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This prospective, phase II study evaluated novel biomarkers as predictors of response to bevacizumab in patients with breast cancer (BC), using serial imaging methods and gene expression analysis. Patients with primary stage II/III BC received bevacizumab 15 mg/kg (cycle 1; C1), then four cycles of neoadjuvant docetaxel doxorubicin, and bevacizumab every 3 weeks (C2-C5). Tumour proliferation and hypoxic status were evaluated using 18 F-fluoro-3'-deoxy-3'-L-fluorothymidine (FLT)- and 18 F-fluoromisonidazole (FMISO)-positron emission tomography (PET) at baseline, and during C1 and C5. Pre- and post-bevacizumab vascular changes were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Molecular biomarkers were assessed using microarray analysis. A total of 70 patients were assessed for treatment efficacy. Significant decreases from baseline in tumour proliferation (FLT-PET), vascularity, and perfusion (DCE-MRI) were observed during C1 ( p ≤ 0.001), independent of tumour subtype. Bevacizumab treatment did not affect hypoxic tumour status (FMISO-PET). Significant changes in the expression of 28 genes were observed after C1. Changes in vascular endothelial growth factor receptor (VEGFR)-2p levels were observed in 65 patients, with a > 20% decrease in VEGFR-2p observed in 13/65. Serial imaging techniques and molecular gene profiling identified several potentially predictive biomarkers that may predict response to neoadjuvant bevacizumab therapy in BC patients.

The new disease outbreak that causes atypical pneumonia named COVID-19, which started in China's Wuhan province, has quickly spread to a pandemic. Although the imaging test of choice for the initial study is plain chest radiograph, CT has proven useful in characterizing better the complications associated with this new infection. We describe the evolution of 3 patients presenting pneumomediastinum and spontaneous pneumothorax as a very rare complication of COVID-19 and their particular interest as a probable prognostic factor.

The debate about surgical resection of primary tumor (PT) in de novo metastatic breast cancer (MBC) patients persists. We explored this approach's outcomes in patients included in a retrospective registry, named El Álamo, of breast cancer patients diagnosed in Spain (1990-2001). In this analysis we only included de novo MBC patients, 1415 of whom met the study's criteria. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Median age was 63.1 years, 49.2% of patients had single-organ metastasis (skin/soft tissue [16.3%], bone [33.8%], or viscera [48.3%]). PT surgery (S) was performed in 44.5% of the cases. S-group patients were younger, had smaller tumors, higher prevalence of bone and oligometastatic disease, and lower prevalence of visceral involvement. With a median follow-up of 23.3 months, overall survival (OS) was 39.6 versus 22.4 months (HR = 0.59, p < 0.0001) in the S- and non-S groups, respectively. The S-group OS benefit remained statistically and clinically significant regardless of metastatic location, histological type, histological grade, hormone receptor status and tumor size. PT surgery (versus no surgery) was associated with an OS benefit suggesting that loco-regional PT control may be considered in selected MBC patients. Data from randomized controlled trials are of utmost importance to confirm these results.

