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Background and Aims:Treatment of recurrent platinum-resistant ovarian cancer remains challenging due to the development of chemo-resistance. Cabazitaxel is a new taxane that has demonstrated effect in prostatic cancer patients resistant to Docetaxel. Therefore, it could be anticipated that it might also have an effect on chemo-resistant ovarian cancer.The presented results originate from the protocol Cabazitaxel vs. Tocotrienol in patients with Recurrent Ovarian Cancer after failure of standard therapy - A phase 2 randomized open-label study. EudraCT number: 2015-002296-18. Tocotrienol failed to reach its primary endpoint at time of interim analysis and the protocol was continued for cabazitaxel only.Methods:Twenty six patients with chemotherapy-resistant epithelial ovarian cancer, fallopian tubal or peritoneal cancer were treated with cabazitaxel at a dose of 25 mg/m2, day 1 q3w, until progression or inacceptable toxicity in the period from September 2015 – April 2018. Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was prescribed to all patients. Two patients are still receiving treatment with cabazitaxel. Results:At time of referral for cabazitaxel treatment, patients had received a median of 3 previous chemotherapy regimens (range 2-8). The median number of cabazitaxel infusions was 4.0 (range 1-18). In general, cabazitaxel was well tolerated in patients with good performance status. In an intention- to- treat analysis, median PFS was 3.9 months (95% C.I; 1.9-5.2) using the combination of CA125 or RECIST (whichever came first). Median OS was 8.9 months (95% C.I; 7.0-10.9). The fraction of patients alive and without progression after three months of treatment was 13/26 patients (50%). Partial response (PR), evaluated by RECIST, was seen in 4/26 patients (15%). The response was confirmed by another scan in 3/26 patients (11.5%). A response rate of 46% (12/26) was detected according to the GCIG CA125 criteria. Conclusions:Our data show that cabazitaxel holds promise as a new drug in ovarian cancer. In general the toxicity was manageable.

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

AIM: To evaluate the pCR rate and toxicity of the addition of weekly carboplatin (Cp) to paclitaxel (wP) and dose-dense (dd) epirubicin/cyclophosphamide (EC) in an open-label phase II study in TNBC patients. METHODS: Patients were included if they had stage II and III TNBC and received wP (80 mg/m2/week) concurrent with weekly Cp (AUC = 2) for 12 weeks, followed by bi-weekly epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) plus granulocyte colony-stimulating factor (G-CSF) for four cycles, followed by surgery. The primary endpoint was the rate of pCR [(ypT0/isypN0)]. Secondary endpoints included safety and drug delivery. RESULTS: Sixty-three eligible patients were included. Median age was 51 years (range 29-74); 88.9% had stage II disease, 46% were clinically node positive, and 77.8% had grade 3 tumors. Fifty-four percent achieved a pCR. Twelve percent missed two or more doses of wP, whereas at least two cycles of EC were missed in 9.5%. The rate of tolerance without delays or dose reductions is very low (16%). Sixty-two percent had G3/4 neutropenia. Febrile neutropenia occurred in 18 patients of which more than eighty percent occurred during EC despite primary prophylaxis with G-CSF. Thrombocytopenia grade 3/4 was noticed in 11 pts. Three patients developed grade 3 peripheral neuropathy. CONCLUSION: The addition of weekly carboplatin to neoadjuvant paclitaxel and dd EC leads to a pCR rate comparable to prior studies (54%). However, hematological toxicity and febrile neutropenia rate was unexpectedly high. Future investigations could focus on reversing the sequence, which may lead to better hematological tolerability.

