Megestrol acetate: Phase II study of a single daily administration in advanced breast cancer

Summary A new formulation of megestrol acetate, a semisynthetic oral progestin used in the hormonal treatment of breast cancer, allows the administration of 160 mg of the drug in a single daily dose. Sixty-nine postmenopausal patients with advanced breast cancer have been treated with this regimen: five patients received megestrol acetate as first-line treatment of their metastatic disease, while all the others had been previously treated with one or more regimens of chemotherapy and/or hormone therapy. The median duration of the treatment for evaluable patients was 3 months (range 1–13+). Among 65 evaluable patients 2 complete responses and 12 partial responses (objective response rate 21.5%; 95% confidence limits 12.31%–33.49%) were observed. Median duration of response was 7 months (range 2–12+). Responses were observed both in visceral and in non-visceral sites of disease. Twenty-nine patients obtained a stabilization of disease (44.7%), and twenty-two progressed (33.8%). Median duration of stabilization was 4 months (range 3–13+). Median survival for all patients from the start of megestrol acetate was 9 months (range 1–22+). The most common side effect of therapy was weight gain, occurring in 36% of patients. Megestrol acetate on a single-daily-dose schedule can be considered as an interesting hormonal treatment for advanced breast cancer, especially in the clinical instance of patients who, after having obtained a remission or stabilization of disease with tamoxifen, need further palliative treatment.     

High-dose epirubicin and cyclophosphamide every two weeks as first-line chemotherapy for relapsing metastatic breast cancer patients

Background: Metastatic breast cancer remains incurable with conventional chemotherapy. For any specific chemotherapy, higher dose intensity may be achieved with either increased doses per cycle, or shortened intervals between courses, or both. We demonstrate here the feasibility and encouraging results of a high-dose combination regimen administered every two weeks.Patients and methods: Women with metastatic breast cancer were treated every 14 days for 6 courses with 75 mg/m² epirubicin and 1200 mg/m² cyclophosphamide, followed by conventionally-delivered (q 3–4 weeks) chemotherapy. The treatment was to be resumed regardless of the neutrophil count, except in instances of febrile neutropenia. Prophylactic oral antibiotherapy was given, while hematopoietic growth factors and stem cell support were not employed.Results: Eighty-six patients were treated between May 1986 and June 1995. Their median age was 43 years (26–69). Grade 3–4 neutrophil toxicity was observed after 86% of the courses, resulting in febrile neutropenia in 5%–18% of the patients, and the rehospitalization of 5%–10%. The median given/planned dose intensity was 97% (79–106). The objective response rate in 84 evaluable patients was 54% (95% confidence interval (95% CI): 43–65), with a complete response rate of 11%, and a 14% rate of outright progression. Median progression-free survival was 16 months and median overall survival 32 months. Multivariate analysis retained previous adjuvant chemotherapy as a negative survival prognostic factor.Conclusions: This dose-intensive anthracycline-based regimen is feasible with manageable morbidity despite pronounced myelotoxicity, and yields encouraging survival rates.     

Phase II study of weekly mitoxantrone, 5-fluorouracil,and leucovorin in metastatic breast cancer

Summary A phase II study to test the toxicity and the efficacy of a weekly combination of Mitoxantrone, 5-Fluorouracil and L-Leucovorin (MFL) was carried out in 43 patients with metastatic breast cancer. Chemotherapy consisted of mitoxantrone 4 mg/m², 5-fluorouracil 375 mg/m², and L-leucovorin 100 mg/m² on day 1, weekly. Patient characteristics were: median age 53 years (range 36–65); estrogen receptor (ER) status was known in 26 patients and of these 15 (57.7%) patients were ER-positive and 11 (42.3%) ER-negative. Of the 43 patients, 25 (58.1%) and 18 (41.9%) patients had received prior adjuvant chemotherapy and prior adjuvant endocrine treatment, respectively. MFL was administered to 22 (51.1%) patients as first line chemotherapy for advanced disease, while 21 (48.9%) patients had received 1 to 2 cytotoxic regimens for metastatic disease. The dominant sites of metastases were: soft tissue in 11 (25.5%) patients, bone in 8 (18.6%) patients and viscera in 24 (55.9%). All patients were assessable for toxicity: only 8 patients experienced WHO grade 3 leukopenia. Thrombocytopenia, diarrhea, stomatitis, and nausea/vomiting were negligible. Anemia and alopecia were not observed. Thirty-nine patients were assessable for response: overall response rate was 28.2% (complete response 7.7% and partial response 20.5%). Median duration of response was 12 months (range 6–34). Patients with no prior anthracyclines had a 42.1% response rate compared to 15% in patients who had received anthracyclines. Median overall survival of the 43 patients was 6 months (range 1–34). Weekly MFL is a well-tolerated and a moderately effective regimen for the treatment of metastatic breast cancer.     

