Clinical outcomes of oral metronomic vinorelbine in advanced non-small cell lung cancer: correlations with pharmacokinetics and MDR1 polymorphisms.

PURPOSE: This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms. METHODS: Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20-30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints. RESULTS: Median OS and treatment duration were 27 weeks (range 1.3-183) and 15 weeks (range 1.3-144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r2 = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r2 = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3-4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms. CONCLUSIONS: Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.

Oral Metronomic Vinorelbine (OMV) in elderly or pretreated patients with advanced non small cell lung cancer: outcome and pharmacokinetics in the real world.

Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit.

Age affects pegylated liposomal doxorubicin elimination and tolerability in patients over 70 years old.

PURPOSE: Pegylated liposomal doxorubicin (PLD) is often used in elderly people, due to its improved tolerability. However, clinical and pharmacological data in the subset of patients over 70 are scanty. METHODS: PLD safety was evaluated in 35 patients (aged ≥70 years) who were treated with PLD as a single agent for 165 cycles. Doxorubicin plasma levels, leukocyte DNA breaks and monocyte count variations were measured as markers of drug exposure, DNA repair capability and reticuloendothelial system activation, respectively. A correlation between these markers and age was sought. RESULTS: Treatment was generally well tolerated. Skin erythrodysesthesia was the most frequent side effect, and no severe (G4) toxicity occurred. PLD plasma half-life generally correlated with age (P < 0.001) and was particularly prolonged in octogenarians (P = 0.005). Doxorubicin clearance significantly declined up to 70 % at cycle 7. DNA breaks increased over the first two cycles (P = 0.007) and were inversely correlated with age (P = 0.007) and directly with clearance (P = 0.006). Pre-treatment monocyte counts increased over cycles (P < 0.001) and were associated with an increase in clearance at cycle 3 (P = 0.015). The hand-foot-skin syndrome was significantly more severe in patients of advanced age or longer PLD half-life. CONCLUSIONS: This study showed (1) increased systemic drug exposure over subsequent cycles; (2) association of age with increased drug exposure, reduced DNA repair capability and worse skin toxicity; (3) a relation between monocyte count and drug clearance.

Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours.

AIM: Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance. METHODS: Forty-seven patients received GEM 1000-1250mgm(-2) i.v. over 30min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA. RESULTS: Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration-time curve from time 0 to infinity (AUC(0,∞)) (r(2) = 0.77). CONCLUSIONS: Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time.

18F-FDG-PET/CT in patients with breast cancer and rising Ca 15-3 with negative conventional imaging: a multicentre study.

OBJECTIVES: Breast cancer is the second cause of death in women in Europe and North America. The mortality of this disease can be reduced with effective therapy and regular follow up to detect early recurrence. Tumor markers are sensitive in detecting recurrent or residual disease but imaging is required to customize the therapeutic option. Rising tumor markers and negative conventional imaging (US, X-mammography, CT and MR) poses a management problem. Our aim is to assess the role of 18F-FDG-PET/CT in the management of post-therapy patients with rising markers but negative conventional imaging. MATERIALS AND METHODS: In the period from January 2008 to September 2009, 89 female patients with breast cancer who developed post-therapy rising markers (serum Ca 15-3 levels=64.8±16.3 U/mL) but negative clinical examination and conventional imaging were investigated with 18F-FDG-PET/CT. RESULTS: Tumor deposits were detected in 40/89 patients in chest wall, internal mammary nodes, lungs, liver and skeleton. The mean SUVmax value calculated in these lesions was 6.6±1.7 (range 3.1-12.8). In 23/40 patients solitary small lesion were amenable to radical therapy. In 7 out of these 23 patients a complete disease remission lasting more than 1 year was observed. CONCLUSIONS: 18F-FDG-PET/CT may have a potential role in asymptomatic patients with rising markers and negative conventional imaging. Our findings agree with other studies in promoting regular investigations such as tumor markers and 18F-FDG-PET/CT rather than awaiting the developments of physical symptoms as suggested by current guidelines since the timely detection of early recurrence may have a major impact on therapy and survival.

