Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

A phase I study of vinflunine in combination with capecitabine in patients with metastatic breast cancer previously treated with anthracyclines and taxanes.

PURPOSE: A phase I study was performed to determine the maximal tolerated dose (MTD), recommended dose (RD), safety and efficacy of vinflunine when combined with capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes, with pharmacokinetic blood sampling to test potential drug-drug interactions. PATIENTS AND METHODS: Sixteen patients with MBC who had received anthracyclines and taxanes in the neo/adjuvant setting, if progression occurred during or within 12 months of chemotherapy completion, and/or as first-line chemotherapy of MBC were enrolled. Vinflunine (VFL) was given on day 1 with capecitabine (CAPE) twice daily from days 1 to 14, every 3 weeks. Three dose levels (DL) were investigated (DL1: VFL 280 mg/m² and CAPE 1,650 mg/m²/day, DL2: VFL 320 mg/m² and CAPE 1,650 mg/m²/day and DL3: VFL 280 mg/m² and CAPE 2,000 mg/m²/day). RESULTS: The RD was established as vinflunine 280 mg/m² on day 1 plus capecitabine 1,650 mg/m²/day on days 1 to 14 given every 3 weeks. Dose-limiting toxicities were grade 4 neutropenia lasting at least 7 days for 2 patients, anorexia with fatigue for 1 patient and diarrhoea with fatigue, anorexia and febrile neutropenia for 1 patient. Neutropenia was the main toxicity of the combination, it was reported in 15 patients (93.8%) with grade 3 in 7 patients (43.8%) and 22.6% of cycles and grade 4 in 7 patients (43.8%) and 19.8% of cycles. Complications were rare with only one patient experiencing febrile neutropenia at DL exceeding the RD. The most frequent non-haematological toxicities were fatigue and gastrointestinal disorders; however, no grade 3 or 4 episode was observed at the RD. Hand-foot syndrome was reported in 5 patients (31.3%) and 22.6% of cycles, no episode of grade 3 was seen. Concerning pharmacokinetics, no modifications were detected for VFL, while slight accumulation between days 1 and 14 was observed for 5-FU formed from CAPE. The risk of clinical significant drug-drug interaction was considered weak. Objective partial responses were reported in 7 patients, yielding a response rate of 43.8% in the all-treated population according to the investigator assessment. CONCLUSIONS: The combination of vinflunine and capecitabine is safe and showed promising antitumour activity in MBC patients who have failed prior anthracyclines and taxanes. Further clinical development of this combination is warranted.

Evaluation of the safety of C-1311 (SYMADEX) administered in a phase 1 dose escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumours.

PURPOSE: C-1311 is a member of the novel imidazoacridinone family of anticancer agents. This phase 1 trial was designed to investigate the safety, tolerability and preliminary anti-tumour activity of C-1311. PATIENTS AND METHODS: This was a phase 1, inter-subject dose escalating and pharmacokinetic study of intravenous (IV) C-1311, administered weekly during 3consecutive weeks followed by 1week rest (constituting 1 cycle) in subjects with advanced solid tumours. RESULTS: Twenty-two (22) patients were treated with C-1311, the highest dose given was 640mg/m(2). All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1-2, except for the blood and lymphatic system disorders, which were primarily of grades 3-4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3weeks every 4weeks is 480mg/m(2), with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7days. Treatment at this dose offers a predictable safety profile and excellent tolerability. CONCLUSION: The safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound.

Lapatinib in metastatic breast cancer.

Lapatinib is an oral, small-molecule, dual kinase inhibitor that targets both HER2 and the EGF receptor. Lapatinib was approved in June 2008 in Europe for the treatment of advanced HER2-positive breast cancer. Promising results in trastuzumab-refractory metastatic breast cancer were obtained from Phase I, II and III studies in combination with chemotherapy. Diarrhea and rash are the most common side-effects and are mostly moderate and treatable. Cardiac toxicity occurs rarely and mostly as an asymptomatic and reversible decrease of left ventricular ejection fraction. Unlike trastuzumab, some data show that lapatinib could cross the blood-brain barrier, with some evidence of activity in treating or preventing brain metastases. Its evaluation is actively ongoing, in combination with trastuzumab and in the adjuvant setting.

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours.

Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m(-2) on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33-69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m(-2), warranting further clinical investigation.

Prognostic impact of syndecan-1 expression in invasive ductal breast carcinomas.

Carcinoma cells lack syndecan-1 expression when they are transiting from an epithelial to a less-differentiated mesenchymal phenotype (epithelial-mesenchymal transition, EMT). Furthermore, a shift of syndecan-1 expression from malignant epithelial cells to reactive stromal cells has also been observed during progression of many carcinomas. Finally, epithelial and/or stromal syndecan-1 expression is of prognostic value in many carcinomas. Because recent results are contradictory in breast carcinomas, we have re-evaluated the prognostic significance of syndecan-1 expression in a cohort of 80 patients with invasive ductal breast carcinomas. The tumours from 80 patients diagnosed with invasive ductal breast carcinomas were used to construct a tissue microarray, which was stained with syndecan-1 by immunohistochemistry. We correlated syndecan-1 expression with clinicopathologic parameters and relapse-free survival (RFS). Exclusive epithelial expression of syndecan-1 is observed in 61.25% of the patients, whereas exclusive stromal expression is observed in 30% of the patients. Only 8.75% of the patients had both stromal and epithelial expressions of syndecan-1. A significant correlation was found between the loss of syndecan-1 epithelial expression and the syndecan-1 stromal expression with high grade of malignancy (P=0.011). The loss of syndecan-1 epithelial expression is correlated with RFS (P=0.001). Using multivariate Cox analysis, loss of epithelial syndecan-1 expression was the only prognostic indicator (P<0.001). We concluded that the loss of syndecan-1 epithelial expression was of strong prognostic value in breast carcinomas.

