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Background: CirCe01 trial aimed to assess the clinical utility of circulating tumour cell (CTC)-based monitoring in metastatic breast cancer (MBC) patients beyond the third line of chemotherapy (LC)., Methods: CirCe01 was a prospective, multicentre, randomised trial (NCT01349842) that included patients with MBC after two systemic LC. Patients with ≥5 CTC/7.5 mL (CellSearch®) were randomised between the CTC-driven and the standard arm. In the CTC arm, changes in CTC count were assessed at the first cycle of each LC; patients in whom CTC levels predicted early tumour progression had to switch to a subsequent LC., Results: Greater than or equal to 5 CTC/7.5 mL were observed in N = 101/204 patients. In the CTC arm (N = 51), 43 (83%) and 18 (44%) patients completed CTC monitoring in the third and fourth lines, respectively, and 18 (42%) and 11 (61%) of these patients, respectively, had no CTC response. Thirteen (72%) and 5 (46%) of these patients underwent early switch to the next LC. Overall survival was not different between the two arms (hazard ratio = 0.95, 95% confidence interval = [0.6;1.4], p = 0.8). In subgroup analyses, patients with no CTC response who switched chemotherapy experienced longer survival than patients who did not., Conclusions: Due to the limited accrual and compliance, this trial failed to demonstrate the clinical utility of CTC monitoring., Clinical Trial Registration: NCT, NCT01349842, https://clinicaltrials.gov/ct2/show/NCT01349842 , registered 9 May 2011.

Background: According to international guidelines, endocrine therapy (ET) is the preferred option for hormone receptor-positive (HR+) HER2-negative (HER2-) metastatic breast cancer. In spite of clear recommendations, these are not strictly followed in daily practice. The objectives of this study were to investigate the effect of the first anti-metastatic treatment therapy choice on progression-free survival (PFS) and overall survival (OS)., Methods: In this population-based study, we included patients with HR+/HER2- metastatic breast cancer recorded in the Côte d'Or Breast Cancer Registry. Differences in PFS and OS between patients initially treated with chemotherapy (CT) or ET were analysed in Cox proportional hazards models. In a sensitivity analysis, we used a propensity score (PS) to limit the indication bias., Results: Altogether, 557 cases were included, 280 received initial ET and 277 received initial CT. PFS and OS in patients initially treated with ET was improved significantly when compared to patients with initial CT (respectively, HR = 0.83 (95% CI 0.69-0.99) and HR = 0.71 (95% CI 0.58-0.86)). The results of the sensitivity analysis supported these findings., Conclusion: This study shows that treating patients with HR+/HER2- metastatic breast cancer with initial ET could provide a survival advantage in comparison with initial CT.