Background: VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first-line treatment regimen for patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co-infusion of pertuzumab and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co-infused, followed by vinorelbine., Patients and Methods: During cycle 1, patients with HER2-positive locally advanced or MBC received loading doses of pertuzumab (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m 2 ) on days two and nine. From cycle 2 onwards, patients received a co-infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30-35 mg/m 2 ) on days one and eight (or days two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression-free survival (PFS) and safety., Results: Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0-73.6) in patients with measurable disease (91/107; 85.0%). Median PFS was 11.5 months (95% CI 10.3-15.8). The most common adverse events [AEs] were diarrhea (57.9%), neutropenia (57.0%), and nausea (41.1%). Grade ≥3 AEs occurred in 85 patients (79.4%) and serious AEs in 44 patients (41.1%). Eighteen patients (16.8%) had AEs suggestive of congestive heart failure., Conclusion: These results support the feasibility of pertuzumab and trastuzumab co-infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017;22:1160-1168 IMPLICATIONS FOR PRACTICE: Combined treatment with pertuzumab, trastuzumab, and docetaxel is the standard of care for first-line HER2-positive metastatic breast cancer. However, some patients cannot, or choose not to, receive docetaxel. VELVET Cohort 2 results support the results from Cohort 1 that suggest that pertuzumab plus trastuzumab and vinorelbine is a suitable alternative for these patients. In addition to this, results from Cohort 2 support the feasibility of administering pertuzumab and trastuzumab together in a single infusion bag, which has the potential to offer greater patient convenience and reduce active health care professional time and medical resource utilization compared with administering them separately., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© 2017 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Purpose: To converge on an expert opinion to define aggressive disease in patients with HER2-negative mBC using a modified Delphi methodology., Methods: A panel of 21 breast cancer experts from the Spanish Society of Medical Oncology agreed upon a survey which comprised 47 questions that were grouped into three sections: relevance for defining aggressive disease, aggressive disease criteria and therapeutic goals. Answers were rated using a 9-point Likert scale of relevance or agreement., Results: Among the 88 oncologists that were invited to participate, 81 answered the first round (92%), 70 answered the second round (80%), and 67 answered the third round (76%) of the survey. There was strong agreement regarding the fact that identifying patients with aggressive disease needs to be adequately addressed to help practitioners to decide the best treatment options for patients with HER2-negative mBC. The factors that were considered to be strongly relevant to classifying patients with aggressive HER2-negative mBC were a high tumor burden, a disease-free interval of less than 12-24 months after surgery, the presence of progressive disease during adjuvant or neoadjuvant chemotherapy and having a triple-negative phenotype. The main therapeutic goals were controlling symptoms, improving quality of life and increasing the time to progression and overall survival., Conclusions: High tumor burden, time to recurrence after prior therapy and having a triple-negative phenotype were the prognostic factors for which the greatest consensus was found for identifying patients with aggressive HER2-negative mBC. Identifying patients with aggressive disease leads to different therapeutic approaches.

Background: Pertuzumab, trastuzumab, and docetaxel is standard of care for first-line treatment of HER2-positive metastatic breast cancer (MBC). However, alternative chemotherapy partners are required to align with patient/physician preferences and to increase treatment flexibility. We report VELVET Cohort 1 results in which the efficacy and safety of pertuzumab and trastuzumab, administered sequentially in separate infusions, followed by vinorelbine, were evaluated. Cohort 2, where pertuzumab and trastuzumab were administered in a single infusion, followed by vinorelbine, recruited after Cohort 1 was fully enrolled, will be reported later., Methods: In this multicenter, two-cohort, open-label, phase II study, patients with HER2-positive locally advanced or MBC who had not received chemotherapy or biological therapy for their advanced disease received 3-weekly pertuzumab (840 mg loading, 420 mg maintenance doses) and trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses), followed by vinorelbine (25 mg/m 2 initial dose, 30-35 mg/m 2 maintenance doses) on days 1 and 8 or 2 and 9 of each 3-weekly cycle. Study treatment was given until investigator-assessed disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) in patients with measurable disease at baseline per RECIST v1.1. Secondary endpoints included progression-free survival (PFS) and safety., Results: Cohort 1 enrolled 106 patients. Investigator-assessed ORR was 74.2% (95% CI 63.8-82.9) in intent-to-treat patients with measurable disease (89/106 [84.0%]). Median PFS was 14.3 months (95% CI 11.2-17.5) in the intent-to-treat population. Treatment was reasonably well tolerated, with no unexpected toxicities. Diarrhea (61/106 patients [57.5%]) and neutropenia (54/106 [50.9%]) were the most common adverse events (AEs); neutropenia (33/106 [31.1%]) and leukopenia (14/106 [13.2%]) were the most common grade ≥3 AEs. Serious AEs were reported in 32/106 (30.2%) patients. AEs led to study drug discontinuation in 36/106 patients (34.0%). Eighteen of 106 patients (17.0%) had AEs suggestive of congestive heart failure; however, there were no confirmed cases., Conclusions: The vinorelbine, pertuzumab, and trastuzumab combination is active and reasonably well tolerated. This regimen offers an alternative for patients who cannot receive docetaxel for first-line treatment of HER2-positive locally advanced or MBC., Trial Registration: ClinicalTrials.gov: NCT01565083 , registered on 26 March 2012.

