TITAN: phase III study of doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early-stage triple-negative breast cancer

Purpose

Ixabepilone is a microtubule stabilizer with activity in taxane-refractory metastatic breast cancer and low susceptibility to taxane-resistance mechanisms including multidrug-resistant phenotypes and high β-III tubulin expression. Since these resistance mechanisms are common in triple-negative breast cancer (TNBC), ixabepilone may have particular advantages in this patient population. This study evaluated the substitution of ixabepilone for paclitaxel following doxorubicin/cyclophosphamide (AC) in the adjuvant treatment of early-stage TNBC.

Methods

Patients with operable TNBC were eligible following definitive breast surgery. Patients were randomized (1:1) to receive four cycles of AC followed by either four cycles (12 weeks) of ixabepilone or 12 weekly doses of paclitaxel.

Results

614 patients were randomized: 306 to AC/ixabepilone and 308 to AC/paclitaxel. At a median follow-up of 48 months, 59 patients had relapsed (AC/ixabepilone, 29; AC/paclitaxel, 30). The median time from diagnosis to relapse was 20.8 months. The 5-year disease-free survival (DFS) rates of the two groups were similar [HR 0.92; ixabepilone 87.1% (95% CI 82.6–90.5) vs. paclitaxel 84.7% (95% CI 79.7–88.6)]. The estimated 5-year overall survival (OS) rates were also similar [HR 1.1; ixabepilone 89.7% (95% CI 85.5–92.7) vs. paclitaxel 89.6% (95% CI 85.0–92.9)]. Peripheral neuropathy was the most common grade 3/4 event. Dose reductions and treatment discontinuations occurred more frequently during paclitaxel treatment.

Conclusions

Treatment with AC/ixabepilone provided similar DFS and OS in patients with operable TNBC when compared to treatment with AC/paclitaxel. The two regimens had similar toxicity, although treatment discontinuation, dose modifications, and overall peripheral neuropathy were more frequent with AC/paclitaxel. Trial registration: Clinical Trials.gov Identifier, NCT00789581.

     

A phase III randomized study on the sequencing of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer

PURPOSE: To compare two different timings of radiation treatment in patients with breast cancer who underwent conservative surgery and were candidates to receive adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. METHODS AND MATERIALS: A total of 206 patients who had quadrantectomy and axillary dissection for breast cancer and were planned to receive adjuvant CMF chemotherapy were randomized to concurrent or sequential radiotherapy. Radiotherapy was delivered only to the whole breast through tangential fields to a dose of 50 Gy in 20 fractions over 4 weeks, followed by an electron boost of 10-15 Gy in 4-6 fractions to the tumor bed. RESULTS: No differences in 5-year breast recurrence-free, metastasis-free, disease-free, and overall survival were observed in the two treatment groups. All patients completed the planned radiotherapy. No evidence of an increased risk of toxicity was observed between the two arms. No difference in radiotherapy and in the chemotherapy dose intensity was observed in the two groups. CONCLUSIONS: In patients with negative surgical margins receiving adjuvant chemotherapy, radiotherapy can be delayed to up to 7 months. Concurrent administration of CMF chemotherapy and radiotherapy is safe and might be reserved for patients at high risk of local recurrence, such as those with positive surgical margins or larger tumor diameters.     

Managing early-stage breast cancer in your older patients

As the aging population in the United States continues to grow, the incidence of diseases of the elderly, such as breast cancer, are increasing. Many more elderly women are expected to be diagnosed with new breast cancers, most of them in an early stage. Appropriate treatment of these women is important, as they have poorer outcomes when undertreated. In this review, we will discuss the biology and treatment of early breast cancer in elderly women. We will focus on the role of comorbidity and its effect on life expectancy, treatment decisions, current recommendations for primary treatment with surgery, radiation and neoadjuvant strategies, and adjuvant treatment including local radiation therapy and systemic treatment with endocrine therapy, chemotherapy, and newer agents. Finally we will discuss the importance of clinical trials in the elderly.     