Background. Docetaxel is a highly effective treatment of a wide range of malignancies but is often associated with peripheral neuropathy. The genetic variability of genes involved in the transportation or metabolism of docetaxel may be responsible for the variation in docetaxel-induced peripheral neuropathy (DIPN). The main purpose of this study was to investigate the impact of genetic variants in GSTP1 and ABCB1 on DIPN.Material and methods. DNA was extracted from whole blood from 150 patients with early-stage breast cancer who had received adjuvant docetaxel from February 2011 to May 2012. Two polymorphisms in GSTP1 and three in ABCB1 were selected for the primary analysis, and a host of other candidate genes was explored and compared between 75 patients with clinician-reported DIPN grade ≥ 2 and 75 patients without DIPN.Results. Patients with the genetic variants GSTP1 rs1138272 C/T or T/T (114Ala/114Val or 114Val/114Val) genotype had an adjusted odds ratio of 3.82; 95% confidence interval 1.34–11.09 of developing DIPN. This result was confirmed in both analysis of cumulated docetaxel dose and haplotype analysis. None of the explorative genes investigated were significantly correlated with DIPN. Patients with a BMI ≥ 30 were five-fold more likely to have DIPN than patients with BMI < 25.Conclusion. We found that GSTP1 Ala114Val polymorphism is associated with occurrence of DIPN. This supports the theory that oxidative stress is involved in DIPN pathophysiology. If confirmed, this may be helpful in the risk assessment of DIPN and perhaps help to achieve better management of neurotoxicity.

BACKGROUND: This study evaluates persistence and severity of docetaxel-induced neuropathy (peripheral neuropathy (PN)) and impact on health related quality of life in survivors from early-stage breast cancer.METHODS: One thousand and thirty-one patients with early-stage breast cancer, who received at least one cycle of docetaxel and provided information on PN during treatment, completed questionnaires on PN as an outcome (Common Toxicity Criteria (CTC) scores, European Organisation for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC CIPN20) and EORTC Quality of Life Questionnaire (QLQ)-C30) after 1-3years.FINDINGS: Upon completion of docetaxel treatment, 241 patients (23%) reported PN, grades 2-4. PN persisted for 1-3years among 81 (34%) while PN regressed to grades 0-1 among 160 (66%). Among 790 patients (77%) without PN, 76 (10%) developed PN 1-3years later while 714 (90%) stayed free from PN. Significant risk factors for persistent PN were age ⩾55 (p=0.001), maximum grade of PN during docetaxel treatment (pINTERPRETATIONS: Overall, 15% of breast cancer survivors treated with docetaxel report PN 1-3years after treatment with a significant negative impact on HRQOL.

