Where next with stem-cell-supported high-dose therapy for breast cancer?
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Antineoplastic Agents↗
Biomedical subjects
J Bergh
Publications and source records attributed to J Bergh.
[Adjuvant therapy of breast cancer in the USA].
Explore the source record for details and available documents.
Antineoplastic Agents, Phytogenic↗
Quality of life in patients with metastatic breast cancer receiving either docetaxel or sequential methotrexate and 5-fluorouracil. A multicentre randomised phase III trial by the Scandinavian breast group.
The purpose of this study was to evaluate the effects of two alternative chemotherapy regimes on the quality of life (QoL) of patients with advanced breast cancer. In a multicentre trial, 283 patients were randomised to receive either docetaxel (T) or sequential methotrexate and 5-fluorouracil (MF). QoL was assessed at baseline and before each treatment using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). Initial compliance in the QoL study was 96% and the overall compliance 82%. QoL data were available for 245 patients (T 130 and 115 MF). Both treatment groups showed some improvement in emotional functioning during treatment, with a significant difference favouring the MF group at treatment cycles 5 and 6. In the T group, the scores on the other functional scales remained stable throughout the first six cycles. There were significant differences favouring the MF group on the social functioning scale at treatment cycle 6 and on the Global QoL scale at treatment cycles 5 and 6. On most symptom and single-item scales there were no statistically significant differences between the groups. However, at baseline, the T patients reported more appetite loss, at treatment cycles 2-4, the MF patients reported more nausea/vomiting, and at treatment cycle 6, the T patients reported more symptoms of fatigue, dyspnoea and insomnia. There were no statistically significant differences between the groups in the mean change scores of the functional and symptom scales. Interindividual variance was, however, larger in the T group. Differences in QoL between the two treatment groups were minor. Hence, given the expectancy of comparable QoL outcomes, the choice of treatment should be made on the basis of the expected clinical effect.
Algorithms↗
Evaluation of drug interactions in the established FEC regimen in primary cultures of tumour cells from patients.
BACKGROUND: Chemotherapy using multi-drug regimens is considered more active than single-agent therapy. This may be due to synergistic interactions or, simply, a higher probability of administering an active agent. We investigated in vitro the type of drug interactions in a recognized regimen in relationship to tumour type and drug sensitivity. PATIENTS AND METHODS: The possibility of synergistic and additive interactions between individual cytotoxic drugs was investigated for the component drugs of the established FEC regimen, i.e., 5-fluorouracil, epirubicin and cyclophosphamide, in 243 patient tumour samples representing various drug sensitivity using the non-clonogenic fluorometric microculture cytotoxicity assay. RESULTS: Using a cell survival of < or = 50% as a limit for drug activity and sample sensitivity, the overall response rates to the most active single drug (Dmax) and the combination were 56% and 64%, respectively, with a distribution among diagnoses similar to that in the clinic. For 86% of the samples there was concordance with respect to judgement of activity using either Dmax or the combination. For samples being sensitive to at least one single drug, 95% were also sensitive to the combination whereas for samples with insignificant Dmax effect, only 2% were sensitive to the combination. In samples with modest Dmax effects, i.e., cell survival in the range > 50%- < or = 80%, 45% responded to the combination. The effect of the combination was generally well predicted from the Dmax effect. CONCLUSIONS: The superior antitumour effect of drug combinations compared with single drugs may be due to the higher chance of selecting an active agent. However, for intermediately sensitive tumours, additional interaction effects of a combination may be of clinical significance.
Antineoplastic Combined Chemotherapy Protocols↗
Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors.
p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector containing wt p53 was carried out in patients with metastatic melanoma or breast cancer with increased p53 protein immunoreactivity in pretreatment tumor biopsies. The biological activity of the injected wt p53 was assayed by reverse transcriptase-polymerase chain reaction in tumor tissue. A total of six (five melanoma and one breast adenocarcinoma) patients were treated at dose levels dependent upon tumor size/dose escalation sequence. Five of six patients became positive for the transfer of wt p53 into tumor tissue 2 days after injection of the vector. Of the four patients assayed, all developed anti-adenoviral antibodies. Adverse reactions associated with i.t. injection were mild, with no obvious correlation between the incidence, severity, or relationship of the events and drug dose. p53 gene therapy by i.t. injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective (with respect to transduction frequency) in patients with either metastatic melanoma or breast cancer.
