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Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment., Highlights • Combination of chemotherapy plus anti HER-2 agents is the standard treatment of HER-2 positive breast cancer. • Combination of trastuzumab and metronomic chemotherapy is an alternative therapeutic approach. • Metronomic therapy allows long-term administration of drugs. • Mild toxicity in advanced breast cancer is desirable.

Aim: We report the outcomes observed with nivolumab in metastatic renal cell carcinoma patients with poor prognostic features enrolled in the Italian expanded access program. Patients & methods: Nivolumab was available for patients who relapsed after at least one prior systemic treatment in the advanced or metastatic setting. Results: Of 389 patients, 32 (8%) had brain metastasis, 129 (33%) had liver and 193 (50%) had bone metastasis. These subpopulations achieved a disease control rate of 53, 45 and 47%, respectively. Fifty-one patients had G4 tumor, and they showed 23% objective response rate. The safety profile of the subgroups was in line with the expanded access program population. No new safety signals were reported. Conclusion: Patients with poor prognostic features may derive relevant benefits from nivolumab.

Background:The expanded access “BALLET” study has been designed toevaluate the safety of EVE plus EXE combination in hormone receptor-positive (HR+), human epidermal growth factor-receptor-2-negative (HER2-) metastatic Breast Cancer (mBC). The Italian population was predominantly enrolled in trial. Patients and methods: Patients has been included according to the inclusion and exclusion criteria provided previously in the BALLET study. The aim of our analysis was the safety everolimus and exemestane analysed in two sets of population: a subpopulation including only patients who never received chemotherapy in metastatic setting (416 patients – 36.1% of the safety population) and a subpopulation including only patients who received at least one chemotherapy in metastatic setting, whatever the line of treatment (735 patients – 63.9%). Results:One thousand two hundred seventy nine (1279) Italian female patients were screened, 1153 (90.1% of the screened set) out of these were included in the analysis and 1151 (90.0% of the screened set) were included in the safety population. 1116 (97.0% of the safety population) prematurely discontinued the study drug and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%) and adverse event(s) (16.1%). The mean duration of study treatment exposure was 158.3±106.79 days (median 139.5) for exemestane and 153.9±108.48 days (median 135.0) for everolimus with a treatment compliance (higher than 90%) of 94.4% and 58.6% and (lower than 60%) of 0.1% and 15.1% for exemestane and everolimus, respectively. 92.5% of patients of the safety population (91.1% and . 93.3% patients without and with chemotherapy respectively) experienced at least one adverse event: gastrointestinal disorders” (67.3% vs. 64.6% in without and with chemo group); general disorders (48.6% vs. 48.3%); metabolism and nutrition disorders (35.6% vs. 37.4%) and skin and subcutaneous tissue disorders (32.2% vs. 27.5%). The incidence of everolimus related adverse events was higher (83.9%) when compared to those which occurred with exemestane. The most commonly reported adverse event was stomatitis (51.3% of patients) with 22.5% Grade 1; 18.2% Grade 2; 10.5% Grade 3; 0.2% Grade 4. The 49.7% of the patients experienced at least one stomatitis related to everolimus. No relevant difference was observed between the two groups of patients without and with chemo in metastatic setting. Conclusions: The administration of chemotherapy before starting EVE plus EXE combination did not affect the safety profile of EXE/EVE in the treatment of mBC. The stomatitis is the most frequent and relevant adverse event to be clinically focused on. Citation Format: Generali D, Bordonaro R, Febbraro A, Madoffa A, Romito S, Michelotti A, Savastano C, Mariani G, Tondini C, Piovano P, Iona MT, Bighin C, Roviello G, Ascione G, Goffredo F, Sartori D, Frassoldati A, Simoncini E. Safety of the combination of everolimus plus exemestane in the Italian cohort of patients enrolled in the expanded access “BALLET” study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-17.

