Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. MATERIAL AND METHODS: TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. RESULTS: From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was <1%. CONCLUSIONS: The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov, registration number: NCT0064660.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Live concerts reduce cancer inpatients' anxiety.

In Italy a new experience of music medicine called "The Music Givers" is spreading among Oncology Units; it aims to organise weekly live concerts (length 45-60 min) followed by a buffet. Purpose of the present study is to evaluate the effect of the format of The Music Givers on cancer in-patients' anxiety. State-Trait Anxiety Inventory (STAI-Y) was administered to 111 in-patients before and after the concerts. After the concerts we observed a 3.87 point decrease in state anxiety (p < .001) and statistically significant differences in most of the domains assessed by STAI-Y. These results invite a reflection on the importance of offering to inpatients events such as live music concerts, in order to improve their psychological condition during hospitalisation.

Phase III trial comparing 3-6 months of adjuvant FOLFOX4/XELOX in stage II-III colon cancer: safety and compliance in the TOSCA trial.

BACKGROUND: Six months of oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. A shorter duration of therapy, if equally efficacious, would be advantageous for patients and Health-Care Systems. PATIENTS AND METHODS: TOSCA ['Randomized trial investigating the role of FOLFOX-4 or XELOX (3 versus 6 months) regimen duration and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer] is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months (arm 3 m) versus 6 months (arm 6 m) of FOLFOX4/XELOX. Primary end-point was relapse-free survival. We present here safety and compliance data. RESULTS: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Treatment completion rate without any modification was 35% versus 12% and with delays or dose reduction 52% versus 44% in arm 3 and 6 m. Treatment was permanently discontinued in 8% (arm 3 m) and 33% (arm 6 m). In arm 6 m, 50% of patients discontinuing treatment did so after completing 80% of planned program. Grade 3+ toxicities were higher in arm 6 m than that in 3 m. Grade 2+ neuropathy was 31.2% versus 8.8% (P < 0.0001) while grade 3+ was 8.4 versus 1.3 (P < 0.0001), in arm 3 and 6 m. Seven deaths within 30 days from last treatment administration in arm 6 m and three deaths in arm 3 m were observed (0.3% versus 0.1%, P = 0.34). CONCLUSIONS: TOSCA is the first trial comparing 3 versus 6 months of adjuvant chemotherapy completing accrual within the international initiative of treatment duration evaluation (International Duration Evaluation of Adjuvant, IDEA). High compliance to treatment in control arm will allow a correct assessment of potential differences between the two treatment durations. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT00646607.

Complementary needs behind complementary therapies in cancer patients.

OBJECTIVE: Although many studies indicate that the use of complementary and alternative medicine by cancer patients is common and widespread, few studies have focused on unmet needs of patients using complementary therapies (CTs). The aim of the present study was to evaluate, through a quantitative approach, possible associations between the use of CTs and the presence of specific unmet needs in cancer patients. METHODS: In six Italian oncology departments, 783 patients were interviewed about CTs use and completed the Needs Evaluation Questionnaire. Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. RESULTS: At the time of the survey, 38.3% of patients were using one or more types of CTs. According to Needs Evaluation Questionnaire, the use of CTs was associated (p < .05) with the need to be more involved in therapeutic choices (40% vs. 31.7%), the need to have a better dialogue with clinicians (44.4% vs. 37.2%), and the need to have more economic-insurance information in relation to their illness (46.1% vs. 36.4%). Statistical significance was confirmed with multivariable analysis for the last two items, whereas three more needs were associated with the use of CTs after adjustment: to receive more explanation on treatments (46.8% vs. 41.0%), to receive more comprehensible information (38% vs. 31.9%), and to receive more attention from nurses (16% vs. 12.1%). CONCLUSIONS: Our study shows interesting differences regarding perceived needs between cancer patients who use and who do not use CTs. Unmet needs that are more expressed in CTs users should be known and, when possible, could be taken into account to improve both psychosocial interventions in the context of conventional care process and the quality of the relationship between patient and medical and nursing staff.

Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study.

BACKGROUND: Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is up-regulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001-everolimus-in patients with BTC progressing after prior chemotherapy. PATIENTS AND METHODS: This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in eight sites in Italy. Patients with locally advanced, metastatic or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary end points were disease control rate (DCR) and objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS) and time-to-progression (TTP). RESULTS: Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. The median (95% confidence interval) PFS was 3.2 (1.8-4.0) months, and the median OS was 7.7 (5.5-13.2) months. The median TTP was 2.0 (1.7-3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events. CONCLUSION: Everolimus demonstrated a favourable toxicity profile and encouraging anti-tumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC. EUDRACT 2008-007152-94.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.

BACKGROUND: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01640782.

Breast metastases from oligodendroglioma: an unusual extraneural spread in two young women and a review of the literature.

