Departments of 1Gynecology and Obstetrics, 2Internal Medicine V and 3Pathology, University of Heidelberg, Heidelberg; 4Department of Hematology and Oncology, University of Düsseldorf, Düsseldorf, Germany
Received 27 September 2001; revised 14 December 2001; accepted 17 January 2002.
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Abstract |
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The purpose of this study was to characterize long-term progression-free survivors (LTPFS) of metastatic breast cancer (MBC) following high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) and to assess the influence of chemotherapy dose in order to identify patients who derive major benefit from this approach.
Patients and methods
We compared patient and tumor characteristics of 16 LTPFS with the characteristics of 118 MBC patients who received HDCT with ASCT at our institution between 1992 and 2000. To estimate the cumulative dose of chemotherapy received, the summation dose intensity product (SDIP) of the different chemotherapy regimens was calculated as recently described by Hryniuk et al. The SDIP of the induction regimens was added to that of the HDCT regimens to yield the total SDIP of the chemotherapy received. Multivariate analysis was performed to describe the influence of the total SDIP and other prognostic factors on progression-free survival (PFS).
Results
LTPFS were mostly 50 years of age and had limited, chemotherapy-sensitive, hormone-responsive MBC. Due to an apparent dosesurvival relationship, an increase by 10 units (U) in the SDIP increased the PFS time by 3 months. Independent predictors of an improved PFS were positive estrogen receptors (P = 0.001), positive combined hormone receptors (P = 0.020), and a complete remission/no evidence of disease status after HDCT (P <0.001). In patients who had a disease-free interval (DFI) >24 months after primary surgery, an SDIP of >55 U was independently associated with a longer PFS [hazard ratio (HR) = 2.73; 95% confidence interval 1.295.81; P = 0.009].
Conclusion
HDCT can achieve long-term PFS in young MBC patients with limited, hormone-responsive and chemotherapy-sensitive disease. After a DFI >24 months, a longer PFS is associated with a higher chemotherapy dose as measured by SDIP. These retrospective analyses suggest SDIP might be a tool for studying cumulative dose as a determinant of outcome of MBC chemotherapy. Thus far, however, we cannot clearly identify any subgroup of MBC patients in whom HDCT with ASCT is of particular benefit.
Key words: high-dose chemotherapy, long-term progression-free survival, metastatic breast cancer, summation dose intensity product
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Introduction |
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Hryniuk et al. [13] created a single scale, the summation dose intensity (SDI), with which the dose intensity of all chemotherapy regimens in breast cancer can be compared. In randomized trials that tested dose intensity in MBC in the conventional range, response rates and median survival correlated linearly with the SDIs of the scheduled treatments. To account not only for different dose intensities but also for different cumulative doses of treatment regimens, Hryniuk et al. [14] proposed using the SDI product (SDIP) as a tool to compare chemotherapy regimens.
In order to characterize further MBC patients who might derive benefit from HDCT, we compared patient and tumor characteristics of our long-term progression-free survivors (LTPFS) with the characteristics of all 118 MBC patients who received at least one stem cell-supported HDCT as front-line (110 patients) or second-line treatment at our institution between 1992 and 2000. We correlated the SDIP of the different chemotherapy regimens with the patient outcome, and performed univariate and multivariate analyses to describe the influence of SDIP and other prognostic factors on PFS.
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Patients and methods |
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For all 118 patients, the following factors were examined in a univariate analysis: SDIPTOT (55 U versus >55 U), ER status (ER-positive/unknown versus negative), combined hormone receptor status [ER- or progesterone receptor (PgR)-positive/unknown versus ER- and PgR-negative], DFI after primary surgery (
24 months versus >24 months), visceral disease (yes versus no), number of metastatic sites (
2 versus >2), Possinger score (
10 versus >10), status after HDCT (CR/NED versus no CR/NED), and number of cycles of HDCT (one or two versus three). Variables that were significant in the univariate analysis were included in a multivariate analysis as stated above. Additionally, we examined the influence of SDIPTOT (
55 U versus >55 U) as a prognostic factor for PFS in various subgroups of patients, as listed in Table 4. If SDIPTOT (
55 U versus >55 U) proved to be significant according to univariate analysis, we performed a multivariate analysis including all the aforementioned factors, i.e. ER status, combined hormone receptor status, DFI after primary surgery, visceral disease, number of metastatic sites, Possinger score, status after HDCT, and number of cycles of HDCT.
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Results |
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Discussion |
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Our data confirm that 20% of MBC patients remain progression-free for >3 years following HDCT. The prerequisite was the achievement of a CR/NED status, as in all other patients disease progressed within 38 months. Achievement of CR/NED and no progression for longer than 3 years was more likely in younger patients (
50 years) with a lower tumor burden, i.e. with soft tissue metastases at one site only and a Possinger score
10. The response to HDCT was not related to the ER or combined hormone receptor status. LTPFS, however, were more often receptor-positive. This reflects, at least in part, the efficacy of antihormonal treatment in hormone-responsive MBC [19].