Purpose: Tumour-infiltrating lymphocyte (TIL) detection by histology is associated with outcomes in breast cancer; nevertheless, analysis standardisation is difficult. We determined whether transcriptomic data could generate a genomic signature that estimated TIL infiltrates and determined patient prognosis in localised breast cancer., Experimental Design: Using 1928 transcriptomic profiles of pure cells, we generated a genetic signature specific to lymphocyte, myeloid, stromal and cancer cells. We then computed a score based on this signature and tested the association between the score and the TILs estimated for patients in an adjuvant setting from public and private data sets. We tested the capacity of the transcriptomic RNA TIL score to predict disease-free survival (DFS) or overall survival (OS) through multivariate Cox models adjusted for classical clinical variables and PAM50 molecular classification in two public data sets (Carte d'Identité des Tumeurs [CIT], n = 530; Metabric, n = 1832)., Results: A high RNA TIL score was significantly associated with the presence of a high level of TILs as assessed by histology. The score was also associated with DFS and OS in multivariate Cox models adjusted for molecular and clinical variables (CIT: OS hazard ratio [HR] = 0.15 [0.04, 0.61], p-value = 0.007; DFS: 0.27 [0.08, 0.8] p-value = 0.02; Metabric: OS HR = 0.87 [0.77, 0.97], p-value = 0.01). The association between the RNA TIL score and survival was tested by univariate analysis in each molecular subgroup; the RNA TIL score was associated with survival only in basal-like tumours., Conclusions: Determination of the TIL rate using a transcriptomic signature is feasible and has a high prognostic value in patients with basal-like tumours in an adjuvant setting., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Cisplatin-based combination chemotherapy is the standard treatment of advanced urinary tract cancer (aUTC), but 50% of patients are ineligible for cisplatin according to recently published criteria. We used a multinational database to study patterns of chemotherapy utilization in patients with aUTC and determine their impact on survival., Patients and Methods: This was a retrospective study of patients with: UTC (bladder, renal pelvis, ureter or urethra); advanced disease (stages T4b and/or N+ and/or M+); urothelial, squamous or adenocarcinoma histology. Primary objective was overall survival (OS). Eligibility-for-cisplatin was defined by Eastern Cooperative Oncology Group performance status ≤ 1, creatinine clearance ≥ 60 ml/min, no hearing loss, no neuropathy and no heart failure. Cox regression multivariate analyses were used to establish independent associations of cisplatin versus noncisplatin-based chemotherapy on OS., Results: 1794 patients treated between 2000 and 2013 at 29 centers were analyzed. Median follow-up was 29.1 months. About 1333 patients (74%) received first-line chemotherapy: the use of first-line chemotherapy was associated with longer OS: [hazard ratio (HR): 1.91, 95% confidence interval (CI): 1.67-2.20]. Type of first-line chemotherapy received was: cisplatin-based 669 (50%), carboplatin-based 399 (30%) and other 265 (20%). Cisplatin use was an independent favorable prognostic factor (HR: 1.54, 95% CI: 1.35-1.77). This benefit was independent of baseline characteristics or comorbidities but was associated with eligibility-for-cisplatin: eligible patients treated with cisplatin lived longer than those who were not (HR: 1.74, 95% CI: 1.36-2.21), while such benefit was not observed among ineligible patients. About 26% of patients who did not receive cisplatin were eligible for this agent. Median OS of ineligible patients was poor irrespective of the chemotherapy used., Conclusions: The importance of applying published criteria of eligibility-for-cisplatin was confirmed in a multinational, real-world setting in aUTC. The reasons for deviations from these criteria set targets to improve adherence. Effective therapies for cisplatin-ineligible patients are needed.

Background: This phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy., Patients and Methods: Patients were randomly assigned (1 : 1) to receive tasquinimod (0.25-1.0 mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire and analgesic use. Quality of life was measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and by the EuroQol-5 Dimension Quality of Life Instrument (EQ-5D). Adverse events were recorded., Results: A total of 219 patients were screened and 144 patients randomized. The median duration of treatment was 18.7 weeks (range 0.6-102.7 weeks) for the tasquinimod arm and 19.2 weeks (range 0.4-80.0 weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3-53.7) and 22.7 (16.1-25.9) weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4-0.9), P = 0.0162]. The median OS was not reached because only 14 deaths occurred by the cut-off date. No statistically significant differences between treatment arms were noted for symptomatic PFS, PFS 2, BPI score, FACT-P score, or EQ-5D. The incidence of any treatment emergent adverse event (TEAE) was similar in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3-5) incidence was higher in the tasquinimod group (50.7% versus 27.1%)., Conclusions: Randomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate-resistant prostate cancer. Maintenance tasquinimod therapy significantly reduced the risk of rPFS by 40%., Clinicaltrials: gov identifier NCT01732549., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients., Objective: To develop a new model based on real-world patients., Design, Setting, and Participants: Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011., Intervention: First-line, platinum-based, combination chemotherapy., Outcome Measurements and Statistical Analysis: The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms., Results and Limitations: A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670)., Conclusions: We developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC., Patient Summary: We proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer., Methods: We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab., Results: Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis., Conclusion: Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab., (© 2016 by American Society of Clinical Oncology.)

Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan-based chemotherapy increases the incidence of grade 3-4 diarrhea. We performed systematic colonic biopsies in three patients with grade 3 diarrhea after introduction of fluorouracil, leucovorin, irinotecan and aflibercept treatment for mCRC. For each patient, the diarrhea necessitated treatment discontinuation. Colonoscopy showed normal colonic mucosa. However, histopathological examination of the biopsies performed in these three patients revealed typical features of microscopic colitis. All three patients were treated with budesonide and mesalazine, leading to rapid regression of clinical symptoms. Chemotherapy was reintroduced in all patients, with only mild, grade 1 diarrhea under mesalazine and budesonide treatment. These are the first observations of aflibercept-induced microscopic colitis, and support the use of specific treatment on top of anti-diarrheal treatment in case of important digestive adverse events.