Background Gastric cancer is the fifth most common cancer worldwide. In "Western" countries, most people are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. In people with advanced disease, significant benefits from targeted therapies are currently limited to HER-2 positive disease treated with trastuzumab, in combination with chemotherapy, in first-line. In second-line, ramucirumab, alone or in combination with paclitaxel, demonstrated significant survival benefits. Thus, systemic chemotherapy remains the mainstay of treatment for advanced gastric cancer. Uncertainty remains regarding the choice of the regimen. Objectives To assess the efficacy of chemotherapy versus best supportive care (BSC), combination versus single-agent chemotherapy and different chemotherapy combinations in advanced gastric cancer. Search methods We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase up to June 2016, reference lists of studies, and contacted pharmaceutical companies and experts to identify randomised controlled trials (RCTs). Selection criteria We considered only RCTs on systemic, intravenous or oral chemotherapy versus BSC, combination versus single-agent chemotherapy and different chemotherapy regimens in advanced gastric cancer. Data collection and analysis Two review authors independently identified studies and extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. Main results We included 64 RCTs, of which 60 RCTs (11,698 participants) provided data for the meta-analysis of overall survival. We found chemotherapy extends overall survival (OS) by approximately 6.7 months more than BSC (hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.24 to 0.55, 184 participants, three studies, moderate-quality evidence). Combination chemotherapy extends OS slightly (by an additional month) versus single-agent chemotherapy (HR 0.84, 95% CI 0.79 to 0.89, 4447 participants, 23 studies, moderate-quality evidence), which is partly counterbalanced by increased toxicity. The benefit of epirubicin in three-drug combinations, in which cisplatin is replaced by oxaliplatin and 5-FU is replaced by capecitabine is unknown.Irinotecan extends OS slightly (by an additional 1.6 months) versus non-irinotecan-containing regimens (HR 0.87, 95% CI 0.80 to 0.95, 2135 participants, 10 studies, high-quality evidence).Docetaxel extends OS slightly (just over one month) compared to non-docetaxel-containing regimens (HR 0.86, 95% CI 0.78 to 0.95, 2001 participants, eight studies, high-quality evidence). However, due to subgroup analyses, we are uncertain whether docetaxel-containing combinations (docetaxel added to a single-agent or two-drug combination) extends OS due to moderate-quality evidence (HR 0.80, 95% CI 0.71 to 0.91, 1466 participants, four studies, moderate-quality evidence). When another chemotherapy was replaced by docetaxel, there is probably little or no difference in OS (HR 1.05; 0.87 to 1.27, 479 participants, three studies, moderate-quality evidence). We found there is probably little or no difference in OS when comparing capecitabine versus 5-FU-containing regimens (HR 0.94, 95% CI 0.79 to 1.11, 732 participants, five studies, moderate-quality evidence) .Oxaliplatin may extend (by less than one month) OS versus cisplatin-containing regimens (HR 0.81, 95% CI 0.67 to 0.98, 1105 participants, five studies, low-quality evidence). We are uncertain whether taxane-platinum combinations with (versus without) fluoropyrimidines extend OS due to very low-quality evidence (HR 0.86, 95% CI 0.71 to 1.06, 482 participants, three studies, very low-quality evidence). S-1 regimens improve OS slightly (by less than an additional month) versus 5-FU-containing regimens (HR 0.91, 95% CI 0.83 to 1.00, 1793 participants, four studies, high-quality evidence), however since S-1 is used in different doses and schedules between Asian and non-Asian population, the applicability of this finding to individual populations is uncertain. Authors' conclusions Chemotherapy improves survival (by an additional 6.7 months) in comparison to BSC, and combination chemotherapy improves survival (by an additional month) compared to single-agent 5-FU. Testing all patients for HER-2 status may help to identify patients with HER-2-positive tumours, for whom, in the absence of contraindications, trastuzumab in combination with capecitabine or 5-FU in combination with cisplatin has been shown to be beneficial. For HER-2 negative people, all different two-and three-drug combinations including irinotecan, docetaxel, oxaliplatin or oral 5-FU prodrugs are valid treatment options for advanced gastric cancer, and consideration of the side effects of each regimen is essential in the treatment decision. Irinotecan-containing combinations and docetaxel-containing combinations (in which docetaxel was added to a single-agent or two-drug (platinum/5-FUcombination) show significant survival benefits in the comparisons studied above. Furthermore, docetaxel-containing three-drug regimens have increased response rates, but the advantages of the docetaxel-containing three-drug combinations (DCF, FLO-T) are counterbalanced by increased toxicity. Additionally, oxaliplatin-containing regimens demonstrated a benefit in OS as compared to the same regimen containing cisplatin, and there is a modest survival improvement of S-1 compared to 5-FU-containing regimens.Whether the survival benefit for three-drug combinations including cisplatin, 5-FU, and epirubicin as compared to the same regimen without epirubicin is still valid when second-line therapy is routinely administered and when cisplatin is replaced by oxaliplatin and 5-FU by capecitabine is questionable. Furthermore, the magnitude of the observed survival benefits for the three-drug regimens is not large enough to be clinically meaningful as defined recently by the American Society for Clinical Oncology (Ellis 2014). In contrast to the comparisons in which a survival benefit was observed by adding a third drug to a two-drug regimen at the cost of increased toxicity, the comparison of regimens in which another chemotherapy was replaced by irinotecan was associated with a survival benefit (of borderline statistical significance), but without increased toxicity. For this reason irinotecan/5-FU-containing combinations are an attractive option for first-line treatment. Although they need to be interpreted with caution, subgroup analyses of one study suggest that elderly people have a greater benefit form oxaliplatin, as compared to cisplatin-based regimens, and that people with locally advanced disease or younger than 65 years might benefit more from a three-drug regimen including 5-FU, docetaxel, and oxaliplatin as compared to a two-drug combination of 5-FU and oxaliplatin, a hypothesis that needs further confirmation. For people with good performance status, the benefit of second-line chemotherapy has been established in several RCTs.