Adenocarcinoma↗
Subclinical cardiotoxicity following adjuvant dose-escalated FEC, high-dose chemotherapy, or CMF in breast cancer.
We compared adjuvant chemotherapy-related myocardial damage by antimyosin scintigraphy in patients who received either nine cycles of FEC (fluorouracil, epirubicin and cyclophosphamide) where the doses of epirubicin and cyclophosphamide were escalated according to the leucocyte nadir (group I, n = 14), three cycles of FEC followed by high-dose chemotherapy with alkylating agents (CTCb) given with the support of peripheral blood stem cell transplantation (group II, n = 14), or six cycles of standard intravenous CMF (cyclophosphamide, methotrexate and fluorouracil; group III, n = 8). The cardiac uptake of In-111-antimyosin-Fab (R11D10) antibody was measured and the heart-to-lung ratio (HLR) calculated 8-36 months after the last dose of chemotherapy. Cardiac antimyosin antibody uptake was considerably higher among patients treated with nine cycles of dose-escalated FEC than among those who were treated with three cycles of FEC and high-dose CTCb (HLR, median 1.98; range 1.36-2.24 vs median 1.51; range 1.20-1.82; P < 0.001), or those treated with CMF (median 1.44; range 1.15-1.68; P < 0.001). The difference between groups II and III was not significant (P > 0.1). A linear association was found between the cumulative dose of epirubicin and the cardiac antimyosin uptake (P < 0.001). We conclude that subclinical cardiac damage caused by three cycles of conventional-dose FEC followed by one cycle of high-dose CTCb chemotherapy is small as compared with the damage caused by dose-escalated FEC.
Adult↗
Evaluation of new sclerotic bone metastases in breast cancer patients during treatment.
PURPOSE: According to the World Health Organization (WHO) criteria for response of bone metastases to therapy, new lesions indicate progressive disease. We intended to prove that a new sclerotic lesion on conventional radiography may also be a sign of a positive therapeutic response in a previously undetectable lytic metastasis. MATERIAL AND METHODS: In a previous placebo-controlled clinical trial of clodronate (Ostac) therapy, 139 breast cancer patients with bone metastases underwent both conventional radiography and bone scan every 6 months for 2 years with 99mTc before and during clodronate treatment. WHO criteria were applied for therapy response evaluation. RESULTS: In 24 patients, 52 new sclerotic lesions observed during therapy were selected for re-evaluation of conventional radiographs and bone scans. In 8 of the 24 patients, 17 of 52 new sclerotic lesions (33%) had showed positive uptake on previous bone scans. These lesions were possibly misinterpreted as new when applying WHO criteria. CONCLUSION: For better assessment of new sclerotic lesions during treatment, more sensitive techniques, e.g. bone scan, are needed as a complement to conventional radiography.
Adult↗
Local breast cancer recurrence caused by mammographically guided punctures.
PURPOSE: To evaluate the risk of needle track seeding or tumor cell implantation as the cause of locally recurrent breast cancer after breast conserving surgery. MATERIAL AND METHODS: We reviewed recurrences from a consecutive series of 303 clinically nonpalpable breast cancers treated with breast conserving surgery after pre-operative localization. The median mammographic follow-up was 5.4 years. The suspicion of seeding or implantation was based on the location of the recurrent lesion in comparison with the needle path in two orthogonal mammographic projections. Pre-operative percutaneous biopsies had been done in 71% (214/303) of the cases. Postoperative radiotherapy was administered to 82% (194/238) of the invasive cancers and to 28% (18/65) of the ductal cancers in situ (DCIS). RESULTS: Locally recurrent cancer occurred in 11% (33/303) of the cases. Radiotherapy demonstrated a protective effect from relapse among invasive cancers but not for DCIS. Seeding or implantation was suspected in 3 recurrent invasive cancers which had not been subject to radiotherapy. The histopathological diagnosis of the primary cancer and the recurrent cancer were the same in these cases: adenoid cystic, mucinous and tubuloductal cancer. CONCLUSION: Seeding or implantation was suspected as the cause of local recurrence in 7% (3/44) of the invasive cancers which did not receive radiotherapy.
