Primary chemotherapy or hormonotherapy for patients with breast cancer.

Scientific rationale for primary treatment of breast cancer relies on experimental data showing that the incidence and growth of disease correlate with the primary tumour mass and tumoral angiogenesis. Although the strategy may be applied to both chemotherapy and hormonotherapy, only the first was extensively explored for patients with locally advanced breast cancer in order to improve survival and to avoid mastectomy through the achievement of a downstaging of the tumour. Encouraging results obtained in this clinically advanced setting combined with renewed interest for tumoral angiogenesis brought clinicians to apply this strategy to smaller tumours. Despite high clinical and radiological response rates, only pathologic information, carefully assessed in both the primary and axillae lymph nodes, stands out as the major source of prognostic information on patients' outcome. Recent developments in chemotherapy (dose-intensity, new drugs) do not seem to influence these results, indicating the possible limitations of recent developments in chemotherapy. Of 6 published randomized trials comparing primary vs adjuvant chemotherapy, none showed any significant impact of primary chemotherapy on survival, with a trend towards delayed/less distant recurrences in patients treated by primary chemotherapy in some. Some recent reports suggest that local relapse rate might be increased after conservative treatment following induction chemotherapy in subgroups analyse and this should cause oncologists to revise and define the role for conservative surgery after primary medical treatment without calling into question the global strategy. Through sequential samplings, neoadjuvant medical treatment provides indeed the opportunity (a) to identify molecular mechanisms associated with pathologic response and (b) to study the possibility to guide the choices for induction treatment and patient populations submitted to primary medical treatment.     

Neoadjuvant taxanes in the treatment of non-metastatic breast cancer: a systematic review

In recent years the role of neoadjuvant (primary, preoperative) chemotherapy has undergone rapid progress. Initially, neoadjuvant chemotherapy use was limited to those patients with inoperable locally advanced breast cancer in an attempt to try to down-size the tumour to make effective surgery possible. The advent of more effective chemotherapy regimens has led to an increased use of neoadjuvant therapy to shrink potentially operable tumours to allow for breast conservation when a mastectomy would have been required previously. While neoadjuvant treatment for operable tumours has indeed allowed increased rates of breast conserving surgery, it has not yet demonstrated any survival benefit over standard postoperative anthracycline-based chemotherapy. Echoing the evolution of taxane based chemotherapy from the metastatic setting through to the adjuvant situation, there has been increased interest in the role of taxanes in neoadjuvant regimens. The use of taxane-based therapies in this setting has so far shown improvements over more standard regimens in terms of clinical response rates, breast conservation, pathologic response rates, disease free survival, and overall survival. The aim of this review is to systematically summarize and interpret the results of published randomized controlled trials of neoadjuvant taxane chemotherapy for women with non-metastatic breast cancer.     

Initial medical treatment for breast cancer]

Rationale for primary medical treatment of breast cancer relies on experimental data showing that the incidence of metastatic disease is dependent on the primary tumour mass and tumoral angiogenesis. Although this concept may be applied to both chemotherapy and hormonotherapy, only the first was extensively explored for patients with locally advanced breast cancer, and more recently in smaller tumours. Despite high clinical +/- radiological response rates, only pathologic information, carefully assessed in both the primary and axillae lymph nodes, stands out as the major source of prognostic information on patients' outcome. Recent developments in chemotherapy (dose-intensity, new drugs) do not seem to influence these results, indicating the possible limitations of conventional chemotherapy. Of 6 published randomized trials comparing neo versus adjuvant strategy, none showed any significant impact of primary chemotherapy on survival, with in some a trend towards delayed and/or distant recurrences if neoadjuvant treatment given. That some recent reports suggest that local relapse rate might be increased after conservative treatment following induction chemotherapy in subgroups analyses should cause oncologists to revise the role for post neoadjuvant treatment conservative surgery without calling into question the global strategy. Through sequential samplings, neoadjuvant medical treatment provides indeed the opportunity (a) to identify molecular mechanisms associated with pathologic response and (b) to study the possibility to guide the choices for induction treatment and patients' populations submitted to primary medical treatment.     