Background: In the last years different studies have reported an increase of amyotrophic lateral sclerosis (ALS) incidence, highlighting the role of the environment in this disease. This prompted us to review ALS cases diagnosed at our hospital in the last decade and to compare them with a previous ALS series reported in our region 30 years ago., Methods: We reviewed those ALS cases diagnosed at our centre between 2004 and 2013. Subsequently, we compared them with the previous series regarding clinical and epidemiological features., Results: A total of 53 patients (30 males, 23 females) were included. The annual incidence was 1.7 cases per 100,000 inhabitants (2.2 and 1.2 per 100,000 in males and females, respectively), which was significantly higher than in the previous series (1 case per 100,000 inhabitants). Otherwise, the clinical and epidemiological features were similar in both series. The median age at symptom onset was 67 years, with a median diagnosis delay of 6 months. About two thirds of the patients presented with systemic ALS, whereas the remaining had a bulbar onset. Weakness, dysphagia, and dysarthria were the most common clinical symptoms at diagnosis. The median survival from symptom onset was 22 months., Conclusion: After 3 decades, the annual incidence of ALS has almost doubled in our region. We did not find significant differences regarding other clinical or epidemiological features., (© 2016 S. Karger AG, Basel.)

Purpose: Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC., Patients and Methods: Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m(2), respectively, × four cycles), followed by docetaxel (100 mg/m(2) × four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m(2), respectively, × four cycles), followed by capecitabine (1,250 mg/m(2) twice a day on days 1 to 14, × four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS)., Results: After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months)., Conclusion: Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms., (© 2015 by American Society of Clinical Oncology.)

Background: Antiangiogenic drugs are being used in the treatment of locally advanced breast cancer. The effect of these drugs can be monitorized using high temporal resolution dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)., Purpose: To evaluate changes in tumor microvasculature induced by bevacizumab and the usefulness of these changes predicting response to further neoadjuvant therapy., Material and Methods: Seventy patients with locally advanced breast cancers were treated with one cycle of bevacizumab followed by neoadjuvant therapy, combining bevacizumab and cytotoxic chemotherapy. Two DCE-MRI were performed before and after bevacizumab. Changes in tumoral volume, pharmacodynamic curves, and pharmacokinetic variables (K(trans), Kep, Ve, AUC90) in a ROI (ROI 1) encompassing the entire tumor and in another ROI (ROI 2) in the area of higher values of K(trans) were analyzed. Correlations with pathological response were made: parametrical and non-parametrical statistical analysis and ROC curves were used; a P < 0.05 was considered significant., Results: Significant changes in tumoral volume (-4%), pharmacodynamic curves, and pharmacokinetic variables in ROI 1 K(trans) (-45%), Kep (-38%), Ve (-11%), and AUC90 (-44%) and ROI 2 K(trans) (-43%), Kep (-39%), Ve (-5%), and AUC90 (-45%) were observed after bevacizumab (P < 0.05). The effect of bevacizumab was not different between responders and non-responders (P > 0.05), and these changes could not predict response to further neoadjuvant therapy., Conclusion: Bevacizumab induces remarkable tumoral volume, pharmacodynamics, and pharmacokinetic changes. However, these changes could not be used as early predictors for response to further neoadjuvant therapy., (© The Foundation Acta Radiologica 2014.)

