Search

Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 (UGT1A1) genetic variants, but they are poorly applied in clinical practice. This review highlighted clinically validated pharmacogenetic markers, to underline the need of their implementation in the multidisciplinary molecular board for individual CRC patients in clinical practice. Five clinically relevant DPYD variants with different prevalence impair enzymatic effectiveness and significantly increase toxicity: c.1236 G>A (c.1129-5923 C>G, HapB3), 4.1-4.8%; c.1679 T>G (DPYD*13), c.1905+1G>A (DPYD*2A), c.2846 A>T, c.2194 A>T (DPYD*6) 1% each. c.1679T>G and c.1905+1G>A are most deleterious on DPD effectiveness, moderately reduced in c.1236/HapB3 and c.2846A>T. Cumulatively, these variants explain approximately half of the estimated 10-15% fluoropyrimidine-related gastrointestinal and hematological toxicities due to DPD. Prevalent UGT1A1 gene [TA]7TAA promoter allelic variant UGT1A1*28, characterized by an extra TA repeat, is associated with low transcriptional and reduced enzymatic effectiveness, decreased SN38 active irinotecan metabolite glucuronidation, vs wild-type UGT1A1*1 [A(TA)6TAA]. Homozygote UGT1A1*28 alleles patients are exposed to higher hematological and gastrointestinal toxicities, even more than heterozygote, at >150 mg/m2 dose. Dose reduction is recommended for homozygote variant. Wild-type UGT1A1*28 alleles patients could tolerate increased doses, potentially affecting favorable outcomes. Implementation of up-front evaluation of the five validated DPYD variants and UGT1A1*28 in the multidisciplinary molecular tumor board, also including CRC genetic characterization, addresses potential treatments with fluoropyrimidines and irinotecan associations at proper doses and schedules, particularly for early CRC, MCRC patients fit for intensive regimens or unfit for conventional regimens, requiring treatment modulations, and also for patients who experience severe, unexpected toxicities. Integration of individual evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), an innovative indicator of toxicity burden in individual patients, may be useful to better evaluate relationships between pharmacogenomic analyses with safety profiles and clinical outcomes.

Background Hepatic artery infusion (HAI) and drug selection by liquid biopsy precision oncotherapy are under investigation for the multidisciplinary treatment of unresectable colorectal liver metastases (CRCLM) in progression after systemic therapy. Here, we compare the safety and efficacy of third-line HAI followed by target therapy with drug regimes selected by liquid biopsy precision oncotherapy to third-line systemic therapy with drug regimes selected partly by tissue biopsy precision oncotherapy, in a retrospective real-life study of 106 unresectable CRCLM patients. Methods Drug regimens for HAI/target therapy were selected by assessing the sensitivity of purified circulating tumor cell (CTCs) to 5-fluorouracil, carboplatin, cisplatin, oxaliplatin, irinotecan, doxorubicin, mitomycin, raltitrexed, and melphalan in-vitro and by real-time qRT-PCR gene expression assays, and for the Systemic therapy cohort were selected by age, comorbidity, performance status, and absence of RAS mutations. Therapeutic responses, adverse events, and quality of life were evaluated by RECIST 1.1, CTCAE 4.03, and ECOG criteria, respectively, and chemo-filtration performed following HAI to reduce systemic toxic effects. Results HAI/target therapy with drugs selected by liquid biopsy precision oncotherapy (44 patients), resulted in 2.27% CRs, 38.63% PRs, 56.81% SD,s and 2.27% PDs; ECOG 2 to 1 improvement, but no infusion-related technical or vascular complications, or deaths. Systemic therapy (62 patients) resulted in 1.6% CRs, 17.74% PRs, 37.09% SDs, and 45.16% PDs; more grade 1–2 adverse events and 4.84% ECOG 1 to 2 worsening. The median 5 month PFS in the HAI/target therapy cohort was significantly longer than 3 months in the systemic cohort (P Conclusions HAI plus chemo-filtration followed by target therapy, with drug regimens selected by liquid biopsy precision oncotherapy, is a safe and efficacious alternative therapeutic strategy for unresectable CRCLM in progression after two lines of systemic therapy and should be considered for a multicentre prospective phase III study, to fully confirm this potential.

Background Third line innovative systemic treatments and loco-regional chemotherapy by hypoxic pelvic perfusion (HPP) have both been proposed for the treatment of unresectable not responsive recurrent rectal cancer (URRC). In the present study, we have compared the safety and efficacy of HPP/target therapy, using drug regimens selected by liquid biopsy precision oncotherapy, to third-line systemic therapy based on tissue specimens precision oncotherapy. Methods HPP/target therapy regimens were selected based on precision oncotherapy, including assays for chemosensitivity and viability, and qRT-PCR for tumor-related gene expression. In the control group, systemic third-line and further lines of therapy were defined according to clinical and biological parameters. Results From 2007 to 2019, 62 URRC patients were enrolled, comprised of 43 patients in the HPP/target-therapy group and 19 patients in the systemic therapy control group. No HPP related complications were reported and the most common adverse events were skin and bone marrow toxicity. In the HPP/target-therapy group, the ORR was 41.8% whereas in the systemic therapy control group was 15.8%. DCR of the HPP/target-therapy group was significantly improved over the systemic therapy group (P = 0.001), associated with a PFS of 8 vs 4 months (P = 0.009), and OS of 20 vs 8 months (P = 0.046). Conclusions The present data indicate that in URCC patients, the integration of HPP/target-therapy and precision oncotherapy based upon liquid biopsy is as effective and efficacious as third-line treatment in local disease control and, therefore, deserves to be further assessed and compared to conventional systemic treatments in future prospective randomized trials.

Background Neuroendocrine tumors (NETs) are heterogeneous, widely distributed tumors arising from neuroendocrine cells. Gastrointestinal (GI)-NETs are the most common and NETs of the rectum represent 15, 2% of gastrointestinal malignancies. Poorly differentiated neuroendocrine carcinomas of the GI tract are uncommon. We report a rare case of poorly differentiated locally advanced rectal neuroendocrine carcinoma with nodal and a subcutaneous metastasis, with a cytoplasmic staining positive for Synaptophysin and Thyroid Transcription Factor-1. Case presentation A 72-year-old male presented to hospital, due to lumbar, abdominal, perineal pain, and severe constipation. A whole-body computed tomography scan showed a mass of the right lateral wall of the rectum, determining significant reduction of lumen caliber. It also showed a subcutaneous metastasis of the posterior abdominal wall. Patient underwent a multidisciplinary evaluation, diagnostic and therapeutic plan was shared and defined. The pathological examination of rectal biopsy and subcutaneous nodule revealed features consistent with small-cell poorly differentiated neuroendocrine carcinoma. First line medical treatment with triplet chemotherapy and bevacizumab, according to FIr-B/FOx intensive regimen, administered for the first time in this young elderly patient affected by metastatic rectal NEC was highly active and tolerable, as previously reported in metastatic colo-rectal carcinoma (MCRC). A consistent rapid improvement in clinical conditions were observed during treatment. After 6 cycles of treatment, CT scan and endoscopic evaluation showed clinical complete response of rectal mass and lymph nodes; patient underwent curative surgery confirming the pathologic complete response at PFS 9 months. Discussion and conclusions This case report of a locally advanced rectal NEC with an unusual subcutaneous metastasis deserves further investigation of triplet chemotherapy-based intensive regimens in metastatic GEP NEC.