Treatment of unresectable, locally advanced pancreatic adenocarcinoma with combined radiochemotherapy with 5-fluorouracil, leucovorin and cisplatin

Although clinical response to primary chemotherapy in stage II and III breast cancer is associated with a survival advantage, it is the degree of pathological response in the breast and ipsilateral axilla that best identifies patients with a good long-term outcome. A mathematical model of the initial response of 39 locally advanced tumours to anthracycline-based primary chemotherapy has been previously shown to predict subsequent clinical tumour size. This model allows for the possibility of primary resistant disease, the presence of which should therefore be associated with a worse outcome. This study reports the application of this model to an additional five patients with locally advanced breast cancer, as well as to 63 patients with operable breast cancer, and confirms the biological reality of the model parameters for these 100 breast cancers treated with primary anthracycline-based chemotherapy. The tumours that responded to chemotherapy had higher cell-kill (P < 0.0005), lower resistance (P < 0.0001) and slower tumour regrowth (P < 0.002). Furthermore, ER-negative tumours had higher cell-kill (P < 0.05), as compared with ER-positive tumours. All patients with a pathological complete response had zero resistance according to the model. Furthermore, the long-term implication of chemo-resistant disease was demonstrated by survival analysis of these two groups of patients. At a median follow-up of 3.7 years, there was a statistically significantly worse survival for the 37 patients with locally advanced breast cancer identified by the model to have more than 8% primary resistant tumour (P < 0.003). The specificity of this putative prognostic indicator was confirmed in the 63 patients presenting with operable disease where, at a median follow-up of 7.7 years, those women with a resistant fraction of greater than 8% had a significantly worse survival (P < 0.05). Application of this model to patients treated with neoadjuvant chemotherapy may allow earlier identification of clinically significant resistance and permit intervention with alternative non-cross-resistant therapies such as taxoids.     

Tumour microvessel density as predictor of chemotherapy response in breast cancer patients

The aim of this study was to evaluate the predictive value of intratumoural microvessel density in breast cancer. We studied immunohistochemically primary tumours of 104 patients with metastasised breast cancer who took part in a randomised multicentre trial comparing docetaxel to sequential methotrexate and 5-fluorouracil. Vessels were highlighted with factor VIII staining and counted microscopically. Microvessel density was compared with clinical response to chemotherapy and patient survival. The microvessel density of the primary tumour was not significantly associated with patient's response to chemotherapy, time to progression or overall survival in the whole patient population or in the docetaxel or methotrexate and 5-fluorouracil groups. However, disease-free survival was longer in patients with low microvessel density (P=0.01). These findings suggest that microvessel density of the primary tumour cannot be used as a predictive marker for chemotherapy response in advanced breast cancer.     

Primary chemotherapy for breast cancer: the evidence and the future.

The first generation of randomised trials assessing the role of primary chemotherapy in breast cancer has failed to demonstrate the expected survival benefit. However, it has established the role of this treatment in 'downstaging' tumours of patients with locally advanced disease and, consequently, in improving breast conservation rates. Also, a number of surrogates of outcome have been identified, which will hopefully lead to earlier results in breast cancer clinical trials. Encouraging results have also been reported in trials investigating a number of novel approaches.     

Neoadjuvant endocrine therapy of breast cancer: a surgical perspective

Neoadjuvant treatment with chemotherapy or endocrine agents is being used increasingly to downstage locally advanced and large operable breast cancers. Following these treatments, inoperable breast cancer often becomes fully resectable, and initially operable tumours requiring mastectomy may be successfully removed by breast-conserving surgery. Patient selection is important to optimise neoadjuvant endocrine therapy: only patients with oestrogen receptor (ER)-rich breast cancer are candidates, and postmenopausal women are likely to benefit the most. Such patients can expect a high probability of responses over a 3-month treatment period. Response to therapy should be monitored by clinical examination as well as by ultrasound, mammography, or other imaging procedures. Third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen in this treatment setting. In a large randomised trial of neoadjuvant endocrine therapy in postmenopausal women, letrozole achieved significantly higher response rates than tamoxifen, and a correspondingly higher rate of breast-conserving surgery was possible in the letrozole-treated patients. There is some evidence to suggest that the nature of the tumour response is different for preoperative endocrine therapy compared with chemotherapy. This difference may result in a higher rate of complete tumour excisions following breast-conserving surgery after neoadjuvant endocrine treatment. There appears to be a low rate of subsequent local recurrence in patients having breast-conserving therapy after neoadjuvant endocrine therapy.     