Background: Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting., Methods: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC., Results: In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48)., Conclusions: Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice., (© 2015 American Cancer Society.)

Purpose: Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and second-line metastatic colorectal cancer (mCRC). However, to date, there is no current biomarker predictive for the benefit of bevacizumab use for these patients. Preclinical data suggest that the presence of the primary tumor could be involved in less efficient antitumor activity of antiangiogenic agents, but no clinical data currently support this hypothesis., Methods: We performed a retrospective analysis of factors associated with overall survival (OS) in a study cohort of 409 mCRC patients. Univariate and multivariate Cox proportional hazard regression models were used to assess the influence of primary tumor resection and bevacizumab use on OS. We evaluated associations linking bevacizumab use and OS among patients who previously underwent or did not undergo primary tumor resection. Results were externally validated in a second independent cohort of 328 mCRC patients., Results: In the study cohort, bevacizumab use and resection of the primary tumor were associated with improved OS. However, subgroup analyses indicate that bevacizumab did not influence survival of patients bearing a primary colorectal tumor (hazard ratio (HR) 0.98, 95 % confidence interval (CI) 0.60-1.61, log-rank test P = 0.6). By contrast, the survival benefit of bevacizumab was restricted to patients who previously underwent primary tumor resection (HR 0.71, 95 % CI 0.55-0.92, P = 0.009). Similar results were observed in the validation cohort., Conclusions: Addition of bevacizumab to chemotherapy is associated with improvement of OS only in patients with primary tumor resection. These data support the rationale to validate prospectively the influence of primary tumor resection on bevacizumab antitumor effect in synchronous mCRC.

Background: To examine the association between baseline body mass index (BMI), and disease-free survival (DFS) and overall survival (OS) in a large French early-stage breast cancer population included in the UNICANCER Programme d'Action Concerté Sein-01 (PACS01) and PACS04 phase III randomised trials., Methods: After a median follow-up of 5.9years, this report analyses 4996 patients with node-positive breast cancer, and randomly assigned to adjuvant anthracycline-based chemotherapy combined or not with taxanes. Univariate analyses were used to study the effects of well known prognostic factors and BMI on DFS and OS. BMI was obtained at baseline, before chemotherapy initiation, and obesity was defined as a BMI⩾30kg/m(2). Cox proportional hazards regression models were secondly used to assess the influence of BMI after adjusting for other factors. Exhaustive analysis of the dose intensity delivered was also studied for comparison between obese and non-obese patients., Results: Obese patients initially present with more advanced disease at diagnosis compared to non-obese patients. By univariate analysis, obesity was moderately associated with poorer DFS (hazard ratio (HR)=1.18 [1.01-1.39] P=0.04), but mostly with poorer OS (HR=1.38 [1.13-1.69] P=0.002). Delivered dose intensity of anthracyclines and taxanes was not significantly different between obese and non-obese patients. After adjustment for disease characteristics, BMI had no influence either on DFS or OS., Conclusion: This report suggests that in a French population, obesity has no impact on breast cancer prognosis when modern adjuvant chemotherapy, at the appropriate dose intensity, is delivered., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Recently, follicle stimulating hormone receptor was found to be selectively expressed by endothelial cells on tumor-associated blood vessels in a wide range of human cancers. In this context, we hypothesized that degarelix, a new gonadotropin-releasing hormone receptor antagonist developed for patients with prostate cancer, may have antiangiogenic effects via its capacity to block follicle stimulating hormone (FSH) production. We report the case of a patient with metastatic colon cancer exhibiting tumor progression after failure of all conventional chemotherapeutic regimens. The addition of degarelix to the last chemotherapeutic regimen was proposed as compassionate treatment. Degarelix induced a rapid decrease in FSH level. This treatment induced radiological stabilization and carcinoembryonic antigen stabilization during 1 year. Contrast-enhanced ultrasonography demonstrated reduction of tumor vasculature. This case represents the first report of an antitumoral effect of degarelix in metastatic colon cancer and suggests an antiangiogenic property of this drug.