Introduction: Intensive oncological treatment integrated with resection of metastases raised the clinical outcome of metastatic colorectal cancer (MCRC). In clinical practice, complex evaluation of clinical (age, performance status, comorbidities), and biological (tumoral genotype, pharmacogenomic) parameters addresses tailored, personalized multidisciplinary treatment strategies. Patients with MCRC unsuitable for first-line intensive medical treatments are prevalent and showed worse clinical outcome. After progression to oxaliplatin-based chemotherapy, aflibercept/FOLFIRI significantly improved clinical outcome, even if no survival benefit was reported in adjuvant fast relapsers by aflibercept addition. The case reported a young-elderly (yE) patient with KRAS mutant colorectal cancer rapidly progressing to adjuvant chemotherapy, unfit owing to comorbidities, with multiple pharmacogenomic alterations, who gained long-term survival in clinical practice by multidisciplinary treatment strategy consisting of first-line and re-introduction of aflibercept-containing chemotherapy and two-stage lung metastasectomies.Case presentation: A 71-years-old yE patient, unfit for intensive oncological treatments owing to Cumulative Illness Rating Scale (CIRS) stage secondary, affected by KRAS c.35 G>T mutant colorectal cancer, rapidly progressing with lung metastases after adjuvant XelOx chemotherapy, reached long-term survival 66 months with no evidence of disease after first-line and re-introduction of tailored, modulated aflibercept (4 mg/kg) d1,15-irinotecan (120 mg/m2) d1,15-5-fluorouracil (750 mg/m2/day) dd1–4, 15–18; and secondary radical bilateral two-stage lung metastasectomies. Safety profile was characterized by limiting toxicity syndrome at multiple sites (LTS-ms), requiring 5-fluorouracil discontinuation and aflibercept reduction (2 mg/kg), because of G2 hand-foot syndrome (HFS) for >2 weeks, and G3 hypertension. Pharmacogenomic analyses revealed multiple alterations of fluoropyrimidine and irinotecan metabolism: severe deficiency of fluorouracil degradation rate (FUDR), single nucleotide polymorphisms of UGT1A1*28 variable number of tandem repeats (VNTR) 7R/7R homozygote, ABCB1 c.C3435T, c.C1236T, MTHFR c.C667T homozygote, DPYD c.A166G, TSER 28bp VNTR 2R/3R heterozygote.Conclusions: In clinical practice, a complex management evaluating clinical parameters and RAS/BRAF genotype characterizing an individual patient with MCRC, particularly elderly and/or unfit owing to comorbidities, is required to properly address tailored, multidisciplinary medical and surgical treatment strategies, integrated with careful monitoring of superimposing toxicity syndromes, also related to pharmacogenomic alterations, to gain optimal activity, and long-term efficacy.

// Gemma Bruera 1, 2, * , Francesco Pepe 3, * , Umberto Malapelle 3 , Pasquale Pisapia 3 , Antonella Dal Mas 4 , Daniela Di Giacomo 1, 2 , Giuseppe Calvisi 4 , Giancarlo Troncone 3 and Enrico Ricevuto 1, 2 1 Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3 Department of Public Health, University Federico II, Napoli, Italy 4 Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy * These authors equally contributed to this work Correspondence to: Enrico Ricevuto, email: enrico.ricevuto@univaq.it Keywords: FIr-B/FOx intensive first line triplet chemotherapy plus bevacizumab; metastatic colorectal cancer; next generation sequencing; RAS/BRAF mutations; 50 genes panel Received: October 06, 2017 Accepted: April 05, 2018 Published: May 29, 2018 ABSTRACT Background: First line triplet chemotherapy/BEV significantly improved clinical outcome of MCRC. KRAS/NRAS/BRAF mutations were evaluated by next generation sequencing (NGS) in MCRC patients treated with first line FIr-B/FOx. Methods: KRAS exons 2-4 ( KRAS 2-4 ), NRAS 2-4 , BRAF 15 were evaluated in 67 tumours by ION Torrent platform. Mutation detection criteria: >500×sequence coverage (cov); >1% mutant allelic fraction (AF). Clinical outcomes were compared by log-rank. Results: In 63 samples, KRAS 2-4 / NRAS 2-4 / BRAF 15 wild-type (wt) were 14 (22.2%), mutant (mut) 49 (77.8%): KRAS 2-4 42 (66.7%); NRAS 2-4 11 (16.4%); BRAF 15 5 (7.5%). Sixty mutations were detected, range 1-3 mut: 43 (71.7%) >1000×cov/>5% AF; 9 (15%) >500×cov/>5% AF; 8 (13.3%) >1000×cov/ 1000×cov/>5% AF, 8 (12.7%) >500×cov/>5% AF, 1 (1.6%) >1000×cov/ 500×cov/>5% AF, 4 (6%) >1000×cov/ A; c.1406 G>C; c.1756 G>A, 2 samples; c.1796 C>T. At 21 months (m) follow-up, clinical outcome wt compared to mut was not significantly different: in KRAS 2-4 / NRAS 2-4 / BRAF 15 , progression-free survival (PFS) 18/12 m, overall survival (OS) 28/22 m; 1/≥2 mutations, PFS 14/11, OS 37/22. PFS was trendy worse in RAS / BRAF wt vs ≥2 mut genes ( P 0.059). Conclusions: Most MCRC harboured KRAS 2-4 / NRAS 2-4 / BRAF 15 mutations by NGS, often multiple and affecting few tumoral clones; 22% were triple wt. Clinical outcome is not significantly affected by KRAS 2-4 / NRAS 2-4 / BRAF 15 genotype, trendy different in triple wt, compared with KRAS 2-4 / NRAS 2-4 / BRAF 15 ≥2 mut.

BACKGROUND Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy may be candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. METHODS Thirty-seven patients with unresectable recurrent rectal cancer in progression after standard treatments underwent repeated HPP with mitomycin C (25 mg/m2) and cisplatin (70 mg/m2). Twenty patients, exhibiting epidermal growth factor receptor (EGFR) overexpression, also received cetuximab targeted-therapy, following the ultimate HPP treatment. RESULTS Following initial HPP treatment, median progression-free survival was 7 months (range: 5-19 months), median time-to-death or termination of follow-up was 13 months (range: 9-18 months), one-year survival-rate was 59.45%, two-year survival rate was 10.81%, and three-year survival rate was 2.7%. Survival was significantly influenced by cetuximab targeted-therapy post-HPP and the presence of additional metastatic sites (P