BACKGROUND: Extraneural dissemination of oligodendroglioma is rare. Cases of breast metastases have never been described in the literature. CASE REPORTS: We report the first two cases of young women with initial diagnosis of anaplastic oligodendroglioma who experienced mammary gland metastases and a review of the literature. RESULTS: Immunohistochemical analysis performed on material from both primary and metastatic sites did not allow to draw any conclusion on possible etiopathogenetic hypothesis. A review of literature yielded 35 cases of extracranial metastatic oligodendroglioma from 1989 to 2012. CONCLUSION: Though rare, extracranial dissemination from oligodendroglioma may occur not only in long surviving heavily pre-treated patients. The review of literature and these two cases suggest that spread is primarily to bone and then from bone to other organs through hematogenous route mostly due to leptomeningeal or dura mater invasion. Chemotherapy regimens similar to those commonly used for non metastatic oligodendroglioma are recommended for patients with good performance status.

Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is an emerging treatment for patients with locally advanced pancreatic carcinoma, and can be combined with radiochemotherapy and intra-arterial plus systemic chemotherapy. METHODS: This observational study compared two groups of patients with locally advanced pancreatic carcinoma treated with either primary RFA (group 1) or RFA following any other primary treatment (group 2). RESULTS: Between February 2007 and May 2010, 107 consecutive patients were treated with RFA. There were 47 patients in group 1 and 60 in group 2. Median overall survival was 25·6 months. Median overall survival was significantly shorter in group 1 than in group 2 (14·7 versus 25·6 months; P = 0·004) Patients treated with RFA, radiochemotherapy and intra-arterial plus systemic chemotherapy (triple-approach strategy) had a median overall survival of 34·0 months. CONCLUSION: RFA after alternative primary treatment was associated with prolonged survival. This was further extended by use of a triple-approach strategy in selected patients. Further evaluation of this approach seems warranted.

Low dose fractionated cisplatin plus gemcitabine for elderly patients with advanced non small cell lung cancer: a retrospective analysis.

The aim of the study was to evaluate safety and efficacy of gemcitabine-cisplatin in elderly patients with advanced non small cell lung cancer (NSCLC). This study included 59 patients aged >70 years consecutively admitted to our Department. treatment consisted of gemcitabine 1000 mg/m(2) on days 1 and 8, and low-dose fractionated cisplatin 20 mg/m(2) on days 1, 2, 3 of a 21-day cycle. Toxicity was graded according to the world Health Organization (WHO) criteria.A total of 281 cycles was administered. Hematological toxicities of grade 3 and 4 were seen in 17% and 5% of patients, respectively. Grade 3 gastrointestinal toxicity was 3%, grade 2 neuropathy was 2%. Twenty-nine partial responses with an objective response rate of 49% were obtained. No complete responses were observed. The median progression-free survival (PFS) and overall survival (OS) were 7.8 and 15.5 months respectively. Cisplatin-based combination chemotherapy at low doses appears to be safe and active in older patients with advanced NSCLC.

A multi-centre retrospective review of second-line therapy in advanced pancreatic adenocarcinoma.

INTRODUCTION: Limited information on second-line treatment in patients with pancreatic adenocarcinoma is available. At time of first-line treatment failure, approximately half of the patients are candidates for further treatment. MATERIAL AND METHODS: A retrospective review of 183 patients submitted to second-line therapy has been performed to identify prognostic factors, provides useful information for patients counseling and generates hypotheses for future studies. Inclusion criteria were: cytological or histologic diagnosis of pancreatic adenocarcinoma and prior gemcitabine-including chemotherapy. Any age, performance status (PS) and chemotherapy regimen were considered. RESULTS: One hundred and eighty-three patients (106 males; 168 metastatic; median age 62 years; median PS 1; 63 submitted to prior curative surgery, 32 to prior radiotherapy) with a median previous progression-free survival (PFS) of 6.7 months were included. Median and 6-month PFS after initiation of salvage therapy were 3.0 months and 20%. Median, 1 and 2 years, overall survival after initiation of salvage therapy were 6.2 months, 17 and 4%, respectively. Previous PFS, CA19.9 levels and age independently predicted OS. CONCLUSION: Re-challenge with gemcitabine and 5-fluorouracil administration may have a role in selected patients.

Hypoxic abdominal stop-flow perfusion in the treatment of advanced pancreatic cancer: a phase II evaluation/trial.

