Sex differences in mandibular repositioning device therapy effectiveness in patients with obstructive sleep apnea syndrome.

PURPOSE: Mandibular repositioning devices (MRDs) are an effective treatment option for obstructive sleep apnea syndrome (OSAS), particularly in patients who refuse or cannot tolerate continuous positive airway pressure (CPAP). However, sex differences in the response to therapy and predictors of response are not clearly defined. This analysis of data from the long-term prospective ORCADES trial compared MRD efficacy in men and women with OSAS. METHODS: The ORCADES study included patients with newly diagnosed mild-to-moderate or severe OSAS who refused or were non-compliant with CPAP. MRD therapy was titrated over 3-6 months. The primary endpoint was treatment success (≥ 50% decrease in apnea-hypopnea index (AHI)). Complete response was defined using a range of AHI cut-off values (< 5/h, < 10/h, < 15/h). RESULTS: Overall treatment success rates were 89% in women and 76% in men (p = 0.019); corresponding rates in those with severe OSAS (AHI > 30/h) were 100% and 68% (p = 0.0015). In women vs. men, overall complete response rates at AHI cut-off values of < 5/h, <10/h, and < 15/h were 49 vs. 34% (p = 0.0052), 78 vs. 62% (p = 0.016), and 92 vs. 76% (p = 0.0032). On multivariate analysis, significant predictors of MRD treatment success were overbite and baseline apnea index in men, and neck circumference and no previous CPAP therapy in women. There were sex differences in the occurrence of side effects. Temporomandibular joint pain was the most common reason for stopping MRD therapy. CONCLUSIONS: MRD therapy was effective in women with OSA of any severity, with significantly higher response rates compared with men especially in severe OSAS. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01326143).

Sequential addition of an anthracycline-based regimen to docetaxel as neoadjuvant chemotherapy in patients with operable breast cancer.

BACKGROUND: The objective of this phase II study was to attempt to maximize response and survival in patients with bulky, operable breast cancer by combining sequential neoadjuvant docetaxel to a semi-intensive anthracycline-based regimen. PATIENTS AND METHODS: Eligible patients (N = 53) were included to receive 4 cycles of docetaxel, followed by a maximum of 4 cycles of TNCF (THP [theprubican]-doxorubicin/vinorelbine/cyclophosphamide/5-fluorouracil) every 21 days before definitive surgery and radiation therapy. RESULTS: After a median number of 4 cycles of docetaxel and 2 cycles of TNCF, the overall clinical response rate was 81.1%, including a 13.2% complete remission rate and only 2 incidences of progressive disease. Breast conservation was achieved in 87% of patients. According to Chevallier classification, a pathologic complete response in breast and axilla was confirmed in 6 patients (11.3%) and in 9 patients (17%) using the Sataloff's classification. The important myelosuppression observed in this trial was expected but limited by the prophylactic use of growth factors. After a median follow-up of 40.4 months, only 5 recurrences were documented, with a median time to first recurrence of 12.8 months. CONCLUSION: Despite disappointing results of this trial for pathologic complete response rate, possibly because of the order of drug administration, clinical response, breast conservation, and survival were optimized.

High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer.

Prognostic factors are used to help clinical decision-making in selecting the appropriate treatment for individual patients. The purpose of this retrospective study was to identify one or more factors associated with overall survival (OS) and disease-free survival (DFS), in 710 patients with operable breast cancer, subjected to neoadjuvant chemotherapy followed by surgery, radiotherapy and adjuvant treatments. At a median follow-up of 7.6 years, univariate analysis showed that pathological complete response (pCR) was significantly related to survival (p < 0.003), as well as accepted prognostic factors, as SBR and MSBR grades, hormonal receptors or node involvement at surgery, who remained significant in our study (p < 0.001). The revised Nottingham prognostic index (NPI) and related indices (BGI, MNPI and MBGI) were also significantly associated to survival (p < 0.003). In multivariate analysis, node involvement and MSBR grade remained prognostic factors for OS and DFS (p < 0.0003 and p < 0.02, respectively). The MNPI and pCR were significantly related with OS (p = 0.04) and pts with hormonal receptor-positive tumours had a better DFS than others (p = 0.004). Among all clinical and pathological parameters, axillary dissection after neoadjuvant chemotherapy is still important to determine node involvement, a major prognostic factor. Moreover, MSBR grade seemed to be more accurate and predictive of long-term outcome than the standard SBR grade. It is concluded that, outside any other 'biological' factor, residual disease in breast and nodes must be strongly considered after an induction chemotherapy so as to choose adjuvant treatment for the individual patient.

Pathological and clinical response of a primary chemotherapy regimen combining vinorelbine, epirubicin, and paclitaxel as neoadjuvant treatment in patients with operable breast cancer.

This phase II study investigated the efficacy and tolerability of a primary chemotherapy regimen combining vinorelbine, epirubicin, and paclitaxel (VEP protocol) in women with stage II/III operable breast cancer. Patients (n = 50) were treated with six cycles of VEP according to the following schedule: vinorelbine (Navelbine); Pierre Fabre, Boulogne, France; http://www.pierre-fabre.com) 20 mg/m2, epirubicin (Farmorubicin; Pharmacia, New York, NY; http://www.pnu.com) 35 mg/m2 given on days 1 and 8, paclitaxel (Taxol; Bristol-Myers Squibb, New York, NY; http://www.bmsoncology.com) 175 mg/m2 given on day 9, and G-CSF 5 mg/kg/day given on days 10-20 of a 21-day cycle, followed by surgery and radiotherapy. After six cycles of VEP, the pathological response rate (pCR) in breast was confirmed in six patients (12%; 95% confidence interval [CI]: 3-21)) using Chevallier's classification and in nine patients (18%; 95% CI: 7.4-28.6) using Sataloff's classification. The clinical response rate was 42% (95% CI: 28.3-55.7), including 26% complete responses. Breast conservation was achieved in 68% of patients. After a median follow-up of 48 months (range, 34-62 months), 16 relapses were observed. The overall and disease-free survivals at 5 years were 54.1% (95% CI: 40.3-67.9) and 38% (95% CI: 24.1-51.9), respectively. The principal toxicities of VEP were grade 3/4 neutropenia observed in 30% of patients and grade 3 anemia observed in 12% of patients. There was no case of severe cardiac toxicity, thrombocytopenia, or any other serious adverse events. In conclusion, whereas this regimen was relatively well tolerated, it appears inferior to other regimens and its use is not recommended.