Background: Intensive triplet chemotherapy/bevacizumab significantly increased metastatic colorectal cancer (MCRC) outcome. This phase II study investigated the safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line RAS wild-type and the prediction of individual limiting toxicity syndromes (LTS) by pharmacogenomic biomarkers. Methods: A Simon two-step design was used: p0 70%, p1 85%, power 80%, α5%, β20%; projected objective response rate (ORR) I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-timed flat infusion 900 mg/m2 d1–2, 8–9, 15–16, 22–23; irinotecan (CPT-11) 160 mg/m2 d1 and 15, oxaliplatin 80 mg/m2 d8 and 22; CET 400mg/m2 then 250 mg/m2 d1, 8, 15, 22; every 28 days. Toxicity, and individual LTS were evaluated, compared by a Chi-square test; and activity/efficacy by log-rank. 5-FU/CPT-11 pharmacogenomic biomarkers, 5-FU degradation rate (5-FUDR), single nucleotide polymorphisms (SNPs) ABCB1, CYP3A4, DYPD, UGT1A1 were evaluated in patients with LTS and at a recommended dose. Results: A total of 29 patients 2. In the intent-to-treat analysis, the ORR was 58.6%. The primary endpoint was met in patients who received the planned three treatment cycles: the objective response (OR) was 14/18 (78%). At a median follow up of 18 months, progression-free survival (PFS) was 12, and overall survival (OS) was 23 months. At the recommended doses (received dose intensity >80%), grade 3–4 toxicities were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS 19 (65.5%), with 83% in yE patients. LTS prevalently multiple (ms) versus single site were 59% versus 7% ( p = 0.006). The prevalence of reduced FUDR was 56%, SNPs CYP3A4 22%, UGT1A1 71%, and of >2 positive pharmacogenomics biomarkers was 78%, prevalently reported in patients who developed gastrointestinal LTS. Conclusions: FIr-C/FOx-C is highly active and tolerable at recommended doses in non-elderly RAS wild-type MCRC patients. LTS provided an evaluation of the toxicity burden in individual patients. Reduced FUDR, CYP3A4, and UGT1A1 SNPs may predict individual LTS-ms in patients at risk of limiting gastrointestinal toxicity. Trial registration: The trial was registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009-016793-32.

// Gemma Bruera 1, 2 , Silvia Massacese 3 , Antonio Galvano 4 , Antonella Dal Mas 5 , Stefano Guadagni 6, 2 , Giuseppe Calvisi 5 , Eugenio Ciacco 3 , Antonio Russo 4 , Enrico Ricevuto 1, 2 , on behalf of Oncology Network ASL1 Abruzzo, Italy 1 Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3 Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy 4 Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy 5 Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy 6 Universitary General Surgery, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy Correspondence to: Antonio Russo, email: antonio.russo@usa.net Keywords: docetaxel, 5-fluorouracil, and oxaliplatin; FD/FOx intensive regimen; dose-finding study; first-line triplet chemotherapy; metastatic gastric cancer Received: January 24, 2018 Accepted: March 07, 2018 Published: April 17, 2018 ABSTRACT Introduction: Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Methods: Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m 2 /d 1-2, 8-9, 15-16, 22-23, with 100 mg/m 2 /d increase for dose level; DTX 50 mg/m 2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m 2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. Results: Ten fit

673 Background: Intensive first line bevacizumab added to triplet, and cetuximab (CET) to doublet in RAS wild-type MCRC significantly increased outcomes. We investigated safety/activity of FIr-C/FOx-C adding CET to triplet in RAS wild-type. Methods: Phase II study according to Simon two-step design: delta 15% (p070%, p185%), power80%, α5%, β20%; projected ORR I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-TFI 900 mg/m2 days (d) 1-2,8-9,15-16,22-23 associated to weekly alternating irinotecan (CPT-11) 160 mg/m2 d1,15 or oxaliplatin 80 mg/m2 d8,22; CET loading dose, then 250 mg/m2 d1,8,15,22; every 28d. Toxicity, LTS evaluated/compared by chi-square test; activity/efficacy by log-rank. Pharmacogenomic biomarkers of 5-FU/CPT-11, 5-FU degradation rate (5-FUDR), Single Nucleotide Polimorphisms (SNP) ABCB1, CYP3A4, DYPD, UGT1A1, evaluated in individual patients with limiting toxicity syndromes (LTS) and at recommended dose. Results: 29 patients < 75 years, primary/intermediate CIRS. From April 2014, KRAS/NRAS wild-type eligible: median age 59; young-elderly (yE) 7, 24%; liver-limited (L-L) 7, 24%. Recommended CPT-11/5-FU doses 120/750 mg/m2. Activity met primary endpoint: OR 14/18 evaluable as-treated (76%), confirmed in preliminary phase II, 17/23 intent-to-treat (74%). Liver metastasectomies 14%, 57% L-L. At median follow-up 18 months, PFS 12, OS 23 months. At recommended doses, received DI > 80% for each drug; cumulative G3-4 toxicities: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS, consisting of the LT, associated or not to G2 or other LT, in 19 patients (65.5%), 83% yE. LTS prevalently multiple than single site (59 vs 7% p0.006). Reduced FUDR, CYP3A4 and UGT1A1 SNPs, frequently associated, prevalently in patients with gastrointestinal LTS, while not without LTS. Conclusions: Intensive first-line FIr-C/FOx-C at recommended dose is tolerable, highly effective in RAS wild-type. Reduced FUDR, CYP3A4, UGT1A1 SNPs may predict individual LTS to select fit patients. Prospective studies will confirm efficacy and personalization by companion toxicity biomarkers. Clinical trial information: EudraCT 2009-016793-32.

// Gemma Bruera 1, 2 , Mario Di Staso 3 , Pierluigi Bonfili 3 , Antonio Galvano 4 , Rosa Manetta 5 , Gino Coletti 6 , Roberto Vicentini 7 , Stefano Guadagni 2, 8 , Corrado Ficorella 2, 9 , Ernesto Di Cesare 2, 3 , Antonio Russo 4 and Enrico Ricevuto 1, 2 1 Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3 Radiotherapy, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy 4 Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy 5 Radiology, S. Salvatore Hospital, L’Aquila, Oncology Network ASL1 Abruzzo, Italy 6 Pathology, S. Salvatore Hospital, L’Aquila, Oncology Network ASL1 Abruzzo, Italy 7 Hepatobiliar-pancreatic Surgery, S. Salvatore Hospital, L’Aquila, Oncology Network ASL1 Abruzzo, Italy 8 Universitary General Surgery, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy 9 Medical Oncology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy Correspondence to: Antonio Russo, email: antonio.russo@usa.net Keywords: capecitabine; chemoradiotherapy; dose-finding; locally advanced rectal cancer; oxaliplatin Received: December 07, 2017 Accepted: February 27, 2018 Published: April 03, 2018 ABSTRACT Introduction: Proper administration timing, dose-intensity, efficacy/toxicity ratio of oxaliplatin added to fluoropyrimidin should be improved to safely perform two-drugs intensive preoperative chemoradiotherapy in locally advanced rectal cancer (LARC). This dose-finding study investigated recommended oxaliplatin dose, safety of oxaliplatin/capecitabine regimen and preliminary activity. Methods: Schedule: oxaliplatin dose-levels, 35-40 mg/m 2 /week; capecitabine 825 mg/m 2 / twice daily, radiotherapy on rectum/nodes, 50/45 Gy, 45 and 9 boost/45 Gy, in first 5 and subsequent patients, 5 days/week, respectively; for 5 weeks. Pathologic complete response (pCR) 10% was projected in order to positively affect clinical outcome. Results: Seventeen fit

Summary We describe a metastatic colorectal cancer patient, treated with first-line 5-fluorouracil, irinotecan, bevacizumab, and oxaliplatin (FIr-BFOx) therapy, with aggressive and resistant disease. KRAS , NRAS , BRAF , and PI3KCA were analyzed in primary tumor and liver metastasis. KRAS c.34G>A mutation was detected in primary tumor and liver metastasis, which additionally revealed 2 rare PI3KCA mutations (c.1633G>C and c.1645G>C). The c.1645G>C was never reported in colorectal cancer. Akt/p-Akt Ser473 , phosphatase and tensin homolog, mismatch repair, and epidermal growth factor receptor expression was evaluated. Normal mismatch repair and epidermal growth factor receptor expression was detected. Akt was shown by primary tumor and liver metastasis, whereas p-Akt Ser473 was identified only in the latter, despite positive phosphatase and tensin homolog expression. Patient showed 7 months of progression-free survival and 15 months of overall survival, lower than median values reported in KRAS exon 2–mutant patients treated with the same therapy. Results lead to the hypothesis of a putative role of these mutations in worsening of the disease and are open to further confirmatory studies.

