Director, Medical Oncology A, Istituto Nazionale Tumori, Milan, Italy
The results of two studies of high-dose chemotherapy (HDCT) for the management of breast cancer appear in this issue of Annals of Oncology [1, 2]. The two reports come at a time when the field of HDCT for breast cancer appears in a protracted phase of very little appeal to doctors and patients alike. The very high expectations and excitement surrounding HDCT in the 1990s were countered by the preliminary results of large randomized studies showing that HDCT added only minor or no benefit to conventional-dose therapy [37]. In addition, the oncological community was set back by the shocking knowledge that the Bezwodas trials, reporting a therapeutic advantage from HDCT, were plagued by fabricated data [8, 9]. In such a scenario of minor or even bluntly negative consideration for the role of the HDCT approach, the articles appearing in this issue of Annals of Oncology rank among the list of negative reports. As such, should they simply be viewed as confirming evidence that HDCT has no role for women with breast cancer?
The field of HDCT for breast cancer has suffered in a major way from the fact that such a demanding and sophisticated therapeutic approach was acclaimed and widely applied to women at all stages of breast cancer based on expectations rather than data. Now data are becoming available, they should be considered without the distraction and impediment originating from the unmet expectations.
The work of Schrama et al. [1] updates, at 7 years of follow-up, the results of a phase II randomized study that was the basis for the large Dutch National phase III study [10]. As such, it is the first report of mature data for HDCT in the adjuvant setting. The fact that it does not show a statistically significant relapse-free survival advantage in favor of HDCT does not necessarily lead to the conclusion that the therapeutic modality is useless. As the authors rightly point out, the size of the study, that mainly had the practical goal of exploring the feasibility of the approach in view of launching a subsequent nation-wide multicenter initiative, could not detect any difference smaller than 30% between arms. Indeed, differences in favor of HDCT may be present for women with smaller tumor size at diagnosis, and fewer axillary lymph nodes after induction chemotherapy, as suggested by their univariate analyses [1]. This trend is in keeping with the report of the preliminary findings of the larger Dutch National study showing a 20% reduction of the odds of relapse at almost 3 years of follow-up [10]. Of note, fewer relapses in the high-dose arm were also reported in a recent update of the American Intergroup trial, which failed to show a significant advantage probably because of the high toll of toxic deaths that occurred in the first years of the study [5]. In addition, a trend towards an advantage for younger women (age <35 years) and women with four to nine involved axillary lymph nodes was also shown in the Italian study of the Michelangelo Group, in spite of a lack of an overall benefit after median 5 years of follow-up [6].
In summary, the data presented by Schrama et al. [1] do not close the door on HDCT for breast cancer, in the adjuvant setting. Rather, they suggest, together with the preliminary data from other trials and from the tandem Dutch National study, that the benefit for the average patient with high risk breast cancer is not of the large magnitude that would show as a significant difference with the relatively small adopted sample size. This point is not only legitimate, but also appropriate when considering that almost all trials of HDCT for high risk breast cancer were designed in the early 1990s and the numbers of patients to be accrued were calculated based on the historical results available at those times. Indeed, the comparison of non-randomized series with historical controls indicated a possible large therapeutic benefit [11]. As they are coming to fruition, the results of almost all prospective randomized trials show a performance of the conventional-dose comparator arm that is substantially better than predicted. Such a consistent finding suggests that something different from bad planning has occurred. Indeed, in the years when the HDCT trials have been enrolling their patients the use of hormonal therapy has become customary. The application of irradiation has become similarly widespread, along with doctors awareness that appropriate dose-intensity should be maintained at the cost of some additional toxicity when administering conventional doses of adjuvant chemotherapy. As predicated by R. Peto when commenting on the important trend towards a sizeable reduction in breast cancer mortality in several countries in the past 10 years [12], small improvements may add up to a large beneficial effect, and a similar explanation may well apply to the unexpected performance of conventional therapy in the comparator arms of HDCT trials. This once again suggests that we should wait before commemorating the failure of adjuvant HDCT for high risk breast cancer, but also calls for the introduction of greater scrutiny of data that caters for the growing demand for treatment tailoring. A minor advantage for the average patient may hide a large benefit in a small subgroup. In this respect, the study by Schrama et al. was of a size that did not allow for detection of such a group of patients [1]. However, the larger American and European studies should be thoroughly investigated to uncover those characteristics that define any subgroup of women who benefit more from the application of HDCT than from conventional-dose chemotherapy. The opportunities offered by current biological knowledge and available technology can make this type of investigation very powerful and fruitful.
The need for identifying patients who derive advantage from HDCT is the driving rationale behind the other report appearing in this issue of Annals of Oncology, in which Schneeweiss et al. retrospectively explore whether women with metastatic breast cancer who underwent HDCT and are long-term progression-free survivors had any distinctive characteristics that could define a separate subgroup for whom HDCT may be justified [2]. Only 16 such patients were identified compared with 118 patients with metastatic breast cancer who also underwent HDCT at the same institution. While confirming that around 20% of patients with metastatic breast cancer remain free of progression after HDCT, the data presented by Schneeweiss et al. indicate that HDCT can achieve long-term progression-free survival in women with hormone-responsive, chemotherapy-sensitive, oligometastatic disease [2] who cannot otherwise be better and more specifically characterized. This observation is not new, as it also appears in other analogous and even recent reports in the breast cancer literature [1315].
New information emerging from the work of Schneeweiss et al. is that maintainance of a long progression-free survival is associated with a higher summation dose intensity product (SDIP). This is a far from intuitive measure proposed by Hryniuk et al [16] that takes into account the sum of the planned dose-intensity of individual drugs divided by their unit dose intensity, the intended treatment interval between cycles, and the number of administered cycles. As such it is a measure of dose size, dose intensity and cumulative dose, and also a measure of the duration of the entire treatment administered to a patient. Overall, that measure proved to be an independent predictor of progression-free survival only in the subset of patients with a disease-free interval longer than 24 months, and only when the SDIP of induction chemotherapy was added to the SDIP of the HDCT [2]. Because of this, the article does not contribute to answering the critical question of whether that subgroup of oligometastic patients would have derived a similar benefit from conventional chemotherapy of similar SDIP. Such a point could only be addressed and solved by a controlled trial. The relevance of addressing such a question is not minor because the possibility of achieving a cure, even in a subset of metastatic breast cancer patients, would not only support the ad hoc application of HDCT, but would also justify a more intensive monitoring of patients in follow-up after adjuvant therapy to allow for the early diagnosis of metastases and identification of patients as candidates for HDCT [17].
In summary, the two articles in this issue of Annals of Oncology do not contribute to burying the application of HDCT for women with breast cancer. Even if unsupported expectations were disappointed, application of HDCT is no longer associated with a high risk of mortality and remains a therapeutic option capable of very high antitumor activity. Addition of novel agents to a state of minimal residual disease after HDCT may contribute to eradicating breast cancer in an adjuvant setting as well as in metastatic disease [18, 19]. Now that initial enthusiasm has waned, the field, that has already contributed so much in terms of technological advances and medical care, is ready to review the administration of HDCT as one of the normal therapeutic options in search of appropriate, specific indications. These two articles point in this direction. The maturing of data from large controlled trials will represent a unique opportunity for defining such indications and promoting better trial designs. Overall, the possibility that HDCT for breast cancer will contribute to the unrelenting sum of advances that are improving the breast cancer mortality rate is still fully conceivable and possible.
L. Gianni
Director, Medical Oncology A, Istituto Nazionale Tumori, Milan, Italy
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