Neoadjuvant treatment for early-stage breast cancer: opportunities to assess tumour response

Primary, preoperative, or neoadjuvant chemotherapy was introduced in the early 1970s as part of an integrated therapeutic approach to treat inoperable locally advanced breast cancer. The approach resulted in high responses, and sufficient downstaging to allow mastectomy in some patients. In addition, a small number of pathological complete responders were reported. Gradually, the idea of preoperative chemotherapy was extended to include patients with large but operable early-stage breast cancer, with the possibility in some cases of downstaging the primary tumour to avoid mastectomy, and to allow breast-conserving surgery to be done. This approach allows the tumour to be used as a measure of treatment response in vivo. More recently, the possibility has opened up for neoadjuvant chemotherapy to provide information on the use of clinical, pathological, and molecular endpoints, which can be used as surrogate markers to predict long-term outcome in the adjuvant setting. In addition, the anatomical accessibility of the breast provides the potential for serial biopsies to investigate molecular changes during treatment.     

Neoadjuvant Therapy of Breast Cancer

Primary systemic therapy is defined as the first systemic treatment a patient receives after cancer is diagnosed, and indicates that subsequent therapies are intended. It is also known as preoperative, induction, or neoadjuvant systemic therapy. Because of high tumor regression rates, primary systemic chemotherapy has become part of the standard of multidisciplinary care for patients with locally advanced and inflammatory breast cancer. An expert panel has reviewed all large randomized clinical trials of primary systemic chemotherapy versus adjuvant systemic therapy in operable breast cancer and concluded that both result in equivalent disease-free, local recurrence-free, and overall survival rates when compared head to head. However, the rate of successful breast-conserving surgery is statistically significantly increased in patients who receive primary chemotherapy; thus, primary systemic therapy is a reasonable alternative for patients with operable breast cancer who are deemed to be appropriate candidates for mastectomy but who desire breast-conserving surgery, or for those patients who desire less extensive breast-conserving surgery. The addition of taxanes or trastuzumab to primary systemic chemotherapy results in a significant increase in the overall and complete clinical response rates and in pathologic complete response (pCR) rates. A poor response to primary systemic chemotherapy is a predictor of poor prognosis and of a high risk of recurrence, irrespective of the type of surgery performed. In contrast, a pCR of the tumor or of cytologically documented axillary lymph node disease correlates strongly with both prolonged disease-free survival and overall survival, and occurs in 6–31% of patients, depending on the breast cancer subtype, the particular chemotherapy regimen used, and on the definition of what constitutes a pCR that is used by the particular group. Thus, pCR may be regarded as one major goal of primary systemic chemotherapy. Emerging data suggest that the achievement of pCR is associated with an excellent long-term outcome, regardless of the therapy regimen that results in pCR. If this association of pCR with outcome, regardless of the therapy regimen resulting in pCR, is confirmed, the application of newer gene- or protein-based technologies to predict at diagnosis which patients will achieve pCR in response to various biologic therapies and chemotherapies will have important clinical implications. In addition, the ability of pCR to predict an excellent long-term outcome may, with further study, become routinely applicable to the study of novel anticancer agents in the adjuvant setting, perhaps ultimately allowing us to avoid the need to perform large expensive trials with many years of follow-up.     

Breast conservative surgery for operable invasive ductal carcinoma after neoadjuvant chemotherapy or hormonal therapy- a challenge for breast surgeon: a review based on literature and experience

Neoadjuvant chemotherapy or hormonal therapy is based on biological data and enables more patients to be treated with breast conserving surgery for locally advanced T2 and T3 without significantly increasing the rates of ipsilateral breast recurrence. Careful consideration of an optimal preoperative planning aims at accurately determining the patterns of primary tumour down staging and at the amount and location of any residual tumour in the breast, besides converting patients from mutilating surgery candidates to candidates for breast conservative procedure. The use of induction chemotherapy has the potential to improve the cosmetic results but free margins must be achieved and surgery must be planned in onco-plastic surgery. Axillary lymph node clearance is still the gold standard surgery in the treatment of the axilla. Sentinel lymph node biopsy can be done for clinically N0 patients but only in control trials. Keywords: Neoadjuvant systemic therapy, breast cancer surgery.     