Background The aim of the study is to present the results in a consecutive series of patients affected by aortic abdominal aneurysm and to underline the aneurysmal growth and evolution in oncological patients submitted to dedicated oncological medical therapy. Methods Between January 2010 and June 2016 we treated in our center 19 patients for coexisting aortic aneurysms (>3 cm) and malignancy. We observed patients undergoing oncological treatment and patients who did not undergo medical treatment. We studied computed tomography (CT) scan at the time when patients were addressed at our follow-up or treatment and we analyzed retrospectively prior CT scan at 6 and 12 months. Results Among those 19 patients, 7 patients were affected by colorectal cancer (36.8%), 6 by urinary tract cancer (31.6%), 4 by lymphoma (21%), and 2 by lung cancer (10.6%). In 8 patients who did not undergo oncological therapy, we did not observe any aortic growth; instead, in other 4 patients who underwent oncological medical therapy (3 abdominal aortic aneurysms and 1 thoracic aneurysm), we observed a mean sac growth of 2.9 cm in 6 months with 2 cases of aortic rupture treated in urgent fashion. The treatment was open surgery in 2 cases and endovascular in other cases. Conclusions We observed that oncological drugs may play a role in aneurysm growth. Few case reports are found in the literature and more evidences are to be found. Those information may influence intention-to-treat small aneurysms in short life expectancy patients.

// Gemma Bruera 1, 2 , Antonio Russo 3 , Antonio Galvano 3 , Sergio Rizzo 3 and Enrico Ricevuto 1, 2 1 Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3 Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy Correspondence to: Antonio Russo, email: antonio.russo@usa.net Keywords: elderly, intensive treatment, metastatic colorectal cancer, triplet chemotherapy plus bevacizumab, unfit Received: June 07, 2016 Accepted: November 24, 2016 Published: December 28, 2016 ABSTRACT Introduction: Bevacizumab addiction to triplet chemotherapy, according to FIr-B/FOx schedule, as first-line treatment in young-elderly metastatic colorectal CANCER (MCRC) patients may be more effective. Tailored treatments show worse clinical outcome in unfit patients. Methods: Elderly patients were clinically evaluated according to age and comorbidity (Cumulative Illness Rating Scale) to select FIr-B/FOx regimen in fit or tailored treatments in unfit elderly. Limiting toxicity syndromes (LTS) were evaluated. Results: At 17 months follow-up, in 28 young-elderly patients treated with first line FIr-B/FOx: objective response rate (ORR) 79%, progression-free survival (PFS) 11 months, overall survival (OS) 21 months. Clinical outcome was not significantly different according to KRAS genotype. G3-4 toxicities were diarrhea 21%, mucositis 11%, neutropenia 11%. LTS were 46%, significantly more multiple than single site. At 8 months follow-up, in 37 unfit patients: ORR 37%, PFS 7 months, OS 13 months. PFS was significantly different in KRAS wild-type compared to mutant patients, while not OS. PFS and OS were significantly worse in KRAS c.35 G > A compared to wild-type and/or other mutant. Conclusions: Careful decision-making process including evaluation of patient’s fitness, and individual safety should be included to select FIr-B/FOx intensive first line regimen in young-elderly MCRC patients. KRAS , and specifically c.35 G > A mutant genotype, may significantly affect clinical outcome in patients unfit for FIr-B/FOx.

e15013 Background: Cancer treatments induce symptoms and signs superimposing on clinical and cancer-related status of individual patient, defining heterogenous toxicity syndromes (TS). We reviewed intensive first line triplet chemotherapy-based regimens developed in fit metastatic gastro-intestinal cancers (mGI), based on FIr/FOx schedule including fluorouracil and weekly alternating irinotecan and oxaliplatin. Methods: Metastatic colorectal (mCRC), pancreatic ductal adenocarcinoma (mPDAC), gastric carcinoma (mGC) patients were enrolled by careful decision-making in real life phase II studies: FIr-B/FOx, adding bevacizumab (BEV), in overall, and FIr-C/FOx-C, adding cetuximab (CET), in KRAS/NRAS wild-type mCRC, respectively; FIr/FOx in mPDAC; FD/FOx, adding docetaxel (D), in mGC. Toxicity, and individual limiting toxicity syndromes (LTS), classified as limiting toxicity alone (LTS-single site, LTS-ss) or associated to other limiting or G2 toxicities (LTS-multiple sites, LTS-ms) were evaluated and compared by chi-square test. Results: FIr-B/FOx and FIr-C/FOx-C in mCRC, FIr/FOx in mPDAC, FD/FOx in mGC, respectively reported activity, efficacy and limiting toxicities similar to other triplet chemotherapy-based regimens. Reported LTS: FIr-B/FOx in mCRC 44%, LTS-ms 24% and LTS-ss 20%, in young elderly (yE) 46%, LTS-ms significantly increased vs LTS-ss; FIr-C/FOx-C in KRAS/NRAS wild-type mCRC 65.5%, significantly increased LTS-ms vs LTS-ss, in yE 83%; FIr/FOx in mPDAC 27.5%, mostly LTS-ms, in yE 38.4% all LTS-ms; FD/FOx in mGC 30%, all LTS-ms, in yE 25%. Conclusions: LTS meet the need of an innovative clinical parameter of patient-related toxicity burden, indicating global and individual tolerability, including differential spectrum and intensities of TS related to cancer treatment and according to clinical status of the individual patient. LTS integrated with conventional toxicity evaluation may help properly select patients fit for intensive medical treatments in mGI cancers.

Clinical outcome post-progression to first-line triplet chemotherapy (CT) plus bevacizumab (FIr-B/FOx) was evaluated in metastatic colorectal cancer (MCRC) patients (pts). Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank analysis. Among 54 pts, median overall survival (OS) post-progression was 12 months, significantly better in 40 (74.1%) treated compared to 14 (25.9%) who died without further treatment. Second-line surgical treatment, 4 pts (7.4%), medical treatment, 36 pts (66.7%): triplet CT plus targeted agent, 10 (18.5%); triplet regimens, 19 (35.2%); doublet/monotherapy, 7 (13%). At follow-up of 14 months, objective response rate (ORR) was 38%, metastasectomies 12.5%, progression-free survival (PFS) 10 months, OS 14 months. According to treatment, ORR, metastasectomies, PFS and OS were significantly favourable in triplet CT plus targeted agent compared to triplet, respectively: 80%, 40%, 13 months, not reached; 28%, 6%, 8 months, 11 months. PFS and OS were significantly worse in c.35 G>A mutant compared to wild-type and/or other mutant patients. Prognosis after progression to first-line FIr-B/FOx may be significantly favourable in MCRC pts re-challenged with intensive regimens, and unfavourable in c.35 G>A KRAS mutant patients.

This paper evaluates a recent study whereby a four-drug combination regimen adding bevacizumab to triplet fluorouracil, oxaliplatin and irinotecan chemotherapy is described for the first-line treatment of metastatic colorectal cancer. It extends the use of intensive medical treatments combining chemotherapy and the VEGF inhibitor bevacizumab, opening new perspectives for the design of four-drug intensive regimen-associating chemotherapy and targeted agents. In the future, these four-drug intensive regimens should be further improved for efficacy:toxicity ratio and verification in randomized trials.

e15517Background: Intensive triplet chemotherapy/bevacizumab significantly increased MCRC outcome. Phase II study investigated safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line R...