A rare gynecological case of paraneoplastic cerebellar degeneration discovered by FDG-PET.

BACKGROUND: PET/CT may be particularly useful to detect the primary cancer in paraneoplastic cerebellar degeneration (PCD) with anti-Yo which is most commonly associated with breast, ovarian and other gynecological cancers. CASE: A 60-year-old woman developed a PCD associated with anti-Yo antibodies in serum and cerebrospinal fluid. Conventional imaging was negative. FDG-PET showed an abnormal hot spot in the right ovarian area associated with lombo aortic lymph nodes. The diagnosis was confirmed by surgery as an ovarian adenocarcinoma. CONCLUSION: In this case report, FDG-PET played a crucial role in detecting the unknown primary tumor in a patient with PCD.

Phase I dose-escalation study of a novel antitumor agent, SR271425, administered intravenously in split doses (d1-d2-d3) in patients with refractory solid tumors.

BACKGROUND: SR271425 is a novel DNA-binding cytotoxic agent with a broad spectrum of antitumor activity in preclinical models,across a variety of the schedule of administration. In toxicological studies, it has been reported to prolong QTc proportionally to C (max). In order to circumvent this C (max)-related QTc prolongation, 5 phase I studies were initiated to investigate 1-h, 24-h, weekly, and split iv infusions. This phase I study assessed a split-dose regimen (a 1-h infusion on each of Days 1 to 3, repeated every 3 weeks) to establish the dose limiting toxicities (DLT), to recommended a phase II dose, and to characterize PK/PD. METHODS: Patient with advanced solid tumors, adequate bone marrow, hepatic, renal function and on specific cardiac criteria were eligible and "3 + 3" design was used for dose escalation. That dose escalation was guided by PK data, toxicities observed and information from other ongoing phase I studies with SR271425. SR271425 plasma levels (PK samples) were measured using a validated LC-MS/MS method. Careful monitoring of ECGs was done, and ECGs were read centrally. RESULTS: Three centers enrolled 19 heavily pretreated patients to six dose levels, from 75 to 450 mg/m(2)/day (i.e., 225-1,350 mg/m(2)/cycle): 12 males and 7 females. Median age 56. Median ECOG, PS = 1. Main tumor types were brain, breast, gynecological, and urological. Patients received a median of 2 cycles (range: 1-6). NCI-CTC Grade 1-2 toxicities included nausea, vomiting, asthenia, rash, and yellow skin discoloration. No DLTs were reported, and there were no dose-limiting prolongations of QTc. Both C (end) and AUC increased in a dose-related manner, with no evidence of accumulation between Day 1 and Day 3, consistent with the mean (+/-SD) terminal elimination half-life of 5.11 +/- 1.21 h. Stable disease was observed in five cases. CONCLUSION: Split doses allow high cumulative exposure to SR271425 without significant toxicity, especially without QTc prolongation. MTD was not reached due to the early termination of the SR271425 program by the sponsor.

Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy.

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m(-2) q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9-43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2-7.2), median progression-free survival was 3.7 months (95% CI: 2.8-4.2) and median overall survival was 14.3 months (95% CI: 9.2-19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease.

Brown fat in breast cancer patients: analysis of serial (18)F-FDG PET/CT scans.

PURPOSE: It has recently been suggested that FDG accumulation in the brown adipose tissue varies as a function of age, sex and outdoor temperature. The aim of this study was to assess changes in FDG uptake in brown fat in patients based on serial PET/CT scans and to compare our results with previous findings. METHODS: Early response to neoadjuvant chemotherapy in 33 female breast cancer patients was assessed by FDG PET. Five PET/CT scans were performed for each patient. PET/CT images were analysed retrospectively. PET scans were considered positive when diffuse, symmetrical, abnormal "USA" (uptake in supraclavicular area) fat was detected. RESULTS: A total of 163 PET images were analysed. Seventy-four PET scans (45%) revealed abnormal FDG uptake in the supraclavicular area. These foci were present on uncorrected and attenuation-corrected images. FDG uptake was identical on all five scans in only five patients. No significant relationship was found between abnormal FDG uptake and outdoor temperature, age or time interval between chemotherapy and PET. Abnormal FDG uptake in the neck seemed to predominantly occur in patients with a low body mass index (p<0.05). Most significant changes in the PET/CT scan results were observed during chemotherapy with docetaxel (p<0.05). When observed, bilateral uptake in the neck was more intense than background uptake (p<0.00001). CONCLUSION: This study shows that FDG uptake in the neck varies as a function of time, that it is unrelated to age or outdoor temperature, and that bilateral uptake is generally intense.