Eribulin is indicated in the EU for advanced/metastatic breast cancer patients following ≥1 prior chemotherapy for advanced disease, and anthracycline and taxane in adjuvant/metastatic setting. We pooled 1644 patients from two phase III trials and found that eribulin significantly increased survival versus control, particularly in some subgroups of interest like HER2- and triple-negative disease., Background Based on data from two multicenter, phase III clinical trials (Studies 301 and 305), eribulin (a microtubule dynamics inhibitor) is indicated in the European Union (EU) for patients with locally advanced or metastatic breast cancer (MBC) after ≥1 prior chemotherapy for advanced disease, including an anthracycline and a taxane in either the adjuvant or metastatic setting. Data from Studies 305 and 301 were pooled to investigate the efficacy of eribulin in various subgroups of patients who matched the EU label, including those with human epidermal growth factor receptor 2 (HER2)-negative and triple-negative disease. Patients and methods In Study 305 (NCT00388726), patients were randomized 2:1 to eribulin mesylate 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2 [expressed as free base]) intravenously on days 1 and 8 every 21 days] or treatment of physician's choice after 2–5 prior chemotherapies (≥2 for advanced disease), including an anthracycline and a taxane (in early/advanced setting). In Study 301 (NCT00337103), patients were randomized 1:1 to eribulin (as above) or capecitabine (1.25 g/m2 orally twice daily on days 1–14 every 21 days) following ≤3 prior chemotherapies (≤2 for advanced disease), including an anthracycline and a taxane. Efficacy end points were investigated in the intent-to-treat population and subgroups, pooled as discussed above. Results Overall, 1644 patients were included (eribulin: 946; control: 698); baseline characteristics were well matched. Overall survival was significantly longer with eribulin versus control (P < 0.01), as were progression-free survival and clinical benefit rate (both P < 0.05). Significant survival benefits with eribulin versus control were observed in a wide range of patient subgroups, including HER2-negative or triple-negative disease (all P < 0.05). Conclusion Our findings underline the survival benefit achieved by eribulin used according to EU label in the overall MBC population and in various subgroups of interest, including patients with HER2-negative and triple-negative disease.

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

TP53 has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutated TP53 than in those with wild-type TP53.In an open-label, phase 3 study, women (age71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m² every 21 days [FEC100], or fluorouracil 600 mg/m², epirubicin 75 mg/m², cyclophosphamide 900 mg/m² [tailored FEC] starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m², intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m² and docetaxel 75 mg/m² on day 1 every 21 days [T-ET]) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov, number NCT00017095.928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients with TP53-mutated tumours, 5-year PFS was 59·5% (95% CI 53·4-65·1) in the T-ET group (n=326) and 55·3% (49·2-60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63-1·14; p=0·17). In patients with TP53 wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4-71·6) in the T-ET group (n=398) and 64·7% (59·6-69·4) in the FEC group (n=427; 0·89, 98% CI 0·68-1·18; p=0·35). For all patients, irrespective of TP53 status, 5-year PFS was 65·1% (95% CI 61·6-68·3) in the T-ET group and 60·8% (57·3-64·2) in the FEC group (0·85, 98% CI 0·71-1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 [9%] of 803 vs 173 [21%] of 809, respectively), and neutropenia (653 [81%] vs 730 [90%], respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten [8%] of 118 vs 26 [22%] of 116, respectively), and neutropenia (100 [85%] vs 115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group).Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy.US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.

Objective: To report a case of intraocular metastasis from breast carcinoma. Clinical Presentation and Intervention: A 54-year-old woman diagnosed with multifocal ductal adenocarcinoma, grade III, of the left breast presented with blurred vision of the left eye. Funduscopy under pupil dilation in the left eye revealed a plateau-shaped, yellow choroidal focus measuring 4 optic disc diameters and located 3 optic disc diameters below the fovea. The patient was treated with two cycles of docetaxel and capecitabine. One month later the patient’s visual acuity improved. Funduscopy confirmed reduction of oedema. Conclusion: This case shows that impaired vision can be an alarming symptom in a breast cancer patient and a description is given of the morphological features that could help in recognizing the smallest detectable breast cancer metastasis.

