Chemohormonal therapy for advanced breast cancer with tamoxifen, adriamycin, and cyclophosphamide (TAC)

Combined chemohormonal therapy is an attractive therapeutic strategy for the treatment of Stage IV breast cancer. Between 1977 and 1979, the authors evaluated a new chemohormonal therapy program in 63 evaluable women with advanced breast cancer who previously had not received cytotoxic chemotherapy or tamoxifen. The chemohormonal therapy consisted of 21- to 28-day cycles of tamoxifen (10 mg orally twice daily), Adriamycin (doxorubicin) (40 mg/m2 intravenously on day 1) and cyclophosphamide (200 mg/m2 orally on days 3-6) (TAC). Objective responses were observed in 82% of the patients (22% complete response, 60% partial response). With a median follow-up of 104 weeks (2 years), the median relapse-free survival for the 52 responding patients was 80 weeks. The median survival for the entire group of 63 patients was 118 weeks. Eleven pretreatment patient characteristics were evaluated via univariate and multivariate analysis to determine their effect on response and survival. Prognostic factors with a significant association with longer survivals were as follows: a lack of soft tissue involvement, a lack of pleural involvement, and a long disease-free interval (DFI). Estrogen receptor (ER)-unknown patients, being composed primarily of postmenopausal patients with a long DFI and single-organ involvement (primarily bone), comprised 62% of the patient population and achieved a survival similar to the smaller number of ER-positive patients and was superior to the survival of ER-negative patients. Toxicities were recorded on all patients and overall the treatment was well tolerated. Combined chemohormonal therapy with TAC resulted in a high objective response rate and a long median survival. This study would support additional trials of chemohormonal therapy in patients with ER-positive tumors or in those whose tumors are likely to be ER-positive (e.g., postmenopausal patients with long DFIs).     

Paclitaxel and Mitoxantrone in the Treatment of Metastatic Breast Cancer: A Phase II Trial of the Minnie Pearl Cancer Research Network

Background and rationale: The combination of paclitaxel and doxorubicin is highly active in the treatment of metastatic breast cancer, but is associated with substantial toxicity. In this phase II trial, we evaluated the combination of paclitaxel and mitoxantrone in an attempt to maintain efficacy and improve tolerability of this regimen.

Patients and methods: Sixty-three patients with metastatic breast cancer were treated with paclitaxel 200 mg/m², 1 hr IV infusion, and mitoxantrone 10 mg/m² IV, every 21 days. Responding patients received at least six courses of therapy. Ninety-three percent of patients in this trial were receiving first-line treatment for metastatic breast cancer; 62% of patients had received previous adjuvant chemotherapy, and 26% had received previous doxorubicin.

Results: Objective responses were seen in 24 of 61 evaluable patients (39%). Median response duration was 9 months (range 4-37+ months); actuarial 1-, 2-, and 3-year survivals were 62, 32, and 25%, respectively. The treatment was generally well tolerated; 78% of patients had grade 3 or 4 leukopenia at sometime during their treatment course, but only 14 hospitalizations for neutropenia and fever were necessary (4% of courses). Grade 3 fatigue was experienced by 30% of patients. Cardiotoxicity was not observed.

Conclusions: The combination of paclitaxel and mitoxantrone is active, easily administered, and well tolerated in the treatment of metastatic breast cancer. Its activity appears similar to several other taxane-based combination regimens recently evaluated for the treatment of advanced breast cancer.     

Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group.

