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2522 Background: NGR-hTNF consists of tumor necrosis factor fused with the peptide NGR, which selectively binds to CD13 overexpressed on tumor blood vessels. Maximum tolerated dose (MTD) of NGR-hTN...

2521 Background: Combined targeting of ERBB receptors and VEGF-dependent signaling pathways has proven to be a successful strategy in preclinical studies. L is a dual HER2/EGFR tyrosine kinase inhi...

4115 Background: S is the only targeted agent that has been shown to improve survival in advanced HCC. It is not known whether a rebound phenomenon occurs after discontinuation of treatment after radiological progression (PD), or if continuation of treatment beyond this endpoint further delays tumor progression. The present trial was proposed to address this question. Methods: This phase II randomized trial evaluated the feasibility and efficacy of increased-dose S (600 mg bid) after PD (RECIST criteria) on S 400 mg bid (standard dose). The primary aim was PFS from PD. Patients (pts) with histologically proven advanced HCC unsuitable for loco-regional therapies, Child-Pugh class A/B cirrhosis, were randomized 1:1 to increased-dose S + BSC vs BSC. Written informed consent was obtained from all pts. S was continued until disease progression or unacceptable toxicity. Results: From April 2007 to July 2008, 300 pts were prospectively treated with S 400 mg bid. At documented PD, 101 pts (34%) were randomized: 4...

The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate. Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC. Nevertheless, in clinical practice, some patients are discontinuing this drug because of side effects, and misinterpretation of radiographic response may contribute to this. We highlight the importance of prolonged sorafenib administration, even at reduced dose, and of qualitative and careful radiographic evaluation. We observed two partial and two complete responses, one histologically confirmed, with progression-free survival ranging from 12 to 62 mo. Three of the responses were achieved following substantial dose reductions, and a gradual change in lesion density preceded or paralleled tumor shrinkage, as seen by computed tomography. This report supports the feasibility of dose adjustments to allow prolonged administration of sorafenib, and highlights the need for new imaging criteria for a more appropriate characterization of response in HCC.

e13565 Background: Sorafenib (S) is an oral multitarget drug inhibiting tumor proliferation, reducing tumor vasculature, and promoting apoptosis. S is a standard treatment in renal cell carcinoma (...

4092 Background: Evidence suggests that AFP response predicts survival in HCC patients (pts) treated with locoregional procedures or systemic therapies. Its impact on outcome prediction in pts rece...

e14057 Background: Prognosis for metastatic colorectal-cancer (mCRC) patients is unfavorable. Futhermore mCRC patients with tumors harboring a mutation in the KRAS gene do not derive benefit from the administration of cetuximab. We hypothesized that KRAS mutated CRC cells may be susceptible to cetuximab-induced ADCC mediated by healthy donor NK cells. Methods: Purified allogeneic NK cells or preincubated with IL-2 or IL-15 were used as effectors. Seven different CRC cell lines (DLD1, HCT-116, HT-29, LOVO, SW620, SW48, SW480) labeled with 51Cr were used as target cells alone or preincubated with cetuximab for ADCC assay. Results: All but one (SW620) cell lines express EGFR and MHC molecules; 4/7 harbor KRAS mutation (DLD 1, HCT-116, SW620, SW480). All cell lines were susceptible to unstimulated NK cells lysis (mean 20% ± 4.57, at ratio 25:1; mean 15% ± 3.65, at ratio 12:1) and lytic activity is strongly enhanced by IL-2 or IL-15 (mean 48% ± 5.8, at ratio 25:1; mean 38% ± 4.3, at ratio 12:1) (p < 0.05). No ...

e13091 Background: NGR-hTNF is a vascular targeting agent exploiting a tumor homing peptide (NGR) that selectively binds an aminopeptidase N overexpressed on tumor blood vessels. Previously, a phas...