There is considerable heterogeneity in the use of chemotherapy in early breast cancer (BC), despite international recommendations issued from the NCCN, NIH and the St.Gallen bi-annual conference.We included 1,535 patients from seven Swiss cancer registries between 2003 and 2005 receiving chemotherapy for stage I to III BC. Chemotherapy was categorised into (a) FAC/FEC, anthracyclines followed by CMF or anthracycline-taxane combinations (FAC-T) (781 patients) and (b) other chemotherapy regimens such as CMF/AC (EC) (754 patients). Predictors for choosing FAC-T over non-FAC-T chemotherapy were separately determined in all patients and in ER-negative patients (n = 496) by multivariate logistic regression analysis.The use of FAC-T increased significantly over time, from 44% in 2003 to 55% in 2005. BC stage III (versus stage I-II) and nodal positivity were the predominant predictors for using FAC-T chemotherapy in the adjusted model (odds ratio (OR) 4.1, 95%-confidence intervals (CI) 2.6-6.3 and OR 3.0, 95%-CI 2.0-4.4, respectively). In high-risk ER-negative BC patients, poor histological differentiation was more important to choose FAC-T chemotherapy (OR 3.8, 95%-CI 1.9-7.5) than tumour stage or nodal status. The use of FAC-T chemotherapy varied substantially among the seven geographic regions, from 20% in rural Grisons-Glarus to 73% in Zurich.Tumour biology is a predominant factor for choosing FAC-T over older chemotherapy regimens in patients with ER-negative early BC, but improvements should be made to reduce the substantial regional heterogeneity. Further epidemiological studies should assess how the use of FAC-T chemotherapy is affecting clinical outcome in patients with early BC and different risk profiles.

AIM: To investigate feasibility, morbidity and surgical mortality of a docetaxel-based chemotherapy regimen randomly administered before or after gastrectomy in patients suffering from locally-advanced resectable gastric cancer. METHODS: Patients suffering from locally-advanced (T3-4 any N M0 or any T N1-3 M0) gastric carcinoma, staged with endoscopic ultrasound, bone scan, computed tomography, and laparoscopy, were assigned to receive four 21 d/cycles of TCF (docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2) per day for days 1-14), either before (Arm A) or after (Arm B) gastrectomy. Operative morbidity, overall mortality, and severe adverse events were compared by intention-to-treat analysis. RESULTS: From November 1999 to November 2005, 70 patients were treated. After preoperative TCF (Arm A), thirty-two (94%) resections were performed, 85% of which were R0. Pathological response was complete in 4 patients (11.7%), and partial in 18 (55%). No surgical mortality and 28.5% morbidity rate were observed, similar to those of immediate surgery arm (P = 0.86). Serious chemotherapy adverse events tended to be more frequent in arm B (23% vs 11%, P = 0.07), with a single death per arm. CONCLUSION: Surgery following docetaxel-based chemotherapy was safe and with similar morbidity to immediate surgery in patients with locally-advanced resectable gastric carcinoma.

Introduction. Taxane/platinum combinations exhibit synergistic cytotoxicity and activity against a broad range of solid tumours. We sought to optimise the regimen as a suitable outpatient palliative treatment for cancer of unknown primary (CUP). Patients and methods. Eligible CUP patients with adenocarcinoma or poorly differentiated carcinoma, performance status of 0-2, adequate organ function and assessable disease were treated with docetaxel 75 mg/m2 and carboplatin at an area under the concentration time-curve (AUC) of 5, both as 30-minute intravenous infusions, every three weeks. Patients with isolated axillary adenopathy, squamous cell cervical or inguinal adenopathy and PSA or germ-cell serum tumour markers were excluded. Results. Forty-seven patients entered the trial, 24 with predominantly nodal disease or non-mucinous peritoneal carcinomatosis (favourable risk) and 23 with visceral metastases (unfavourable risk). A median of 6 cycles of chemotherapy were administered, with relative dose intensities of both drugs >90%. Response rates were 32% (46% in favourable risk, 17% in unfavourable), comparable to the activity of paclitaxel/platinum regimes, though complete remissions were seen only in favourable risk patients. Granulocyte-colony stimulating factor support was used in a third of treatment cycles. Toxicity was mild and manageable, with grade 3-4 neutropenia in 26% of patients, febrile neutropenia in 7% and severe non-hematologic side-effects in less than 8% of patients. No toxic deaths or severe neurotoxicity were seen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 16.2 months respectively. Survival was driven mainly by favourable-risk patients (22.6 months), as those with visceral metastases had a poor median survival of only 5.3 months. Good performance status and low-volume disease predicted for superior outcome, while docetaxel relative dose-intensity was a positive prognosticator only in favourable-risk patients. Conclusions. One-hour docetaxel/carboplatin is a convenient, safe and effective outpatient palliative treatment for CUP patients, providing meaningful survival prolongation only in favourable-risk patients. Insights in the molecular biology of CUP are needed for the development of targeted therapeutic manipulations of malignant resistance and progression. © 2008 Taylor & Francis. 47 6 1148 1155

