Role and limits of salvage chemotherapy in breast cancer patients treated with high-dose chemotherapy

Z. Sirotovà*, A. Tartarone, M. Aieta, F. Morelli and S.S. Toma

Casa Sollievo della Sofferenza Hospital, via Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy

*E-mail: zuzka@virgilio.it

High-dose chemotherapy (HDC) with autologous peripheral blood progenitor cell support for breast cancer has been widely investigated in phase III clinical trials [1]. The majority of transplanted patients relapse, but the most appropriate treatment for them has not yet been established. In the literature, there are few data regarding salvage chemotherapy after HDC. Martin et al. used a combination of methotrexate, oral tegafur plus uracil and leucovorin to treat 24 patients with metastatic breast cancer who had relapsed after HDC [2]. The response rate was 38%, including one patient who achieved a complete response, while median progression-free survival and overall survival (OS) were 6 and 9 months, respectively. Zambelli et al. published data on salvage treatment with a 4-day infusion of fluorouracil plus vinorelbine in 48 heavily pretreated metastatic breast cancer patients (14 of 48 relapsed after HDC) [3]. The authors reported an overall response rate of 50%, with a median duration of response of 9 months and a median survival of 16 months. In our single institutional trial, with 32 metastatic breast cancer patients treated with epiribicin and/or paclitaxel at relapse after HDC, we obtained an overall response rate of 57%, with a median time to progression and a median survival of 7 and 27.5 months, respectively [4]. The main reported toxicity was a World Health Organization (WHO) grade 3–4 neutropenia observed in 25% of patients. The patients who relapsed again after this salvage treatment underwent another line of chemotherapy with infusional fluorouracil and vinorelbine, obtaining an overall response rate of 23%, including one complete response, with a median time to progression of 8 months and a median OS of 16.5 months [5].

The role of a second course of HDC as salvage treatment was investigated by Bearman et al. in 26 metastatic breast cancer patients [6]. The authors concluded that second transplants as salvage treatment are generally well tolerated, but their efficacy is modest. Recently, Rodenhuis et al. published the largest randomised trial comparing HDC with standard dose chemotherapy, conducted in the adjuvant setting [7]. In this trial 885 patients were randomised to receive (post-operatively) five cycles of 5-fluorouracil 500 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 500 mg/m2; q21 (FEC) or four cycles of FEC followed by HDC. The 5-year relapse-free survival rates were 59% in the conventional-dose group and 65% in the high-dose group (in the group with >=10 positive nodes, the relapse-free survival rates were 51% and 61% in the conventional-dose and HDC groups, respectively), while at a median follow-up of 57 months there was no significant difference in OS between the two groups. In this study, the influence on survival of subsequent treatments was not investigated; however, considering that at relapse all patients underwent similar regimens, the results in terms of survival were equivalent in the two patient groups.

How then should patients who relapse after HDC be treated? As with patients pretreated with standard-dose chemotherapy, the goals of chemotherapy in HDC patients are to obtain maximum control of symptoms, to prevent serious complications and to increase survival with an acceptable side-effect profile. The problem of toxicity has been particularly emphasised in HDC-pretreated patients. However, from the reported review of clinical trials and from our own experience, it seems that previous HDC does not significantly modify tolerability of subsequent chemotherapy. Even if most transplanted patients have already received anthracycline–taxane-containing regimens, several drugs in combination or as single agents are currently available for this purpose, including docetaxel (in patients pretreated with paclitaxel), fluorouracil, gemcitabine, vinorelbine, mitomycin c and novel oral therapies (capecitabine, vinorelbine).

Finally, patients who have failed a previous transplant would be ideal candidates for novel approaches, such as use of new agents, molecular targeted therapy, antiangiogenetic factors and gene therapy.

Z. Sirotovà*, A. Tartarone, M. Aieta, F. Morelli & S.S. Toma

Casa Sollievo della Sofferenza Hospital, via Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy (*E-mail: zuzka@virgilio.it)

References

1. Nieto Y. The verdict is not in yet. Analysis of the randomised trials of high-dose chemotherapy for breast cancer. Haematologica 2003; 88: 201–211.[ISI][Medline]

2. Martin M, Casado A, Lopez-Martin JA et al. UFT/methotrexate/leucovorin for breast cancer patients in progression after HDCT/PBPC support. Oncology 1997; 11: 82–85.

3. Zambelli A, Robustelli della Cuna FS, Ponchio L et al. Four-day infusion of fluorouracil plus vinorelbine as salvage treatment of heavily pretreated metastatic breast cancer. Breast Cancer Res Treat 2000; 61: 241–247.[CrossRef][ISI][Medline]

4. Tartarone A, Sirotovà Z, Aieta M et al. Salvage treatment with epirubicin and/or paclitaxel in metastatic breast cancer patients relapsed after high-dose chemotherapy with peripheral blood progenitor cells. Tumori 2001; 87: 134–137.[ISI][Medline]

5. Sirotovà Z, Cilenti G, Aieta M et al. Salvage treatment with vinorelbine and protracted 5-fluorouracil infusion in metastatic breast cancer patients relapsed after high-dose chemotherapy. Rome: Associazione Italiana di Oncologia Medica 2003; In press (Abstr A18).

6. Bearman SI, Vredenburgh JJ, Cagnoni PJ et al. High-dose therapy with autologous hematopoietic cell support as salvage treatment for patients with breast cancer who have relapsed after previous high-dose chemotherapy. Bone Marrow Transplant 1999; 24: 491–495.[CrossRef][ISI][Medline]

7. Rodenhuis S, Bontenbal M, Beex LVAM et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003; 349: 7–16.[Abstract/Free Full Text]





This Article
Full Text (PDF)
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Sirotovà, Z.
Articles by Toma, S.S.
PubMed
PubMed Citation
Articles by Sirotovà, Z.
Articles by Toma, S.S.