Background: The aim of this study was to evaluate the efficacy and tolerability of hepatic arterial infusion (HAI) of gemcitabine plus oxaliplatin as second-line treatment for unresectable locally advanced intrahepatic cholangiocarcinoma., Patients and Methods: We retrospectively analyzed the outcome of 12 consecutive patients with unresectable locally advanced intrahepatic cholangiocarcinoma treated with HAI of gemcitabine (1,000 mg/m(2) over 30 min) followed by oxaliplatin (100 mg/m(2) over 2 h), which was repeated every 2 weeks., Results: All patients presented with disease limited to the liver and all had failed at least one line of chemotherapy with gemcitabine and oxaliplatin. The best tumor responses using RECIST criteria were partial responses in 8 patients and stable disease in 3 patients for at least 3 months; in 1 patient, disease progressed, resulting in a disease control rate of 91% (95% CI 45-100%). The median overall survival and time to progression were 9.1 months (95% CI 4.9-8.1) and 20.3 months (95% CI 13.2-49.7), respectively. Partial responses enabled R0 liver surgery in 2 patients and stereotactic radiation therapy in 3 patients. Grade 3/4 toxicities included neutropenia in 2 patients, thrombocytopenia in 2 patients, and oxaliplatin allergy in 2 patients., Conclusions: HAI combining gemcitabine and oxaliplatin showed promising efficacy and safety as second-line treatment for locally advanced intrahepatic cholangiocarcinoma.

Background: The optimal chemotherapeutic regimen suitable for metastatic colorectal cancer (mCRC) patients previously treated with 5-fluorouracil (5FU), oxaliplatin, irinotecan and biotherapies remains an unresolved issue. The aim of this study was to evaluate the activity of bevacizumab combined with FOLFIRI-3 in mCRC after failure of prior chemotherapy including fluoropyrimidine, irinotecan and oxaliplatin., Methods: Patients were treated with bevacizumab in combination with FOLFIRI-3 every 14 days. The association between treatment efficacy and visceral fat area as measured by CT scan or Carcinoembryonic Antigen (CEA) change after 2 months was also studied., Results: Forty-nine consecutive patients were treated. Four hundred and twenty four cycles of chemotherapy were delivered. Median follow-up was 11 months. Eleven patients (22.4%) had an objective partial response and 26 (53.1%) were stabilized. Median progression-free survival (PFS) and overall survival (OS) were 7 and 13 months respectively. Four grade 4 adverse events occurred (1 digestive perforation, 1 rectal ulcer, 1 pulmonary embolism, and 1 febrile aplasia) but no toxic death was observed. Grade 3 adverse events occurred in 18 patients (38%) including asthenia in 15 patients (30%), nausea and vomiting in 4 patients (8%), diarrhea in 11 patients (22%), anemia in 4 patients (8%), neutropenia in 10 patients (20%) and thrombopenia in 4 patients (8%). Visceral Fat area was significantly lower in responder patients. CEA change at 2 months predicted improved overall survival., Conclusion: This study suggests that bevacizumab combined with FOLFIRI3 may be active in mCRC patients after failure of all classical lines of chemotherapy.

Background: The usual treatments for pleural malignancies are mostly palliative. In contrast, peritoneal malignancies are often treated with a curative intent by cytoreductive surgery and intraperitoneal chemotherapy. As pressure has been shown to increase antitumor efficacy, we applied the concept of high-pressure intracavitary chemotherapy to the pleural space in a swine model., Methods: Cisplatin and gemcitabine were selected because of their antineoplasic efficacy in vitro in a wide spectrum of cancer cell lines. The pleural cavity of 21 pigs was filled with saline solution; haemodynamic and respiratory parameters were monitored. The pressure was increased to 15-25 cm H2O. This treatment was associated with pneumonectomy in 6 pigs. Five pigs were treated with chemotherapy under pressure., Results: The combination of gemcitabine (100 mg/l) and cisplatin (30 mg/l) was highly cytotoxic in vitro. The maximum tolerated pressure was 20 cm H20, due to haemodynamic failure. Pneumonectomy was not tolerated, either before or after pleural infusion. Five pigs survived intrapleural chemotherapy associating gemcitabine and cisplatin with 20 cm H2O pressure for 60 min., Conclusions: High-pressure intrapleural chemotherapy is feasible in pigs. Further experiments will establish the pharmacokinetics and determine whether the benefit already shown in the peritoneum is also obtained in the pleura.