A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer.

BACKGROUND: This pilot trial was performed to evaluate the safety, toxicity and pharmacokinetics of chronic therapy with the matrix metalloproteinase inhibitor marimastat in the adjuvant treatment of breast cancer. PATIENTS AND METHODS: Patients with high-risk node negative or node positive breast cancer received marimastat either 5 or 10 mg p.o. b.i.d. for 12 months. Marimastat was given either as a single agent following completion of adjuvant chemotherapy or concurrently with tamoxifen. RESULTS: Sixty-three patients were enrolled from June 1997 to May 1998. All patients have completed 12 months of treatment or have discontinued therapy due to toxicity, relapse or intercurrent illness. Moderate (WHO criteria) arthralgia/arthritis was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis was reported by 6% and 23% of patients, respectively. Six patients (19%) receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. Trough plasma levels were rarely within the target range for biological activity (40-200 ng/ml) with mean concentration for patients receiving: 5 mg b.i.d. = 7.5; 5 mg b.i.d. plus tamoxifen = 6.9; 10 mg b.i.d. = 11.9; 10 mg b.i.d. plus tamoxifen = 12.8. CONCLUSIONS: A randomized adjuvant trial with marimastat is not warranted as chronic administration cannot maintain plasma levels with the target range.     

Preoperative breast MRI in early-stage breast cancer

Rapid uptake of new imaging technology is a major contributor to rising healthcare costs. Preoperative breast magnetic resonance imaging (MRI) for patients with early-stage breast cancer has dramatically increased in use without the evidence of improved outcomes compared to standard assessment and is associated with higher rates of mastectomy. A decision analytic model was developed to evaluate the impact of adding breast MRI to the preoperative evaluation of women with early-stage breast cancer who were candidates for breast-conserving therapy on patient outcomes measured in quality-adjusted life years (QALYs). Model inputs, including survival, recurrence rates, and health utilities, were obtained from a comprehensive literature review. One-way sensitivity analyses were performed to estimate threshold values for key parameters at which adding MRI would become the optimal imaging strategy over standard assessment. Preoperative MRI resulted in 17.77 QALYs compared to 17.86 QALYs with standard assessment, a decrease of 0.09 QALYs or 34?days. In sensitivity analyses, standard assessment was associated with better patient outcomes than preoperative breast MRI across all plausible probabilities for mastectomy, local recurrence, and health utilities. For routine preoperative breast MRI to become the optimal strategy, the conversion rate to mastectomy after preoperative MRI would need to be <1?% (versus the range of 3.6-33?% reported in the literature). Routine preoperative breast MRI appears to confer no advantage over the standard diagnostic evaluations for early-stage breast cancer and may lead to worse patient outcomes.     

Hypofractionation with no boost after breast conservation in early-stage breast cancer patients

The aim of this study was to evaluate local control, survival and toxicity profile of a consecutive cohort of early-stage breast cancer (EBC) patients treated with adjuvant hypofractionated radiotherapy (HF) with no boost delivered to the lumpectomy cavity, after breast-conserving surgery (BCS). Between 2005 and 2015, a total of 493 women affected with EBC were treated with HF (46 Gy/20 fractions or 40.05 Gy/15 fractions) to the whole breast without boost to tumor bed, because of age and/or favorable tumor characteristics. The primary endpoint was 5-year actuarial local control (LC); secondary endpoints included survival, toxicity profile and cosmesis. Median follow-up was 57 months (range 6–124). Actuarial 5-year overall, cancer-specific, disease-free survival and LC were 96.3, 98.9, 97.8 and 98.6 %, respectively. On multivariate analysis, tumor stage (T1 vs. T2) and hormonal status (positive vs. negative estrogen receptors) were significantly correlated with LC. Only 2 % of patients experienced ≥G3 acute skin toxicity. Late toxicity was mild with only 1 case of G3 fibrosis. Most of the patients (95 %) had good–excellent cosmetic results. HF to the whole breast with no boost delivered to the tumor bed is a safe and effective option for a population of low-risk breast cancer patients after BCS, with excellent 5-year LC, mild toxicity profile and promising cosmetic outcome. A subgroup of patients with larger tumors and/or with no estrogen receptor expression may potentially benefit from treatment intensification with a boost dose to the lumpectomy cavity.     