Background The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. Methods The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. Results A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P P P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). Conclusions The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment. Trial registration EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

BACKGROUND: Everolimus, an mTOR inhibitor, in combination with exemestane is approved for hormone receptor (HR) positive advanced breast cancer (ABC), after failure of treatment with non-steroidal aromatase inhibitor (NSAI). We assessed the toxicity of the combination and the correlation between dose intensity and response to therapy, in a real world population of ABC from 11 Italian centers. Moreover, we evaluated OS of the whole population, RR and PFS according to line of treatment (from 1rd to 3th and from 4th on). METHODS: 154 pts were treated with combination of everolimus 10 mg and exemestane 25 mg daily from 05/2011 today. Median age was 62 (47-82). Median time to metastatic disease was 49 months (0-269). Median number of metastatic sites was 2 (55.2% of pts visceral versus 44.8% non visceral disease). N=117 (75.9%) pretreated with HT as adjuvant; N=126 pts (81.8%) treated with HT for advanced disease prior to EVE/EXE, with a median of one line (0-5). N=102 pts (66.2%) treated with chemotherapy for metastatic disease, with a median of one line (0-6) before everolimus treatment. RESULTS: Sixteen pts received EVE/EXE as 1st line (10.4%), 39 as 2nd (25.3%), 37 as 3rd (24%), 62 as 4th or more (40,3%). Response was evaluable in 127 out of 154 pts; CR/PR/SD respectively 5/27/56 pts. RR according to line (from 1st to 3rd vs ≥ 4th) was respectively 22.8% vs 26.4% (p=0,864). The median PFS for all population (150 pts) was 38 weeks (95% CI: 33-42). The PFS according to line (1st- 3rd vs ≥ 4th) was 38 wks in both subgroups, p=0.73. OS (126/154 pts) was 28 mths (95% CI: 31-38). The most frequent adverse events were collected in the table. Adverse eventsOverall %Grade 3-4 %Stomatitis55.810.4Hypercholesterolemia47.40.0Asthenia42.95.2Hyperglycemia36.45.8Hypertriglyceridemia29.20.6Anemia28.63.9Peripheral edema24.71.3Rash23.40.6Increased ALT/AST/GGT21.46.5Thrombocytopenia19.53.9Diarrhea18.81.9Weight loss18.21.3Dysgeusia17.50.6Pneumonitis15.61.9Cutaneous toxicity14.90.6Infection14.33.2Neutropenia11.71.9Nausea11.70.0Anorexia (without stomatitis)10.41.3Electrolyte alterations9.71.3Urea/creatinine increase6.51.3Vomiting6.50.0Uric acid increase4.50.0 Median duration of treatment with everolimus 10 mg and 5 mg was respectively 180 (9-854) and 129 days (3-738). Fifty-eight pts (37,6%) never stopped treatment with everolimus 10 mg; 16 pts (10,4%) definitively stopped everolimus for toxicity; 80 pts (52,0%) temporarily interrupted the treatment, resuming at dose level 10 mg (31 pts) or reducing at 5 mg (49 pts). Main reason for discontinuation/interruption was stomatitis G2-G3. RR and PFS evaluated according to dose intensity, 10 mg vs 5 mg, were respectively 25.9% vs 30% p=0.779, 38 wks (27-44) vs 40 wks (31-48) P=0.614 CONCLUSIONS: efficacy in terms of RR and PFS of the combination EVE/EXE is not related to dose intensity (10 mg vs 5 mg), the discontinuation of the treatment is high with the starting dose of 10 mg, the toxicity is consistent with previous phase II-III studies although we collected some different toxicities. Citation Format: Forcignanò R, Petrucelli L, Cazzaniga ME, Lupo LI, Chiuri VE, Cairo G, De Matteis E, Febbraro A, Giordano G, Campidoglio S, Fabi A, Giampaglia M, Bilancia D, La Verde N, Maiello E, Morritti M, Giotta F, Lorusso V, Scavelli C, Romito S, Cusmai A, Palmiotti G, Tornesello A, Ciccarese M. Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real world population of hormone receptor positive advanced breast cancer: A multicenter Italian experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-15.