Background: There are currently no internationally agreed recommendations for the management of adjuvant chemotherapy in women aged >70 years with high-risk breast cancer. The purpose of this study was to assess the feasibility and the tolerance of adjuvant weekly sequential epirubicin-paclitaxel combination in this setting., Patients and Methods: From 2005 to 2009, 59 women over 70 years of age with operable breast cancer and who required adjuvant chemotherapy were proposed weekly sequential epirubicin-paclitaxel chemotherapy schedule, and were prospectively registered. Compliance and treatment tolerance were studied. We also report preliminary results of disease-free survival (DFS) and overall survival (OS)., Results: Weekly sequential epirubicin-paclitaxel was well tolerated. No grade 4 adverse event occurred. No secondary malignancy was observed. Compliance with chemotherapy was good: 95% of patients received the six planned cycles. After a median follow-up of 24 months, median DFS and OS were not reached, there were only three relapses, and two cancer-related deaths were reported., Conclusion: This study conducted in patients over 70 years of age demonstrates the feasibility of weekly adjuvant chemotherapy including anthracyclines and taxanes in a sequential schedule. This regimen is safe in terms of hematologic, nonhematologic, and cardiac toxicities, and showed encouraging efficacy, justifying further studies in geriatric patients., (Copyright © 2011. Published by Elsevier Inc.)

Background: In HER2-overexpressing breast cancer, accumulating preclinical evidences suggest that some chemotherapies, like trastuzumab, but also taxanes, are able to trigger a T helper 1 (Th1) anticancer immune response that contribute to treatment success. T helper 1 immune response is characterised by the expression of the transcription factor T-bet in CD4 T lymphocytes. We hypothesised that the presence of such T cells in the tumour immune infiltrates following neoadjuvant chemotherapy would predict patient survival., Methods: In a series of 102 consecutive HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy incorporating antracyclines or taxane and trastuzumab, we studied by immunohistochemistry the peritumoral lymphoid infiltration by T-bet+ lymphocytes before and after chemotherapy in both treatment groups. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS)., Results: Fifty-eight patients have been treated with trastuzumab-taxane and 44 patients with anthracyclines-based neoadjuvant chemotherapy. The presence of T-bet+ lymphocytes in peritumoral lymphoid structures after chemotherapy was significantly more frequent in patients treated with trastuzumab-taxane (P=0.0008). After a median follow-up of 40 months, the presence of T-bet+ lymphocytes after neoadjuvant chemotherapy confers significantly better RFS (log-rank test P=0.011) only in patients treated with trastuzumab-taxane. In this population, multivariate Cox regression model showed that only the presence of T-bet+ lymphocytes in peritumoral lymphoid structures after neoadjuvant chemotherapy was independently associated with improved RFS (P=0.04)., Conclusion: These findings indicate that the tumour infiltration by T-bet+ Th1 lymphocytes following neoadjuvant trastuzumab-taxane may represent a new independent prognostic factor of improved outcome in HER2-overexpressing breast carcinoma.

Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. However, the predictive value of tumour-infiltrating lymphocytes after neoadjuvant chemotherapy for breast cancer remains unknown. We hypothesized that the nature of the immune infiltrate following neoadjuvant chemotherapy would predict patient survival. In a series of 111 consecutive HER2- and a series of 51 non-HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy, we studied by immunohistochemistry tumour infiltration by FOXP3 and CD8 T lymphocytes before and after chemotherapy. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS) and overall survival (OS). A predictive scoring system using American Joint Committee on Cancer (AJCC) pathological staging and immunological markers was created. Association of high CD8 and low FOXP3 cell infiltrates after chemotherapy was significantly associated with improved RFS (p = 0.02) and OS (p = 0.002), and outperformed classical predictive factors in multivariate analysis. A combined score associating CD8/FOXP3 ratio and pathological AJCC staging isolated a subgroup of patients with a long-term overall survival of 100%. Importantly, this score also identified patients with a favourable prognosis in an independent cohort of HER2-negative breast cancer patients. These results suggest that immunological CD8 and FOXP3 cell infiltrate after treatment is an independent predictive factor of survival in breast cancer patients treated with neoadjuvant chemotherapy and provides new insights into the role of the immune milieu and cancer., (Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: There is currently no standard of treatment for patients with hormone refractory prostate cancer (HRPC) after failure of docetaxel-based chemotherapy. The purpose of this study was to assess the anticancer activity and tolerance of metronomic cyclophosphamide prednisolone combination in this setting., Patients and Methods: From 2005 to 2010, patients with HRPC who failed at least docetaxel-based chemotherapy were proposed metronomic cyclophosphamide-prednisolone regimen, and were prospectively registered. Twenty-three patients received 50 mg cyclophosphamide and 10 mg prednisolone per os daily until disease progression. Treatment tolerance and efficacy on PSA decrease and pain were studied., Results: Metronomic cyclophosphamide prednisolone was safe, well tolerated, and demonstrated interesting clinical activity, yielding a prostate specific antigen decrease by ≥50% in 26% of patients and decrease by ≥30% in 48% of patients, but also favorable palliative effects on pain in 43% of patients. The median progression-free survival was 6 months (95% CI: 4-8 months) and the median overall survival was 11 months (95% CI: 7-19 months)., Conclusion: For this patient population, low dose metronomic cyclophosphamide prednisolone might be a viable alternative. Its convenient oral administration, low cost, and lack of toxicity justify further studies alone, or in combination with other agents in HRPC patients.