PURPOSE: To evaluate the efficacy and toxicity of combination and sequential dose-dense chemotherapy with doxorubicin and docetaxel (Taxotere; Rh?ne-Poulenc Rorer, Collegeville, PA) as primary chemotherapy of breast cancer. PATIENTS AND METHODS: Patients with newly diagnosed stage II or noninflammatory stage III breast cancer were randomly assigned to receive the same total doses of doxorubicin and docetaxel over a 12-week period before definitive surgery. Patients in arm A received sequential therapy with doxorubicin 75 mg/m(2) every 2 weeks for three cycles followed by docetaxel 100 mg/m(2) every 2 weeks for three cycles. Patients in arm B received combination therapy with doxorubicin 56 mg/m(2) plus docetaxel 75 mg/m(2) every 3 weeks for four cycles. Granulocyte colony-stimulating factor was administered on days 2 to 12 of each cycle in both groups. RESULTS: Forty patients were entered onto the trial. Pretreatment tumor size averaged 5.7 cm with clinically positive axillary lymph nodes in 23 patients (57%). As expected, myelosuppression was severe in both groups; however, >/= 80% of planned dose-intensity was delivered. Hand-foot syndrome was more common after sequential therapy. Clinical responses were similar in both groups, with an overall response rate of 87%, including 20% clinical complete remissions. Pathologic complete remission or residual in situ disease only was confirmed in five patients (12.8%). Patients who received sequential therapy had fewer positive lymph nodes (mean, 2.17 v 4.81; P <.037) at definitive surgery. CONCLUSION: Primary chemotherapy with doxorubicin and docetaxel is well tolerated and highly active. A sequential treatment schedule increases toxicity but may result in more substantial lymph node clearance than combination therapy.     

Prospective randomized trial of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus paclitaxel and FAC (TFAC) in patients with operable breast cancer: impact of taxane chemotherapy on locoregional control

A previous randomized trial (CALGB 9344/Intergroup 0148) compared four cycles of adjuvant doxorubicin/cyclophosphamide (AC) to four cycles of AC plus four cycles of paclitaxel (AC + T) and demonstrated that the addition of paclitaxel improved locoregional control (LRC) in patients with node-positive breast cancer. However, it could not be determined whether it was the paclitaxel or the increased duration of chemotherapy that led to this improvement. The present study aimed to analyze whether the addition of paclitaxel to a doxorubicin-based regimen improves LRC in a cohort of patients who all received eight total cycles of chemotherapy. Five hundred eleven women with operable breast cancer were randomized on a single-institution prospective trial to receive 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) × 8 cycles (n = 252) or FAC × 4 cycles plus paclitaxel × 4 cycles (TFAC) (n = 259). Rates of LRC and overall survival (OS) were analyzed. Median follow-up was 124 months (range 5-167 months). The 10-year LRC rate was 92.6 versus 93.1% in the FAC versus TFAC arms, respectively (P = 0.26). The LRC between treatment arms did not differ when analyzed by locoregional treatment group: breast conservation therapy (BCT), mastectomy alone (M), and mastectomy + radiation (M + RT). The 10-year LRC rates were 95.1% (FAC) versus 91.2% (TFAC) after BCT (P = 0.98), 89.5% (FAC) versus 93.4% (TFAC) after M (P = 0.24), and 94.7% (FAC) versus 96.5% (TFAC) after M + RT (P = 0.59). Additionally, there was no difference in OS between the treatment arms, with 10-year OS rates of 78.4% (FAC) versus 81.7% (TFAC) (P = 0.93). The addition of paclitaxel to a doxorubicin-based regimen had no impact on LRC, regardless of the type of local therapy received. Historically inferior LRC with AC chemotherapy alone versus AC + T may have been due to an inadequate duration of systemic therapy and not due to the absence of paclitaxel.     

The effect of systemic therapy on local-regional control in locally advanced breast cancer.

One hundred and seven patients with locally advanced breast cancer were prospectively referred for multimodality treatment on protocol using chemohormonal therapy to maximal response followed by local treatment and maintenance therapy. Forty-eight patients (45%) were diagnosed with Stage IIIA disease, 46 (43%) with Stage IIIB inflammatory cancer, and 13 (12%) with Stage IIIB non-inflammatory disease. Induction therapy consisted of cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil with hormonal synchronization using tamoxifen and conjugated estrogens. Local treatment was determined by response to chemotherapy. Patients with a clinical parital response underwent mastectomy followed by local-regional radiotherapy while patients with a clinical complete response were biopsied for pathologic correlation. Those with residual disease received mastectomy followed by radiotherapy while those with a pathologic complete response received radiation only to the intact breast and regional nodes. With a median follow-up of 64 months, patients with IIIA disease had a significantly lower local-regional failure rate compared to IIIB inflammatory patients, with the 5-year actuarial local-regional failure rate as only site of first failure 3% for IIIA disease versus 21% for IIIB inflammatory cancer (p = .02), and local-regional failure as any component of first failure 12% versus 36% (p = .01), respectively. When local-regional failure was analyzed by repeat biopsy, 5/31 (16%) patients with a pathologic complete response treated with radiation only developed a local-regional failure versus 2/53 (4%) with residual disease treated with mastectomy and postoperative radiotherapy. The 5-year actuarial local-regional failure rate as first site of failure was 23% for radiation only versus 5% for mastectomy and post-operative radiotherapy (p = .07). The response to chemotherapy did not reliably predict local-regional control. Both relapse-free survival and overall survival were significantly better for IIIA versus IIIB patients; stratification by repeat biopsy did not however, significantly affect either relapse-free or overall survival.     