Background: Intensive-first line bevacizumab (BEV) addition to triplet chemotherapy significantly increased clinical outcome in metastatic colorectal cancer (MCRC) patients. Cetuximab (CET) addition to doublet chemotherapy significantly increased clinical outcome in RAS wild-type MCRC. This phase II study investigated safety and activity of FIr-C/FOx-C schedule of weekly CET added to triplet chemotherapy in first line RAS wild-type MCRC. Methods: The phase II study was planned according to Simon two-step design: delta 15% (p0 70%, p1 85%), power 80%, α 5%, β 20%; projected objective responses (ORR), I step 14/19 patients. FIr-C/FOx-C schedule: 5-fluorouracil (5-FU) 12h-timed-flat-infusion 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; associated to weekly alternating irinotecan (CPT-11) 160 mg/m2, days 1,15 or oxaliplatin (OXP) 80 mg/m2, days 8, 22; CET 400 mg/m2 loading dose, then 250 mg/m2 days 1,8,15,22; every 4 weeks. Toxicity and limiting toxicity syndromes (LTS) were evaluated and compared using chi-square test; activity and efficacy using log-rank test. 5-FU degradation rate (5-FUDR) and single nucleotide polymorphisms (SNP) of 4 genes (DYPD, CYP3A4, ABCB1, UGT1A1) involved in metabolism of 5-FU and CPT-11 were evaluated in individual patients showing LTS and at the recommended doses as predictive biomarkers of toxicity. Results: Twenty-nine consecutive patients 80% for each drug and cumulative G3-4 toxicities in 13 patients were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%. LTS, consisting of the LT, associated or not to G2 or other LT, were observed overall in 19 patients (65.5%), 83% in yE. LTS were prevalently multiple than single site (59% versus 7%, chi square 7.703, p = 0.006). Reduced FUDR, CYP3A4 and UGT1A1 SNPs, also frequently associated, were particularly observed in patients showing gastrointestinal LTS, while not in patients without LTS. Conclusion: Intensive first-line FIr-C/FOx-C regimen at the modified recommended doses is tolerable and highly effective in RAS wild-type MCRC patients, with significantly increased LTS multiple sites, justifying careful selection of fit patients using a panel of 5 predictive biomarkers of 5-FU and CPT11 toxicity. Citation Format: Gemma Bruera, Silvia Massacese, Antonella Dal Mas, Corrado Ficorella, Eugenio Ciacco, Giuseppe Calvisi, Maurizio Simmaco, Enrico Ricevuto. Predictive wild-type RAS/BRAF and pharmacogenetic biomarkers drive selection of metastatic colorectal cancer patients fit for intensive first-line FIr-C/FOx-C schedule adding cetuximab to triplet chemotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A052.

Author Summary Background. Anthracyclines and taxanes are effective drugs in breast cancer (BC), but their toxicity profiles limit their use in combination. A dose-finding study was performed to determine maximum tolerated doses (MTDs) of nonpegylated liposomal doxorubicin (TLC-D99) and docetaxel (DTX) as a dose-dense schedule, to maintain dose intensity, and to limit toxicity, particularly cardiac. Methods. Twenty-four patients were enrolled, 12 with metastatic BC, 5 with locally advanced BC, and 7 with early BC. An intra- and interpatient approach was planned in two sequential steps. In the first step, TLC-D99 was administered at dose levels of 40, 45, and 50 mg/m2 plus DTX at a fixed dose of 50 mg/m2. In the second step, TLC-D99 was administered at the dose established in the first step plus DTX at dose levels of 55, 60, and 65 mg/m2. Every treatment cycle was delivered on day 1 every 14 days. Pegylated granulocyte colony-stimulating factor was scheduled on day 2. Dose-limiting toxicities (DLTs) were defined as G4 hematological; G3 nonhematological; ≥10% or ≥20% left ventricular ejection fraction (LVEF) reduction if the final value was Results. Five DLTs occurred (20.8%). No cardiac event of congestive heart failure was reported; 2 events of grade 3 cardiac dysfunction (8.3%), including a ≥20% LVEF reduction in 1 patient and symptomatic arrhythmia in another; 2 incidences of G4 neutropenia (8.3%); and 1 occurrence of G3 asthenia (4.2%) were reported. MTDs were not reached. The recommended doses were established as TLC-D99 50 mg/m2 and DTX 65 mg/m2. Cumulatively, mild (G1–G2) cardiac dysfunction was observed in 58.4% of patients: G1 cardiac arrhythmia was noted in 50%, G1–G2 general cardiac toxicity occurred in 25%, and concomitant toxicity was present in 17%. cTnI never increased. pBNP was increased in 25% and was associated with limiting arrhythmia in 4% and cardiac dysfunction in 16%. Conclusion. Dose-dense TLC-D99 50 mg/m2 and DTX 65 mg/m2 can be safely administered in combination every 2 weeks for breast cancer, with the highest projected dose intensity for each drug at 25 and 32.5 mg/m2 per week, respectively.

The treatment with poly ADP-ribose polymerase (PARP) inhibitors represents a peculiar targeted therapy specifically destroying cancer cells harboring a relevant DNA damage repair dysfunction, through the inhibition of a different other pathway of DNA repair, thus realizing the synthetic lethality. PARP inhibitors target key enzymes of the base excision repair pathway, involved in repairing DNA single-strand breaks, more specifically when the preferred homologous recombination (HR) mechanism for repairing double-strand breaks is lost due to BRCA1 dysfunction. HR defects such as occurring in cancers harboring BRCA1/BRCA2 predisposition are extremely sensitive to PARP inhibitors.

Bevacizumab-containing chemotherapy differently predict increased efficacy in KRAS exon 2 mutant and wild-type metastatic colorectal cancer (MCRC) patients. Mutant compared to wild-type status did not significantly affect progression-free survival (PFS) and overall survival (OS) in patients fit for first line bevacizumab-containing FIr-B/FOx regimen, and after progression. In patients unfit for intensive regimens, mutant status significantly affected PFS, while not OS. Codon 12 KRAS mutations differentially affect GTPase function, and confer worse clinical behaviour. Prognostic relevance of the prevalent c.35 G. >. A KRAS mutation was retrospectively evaluated. Fit c.35 G. >. A mutant patients showed significantly worse OS compared to wild-type and to other mutant. After progression and in unfit patients, c.35 G. >. A mutation affected significantly worse PFS and OS. c.35 G. >. A mutant status does not significantly affect worse PFS in patients fit for first line FIr-B/FOx, and it may depend upon effectiveness of anti-VEGF-containing intensive regimen.