Four-drug sequential regimen in advanced breast cancer

Summary The results of two empirically designed and potentially non-cross-resistant combinations administered sequentially in advanced breast cancer with the intent of achieving a high rate of durable complete remissions were analyzed. The two drug combinations consisted of cyclophosphamide plus Adriamycin and high-dose methotrexate plus cisplatin given for a total of three cycles; twenty evaluable patients, not previously treated with chemotherapy, were entered into the study. Ten patients were allocated to receive cyclophosphamide and Adriamycin first followed by high-dose methotrexate and cisplatin, while the remaining patients received the opposite sequence. The overall response rate for the entire group was 85% (17 of 20). However, only three of 20 (15%) patients achieved complete remission. One additional complete response was observed when treatment was prolonged for an additional complete cycle. The overall median duration of response was 13 months (range, 5–20⁺ months). Responses were similarly distributed among different sites of lesions. Myelosuppression and gastrointestinal toxicity were mild and transient. Reversible acute renal failure was observed after methotrexate administration in three cases. Present results indicate that overall this sequential treatment appears effective in patients with advanced breast cancer. However, the lack of an increased complete remission rate over conventional regimens coupled with a potential risk of renal toxicity prevents further studies with this multiple drug combination.     

Phase II trial of 5-fluorouracil and folinic acid in the treatment of advanced breast cancer

Summary Standard combination chemotherapy for metastatic breast cancer produces response rates between 30–60% with limited impact on survival. We undertook a phase II trial to determine the activity of 5 fluorouracil (5FU) and folinic acid (FA) in patients with measurable metastatic or recurrent breast cancer who had received no prior chemotherapy. Patients meeting the eligibility criteria received 5FU 370 mg/m²/day and FA 200 mg/m²/day for 5 days repeated every 28 days, toxicity allowing. Response defined by standard criteria was assessed every 8 weeks and toxicity according to WHO criteria was determined on every course. Thirty-three patients were entered on trial. Thirty-two patients were evaluable for response and 33 for toxicity. The dose limiting toxicity was stomatitis with 7/32, 19/32, and 5/32 patients experiencing grade 1, 2, and 3 toxicity. Grades 1 and 2 diarrhea occurred in 17/32 and 11/32 patients respectively. Myelosuppression was not significant. Two complete and 11 partial responses were observed. The overall response rate was 41% (95% CI, 24–58%). Responses were seen in soft tissue and visceral sites. Patients who had received adjuvant chemotherapy more than 6 months prior to receiving 5FU and FA responded also. Six of 29 patients receiving standard combination chemotherapy as second line treatment responded subsequently. We concluded: 1) 5FU and FA is an active combination in the treatment of breast cancer warranting further evaluation in combination with other drugs; 2) the dose-limiting toxicity of stomatitis is tolerable; 3) patients receiving 5FU and FA as first line therapy can respond to conventional combination chemotherapy as second line treatment.     

多西紫杉醇联合长春瑞滨治疗蒽环类耐药性转移性乳腺癌的疗效分析

目的：观察多西紫杉醇、长春瑞滨联合方案在对蒽环类耐药转移性乳腺癌治疗中的疗效及不良反应。方法：蒽环类耐药性转移性乳腺癌35例，予多西紫杉醇联合长春瑞滨化疗，21天为1周期，至少用2周期。用世界卫生组织的疗效和抗肿瘤药急性及亚急性毒性反应分度标准评价疗效及毒性。结果：在35例可评价疗效的患者中，完全缓解10例，部分缓解13例，有效率为65．7％，临床获益率91．4％。不良反应主要骨髓抑制、脱发、消化道反应，但均可耐受，无化疗相关死亡。结论：该方案治疗蒽环类耐药性转移性乳腺癌患者，疗效较好，不良反应可耐受。     

A phase II trial of circadian-timed paclitaxel and cisplatin therapy in metastatic breast cancer