Uncontrolled local recurrence after treatment of breast cancer with breast conservation

Three hundred fifty-six patients with early (Stage I and II) breast cancer and 55 with advanced (Stage III and IV) breast cancer were treated between 1979 and 1985 with a consistent policy of breast conservation irrespective of tumor site, size, or histologic features. Only three patients underwent primary mastectomy (Stage III), and the remainder were treated either by wide local excision and postoperative radiotherapy (357 cases) or by needle biopsy and primary irradiation (51 cases). A total of seven of 356 (2%) Stage I and II patients have developed uncontrolled local or nodal recurrence at a median follow-up of 5 years, and nine of 55 (16%) of Stage III and IV patients. Of the 62 Stage I and II patients who have died, seven (11%) have died with uncontrolled locoregional disease. Of the 22 Stage III and IV patients who have died, eight (36%) have died with uncontrolled locoregional disease. Although the majority of local recurrences within the conserved breast could be salvaged by secondary surgery (37/38 Stage I and II patients), the development of chest wall or nodal recurrence was usually associated with the appearance of distant metastases and a poor prognosis. Data on uncontrolled local recurrence should be given in all studies of breast cancer treatment, since it represents an important end-point of therapy and a difficult clinical problem.     

A case of advanced breast cancer markedly responding to chemo-endocrine therapy with only slight alopecia

We report a case of good response to chemo-endocrine therapy with slight alopecia. A 55-year-old woman was diagnosed as advanced breast cancer with T4c, N3, M1, Stage IV, who was left cervical node-positive. She received 4 cycles of CTF (cyclophosphamide 100 mg/body/day 1-14, THP 30 mg/body/days 1,8, and 5-FU 750 mg/body/days 1, 8 4 wq) therapy in addition to oral tamoxifen (20 mg/body) administration. After this treatment, the primary tumor was markedly reduced (PR), and only slight alopecia was observed. Generally, 3 cycles of CAF (CEF) therapy induced severe alopecia (grade 3). But this CTF regimen caused grade 1 alopecia. Most women have strong resistance to alopecia. It seems that the quality of life for breast cancer patients was affected by the extent of the alopecia. Therefore, CTF therapy should be considered effective for advanced breast cancer patients while reducing the extent of alopecia.     

Pegylated liposomal doxorubicin (Doxil) for metastatic breast cancer: the Cancer Research Network,Inc., experience

Pegylated liposomal doxorubicin (Doxil) was formulated to improve the safety profile of doxorubicin. The major toxicities, mucositis and palmar-plantar erythrodysesthesia, are dose and schedule dependent, respectively. Anecdotal experience suggests that a dosage of 40 mg/m2 every 4 weeks is well tolerated. To evaluate the safety and efficacy of this regimen in women with metastatic breast cancer, we performed a retrospective chart review at a private practice. Forty women received a median initial dose of 42.5 mg/m2 usually every 4 weeks and a median cumulative dose of 135 mg/m2 (range: 40-595 mg/m2). There were 10 partial responses and seven patients with stable disease for more than 6 months resulting in a clinical benefit rate of 43% in the intent-to-treat analysis. The median time to progression was 4 months in all patients, 6.5 months in patients who had partial responses, and 10 months in patients who had stable disease for more than 6 months. There was no grade 4 toxicity. The only grade 3 toxicities were leukopenia in seven (18%) patients, mucositis in one (3%), and palmar-plantar erythrodysesthesia in one (3%). More studies are warranted to confirm our findings, which suggest that pegylated liposomal doxorubicin at a dosage of 40-45 mg/m2 every 4 weeks is clinically active in, and well tolerated by, women with metastatic breast cancer.     

Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.     

Maximized reduction of primary breast tumor size using preoperative chemotherapy with doxorubicin and docetaxel.