Purpose: Adding taxanes to anthracycline-based adjuvant therapy improves survival outcomes of patients with node-positive breast cancer (BC). Currently, however, most patients with BC are node negative at diagnosis. The only pure node-negative study (Spanish Breast Cancer Research Group 9805) reported so far showed a docetaxel benefit but significant toxicity. Here we tested the efficacy and safety of weekly paclitaxel (wP) in node-negative patients, which is yet to be established., Patients and Methods: Patients with BC having T1-T3/N0 tumors and at least one high-risk factor for recurrence (according to St. Gallen 1998 criteria) were eligible. After primary surgery, 1,925 patients were randomly assigned to receive fluorouracil, doxorubicin, and cyclophosphamide (FAC) × 6 or FAC × 4 followed by wP × 8 (FAC-wP). The primary end point was disease-free survival (DFS) after a median follow-up of 5 years. Secondary end points included toxicity and overall survival., Results: After a median follow-up of 63.3 months, 93% and 90.3% of patients receiving FAC-wP or FAC regimens, respectively, remained disease free (hazard ratio [HR], 0.73; 95% CI, 0.54 to 0.99; log-rank P = .04). Thirty-one patients receiving FAC-wP versus 40 patients receiving FAC died (one and seven from cardiovascular diseases, respectively; HR, 0.79; 95% CI, 0.49 to 1.26; log-rank P = .31). The most relevant grade 3 and 4 adverse events in the FAC-wP versus the FAC arm were febrile neutropenia (2.7% v 3.6%), fatigue (7.9% v 3.4%), and sensory neuropathy (5.5% v 0%)., Conclusion: For patients with high-risk node-negative BC, the adjuvant FAC-wP regimen was associated with a small but significant improvement in DFS compared with FAC therapy, in addition to manageable toxicity, especially regarding long-term cardiac effects.

Aim: The COSTABRAX study evaluated the cost-effectiveness of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) versus polyethylated castor oil-based standard paclitaxel (sb-paclitaxel) in the treatment of patients with previously treated metastatic breast cancer in Spain., Materials & Methods: Efficacy data were obtained from the CA012 trial (nab-paclitaxel administered every 3 weeks [q3w] and sb-paclitaxel q3w) and indirect comparison (sb-paclitaxel administered weekly), and were modeled to a time horizon of 5 years using a Markov model. The analysis was performed from the National Health Service perspective. Use of resources and key assumptions of the model were validated by a panel of 22 local oncologists., Results: Compared with sb-paclitaxel q3w, nab-paclitaxel q3w was cost effective, with a cost per life year gained of €11,088 and a cost per quality-adjusted life year of €17,808. Compared with sb-paclitaxel administered weekly, it showed savings of €711 per patient., Conclusion: The COSTABRAX study showed that nab-paclitaxel q3w is a cost-effective alternative compared with sb-paclitaxel q3w and a cost-saving alternative to sb-paclitaxel administered weekly in Spain.

To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel.

Background: A regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) is superior to a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) when used as adjuvant therapy in women with node-positive breast cancer. The value of taxanes in the treatment of node-negative disease has not been determined., Methods: We randomly assigned 1060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence (according to the 1998 St. Gallen criteria) to treatment with TAC or FAC every 3 weeks for six cycles after surgery. The primary end point was disease-free survival after at least 5 years of follow-up. Secondary end points included overall survival and toxicity., Results: At a median follow-up of 77 months, the proportion of patients alive and disease-free was higher among the 539 women in the TAC group (87.8%) than among the 521 women in the FAC group (81.8%), representing a 32% reduction in the risk of recurrence with TAC (hazard ratio, 0.68; 95% confidence interval [CI], 0.49 to 0.93; P=0.01 by the log-rank test). This benefit was consistent, regardless of hormone-receptor status, menopausal status, or number of high-risk factors. The difference in survival rates (TAC, 95.2%; FAC, 93.5%) was not significant (hazard ratio, 0.76; 95% CI, 0.45 to 1.26); however, the number of events was small (TAC, 26; FAC, 34). Rates of grade 3 or 4 adverse events were 28.2% with TAC and 17.0% with FAC (P<0.001). Toxicity associated with TAC was diminished when primary prophylaxis with granulocyte colony-stimulating factor was provided., Conclusions: As compared with adjuvant FAC, adjuvant TAC improved the rate of disease-free survival among women with high-risk, node-negative breast cancer. (Funded by GEICAM and Sanofi-Aventis; ClinicalTrials.gov number, NCT00121992.).