Primary (neoadjuvant) chemotherapy with docetaxel in breast cancer

The use of primary or neoadjuvant chemotherapy for locally advanced breast cancer, including those patients with inflammatory breast cancer, is well established. The use of primary chemotherapy has also been investigated in patients with operable breast cancer. The potential benefit of using primary chemotherapy is the opportunity to administer systemic therapy at an earlier timepoint, where it may be more effective against microscopic disease. In addition, primary chemotherapy for patients with operable breast cancer may also result in higher rates of breast conservation, axillary nodal downstaging, and potential improvement in patient outcome. A variety of different chemotherapy drugs have been evaluated in the primary chemotherapy setting. One of the most common approaches is to use an anthracycline-based regimen for 4 or more cycles of treatment before considering definitive local therapy. Although high tumor response rates have been reported using anthracycline-based regimens, the fraction of patients actually attaining a pathologic complete response has remained small (less than 20%). With the introduction of new chemotherapy drugs, such as docetaxel, which is associated with a very high tumor response rate in metastatic disease, a natural evolution of clinical investigation is to use docetaxel in the neoadjuvant or primary chemotherapy setting. Some of the recent trials that have evaluated single-agent docetaxel, docetaxel-based chemotherapy combinations, and novel sequencing strategies that include docetaxel in the neoadjuvant setting are reviewed. The results from these trials clearly suggest that docetaxel-containing treatment strategies can be considered a standard in the primary chemotherapy setting     

Kurative Therapie des Ösophaguskarzinoms

The prognosis of patients with oesophageal carcinoma is poor since the tumours are usually advanced at first diagnosis. Treatment is based on the tumour stage and the histology as well as the location of the primary. In Europe surgery is regarded as the standard of care in resectable tumours. R0 resection is required to provide long-term survival. Even after R0 resection long-term survival decreases to 30% in the case of tumour involvement in regional lymph nodes. Combined chemoradiation is an alternative for patients medically unfit to undergo surgery. Data from randomised comparison to surgery alone are missing. Multimodal treatment is generally accepted in patients with locally advanced tumours. In Germany, preoperative chemo- or chemoradiotherapy is usually preferred. The tumour response to induction treatment proved to be the most important prognostic factor for multimodal therapy. Phase III trials in locally advanced squamous cell carcinomas point out that the responders to induction therapy have a good prognosis, independent of whether definitive chemoradiation or chemoradiation with surgery is applied. Future studies should answer the question of which approach based on tumour response offers the best chance for curing these patients. In any case it should be required that patients with localized oesophageal cancer be treated in experienced centres.     

The influence of site of metastasis on tumour growth and response to chemotherapy.

Drug screening trials and general treatment of solid tumours in advanced cancer patients have been concerned only with the site of primary origin, regardless of where metastases might have seeded. Since the environment for tumour growth can differ appreciably at various anatomical sites, an investigation was undertaken to determine the effect of metastatic site on response to chemotherapy. Data from 1961 to 1965 of the screening trials of the Eastern Clinical Drug Evaluation Program were utilized. Response and location data extensive enough for analysis represented 6 sites of primary origin and 6 metastatic site groups, totalling 1687 lesions. Analysis of percentage reduction in tumour size after chemotherapy regimens of up to 60 days revealed a significant amount of variation associated with metastatic sites and a non-significant amount associated with sites of primary origin. Advanced primary tumours showed marked variation in responsiveness and some showed a difference in response to different drug groups. Generally, metastases responded better than the advanced primaries from which they were derived, except for those from breast tumours.     

Size of invasive breast cancer and risk of local recurrence after breast-conservation therapy

Risk of local recurrence is one important factor that determines a woman's suitability for breast-conservation therapy. With the evolution of oncoplastic surgery, tumours of a size that traditionally require mastectomy may be treated by breast conservation and partial breast reconstruction. This article reviews the evidence relating to tumour size as a risk factor for local recurrence to assess whether this change in practice is appropriate. A literature review through Medline and Pubmed was performed. All pathological studies analysing tumour size as a predictor of multifocality and all randomised trials and large case series of breast conservation including tumours larger than 2 cm were reviewed and critically interpreted. Pathological studies report consistent evidence that tumour size is not predictive of multifocality. Randomised trials and clinical series of breast conservation report conflicting evidence relating to tumour size as a risk factor for local recurrence, although most studies report no association. Evidence relating to cancers over 3 cm is limited. There is little evidence to justify the use of tumour size alone as an exclusion criterion for breast-conservation therapy. A registration study of patients with cancers larger than 3 cm treated by breast conservation with or without partial breast reconstruction is proposed.     