Abstract 5119 Purpose Prognosis for metastatic colorectal-cancer (mCRC) patients is unfavorable, median survival from diagnosis varying between sixteen and twenty-four months. Numerous clinical trials have demonstrated a clinical advantage for patients treated with a combination of chemotherapy and cetuximab. However recent retrospective evidence from several randomized studies, has established that mCRC patients with tumors harboring a mutation in the KRAS gene do not derive benefit from the administration of cetuximab. We hypothesized that KRAS mutated CRC cells may be susceptible to cetuximab-induced ADCC mediated by healthy donor NK cells. Experimental Design 7 different CRC cell lines (DLD 1, HCT-116, HT-29, LOVO, SW620, SW48, SW480) were analyzed for EGFR membrane expression levels, tested for KRAS mutational status and MHC class I-II expression. CD56+CD3- NK cells were purified from volunteer healthy donors peripheral blood mononuclear cells, by a two-steps CD3+ cells negative selection followed by CD56+ cells positive selection by MACS cell separation columns (Miltenyi biotec). Purified NK cells were incubated overnight with medium alone or stimulated with IL-2 (100U/ml) or IL-15 (20U/ml). CRC cell lines, were labeled with 51Cr overnight, and used as target cells for NK assay or incubated at 4°C for 30 minutes with Cetuximab 100 ug/ml for ADCC assay. Cytotoxic activity was evaluated in a 4-hour cytotoxicity assay, at an effector/target (E/T) ratio ranging between 100:1 and 2:1. Results all but one (SW620) CRC cell lines express EGFR (range 40-90%) and MHC class I-II molecules; 4/7 harbor KRAS mutation (DLD 1, HCT-116, SW620, SW480). All CRC cell lines were susceptible to unstimulated allogeneic NK cells lysis (mean 20% ± 4,57, at ratio 25:1; mean 15% ± 3,65, at ratio 12:1) and lytic activity is significantly enhanced (p Conclusions allogeneic NK cells from different healthy donors are able to lyse all tested CRC lines (4 KRAS mutated). IL-2 and IL-15 activation significantly enhances NK cytotoxicity; moreover lytic activity of thawed and fresh NK cells is similar allowing the use of both populations in clinical trials. In ADCC assay NK cell lytic activity is significantly enhanced by cetuximab; surprisingly cetuximab mediated ADCC activity is independent from CRC cell lines KRAS oncogene mutational status and require EGFR membrane expression. Pre-coating with cetuximab also increase lytic activity of IL-2 and IL-15 activated NK cells. Further experiments are in progress to evaluate the susceptibility to the lysis of primary tumor cells derived from KRAS mutated and wild type CRC patients, in NK and ADCC assays in order to confirm data obtained against established CRC cell lines and to correlate cetuximab-mediated ADCC with EGFR membrane expression. These findings support a phase I study with allogeneic NK cells infusions in association with cetuximab and IL-2 in mCRC patients harboring a mutation in the KRAS gene. Disclosures No relevant conflicts of interest to declare.

Background: NGR-hTNF is a VTA consisting of TNF-α fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Methods: CRC pts failing standard therapies received low-dose NGR-hTNF given at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w; triweekly cohort). Progression-free survival (PFS) was the primary study objective with restaging performed q6w. A 2-stage design was used, with 16 and 27 pts to be recruited. Ultimately, an additional 13 pts were treated with 0.8 μg/m2 on a weekly basis (weekly cohort). Results: In the triweekly cohort, 111 cycles (range, 1-10) were delivered to 33 pts with radiologically-documented progression after last therapy. Pts characteristics were: median age: 65 years (range, 5379); M/F 16/17; PS 0/1 26/7. Median number of prior lines was 3 (range, 2-5), whereas 8 pts (25%) had received ≥4 lines and 22 (67%) biologicals. No grade 3-4 drug-related toxicity was observed. Predominant grade 1-2 toxicities were short-lived, infusion-related chills (53%). The median PFS was 2.5 months (95% CI, 2.2-2.8) and the PFS rates at 3 and 4.5 months were 31% and 16%, respectively. The disease control rate was 39% (95% CI, 23-55), with one partial response (3%) and 12 stable diseases (36%). In pts with disease control, the median PFS time was 3.8 months and the 3and 4.5-month PFS rates were 67% and 42%, respectively. With a median follow-up of 18.4 months (95% CI, 18.318.5), the median OS time was 13.1 months (95% CI, 8.7-17.5). The proportions of pts alive at 18 and 24 months were 33% and 25%, respectively. Pts who achieved disease control had a median OS of 15.4 months, while those who did not had 9.3 months. Median OS in pts pretreated with

