Metastatic breast cancer belongs to the group of moderately chemosensitive malignant tumors. Traditional combination chemotherapy regimens, such as cyclophosphamide/methotrexate/fluorouracil (CMF), fluorouracil/Adriamycin/cyclophosphamide (FAC), and others, are associated with objective response rates of 60% to 80%, including nearly 15% complete responses. The introduction of new active drugs such as paclitaxel (Taxol) and docetaxel (Taxotere) [2,3] has produced higher rates of objective and complete responses, but the disease essentially remains incurable, and the median survival of patients has not improved.
Newer strategies for effectively treating patients with metastatic breast cancer are clearly needed. Among the approaches under investigation, high-dose chemotherapy (HDCT) with autologous peripheral blood progenitor cell (PBPC) or bone marrow support has been extensively tested during the past 10 years. The results of phase II studies of metastatic breast cancer treated with conventional induction chemotherapy followed by HDCT have shown a complete remission rate of nearly 50%, with 15% to 20% long-term, disease-free survival.[4-6] Whether these results are due to the intrinsic antitumor activity of HDCT or reflect a bias due to the selection of good-risk patients is under discussion. Whatever the answer, more than 80% of patients with metastatic breast cancer treated with HDCT will eventually relapse. It is not known whether these relapsed patients are sensitive to or could tolerate chemotherapy.
To address that question, in 1993 the Hospital Universitario San Carlos initiated a pilot trial of salvage chemotherapy for patients with metastatic breast cancer that had progressed after HDCT with PBPC support. We designed a regimen exclusively composed of oral and intramuscular antimetabolites with activity in breast cancer,[1,7] in addition to biochemical modulation, with intramuscular methotrexate, oral UFT (tegafur and uracil), and leucovorin (the MUL regimen). This regimen was selected to avoid the chemotherapeutic side effects that could raise important concerns for the clinician as well as for the patient (ie, myelosuppression, alopecia, and intravenous administration of drugs).
The preliminary results of our study of salvage MUL chemotherapy in the treatment of metastatic breast cancer that has progressed after HDCT with PBPC support are presented here.
Eligibility criteria included histologically proven breast cancer, progressive metastatic tumor following HDCT with PBPC support, measurable or clearly evaluable disease, no central nervous system involvement, Karnofsky performance status
³ 50%, life expectancy of at least 2 months, and adequate liver and renal functions. A platelet count of at least 70,000/µL and a neutrophil count of at least 1,500/µL were also required.
Baseline assessment included a full history and complete physical examination with a specific record of all measurable and evaluable sites of neoplastic disease, complete blood cell (CBC) counts with differential, electrolytes, liver function chemistries, and a chest x-ray. Additional radiographic and echographic studies, as well as photographic records of all apparent cutaneous or nodal lesions, were obtained as clinically indicated to document measurable or evaluable disease. To avoid venous punctures, the CBC count, with differential, electrolytes, and liver function chemistries, was obtained only at the beginning of each new course of MUL chemotherapy. Echotomographies or computed tomographies (liver), chest x-rays (lung), bone x-rays (bone), and photographs (cutaneous/nodal lesions) were repeated every 2 courses to document the response to MUL.
The MUL regimen, shown in Table 1, consisted of intramuscular methotrexate, oral UFT (tegafur and uracil at a 1:4 molar ratio) in capsules containing 100 mg of Tegafur each, and oral leucovorin. Treatment was repeated every 21 days until the development of disease progression or life-threatening toxicity.
Prophylactic antiemetics were not used routinely. Patients who experienced some degree of nausea or vomiting were given oral thiethylperazine (6.5 mg twice a day). A 25% reduction in the dose of UFT was planned for courses subsequent to development of World Health Organization grade 4 myelosuppression during MUL administration. In the case of grade 3/4 diarrhea or mucositis, the treatment was stopped until recovery and then resumed with a 25% reduction of UFT.
Patients received at least two courses of MUL before response was evaluated according to World Health Organization criteria, with the exception of those with overt disease progression after the first course of treatment. These patients were categorized as having progressive disease and were considered assessable for response. Patients with stable disease, partial response, or complete response received MUL chemotherapy until progressive disease was evident or toxicity prevented the continuation of treatment. Response and toxicity were categorized according to World Health Organization criteria. At least 3 months of no changes were required to categorize the response as stable disease.