Aim: This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. Methods: 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). Results: RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7–11) (A), 10 months (95% CI 9–11) (B), and 5 months (95% CI 2–8) (C), p = 0.956. OS was 38 months (95% CI 24–38) (A), median not reached (B), and 13 months (95% CI 10–25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3–4), asthenia 46.0% (6.1% grade 3–4), hypercholesterolemia 46.0% (0.6% grade 3–4), and hyperglycemia 35.6% (5.5% grade 3–4). The main reason for discontinuation/interruption was grade 2–3 stomatitis. Conclusions: No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

// Francesca Maddalena 1 , Vittorio Simeon 1 , Giulia Vita 2 , Annamaria Bochicchio 3 , Luciana Possidente 2 , Lorenza Sisinni 1 , Giacomo Lettini 1 , Valentina Condelli 1 , Danilo Swann Matassa 4 , Valeria Li Bergolis 5 , Alberto Fersini 6 , Sante Romito 5 , Michele Aieta 3 , Antonio Ambrosi 6 , Franca Esposito 4 , Matteo Landriscina 1, 5 1 Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 2 Pathology, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 3 Medical Oncology Units, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 4 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy 5 Medical Oncology, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy 6 General Surgery Units, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy Correspondence to: Matteo Landriscina, email: matteo.landriscina@unifg.it Franca Esposito, email: franca.esposito@unina.it Keywords: TRAP1, client proteins, colorectal carcinoma, protein signature, overall survival Received: November 02, 2016 Accepted: January 09, 2017 Published: February 03, 2017 ABSTRACT TRAP1 is a HSP90 molecular chaperone upregulated in colorectal carcinomas and involved in control of intracellular signaling, cell cycle, apoptosis and drug resistance, stemness and bioenergetics through co-traslational regulation of a network of client proteins. Thus, the clinical significance of TRAP1 protein network was analyzed in human colorectal cancers. TRAP1 and/or its client proteins were quantified, by immunoblot analysis, in 60 surgical specimens of colorectal carcinomas at different stages and, by immunohistochemistry, in 9 colorectal adenomatous polyps, 11 in situ carcinomas and 55 metastatic colorectal tumors. TRAP1 is upregulated at the transition between low- and high-grade adenomas, in in situ carcinomas and in about 60% of human colorectal carcinomas, being downregulated only in a small cohort of tumors. The analysis of TCGA database showed that a subgroup of colorectal tumors is characterized by gain/loss of TRAP1 copy number, this correlating with its mRNA and protein expression. Interestingly, TRAP1 is co-expressed with the majority of its client proteins and hierarchical cluster analysis showed that the upregulation of TRAP1 and associated 6-protein signature (i.e., IF2α, eF1A, TBP7, MAD2, CDK1 and βCatenin) identifies a cohort of metastatic colorectal carcinomas with a significantly shorter overall survival (HR 5.4; 95% C.I. 1.1-26.6; p=0.037). Consistently, the prognostic relevance of TRAP1 was confirmed in a cohort of 55 metastatic colorectal tumors. Finally, TRAP1 positive expression and its prognostic value are more evident in left colon cancers. These data suggest that TRAP1 protein network may provide a prognostic signature in human metastatic colorectal carcinomas.

Autologous stem cell transplantation is considered the best post-induction therapy for multiple myeloma (MM). Therefore, therapy for myeloma should be chosen not only on the basis of efficacy, but also taking into account their impact on the hematopoietic stem cell compartment. We describe the case of a MM patient in which a successful mobilization of peripheral stem cells was obtained with bortezomib, cyclophosphamide and G-CSF, after two failed attempts in the framework of Total Therapy 2. The patient underwent an autologous transplantation, showing a rapid and complete post-transplant hematological recovery. Our experience suggests that bortezomib is an effective anti-myeloma agent without negative impact on stem cell mobilization, even in patients with a previous history of failed harvest.