Purpose: In a phase II study with combination paclitaxel and cisplatin inmetastatic breast cancer using circadian timing, we attempted to maximiseresponse and minimise toxicity.Materials and methods: Forty-one patients with histologically-provenmetastatic breast cancer with or without previous chemotherapy were treatedwith Paclitaxel 135 mg/m² administered as a three-hourinfusion at 06.00 hours followed by cisplatin 75 mg/m² as aone-hour infusion at 18.00 hours utilising circadian timing. Six cycles wereplanned once every 21 days. Response assessment was performed every twocycles, and toxicity was measured using WHO criteria.Results: All patients were evaluable for response and toxicity. There werenine (22%) complete responses (CR), and 24 (59%) partialresponses (PR), for an overall response rate of 80% (95%confidence interval (CI) 69–92). Responses were seen in patientspreviously treated with anthracyclines (75%) (95% CI57–92), and in patients who had had no prior chemotherapy (90%)(95% CI 71–100). Responses were seen in all metastatic sites:liver 80%, lung 76%, bone 69%, and soft tissues71%. The overall median response duration was seven months (range3–26, 95% CI 5.0–9.8), and 14 of the responses(42%), (95% CI 28–62) were durable. A total of 212 cyclesof chemotherapy were given. There were 15 episodes (7%) of grade3–4neutropenia, seven (3.2%) of grade 3–4 neurologic toxicity, andthree(1.4%) of grade 3–4 nephrotoxicity. There were no toxic deaths.Conclusion: The combination of paclitaxel and cisplatin is very effectivein metastatic breast cancer, and with application of circadian timing,toxicity has been acceptable. This combination is being tested as primarytherapy in locally-advanced breast cancer at our institution.     

Docetaxel plus vinorelbine as salvage chemotherapy in advanced breast cancer: a phase II study

Précis Administration of a combined regimen of docetaxel plus vinorelbine every 4 weeks is feasible and shows activity in heavily pretreated patients with advanced breast cancer. Purpose. To determine the activity and tolerance of docetaxel plus vinorelbine in heavily pretreated patients with advanced breast cancer. Methods. Thirty-five metastatic breast cancer patients with ECOG performance status of 0–2 received docetaxel (80 mg/m² given intravenously) on day 1 and vinorelbine (30 mg/m² given intravenously) on days 1 and 14, every 4 weeks. The median number of prior chemotherapy regimens was 2 (range: 1–4). Twenty-five patients (71.4%) had been treated previously using intensive therapy approaches with peripheral blood-derived stem cell (PBSC) support, including high-dose chemotherapy (11 patients), multicyclic dose-intensive chemotherapy supported with repeated PBSC infusions (seven patients), or both (seven patients). Twenty-eight patients (80%) received previous chemotherapy for metastatic disease. Adjuvant therapy in the remaining seven patients consisted of high-dose chemotherapy and PBSC support or an anthracycline-containing regimen. Results. The total number of courses was 229, and the median number of courses per patient was 6 (range: 1–16). There was one toxic death (2.8%). Grade 3–4 toxicities included mucositis (17.1%), neutropenia (37.1%), anemia (5.7%), vomiting (2.9%), and asthenia (14.3%). Eighteen patients (58%; 95% CI: 40.6–75.4%) achieved an objective response, including four complete responses (12.9%) and 14 partial responses (45.1%). Overall response rate was 51.4% (95% CI: 34.8–67.9%). After a median follow-up of 20 months (range: 2–42), overall survival was 20 months (95% CI: 16–24), and median time to progression was 13 months (95% CI: 7–19). Conclusion. This combination shows activity and an acceptable toxicity profile in patients with advanced breast cancer.     

Late intensification with high-dose melphalan and autologous bone marrow support in breast cancer patients responding to conventional chemotherapy

Summary Fifteen patients with advanced breast cancer who had achieved either a good partial or a complete response to conventional chemotherapy were selected to receive intensification treatment with high-dose melphalan 140–200 mg/m² (HDM). All patients received autologous bone marrow rescue. All patients experienced marked haematological toxicity, and most experienced moderate or mild gastrointestinal side effects. There were three treatment-related deaths. Of twelve assessable patients eleven have relapsed; median time to relapse after HDM is 7 months. Nine of these eleven have died from recurrent breast cancer. Of the three patients remaining alive, only one is disease-free, at 18 months after HDM. Analysis of the pattern of metastatic relapse suggests that recurrence was due to failure of HDM to eradicate residual disease in the patient, rather than reinfusion of viable tumour cells. Treatment intensification with HDM has not succeeded in prolonging survival in patients already in good remission.     