The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery.

PURPOSE: In patients with locally advanced rectal cancer (LARC) staging and, after preoperative chemo-radiation therapy (CRT), restaging workup could be useful to tailor therapeutic approaches. Fluorine-18-fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a promising tool for monitoring the effect of antitumor therapy. This study was aimed to evaluate the possible role of dual time sequential FDG-PET scans in the staging and restaging workup of LARC. METHODS AND MATERIALS: Eighty-seven consecutive patients with LARC were enrolled. CRT consisted of external-beam intensified radiotherapy (concurrent boost), with concomitant chemotherapy PVI 5-FU (300 mg/m(2)/day) followed 8-10 weeks later by surgery. All patients underwent [(18)F]FDG-PET/CT before and 5-6 weeks later after the completion of CRT. Measurements of FDG uptake (SUV(max)), and percentage of SUV(max) difference (Response Index = RI) between pre- and post-CRT [(18)F]FDG-PET scans were evaluated. RESULTS: Six of 87 patients were excluded due to protocol deviation. Following CRT, 40/81 patients (49%) were classified as responders according to Mandard's criteria (TRG1-2). The mean pre-CRT SUV(max) was significantly higher than post-CRT (15.8, vs 5.9; p < 0.001). The mean RI was significantly higher in responders than in nonresponder patients (71.3% vs 38%; p = 0.0038). Using a RI cut-off of 65% for defining response to therapy, the following parameters have been obtained: 84.5% sensitivity, 80% specificity, 81.4% positive predictive value, 84.2% negative predictive value, and 81% overall accuracy. CONCLUSION: These results suggest the potential role of [(18)F]FDG-PET in the restaging workup after preoperative CRT in LARC. RI seems the best predictor to identify CRT response.

Sequential FDG-PET/CT reliably predicts response of locally advanced rectal cancer to neo-adjuvant chemo-radiation therapy.

PURPOSE: Prediction of rectal cancer response to preoperative, neo-adjuvant chemo-radiation therapy (CRT) provides the opportunity to identify patients in whom a major response is expected and who may therefore benefit from alternative surgical approaches. Traditional morphological imaging techniques are effective in defining tumour extension in the initial diagnostic and staging work-up, but perform poorly in distinguishing residual neoplastic tissue from scarring post CRT, when restaging the patient before surgery. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) is a promising tool for monitoring the effect of anti-tumour therapy. The aim of this study was to prospectively assess the value of sequential FDG-PET scans in predicting the response of locally advanced rectal cancer to neo-adjuvant CRT. METHODS: Forty-four consecutive patients with locally advanced (cT3-4) primary rectal cancer and four patients with pelvic recurrence of rectal cancer were enrolled in this prospective study. Treatment consisted of external beam intensified radiotherapy (50 Gy to the posterior pelvis, 56 Gy to the tumour), chemotherapy (in most cases PVI 5-FU at 300 mg/m(2) per day) and, 8-10 weeks later, surgery with curative intent. All patients underwent FDG-PET/CT both before CRT and 5-6 weeks after completing CRT. One patient died before surgery because of acute myocardial infarction, and was therefore excluded from further analysis. Semi-quantitative measurements of FDG uptake (SUV(max)), absolute difference (DeltaSUV(max)) and percent SUV(max) difference (Response Index, RI) between pre- and post-CRT PET scans were considered. Results were correlated with pathological response, assessed both by histopathological staging of the surgical specimens (pTNM) and by the tumour regression grade (TRG) according to Mandard's criteria (patients with TRG1-2 being defined as responders and patients with TRG3-5 as non-responders). RESULTS: Following neo-adjuvant CRT, of the 45 patients submitted to surgery, 23 (51.1%) were classified as responders according to Mandard's criteria (8 TRG1 and 15 TRG2), while the remaining 22 (48.9%) were non-responders (9 TRG3 and 13 TRG4-5). Considering all patients, the mean pre-CRT SUV(max) was 15.6, significantly higher than the mean value of 5.4 post CRT (p < 0.001). Nevertheless, when stratifying patients according to response to CRT (using Mandard's criteria), the mean RI was significantly higher in responders than in non-responders (75.9% versus 46.9%,p = 0.0015). Using a 66.2% SUV(max) decrease as the cut-off value (identified by ROC analysis) for defining response to therapy, the following parameters were obtained: 79.2% specificity, 81.2% sensitivity, 77% positive predictive value, 89% negative predictive value and 80% overall accuracy. CONCLUSION: The results suggest the potential utility of FDG-PET as a complementary diagnostic and prognostic procedure in the assessment of neo-adjuvant CRT response of locally advanced rectal cancer. DeltaSUV(max) and RI seem the best predictors of CRT response.