Introduction Despite the large number of drugs active in AGC, no combination can be considered as the gold standard treatment. Modest increase have been obtained in overall survival with the most widely employed regimens such as CF or ECF, often obtained at expense of increased toxicity. So there is a strong need to develop new active drugs to improve the clinical outcome. Taxotere showed to be effective in preclinical studies and some phase II trials confirmed its clinical efficacy. Recently, the addition of TXT to CDDP + FU (TCF regimen), obtained, in a large randomised phase III trial, better survival than CF alone. However the toxicity of this combination was relevant and mainly due to the association with CDDP. Considering these data the GOIM started a phase II study aiming to evaluate efficacy and safety of a three drugs combination, employing EPI instead of CDDP. Materials and methods Forty-one histologically proven untreated gastric cancer patients, with advanced measurable disease, age between 18 and 75 years, performance status ⩾ 70 (Kfsky scale) and available to sign written informed consent, were enrolled. They received the following treatment: Epirubicin at 60 mg/m 2 on day 1, Taxotere at 50 mg/m 2 on day 1, Folinic Acid at 100 mg/m 2 on days 1–2, Fluorouracil bolus at 400 mg/m 2 on days 1–2 and Fluorouracil 22 h continuous infusion on days 1–2 every three weeks. Results Amongst the 38 evaluable patients we observed 5 CR (13%), 9 PR (24%), 9 SD (24%) and 15 PD (39%) for an ORR of 37% (95% CI: 22–52) and a tumor growth control rate of 61%. The median time to progression was 4 months and the median survival was 9 months. The treatment was well tolerated. The main grade III–IV haematologic toxicities were leucopenia 7%, neutropenia 5% and anemia 5% while non-haematologics were diarrhoea 2%, alopecia 2% and cardiac 2%. Conclusion The three drugs combination of Taxotere, Epirubicin and Fluorouracil is active and well tolerated first-line treatment in advanced gastric cancer patients.

Purpose We performed this phase III study to compare the irinotecan, leucovorin (LV), and fluorouracil (FU) regimen (FOLFIRI) versus the oxaliplatin, LV, and FU regimen (FOLFOX4) in previously untreated patients with advanced colorectal cancer. Patients and Methods A total of 360 chemotherapy-naive patients were randomly assigned to receive, every 2 weeks, either arm A (FOLFIRI: irinotecan 180 mg/m2 on day 1 with LV 100 mg/m2 administered as a 2-hour infusion before FU 400 mg/m2 administered as an intravenous bolus injection, and FU 600 mg/m2 as a 22-hour infusion immediately after FU bolus injection on days 1 and 2 [LV5FU2]) or arm B (FOLFOX4: oxaliplatin 85 mg/m2 on day 1 with LV5FU2 regimen). Results One hundred sixty-four and 172 patients were assessable in arm A and B, respectively. Overall response rates (ORR) were 31% in arm A (95% CI, 24.6% to 38.3%) and 34% in arm B (95% CI, 27.2% to 41.5%; P = .60). In both arms A and B, median time to progression (TTP; 7 v 7 months, respectively), duration of response (9 v 10 months, respectively), and overall survival (OS; 14 v 15 months, respectively) were similar, without any statistically significant difference. Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensorial were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed. Conclusion There is no difference in ORR, TTP, and OS for patients treated with the FOLFIRI or FOLFOX4 regimen. Both therapies seemed effective as first-line treatment in these patients. The difference between these two combination therapies is mainly in the toxicity profile.