Dosimetric evaluation of whole breast radiotherapy using field-in-field technique in early-stage breast cancer

Background  

The purpose of this study is to evaluate the dosimetric benefits of whole breast radiotherapy (WBRT) using the field-in-field technique compared with conventional tangential field radiotherapy with physical wedges for WBRT.     

Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]

Introduction

Experimental and clinical data show that the oral bisphosphonate clodronate (Bonefos^®) can inhibit tumor-induced osteoclastic bone resorption. This randomized, double-blind, placebo-controlled, multicenter trial was designed to determine if the addition of oral clodronate to standard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival.

Methods

1,069 patients with primary operable stage I-III breast cancer were randomized to receive oral clodronate (1,600 mg/day) or placebo for 2 years, in conjunction with standard treatment for primary breast cancer including surgery, radiotherapy, adjuvant chemotherapy, and/or tamoxifen. All patients were assessed for bone metastases at two and five years and additionally when clinically indicated. Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years. The treatment arms were compared using the unstratified log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated.

Results

Oral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period (51 patients versus 73 patients with placebo; HR = 0.692, P = 0.043); the difference was also statistically significant over the 2 year medication period (19 patients versus 35 patients with placebo; HR = 0.546, P = 0.031). These differences were most pronounced in patients with stage II/III disease (39 patients versus 64 patients with placebo, HR = 0.592, P = 0.009 over 5 years; 16 patients versus 32 patients with placebo, HR= 0.496, P = 0.020 over 2 years). Survival data also favoured the clodronate arm (HR for all patients = 0.768, P = 0.048; HR for stage II/III disease = 0.743, P = 0.041), although this was not significant due to multiple analyses. Oral clodronate was well tolerated, with mild-to-moderate diarrhoea being the most frequently reported adverse event.

Conclusion

These results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer.     

Elective regional nodal irradiation in patients with early-stage breast cancer

Elective regional lymph nodal irradiation is controversial in patients with early stage breast cancer. Under the "Halstedian" model of tumor progression, elective nodal irradiation would be expected to provide some gain in both regional control and survival. Nevertheless, the data are inconclusive. When the axillary nodes are positive, there is uncertainty regarding the utility of elective irradiation of the supraclavicular and internal mammary areas. Similarly, in patients with a clinically negative axilla, the role of elective irradiation of the axilla and other nodal sites is also controversial. This article reviews data from trials that address the utility of elective regional nodal treatment, with regard to both tumor control (local control and survival) and morbidity.     

Positron emission tomography using [18F]fluorotamoxifen to evaluate therapeutic responses in patients with breast cancer: preliminary study