Background: Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting., Methods: After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided., Results: Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment., Conclusions: Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.

Background: The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG)., Patients and Methods: This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment)., Results: The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2-4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P<0.03)., Conclusions: The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment.

The efficacy of vinorelbine given as a continuous infusion was evaluated in 47 patients with breast cancer who had received previous treatment with first-line, second-line, and third-line chemotherapy including taxanes and/or anthracyclines. For inclusion into the study, patients were required to have histology-proven bi-dimensionally measurable disease. The treatment schedule was a bolus injection of vinorelbine 8 mg/m(2) administered over 5-10 minutes on day 1 followed by vinorelbine 8 mg/m(2) continuous infusion on days 1-4, every 21 days for 6 cycles. On an intent-to-treat basis, a 2% complete response rate and a 17% partial response rate were observed. The median time to progression was 2.4 months (95% CI, 1.83-2.97). Median survival was 7.73 months (95% CI, 4.48-10.98; range, 0.33-55.0 months). Major toxicities included febrile neutropenia in 40 cycles (24%) affecting 24 patients (51%) and 1 toxic death. Other nonhematologic toxicities included stomatitis (13%) and asthenia (13%). We conclude that this treatment shows considerable therapeutic activity, albeit at considerable toxicity costs, even in patients who have had multiple lines of prior chemotherapy. However, the results do not indicate clear advantages compared to the conventional weekly scheme of administration.

Purpose: This is one of the first reports of weekly docetaxel (Taxotere) in the neoadjuvant treatment of stage II and III breast cancer. We evaluated docetaxel's efficacy and safety and analyzed correlations between response and the expression of c-erbB2, ER status, and Ki-67 labeling index., Experimental Design: Patients with previously untreated, stage II and III breast cancer were entered into the study. Docetaxel (40 mg/m(2)) was given i.v. once weekly for the first 6 weeks of an 8-week cycle for 2 cycles., Results: A total of 56 patients were evaluated by intention-to-treat analysis for efficacy and safety. The overall clinical response rate was 68% (complete and partial response, 29 and 39%, respectively). Nine patients (16%) achieved a pathological complete response. There was no correlation between response to docetaxel and the expression of molecular markers, however, the majority of the pathological complete responses were observed in patients with c-erbB2-negative tumors. Nonhematological toxicity was more common than hematological toxicity, with alopecia and asthenia the most frequently reported adverse events (89 and 77% of patients, respectively). Severe hematological toxicity was rare., Conclusions: Weekly docetaxel appears to be very effective in the neoadjuvant setting. A high pathological response rate was achieved with tolerable toxicity.

Purpose: To evaluate the efficacy and the toxicity profile of the sequential administration of doxorubicin and docetaxel as first-line chemotherapy in metastatic breast cancer (MBC)., Patients and Methods: Eighty-one patients received a total of 436 cycles of chemotherapy: 236 of doxorubicin (75 mg/m2) and 200 of docetaxel (100 mg/m2 every 21 days). The first 35 patients received doxorubicin every 14 days with G-CSF support, and in the other 46 cases doxorubicin was administered every 21 days without G-CSF., Results: After entire treatment the overall response rate was 65% (18 complete responses). With a median follow-up of 19 months (range, 1-48 months), the median time to progression was 11.3 months and the median survival time was 31 months. As expected, febrile neutropenia was the most important toxicity and it appeared in 26 cycles (6%) and 19 patients (23%). In the patients that received doxorubicin every 14 days, the febrile neutropenia incidence was higher during docetaxel treatment, especially after its first administration., Conclusions: The dose and schedule of doxorubicin and docetaxel used in this trial seems to be active in first-line treatment of patients with MBC. The toxicity profile appears to be better than observed with concomitant schedules.

