a poor prognostic factor independently from other variables.

The recent meta-analyses of individual patient data from the HRBC phase III trials (15) has allowed a more precise definition of results with better statistical power overall and an improved likelihood of finding a subset effect. Of 6210 patients with HRBC who were randomized in the 15 trials, HDC achieved a significant 13% reduction in the risk of recurrence (hazard ratio [HR] = 0.87; 95% confidence interval [CI] = 0.81 to 0.93; P = .001) but no significant reduction in the risk of death (HR = 0.94; 95% CI = 0.87 to 1.02; P = .13), after a median follow-up of 6 years.

Are Toxicity and Costs a Limitation for HDC?

HDC has become substantially less toxic over time and today it should be considered a safe procedure (11,13) with a mortality rate and quality-adjusted survival parameters (38), similar to CCT. In fact, transplant-related mortality and morbidity has progressively decreased since the early times, possibly related to the widespread switch from bone marrow to peripheral blood HSC, the latter resulting in more rapid and durable trilineage hematopoietic recovery after HDC (39), and a better knowledge of the whole procedure and supportive measures (40,41). In addition, more toxic HDC regimens associated with high morbidity and mortality especially in low volume transplant centers with limited experience in this setting (8) are no longer used. Early studies included in the meta-analysis (15) showed unacceptably high transplant-related mortality (26,27), and these might distort the overall results (17). Indeed, when patients whose deaths attributed to toxicity were excluded, an advantage in terms of OS was observed in the HDC arm (HR = 0.90, 95% CI = 0.83 to 0.99; P = .011) (42). This does not obviously means that it is superior to CCT but this point should be regarded at least as hypothesis-generating.

In HRBC, complications occurring in the long term were similar in the two comparison groups of meta-analysis (15). Secondary malignancies categorized as myelodysplastic syndrome or acute myelogenous leukemia and organ toxicities were similar in patients receiving HDC or CCT. HDC does not seem detrimental to the chances of giving subsequent lines of CT in case of recurrence (39,40,43).

Myeloablative CT with HSCT is an highly expensive treatment modality as it requires extended hospitalization, intensive nursing care, and costly supportive measures (44,45). In contrast, when transplant of adequate number of peripheral blood HSC (10) is performed as a supportive measure following nonmyeloablative courses of CT, parenteral nutrition, intravenous antibiotics and transfusions are not often required and the procedure is feasible and safe even in the outpatient setting (46,47). Cost savings associated with outpatient-based HSCT, feasible in BC patients undergoing less intensive CT regimens (48), are relevant (49).

Finally, the question here is what is the real impact in terms of costs of HDC given in a limited number of patients, in comparison to the overall cost of conventional treatments often including the highly expensive target therapies?

Adequate Conventional Arm in HDC Randomized Trials?

HDC regimens, in terms of chemotherapeutic agents and drug dosage, varied among the randomized trials (Table 1). This is also the case for the standard arms; in some studies being radically different from what is considered CCT (27,32). The result of such heterogeneity is that the dose intensity, considered an important factor for outcome, may not always be greater in the HDC arm. Berry et al. carefully investigated this point by using the method of Hryniuk et al. (50), to check the average weekly dose intensity (the summation dose intensity [SDI]) and the total dose intensity over both the induction phase and the treatment phase (the SDI product). Both SDI and SDI product were associated with a statistically significant reduction in the risk of disease recurrence and death. Importantly, the total dose intensity over both the induction phase and the treatment phase, varied widely across trials, to such an extent that control arms had greater dose intensity than HDC arms in five of 15 trials (15). Over the 10 trials in which SDI product was greater in the HDC arm, a statistical significantly improvement of OS was observed. Some have argued that results of HDC are irrelevant as they were compared with “old fashioned” conventional treatments (51). However, among new antineoplastic agents introduced in the last two decades, taxanes are the only ones to show additional benefit over conventional antracycline-based schedules, and these have produced only limited survival advantage, if any, in the higher risk population for nodal status, that is, greater than three lymph nodes (52,53). As for targeted therapies, anti-HER2 molecules have considerably improved outcome in HER2-positive BC, which is the population unlikely to benefit from HDC (14,54). Other molecular-targeted agents, that is, bevacizumab and poly ADP ribose polymerase (PARP) inhibitors, the latter creating great expectations in TN disease from early studies, did not fulfill their promise when tested in prospective trials (55,56).

Finally, while taxanes and targeted therapies were not included in the control arms of all but two (34,36) of the HDC studies, they were also excluded from the HDC arms.

RFS as Primary Endpoint of the Effectiveness of a New Treatment?

