Andrew W. Hutcheon

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.

Positron Emission Tomography Using [18F]-Fluorodeoxy-d-Glucose to Predict the Pathologic Response of Breast Cancer to Primary Chemotherapy

PURPOSE To determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy. PATIENTS AND METHODS Thirty patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens. RESULTS Thirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P =.037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or complete microscopic (P =.001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P =.076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P =.037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P =.038; K, P =.012). CONCLUSION [(18)F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.

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.

Psychological factors can predict the response to primary chemotherapy in patients with locally advanced breast cancer

This study evaluated the possible value of psychological variables in predicting clinical and pathological response to primary chemotherapy. 96 women with newly diagnosed large, or locally advanced, breast cancer (T2 > 4 cm, T3, T4, N2 and M0) participated in a prospective, randomised trial to evaluate the effects of relaxation training with guided imagery and L-arginine on response to primary chemotherapy. Before the first of six cycles of primary chemotherapy, women were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Eysenck Personality Questionnaire (EPQ). The primary outcomes were clinical response (evaluated using standard International Union Against Cancer (UICC) criteria) and pathological response (graded by means of a previously published 5-point scale) following primary chemotherapy. Stepwise linear regressions were used to estimate the predictive value of age, menopausal status, clinical nodal status, tumour size at diagnosis, oestrogen receptor status, dietary supplementation (L-arginine versus placebo), personality (EPQ-L scores), mood (HADS scores) and a psychological intervention. HADS depression score was a significant independent predictor of pathological response to chemotherapy. HADS anxiety score was a significant independent predictor of clinical response. Because the original tumour size before chemotherapy (also a significant predictor of clinical and pathological responses) was taken into account in the analyses, the results cannot be explained in terms of psychobiological factors related to tumour size. This study supports the importance of psychological factors as independent predictors of response to primary chemotherapy in patients with breast cancer. If they can be replicated, these findings have major implications for the management of women with breast cancer. Psychological factors need to be assessed and evaluated in future trials of chemotherapy.

Treatment of large and locally advanced breast cancers using neoadjuvant chemotherapy

BACKGROUND Neoadjuvant (primary) chemotherapy is being used increasingly in the treatment of patients with large and locally advanced breast cancer with the aim of reducing the size of the primary tumor and eliminating micrometastatic disease. Response rates to, compliance with, and survival of patients following neoadjuvant chemotherapy have been variable. We report the results of a consecutive series of 77 patients with breast cancer who received neoadjuvant chemotherapy. METHODS Seventy-seven patients with locally advanced breast cancers were treated with multimodality therapy comprising up to six cycles of chemotherapy (cyclophosphamide, vincristine, doxorubicin, and prednisolone), radiotherapy, and then surgery. The median follow-up was 54 months. Clinical response rates to therapy and overall survival have been documented. In addition, prognostic factors for survival were identified using the Cox proportional hazards model. RESULTS The overall objective response rate of the primary tumor to chemotherapy alone was 87% (25% complete and 62% partial responses, UICC criteria). Following radiotherapy the response rate was 90% (52% complete and 38% partial responses). The overall 5-year survival for all patients was 0.48. However, the probability of survival at 5 years was 0.74 in those with a complete response, and 0.36 if there was a partial clinical response, but no patients who had either stasis of disease or progression survived for 5 years. Independent predictors of better survival that were identified were a complete histopathological response after chemotherapy and radiotherapy, a complete clinical response to chemotherapy, and five or six cycles of chemotherapy versus four or less. CONCLUSIONS Neoadjuvant chemotherapy in patients with large and locally advanced breast cancers can result in satisfactory local control and overall survival rates, especially in patients with a complete clinical or histopathological response after treatment.

Neoadjuvant Docetaxel in Locally Advanced Breast Cancer

Neoadjuvant chemotherapy produces substantial increases in clinical response rates and rates of breast conserving therapy. Pathologic response rate, though generally low, is an important outcome as it is presumably associated with eradication of micrometastatic disease and may likely result in improved outcomes. Anthracyclines have long been considered the most efficacious chemotherapy agents for neoadjuvant therapy of early breast cancer. Unfortunately, not all patients respond to neoadjuvant anthracycline-based chemotherapy. In an effort to improve primary tumor response, docetaxel, an active agent in breast cancer, has been evaluated in the neoadjuvant setting. Several randomized trials, including the NSABP B-27, GEPAR-duo, and the Aberdeen trial, evaluating docetaxel in sequence with a doxorubicin-based neoadjuvant regimen have been reported, with encouraging findings. We designed the Aberdeen trial with two primary aims: (1) to evaluate primary docetaxel in patients that initially fail a neoadjuvant anthracycline-based polychemotherapy regimen, and (2) to compare a docetaxel-based neoadjuvant regimen with a standard anthracycline-based regimen in patients who do respond to the first four cycles of the anthracycline-based regimen. Eligible patients (n = 162) had previously untreated large (≥3 cm) or locally advanced (T3, T4, TxN2) breast cancer. All received four cycles of CVAP, after which clinical response was assessed. Responding patients were then randomized to four additional cycles of CVAP or to docetaxel 100 mg/m2 every 3 weeks for four cycles. Patients failing to respond to CVAP received the docetaxel regimen. After the first four cycles of CVAP, the overall response rate (ORR) was 67%. Ultimately, responses were higher in the group randomized to docetaxel compared with those continuing CVAP (cCR: 94% v.s. 66%; p = 0.001; pCR 34% v.s. 16%; p = 0.04). The addition of docetaxel improved overall survival and disease-free survival for patients responding to four cycles of CVAP as compared with those receiving eight cycles of CVAP. Relative dose intensity was higher and the incidence of severe leukopenia was lower in the group randomized to docetaxel. These data and data from the NSABP B-27 and GEPAR-duo trials strongly support a combined anthracycline/docetaxel regimen in the neoadjuvant setting.

