Immuno-modulatory effects of relaxation training and guided imagery in women with locally advanced breast cancer undergoing multimodality therapy: a randomised controlled trial.

Eighty women undergoing multimodality treatment for large (>4cm) or locally advanced (T3, T4, Tx, N2), breast cancers participated in a randomised controlled trial (RCT) to evaluate the immuno-modulatory effects of relaxation training and guided imagery. Patients underwent chemotherapy followed by surgery, radiotherapy, and hormone therapy. Those in the intervention group were taught relaxation and guided imagery. Patients kept diaries of the frequency of relaxation practice and imagery vividness. On 10 occasions during the 37 weeks following the diagnosis, blood was taken for immunological assays CD phenotyping: T cell subsets (helper, cytotoxic), natural killer (NK) and lymphokine activated killer (LAK) cells, B lymphocytes and monocytes; cytotoxicity: NK and LAK cell activities; cytokines interleukin 1 beta (1beta), 2, 4 and 6 and tumour necrosis factor alpha. Significant between-group differences were found in the number of CD25+ (activated T cells) and CD56+ (LAK cell) subsets. The number of CD3+ (mature) T cells was significantly higher following chemotherapy and radiotherapy, in patients randomised to relaxation and guided imagery. Using a median split, women who rated their imagery ratings highly had elevated levels of NK cell activity at the end of chemotherapy and at follow-up. Significant correlations were obtained between imagery ratings and baseline corrected values for NK and LAK cell activity, and IL1beta. Relaxation frequency correlated with the number of CD4+ (T helper) cells, the CD4+:8+ (helper:cytotoxic) ratio, and IL1beta levels. Relaxation training and guided imagery beneficially altered putative anti-cancer host defences during and after multimodality therapy. Such changes, to the best of our knowledge, have not been previously documented in a RCT.

Patterns of local and distant disease relapse in patients with breast cancer treated with primary chemotherapy: do patients with a complete pathological response differ from those with residual tumour in the breast?

This study aimed to evaluate patterns of local and distant disease recurrence in patients having primary chemotherapy and compared patterns of relapse in patients with a complete pathological response with those who had residual breast disease. This is an observational study using a sequential series of patients treated with primary chemotherapy. They were followed up for a minimum of 5 years. All data was collected prospectively. Three hundred forty-one consecutive patients with breast cancer were treated with up to eight cycles of doxorubicin-based chemotherapy. Clinical and pathological response rates were evaluated and patients were followed up for disease recurrence (local and distant) and overall survival. Fifty-two patients (16.5%) had a complete pathological response to chemotherapy. Distant disease recurrence occurred in nine patients (17.3%) but no local recurrence was observed. In patients not having a complete pathological response, 86 patients (32.6%) subsequently developed metastases. Local recurrence of disease occurred in 12 (4.5%). There was a statistically significant difference in overall survival between patients whose tumours had a complete pathological response compared with patients who had residual disease in the breast following chemotherapy (88% versus 70% at 5 years, p = 0.036). Following primary chemotherapy, about 84% of patients had residual disease in the breast. Surgery is necessary to ensure complete removal of residual tumour and excellent rates of local control are achievable. A complete pathological response is associated with fewer local and distant recurrences as well as improved survival although there are no differences in time to development of metastatic relapse.

Can patients' likelihood of benefiting from primary chemotherapy for breast cancer be predicted before commencement of treatment?

PURPOSE: Primary chemotherapy is commonly used in patients with breast cancer to downstage the primary tumour prior to surgery. There is a need to establish, prior to commencement of chemotherapy, predictors of clinical and pathological response, which may then be surrogate markers for patient survival and thus allow identification of patients who are most likely to benefit from such treatment. PATIENTS AND METHODS: A total of 104 patients with large and locally advanced breast cancers received an anthracycline/docetaxel-based regimen prior to surgery. Immunohistochemistry was carried out on pre-treatment core biopsies of the tumour to detect hormone receptors (oestrogen-ER; progesterone-PR), a proliferation marker (MIB-1), the oncoprotein Bcl-2, an extracellular matrix degradation enzyme (cathepsin D), p53, and an oestrogen associated protein (pS2). Both clinical and pathological response were assessed following completion of chemotherapy. RESULTS: Patients whose tumours did not express oestrogen receptor (p = 0.02) or did not express Bcl-2 (p < 0.01) had a better pathological response in a univariate analysis. However, in a multivariate model, it was only the absence of detectable Bcl-2 protein that predicted a better pathological response (p = 0.001). CONCLUSIONS: This study has identified that patients whose breast cancers are most likely to experience the greatest degree of tumour destruction by primary chemotherapy do not express either oestrogen receptors or Bcl-2. This may have important implications in the selection of patients with breast cancer for primary chemotherapy who are most likely to gain a survival benefit.

A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival.