Background: The purpose of this study was to analyze whether the addition of granulocyte-colony stimulating factor (G-CSF) to platinum-based combination chemotherapy could increase platinum dose intensity and response rates and decrease hematologic toxicity in patients with advanced epithelial ovarian carcinoma., Methods: Patients with untreated advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage IIC-IV) were treated after maximum debulking surgery with cyclophosphamide, 750 mg/m2, and carboplatin, 350 mg/m2, on Day 1 plus cisplatin, 75 mg/m2, on Day 14 when clinically indicated (adequate bone marrow and renal function). Patients were randomized to receive chemotherapy alone (Arm A) or chemotherapy supported with G-CSF (5 microg/kg subcutaneously on Days 2-13; Arm B)., Results: Between November 1993 and April 1995, 80 patients were included. Seventy-eight patients were evaluable for dose intensity calculations. Both groups were well matched with regard to age, Eastern Cooperative Oncology Group performance status, histopathologic subtype, tumor grade, FIGO stage, and residual tumor after surgery. The dose intensities calculated in mg/m2/week for cyclophosphamide and carboplatin were similar in both groups; however, the dose intensity of cisplatin was higher in Arm B (5.7 mg/m2 vs. 10.3 mg/m2). The occurrence of Common Toxicity Criteria Grade 3-4 neutropenia was less common in the G-CSF arm (55% vs. 7.7%). Response rates (52% vs. 68%) and pathologic complete responses (32% vs. 25%) were similar in both groups. CONCLUSIONS; The addition of G-CSF to this platinum-based chemotherapy regimen in patients with advanced ovarian carcinoma resulted in a modest increment in platinum dose intensity and appeared to reduce the incidence of Grade 3-4 neutropenia.

Purpose: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer., Patients and Methods: A total of 306 patients were randomized to receive either 5-FU 425 mg/m2 given by bolus injection on days 1-5 plus intravenous (i.v.) LV 20 mg/m2 every four to five weeks or 5-FU 3.5 g/m2/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms., Results: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3-4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm., Conclusions: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3-4 toxicity.

To assess the effectiveness and safety of an implanted portal with a central venous brachial implanted catheter, P.A.S. Port TM(P-P), and the accuracy of its Cath Finder TM tracking system (C-F), (Pharmacia Deltec) vs. radiology, a phase II multicentric study was designed. The catheter was implanted in 53 oncologic patients treated with chemotherapy and the performance of the catheter was evaluated for 3 months. No problems arose during the implantation in 77% of the cases and in all cases radiologic location of the catheter tip coincided with the C-F. We can conclude that P-P is easy to implant and to maintain in the arm and that it is well tolerated by the patients. C-F is an accurate and reliable system for locating the catheter tip. The use of both systems is an attractive alternative to the standard ones.

Eleven patients with solid tumors for whom effective therapy was not available entered a phase I study of mitonafide given as a short intravenous (i.v.) infusion daily for 3 consecutive days. The initial dose level was selected according to the experience from another phase I study using a 5-day administration schedule. Six patients entered the first dose level (180 mg/m2/day x 3 days) and 4 of them had grade 3-4 leukopenia. This level was considered to be the maximum tolerated dose (MTD) and no further dose escalations were attempted. The following 5 patients received a dose approximately 10% inferior to the previous one (160 mg/m2/day x 3 days). Three of them had grade 3-4 neutropenia. Three partial responses were observed in total. After inclusion of 11 patients, an unexpected toxicity, central nervous system (CNS) toxicity, consisting of severe loss of memory, temporospatial disorientation and high integrative function impairment was observed in 5 patients (46%). A median patients' follow-up of 3 months after treatment discontinuation showed that these alterations were progressive and not reversible. This disabling toxicity prompted us to an early study interruption. In conclusion, mitonafide, when administered as a short 3-day i.v. infusion, can induce severe and irreversible CNS toxicity. Nevertheless, since antitumor activity has been observed, further development of the drug is recommended with different schedules of administration that have shown not to produce neurotoxicity, i.e., 5-day continuous infusion.