Introduction: Platinum-based chemotherapy is the gold standard in advanced non-small cell lung cancer (NSCLC), although with relevant toxic effects. Both docetaxel (DCT) and gemcitabine (GEM) have shown activity as single agent in advanced NSCLC with a different toxicity profile and a lack of cross-resistance. Materials and methods: From April 2000 to May 2001, 47 consecutive patients were enrolled in a multicenter phase II trial. Main inclusion criteria included untreated patients with histologically confirmed NSCLC, age⩽70 years, stage IIIB/IV, Eastern Cooperative Oncology Group performance status (PS) 0–2, measurable disease, adequate hematologic, cardiac, hepatic and renal functions, and written informed consent. Treatment schedule consisted of DCT at the dosage of 50 mg/m 2 with conventional steroid premedication and GEM at the dosage of 2000 mg/m 2 . Both drugs were administered every 2 weeks without prophylactic use of growth factors. Results: Enrolled patients included 40 males and seven females with a median age of 65 years, and a median PS 1. There were 26 squamous carcinomas, 13 adenocarcinomas, and eight others, 13 stage IIIB and 34 stage IV. A total of 371 cycles were administered. Overall 18 partial responses were observed (38.3%); 14 patients were considered as stable disease and 13 showed progressive disease. Two treatment-not related deaths occurred before the first disease evaluation was performed. Median duration of response was 6 months (range 2–10) and median duration of survival was 10.5 months (range 1–25+). One year survival probability was 38% (95% CI 25–54%). In a statistical analysis responses were independent to histology or stage. Grade 3–4 toxicity, according NCI criteria, was mild with neutropenia in eight patients (17%), anemia in two patients (4%). Asthenia affected two patients and mucositis occurred in one patient. Conclusions: In our experience the biweekly combination of DCT and GEM is active and well tolerated and can be administered without G-CSF primary prophylaxis reducing treatment costs. It should be considered as a promising alternative to more toxic platinum-based regimens.

ABSTRACT: Aim: To evaluate whether pyrosequencing (PS) improves the KRAS mutational status predictive value. Patients & methods: A retrospective analysis of KRAS mutations by PS and direct sequencing (DS) in 192 metastatic colorectal carcinomas (mCRCs), subgrouped in 51 KRAS mutated at PS and 141 KRAS wild-type at DS. Results: DS failed to detect low-frequency KRAS mutations in four out of 51 mCRCs, whereas PS detected 12 additional low-frequency KRAS mutations in 141 mCRCs KRAS wild-type at DS. After reanalyzing by PS 97 KRAS wild-type tumors treated with anti-EGF receptor (EGFR) antibodies, nine additional mutations were revealed in nonresponders, whereas none of responders exhibited a KRAS-mutated genotype. Of note, KRAS-mutated tumors upon PS showed a worst progression-free survival after EGFR therapy. Finally, PS allowed the detection of additional NRAS, BRAF and exon 20 PIK3CA mutations mostly in KRAS wild-type mCRCs resistant to EGFR therapy. Conclusion: PS detection of low-frequency mutations may improve the KRAS predictive value for EGFR therapy selection.

We conducted a phase III multicenter randomized trial to compare the efficacy of the combination of liposome encapsulated doxorubicin (Myocet(©)) plus either cyclophosphamide (MC) or vinorelbine (MV). Since July 2006, 233 patients affected with metastatic breast cancer were randomized to receive the combination of Myocet (M) 60 mg/m(2) i.v. plus cyclophosphamide (C) 600 mg/m2 on Day 1 of a 21‑day cycle (Arm A) or Myocet (M) at 50 mg/m2 plus vinorelbine (V) 25 mg/m2 i.v. on Day 1 and V 60 mg/m2 orally on Day 8 on a 21‑day cycle (Arm B). The primary endpoints of the study was time to progression (TTP); secondary endpoints were RR, toxicity and OS. Response was observed in 53/116 (45.7%) evaluable patients of Arm A vs. 51/112 (45.5%) of Arm B, respectively (P=NS). Median TTP was 41 weeks (95% CI, 32‑51) and 34 weeks (95% CI, 26‑39), for M/C and M/V, respectively (P=0.0234). The difference in median OS was not statistically significant (131 vs. 122 weeks; P=0.107). With regard to toxicity, patients treated with MV showed a slight increase of neutropenia and constipation, as compared to those treated with MC. No clinical signs of cardiotoxicity were observed. The MC combination remains as an unbeaten 'standard' in first line treatment of MBC.

