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Introduction Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. Methods MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. Results An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. Conclusion Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. Implications for practice The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.

Background Recent data suggest a potential activity and a good tolerability of capecitabine in advanced hepatocellular carcinoma (HCC). Aims To evaluate capecitabine activity and safety in a wide cohort of advanced HCC patients. Methods Retrospective analysis of 143 capecitabine-treated patients (January 2010 to December 2017) in three centers of the Veneto Oncology Network. Results Capecitabine was administered in second and third line, but also in first line instead of sorafenib in Child-Pugh B patients (70%), compromised clinical conditions (14%) or contraindications to antiangiogenetics (16%). Median overall survival (OS) and time to progression (TTP) were 6.9 and 2.8 months, respectively. There were no differences in OS and TTP between the 32 patients treated with non-metronomic scheme (2000 mg/day for 14 days) and the 111 patients treated with metronomic scheme (1000 mg/day) after correction for prognostic factors at baseline with a propensity score analysis. Capecitabine was more active in patients intolerant to sorafenib than in those progressing during treatment (p = 0.024). At least one adverse event (mainly hematological) was experienced by 73% of patients but discontinuation was necessary only in 11 (8%). Conclusions Capecitabine can be considered an active and safe option in advanced HCC, especially for patients unfit for other treatments.

A large body of biomedical evidence indicates that activation of Nrf2 by curcumin increases the nucleophilic tone and damps inflammation cumulatively supporting the malignant phenotype. Conversely, genetic analyses suggest a possible oncogenic nature of constitutive Nrf2 activation since an increased nucleophilic tone is alleged increasing chemoresistance of cancer cells. Aiming to contribute to solve this paradox, this study addressed the issue of safety and efficacy of curcumin as complementary therapy of gemcitabine on pancreatic cancer. This was a single centre, single arm prospective phase II trial. Patients received gemcitabine and Meriva®, a patented preparation of curcumin complexed with phospholipids. Primary endpoint was response rate, secondary endpoints were progression free survival, overall survival, tolerability and quality of life. Analysis of inflammatory biomarkers was also carried out. Fifty-two consecutive patients were enrolled. Forty-four (13 locally advanced and 31 metastatic) were suitable for primary endpoint evaluation. Median age was 66 years (range 42–87); 42 patients had Eastern Cooperative Oncology Group performance status 0–1. The median number of treatment cycle was 4.5 (range 2–14). We observed 27.3% of response rate and 34.1% of cases with stable disease, totalizing a disease control rate of 61.4%. The median progression free survival and overall survival were 8.4 and 10.2 months, respectively. Higher IL-6 and sCD40L levels before treatment were associated to a worse overall survival (p

Aim: We investigated the behavior of circulating endothelial cells (CEC) in patients with hepatocellular carcinoma (HCC) receiving sorafenib, and whether CEC levels were associated with time to progression (TTP). Materials & methods: CECs in advanced HCC patients receiving sorafenib were counted at baseline and every 4 weeks. Results: Twenty four HCC patients were enrolled in the study. Median TTP was 3.2 months (1–6). Median baseline CEC levels were 67 cells/ml, with an increase of 169.8% after 4 weeks of treatment. Any time CEC levels in patients with a TTP lower than 4 months were higher, but not statistically significant, compared with those in patients with TTP more than 4 months. Conclusion: Treatment with sorafenib changed CEC levels in HCC patients.

Aims and background The aggressiveness of cancer care near the end of life and the consumption of opioids are potential indicators of quality of care in palliative and end-of-life settings. The purpose of this article is to present a retrospective analysis regarding these themes and the adopted procedures to improve quality of care. Methods We evaluated all cancer patients treated and deceased during 2008 and considered those who died and received any antiblastic therapy within 14 and 30 days prior to death. Moreover, we evaluated the annual consumption of pure opioids during 2007 and 2008 in our inpatient clinic. We found that 5% and 9% of all treated patients were still receiving antiblastic treatment near the end of life within respectively 14 and 30 days prior to death (respectively 29.6% and 51.5% of deceased patients). All but 2 patients died from progressive disease, one patient died from acute myocardial infarction during chemotherapy, and one of severe sepsis after chemotherapy for non-Hodgkin lymphoma. As regards the annual consumption of strong opioids, there was a 179% increase in the use of morphine-equivalent doses of oral long-acting opioids (+228% for oxycodone) after the introduction of daily pain measurement through a numerical rating scale. Conclusions To reduce the administration of chemotherapy near the end of life, we introduced the palliative prognostic score, to be administered to all advanced cancer patients with performance status of at least 2. To evaluate the effectiveness of analgesics and to reduce the cases of undertreatment of cancer pain, we adopted, in addition to the numerical rating scale, Cleeland's Pain Management Index. We are convinced that attempts to improve the quality of care can be achieved by the collaboration of all health professionals, patients and care givers.