The aim of this study was to evaluate the efficacy and safety of combined hepatic arterial infusion (HAI), which is a combination of raltitrexed and oxaliplatin, in refractory colorectal carcinoma with only liver metastases. Seventeen consecutive patients with unresectable metastatic colorectal cancer, after the failure of two lines of systemic chemotherapy, were treated with HAI raltitrexed (3 mg/m over 1 h) followed by oxaliplatin (130 mg/m over 2 h) every 3 weeks between January 2006 and January 2009. All patients presented with the metastatic disease limited to the liver and had failed at least two lines of chemotherapy, which contained oxaliplatin, irinotecan and a fluoropyrimidine. The median number of cycles was six (range 1-15). We observed three complete responses and eight partial responses among assessable patients (overall response rate in intention to treat, 65%; 95% confidence interval, 44.3-87.7%). The median time to progression was 10.5 months and the median survival time was 27.5 months. Toxicity included grade 3-4 neutropenia (in 17%), grade 3-4 thrombopenia (in 17%), and grade 2 abdominal pain (in 47%). In conclusion, the combination regimen of HAI raltitrexed and oxaliplatin is feasible and promising in patients who presented isolated hepatic metastases of colorectal cancer after failure of irinotecan and oxaliplatin treatment. Further evaluation of this combination is required.

Hepatic arterial infusion (HAI) of chemotherapy can be performed in cases of liver-confined metastatic disease, resulting in increased local drug concentrations. Here we report the case of a 61-year-old man who presented with an isolated large unresectable liver metastasis of colon cancer after failure of surgery and multiple administration of systemic chemotherapy. The patient was treated with a combination of gemcitabine and oxaliplatin using HAI. The tolerance was excellent and a radiological complete response was obtained after 8 cycles of HAI. The rationale for the use of gemcitabine and oxaliplatin as well as that for the combination of the 2 drugs is discussed in this paper. HAI of gemcitabine-oxaliplatin should be evaluated in further clinical trials.

Aim: To evaluate the efficacy and the safety of combined 5-Fluorouracil, irinotecan, bevacizumab and sirolimus in refractory advanced colorectal carcinoma., Methods: We initiated a regimen with at day 1 an injection (iv) of bevacizumab at 5 mg/kg, followed by 180 mg/m(2) irinotecan, followed by Leucovorin 400 mg/m(2), followed by a 5-Fluorouracil bolus 400 mg/m(2); and a 46-h infusion 2400 mg/m(2). Sirolimus was given orally as continuous administration of 2 mg twice a day every days. This treatment was repeated every 14 d., Results: A total of 12 patients were enrolled. All patients presented with metastatic disease that had failed at least three lines of chemotherapy that contained oxaliplatin, irinotecan and bevacizumab. Cetuximab failure was also observed in all K-Ras wild-type patients. The median number of cycles was 8.5 (range 2-20) and clinical benefit was observed in eight patients. The median time to progression was 5 mo and the median survival was 8 mo. Grade 3 neutropenia developed in four patients, and grade 3 diarrhea and stomatitis in two., Conclusion: The combination regimen of 5-Fluorouracil, irinotecan, bevacizumab and sirolimus in advanced colorectal carcinoma after failure of classical treatment is feasible and promising. Further evaluation of this combination is required.