PURPOSE: To assess the toxicity and efficacy of preoperative chemotherapy with doxorubicin and docetaxel in patients with primary operable breast cancer. PATIENTS AND METHODS: Forty-two patients with histologically confirmed primary breast cancer tumors of at least 2 cm in diameter received doxorubicin (50 mg/m(2) intravenously [IV] over 15 minutes) and docetaxel (75 mg/m(2) IV over 1 hour) every 14 (24 patients) or 21 (18 patients) days for four cycles. RESULTS: The median size of the primary tumor decreased significantly, from 4 cm (range, 2 to 10 cm) to 2 cm (range, 0 to 5 cm) on physical examination and from 3.4 cm (range, 1 to 8 cm) to 1. 8 cm (range, 0 to 4 cm) on sonography (P <.001). The overall response rate as assessed by physical examination was 93%, and complete remission of the primary tumor occurred in 33% of patients. The remission rate as assessed by sonographic measurement was 67%. Two patients (5%) had histologically confirmed complete responses. Sonography was more reliable than palpation in predicting histologically determined response. No grade 4 toxicity was noted, and grade 3 toxicity was reported with alopecia (95%), lethargy (17%), loss of appetite (10%), stomatitis (7%), leukopenia (5%), skin desquamation (5%), infection (5%), motor neuropathy (2%), and nausea (2%). The 3-week schedule was associated with less toxicity than the 2-week schedule. CONCLUSION: Preoperative combination chemotherapy with doxorubicin and docetaxel is highly effective and feasible in primary operable breast cancer.     

The use of skin sparing mastectomy in the treatment of breast cancer: The Emory experience

INTRODUCTION: Long-term follow-up of the use of skin sparing mastectomy (SSM) in the treatment of breast cancer is presented to determine the impact of local recurrence (LR) on survival. METHODS: 565 cases of breast cancer were treated by SSM and IBR from 1/1/1989-12/31/1998. The AJCC pathological staging was Stage 0 175 (31%), Stage I 135 (23.9%), Stage II 173 (30.6%), Stage III 54 (9.6%), Stage IV 8 (1.4%), recurrent 20 (3.5%). Forty-one patients received postoperative adjuvant radiation therapy. RESULTS: Thirty-one patients developed a LR during the follow-up including five who received adjuvant radiation. The distribution of LR stratified by cancer stage was Stage 0 1 (3.2%), Stage I 5 (16.1%), Stage II 17 (54.8%), Stage III 6 (19.4%), and recurrent 2 (6.5%). The overall LR was 5.5%. Isolated LRs were treated with surgical resection and radiation therapy if not previously administered. Twenty-four patients (77.4%) developed a systemic relapse and 7 (22.6%) patients remained free of recurrent disease at a mean follow-up of 78.1 months. The cancer stage of those remaining disease free was Stage 0 1, Stage I 4, and Stage II 2. CONCLUSIONS: LR of breast cancer after SSM is not always associated with systemic relapse.     

Phase II evaluation of menogaril in women with metastatic breast cancer after failure of first-line chemotherapy

A total of 25 patients with metastatic breast cancer who had failed one prior chemotherapy regimen and had not received prior treatment with doxorubicin were treated with menogaril (200 mg/m2 i.v. over 1 h) every 4 weeks. Four patients (16%) achieved partial regressions lasting a median of 46 days. The median time to progression for all patients was 60 days and the median survival was 264 days. Seventeen patients subsequently received doxorubicin after removal from protocol and six (35%) achieved objective regression. We conclude that menogaril administered by the method that we employed has marginal activity in women with metastatic breast cancer after failure of prior chemotherapy. Failure to respond to menogaril does not preclude response to subsequent treatment with doxorubicin.     