Background: Many systemic nonhormonal regimens have been evaluated across several hundreds of randomized trials in advanced breast cancer. We aimed to quantify the relative merits of these regimens in prolonging survival. Methods: We performed a systematic review of all trials that compared different regimens involving chemotherapy and/or targeted therapy in advanced breast cancer (1973-2007). Regimens were categorized a priori into different treatment types. We performed multiple-treatments meta-analysis and calculated hazard ratios for each treatment category relative to monotherapy with old agents (ie, regimens not including anthracyclines, anthracenediones, vinorelbine, gemcitabine, capecitabine, taxanes, marimastat, thalidomide, trastuzumab, lapatinib, or bevacizumab). Results: We identified 370 eligible randomized trials (54 189 patients), of which 172 (31 552 patients) compared different types of treatment. Survival data from 148 comparisons pertaining to 128 of the 172 trials (26 031 patients, 22 different types of treatment) were available for inclusion in the multiple-treatments meta-analysis. Compared with single-agent chemotherapy with old nonanthracycline drugs, anthracycline regimens achieved 22%-33% relative risk reductions in mortality (ie, hazard ratio [HR] for standard-dose anthracycline-based combination: 0.67, 95% credibility interval [CrI] 0.57-0.78). Several newer regimens achieved further benefits (eg, HR [95% CrI] 0.67 [0.55-0.81] for single-drug taxane, 0.64 [0.53-0.78] for combination of anthracyclines with taxane, 0.49 [0.37-0.67] for taxane-based combination with capecitabine or gemcitabine), and similar benefits were seen with several regimens including molecular targeted treatments. Most regimens had very similar efficacy profiles (

Purpose This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy. Patients and Methods Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status ≤ 1, and adequate hematologic, hepatic, and renal function randomly received ≤ eight 3-weekly cycles of ECF (epirubicin 50 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and fluorouracil [FU] 200 mg/m2/d on days 1 to 21), TC (docetaxel initially 85 mg/m2 on day 1 [later reduced to 75 mg/m2 as a result of toxicity] and cisplatin 75 mg/m2 on day 1), or TCF (TC plus FU 300 mg/m2/d on days 1 to 14). Study objectives included response (primary), survival, toxicity, and quality of life (QOL). Results ORR was 25.0% (95% CI, 13% to 41%) for ECF, 18.5% (95% CI, 9% to 34%) for TC, and 36.6% (95% CI, 23% to 53%) for TCF (n = 119). Median overall survival times were 8.3, 11.0, and 10.4 months for ECF, TC, and TCF, respectively. Toxicity was acceptable, with one toxic death (TC arm). Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel (TC, 49%; TCF, 57%; ECF, 34%). Global health status/QOL substantially improved with ECF and remained similar to baseline with both docetaxel regimens. Conclusion Time to response and ORR favor TCF over TC for further evaluation, particularly in the neoadjuvant setting. A trend towards increased myelosuppression and infectious complications with TCF versus TC or ECF was observed.