Neoadjuvant FEC 100 for operable breast cancer: eight-year experience at Centre Jean Perrin.

This study investigated the efficacy and tolerability of FEC 100 (epirubicin 100 mg/m2 with 5-fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2) every 21 days as neoadjuvant chemotherapy in women with stage I-III primary operable breast cancer. Forty patients were treated with 6 cycles of FEC 100, followed by surgery and radiation therapy. In addition, most patients also received an adjuvant treatment for residual disease (11 chemotherapies and 31 tamoxifen). After 6 cycles of FEC 100, the overall clinical response rate of 75% (CI 95%, 61.6-88.4) was achieved, 22.5% of which were complete responses. Breast conservation was achieved in 70% of patients. A pathologic complete response was confirmed in 6 patients (15%; CI 95%, 3.9-26.1) using Chevallier's classification and in 10 patients (25%; CI 95%, 11.6-38.4) using Sataloff's classification. After a median follow-up of 29.5 months, 3 metastatic relapses were observed. The principal toxicity of FEC 100 was myelosuppression; 51.3% of patients developed grade 3/4 neutropenia. Neoadjuvant FEC 100 was both effective and well tolerated in patients with early-stage operable breast cancer.

Induction chemotherapy for breast carcinoma: predictive markers and relation with outcome.

Induction chemotherapy provides an excellent model for evaluation of potential predictive factors. We studied expression of SBR grade, estrogen (ER) and progesterone (PR) receptors, HER2, Ki67 and P53 on core biopsies before and after chemotherapy in a series of 115 patients, who received anthracycline-based induction chemotherapy for primary breast cancer. HER2 overexpression independently predicted response to neoadjuvant anthracycline-based chemotherapy. Patients with HER2-positive status are 4.54 times more likely to have a pathological complete response than those with negative status (p<0.005). HER2, ER and PR status were stable during treatment. P53 and Ki67 significantly increased after treatment (p<0.005 and p<0.0005). SBR grade, proliferation markers, ER evaluated before and after treatment predicted disease-free survival (DFS) in univariate analysis.

Prognostic value of residual node involvement in operable breast cancer after induction chemotherapy.

The purpose of this retrospective study was to evaluate the influence of axillary disease on patients' survival after neoadjuvant chemotherapy and to assess patient and tumor characteristics associated with post-chemotherapy axillary involvement. After six induction cycles, 277 patients with operable breast cancer (stage II-III) underwent surgery with axillary dissection, followed by radiotherapy (n = 267) or additional chemotherapy (n = 63) and adjuvant tamoxifen therapy (n = 138). At a median follow-up of 8.5 years, overall survival (OS) and disease-free survival (DFS) were analyzed as a function of node involvement. The differences in OS and DFS according to the number of positive nodes were highly statistically significant with a decreased survival associated with the increasing number of nodes (p = 5 x 10(-6) and 9 x 10(-7), respectively). Upon multivariate analysis, the node number after chemotherapy appeared as the most significant prognostic factor (p = 7 x 10(-4) for OS and p = 3 x 10(-5) for DFS). All the other classical prognostic factors were insignificant, except post-chemotherapy Scarff-Bloom-Richardson (SBR) grading for OS (p = 8 x 10(-4)) and adjuvant hormonotherapy for DFS (p = 1 x 10(-2)). Although constituting a different parameter from primary surgery data, the number of positive nodes after chemotherapy could still remain a valuable prognostic factor at secondary surgery, raising the question for high risk patients of a second non-cross-resistant adjuvant regimen, or high dose chemotherapy with peripheral blood stem cells support.

Scarff-Bloom-Richardson (SBR) grading: a pleiotropic marker of chemosensitivity in invasive ductal breast carcinomas treated by neoadjuvant chemotherapy.

The Scarff-Bloom-Richardson (SBR) grade, an important prognostic factor in breast cancer, was also associated with cell proliferation, a consistent indicator of response to chemotherapy. The determination of an association between SBR grade and responsiveness would be clinically useful. We explored the influence of SBR grade on response to neoadjuvant chemotherapy in patients with invasive ductal breast carcinoma. The present study centered on 431 patients registered onto one of four prospective phase II trials. SBR grading was performed according to the Elston method on needle core biopsies prospectively collected prior to treatment from 290 patients and on residual tumour at surgery from 171 patients. The post-operative grades were then compared with those obtained at diagnosis. Univariate and multivariate analysis were used to evaluate the significance of SBR grade on response to neoadjuvant chemotherapy. Both statistical analysis revealed that SBR grade III tumours responded better to neoadjuvant treatment than SBR grade I (p<10(-6)). None of the other patient and tumour characteristics tested correlated with response. Moreover, tumour responsiveness was significantly related to changes of the SBR grade (p=7 x 10(-3)). As a conclusion, we showed that SBR grade is a strong predictive factor of response to induction chemotherapy in breast cancer, independently of the type of regimen used. The association between evolution of the histological grade following chemotherapy and response to treatment may prove valuable for clinicians as they make their decision regarding patient therapy.