Until recently, only therapy with docetaxel and prednisone has been shown to prolong survival in men with hormonorefractory metastatic prostate cancer. With approvals of sipuleucel-T, cabazitaxel, and abiraterone acetate, all based on improvement in overall survival, the scenary for management of men with metastatic prostate cancer has dramatically changed. Abiraterone acetate was developed to specifically inhibit cytochrome P450 (CYP)17A1, which is an essential enzyme in the biosynthesis of testosterone. In the phase III, the trial treatment with abiraterone acetate plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration-resistant prostate cancer who have disease progression after treatment with docetaxel and associated with an acceptable tolerability profile, which was generally similar to that of the placebo plus prednisone group. However, adverse events resulting from elevated mineralocorticoid levels because of CYP17A1 inhibition, fluid retention and oedema, hypokalaemia, hypertension occurred in significantly more in abiraterone acetate plus prednisone than in placebo plus prednisone.

Schwannomas are degenerate peripheral nerve sheath tumors that very rarely occur in the retroperitoneum. They are usually benign than malignancy is very rare and is usually observed in patients with von Recklinghausen disease. We report a case of female adult patient who presented with vague abdominal discomfort. The preoperative diagnosis was difficult and the treatment was complete surgical excision. The patient is with no evidence of recurrence more than four years after surgery.

Background This randomized, multicenter, phase III trial evaluated the efficacy and safety of the combination of epirubicin, leucovorin, 5-fluorouracil and etoposide (ELFE regimen) as adjuvant therapy for radically resected gastric cancer patients. Patients and methods From June 1996 to June 2001, 228 stage IB–IIIB gastric cancer patients were enrolled. All patients received a total or subtotal gastrectomy with at least a D1 lymphoadenectomy and were randomly assigned to receive surgery alone or surgery followed by chemotherapy. Results A total number of 630 cycles was delivered with a median number of 5. With a median follow-up of 60 months, the 5-year overall survival (OS) was 48% in the treatment arm and 43.5% in the control arm [hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.69–1.21; P = 0.610); the 5-year disease-free survival (DFS) was 44% in the treatment arm and 39% in the control arm (HR 0.88; 95% CI 0.78–0.91; P = 0.305). In node-positive patients, the 5-year OS was 41% in the treatment arm and 34% in the control arm (HR 0.84; 95% CI 0.69–1.01; P = 0.068), while the 5-year DFS was 39% in the treatment arm and 31% in the control arm (HR 0.88; 95% CI 0.78–0.91; P = 0.051). The most common grade 3–4 toxic effects according to World Health Organization criteria were hematological and gastrointestinal. Conclusions In radically resected gastric cancer patients, adjuvant chemotherapy with ELFE regimen does not improve OS over surgery alone.

Topotecan is able to cross the blood-brain barrier (BBB) and has been demonstrated to be active in brain metastases from small cell lung cancer (SCLC).The aim of this study was to evaluate the efficacy and toxicity of topotecan at a dosage of 1.5 mg/m2 for 5 consecutive days every 3 weeks in patients with brain metastases from various neoplasms.Among the 19 patients enrolled, objective responses were observed in 2 out of 3 patients affected by brain metastases from SCLC. Stable disease was observed in 8 more patients (4 breast, 3 non-SCLC and 1 colon). According to the Simon two-step design, patient accrual was stopped because of the low response rate observed in the first 19 patients treated (early stopping rule). The G 3/4 haematological toxicity was severe, with 37% neutropenia, 21% thrombocytopenia and 16% anaemia, respectively.Our data do not support the use of topotecan in patients with brain metastases, except for SCLC. In addition, the haematological toxicity prevents the use of this regimen in elderly and poor performance status patients.