INTRODUCTION: This study evaluated the prognostic role of vascular epidermal growth factor (VEGF), thymidylate synthase (TS), topoisomerase I (Topo-I), topoisomerase IIalpha (Topo-IIalpha) and E-cadherin (E-cadh) tumor expression, in patients with resectable gastric cancer, who were treated postoperatively with the docetaxel/irinotecan combination. PATIENTS AND METHODS: Forty-five patients with resectable gastric cancer were treated with 6 cycles of docetaxel 30 mg/m2 and irinotecan 110 m/m2 on day 1 and d8 every 21 days. All specimens were examined by using immunohistochemistry (IHC) for the expression of VEGF, TS, Topo-I, Topo-IIalpha and E-cadh. RESULTS: Positivity for TS was significantly correlated with age and for VEGF with diffuse histological type and good PS. No significant correlation was observed among Topo-I, Topo-IIalpha and E-cadh positivity with any of the clinicopathological parameters studied. Median overall survival (OS) was 31.7, and disease-free survival (DFS) 26 months, respectively. None of the above-investigated molecular markers were significantly associated with OS and DFS. Finally, according to the univariate analysis for survival, only advanced stages (III, IV) of the disease implied risk of death, mainly due to lymph node involvement and, to a lesser extent, tumor size. None of the studied molecular markers were found to be independent prognostic markers. CONCLUSION: These results should be interpreted very cautiously, due to the limited number of patients studied, as well as the limitations of the IHC technique. Anticancer Res

Carcinoma of unknown primary (CUP) is characterized by dismal patient survival. The outcome of patients with two favourable risk CUP subsets was studied. Eighty patients diagnosed with either midline lymph node metastases (n =33) or peritoneal carcinomatosis (n = 47) were analysed retrospectively. The majority had poorly differentiated adenocarcinoma or undifferentiated carcinoma, treated with platinum-taxane based chemotherapy from 1996 till 2002. Females with peritoneal carcinomatosis also underwent surgical debulking. Objective tumour regression was present in 44% of patients (nodal group 30% versus peritoneal group 53%, p=0.066). Complete responses were seen more often in peritoneal carcinomatosis patients (nodal group 9%, peritoneal group 36%, p = 0.008). At a median follow up of 60 months, median progression-free and overall survival were 5 and 10 months respectively in the nodal group, 7 and 15 months in the peritoneal group. Five-year survival was 7% (nodal group 0% vs. peritoneal group 10%, p = 0.05). Complete responders fared better than non-CR patients. Fewer than four metastatic sites, elevated CA 125, and normal CA 19-9 levels were favourable prognostic factors for survival. Modern combination chemotherapy has satisfactory activity, with a minority of CUP patients enjoying long-term responses. Research efforts towards complete remission consolidation and molecular profiling are imperative. © 2005 Taylor & Francis. 44 2 155 160

BACKGROUND: A phase I-II multicenter trial was conducted to define the maximum tolerated dose (MTD) according to tolerance and toxicity (primary objective), as well as to describe the clinical activity, in terms of response and survival (secondary objectives), of a combination of 5-fluorouracil (5-FU) in protracted continuous intravenous infusion (p.i.v.) with docetaxel and cisplatin for patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with measurable unresectable and/or metastatic gastric carcinoma, World Health Organization performance status < or =1, normal hematological and renal functions, adequate hepatic function and not pretreated for advanced disease by chemotherapy, received up to eight cycles of a combination of docetaxel on day 1, cisplatin on day 1 and 5-FU p.i.v. on days 1-14 (TCF) every 3 weeks, which was escalated up to the MTD, defined by the occurrence of dose-limiting toxicity in two patients in one dose level. RESULTS: Fifty-two patients were accrued and treated (43 in the phase I part of the trial and nine additional at the recommended dose level). A median of five cycles/patient was given. The recommended dose of TCF was docetaxel 85 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1 and 5-FU p.i.v. 300 mg/m(2)/day on days 1-14. Grade > or =3 toxicities were neutropenia 79%, alopecia 46%, fatigue 23%, mucositis 10%, diarrhea 19%, nausea/vomiting 13%, neurological 4% and palmar-plantar 2%. Ten non-fatal febrile neutropenia episodes were recorded in eight patients. There were no treatment-related deaths. Among 41 patients with measurable disease (79%), we observed one complete and 20 partial responses for an overall intent-to-treat response rate of 51% (95% confidence interval 35-67%). Five patients (20%) had stable disease for > or =12 weeks (four cycles). The median overall survival was 9.3 months. CONCLUSIONS: 5-FU p.i.v. at 300 mg/m(2)/day for 2 weeks out of three could be safely added to the docetaxel-cisplatin (TC) combination, but the dose of docetaxel had to be reduced to 75 mg/m(2) in a subsequent phase II trial. This drug regimen seems to be very active in advanced gastric cancer. Comparison with both TC and ECF in a randomized SAKK trial is ongoing.