A total of 37 men with epidermoid head and neck cancer whose disease had recurred following primary treatment (surgery and/or radiotherapy) received first-line chemotherapy with ifosfamide at i.v. doses of 3 g/m2 given daily on 3 consecutive days in combination with mesna (600 mg/m2 x 3 oral daily doses on days 1-3) every 3 weeks. In all, 7 patients showed a partial response and 2 patients achieved a complete response, for an overall objective response rate of 26% (9 of 35 eligible patients; 95% confidence interval, 12.5%-43%). Excluding the 5 early nontoxic deaths observed during the first 3 weeks of therapy, the objective response rate was 30% (9 of 30 patients; 95% confidence interval, 15%-49.5%). Responses were seen in lung metastases (2 patients), lymph nodes (2 patients), skin (3 patients), and cases of local recurrence (5 patients). The median duration of responses was 3 months (range, 2-5 months). The main side effects of ifosfamide were alopecia (83% of patients), emesis (80%), granulocytopenia (23%), and mild mucositis (20%). Two poor-risk patients suffered severe CNS complications that were probably related to treatment. Three patients died due to chemotherapy-related complications (2 patients with CNS toxicity and 1 patient with granulocytopenic sepsis). In conclusion, ifosfamide appears to be an active drug in epidermoid head and neck cancer and merits further evaluation in this disease.

The effects of oral and intravenous magnesium supplementation on cisplatin (CDDP)-induced hypomagnesemia were investigated in 41 patients treated with 100 mg/m2 CDDP. Patients were randomly allocated to receive no magnesium supplementation, intravenous magnesium supplementation (magnesium sulphate, 3 g before each CDDD administration) or oral magnesium supplementation (magnesium pidolate, 2 g orally every 8 hours on days 2 to 21 of each CDDP course) during the first 4 courses of CDDP treatment. Patients in both supplementation arms showed significantly higher magnesium levels than control patients from the second course on (oral magnesium arm) or from the third course on (intravenous magnesium arm). Three of the 9 patients (33%) in the intravenous magnesium arm and 4 of the 9 (44%) in the oral magnesium arm developed hypomagnesemia after the fourth course of CDDP, compared with 9 of the 10 (90%) unsupplemented patients. There were no magnesium-related side effects in patients on intravenous magnesium supplementation. Two patients treated with oral magnesium developed mild gastrointestinal symptoms (emesis and diarrhea), probably from magnesium therapy. Our study showed that both intravenous and oral magnesium supplementations appear to be safe and efficacious in the prevention of CDDP-induced hypomagnesemia. Since patients were not completely protected, and since the analysis was limited to the first four courses of chemotherapy, additional studies are needed to determine the best schedule of magnesium supplementation, especially in patients who receive more than four courses of CDDP chemotherapy.