644 Background: RAS/BRAF genotype guide MCRC treatment. First line triplet chemotherapy/BEV significantly improved PFS and OS. OS was significantly worse in KRAS c.35G > A and BRAF mutant (mt). Most CRC (86%) harbored mt genes, prevalently TP53, RAS, BRAF, PIK3CA. Methods: MCRC samples of 67 pts treated with FIr-B/FOx (77% overall) were analyzed through a 50 genes panel (PGM/Colon Lung Cancer) by ION Torrent: 57 (85%) primary, 10 (15%) metastatic samples; 59 (88%) pre-, 8 (12%) post-treatment. Molecular diagnostic criteria: > 50% coverage; > 1% mutant allelic fraction. Clinical outcomes were evaluated and compared by log-rank. Results: All wild-type (wt) and mt MCRC were 6 (8.9%) and 61 (91.1%), respectively; median mt genes 3 (1-12). Mt genes, 35 (%): KRAS 44 (65.6%), TP53 38 (56.7%), APC 26 (38.8%), KIT 23 (34.3%), PDGFRA 19 (28.3%), PIK3CA 18 (26.8%), EGFR and NRAS 15 (22.3%), SMAD4 10 (14.9%), FBXW7 and MET 7 (10.4%), GNAS and PTEN 6 (8.9%), BRAF and NOTCH1 5 (7.4%), ATM, PTPN11 and SMARCB1 4 (5.9%), HRAS, KDR, JAK3 and VHL 3 (4.4%), ERBB2, FGFR2, FGFR3, IDH1 and STK11 2 (2.9%), ABL1, AKT1, CDKN2A, FGFR1, FLT3, HNF1A, RB1, RET 1 (1.4%). BRAF mutations: c.1756G > A, 1796C > T, 1405G > A, 1406G > C. Median follow-up 21 months (m), overall PFS 13, OS 27m: KRAS exon 2 ( KRAS2) wt/mt, PFS 14/12m, OS 28/21m, respectively, not significantly different; c.35G > A KRAS mt showed trendly worse OS 14m; BRAF mt significantly worse PFS (8 vs 14m, p .026) and OS (11 vs 28m, p .002); RAS2-4/ BRAF15 wt/mt, PFS 18/13m (p .954), OS 28/22m (p .956). TP53 wt/mt, PFS 14/12m, OS 28/23m. All wt, PFS 24, OS 44m, not significantly different vs ≥ 1 mt gene. Conclusions: Multigenic analysis of MCRC patients treated with FIr-B/FOx shows worse clinical outcome conferred by uncommon BRAF mutations.

Both Aurora-A and -B kinases have been implicated in tumorigenesis; and as such, they represent an attractive therapeutic target. Recent studies found that Aurora-A is a downstream target of mitogen-activated protein kinase 1/ERK2, while Aurora-B has been found to be a prognostic/predictive therapeutic target for epithelial cancer. In a wide range of human cancers, the Ras/Raf/MEK/ERK/MAP kinase pathway is enhanced and the cellular response to growth signals is known to increase. The purpose of this study was to investigate whether the MEK/ERK cascade regulates tumorigenic signaling and radioresistance via the Aurora-B-mediated pathway in a panel of gynecological cancer cell lines. Exponentially growing human endometrial (Ishikawa), cervical (HeLa), cervical (CASKI) and vulva (SiHa) cancer cells were used in culture treated with either control or MEK/ERK inhibitor or AZD1152 before and after irradiation. Western blotting, ERK1/2 siRNA transfection, growth assay in modified monolayer, Annexin V and migration/invasion assays were performed. The specific MEK/ERK inhibitor U0126 decreased the tumorigenic potential and improved the radiation response in all cellular models. The modulation of radioresponse upon U0126 treatment positively correlated with the inhibition of phospho-ERKs and the reduction of Aurora-B kinase expression. In addition, upon U0126 treatment DNA-PKcs protein expression was found to be downregulated, indicating that the improved radiation response may be caused by decreased DNA double-strand damage repair mechanisms. The knockdown of ERK by siRNA confirmed the MEK/ERK-dependent Aurora-B kinase expression. The use of AZD1152, a selective Aurora-B inhibitor, counteracted tumorigenic potential and radioresistance phenotype by highly increasing apoptotic mechanisms in all gynecological cancer cell lines used. Evidence from our experiments show that tumorigenic potential and radiation response in gynecological cancer cells may ensue from a MEK/ERK or Aurora-B inhibition. Together with the close correlation of MEK/ERK and Aurora-B protein expression, this study underlines the potential role of a MEK/ERK/Aurora-B axis whose interruption recovers the antitumor effects of radiotherapy.

hepatocellular carcinoma, haemophilia, treatment

Background Prognosis of KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients (pts) treated with bevacizumab (BEV)-containing chemotherapy is not significantly different. Since specific KRAS mutations confer different aggressive behaviors, the prognostic role of prevalent KRAS mutations was retrospectively evaluated in MCRC pts treated with first line FIr-B/FOx, associating BEV to triplet chemotherapy. Methods Tumor samples were screened for KRAS codon 12, 13 and BRAF V600E mutations by SNaPshot and/or direct sequencing. MCRC pts 2 on days 1,2, 8, 9, 15, 16,22, 23), irinotecan plus BEV (160 mg/m2 and 5 mg/kg, respectively, on days 1,15); and oxaliplatin (80 mg/m2, on days 8,22). Pts were classified as liver-limited (L-L) and other/multiple metastatic (O/MM). Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test. Results Fifty-nine pts were evaluated at a median follow-up of 21.5 months. KRAS mutant pts: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). The objective response rate (ORR), PFS and OS were, respectively: c.35 G > A mutant, 71%, 9 months, 14 months; other than c.35 G > A mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G > A pts compared to KRAS wild-type (P = 0.002), KRAS/BRAF wild-type (P = 0.03), other MCRC patients (P = 0.002), other than c.35 G > A (P = 0.05), other codon 12 (P = 0.03) mutant pts. OS was not significantly different compared to c.35 G > T KRAS mutant (P = 0.142). Conclusions KRAS c.35 G > A mutant status may be significantly associated with a worse prognosis of MCRC pts treated with first line FIr-B/FOx intensive regimen compared to KRAS/BRAF wild type and other than c.35 G > A mutant pts.

Four-drug regimens, such as FIr-B/FOx schedule, can improve efficacy of first-line treatment of metastatic colorectal cancer (MCRC) patients. The present study specifically evaluates feasibility of FIr-B/FOx first-line intensive regimen in fit young-elderly MCRC patients, representing approximately 40% of overall MCRC patients. Activity, efficacy, and safety were equivalent to overall MCRC patients, not significantly different according toKRASgenotype. Clinical outcome was significantly prolonged in liver-limited compared to other/multiple metastatic disease. Safety evaluation of the individual young-elderly patient showed that limiting toxicity syndromes (LTS) in multiple sites were significantly increased, compared to LTS in single site, with respect to non-elderly patients.

Background Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated. Methods Tumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients 2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test. Results In all, 59 patients were evaluated: 31 KRAS wild-type (53%), 28 KRAS mutant (47%). At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively. Conclusions The KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.

A major problem concerning the addition of more drugs in a chemotherapy combination is designing a proper schedule assuring the balance between dose intensity of each drug, efficacy of the combination, and tolerability lessening the burden of drug toxicity. We evaluated triplet chemotherapy-based intensive regimens proposed as first-line treatment in patients with metastatic colorectal cancer. Using a FOLFOXIRI (5-fluorouracil [5-FU], irinotecan, and oxaliplatin) combination regimen, patients with metastatic colorectal cancer now have the possibility of longer survival, but disappointingly, with increased toxicities. Triplet chemotherapy regimen according to 5-fluorouracil, irinotecan /5-fluorouracil, oxaliplatin, characterized by timed flat-infusion 5-FU administration, without leucovorin, obtained efficacy equivalent to other reported similar combination regimens (5-FU, irinotecan, and oxaliplatin), with increased received 5-FU dose intensity and lower grade 3 to 4 neutropenia. To guarantee the proper balance between dose intensities, efficacy, and toxicity, triplet chemotherapy schedules could be further improved by abrogation of folinic acid and bolus 5-FU, a new and easy modality of 5-FU administration, such as timed flat-infusion 5-FU, associated with alternating irinotecan and oxaliplatin; this could favor diffusion of this intensive treatment in clinical practice.