High-dose induction chemotherapy of metastatic breast cancer in protected environment: a prospective randomized study

To test the hypothesis of whether high doses of chemotherapy in combination achieve higher response rates and longer durations of response and survival, we treated 33 pre- and perimenopausal patients with good performance status in a prospective trial with escalating doses of fluorouracil, doxorubicin and cyclophosphamide (FAC). Patients were randomly assigned to be treated within a protected environment (laminar air flow room), with prophylactic antibiotics, or in a standard hospital room. Important patient characteristics were equally distributed in the two treatment arms. A major objective response was observed in 27 of the 32 evaluable patients (84%), and 11 (34%) achieved a complete remission (CR). There was no significant difference in overall and complete response rates between the two treatment arms, nor was there a substantial difference in times to progression or survival between the groups treated in or out of the protected environment. Comparison of the results of this study with previously reported programs of FAC chemotherapy in patients with metastatic breast cancer shows that this study achieved higher overall and complete response rates. However, neither the time to progression, nor the survival of responders or the entire patient group was different from our previous experience with standard FAC chemotherapy. When the study was initiated in 1976, the proposed dose escalation represented high-dose chemotherapy. In retrospect, even the "high" doses used in this study represent only a modest increase over standard doses of chemotherapy. Much steeper dose escalations will be needed to evaluate the efficacy of high-dose chemotherapy in breast cancer, as well as the protective value of the protected environment and prophylactic antibiotics in metastatic breast cancer.     

Combined chemoimmunotherapy for advanced breast cancer: a comparison of BCG and levamisole.

One hundred and fourteen evaluable patients with metastatic breast cancer were treated with a program consisting of 5-FU, Adriamycin, cyclophosphamide (FAC) and nonspecific immunotherapy with Levamisole. The results of this treatment program were compared to those observed with FAC and Bacillus Calmette Guerin (BCG) and FAC chemotherapy alone, both groups treated prior to the study reported in this paper. The overall response rates and complete response rates for all three treatment regimens were identical. The duration of remission, survival of all patients and survival of responders was similar for both chemoimmunotherapy regimens, being superior to the FAC chemotherapy alone group. Immunotherapy with Levamisole was well tolerated and side-effects were experienced by less than one-fourth of the patients. Overall, Levamisole was better tolerated than BCG and was easier to administer than the latter drug. These results suggest than nonspecific immunotherapy with Levamisole might prolong remission and survival of patients with metastatic breast cancer. Since the results achieved with BCG and Levamisole appear similar, the therapeutic ratio favors the use of Levamisole.     

Vinorelbine, cisplatin and continuous infusion of 5-fluorouracil (ViFuP) in metastatic breast cancer patients: A phase II study

Purpose:Chemotherapy regimens for patients with advanced breastcancer or large primary tumours (including locally advanced disease) usuallycontain anthracyclines, taxanes or both. We investigated a multi-agent regimenfor patients for whom anthracyclines and/or taxanes may not be suitable. Weassessed efficacy in terms of response rate and time to progression of acombination with continuous infusion 5-fluorouracil (5-FU), vinorelbine andcisplatin (ViFuP regimen), as a first or subsequent line treatment formetastatic breast cancer patients. Patients and methods:One hundred consecutive patients withadvanced breast cancer were treated with 5-FU 200 mg/m²administered continuously through a permanent central venous line; vinorelbinewas given on days 1 and 3 at a dose of 20 mg and cisplatin was administeredat 60 mg/m² on day one. Therapy was given every three weeks. Themedian age was 50 years (range 23–72). Fifty-two patients had receivedprior chemotherapy for metastatic breast cancer, and sixty-one percent hadpreviously received anthracyclines, thirty-five percent taxanes andtwenty-nine percent 5-FU as a bolus injection. All patients were assessablefor toxicity, four patients were not assessable for response. Results:There were four complete responses (4%).Forty-nine patients had a partial response (overall response rate, 55%;95% confidence interval (CI): 45%–65%). After amedian follow-up of 10.2 months, median duration of response is 5.2 months(range 1.5–20.7+ months), time to progression (TTP) is 6.8 months (range0.3–24.7 months). Acute toxicity, including myelosuppression, was mild:only 18% of patients had grade 4 granulocytopenia and one patientexperienced grade 4 diarrhea. Only 15% of patients had anynon-hematological grade 3 toxicity including nausea (4%), stomatitis(4%), diarrhea (2%), fatigue (1%), fever (1%),photosensitivity (1%), hand–foot syndrome (1%). Grade 2alopecia was observed only in six patients (6%). Eleven patientsdeveloped a right diaphragmatic supra elevation, while deep vein thrombosis,central venous catheter associated, occurred in eight patients. Conclusions:We identified a combination chemotherapy withnoteworthy efficacy and well tolerated subjectively as either a first- orsecond-line treatment for metastatic breast cancer patients. The regimenwarrants further development focusing on the comparison with either continuousadministration of oral fluoropyrimidine derivatives.     