A Phase II Randomized Crossover Study of Liposomal Doxorubicin Versus Weekly Docetaxel in the First-line Treatment of Women With Metastatic Breast Cancer

PurposeWe aim to compare the efficacy and toxicity of liposomal doxorubicin and weekly docetaxel as first-line treatments for patients with metastatic breast cancer (MBC).Patients and MethodsPatients who had received no previous chemotherapy for MBC were eligible. Previous hormonal therapy, adjuvant chemotherapy, and radiation therapy were allowed. Patients were randomized to receive liposomal doxorubicin 40 mg/m² intravenously [I.V.] every 28 days or weekly docetaxel 36 mg/m² I.V. days 1, 8, and 15, repeated every 28 days. Patients with objective response or stable disease after 2 cycles continued treatment until tumor progression or unacceptable toxicity. At progression, patients were allowed to cross over to the other regimen. The trial was designed to detect a true difference of 10% in response rate with an 80% power.ResultsBetween March 2001 and July 2007, 102 patients were randomized. The 2 groups had similar demographics; 68% of patients had received previous adjuvant chemotherapy. Liposomal doxorubicin and weekly docetaxel produced similar objective response rates (28% vs. 31%), disease control rates (48% vs. 44%), and progression-free survival (6.5 months vs. 5.5 months). Both agents were well tolerated. Both agents produced crossover responses as second-line treatment (liposomal doxorubicin, 35%; weekly docetaxel, 14%).ConclusionLiposomal doxorubicin is well tolerated and has activity similar to weekly docetaxel in the first-line treatment of patients with MBC.     

Capecitabine in combination with docetaxel and epirubicin in patients with previously untreated,advanced breast carcinoma

BACKGROUND: The objective of this study was to evaluate the activity and safety of oral capecitabine in combination with docetaxel and epirubicin (TEX) as first-line treatment for patients with locally advanced/metastatic breast carcinoma. METHODS: This open-label, Phase II study was conducted at six Italian centers. Treatment consisted of epirubicin, 75 mg/m(2) (intravenous bolus), and docetaxel, 75 mg/m(2) (1-hour infusion), both administered on Day 1, plus oral capecitabine, 1000 mg/m(2) twice daily, on Days 1-14 of each 3-week treatment cycle. RESULTS: A total of 67 patients received 392 cycles of treatment, with a median of 6 cycles in patients with Stage III disease (n = 34 patients) and a median of 8 cycles in patients with Stage IV disease (n = 33 patients). The objective response rate was 82%, including complete responses in 21% of patients. A greater proportion of patients with Stage III disease achieved tumor responses compared with patients who had Stage IV disease (97% vs. 67%, respectively). Among 34 patients with Stage III disease, pathologic complete responses were confirmed in 10 patients (29%). TEX chemotherapy demonstrated an acceptable safety profile. There was a low incidence of Grade 3 adverse events, and Grade 4 adverse events were particularly rare (4%). The most common Grade 3-4 adverse event was febrile neutropenia, which occurred in 16% of patients. CONCLUSIONS: TEX combination therapy has important antitumor activity and an acceptable safety profile in this setting. A large, randomized, Phase III trial is ongoing to compare TEX chemotherapy with an epirubicin plus docetaxel regimen in patients with untreated, advanced breast carcinoma.     

A phase I study of liposomal doxorubicin (Doxil) with topotecan

New therapies are needed for patients with advanced ovarian cancer who relapse after initial treatment with platinum and/or paclitaxel-based regimens. This study sought to determine the toxicities of combined liposomal doxorubicin (Doxil) and topotecan, and to determine a regimen for future phase II testing in ovarian cancer. Nine patients with advanced malignancies were treated with topotecan 1.0 mg/m2/day X 5 days followed by liposomal doxorubicin at a starting dose of 30 mg/m2 on day 5. Cycles were repeated every 28 days. A total of 13 cycles of therapy were administered. Grade IV neutropenia and grade IV thrombocytopenia developed in both of the two patients treated at the first dose level. Subsequent patients received only 20 mg/m2 liposomal doxorubicin. At that dose level, three patients experienced dose-limiting toxicity (one grade IV neutropenia, two grade IV neutropenia and thrombocytopenia). No responses were observed. These data indicate that the described regimen of liposomal doxorubicin and topotecan is not feasible because of excessive hematologic toxicity. Escalation to doses of liposomal doxorubicin or topotecan that have previously demonstrated antitumor activity was not possible. Future strategies to minimize such toxicity may include limiting eligibility to patients with minimal prior therapy, reducing the number of days of topotecan administration, or use of oral topotecan.     