Background Intensive medical treatment increases resection rate of liver metastases in patients with metastatic colorectal cancer (MCRC). The effectiveness of liver metastasectomies was evaluated in patients with MCRC who were treated with previously reported FIr-B/FOx (triplet chemotherapy plus bevacizumab). Patients and Methods Fifty patients with MCRC enrolled in the reported phase II study were classified according to involved metastatic sites (liver-only metastatic site, multiple metastatic sites) and the extent of liver metastases (single, multiple). Surgical resectability of liver metastases was evaluated at baseline and every 3 cycles of FIr-B/FOx treatment. The resection rate of liver metastases, activity, and efficacy were evaluated; progression-free survival (PFS) and overall survival (OS) were compared by using the log-rank test. Results Patients with liver MCRC were 33 of 50 consecutive unselected patients with MCRC: liver limited, 22 patients; multiple metastatic sites, 11 patients. Liver metastasectomies were performed in 13 patients: 26% of 50 patients with MCRC, 39% of 33 patients with liver MCRC. In patients with liver-only MCRC, a secondary liver surgery was performed in 54%: 6 of 9 single and 6 of 13 multiple liver metastases. Also, 1 liver and lung metastasectomy was performed. Pathologic complete responses were achieved in 2 patients (15%). The conversion rate of unresectable liver metastases was 83%. Objective response rate, PFS, OS were, respectively: 84%, 11 and 23 months in 33 liver MCRC; 86%, 17 and 44 months in 22 liver-limited patients. PFS and OS were significantly increased in patients with liver-limited metastases compared with multiple metastatic sites and single compared with multiple liver metastases. Conclusion The FIr-B/FOx regimen may increase the resection rate of liver metastases and improve clinical outcome of patients with liver-only MCRC.

The present study evaluated activity and toxicity of modulated doses of gemcitabine associated to oxaliplatin in patients with secondary CIRS and with locally advanced pancreatic adenocarcinoma (LAPC) and metastatic pancreatic adenocarcinoma (MPC). Since January 2006, untreated LAPC and MPC patients have been assessed with ADL, IADL, CIRS to modulate chemotherapy dosages according to co-morbidity stage. Patiens aged

Background This phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC). Methods Simon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks. Results Fifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%. Conclusion Poker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered. Trial registration Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34

A weekly administration of alternating irinotecan or oxaliplatin associated to 5-Fluorouracil in advanced colorectal cancer was planned in order to evaluate a new schedule maintaining dose intensities of each drug as in double combinations and tolerability of the triplet association. The following weekly schedule was administered: irinotecan, days 1 and 15; oxaliplatin, days 8 and 22; 5-fluorouracil (5-FU) over 12-h (from 10:00 p.m. to 10:00 a.m.) timed flat infusion, days 1-2, 8-9, 15-16 and 22-23, every 4 weeks. Dose- finding and phase II study were planned. Thirteen patients were enrolled in the dose-finding study and 23 in the phase II study. The recommended doses of our study are: irinotecan 160 mg/m(2); oxaliplatin 80 mg/m(2); 5-FU 900 mg/m(2). The dose-limiting toxicity was diarrhea (35% of patients) but no cases of febrile neutropenia were observed. In 30 patients assessable for response two complete (6.7%) and 18 partial (60%) responses were observed, for an overall response rate of 66.7% (alpha 0.05, CI+/-17). The triplet association using this weekly alternating schedule is an active and well-tolerated outpatient regimen. Surgical removal of residual disease was considered in 5 patients and a radical resection was performed in 5 patients (147 %).

e14575 Background: Bevacizumab (BEV) addiction to chemotherapy can predict increased efficacy in KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients. Codon 12 KRAS mutations diff...

512 Background: KRAS genotype does not significantly affect prognosis of MCRC patients treated with bevacizumab-containing chemotherapy. Codon 12 mutations increase aggressiveness by differently modifying mutated KRAS and downstream signalling, thus conferring worse clinical behavior. Prognostic relevance of the prevalent c.35 G > A KRAS mutation in MCRC patients fit and unfit for first-line bevacizumab added to triplet chemotherapy (FIr-B/FOx) was evaluated. Methods: KRAS codon 12/13 mutations were screened. Efficacy was evaluated and compared by log-rank. Results: Fifty-nine fit patients were treated with firstline FIr-B/FOx: wild-type, 31 (53%); mutant, 28 (47%). KRAS mutations: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). Wild-type compared to mutant status did not significantly affect PFS (14 and 11 months) and OS (38 and 20 months). c.35 G > A mutant showed: no significantly different PFS compared to wild-type; significantly worse OS (14 months) compared to wild-type and to other mutant (39 months). After progression, wild-type compared with mutant did not show significantly different PFS (10 months equivalently) nor OS (17 and 12 months); c.35 G > A compared to wild-type and/or other mutant showed significantly worse PFS and OS. Among 39 unfit patients, treated with conventional regimens, wild-type compared to mutant significantly affected PFS (8 and 6 months), and not OS (13 and 8 months); c.35 G > A mutation significantly affected worse PFS and OS compared to wild-type and/or other mutant. Conclusions: KRAS genotype does not significantly affect clinical outcome of MCRC patients treated with first line FIr-B/FOx, while mutant status may significantly affect worse PFS in patients unfit for intensive treatments. c.35 G > A mutant status, compared to wild type and other mutant, may significantly affect worse clinical outcome in MCRC patients treated with first line intensive FIr-B/FOx and after progression, as well as in patients unfit for FIr-B/FOx, due to increased biological aggressiveness. It did not affect worse PFS only in patients treated with FIr-B/FOx, probably due to effectiveness of triplet chemotherapy plus VEGF inhibitor.