Four-day infusion of fluorouracil plus vinorelbine as salvage treatment of heavily pretreated metastatic breast cancer

Aims.Anthracyclines-taxanes containing regimens are widely used for breast cancer treatment both in neoadjuvant–adjuvant setting and in metastatic disease. Recently high-dose chemotherapy (HDC) with autologous stem cell support has been introduced as adjuvant treatment for high-risk primary breast cancer and for selected subsets of women with metastatic disease. Therefore, salvage treatment for previously treated patients with progressive disease becomes even more problematic. A regimen of continuous infusion of fluorouracil (FU) and vinorelbine (VNR) has been evaluated in heavily pretreated metastatic breast cancer patients. Patients and methods.Forty-eight women, median age 52 years, with previously treated breast cancer entered the study. All but one received more than one line of prior systemic chemotherapy for metastatic disease. Furthermore 14 women had undergone HDC with peripheral blood progenitor cells transplantation in adjuvant setting (6 pts), or metastatic disease (8 pts). Treatment consisted of four-day infusion of FU (1000mg/m²/day) plus VNR (20mg/m²/iv. day 1 and 5), recycled every 3 weeks for a total of six courses. Drugs administration was discontinued for G₄ toxicity, tumor progression or patient's refusal. Results.Twenty PR and four CR for an overall response rate of 50% (95%C.I. 36–64%) were recorded. The therapeutic efficacy of the tested regimen was documented both in patients unresponsive to previous anthracyclines-taxanes combinations and in those relapsing after HDC. The median duration of response was 9 months and median survival 16 months. One third of patients experienced Grade-3 stomatitis–mucositis, hematological toxicity was mild and no cardiac toxicity was observed. Twentyfive women (52%) suffered from infusion-related phlebitis (in half of patients a central venous device was necessary at some point of the treatment program). Conclusions.The combination of FU infusion and VNR iv is an effective salvage treatment for heavily pretreated metastatic breast cancer patients, and may represent a valid alternative when other cytotoxic regimens are not feasible.     

Phase II study of intensive chemotherapy with autologous bone marrow transplantation in patients in complete remission of disseminated breast cancer

SummaryBackground This trial studied the disease-free survival after high-dose chemotherapy in patients in complete remission of metastatic breast cancer.Patients and methods Thirty women, mean age 42.2 years (range 33–55) with metastatic breast cancer, received high-dose chemotherapy in a phase II study. Patients were eligible if they were 55 years of age, had achieved complete remission within 6 months of the initiation of chemotherapy, and had a WHO performance scale of 0 or 1. The high-dose regimen consisted of melphalan 180 mg/m² and mitoxantrone 60 mg/m² both divided over 3 days. On day 7 bone marrow and/or peripheral stem cells were infused. After bone marrow recovery, external beam radiation was administered to sites of previous metastatic disease in 15 patients.Results Apart from leuko- and thrombocytopenia, mucositis was the major side effect. One patient died during the bone marrow transplant period due to an aspergillus infection. The median follow-up since highdose chemotherapy is 25 months (range 13 to 56 months). The median disease-free survival since high-dose chemotherapy is 27 months and the disease free survival is still 43% with an overall survival of 53% at 3 years. In two patients tumor relapse occurred only in the brain; in one patient the only relapse sign was a meningeal carcinosis. At the moment 17 patients are disease-free (13+–56+) months after high-dose chemotherapy.Conclusion Until now this high-dose regimen in selected patients with complete remission after induction chemotherapy for metastatic breast cancer has a promising disease free survival.     

Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older

Background: Older patients with advanced breast cancer are less likely to receive chemotherapy than younger patients. Vinorelbine is an attractive alternative in this setting because of its clinical activity and low frequency of side effects. This multicenter, phase II trial was designed to assess the safety and efficacy of intravenous vinorelbine as first-line therapy in women 60 years old.Patients and methods: Fifty-six women (median age, 72 years; range 60–84 years), with measurable advanced breast cancer and no prior chemotherapy for metastatic disease, were enrolled and included in the analysis. Vinorelbine 30 mg/m2 was administered weekly for 13 weeks and then every two weeks until development of progressive disease; doses were reduced or delayed to manage toxicity.Results: The objective response rate was 38% (95% confidence interval (95% CI): 24%–51%); median duration of response, nine months; median time to disease progression in all patients, six months. The major dose-limiting toxicity was hematologic, which led to a median dose intensity of 20.6 mg/m2/week. Grade 3–4 nonhematologic toxicity consisted of asthenia (7%); nausea and generalized pain (5%); vomiting, chest pain, abdominal pain, and elevated AST (4%); fever, diarrhea, constipation, and injection site reaction (2%). Neurotoxicity and alopecia were grade 1–2 and relatively infrequent.Conclusions: Vinorelbine offers a promising alternative for the management of advanced breast cancer in elderly patients who are concerned about the subjective side effects of cytotoxic chemotherapy. The dose-limiting toxicity is neutropenia, which is readily managed with dose adjustment. Nonhematologic toxicity, including gastrointestinal side effects, is minimal. Randomized studies are warranted to compare the activity of vinorelbine with that of other regimens in elderly patients.     

Efficacy of chemotherapy in metastatic male breast cancer patients: a retrospective study

Background

The role of chemotherapy in the treatment of metastatic male breast cancer patients remains unknown, and the only available evidence stem from small, retrospective series evaluating outdated drugs and/or regimens.

Methods

In this retrospective study we evaluated the activity of polychemotherapy, consisting of three-drug (anthracycline-containing and anthracycline-free) regimens, as a first-line therapy for metastatic male breast cancer patients who had received at least one prior endocrine therapy.

Results

Fifty patients treated between 1978 and 2013 were included in the present analysis. Regarding best response, we recorded 1 (2%) complete response and 27 (54%) partial responses, for an overall response rate of 56% (95% CI, 42.2-69.8). Considering stable disease, the disease control rate was 84%. Median progression-free survival was 7.2 months (95% CI, 5.9-8.5), and median overall survival was 14.2 months (95% CI, 12.2-16.2). Albeit we observed some differences for all the outcomes explored when comparing anthracycline-containing and anthracycline-free regimens, they were not statistically significant.

Conclusions

Chemotherapy, consisting in both anthracycline-containing and anthracycline-free regimens, showed encouraging antitumor activity in metastatic male breast cancer patients previously treated with endocrine therapy.     

The Duke AFM Program. Intensive induction chemotherapy for metastatic breast cancer

Forty-five patients have completed treatment with AFM, an intensive induction chemotherapy regimen composed of Adriamycin (doxorubicin, Adria Laboratories, Columbus, Ohio), 5-fluorouracil, and methotrexate with folinic acid rescue. This regimen was designed to produce rapid and extensive tumor shrinkage prior to high-dose alkylating agent chemotherapy with autologous marrow support. The overall response rate was 91%, and 38% of patients achieved complete clinical responses after a mean of 70 days on treatment. Hematologic and mucosal toxicity were extensive, but no toxic deaths were noted. AFM is a potent remission induction regimen for metastatic breast cancer, but its considerable toxicity suggests caution in its use for routine breast cancer treatment.     

High-dose epirubicin as primary chemotherapy in advanced breast carcinoma: a phase II study

Summary A total of 40 patients with metastatic breast cancer were treated with 120 mg/m² i.v. epirubicin every 3 weeks for a maximum of 10 cycles. Nine achieved a complete response and 17 showed a partial response, for an objective response rate of 65% (95% confidence interval, 47%–83%); the median duration of response was 7 months (range, 1–15 months) and median survival amounted to 13 months (range, 2–20 months). Leucopenia (grade 2 or 3) was seen in 14 patients on day 21 of the cycle. A subset of nine patients underwent blood counts on day 10, when all had marked neutropenia (<1×10⁹/l). Other toxicity was frequent and included nausea/vomiting (80%), alopecia (95%) and stomatitis (35%). Five patients showed a significant fall in cardiac output, but this reverted to normal after treatment. Epirubicin should have a role in the development of high-dose regimens for the treatment of advanced breast cancer.     