Long-term prognostic value of 18F-FDG PET in patients with locally advanced rectal cancer previously treated with neoadjuvant radiochemotherapy.

OBJECTIVE: The purpose of this study was to assess the prognostic value of (18)F-FDG PET performed at restaging in patients with locally advanced rectal cancer who previously underwent neoadjuvant radiochemotherapy. SUBJECTS AND METHODS: Eighty-eight patients with histologically proven rectal cancer classified at clinical TNM stages II and III were enrolled. Six weeks after radiochemotherapy completion, all patients were restaged by sonography, CT, MRI, endoscopy, and (18)F-FDG PET. Surgery was performed in all patients within 8-9 weeks from completion of radiochemotherapy. Median follow-up after surgery was 38 months (range, 6-66 months). RESULTS: The 5-year overall survival and disease-free survival were 83% and 73%, respectively. Cox multivariate analysis showed that only two parameters at restaging were independent prognostic predictors of both overall survival and disease-free survival: pathologic stage and, especially, after radiochemotherapy (18)F-FDG PET findings. The 5-year overall survival was 91% in patients with a negative PET after radiochemotherapy versus 72% in those with a positive PET (p = 0.024) after radiochemotherapy, whereas disease-free survival was 81% and 62% (p = 0.003) for those with the negative and positive PET findings, respectively. Statistical data were further enhanced when combining the pathologic stage with the (18)F-FDG PET results: 95% 5-year overall survival in the PET-negative pathologic stages 0 and I patients versus 70% in PET-positive pathologic stages II-IV patients (p = 0.001), whereas disease-free survival was 93% and 65% (p = 0.0003) for the negative and positive PETs, respectively. CONCLUSION: In patients with locally advanced rectal cancer previously treated with neoadjuvant radiochemotherapy, the combined evaluation of pathologic stage and after-radiochemotherapy (18)F-FDG PET at restaging identified a subgroup of patients characterized by good response to radiochemotherapy and a more favorable prognosis. In these patients, a conservative surgical approach might be considered.

Additional value of hybrid PET/CT fusion imaging vs. conventional CT scan alone in the staging and management of patients with malignant pleural mesothelioma.

BACKGROUND: Despite being a relatively rare disease, the incidence of malignant pleural mesothelioma (MPM) is expected to increase over the next two decades due to the long time interval elapsing between exposure to causative factors, mainly asbestos, and disease onset. Early disease stages have been reported to benefit from radical surgery. In more advanced disease stages, a multimodality treatment, including various combinations of chemotherapy, external radiotherapy and surgery, may provide some favourable results though the prognosis remains poor. In this regard, an accurate pre-treatment staging plays an important role in offering patients a more appropriate therapeutic planning. In some preliminary studies, (18)F-FDG PET has proven to be able to provide useful information for staging purpose, especially for the detection of metastatic spread to lymph nodes and distant sites. MATERIAL AND METHODS: In the present study, we investigated 15 consecutive patients with histologically proven MPM by means of conventional 2-mm thickness whole-body CT scan with and without contrast medium in comparison with wholebody (18)F-FDG PET/CT fusion imaging. RESULTS: (18)F-FDG PET/CT did not provide additional information about the primary tumour (T) compared to CT scan, but identified a higher number of metastatic mediastinal lymph nodes (N) in 6 patients (40% of cases) and unknown metastatic disease to distant sites (M) in 3 patients (20% of cases). On the basis of PET/CT findings, treatment planning was changed in 5 patients (33.3% of cases). CONCLUSIONS: Our data show that (18)F-FDG PET/CT fusion imaging can play a relevant role in the staging and treatment planning of MPM patients.