Background: Prognosis of MCRC patients treated with bevacizumab and chemotherapy is not significantly different according to KRAS genotype. Specific mutations confer different aggressiveness. In vitro, codon 12 mutations increase aggressiveness by differential KRAS pathways regulation. Different codon 12 mutations modify biological activity of mutated KRAS proteins. Biological aggressiveness of codon 12 mutant tumors confers worse clinical behavior. RAS/RAF/MEK/ERK pathway increases VEGF expression and represses negative angiogenesis regulators; its aberrations stimulate angiogenesis and influence response to anti-VEGF. Prognostic role of prevalent c.35 G>A KRAS mutation in first line FIr-B/FOx, post-progression, and in patients unfit for FIr-B/FOx was evaluated. Methods: KRAS codon 12/13 were screened by SNaPshot and/or sequencing. Efficacy was evaluated and compared according to KRAS genotype, using log-rank. Results: At 21.5 months follow-up, 59 fit MCRC patients were treated with first line FIr-B/FOx: wild-type, 31 (53%); mutant, 28 (47%). KRAS mutations: c.35 G>A (G12D), 15 (25.4%); c.35 G>T, 7 (11.8%); c.38 G>A, 3 (5%); other, 3 (5%). KRAS genotype wild-type compared to mutant did not significantly affect PFS (14 and 11 months) and OS, even if OS seems favorable in wild-type (38 and 20 months). PFS of c.35 G>A mutant compared to wild-type was not significantly different. OS was significantly worse in c.35 G>A patients (14 months) compared to: wild-type (p = 0.002); other mutant (39 months) (p = 0.05). Wild-type compared with mutant did not show significantly different PFS (10 and 10 months) nor OS (17 and 12 months), after progression. PFS and OS after progression were significantly worse in c.35 G>A compared to wild-type and/or other mutant patients. Among patients unfit for FIr-B/FOx, and treated with conventional medical treatments, KRAS genotype wild-type compared to mutant significantly affected PFS (8 and 6 months), while not OS (13 and 8 months). c.35 G>A mutation significantly affected worse PFS and OS compared to wild-type and/or other mutations. Conclusions: KRAS genotype, wild-type compared to mutant, did not significantly affect prognosis in MCRC patients treated with first line FIr-B/FOx, while it significantly affected worse efficacy (PFS) in patients unfit for intensive medical treatments. KRAS c.35 G>A mutant status compared to wild type and other mutant, may significantly affect worse prognosis of patients, treated with first line intensive regimen (FIr-B/FOx), after progression, or unfit for FIr-B/FOx, probably due to increased biological aggressiveness. It did not affect worse PFS only in patients treated with first line FIr-B/FOx, probably due to effectiveness of intensive medical treatment consisting of triplet chemotherapy and VEGF inhibitor. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C35. Citation Format: Gemma Bruera, Katia Cannita, Edoardo Alesse, Corrado Ficorella, Enrico Ricevuto. Different prognostic relevance of KRAS genotype in metastatic colorectal cancer (MCRC) patients fitting for triplet chemotherapy plus VEGF-inhibitor, unfit for intensive medical treatment and post-progression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C35.

e14596 Background: Prognosis of MCRC patients (pts) treated with bevacizumab (BEV) and chemotherapy (CT) is not significantly different according to KRAS genotype. Specificmutations confer different aggressiveness. Prognostic relevance of the prevalent c.35 G > A KRAS mutation was retrospectively evaluated in pts treated with first line FIr-B/FOx, and post-progression. Methods: KRAS codon 12/13 and BRAF mutations were screened by SNaPshot and/or sequencing. FIr-B/FOx: weekly 2 days/12h-timed-flat-infusion/5-fluorouracil 900 mg/m2, weekly alternating irinotecan 160 mg/m2/BEV 5 mg/kg, or oxaliplatin 80 mg/m2. Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank. Results: At 21.5 months, 59 pts were evaluated. KRAS mutant pts: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). ORR, PFS, OS were, respectively: c.35 G > A, 71%, 9 months, 14 months; other mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G > A pts compared to KRAS wild-type (p = 0.002), KRAS/BRAFwild-type (p = 0.03), other pts (p = 0.002), other mutants (p = 0.05), other codon 12 (p = 0.03) mutant pts; PFS was not significantly different. Post-progression, at 14 months follow-up, PFS and OS were significantly worse in c.35 G > A compared to wild-type and/or other mutant pts. ORR of second line treatments was 38%, metastasectomies 12.5%, PFS 10 months, OS 14 months. PFS and OS were significantly favourable in pts treated with triplet CT plus targeted agent compared to triplet, respectively: PFS 13 months versus 8 months; OS not reached versus 11 months. Conclusions: KRAS c.35 G > A mutation may significantly affect worse OS of MCRC pts. It does not significantly affect worse PFS of intensive first line FIr-B/FOx, while after progression significantly affect worse efficacy of second line treatments. Re-challenge of intensive regimens may affect significantly favourable PFS and OS.

Background Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of MCRC (Bruera G et al, BMC Cancer 2010, 10:567), particularly if integrated with secondary liver surgery in liver-limited (L-L) patients (pts) (Bruera G et al, Clin Colorectal Cancer 2012). Clinical outcome of FIr-B/FOx regimen was evaluated according to KRAS genotype in L-L and other MCRC pts. Methods Tumoral and metastatic samples were screened for KRAS codon 12 and 13, and BRAF mutations by SNaPshot and/or direct sequencing. MCRC pts were classified as L-L and other or multiple metastatic (O/MM). Activity and efficacy were evaluated and compared using log-rank test. Results Fifty-nine pts were evaluated: 31 KRAS wild-type, 53%; 28 KRAS mutant, 47%. At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were, respectively: overall in 25 L-L compared to 32 O/MM evaluable pts, 17 and 12 months, 47 and 21 months, significantly different; in KRAS wild-type, 12 L-L compared to 18 O/MM, 21 and 12 months, 47 and 28 months, significantly different; in KRAS mutant, 13 L-L compared to 14 O/MMS, 11 months equivalently, 39 and 19 months, not significantly different. Conclusion First line FIr-B/FOx regimen can increase activity and efficacy of KRAS wild-type and mutant MCRC pts; integration with secondary liver surgery significantly discriminates increased clinical outcome in KRAS wild-type L-L compared to O/MM pts while not in KRAS mutant pts. Disclosure All authors have declared no conflicts of interest.

Three hundred and twenty-nine bone metastatic patients (BMP) followed at Medical Oncology Division, San Salvatore Hospital L'Aquila from 1995 were evaluated. Primary tumors were: breast 113, 55%; prostate 29, 14%; lung 26, 13%. Treatment with bisphosphonates was administered in 204 patients, 62% (male/female, 80/124): zoledronic acid and/or intravenous pamidronate 178, 87%; ibandronate 16, 8%; and ibandronate followed by intravenous bisphosphonate 10, 5%. Median duration of treatment was 7 months (range 1-47months), 19,5 months (range 1-57months) and 27 months (range 9-44months), respectively. Features of bone metastases: multiple bone sites 193 (95%), one bone site 11 (5%); osteolytic 124 (61%), osteosclerotic lesions 35 (17%), mixed 28 (14%), undetermined 17 (8%). Involved sites: spinal column, 172 (84%); pelvis/hip, 146 (72%); long bones, 102 (50%); other skeletal sites, 156 (76%). Overall skeletal–related events (SREs) during follow up were 140 (69%): pathologic fracture, 45 (22%); spinal cord compression, 6 (3%); bone RT, 120 (59%); bone surgery, 14 (7%). The first occurring SRE was: pathologic fracture in 28 patients (20%); spinal cord compression, 3 (2%); bone RT, 108 (77%); bone surgery, 1 (1%). Number of SREs in individual patient was: 1 in 54%; 2 in 25%; 3 in 17%; 4 in 7%; 6 in 1%. SREs before onset of treatment with bisphosphonate were 99 (71%), after treatment were 41 (29%). A baseline mouth assessment with dental visit and/or orthopantomography of the jaws was performed in 58% of patients, 2% also with TAC or RMN. Median survival after diagnosis of bone metastases was 32 months. Median time to first SRE after diagnosis of bone metastases was 15 days. Median survival after first SRE was 29 months. Events related to bisphosphonate were: acute phase reactions (first 3 days), 6 (2,5%); pyrexia, 5 (2%); bone pain, 2 (0,8%); arthralgia, 1 (0,4%); hypercalcemia, 4 (1,7%); hypocalcemia, 7 (2,9%); toothache, 3 (1,25%); osteonecrosis of the jaw (ONJ), 6 (2,5%); uveitis, 1 (0,4%). ONJ before and after introduction of baseline mouth assessment, 4/65 patients (6.1%) and 2/139 patients (1,4%), respectively. Our experience confirms the relevance of SREs and efficacy of bisphosphonate treatment in BMP. Disclosure All authors have declared no conflicts of interest.