Adenocarcinoma↗
Can axillary dissection be avoided by improved molecular biological diagnosis?
Axillary dissection is presently a routine staging procedure in the management of breast cancer. The use of adjuvant systemic treatment is largely based on the diagnosis of axillary metastases. Routine axillary dissection leads to acute and chronic side-effects in a large proportion of patients. The sentinel node technique is presently explored with the aim of decreasing the need for standard axillary dissection. A complementary way forward is to analyse the primary breast cancer for molecular markers with prognostic significance with reference to the risk for metastatic capacity and thereby obtain a 'biological staging' and identify those patients in need of systemic adjuvant therapy. A large number of molecular biological factors have been shown to have prognostic significance in breast cancer e.g. c-erbB-2, p53, uPA, PAI-I and VEGF. This article reviews the expression of these and other factors in the primary breast cancers in relation to the risk for axillary and systemic metastatic disease, with the long-term aim of excluding routine axillary dissection.
Axilla↗
Predictive value of p53, mdm-2, p21, and mib-1 for chemotherapy response in advanced breast cancer.
p53 is a transcription factor that participates in cell cycle checkpoint processes and apoptosis. The protein product of the murine double minute gene 2 (mdm-2) plays a central role in the regulation of p53. In response to DNA-damaging agents, the wild-type p53-activated fragment 1 (WAF1 also known as p21) is an important downstream effector in the p53-specific growth arrest pathway. In breast cancer patients, it is unclear whether measuring p53, mdm-2, or p21 expression provides information on how patients will respond to chemotherapy. Mib-1 monoclonal antibody recognizes the proliferation-related antigen Ki-67. High tumor proliferation has previously been associated with response to chemotherapy. p53, mdm-2, p21, and mib-1 expression were assessed by immunohistochemical methods in primary tumors derived from 134 patients who took part in a randomized multicenter trial comparing docetaxel to sequential methotrexate and 5-fluorouracil (MF) in advanced breast cancer. Low mib-1 staining correlated with negative p53 staining (P = 0.001), and mdm-2 and p21 stainings correlated positively with each other (P < 0.001). p53, mdm-2, p21, and mib-1 expression were not significantly associated with response to chemotherapy, time to progression, or overall survival in the whole patient population or in the docetaxel group. However, in the MF group, a low mib expression (<25%) and a high mdm-2 expression (> or =10%) predicted a better response (P = 0.014 and P = 0.046, respectively) to treatment and a longer time to progression in both univariate and multivariate analyses. p53 staining status was not associated with response to treatment in either group. Interestingly, tumors with both negative mdm-2 and p21 expression, irrespective of p53 status, had a high response rate to docetaxel but no response to MF. Although highly preliminary, the findings suggest that different tumor biological factors may predict response to different chemotherapy regimens with distinct mechanisms of action. The results of our phenotype analysis also indicate that it is more likely that a panel of tumor biological factors instead of only one single factor may be needed for better prediction of chemotherapy response.
Adolescent↗
Elucidation of the mechanism of homozygous deletion of 3p12-13 in the U2020 cell line reveals the unexpected involvement of other chromosomes.
Homozygous deletions in tumor cells have been useful in the localization and validation of tumor suppressor genes. We have described a homozygous deletion in a lung cancer cell line (U2020) which is located within the most proximal of the three regions on the short arm of chromosome 3 believed to be lost in lung cancer development. Construction of a YAC contig map indicates that the deletion spans around 8 Mb, but no large deletion was apparent on conventional cytogenetic analysis of the cell line. To investigate this paradox, whole chromosome, arm-specific, and regional paints have been used. This analysis has revealed that genetic loss has occurred by complex rearrangements of chromosomes 3, rather than simple interstitial deletion. These studies emphasize the power of molecular cytogenetics to disclose unsuspected tumor-specific translocations within the extremely complex karyotypes characteristic of solid tumors.
Carcinoma, Small Cell↗
Ductal carcinoma in situ of the breast from a population-defined cohort: an evaluation of new histopathological classification systems.