Between September 1993 and October 1996, 41 of the 75 metastatic breast cancer patients previously submitted to HDCT with PBPC at our institution presented with progression of the disease. Of those 41, 17 patients (over 40%) were not included in the study for the following reasons: central nervous system involvement (3 patients); neutrophil/platelet counts below protocol inclusion criteria (1); nonmeasurable, nonevaluable disease (4); and treatment in other institutions from which they were referred to the Hospital Universitario San Carlos for HDCT with PBPC (9). Of the 24 patients entered into the protocol, 21 are currently evaluable for response (3 other patients are initiating treatment).
The characteristics of the 21 evaluable patients are shown in Table 2. Most had extensive prior chemotherapy (including HDCT), presented with involvement of two or more organ systems, and had visceral disease. The median number of courses of MUL given per patient was 6, although some evaluable patients are still on treatment (Table 3). One patient received only 1 incomplete course of MUL because of early disease progression. She was considered evaluable for response according to an intention-to-treat analysis. Several patients were able to receive 6 or more MUL courses without developing significant toxicity.
One complete remission and 7 partial remissions have been seen so far among the 21 evaluable patients, for an overall response rate of 38%. An additional seven patients (33%) presented stable disease of at least 3 months duration. The MUL regimen was thus able to stop disease progression for 3 or more months in nearly 75% of the patients. Responses were seen in soft tissues, lymph nodes, lung, and liver. The antitumor activity of MUL was higher among relapsing patients who had been previously transplanted with a low tumor burden (complete remission or surgically resected metastases). Patients transplanted in complete remission or with no evidence of disease showed a 50% (4 of 8) response rate to MUL, while the response rate of patients transplanted in partial remission or with stable disease was 31% (4 of 13). Figure 1 shows the time to progression and overall survival of the 21 evaluable patients, according to the Kaplan-Meier survival estimation analysis. The median time to progression from the start of MUL was 6 months, and the median survival time was 9 months.
Table 4 shows the side effects of MUL. The regimen did not produce significant myelosuppression or alopecia. Diarrhea was the most frequent and troublesome toxicity encountered. Six patients (29%) had grade 2 or 3 diarrhea leading to UFT dose reductions. Emesis was also seen in 7 patients, but it was usually controlled with oral thiethylperazine in subsequent courses of therapy. Mild mucositis was recorded in only 2 patients. No toxic deaths were seen.
The combination of intramuscular methotrexate, oral UFT, and leucovorin seems to possess noticeable antitumor activity in patients with metastatic breast cancer who have progressed after HDCT with PBPC. In addition, the MUL regimen produces manageable toxicity, with diarrhea as the main toxicity. This is relevant to clinical practice, since the tolerance and sensitivity to chemotherapy of this patient population remains undetermined. As a matter of fact, many investigators assume that patients with metastatic breast cancer that has progressed after HDCT are not candidates for further chemotherapy, due to the low probability of response and their poor tolerance to cytotoxic drugs. Contrary to expectations, our study shows that these patients retain some sensitivity to chemotherapy and can tolerate chemotherapy regimens with low myelosuppressive potential. The excellent marrow function seen in our patients transplanted with PBPC autografts even suggests the possibility of using chemotherapy regimens of more myelosuppressive potential.
The preliminary results of our study with the MUL combination suggest that this regimen is active and well tolerated in treatment of patients with metastatic breast cancer that has progressed after HDCT with PBPC. Further follow-up and additional patients are needed to more fully define the activity and toxicity of the treatment. If the results of our study are confirmed, the MUL regimen could play a role as a salvage treatment for this heavily pretreated population. In addition, MUL should be tested as maintenance chemotherapy for metastatic breast cancer following HDCT with PBPC support.
The activity shown in patients transplanted in complete remission or with surgical resection of metastases, whose relapses may be due to regrowth of tumoral cells reinfused with the product of leukapheresis, suggests that post-transplant MUL chemotherapy may play a role as in vivo purging of reinfused tumor cells. MUL could also be effective in eradicating residual tumoral clones of low growth potential, which are postulated to be insensitive to HDCT.
A feasibility pilot study of post-transplant MUL chemotherapy is warranted. If this is found to be well tolerated, the possibility of a randomized study comparing post-transplant MUL chemotherapy with observation in metastatic breast cancer patients treated with HDCT and PBPC should be seriously discussed.
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