Background: There is now much data that suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is a multistep process resulting from an ordered set of events and regulated by positive and negative modulators of microvessels growth and by the expression of various proteolytic enzymes. Materials and methods: We prospectively evaluated VEGF and microvessels density on tumor specimen and cytosolic levels of uPA and PAI-1. Results: We enrolled 81 primary breast cancer patients. The median follow-up was 38 months. Using the median value as cutoff for the statistical analysis, we found significant correlation between cytosolic levels of uPA and PAI-1(r=0.61;p

e20676 Background: Elderly and patients with ECOG PS ≥ 2 often present with medical and physiological characteristics that make the selection of their treatment more challenging. Single-agent vinorelbine improves survival and quality of life compared with best supportive care. At constant effectiveness between two treatments formulations patient preference must be taken into account. Methods: Stage IIIB or IV NSCLC patients candidates to receive a first line chemotherapy with Vinorelbine alone due to age ≥ 70 and Eastern Cooperative Oncology Group (ECOG) Performance status ≤2 or age ≤ 70 but ECOG PS ≥ 2, could enter the study. Patients were randomized to receive: • Arm A: first cycle of IV vinorelbine (30 mg/m2) and second cycle of oral vinorelbine (60mg/m2) • Arm B: first cycle of oral vinorelbine followed by a second cycle of IV vinorelbine. In both arms vinorelbine was administered at day 1 and day 8 every 3 weeks. From the third cycle onwards patients had to choose to continue with oral or intravenous vinorelbine. The dosage of oral vinorelbine could be subsequently increased to 80 mg/m2 at physician’s choice. Treatment continued until disease progression, intolerable toxicity or patient refusal. The primary objective of the study was the patient preference for oral or intravenous vinorelbine. Results: Ninety-three patients entered the study and were randomized. Sixty-two were able to complete the first two cycles and to express a preference (32 in Arm A and 30 in Arm B). Forty-five out of 62 were males and 17 females. Median age was 80 (72-89). Nineteen patients had an ECOG PS of 0, 39 a PS of 1 and 4 a PS of 2 (30.7%, 62.9% and 6.4% respectively). Eighteen patients (29%) decided to continue with IV vinorelbine while 44 patients (71%) expressed a preference for oral vinorelbine p = 0.001 (Gart's test). Regarding secondary enpoints, median OS was 5.7 (4.7-7.7) and 5.5 (3.8-9.1) months and median PFS was 3.5 (2.4-4.4) and 3.5 (3.5-5.0) for arm A and arm B respectively. Conclusions: The study has clearly demonstrated that elderly or frail patients with NSCLC prefer to receive an oral rather than an intravenous chemotherapy. The reasons for the choice were expressed in a questionnaire still in evaluation. Clinical trial information: nct01848613.

The aim of the study was to evaluate peripheral blood progenitor cell mobilization by disease-specific chemotherapy in heavily pretreated patients with germ cell tumor (GCT), scheduled for high-dose chemotherapy. Thirty-four consecutive patients, 29 males and five females, with advanced GCT referred to our department for high-dose chemotherapy were evaluated retrospectively. Sixteen patients were mobilized by vinblastine 0.11 mg/kg on days 1 and 2, ifosfamide 1200 mg/m2 days 1-5 and cisplatin 20 mg/m2 days 1-5 (VeIP). In 10 patients, etoposide 75 mg/m2 days 1-5 was used instead of vinblastine (VIP), while in eight patients the mobilization was attempted by administering 7 g/m2 of cyclophosphamide. The choice of either etoposide or vinblastine was predicated upon which of these two drugs was associated with best results during premobilization chemotherapy. Cyclophosphamide was selected in patients refractory to previous cisplatin-based salvage chemotherapy. Twenty-five out of 34 patients underwent a successful PBPC collection. In 17 of them one leukapheresis procedure was sufficient to collect the target number of CD34+ cells, while in eight patients a double procedure was necessary. Altogether 33 aphereses were performed in 25 patients. In nine patients leukapheresis was not attempted. This was due to the fact that the chemotherapy failed to mobilize the target number of CD34+ cells in eight of them, treated with the VeIP mobilizing regimen, while one patient treated with high-dose cyclophosphamide rapidly progressed during therapy and for this reason leukapheresis was not undertaken. In conclusion, in heavily pretreated patients with GCT, PBPC mobilization is feasible by a further course of salvage chemotherapy. The choice of either etoposide (VIP) or vinblastine (VeIP) can be predicated upon which of these two drugs was associated with best results during premobilization chemotherapy. In our hands, VeIP seems to be less satisfactory as mobilizing treatment than VIP, possibly due to a superior number of premobilization courses of chemo therapy in some patients. Moreover, high-dose cyclophosphamide remains a good alternative for mobilizing patients refractory to salvage chemotherapy.