These results are in line with the findings of Rizzieri et al. [9] who analyzed 425 MBC patients. They found an increased long-term disease-free survival in ER-positive patients with smaller, non-visceral metastases and a longer DFI in those who received immediate or delayed HDCT. In a smaller study of HDCT in 20 MBC patients, all three LTPFS had predominantly nodal disease, and two of them achieved a CR after induction chemotherapy [20]. With respect to these characteristics, LTPFS after HDCT does not differ from LTPFS after conventional chemotherapy [2, 2125]. However, it is noteworthy that in our analysis the proportion of patients with overexpression of HER2/neu, which is associated with poorer outcome after conventional chemotherapy [26], is nearly the same among LTPFS as among all patients. Because of the small sample size one should be cautious in interpreting this observation; nevertheless, it could be hypothesized that HDCT might be able to overcome, at least in part, the unfavorable prognostic impact of HER2/neu overexpression. There was no appreciable impact of p53 positivity, S-phase fraction or DNA index, but too few data are available to draw valid conclusions regarding these factors.
We found no relationship between the PFS and the SDI, which accounts only for dose intensity and activity of each chemotherapy drug (data not shown). However, when we accounted for all three relevant factors, namely dose intensity, activity and cumulative dose of each drug, by using the SDIP, we observed an apparent dosesurvival relationship between the PFS of our patients and the SDIPTOT of the chemotherapy they received. The PFS increased by an average of 3 months for each increase of 10 U SDIPTOT. Besides the patients with an NED status as a result of surgical removal of metastases before chemotherapy, all patients with a PFS of 40 months had achieved a CR after HDCT and had received chemotherapy with an SDIPTOT of >55 U. To the best of our knowledge the relationship between SDIP and PFS in patients with MBC has not been evaluated by others either in the conventional or in the high-dose setting. Reports on most phase II and all phase III trials of HDCT in MBC lack exact information on induction chemotherapy. Therefore, SDIPTOT could not be calculated from the available data [11, 2729]. Hryniuk et al. [13] found a linear correlation between SDI as a single scale and survival of MBC patients in randomized trials that tested the influence of dose intensity in the conventional range. An increment of 1 SDI unit increased the median survival by 3.75 months. To account not only for the dose intensity and activity of different drugs but also for their total dose, the investigators proposed multiplying the SDI by the treatment duration to get an extended score, the SDIP, which was used in this analysis [14].
Positive ERs, positive combined hormone receptors, and CR/NED after HDCT remained independent prognostic factors for PFS in multivariate analysis, which confirmed our preliminary analysis on the first 76 patients [10] and agrees with the findings of others [2, 8]. The number of metastatic sites was no longer an independent prognostic factor, because it correlates with the probability of the achievement of a CR/NED, which has proven to be the strongest predictor of long-term PFS (P <0.001). Considering all 118 patients, only in univariate analysis did we find a non-significant trend towards better PFS for patients who received chemotherapy with an SDIPTOT of >55 U (P = 0.058). In patients with a DFI >24 months, however, an SDIPTOT >55 U was found to be an independent predictor of later relapse after adjustment for all other prognostic factors [HR = 2.73 (95% CI 1.295.81); P = 0.009]. It could be hypothesized that, in those patients, the higher-dosed chemotherapy was more capable of eradicating minimal residual disease, which persists in less aggressively treated patients, thereby leading to earlier relapse and ultimately death. On the other hand, this survival difference could result from a selection bias, as patients in better general condition with no disease progression during chemotherapywho intrinsically have a better prognosistolerated and received more cycles of chemotherapy. However, thus far two or more cycles of stem cell-supported HDCT have not improved survival of MBC patients as compared with one cycle of HDCT [10, 30, 31]. Prospective, randomized trials comparing different chemotherapy regimens as defined by different SDIPs are required to confirm our findings. Provided that an optimal HDCT regimen is chosen, SDIP should be increased by prolonging the induction chemotherapy rather than by adding multiple cycles of HDCT.
So far only one phase III study comparing stem cell-supported HDCT versus a conventional maintenance chemotherapy as consolidation treatment in patients with MBC has been published as a full paper [11]. This trial showed no difference in PFS and OS after 3 years of follow-up. It has, however, a number of limitations: small number of randomized patients (n = 199, only n = 45 complete responders); substantial number of treatment refusals and arm crossover (n = 15); almost twice the cumulative cyclophosphamide dose in the conventionally treated than in the high-dose group; suboptimal high-dose regimen (only 7% conversion from PR to CR); and possible tumor regrowth due to delay in the HDCT of up to 3 months. Three other randomized trials published in abstract form only found an improved PFS for patients treated with early HDCT [2729]. So far, there has been no improvement in OS, but the follow-up time of 23 years in two trials is still too short [28, 29]. Therefore, it is conceivable that a benefit of HDCT in a certain subgroup of patients could have been missed [3, 12]. However, it has to be stressed that thus far with our current knowledge we cannot clearly identify any subgroup of patients with MBC in whom HDCT with stem cell support is of benefit.
In summary, our data suggest that HDCT may be a possible tool for eradicating minimal residual disease, at least in patients 50 years of age or younger with hormone-responsive and chemotherapy-sensitive, limited MBC and a long DFI (>24 months). However, the authors are aware that retrospective analyses such as the present one are only useful for generating hypotheses. Prospective testing of chemotherapy doses as measured by SDIP is required to confirm our findings. Furthermore, HDCT with ASCT will only, if ever, solve the problem of breast cancer for a small group of patients. Therefore, it should be considered as one component of a multistep approach together with new strategies in order to improve long-term survival or even to cure those patients.
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Acknowledgements |
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Footnotes |
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