Positron emission tomography (PET) was used to assess the biodistribution and clinical usefulness of [18F]fluorotamoxifen (FTX) in 10 patients with estrogen-receptor(ER)-positive breast tumors. Ten patients with ER-positive breast cancer were prospectively studied, and the consecutive PET imagings (each takes 15 or 20 min) were obtained for 60 or 80 min after the injection of 88.8-392.2 MBq (2.4-10.6 mCi) of [18F]FTX. Twenty three suspected primary or metastatic lesions in 10 patients were evaluated and the tumor uptakes of [18F]FTX in nineteen tumor lesions were correlated to the response of tamoxifen therapy. Three lesions in three patients were considered to be truly negative for breast cancer on the bases of biopsy specimens and/or clinical course. Five (71.4%) of seven patients and 16 (80.0%) of 20 lesions were interpreted to be truly positive for breast cancer. The mean standardized uptake value (SUV) of the radiotracer in tumor was 3.0 on delayed images. There was no significant correlation between the standardized uptake values of [18F]FTX and the ER concentrations in primary lesions. Nineteen tumor lesions in six patients were evaluable to compare the [18F]FTX uptake with responses to tamoxifen therapy after the PET study. Three patients who had a good response to tamoxifen therapy showed positive lesions on PET images, whereas two of three patients who had a poor response showed negative lesions and one showed mixed results. There was no significant difference of [18F]FTX uptake in bone lesions between good and poor responders. However, when bone lesions were excluded, [18F]FTX uptakes in tumors with good responses were significantly higher than those with poor responses (mean and standard deviation of SUV: 2.46 +/- 0.62 vs 1.37 +/- 0.59, P < 0.05). PET imaging using [18F]FTX provides useful information in predicting the effect of tamoxifen therapy in patients with ER-positive breast cancer. Further study is warranted to confirm the clinical utility of PET using [18F]FTX in breast cancer patients.     

Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer.

PURPOSE: This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS: Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION: Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.     

Pilot study on sentinel node biopsy in breast cancer

BACKGROUND AND OBJECTIVES: Sentinel node biopsy (SNB) in breast cancer using indigo carmine was started in January 1998, and this method has proved feasible and reliable. From our initial experience, sentinel lymph nodes (SLNs) were identified in 65 of 88 cases of breast cancer (74%). METHODS: Lymphatic mapping in breast cancer was assessed using radionuclide, technetium-99m human serum albumin or technetium-99m tin colloid. A pilot study on SNB with dye or a combined method was performed between August 1998 and January 1999. RESULTS: SLNs were identified in 55 of 59 cases (93%). False-negative SLNs were found in 2 cases. The sensitivity and accuracy in all cases were 92% and 96%. SLNs in 52 cases were also diagnosed by immediate frozen sectioning. The sensitivity and accuracy were 89% and 96%. CONCLUSIONS: SNB in the combined method was the best way to identify SLNs in breast cancer.     

Epirubicin or epirubicin and vindesine in advanced breast cancer. A phase III study

One hundred thirty-three evaluable patients with advanced breast cancer entered a randomized trial comparing epirubicin 60 mg/m2 with a combination of epirubicin 45 mg/m2 and vindesine 3 mg/m2 day 1 and 8 every 4 weeks. In all 10 premenopausal women an oophorectomy was performed. Seventy-five patients had previously received cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for advanced disease and 68 had received adjuvant chemotherapy (cyclophosphamide or CMF). Among evaluable patients (72 in the epirubicin group and 61 in the epirubicin + vindesine group) response rates were as follows: complete response--seven versus six; partial response--31 versus 22; no change--16 versus 17 (p greater than 0.40). Median time to disease progression was 6 months in both groups and median survival times were identical (12 months). Thrombocytopenia was less frequent in the epirubicin + vindesine group (p less than 0.01). In the epirubicin + vindesine group, mild to moderate peripheral neuropathy was observed in 40% of the patients. Congestive heart failure developed in one patient with a cumulative dose of epirubicin less than 1000 mg/m2 and in 7 of 15 patients who had greater than 1000 mg/m2. Four died of this cause. In conclusion, epirubicin is effective as a single agent for advanced breast cancer. The combination with vindesine does not increase its efficacy.     