The clinical and complete pathological response of a primary breast cancer to chemotherapy has been shown to be an important prognostic for survival. However, the majority of patients do not experience a complete pathological response to primary chemotherapy and the significance of lesser degrees of histological response is uncertain and the prognostic significance is unknown. The purpose of this study was to evaluate a new histological grading system to assess response of breast cancers to primary chemotherapy and to determine if such a system has prognostic value.A consecutive series of 176 patients with large (> or =4cm) and locally advanced breast cancers were treated with multimodality therapy comprising primary chemotherapy, surgery, radiotherapy and tamoxifen. All underwent assessment of the primary breast tumour before and after completion of chemotherapy. Residual tumour was excised after completion of chemotherapy (mastectomy or wide local excision with axillary surgery). The removed tissue was assessed and response to chemotherapy graded using a five-point histological grading system based with the fundamental feature being a reduction in tumour cellularity; comparison being made with a pre-treatment core biopsy. All patients were followed up for 5 years or more. Pathological responses were compared to 5 year overall survival and disease-free survival using log rank tests. The overall 5-year survival for all patients was 71%, and 5 year disease free interval was 60%. There was a significant correlation between pathological response using this new grading system and both overall survival (P=0.02) and disease-free interval (P=0.04). In a multivariate analysis of known prognostic factors, the Miller/Payne grading system was an independent predictor of overall patient survival. This grading system, which assesses the histological response to primary chemotherapy, can predict overall survival and disease-free interval in patients with large and locally advanced breast cancers treated with such therapy. The relationship of degree of histological response to overall and disease-free survival has been shown in univariate and multivariate analyses and could potentially have an important role in the clinical management of patients with locally advanced breast cancer undergoing primary chemotherapy.

Local recurrence in patients with large and locally advanced breast cancer treated with primary chemotherapy.

BACKGROUND: Primary chemotherapy is being given in the treatment of large and locally advanced breast cancers, but a major concern is local relapse after therapy. This paper has examined patients treated with primary chemotherapy and surgery (either breast-conserving surgery or mastectomy) and has examined the role of factors which may indicate those patients who are subsequently more likely to experience local recurrence of disease. METHODS: A consecutive series of 173 women, with data available for 166 of these, presenting with large and locally advanced breast cancer (T2>/=4 cm, T3, T4, or N2) were treated with primary chemotherapy comprising cyclophosphamide, vincristine, doxorubicin, and prednisolone and then surgery (either conservation or mastectomy with axillary surgery) followed by radiotherapy were examined. RESULTS: The clinical response rate of these patients was 75% (21% complete and 54% partial), with a complete pathological response rate of 15%. A total of 10 patients (6%) experienced local disease relapse, and the median time to relapse was 14 months (ranging from 3 to 40). The median survival in this group was 27 months (ranging from 13 to 78). In patients having breast conservation surgery, local recurrence occurred in 2%, and in those undergoing mastectomy 7% experience local relapse of disease. Factors predicting patients most likely to experience local recurrence were poor clinical response and residual axillary nodal disease after chemotherapy. CONCLUSIONS: Excellent local control of disease can be achieved in patients with large and locally advanced breast cancers using a combination of primary chemotherapy, surgery and radiotherapy. However, the presence of residual tumor in the axillary lymph nodes after chemotherapy is a predictor of local recurrence and patients with a better clinical response were also less likely to experience local disease recurrence. The size and degree of pathological response did not predict patients most likely to experience recurrence of disease.

Neoadjuvant docetaxel in breast cancer: 3-year survival results from the Aberdeen trial.

Over the past 30 years there has been an increased use of neoadjuvant (or primary) chemotherapy for treating patients with breast cancer. However, while it is clear that chemotherapy given in the adjuvant setting after surgery does prolong patients' overall and disease-free survival, the evidence that chemotherapy in the neoadjuvant setting also increases survival remains unproven. In the Aberdeen study, 162 patients with large and locally advanced breast cancer underwent 4 cycles of CVAP (cyclophosphamide/vincristine/doxorubicin/prednisone) primary chemotherapy. Patients with a complete or partial response were then randomized to either 4 further cycles of CVAP or 4 cycles of docetaxel (100 mg/m2). It was shown that the addition of sequential docetaxel (100 mg/m2) to CVAP neoadjuvant chemotherapy resulted in a significantly enhanced clinical response rate (94% vs. 64%) and a substantially increased complete histopathological response rate (34% vs. 16%) when compared to patients receiving CVAP alone. Furthermore, patients receiving docetaxel had an increased breast conservation rate (67% vs. 48%) and an increased survival at a median follow-up of 3 years. It is important to note that this was a small study, and the survival results should be interpreted with caution. The results are encouraging, however, and further studies are urgently required.

Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel.

PURPOSE: To compare the efficacy of neoadjuvant (NA) docetaxel (DOC) with anthracycline-based therapy and determine the efficacy of NA DOC in patients with breast cancer initially failing to respond to anthracycline-based NA chemotherapy (CT). PATIENTS AND METHODS: Patients with large or locally advanced breast cancer received four pulses of cyclophosphamide 1,000 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.5 mg/m(2), and prednisolone 40 mg (4 x CVAP) for 5 days. Clinical tumor response was assessed. Those who responded (complete response [CR] or partial response [PR]) were randomized to receive further 4 x CVAP or 4 x DOC (100 mg/m(2)). All nonresponders received 4 x DOC. RESULTS: One hundred sixty-two patients were enrolled; 145 patients completed eight cycles of NA CT. One hundred two patients (66%) achieved a clinical response (PR or CR) after 4 x CVAP. After randomization, 50 patients received 4 x CVAP and 47 patients received 4 x DOC. In patients who received eight cycles of CT, the clinical CR (cCR) and clinical PR (cPR) (94% v 66%) and pathologic CR (pCR) (34% v 16%) response rates were higher (P =.001 and P =.04) in those who received further DOC. Intention-to-treat analysis demonstrated cCR and cPR (85% v 64%; P =.03) and pCR (31% v 15%; P =.06). Axillary lymph node examination revealed residual tumor in 33% of patients who received 8 x CVAP and 38% of patients who received further DOC. In patients who failed to respond to the initial CVAP, 4 x DOC resulted in a cCR and cPR rate of 55% and a pCR rate of 2%. Forty-four percent of these patients had residual tumor within axillary lymph nodes. CONCLUSION: NA DOC resulted in substantial improvement in responses to DOC.