Sixteen-week dose-intense chemotherapy in the adjuvant treatment of breast cancer

Fifty-three women with breast cancer were treated with a new 16-week dose-intense, chemotherapy regimen. Patients with operable breast cancer with 10 or more histologically positive axillary nodes were treated with this five-drug regimen that incorporated the concepts of weekly chemotherapy, sequential administration of antimetabolites, and continuous infusion of fluorouracil (5-FU). The chemotherapy regimen consisted of eight cycles (each of 2 wk duration) of 100 mg of cyclophosphamide/m2 orally on days 1-7, 40 mg of doxorubicin/m2 intravenous (IV) on day 1, 100 mg of methotrexate/m2 IV on day 1 with 10 mg of leucovorin rescue/m2 every 6 hours for six oral doses on day 2, 1 mg of vincristine IV on day 1, and 600 mg of 5-FU/m2 IV at hour 20 over 2 hours. A continuous infusion of 300 mg of 5-FU/m2 per day was given IV on days 8-9 of each 2-week cycle. The doses and schedule of drug administration were designed to minimize dosage reduction and treatment delay. At a median follow-up of 17 months, there have been eight relapses in the 53 patients. The actuarial 3-year disease-free survival is 80% (95% confidence interval, 62% to 90%). The major side effects were attributable to myelosuppression. Absolute neutrophil counts less than 250/microL were noted in 12 (23%) patients; seven patients (13%) required hospitalization for management of neutropenic fever. No treatment-related deaths occurred. Ninety-four percent of the planned doses were administered, and only 5% of the courses were delayed because of toxic reactions. The encouraging therapeutic data, manageable side effects, and our ability to deliver over 90% of the planned doses provide the rationale for a phase III comparison of this new dose-intense regimen and standard chemotherapy in patients with operable disease and positive axillary nodes.     

High-dose mitoxantrone-vinblastine-cyclophosphamide and autologous stem cell transplantation for stage III breast cancer: final results of a prospective multicentre study.

BACKGROUND: Stage III breast cancer patients continue to suffer high relapse and death rates despite standard chemotherapy regimens. High-dose alkylator chemotherapy does not further improve outcome. This phase II study evaluated a novel high-dose chemotherapy regimen which combined active breast cancer agents with differing mechanisms of action. PATIENTS AND METHODS: Eligibility included at least seven involved axillary nodes (AxLNs) for tumours <5 cm, at least four AxLNs for tumours >5 cm or locally advanced breast cancer (LABC). Patients received four cycles of fluorouracil-adriamycin-cyclophosphamide (FAC) followed by one cycle of mitoxantrone 63 mg/m(2)-vinblastine 12.5 mg/m(2)-cyclophosphamide 6 g/m(2) (MVC) with autologous blood stem cell transplantation (ASCT). RESULTS: Between April 1995 and December 1998, 92 patients aged 21-65 years (median 45 years) were enrolled, of whom 25 were treated preoperatively for LABC and 67 were treated postoperatively. Although there was no early treatment-related mortality, one late death occurred from secondary acute myeloid leukaemia. The 7-year event-free and overall survival rates were 53% (95% confidence interval 42-64%) and 62% (95% CI 52-73%), respectively, with no significant difference between pre- and postoperative groups. CONCLUSION: FAC followed by MVC-ASCT is feasible and reasonably well tolerated, but does not result in improved survival rates compared with other conventional or high-dose regimens for stage III breast cancer.     

Sixteen week dose intense chemotherapy for inoperable,locally advanced breast cancer

Summary Up to 15% of women with breast cancer have locally advanced disease at diagnosis. The poor response of these patients to local therapy alone and the frequent development of disseminated disease suggest that early intensive systemic therapy may benefit these women. Twenty-four patients with non-metastatic, locally advanced, primarily inflammatory, inoperable breast cancer were treated with a 16-week dose-intense chemotherapy regimen as induction therapy. Treatment consisted of 8 repetitive 2-week cycles consisting of 100 mg/m² cyclophosphamide orally D1-7, 40 mg/m² doxorubicin intravenously (IV) D1, 1 mg vincristine IV D1, 100 mg/m² methotrexate IV D1, 10 mg/m² leucovorin every 6 hours for six oral doses D2-3, and 600 mg/m² 5-FU IV over 2 hours D2. A continuous infusion of 300 mg/m² 5-FU per day was given IV D8-9 of each 2-week cycle. After induction all patients had at least a partial clinical response and were operable; 9/24 (37%) achieved a clinical complete response. All patients underwent at least a simple mastectomy. Pathologic examination revealed no evidence of gross macroscopic tumor in 11/24 patients (46%) and no evidence of microscopic disease in 4/24 patients (17%). Seven of 24 patients (29%) had no microscopic disease in the breast. At a median follow-up of 45 months, there have been 10 relapses in the 24 patients treated with this induction regimen. The actuarial relapse-free survival at 5 years is 58%. Actuarial overall survival at 5 years is 75%. We conclude that this regimen is safe and well-tolerated and that the results of this therapy are sufficiently promising to warrant further study of this regimen in patients with locally advanced breast cancer.     