Using aromatase inhibitors in the neoadjuvant setting: evolution or revolution?

Despite improvements in the management of patients with early breast cancer, the prognosis for women with locally advanced breast cancer (LABC) remains poor. The potential goals of neoadjuvant treatment for this disease include down-sizing tumours to allow breast conservation as well as the possibility of improving survival rates. Neoadjuvant treatment was initially dominated by chemotherapy, which increased rates of breast conserving surgery, but to date has demonstrated no survival benefit over standard adjuvant chemotherapy. With recent advances in endocrine therapy, and rapid and routine assessment of predictive factors of response such as estrogen (ER), progesterone (PR) and Her2 nu receptor status, endocrine therapy has come to the forefront of research investigating a neoadjuvant alternative to chemotherapy. Early studies of neoadjuvant endocrine therapy mainly evaluated the role of tamoxifen in the treatment of elderly postmenopausal women with LABC who were unselected for ER/PR status and were unsuitable for either surgery or chemotherapy. Response rates in these patients were found to be inferior to those traditionally obtained from trials with neoadjuvant chemotherapy. Paralleling the superiority that third-generation aromatase inhibitors have shown over tamoxifen in the metastatic and adjuvant settings however, AIs have also demonstrated superiority in the neoadjuvant setting. Recent studies have shown response rates for neoadjuvant treatment with aromatase inhibitors in carefully selected hormone receptor positive patients to be comparable to those seen with neoadjuvant chemotherapy. This is particularly important as hormone receptor positive tumours have repeatedly been shown to have lower response rates to neoadjuvant chemotherapy than hormone receptor negative tumours. Neoadjuvant endocrine treatment with aromatase inhibitors has therefore evolved from being an experimental effort to palliate women with LABC unsuitable for surgery or chemotherapy, to representing a viable and possibly preferred alternative for postmenopausal women with hormone receptor positive large tumours or LABC. Further benefits of neoadjuvant trials include allowing the study of predictive biomarkers of disease in order to provide insight into therapy resistance and sensitivity, and identifying promising systemic therapies for additional testing in larger adjuvant trials.     

A systematic overview of chemotherapy effects in non-small cell lung cancer.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview of the literature on chemotherapy for non-small cell lung cancer (NSCLC) is based on 53 scientific publications including six meta-analyses based on 65 prospective randomised trials comprising 15,607 patients and an additional 32 prospective randomised studies including 8,902 patients. The conclusions reached can be summarised into the following points: In stage IIIB-IV disease, published data demonstrate that cisplatin-based chemotherapy confers a modest, median 1.5-3 months, prolongation of survival. The closely related compound carboplatin seems to provide similar effects. Randomised studies indicate symptomatic relief and improvement of indices of quality of life (QoL) for patients who receive platinum-based combination chemotherapy or single drug therapy with more recent compounds. Data supporting the use of chemotherapy are not available for patients in poor general condition (WHO performance status 3 4) and evidence is limited for elderly patients (above 70-75 years). Platinum-based chemotherapy can be recommended for selective use in routine care of advanced NSCLC although patients should be encouraged to participate in controlled clinical trials to further elucidate the role of chemotherapy in advanced disease. In advanced disease, recent data suggest that the newer agents gemcitabine, paclitaxel, irinotecan and vinorelbine, in combination with cisplatin, provide an additional survival benefit compared with earlier cisplatin-based regimens. Furthermore, paclitaxel, docetaxel and vinorelbine as single agents seemingly provide a survival benefit over supportive care alone comparable to that of older cisplatin-based combinations. A standard regimen for advanced disease cannot yet be defined. Until more data are at hand, it is recommended to be platinum-based and preferably combined with one of the newer agents. At progression after platinum-based chemotherapy for advanced disease, limited data indicate a small survival benefit from docetaxel over supportive care alone. Such second-line chemotherapy of advanced disease can be recommended for selected patients but should preferably be confined to controlled clinical trials. In stage III disease, published data show that induction cisplatin-based chemotherapy before radical radiotherapy modestly prolongs long-term survival and lowers the incidence of distant metastases compared with radiotherapy alone. Furthermore, published data show that concurrent chemo- and radiotherapy with cisplatin or carboplatin may enhance local control and long-term survival. Chemotherapy in this setting can be recommended for selected patients but treatment should preferably be given within a controlled clinical trial. In stage IIIAN2 disease, data from pilot studies demonstrate that surgery after induction chemotherapy is feasible. Pathologically complete remissions have been confirmed in 10-20% of treated patients. Two small randomised studies demonstrate a significant survival advantage for induction chemotherapy followed by surgery compared with surgery alone. Induction chemotherapy can be recommended for selected patients but treatment should preferably be given within a controlled clinical trial. The superiority of induction chemotherapy plus surgery compared with combined chemotherapy and radical irradiation has not been proven in a randomised trial but currently such studies are under way. In the adjuvant setting, published data suggest that cisplatin-based chemotherapy after radical surgery may increase five-year survival from around 50% by a further 5% but the confidence interval for this estimate is too wide for firm conclusions. Large-scale prospective randomised trials are under way to resolve this important issue and adjuvant chemotherapy is, thus, not recommended for routine treatment.     