Background The aim of the study was to verify the efficacy and safety of the addition of celecoxib to FOLFIRI combination therapy in patients affected by advanced colorectal cancer. Patients and methods Eighty-one chemotherapy-naive patients entered in this randomized phase II trial of the GOIM (protocol no. 2301). Patients were randomized to receive FOLFIRI regimen (arm A): irinotecan 180 mg/m2 on day 1 with LV5FU2 regimen (LV at 100 mg/m2 administered as a 2-h infusion before FU at 400 mg/m2 as an intravenous bolus injection, and FU at 600 mg/m2 as a 22-h infusion immediately after 5-FU bolus injection on day 1 and 2); or FOLFIRI plus celecoxib 400 mg twice daily for 14 days (arm B). Both treatments were repeated every 2 weeks. Results Seventy-seven patients (38 in arm A and 39 in arm B) were evaluable for response. The overall response rate was 41% in arm A (95% CI 27% to 57%) and 35% in arm B (95% CI 20% to 50%). When only assessable patients were analyzed, overall response rate was 45% in arm A (95% CI 29% to 61%) and 36% in arm B (95% CI 21% to 51%). Median time to progression, median duration of response and survival were, respectively, 8 months, 9 months and 16 months in arm A, and 7 months, 9 months and 19 months in arm B. All patients were evaluable for toxicity, which was globally mild in both arms; grade 3–4 toxicity was uncommon, and gastrointestinal disturbances were the most common. Conclusions FOLFIRI regimen is effective and well-tolerated as a first-line treatment in patients with advanced colorectal cancer. The addition of celecoxib to FOLFIRI regimen does not improve results.

1041 Background: The combination MC demonstrated to be effective and safe in MBC. Vinorelbine, in combination with anthracyclines, is an active drug as well. This is a multicenter randomized phase ...

4014 Background: In a previous phase II study the ELFE regimen resulted to be active and well tolerated for the treatment of advanced GC (Am J Clin Oncol 22:262;1999). Based on this background the G.O.I.M. conducted a randomised phase III study (trial 9602) to evaluate efficacy and toxicity of ELFE regimen as adjuvant therapy for radically resected GC patients (pts). Methods: All enrolled pts underwent total or subtotal gastrectomy with at least a D1 lymphoadenectomy. After stratification for nodal involvement (N+ vs N-) pts were randomised to follow-up alone (116 pts) or 6 cycles of ELFE regimen ( EPI 60mg/m2 d1, LV100 mg/m2 d 1–5, 5FU 375 mg/m2 d 1–5, VP-16 100 mg/m2 d1–3, every 3 weeks). Results: From June 1997 to June 2001, 228 pts with stage IB-IIIB GC were enrolled. Pts characteristics were: median age 63 yrs (29–70); total gastrectomy 148 pts; N+ 163 pts; PS 0–1 according ECOG scale 210. A total number of 638 cycles were delivered with a median number of 5/pt. During chemotherapy, the most frequent G3–4 side-effects graded according to NCI-CTC included alopecia (32%), neutropenia (26%), diarrhea (26%), nausea/emesis (17%), thrombocytopenia (12%) and stomatitis (11%). With a median follow-up of 60 months, the 5-years overall survival was 48% in the treatment arm and 43.5% in the control arm ( p=0.610); the 5-years disease-free survival was 44% in the treatment arm and 39% in the control arm ( p=0.305). Between patients with positive nodes the 5-years overall survival was 41% in the treatment arm and 34% in the control arm( p=0.068), while the 5-years disease-free survival was 39% in the treatment arm and 31% in the control arm (p=0.052). Multivariate analysis showed TNM stage as the only covariate that was independently associated with overall and disease-free survival. Conclusions: In radically resected GC adjuvantELFE chemotherapy produces an absolute difference in overall survival and disease-free survival at 5 years respectively of 4.5% and 5%, but this advantage was not statistically significant. No significant financial relationships to disclose.

