Adjuvant therapy in elderly patients with breast cancer.

The elderly population has been neglected by the traditional approach to clinical breast cancer research. Elderly women have been underrepresented in breast cancer clinical trials, with the majority of studies being restricted to patients aged < 70 years. Elderly patients frequently have comorbidities and/or impaired organ function. These facts may often lead to death from causes other than cancer, thus nullifying any possible benefit of adjuvant treatment; furthermore, they render extrapolation of standard treatment recommendations to the elderly potentially hazardous, particularly with respect to chemotherapy. Therefore, specific clinical trials are needed to investigate adjuvant treatments tailored for the heterogeneous older population.

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer

BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.

3-year results of docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer: a pilot study.

BACKGROUND: Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, aged < or = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --> Docetaxel (T) --> CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --> T --> CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --> A --> CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF. RESULTS: Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was >2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%). CONCLUSION: The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.

Cancer du sein chez la jeune femme: traitements adjuvants et désir de grossesse [Breast cancer in young women: adjuvant therapy and fertility]

Prognosis of breast cancer women has been dramatically improved by the adjuvant therapies. As the vast majority of patients are cured, the importance of long-term quality of life is growing. The question of the maternity is an essential concern for the young women who have to receive chemotherapy or several years of endocrine therapy. This problem is often underestimated and may lead to emotional distress, depression or anxiety. A regional multidisciplinary working group was set up in order to offer optimal information about fertility and cancer as to propose specific therapeutic reproduction options, when applicable. Specificity of the young patients' breast cancer, the treatment approaches and their impact on fertility are discussed in this paper.

Adjuvant therapy with GnRH agonists/tamoxifen in breast cancer should be a good council for patients with hormone receptor-positive tumours and wish to preserve fertility

Infertility represents one of the main long-term consequences of the chemotherapy used for the adjuvant treatment of breast cancer. Approximately 60-65% of breast cancers express the nuclear hormone receptor in premenopausal women. Adjuvant endocrine therapy is an integral component of care for patients with hormone receptor-positive (HR+) tumours. The GnRH agonist (GnRHa) alone or in combination with tamoxifen produces results at least similar to those obtained with the different chemotherapy protocols in patients with HR+ breast cancer with respect to recurrence-free survival and overall survival. It is time to indicate adjuvant therapy with GnRHa associated with tamoxifen for patients with breast cancer (HR+ tumours) if they want to preserve their reproductive function. The evaluation of ovarian reserve tests: follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume 6 months, and 1 year after the end of therapy with GnRHa/tamoxifen must be realised. The recurrence-free survival and overall survival should be analysed. The major implication of this hypothesis will be to avoid adjuvant chemotherapy for patients with breast cancer (HR+ tumours) that request fertility preservation. It is expected that ovarian function should not be altered in almost all cases and subsequent pregnancy a real possibility. (C) 2012 Elsevier Ltd. All rights reserved.

Adjuvant therapy with GnRH agonists/tamoxifen in breast cancer should be a good council for patients with hormone receptor-positive tumours and wish to preserve fertility

Infertility represents one of the main long-term consequences of combination chemotherapy used for the treatment of breast cancer. Approximately 60%-65% of breast cancers express the nuclear hormone receptor in premenopausal women. Adjuvant endocrine therapy is an integral component of care for patients with hormone receptor-positive (HR+) tumours. The GnRH agonist (GnRHa) alone or in combination with tamoxifen produces results at least similar to those obtained with the different chemotherapy protocols in patients with HR+ tumors with respect to recurrence-free survival and overall survival, Presentation of the hypothesis: It is time to indicate adjuvant therapy with GnRHa associated with tamoxifen for patients with breast cancer (HR+ tumours) if they want to preserve their reproductive function. Testing the hypothesis: Assessment of ovarian reserve tests: follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume 6 months, and 1 year after the end of therapy with GnRHa/tamoxifen. The recurrence-free survival and overall survival should be analysed. Implications of the hypothesis: The major implication will be to avoid adjuvant chemotherapy for patients with breast cancer (HR+ tumours) that request fertility preservation. It is expected that ovarian function should not be altered in almost all cases. © Todos os direitos reservados a SBRA - Sociedade Brasileira de Reprodução Assistida.

Adjuvant therapy with sodium alendronate for the treatment of experimental periodontitis in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Limited efficacy of adjuvant therapy with dexamethasone in preventing hearing loss due to experimental pneumococcal meningitis in the infant rat

Sensorineural hearing loss (SNHL) is the most common sequel of bacterial meningitis (BM) and is observed in up to 30% of survivors when the disease is caused by Streptococcus pneumoniae. BM is the single most important origin of acquired SNHL in childhood. Anti-inflammatory dexamethasone holds promises as potential adjuvant therapy to prevent SNHL associated with BM. However, in infant rats, pneumococcal meningitis (PM) increased auditory brainstem response (ABR) thresholds [mean difference = 54 decibels sound pressure level (dB SPL)], measured 3 wk after infection, irrespective to treatment with ceftriaxone plus dexamethasone or ceftriaxone plus saline (p < 0.005 compared with mock-infected controls). Moreover, dexamethasone did not attenuate short- and long-term histomorphologic correlates of SNHL. At 24 h after infection, blood-labyrinth barrier (BLB) permeability was significantly increased in infected animals of both treatment groups compared with controls. Three weeks after the infection, the averaged number of type I neurons per square millimeter of the Rosenthal's canal dropped from 0.3019 +/- 0.0252 in controls to 0.2227 +/- 0.0635 in infected animals receiving saline (p < 0.0005). Dexamethasone was not more effective than saline in preventing neuron loss (0.2462 +/- 0.0399; p > 0.05). These results suggest that more efficient adjuvant therapies are needed to prevent SNHL associated with pediatric PM.

Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis

Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF-alpha and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.

Does subjective burden of early breast cancer and its treatment affect immune measures during adjuvant therapy?

Psychosocial factors have been described as affecting cellular immune measures in healthy subjects. In patients with early breast cancer we explored bi-directional psycho-immune effects to determine whether subjective burden has an impact on immune measures, and vice versa. Patients (n = 239) operated for early breast cancer and randomized into International Breast Cancer Study Group (IBCSG) adjuvant clinical trials were assessed immediately before the beginning of adjuvant treatment (baseline) and 3 and 6 months thereafter, at the beginning of the corresponding treatment cycle. Cellular immune measures (leukocytes, lymphocytes, lymphocyte subset counts), markers of activation of the cellular immune system (beta2-microglobulin, soluble interleukin-2 receptor serum levels), and self-report subjective burden (global indicators of physical well-being, mood, coping effort) were assessed concurrently. The relationship between subjective burden and gradients of immune measures was investigated with regression analyses controlling for adjuvant treatment. There was a pattern of small negative associations between all variables assessing subjective burden before the beginning of adjuvant therapy with the gradients of the markers of activation of the cellular immune system and NK cell counts. In particular, better mood predicted a decline in the course of beta2-microglobulin and IL-2r at months 3 and 6. The gradient of beta2-microglobulin was associated with mood and coping effort at month 3. However, the effect sizes were very small. In conclusion, in this explorative investigation, there was an indication for subjective burden affecting and being affected by markers of activation of the cellular immune system during the first 3 and 6 months of adjuvant therapy. The question of clinical significance remains unanswered. These associations have to be investigated with refined assessment tools and schedules.

Adjuvant therapy after resection of brain metastases. Frameless image-guided LINAC-based radiosurgery and stereotactic hypofractionated radiotherapy

BACKGROUND: Tumor bed stereotactic radiosurgery (SRS) after resection of brain metastases is a new strategy to delay or avoid whole-brain irradiation (WBRT) and its associated toxicities. This retrospective study analyzes results of frameless image-guided linear accelerator (LINAC)-based SRS and stereotactic hypofractionated radiotherapy (SHRT) as adjuvant treatment without WBRT. MATERIALS AND METHODS: Between March 2009 and February 2012, 44 resection cavities in 42 patients were treated with SRS (23 cavities) or SHRT (21 cavities). All treatments were delivered using a stereotactic LINAC. All cavities were expanded by ≥ 2 mm in all directions to create the clinical target volume (CTV). RESULTS: The median planning target volume (PTV) for SRS was 11.1 cm(3). The median dose prescribed to the PTV margin for SRS was 17 Gy. Median PTV for SHRT was 22.3 cm(3). The fractionation schemes applied were: 4 fractions of 6 Gy (5 patients), 6 fractions of 4 Gy (6 patients) and 10 fractions of 4 Gy (10 patients). Median follow-up was 9.6 months. Local control (LC) rates after 6 and 12 months were 91 and 77 %, respectively. No statistically significant differences in LC rates between SRS and SHRT treatments were observed. Distant brain control (DBC) rates at 6 and 12 months were 61 and 33 %, respectively. Overall survival (OS) at 6 and 12 months was 87 and 63.5 %, respectively, with a median OS of 15.9 months. One patient treated by SRS showed symptoms of radionecrosis, which was confirmed histologically. CONCLUSION: Frameless image-guided LINAC-based adjuvant SRS and SHRT are effective and well tolerated local treatment strategies after resection of brain metastases in patients with oligometastatic disease.

Audit of postoperative chemoradiotherapy as adjuvant therapy for resected gastroesophageal adenocarcinoma: An Australian multicentre experience

Background: Improved disease free and overall survivals were seen in curatively resected patients with gastric and gastroesophageal adenocarcinoma treated with the Intergroup 0116 (INT 0116) protocol of postoperative adjuvant chemoradiotherapy compared to surgery alone. This protocol has not been widely adopted in Australian centres because of perceived risks of toxicity. Methods: We reviewed the case records from 45 consecutive patients treated between May 1998 and August 2003 with the INT 0116 protocol and variations at five Australian institutions. The median age was 61.5 years (range 38-79). Twenty-nine patients had gastric and 12 had gastroesophageal junction primaries. All patients had attempted curative resection, however, seven had involved microscopic margins (R1 resection). Thirty-five had regional node involvement and none had evidence of distant metastasis. Results: The overall National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 2.0 grade 3 and grade 4 toxicity rates for all patients were 37.8% and 4.4%, respectively. There were no treatment related deaths. Gastrointestinal grade 3 toxicity was observed in 20% of patients, while haematologic grade 3 and 4 toxicity was observed in 17.8%. Toxicities experienced led to chemotherapy dose reductions in 22 patients and dose delay in 11 patients. Seven patients had a delay in radiotherapy and two did not proceed with radiotherapy. At a median follow up of 16 months (range 5-35) from surgery, 28 patients have relapsed (six with local recurrence alone) with 22 deaths occurring, all but one caused by cancer. Conclusion: The INT 0116 protocol is a safe and feasible schedule in a multicentre setting with an acceptable rate of toxicity and is an appropriate adjuvant treatment option for high-risk resected gastroesophageal adenocarcinoma.