In recent years, RFS has been often considered an appropriate way of evaluating a therapeutic approach, including adjuvant therapies, as it takes into account the risk of death associated with treatment, and is not influenced by old and newer treatments given after relapse (57). RFS and progression-free survival are indeed appropriate endpoints for the acceptance of new drugs/treatment modalities in oncology clinical practice (58–63).

In clinical decision making, any benefit in survival must be clearly weighed against the greater toxicities of a treatment modality. In the setting of HDC for BC patients, given the current limited toxicities and risk of mortality and the overall quality of life of patients undergoing modern transplant strategies, RFS might well be considered the primary endpoint.

Possible Benefit of HDC in Subgroups of HRBC Patients?

Studies of HDC in BC often lack of biomarker information, in particular the HER2 status. As a result, the meta-analysis (15) could not provide clear evidence of a benefit of HDC in any biomarker-based subgroups. However, an apparent OS benefit from HDC in patients harboring HER2-negative tumors, was documented. The benefit was more marked in the TN population, with a 33% reduction in the risk of death. While only 27% of the tumors had HER2 status available, these results derive from 1695 patients (337 were TN). To address whether this observation was real, Berry et al. compared patients who had hormone receptor–negative tumors and known HER2 status, with those who had hormone receptor–negative tumors but unknown HER2 status. Since little treatment effect was seen in the latter group, substantially less than in those with hormone receptor–negative tumors for which HER2 status was available, the authors concluded that “the triple-negative observation is likely to be spurious.” This additional statistic approach is questionable as not often used in medical oncology (63). A positive effect of HDC in HER2− population, particularly in TN tumors, is biologically plausible and supported by clinical evidence (14,37,53,64).

Additional data from the meta-analysis (15) looking at subsets based on HER2 and hormone receptor status and focusing on studies with high SDI product differences between the HDC and control arms, have been recently released (42). A recent meta-analysis of 10 randomized HR primary BC trials indicated that dose-dense intensification resulted in better RFS and OS with a clear benefit for patients harboring HER2-negative tumors (65).

A great opportunity to clarify the role of HDC in the HER2- population would come from analyzing the large banks of tissues that have been collected in prospective studies but not reported on. While positive results of HDC often included platinum-based regimens, which have proven useful in TNBC, such an analysis would support the hypothesis that particular subpopulations may be selectively benefited by HDC.

Conclusions

The majority of the oncology community believes that HDC is no longer applicable now that we have entered the era of targeted therapies (50) and personalized medicine (66). Such an assumption could be today reconsidered for the following reasons:

  • i) the prognosis of HRBC has changed very little in the past decades; in particular novel targeted therapies had a major impact only in the subset of patients with HER2-positive BC;

  • ii) an advantage in RFS, often sufficient for the approval of new antineoplastic agents, has been observed in most of the studies and in the meta-analyses of HDC for HRBC;

  • iii) In HRBC, two large European studies demonstrated an OS benefit by HDC consistent with the benefit in the HER2-negative (14) and TN populations (37).

  • iv) HDC with HSCT has become a safe and reasonably well-tolerated treatment modality that can be administered even in the outpatient setting.

When defining an HDC strategy, it is crucial to consider CT regimens with a low toxicity profile to avoid the unacceptable morbidity and mortality observed in the early studies. With the introduction of mobilized HSC collection techniques a large amount of HSC, far exceeding the thresholds required for engraftment, can be readily achieved. This permits an approach consisting of multiple cycles of higher doses of CT (nonmyeloablative) followed by the infusion of peripheral blood HSC after each cycle (13,67) in an attempt to increase the intensity of anticancer therapy beyond that achievable with conventional dose, dose dense or with single HDC approach. The “high dose-density” model could be invoked as an even more effective strategy for minimizing residual tumor burden (5,22). It has been used in other malignancies including multiple myeloma (68) and germ cell tumors (69). Recently, a retrospective analysis of the Italian transplant registry (GITMO) evaluating the outcome of 1183 HRBC patients undergoing an HDC program, demonstrated that patients who received multiple HDC had a statistically superior RFS and OS than those receiving a single HDC procedure (70).

In the adjuvant setting of HRBC, HDC with HSCT may still represent a therapeutic option for well-informed patients harboring HER2-negative tumors and having gross involvement of axillary lymph nodes. Further studies of HDC are advisable taking into account the clinical and biological information we currently have (and that are rapidly improving), that can be useful in selecting a target patients population more likely to benefit from CT given at higher than standard doses (71). TN/basal-like disease (72), characterized by: 1) a significantly increased risk of relapse or disease progression as well as distinct patterns of metastatic progress; 2) the lack of conclusive data on the optimal CT regimen to be proposed in HR patients; 3) the rather poor outcome of patients who do not achieve complete pathological remission to preoperative CT, may well represent a BC subtype suitable for investigating a “modern” HDC approach, that is, in the neoadjuvant setting.

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