Purpose: The study was undertaken to assess the antitumor activity of carboplatin 400 mg/m2 intravenously every 4 weeks in metastatic breast cancer (MBC)., Patients and Methods: Thirty-four MBC patients without any prior exposure to chemotherapy entered the study. All patients had measurable disease in at least one site and were assessable for response and toxicity., Results: Of 34 assessable patients, 12 obtained a complete (one) or partial (11) response to carboplatin, resulting in an overall response rate of 35% (95% confidence interval, 19.8% to 53.5%). The median duration of response was 8 months (range, 2+ to 12 months). Responses were seen in lymph nodes (four of six), lung (five of nine), skin and soft tissues (four of nine), breast (two of eight), and liver (three of 11), but not in measurable lytic lesions of the bone. Toxicity was mild, mainly consisting of emesis (81% of the patients; 66% of the courses), leukopenia of World Health Organization (WHO) grade 1 to 2 (47% of the patients; 18% of the courses), and thrombocytopenia (12% of the patients; 3% of the courses). There were no cases of life-threatening toxicity, although one patient developed grade 4 thrombocytopenia without bleeding. Of 22 patients who did not respond to carboplatin, 18 received salvage therapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF; 15 patients); cyclophosphamide, methotrexate, and fluorouracil (CMF; one patient); or hormones (two patients). Objective responses to CAF and hormonal therapy were seen in 11 of 15 and two of two patients, respectively. The remaining patient did not respond to CMF salvage chemotherapy. Overall, the response rate to either first-line carboplatin or second-line salvage therapy was 73.5% (25 of 34 patients). After a median follow-up time of 22 months, the median survival was 19 months., Conclusions: Carboplatin is an active drug in MBC patients without previous exposure to chemotherapy. In our study, the use of an experimental drug as first-line single-agent treatment in MBC did not have a negative influence on patient survival, as the majority of the carboplatin nonresponding patients could be salvaged with a conventional therapeutic regimen.

The antitumor activity of carboplatin (400 mg/m2 intravenously every 4 weeks) in advanced breast cancer was evaluated in two consecutive trials enrolling patients with and without prior exposure to chemotherapy, respectively. All patients had measurable disease in at least one site. The first trial included patients who had received prior chemotherapy (adjuvant, neoadjuvant, or chemotherapy for metastatic disease). All but one of these patients had previously received doxorubicin-containing combinations. There were no objective responses among the first 14 evaluable patients, although 7 of them had stable disease, including 2 with minor responses. The second trial, carried out with patients who had no prior exposure to chemotherapy, is ongoing. Currently, 6 of 19 evaluable patients have obtained a complete (1) or partial (5) response to carboplatin, resulting in an overall response rate of 32%. In both studies, toxicity was mild, mainly consisting of emesis (88%), leukopenia (22%), and thrombocytopenia (12%). Thus, by standard criteria, carboplatin was not found to be active in breast cancer patients with prior exposure to chemotherapy. Preliminary results in patients without such exposure are encouraging, although additional patients are needed to confirm these data.

Twenty-eight patients receiving their first cycle of carboplatin treatment (300-400 mg/m2) entered a prospective study in which the natural course and intensity of postchemotherapy emesis was evaluated. Twenty-five patients (89%) experienced nausea at some time after carboplatin treatment and twenty-three patients (82%) vomited. The median number of emetic episodes was 13.5. In the 23 patients who experienced vomiting, the mean period of latency of vomiting (time from start of carboplatin administration to onset of vomiting) was 6.25 h. The period of maximum incidence of vomiting was between 8 and 12 h (71% of patients with vomiting). Between 6 and 14 h after the start of carboplatin treatment, more than 50% of patients were continuously vomiting. Vomiting declined significantly after 24 h. According to these data, carboplatin is a severely emetic drug. Prospective antiemetic trials are necessary in order to obtain antiemetic schedules which are able to increase the tolerance to carboplatin treatment.

Sixty-two patients with motor neuron disease (MND), encompassing amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP) and progressive muscular atrophy (PMA), were selected from within a defined area (Cantabria) in northern Spain, from 1974 to 1985. The annual incidence of MND was 1.01 per 100,000 inhabitants and the prevalence rate was 3.52 per 100,000. The male to female ratio was 1.78:1. Age-specific incidence rates increased with advanced age, with a maximum between 60 and 69 years for males and over 70 years for females. The median age at onset was 60.5 years. The average interval between the onset symptoms and diagnosis was 11 months. Fifty-three per cent of the patients had conventional or pseudopolyneuritic ALS, 36% had PBP and 11% had PMA. There were three familial cases. Two PMA patients had had acute poliomyelitis. The mean duration of the disease was 26.6 months and was significantly longer in males aged under 60 years. The survival rates in 50 patients with adequate follow-up were 18% after 5 years from onset and 6% after 10 years.