4088 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed by tumor blood vessels. In preclinical models, NGR-hTNF showed antitumor activity both at low and at high doses. Methods: Pts with CRC resistant/refractory to standard treatments, including biological agents, were treated with low-dose NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and 27 pts to be enrolled after first and second stage, respectively. Progression-free survival (PFS) was the primary end-point with reassessment performed q6w. Results: From January to May 2007, 33 pts with radiologically- documented progressive disease after last therapy were evaluated over 111 cycles (range, 1–10). Pts characteristics were: median age: 65 years (range, 53 to 79); M/F 16/17; PS 0/1 26/7. Median number of prior regimens was 3 (range, 2 to 5). Eight pts (25%) were pre-treated with ≥4 lines and 22 (67%) with biological agents. Neither grade 3–4 treatment-related adverse events nor toxicity-related deaths were observed. Main grade 1–2 toxicities per patient were infusion-related chills (47%) and transient blood pressure increase (9%). One partial response (3%) lasting 5 months and 12 stable diseases (36%) were reported. Median PFS was 2.5 months (95% CI, 2.2–2.8). In a post-hoc analysis, no differences in PFS were detected according to baseline characteristics. With a median follow-up time of 18.4 months (95% CI, 18.3–18.5), 11 pts (33%) were still alive. Median overall survival (OS) was 13.1 months and the 2-year OS rate was 22%. In the subset of stable or responder pts, the median PFS and OS were 3.8 months and 15.4 months, respectively. The 6-month PFS rate in the prior-biological and biological-naïve cohorts was 5% and 20%, respectively, whereas 1-year OS rate was 41% and 72%, respectively. Conclusions: Based on the favorable toxicity profile and disease control in heavily pre-treated CRC patients, NGR-hTNF will be further developed in combination with standard chemotherapy. [Table: see text]

4110 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13 highly expressed on tumour blood vessels. NGR-hTNF combines activity on tumour vascular permeability and direct anticancer activity. In preclinical models, NGR-hTNF showed antitumor activity at both low and high doses. Methods: Pts with CRC refractory to standard treatments, including biological agents, were enrolled to evaluate a low dose of NGR-hTNF given at 0.8 mcg/m2 as 1-hour intravenous infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and 27 pts to be enrolled in stage 1 and 2, respectively. Progression-free survival (PFS) was the primary end point and reassessment was performed q6w. Results: 32 pts (16 M/16 F; PS 0/1 26/6; median age: 65 years, range 53–79) received 111 cycles (median 2, range 1–10) and 13 pts (41%) were treated with ≥4 doses. The median number of prior regimens was 3 (range: 2–5), with 8 pts (25%) pre-treated with ≥4 lines. In the...

4135 Background: Mechanisms for intrinsic resistance to cetuximab, a monoclonal antibody against EGFR, are not fully elucidated. KRAS mutations cannot account for all resistant cases. Preclinical d...