4195 Background: In our previous experience the combination of MMC (M) and Irinotecan (I) demonstrated to be active in pretreated advanced gastric cancer pts. Capecitabine (X) more active than fluo...

3656 Background: The combination of Irinotecan (CPT-11) at 180 mg/mq combined with LV5FU2 (FOLFIRI - Douillard regimen), represents a standard first-line therapy for ACRC pts. Celecoxib is a selective anti-Cox2 compound with antineoplastic properties such as angiogenic inhibition and apoptosis induction. Experimental data demonstrated the synegistic interaction of Celecoxib with CPT-11 and Fluorouracil (FU). Taking into account these data the Gruppo Oncologico dell’Italia Meridionale (GOIM), started a phase II randomized study to compare the activity and toxicity of FOLFIRI regimen alone (arm A) or with the addition of Celecoxib (arm B) in ACRC pts. Methods: Pts with hystological/cytological diagnosis of colorectal cancer, measurable disease, ECOG PS ≤ 2, age ≥ 18 and ≤ 75 years, entered into this trial. Pts were randomized to receive: Arm A: CPT-11 180 mg/mq on day 1 and LV5FU2 regimen (Folinic acid 100 mg/mq in 2-hr iv infusion, FU 400 mg/mq iv bolus, and FU 600 mg/mq in 22-hr iv infusion on day 1 and 2...

Twenty-five patients with advanced breast cancer were treated with 4-demethoxydaunorubicin (4-DMDR), a new antitumor analogue of daunorubicin, at the dose of 15-20 mg/m2/day X 3 days by oral route every 3-4 weeks. All patients were previously treated with chemotherapy and/or hormone therapy but none with anfhracyclines. Of 23 evaluable patients, 1 complete and 5 partial remissions (26%) were observed for a median duration of 4+ months. Leukopenia and nausea occurred in 61% of the patients, vomiting in 30%, diarrhea in 17% and alopecia in 43%. There were 2 cases with minimal and transient EKG variations. 4-DMDR, administered orally in advanced breast cancer, was found to be generally well tolerated. Nevertheless, randomized trials with adriamycin or epirubicin are necessary to compare and to define the therapeutic activity and the toxicity of 4-DMDR.

Sixty consecutive previously untreated patients with non-Hodgkin's lymphomas (intermediate or high grade and/or bulky disease and/or presence of constitutional symptoms), were randomized to receive either CHOP-B or CEOP-B (31 and 29 patients, respectively) to compare the therapeutic activity and toxicity. Complete response was observed in 65% of the patients treated with CHOP-B and 62% with CEOP-B; relapse of the disease occurred, respectively, in 5/20 (25%) and 6/18 (33%) of CR. Relapse-free survival and overall survival at 5 yr resulted in both groups (RFS 68% and 62% and overall survival 62% and 62%, respectively). In addition, increasing the dosage of epirubicin did not result in an increase in the haematologic toxicity or percent of CR. The haematologic toxicity was slightly lower in CEOP-B. The cardiologic monitoring (Eco 2D and EKG-Holter) at 400 mg mq-1 of EDX and ADM did not demonstrate variations in cardiac function in the CEOP-B group, while in the ADM patients the ejection fraction was statistically lower as regards basal values. In conclusion, in our randomized study, substitution of ADM with EDX in non-Hodgkin's lymphomas in the CHOP-B regimen, did not decrease the therapeutic activity of the combined chemotherapy, while less toxicity (haematologic and cardiac) was observed. For these reasons, in our opinion, epirubicin can substitute adriamycin in second and third generation regimens for non-Hodgkin's lymphomas in which the major drawback for a wider diffusion is the severe toxicity observed.