Restaging after neoadjuvant chemoradiotherapy for rectal adenocarcinoma: role of F18-FDG PET.

Multimodality treatment of loco-regional advanced rectal cancer has demonstrated to improve local control and overall survival. Proctoscopy, digital rectal examination (DRE), computer tomography (CT), endorectal ultrasound (ERUS), and magnetic resonance imaging (MRI) cannot correctly detect downstaging in rectal tumors after chemo radiation therapy (CRT). New imaging techniques, like 18F-FDG PET, may play some role in predicting the pathologic response to CRT before surgical resection. Aim of the present study was to further investigate the accuracy and predictive value of 18F-FDG PET in a large series of patients with rectal cancer treated with preoperative intensified CRT. Between January 2000 and December 2003, 81 patients with histologically proven adenocarcinoma in clinical stage II-III disease, according to criteria of TNM classification, were included in this study. All patients were submitted to diagnostic staging workup with DRE, proctoscopy with biopsy, ERUS, CT scan of the abdomen and pelvis or pelvic MRI plus liver ultrasonography, coloscopy or barium colonic enema. One month later the end of CRT all patients were submitted to diagnostic restaging work-up (DRW) and 18F-FDG PET. Surgery was performed 8-9 weeks after the end of CRT and pathologic stage was defined. Moreover a pathologic assessment of tumor regression was made with tumor regression grade score (TRG). PET correctly identified 22/28 (79% specificity) patients with complete pathologic response (pCR). However, sensitivity was 45% (24/53) while PPV, and NPV were equal to 77 and 43%, respectively. Total PET accuracy rate was 56%. PET sensitivity increased from 45 to 56% if the end-point was pCR, or TRG score, respectively. The best correlation was found between PET findings and pathologic stage (P <0.01) or TRG score (P <0.01). The accurate identification of rectal cancer patients with major pathological response after preoperative CRT further supports the necessity of designing prospective studies with new and more accurate was imaging technologies with the main object of offering conservative treatment in responder patients.

Bioimpedance vector pattern in cancer patients without disease versus locally advanced or disseminated disease.

OBJECTIVE: Bioelectrical impedance vector analysis allows non-invasive evaluation of soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements. METHODS: Whole-body impedance measurements were made with a single frequency (50 kHz) analyzer (BIA-101, Akern/RJL Systems) in 148 adult, white, male subjects 45 to 85 y old: 56 healthy control subjects, 31 cancer patients after surgical procedure (without disease), and 61 patients with locally advanced (30 patients) or disseminated (31 patients) disease with the same body mass index and age. All patients were free from antineoplastic treatment and active nutritional intervention. RESULTS: Mean vectors of cancer groups without disease and locally advance disease versus the control group were characterized by a comparable normalized resistance component with a reduced reactance component (separate 95% confidence limits, P < 0.05), indicating a comparable ionic conduction (hydration) with loss of dielectric mass (cell membranes and tissue interfaces) of soft tissues. Overlapping 95% confidence limits of their mean vectors indicated comparable electrical tissue properties in less versus more advanced disease. CONCLUSION: Monitoring vector displacement trajectory toward the reference target vector position may represent useful feedback in support therapy planning of individual patients.