Mathematical modelling of tumour response in primary breast cancer.

Although breast cancer is perceived to be relatively chemosensitive, cytotoxic drug therapy only leads to cure in the adjuvant setting. In advanced disease, primary resistance and inadequate cell kill may be important in determining the lack of a durable response to cytotoxics, but for an individual patient''s tumour there is no consistent way of determining the importance of these two factors. An adaptation of Skipper''s log cell kill model of tumour response to chemotherapy was applied to serial tumour measurements of 46 locally advanced primary breast carcinomas undergoing neoadjuvant chemotherapy. Assuming a log-normal distribution of errors in the clinically measured volumes, the model produced, for each tumour separately, in vivo estimates of proportional cell kill, initial resistance and tumour doubling times during therapy. After 4 weeks'' treatment, these data could then be used to predict subsequent tumour volumes with good accuracy. In addition, for the 13 tumours that became operable after the neoadjuvant chemotherapy, there was a significant association between the final volume as predicted by the model and the final pathological volume (P < 0.05). This approach could be usefully employed to determine those tumours that are primarily resistant to the treatment regimen, permitting changes of therapy to more effective drugs at a time when the tumour is clinically responding but destined to progress.     

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.     

P53 mutations in stromal fibroblasts sensitize tumors against chemotherapy

The efficacy of chemotherapy is usually viewed as the outcome of cancer-cell-autonomous processes while the contribution of stroma is being overseen. Here we show that p53 mutations in stromal fibroblasts, a genetic lesion that is detectable in primary breast, prostate and probably other cancers, while they accelerate tumorigenesis they also sensitize tumours against conventional chemotherapy by doxorubicin and cis-platinum. The mechanism by which p53 of stromal fibroblasts affects the response of a tumour against chemotherapy is likely to involve the induction of senescence in the fibroblasts which in turns results in the production of growth factors acting onto the cancer cells by paracrine mechanisms. Our findings identify stromal fibroblasts as important modulators of the efficacy of anticancer therapy.     

Accelerated partial breast irradiation trials: Diversity in rationale and design

Seven randomised trials are currently testing accelerated partial breast irradiation against whole breast radiotherapy after breast conservation surgery. The trials are varied in the techniques used to deliver partial breast radiotherapy, reflecting the range of opportunities offered by advanced brachytherapy and teletherapy modalities. Dose schedules also vary between trials, but the most important point of difference between them reflects alternative concepts of clinical and planning target volumes. These are based mainly on the spatial pattern of relapse in retrospective and prospective studies, which report the majority of first local relapses close to the primary tumour site, and on the assumption that radiotherapy does not prevent the development of new primary tumours developing elsewhere in the breast. However, the pattern of ipsilateral breast tumour relapse is not accurately defined in the clinical literature and does not correspond closely to pathological findings. In addition, published data are consistent with a significant reduction in the rate of other quadrant relapse after whole breast radiotherapy. Regardless of the biological model of local tumour relapse and responsiveness to radiation, the ongoing trials will generate level I evidence for or against accelerated partial breast irradiation, provided patients are followed up long enough before the first reporting of results.