Paclitaxel and mitoxantrone in the treatment of metastatic breast cancer: a phase II trial of the Minnie Pearl Cancer Research Network

BACKGROUND AND RATIONALE: The combination of paclitaxel and doxorubicin is highly active in the treatment of metastatic breast cancer, but is associated with substantial toxicity. In this phase II trial, we evaluated the combination of paclitaxel and mitoxantrone in an attempt to maintain efficacy and improve tolerability of this regimen. PATIENTS AND METHODS: Sixty-three patients with metastatic breast cancer were treated with paclitaxel 200 mg/m2, 1 hr i.v. infusion, and mitoxantrone 10 mg/m2 i.v., every 21 days. Responding patients received at least six courses of therapy. Ninety-three percent of patients in this trial were receiving first-line treatment for metastatic breast cancer; 62% of patients had received previous adjuvant chemotherapy, and 26% had received previous doxorubicin. RESULTS: Objective responses were seen in 24 of 61 evaluable patients (39%). Median response duration was 9 months (range 4-37 + months); actuarial 1-, 2-, and 3-year survivals were 62, 32, and 25%, respectively. The treatment was generally well tolerated; 78% of patients had grade 3 or 4 leukopenia at sometime during their treatment course, but only 14 hospitalizations for neutropenia and fever were necessary (4% of courses). Grade 3 fatigue was experienced by 30% of patients. Cardiotoxicity was not observed. CONCLUSIONS: The combination of paclitaxel and mitoxantrone is active, easily administered, and well tolerated in the treatment of metastatic breast cancer. Its activity appears similar to several other taxane-based combination regimens recently evaluated for the treatment of advanced breast cancer.     

Phase I Study of Nonpegylated Liposomal Doxorubicin plus Trastuzumab in Patients with HER2-Positive Breast Cancer

BackgroundThis was an open-label, nonrandomized, multicenter, 2-stage phase I trial of safety and preliminary efficacy of nonpegylated liposomal doxorubicin (NLD) in combination with trastuzumab in advanced breast cancer, with emphasis on cardiac toxicity.Patients and MethodsForty patients (median age, 48 years; range, 30–74 years) with HER2/neu 2+ or 3+ tumors (by immunohistochemistry) were recruited December 1999 to November 2002. Patients were eligible if they received ≤ 1 previous trastuzumab regimen, ≤ 2 cytotoxic regimens for advanced breast cancer, and lifetime cumulative anthracycline doses ≤ 240 mg/m². The study regimen comprised NLD 60 mg/m² every 3 weeks and trastuzumab loading dose 4 mg/kg followed by 2 mg/kg weekly. Treatment cycles lasted 21 days. Clinical cardiac assessments were performed with multigated acquisition scans every 2 cycles. Patients were evaluated for cardiac toxicity after receiving ≥ 1 cycle. Cardiac safety was assessed after completing ≥ 4 full treatment cycles.ResultsThirty out of 40 patients (75%) received ≥ 4 treatment cycles and were evaluable for cardiac safety. Five patients (13%), 4 who were doxorubicin pretreated, developed left ventricular ejection fraction reductions to < 50%, and 2 (5%) of these patients experienced clinical cardiac toxicity. Fifty percent of the patients had objective tumor responses; median progression-free survival was approximately 21 weeks. Twenty-six patients (65%) had grade 3/4 neutropenia; 2 patients experienced febrile neutropenia.ConclusionNonpegylated liposomal doxorubicin plus trastuzumab is active in HER2-positive patients with advanced breast cancer and is associated with a lower risk of cardiac toxicity than conventional doxorubicin plus trastuzumab.