In the past decade, some authors have reported objective responses and prolonged median survival times using hypoxic abdominal perfusion (HAP) for the treatment of advanced pancreatic cancer. However, these promising results have not been confirmed by others, making it difficult to define the effectiveness of this loco-regional chemotherapy. The aim of this study, therefore, was to evaluate the response rate, time to disease progression and overall survival following HAP treatment of 22 consecutive patients with advanced pancreatic tumors. Within the period from 1999 to 2003, 22 patients with histological diagnosis of unresectable stage III/IV pancreatic cancer, not responsive to systemic chemotherapy, were treated with mitomycin C 30mg/m(2) and cisplatin 60mg/m(2) by HAP (stop flow technique). Immediately after perfusion, hemofiltration was performed to reduce systemic side toxic effects. Responses were assessed by CT-scan 30days from the end of treatment. Minor or partial responses were confirmed by a second CT-scan 4weeks later. Following 26 treatment cycles no death or technical complications were recorded; four patients (18.2%) achieved a partial response, 2 (9.1%) a minimal response and 13 (59.1%) stable disease. The remaining 3 patients (13.6%) showed progression of the disease. The median time to disease progression was 3 months (range 1-10). The median survival time from the start of regional chemotherapy was 6 months (range 1.9-16), with a 1-year survival rate of 9%. Our data show that HAP is a relatively effective second-line treatment for advanced stage pancreatic cancer with a low complication rate. We do not concur with the opinion of others that HAP is an inactive treatment approach. However, taking into account the invasiveness of this procedure, and associated morbidity and cost, HAP would not appear to be preferable to less invasive loco-regional chemotherapeutic alternatives.

Comparison of incidence of sepsis in cancer patients that underwent systemic or loco-regional chemotherapy.

In this retrospective non controlled trial we evaluated the incidence of sepsis in cancer patients in two different periods (January-June 2003 versus January-June 2004). The main difference in these two periods was that in our oncology department we changed from systemic chemotherapy to loco-regional chemotherapy using less myelosuppressive drugs and developed the domiciliary assistance. The aim of the study was to assess the incidence of sepsis in order to demonstrate a reduction of the infection related to the change of chemotherapy. In addition, this study may be able to describe the epidemiology of sepsis in cancer patients afferent to our oncology department. The incidence of sepsis was reduced in the second period from 24.3% to 6.2%. The pathogens more frequently isolated in this study were coagulase-negative staphylococci (CNS) followed by Escherichia coli and Staphylococcus aureus. Less invasive therapy may reduce infective complication of chemotherapy. The epidemiology of sepsis may be very helpful to design empiric therapeutic protocol for febrile patients that have received chemotherapy.

Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer.

OBJECTIVES: This study evaluated the clinical activity and toxicity of combination chemotherapy with irinotecan and oxaliplatin in patients with advanced pancreatic cancer that had progressed despite > or =1 course of a gemcitabine-containing regimen. METHODS: Thirty patients with metastatic pancreatic cancer and Karnofsky performance status > or =70 received oxaliplatin 60 mg/m2 on days 1 + 15 and irinotecan 60 mg/m2 on days 1 + 8 + 15 every 4 weeks. Patients were assessed on the basis of clinical benefit response, changes in serum tumour marker CA 19-9, objective tumour response, time to progressive disease (TTP), and survival. RESULTS: Six patients (20%) had clinical benefit response (median duration of 7.2 months). CA 19-9 levels were reduced > or =50% from baseline in 8 patients (26%) and remained stable in 8 patients. CT scans revealed that 3 patients (10%) had a partial response and 7 (23%) had stable disease. Two patients (7%) were down-staged and underwent surgery. Median TTP was 4.1 months, median survival was 5.9 months and the 1-year survival rate was 23.3%. The most serious adverse events were grade 3-4 leukopenia in 2 patients (6%), grade 3 neuropathy in 2 (6%) and grade 3 diarrhoea in 1 (3%). CONCLUSION: Chemotherapy with irinotecan and oxaliplatin is an active and well-tolerated combination in patients with advanced pre-treated pancreatic cancer.

Intra-arterial hepatic chemoembolization in liver metastases from neuroendocrine tumors: a phase II study.

Neuroendocrine tumors, particularly those of gastrointestinal tract origin, have a predisposition for metastasizing to the liver, causing parenchymal substitution and paraneoplastic syndrome. Lipiodol embolization combined with anticancer drugs is a recent tool in regional therapy. It has been proven that chemoembolization reduces tumor bulk and hormone levels, and that it palliates the symptoms of many patients with liver-dominant neuroendocrine metastases. Beginning in December 1988, ten patients with unresectable and chemotherapy-refractory liver metastatic neuroendocrine tumors were treated with chemoembolization based on a mixture of lipiodol, mitomycin, cisplatin, epirubicin, followed by gelfoam powder and contrast media. Toxicity encountered included: upper right quadrant pain requiring narcotics, elevation of lactate dehydrogenase, alkaline phosphatase, and transaminases. One patient had liver abscess and persistent fever for 2 weeks. We obtained two complete remissions lasting 12 and 34 months and 5 partial remissions. The median survival was 22 months. Four patients had urinary elevation of 5-hydroxyindolacetic acid (5-HIAA). They showed more than a 75% decrease in urinary secretion after treatment. In a patient with transplanted liver we noticed a partial response lasting 7 months. We conclude that chemoembolization will improve the clinical condition of a significant percentage of patients with liver metastases, that future therapy of carcinoid tumors will be based on specific tumor biology and that treatment will be customized for each individual patient combining the use of cytoreductive procedures including radiofrequency ablation, laser treatment and chemoembolization.