women Who Wish Breast Reconstruction: Characteristics, Fears, and Hopes

&NA; The aims of the present study were to identify the characteristics of a consecutive series of women with newly diagnosed breast cancer and to evaluate the perceived benefits and disadvantages of breast reconstruction. A consecutive series of 125 women completed the Breast Reconstruction Questionnaire, the Hospital Anxiety and Depression Scale, and the Eysenck Personality Questionnaire. The median age was 48 years (range, 28 to 75 years). A total of 49.6 percent (n = 62) indicated that, if it were possible, they would like breast reconstruction. Logistic regression (simultaneous entry) revealed that younger women (p = 0.0001) and more depressed women (p = 0.026) were more likely to wish reconstruction. Marital status, tumor size, extroversion, neuroticism, and toughmindedness did not independently predict the desire for reconstruction. If given a choice of reconstruction at 3 months or 6 months after mastectomy, of the women who wished reconstruction, 74 percent would prefer it at 3 months. Of the women who wished reconstruction and expressed a preference, 63 percent were afraid reconstruction might mask recurrence, 39 percent were afraid that reconstruction might cause the cancer to return, and 89 percent thought they would be concerned with their appearance after the operation. Positively, 94 percent considered that reconstruction would be beneficial in terms of their self‐esteem, 86 percent indicated that reconstruction would give greater freedom to wear any clothing, and 86 percent thought that the cosmetic appearance of breast reconstruction was better than that of a prosthesis. Concerns about recurrence were common. A better understanding of the concerns of women with regard to reconstruction would allow more informed preoperative discussion.

The relationship between vascular and metabolic characteristics of primary breast tumours

The objective of this study was to investigate the relationship between vascular and metabolic characteristics of breast tumours in vivo, using contrast-enhanced dynamic MRI and 2-[18F] fluoro-2-deoxy-d-glucose (FDG) PET imaging. Twenty patients with large or locally advanced primary breast cancers were imaged prior to therapy. MRI data were acquired using a dynamic gradient echo sequence and analysed using two pharmacokinetic models. Static PET data were acquired in 2D mode. A significant association (P<0.05) was observed between the calculated exchange rate constants of both pharmacokinetic models and calculated PET FDG dose uptake ratios (DUR). Statistical analysis showed that the exchange rate constants can explain between 27 and 44% of the variance observed in the PET FDG uptake ratios. A relationship was demonstrated between the vascular and metabolic characteristics of primary breast tumours showing that any assessment of tumour metabolic activity using PET may be controlled at least in part by delivery of uptake agent due to the vascular characteristics of the tumour. MRI and PET provide methods of assessing breast tumour vascularity and metabolism in vivo using the exchange rate constants of dynamic MRI, and DUR of PET, respectively, these measures being related but not equivalent.

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.

Primary docetaxel chemotherapy in patients with breast cancer: impact on response and survival.

Primary chemotherapy achieves high clinical response rates and facilitates breast conservation in many patients with large and locally advanced breast cancer. It may also serve to indicate responsiveness to chemotherapeutic agents. A pathological complete response to primary chemotherapy is a primary predictor and surrogate marker of long-term outcome, but occurs in only approximately 15% of patients. Docetaxel is of particular interest in this setting. Primary docetaxel chemotherapy has single-agent activity in both dose-dense and traditional schedules, with acceptable tolerability. Furthermore, concomitant docetaxel–anthracycline schedules have shown promise in Phase II trials, achieving clinical overall response rates (ORRs) of 77–96%, pathological complete responses of up to 24%, and breast conservation in up to 89% of patients.Two Phase III studies have shown that pathological complete response is significantly improved with the addition of docetaxel to anthracycline-based therapy versus the latter alone: the Aberdeen study achieved a rate of 34% versus 16%, respectively (p = 0.04), and the NSABP-B27 study a rate of 26% versus 14%, respectively (p < 0.001). The Aberdeen study has suggested that the addition of docetaxel may yield a survival benefit at 5 years (p = 0.04). The Phase II GEPAR-DUO study hints at a benefit for sequential over concomitant docetaxel-based therapy, with improvements in both clinical response (ORR 87% versus 77%, respectively) and pathological complete response (23% versus 12%, respectively). Non-anthracycline docetaxel-based primary regimens have shown early promise. As we continue to define the optimal regimen, a growing body of evidence supports the use of docetaxel in primary chemotherapeutic regimens for breast cancer.