Skin-sparing radiation using intensity-modulated radiotherapy after conservative surgery in early-stage breast cancer: a planning study

PURPOSE: To evaluate the feasibility of skin-sparing by configuring it as an organ-at-risk (OAR) while delivering whole-breast intensity-modulated radiotherapy (IMRT) in early breast cancer. METHODS AND MATERIALS: Archival computed tomography scan images of 14 left-sided early-breast tumor patients who had undergone lumpectomy were selected for this study. Skin was contoured as a 4- to 5-mm strip extending from the patient outline to anterior margin of the breast planning target volume (PTV). Two IMRT plans were generated by the helical tomotherapy approach to deliver 50 Gy in 25 fractions to the breast alone: one with skin dose constraints (skin-sparing plan) and the other without (non-skin-sparing plan). Comparison of the plans was done using a two-sided paired Student t test. RESULTS: The mean skin dose and volume of skin receiving 50 Gy were significantly less with the skin-sparing plan compared with non-skin-sparing plan (42.3 Gy vs. 47.7 Gy and 12.2% vs. 57.8% respectively; p < 0.001). The reduction in skin dose was confirmed by TLD measurements in anthropomorphic phantom using the same plans. Dose-volume analyses for other OARs were similar in both plans. CONCLUSIONS: By configuring the skin as an OAR, it is possible to achieve skin dose reduction while delivering whole-breast IMRT without compromising dose profiles to PTV and OARs.     

Pilot study of MDR1 gene transfer into hematopoietic stem cells and chemoprotection in metastatic breast cancer patients

A major problem in high-dose chemotherapy with autologous hematopoietic stem cell transplantation is insufficient function of reconstituted bone marrow that limits the efficacy of post-transplantation chemotherapy. Because transduction of hematopoietic stem cells with the multidrug resistance 1 (MDR1) gene might circumvent this problem, we conducted a pilot study of MDR1 gene therapy against metastatic breast cancer. Peripheral blood stem cells were harvested, and one-third of the cells were transduced with MDR1 retrovirus. After the reconstitution of bone marrow function, the patients received high-dose chemotherapy with transplantation of both MDR1-transduced and unprocessed peripheral blood stem cells. The patients then received docetaxel chemotherapy. Two patients received transplantation of the MDR1-transduced cells in 2001. Peripheral blood MDR1-transduced leukocytes were 3-5% of the total cells after transplantation, but decreased gradually. During docetaxel chemotherapy, an increase in the rate of MDR1-transduced leukocytes (up to 10%) was observed. Comparison of docetaxel-induced granulocytopenia in the two patients suggested a bone marrow-protective effect of the MDR1-transduced cells. No serious side-effect was observed, and the patients were in complete remission for more than 3 years. The MDR1-transduced cells gradually decreased and disappeared almost entirely by the end of 2004. Results of linear amplification-mediated polymerase chain reaction of the MDR1-transduced leukocytes suggested no sign of abnormal amplification of the transduced cells. A third patient received transplantation of the MDR1-transduced cells in 2004. These results suggest the feasibility of our MDR1 gene therapy against metastatic breast cancer, and follow-up is ongoing.     

Locally advanced breast cancer: report of phase II study and subsequent phase III trial.

Twenty-four evaluable patients with stage T4 breast cancer were entered into a phase II study and received chemotherapy comprising cyclophosphamide 1,000 mg m-2 i.v., doxorubicin 50 mg m-2 i.v., vincristine 1.4 mg m-2 i.v. and prednisolone 40 mg orally for 5 days, given 3 weekly for four cycles prior to undergoing loco-regional radiotherapy. All patients completed treatment as planned with no major acute toxicity from either chemotherapy or radiotherapy. Subsequently 52 patients with stage T4 breast cancer were randomised in a phase III trial to receive either radiotherapy alone (RT) or this chemotherapy and radiotherapy (CHOP + RT). A significantly higher complete response rate was achieved in the CHOP + RT treatment arm (P = 0.03). However a larger proportion of the RT arm achieved loco-regional control after salvage treatment for relapse such that 50% of the RT arm and 57% of the CHOP + RT arm had no evidence of loco-regional disease at the time of last follow-up or death. There was no statistical difference in time to distant relapse or overall survival. Analysis of the pilot study showed results comparable to the trial CHOP + RT arm. This trial suggests that this cytotoxic therapy used in conjunction with radiotherapy has only marginal value in improving prognosis in locally advanced breast cancer.