The increased incidence of ductal carcinoma in situ of the breast (DCIS) in the era of mammography screening requires a deeper knowledge of the biology of the disease and calls for a suitable classification system to optimise therapy. Our aim was to evaluate the correlation to prognosis for two new classification systems of DCIS. The histopathological specimens from 195 women consecutively diagnosed between 1986 and 1994 with a primary DCIS were re-classified by two separate observers using the system proposed by an European Organization for Research and Treatment of Cancer (EORTC) working group and the Van Nuys system. The relapse-free survival (RFS) by histopathological subgroup and by nuclear grade only was estimated for women treated with breast conserving surgery (n = 149). Thirty-two local recurrences occurred among 149 women (mean follow-up time 59 months). No distant recurrences or breast cancer deaths were reported. The women in the group with the highest differentiation according to the EORTC classification had no recurrences. RFS did not differ appreciably between the two other groups. This was true also after stratification for radiotherapy. We found no statistically significant difference in RFS between the three groups in the Van Nuys classification. There was an overall agreement between the observers in 79% and 64% of the cases, according to the EORTC and Van Nuys systems, respectively. We were able to define one group with highly differentiated lesions and an excellent prognosis with the EORTC classification. Further classification into intermediate and low differentiated lesions did not help predict RFS.
Adult↗
Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group.
The aim of this study was to compare the efficacy and tolerability of docetaxel to methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure. A randomised multicentre trial was conducted in 283 patients with advanced breast cancer who had failed previous anthracycline treatment. Docetaxel at a dose of 100 mg/m2 every 3 weeks (n = 143) was compared with sequential methotrexate and 5-fluorouracil (MF; n = 139) given at day 1 and 8 every 3 weeks at dosages of 200 mg/ m2 and 600 mg/m2, respectively. After progression, crossover to the alternative treatment group was recommended. There was a significantly higher overall response rate in the docetaxel 42% (CR 8% + PR 34%) than in the MF arm 21% (CR 3% + PR 18%) (P < 0.001). The median time to progression (TTP) was 6.3 months in the docetaxel arm and 3.0 months in the MF arm (P < 0.001). Docetaxel also had a significantly higher response rate of 27% following crossover compared with MF (12%). Significantly more side-effects (leucopenia, infections, neuropathy, oedema, asthenia, skin, nail changes, alopecia) were seen in the docetaxel than in the MF group. However, grade 3 and 4 side-effects were infrequent with both drugs, with the exception of fatigue, alopecia and infections. Median overall survival (OS) including crossover phase was 10.4 months in the docetaxel and 11.1 months in the MF arm (P = 0.79). Based on the response rate and the primary endpoint of TTP, docetaxel is superior to sequential methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure.
Adult↗
Cross-comparison of two quality of life instruments used in a randomized study of combination chemotherapy in advanced breast cancer.
Twenty-six patients from a randomized study of combination chemotherapy in advanced breast cancer were included in a cross-comparison between two quality of life instruments: a categorical linear analogue scale (C-LASA) based on the instrument of Priestman and Baum and a Swedish instrument developed by Glimelius et al. Quality of life was assessed on day 1 and day 10 of each chemotherapy cycle and the instruments were compared using correlation and kappa analysis. For the physical dimension, the mean correlation coefficient on day 1 was 0.89 and the kappa coefficient was 0.62; and on day 10 the correlation coefficient was 0.83 and the kappa coefficient 0.62. For the emotional dimension the correlation and kappa coefficients were 0.89 and 0.71 and 0.89 and 0.61 on days 1 and 10, respectively. The corresponding values for the global dimension were 0.76 and 0.56 and 0.80 and 0.57 on days 1 and 10, respectively. A correlation was also demonstrated over time. The instruments gave similar measurements of quality of life for chemotherapy-treated patients with advanced breast cancer, but the feasibility of the C-LASA instrument was better.
Adult↗
FEC mobilized stem cells for high-dose therapy in breast cancer patients. SB6 9401 Study Group.
The feasibility of mobilizing peripheral blood stem cells (PBSC) using anthracycline containing polychemotherapy and G-CSF on the first 50 patients randomized to the high-dose arm in the adjuvant SBG 9401 is investigated. The patients were treated with standard FEC (5-fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2) for two courses followed by a modified third FEC course with a C dose of 1200 mg/m2 supported with subcutaneous G-CSF (filgrastim) at 5 mg/kg followed by harvest around day 11. The mean yield of CD34+ cells per patient was 10.6x10(6)/kg (range 2.6-29.1). The side effects after the third course were low and only one patient developed an uncomplicated granulopenic fever. Our data indicated a correlation between number of transfused CD34+ cells and days to neutrophil and platelet recovery. In conclusion, the modified FEC regimen followed by G-CSF is a feasible method for PBSC mobilization in the adjuvant setting.