High-dose chemotherapy with autologous stem cell rescue in breast cancer

SummaryBackground Because metastatic breast cancer is a lethal disease despite some responsiveness to systemic chemotherapy, high-dose chemotherapy with autologous stem cell rescue is being utilized with increasing frequency. This analysis was undertaken to determine the outcome for such patients treated with intensive chemotherapy between 1989–1994, at the Hoag Cancer Center in Newport Beach, CA.Methods During 1989, only patients with metastatic disease who had failed more than two standard breast cancer chemotherapy regimens were considered eligible for such treatment. They received high-dose BCNU/ cyclophosphamide/cisplatinum chemotherapy with autologous bone marrow rescue. After January 1990, patients with metastatic disease were eligible only if they had received limited prior chemotherapy and demonstrated responsiveness to induction chemotherapy. Beginning June 1990, patients with metastatic disease were to receive mitoxantrone and thiotepa (MiTepa) followed by peripheral blood stem cell rescue, then ifosfamide, carboplatin and etoposide (ICE) chemotherapy followed by peripheral blood stem cell rescue. High-risk adjuvant patients were to receive one course of ICE followed by rescue.Results Between 1/89–12/94, 48 breast cancer patients underwent 65 intensive chemotherapy treatments followed by autologous stem cell rescue. During 1989, three of the eight patients with metastatic disease died within 60 days because of therapy-related complications. The longest failure-free survival (FFS) of these eight was 12.2 months, and the longest overall survival (OS) 20.5 months. Since 1/90, one physician has treated 24 patients with metastatic breast cancer, 17 of whom actually underwent two successive transplants with MiTepa/ICE. For the latter group, median FFS is 23.2 months; median OS is 39.7 months. There were no acute deaths, but two patients died > 60 days after initial transplant from therapy-related complications, venoocclusive disease (5.2 months) and myelodysplastic syndrome (30.5 months), while five died of progressive disease at 22.5, 32.8, 39.4, 46.3, and 51.3 months. For the 24 metastatic patients treated 1990–1994, 1-, 2-, and 3-year FFS rates are 86%, 40%, and 17%, respectively, while OS rates are 91%, 80%, and 65%. Of 11 patients treated in the adjuvant setting, only one has relapsed (9.8 months) with follow-up from 3–61 months.Conclusions Modifications made in the program, including selection of patients responsive to induction chemotherapy, transfusion of peripheral blood stem cells, implementation of hematopoietic colony stimulating factors, and use of tandem intensive treatments has been associated with a low rate of acute morbidity and encouraging survival rates.Presented in part at the 16th Annual San Antonio Breast Cancer Symposium, November 5, 1993     

Continuous 5-fluorouracil infusion in refractory carcinoma of the breast

Twenty-five patients with refractory, metastatic carcinoma of the breast were treated with continuous ambulatory 5-fluorouracil (5 FU) infusion (200 to 300 mg/m²/day) through a chronic indwelling central venous catheter. All patients had had extensive previous treatment, including hormonal therapy in 20/25 patients (80%), radiation therapy in 18/25 patients (72%), and an average of 4.6 previous chemotherapy drugs per patient (range 1–10). Twenty-three of 25 patients (92%) had had previous bolus 5 FU. Seventeen of 25 patients (68%) had two or more metastatic sites of involvement and 17/25 patients (68%) had visceral involvement. Results: complete remission –1/25 (4%), partial remission –7/25 (28%), stable disease –6/25 (24%), and progressive disease –11/25 (44%), for an overall response rate of 8/25 (32%). Median duration of response was 6 months. Toxicities included hand-foot syndrome, mucositis, diarrhea, and nausea and vomiting, and required treatment interruption and/or dose attenuation in 9/25 patients (36%). No myelosuppression or serious catheter-related problems were seen. We conclude that continuous 5 FU infusion is a potentially effective salvage treatment that may provide meaningful palliation in some patients with carcinoma of the breast, in spite of extensive previous treatment.