PURPOSE: A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer. PATIENTS AND METHODS: Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m2 on the first day of each course and 5-FU and LV 350 mg/m2 and 20 mg/m2, respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses. RESULTS: Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m2. Reversible neurologic toxicity occurred in 44.4% of patients. CONCLUSION: Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m2 dosage offered improved dose-intensity compared with the initial dosage.

Irinotecan or CPT-11, a new inhibitor of the nuclear enzyme topoisomerase 1, is active in metastatic colorectal cancer (CRC). CPT-11 appeared to be superior to supportive care and continuous infusion of 5-FU in patients with metastatic CRC after failure to 5-FU (1-3). SN-38 is believed to be the active metabolite of CPT-11 and is produced by the enzyme carboxylesterase (4-7). Hepatic metabolism by glicuronidation and subsequent biliary excretion is the most important route of elimination of SN-38 (8-10).

Liver metastases of colorectal cancer is present in more than 20% of new diagnosed patients and in 40-60% of relapsed patients. It is a life-threatening prognostic aspect. Hepatic resection, when possible, is the best therapeutic modality, although the overall survival rate is still low (30%). Angiography and intraoperative ultrasonography are useful for resection. The number of hepatic metastases and the surgical margin are probably the most significant prognostic factors. Colorectal cancer may spread predominantly to the liver making regional treatment strategies viable options. Subtotal hepatic resections and segmentectomies are potentially curable procedures for single or small numbers of hepatic metastases without other sites of disease. However, there have been no prospective randomized trials comparing patients with unresected liver metastases and resected metastases. Regional chemotherapy with floxuridine seems usefull combined with hepatic resection or as palliative therapy. Gastric ulcer and biliary sclerosis are the main related toxicities. Patients with localized, unresectable hepatic metastases or concomitant bad medical condition may be candidates for radiation, percutaneous ethanol injection, cryosurgery, percutaneous radiofrequency, hypoxic flow-stop perfusions with bioreductive alkylating agents, hepatic arterial ligation, embolization and chemoembolization. These new hepatic-directed modalities of treatment are being investigated and may offer new approaches to providing palliation and prolonging survival. This review will report the possibilities of intra-arterial chemotherapy and other novel hepatic-directed approaches to the treatment of liver metastases from colorectal cancer.

Neurotoxicity is a clinically relevant adverse event observed with the use of ifosfamide. It is usually mild, occasionally severe and seldom fatal. Ifosfamide-induced encephalopathy requires interruption of chemotherapy, intravenous hydration and administration of methylene blue. Less is known about the efficacy of methylene blue in avoiding a second episode of ifosfamide-induced encephalopathy while maintaining chemotherapy with ifosfamide. We report a case of a different clinical manifestation of ifosfamide-induced encephalopathy after continued ifosfamide use and despite methylene blue in a patient with retroperitoneal sarcoma.

352 Background: Hepatocellular carcinoma (HCC) from alcoholic cirrhosis, associated or not with chronic hepatitis C virus (HCV) infection, is a particularly severe liver disease. Scanty and inconsistent data concerning the efficacy of sorafenib in patients (pts) with this disease are available. Methods: Since February 2009 we screened 26 Child-Pugh liver function class A pts bearing the above characteristics. Sixteen of them (61.5%), 15 males and 1 female with median age of 69 years (range 54-79), received 400 mg sorafenib b.i.d. Predominant cause of HCC was alcohol consumption in 13 pts (81.2%), associated with chronic HCV infection in 2 pts (12.5%), and hemosiderosis in 1 pt (6.2%). All pts suffered from multiple comorbidities, and 3 had been previously treated for Burkitt lymphoma, bladder and breast cancer. One pt with prostate cancer was on treatment with androgen blockade. Median number of concomitant medications was 4 (range 2-9). Four pts never received locoregional treatment, and none had received previous antineoplastic therapy. Results: Twelve pts (73%) discontinued sorafenib after a median time of 2 months (range 2-6). The reasons for treatment discontinuation were disease progression (4 pts), liver function deterioration (5 pts), and mild gastrointestinal adverse events (2 pts): 1 pt refused sorafenib treatment after 15 days. 2/4 patients still on treatment with sorafenib at 7, 8, 11, and 18 months showed partial response (RECIST criteria). Seven pts (40%) died because of disease progression at a median time of 5.5 months (range 2-9) and at a median overall survival time of 36 months from diagnosis (range 2-84). Conclusions: Treatment with sorafenib in pts affected by HCC and alcoholic cirrhosis seems effective and well tolerated with high-level compliance. The most common cause of discontinuation was progression of disease and liver function deterioration. No significant financial relationships to disclose.