Antigens, CD34↗
Radiation recall--another call with tamoxifen.
Tamoxifen, a nonsteroidal antioestrogen, has been used as an adjuvant therapy in patients with oestrogen-receptor positive breast cancer for more than 10 years. Few cutaneous adverse side-effects of the skin are found with this therapy. In this study we present 20 cases of adverse skin effects in relation to tamoxifen during 1979-1997 reported to the Swedish Adverse Drug Reaction Register and 1160 skin side-effects reported to he World Health Organisation's International Collaborative Programme on Drug Monitoring. One new case report of radiation recall in conjunction to tamoxifen, with no sign of reactivation despite 18 months treatment with the tamoxifen analogue toremifene is also discussed in detail. This case illustrates that toremifene can be used as a second-line therapy in patients who have received radiation recall, on tamoxifen.
Antineoplastic Agents, Hormonal↗
Is there a role for intensive therapy in breast cancer?
With reference to survival, polychemotherapy has been demonstrated to be statistically significantly more effective than monochemotherapy both in the adjuvant setting and in the metastatic situation. Breast cancer demonstrates a dose-response relationship. Chemotherapy used in the conventional dose range should be given with adequate dose-intensity both in the adjuvant setting and for metastatic patients. More dose-intensive combinations are almost always associated with a higher response rate in patients' metastatic disease, but these results have seldom been translated into an improved survival. For marrow requiring high-dose therapy, repeated phase II studies have demonstrated the possibility of a survival tail, which may be due to stage migration and patient selection. At present we have at least 13 ongoing phase III studies in the adjuvant setting and at least 5 ongoing studies in the metastatic situation. These studies will give a definite answer on whether marrow-supported high-dose therapy is better than conventional therapy or if alternative approaches using tailored therapy will result in an equivalent outcome. In the future we must make better use of the present arsenal of drugs and examine the marked inter-individual variations in pharmacokinetic profiles for the drugs. We have to tailor the therapy to the tumour biological profile, in both the primary tumour and metastases with appreciation of heterogeneity and tumour progression. Based on these prerequisites, therapy can be either dose-intensive or in some instances continuous using lower doses.
Antineoplastic Combined Chemotherapy Protocols↗
10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial.
PURPOSE: To study the long-term effectiveness of postoperative radiotherapy after sector resection for breast cancer in a randomized trial in which mammography is a major pathway to diagnosis. PATIENTS AND METHODS: Three hundred eighty-one women with a unifocal breast cancer < or = 20 mm in diameter on the preoperative mammogram and without histopathologic signs of axillary metastases were treated by sector resection plus axillary dissection. Of these patients, 184 women were randomized to receive postoperative radiotherapy to the breast (XRT group), and 197 women received no further treatment (non-XRT group). RESULTS: The local recurrence rate was 8.5% (95% confidence interval [CI], 3.9% to 13.1%) in the XRT group and 24.0% (95% CI, 17.6% to 30.4%) in the non-XRT group (P =.0001). Survival free from regional and distant recurrence was 83. 3% in the XRT group (95% CI, 77.5% to 89.1%) and 80.0% in the non-XRT group (95% CI, 73.9% to 86.1%) (P =.23). Overall survival was 77.5% in the XRT group (95% CI, 70.9% to 84.1%) and 78% in the non-XRT group (95% CI, 71.7% to 84.3%) (P =.99). A subgroup analysis suggested that women older than 55 years of age without comedo or lobular carcinomas had a low risk of local recurrence of 6.1% (95% CI, 0.1% to 9.1%) in the XRT-group and 11.0% (4.0% to 18.0%) in the non-XRT group (P =.16). CONCLUSION: Sector resection plus radiotherapy resulted in an absolute reduction in local recurrence of 16% at 10 years compared with surgery alone. Women older than 55 years of age without comedo or lobular carcinomas may have a low risk of local recurrence. Postoperative radiotherapy was not shown to reduce distant recurrences or improve overall survival.
Breast Neoplasms↗