Angiogenesis plays a key role in facilitating tumor growth and metastasis of colorectal cancer. Considerable progress has been made in identifying molecular components to develop angiogenesis-based treatments. Vascular endothelial growth factor (VEGF) pathways are specific and critical regulators of angiogenesis. However, other pathways are indirectly involved in angiogenesis promotion and recent studies have confirmed it. This review discusses known mechanisms involved in the action of angiogenesis- related targeted drugs such as cetuximab (Erbitux) and bevacizumab (Avastin), in patients affected by colorectal cancer. It also elucidates the role of oxygen levels in cancer cell damage as well as known alternative pathways used by tumoral cells to escape hypoxic-related death. Hypoxia may in fact select resistant sub-clones and boost tumor progression and growth, while the main subsequent damages may be conferred by eventual re-oxygenation. Therefore, in the light of the consolidated data available from the use of antiangiogenic drugs, we discuss about a paradox that is forming: in the war against tumoral angiogenesis it will be necessary to fight also the hypoxic condition caused by the antiangiogenic drugs.

13562 Background: Until recently, 5-fluorouracil (5-FU) has been the mainstay of treatment for advanced CRC. In the last years, irinotecan and oxaliplatin have been shown to improve survival in combination with 5-FU. It is unclear if this improvement requires the use of these agents as first-line treatment or their sequential use during the course of disease. Methods: In order to assess the impact on prognosis of the first-line chemotherapy regimen, we retrospectively reviewed the outcome of all patients (pts) with advanced CRC treated at our insitution from May 1997 to December 2003. During this period our standard first-line chemotherapy moved from 5-FU and folinic acid (FA) to FOLFIRI to FOLFOX regimens. We analyzed changes in overall survival over time according to administered treatments. Results: From May 1997 to December 2003, 376 consecutive pts with advanced CRC were treated at our institution, 118 from 1997 to 1999, 135 from 2000 to 2001, 123 from 2002 to 2003. Patient characteristics did not vary over time for the 3 cohorts: median age was 62 years (range 26–83), 58% of pts were male, 72% had single metatastic site, liver was the main disease site (72%). In the first cohort (1997–99) the standard first-line treatment was 5-FU/FA, in the second (2000–01) FOLFIRI, and in the third (2002–03) FOLFOX. The number of pts who underwent 1, 2 o 3 lines of treatment for metastatic disease was similar for the 3 cohorts. The median overall survival was 21.4 months (95% CI 19.3–23.3). As shown below, no statistically significant differences were observed among the cohorts. Conclusions: Our retrospective analysis shows that the use of oxaliplatin and irinotecan has pushed the overall median survival to 21 months. The outcome of pts has been similar during the period 1997–2003 despite the shift in standard first-line treatment from 5-FU/FA to FOLFIRI to FOLFOX. These results are reasonably due to the sequential use of all the active regimens. [Table: see text] No significant financial relationships to disclose.

13530 Background: Neoadjuvant chemotherapy has been successfully used in the treatment of patients (pts) affected by liver metastases from colorectal cancer unsuitable for surgery. We evaluated separately the diagnostic accuracy of PET and CT in this setting in a small series of pts. Methods: We retrospectively reviewed the data from 19 consecutive pts (12 males, 7 females; median age 62 years; range 41–79) affected by liver metastases from colorectal cancer. All of the pts underwent systemic chemotherapy and were evaluated with PET and CT at the end of the treatment. Whole-body PET scan was performed in 3D mode on a Siemens Ecat Accel LSO full-ring scanner, 60 minutes after the injection of 310–450 MBq of 18F-FDG. Contrast enhanced, 3 phases, liver CT was performed on a Philips Aura single slice system. Chemotherapy regimens were: FOLFOX (13 pts), FOLFIRI (2 pts), 5-FU-FA (2 pts), UFT-CPT-OXA (2 pts). Overall response rate was 68%. Median time interval between end of chemotherapy and CT was 6 wks (range 3–8), between end of chemotherapy and PET was 8 wks (range 5–13) and between end of chemotherapy and surgery was 10 wks (range 6–18). All pts underwent surgery to remove liver metastases and had histological confirmation of the lesions. Results: In 16 evaluable pts, 53 liver lesions were confirmed by histology. The table shows the results on a per-lesion basis. A complete agreement between PET or CT and histology was documented in 3 and 4 pts respectively. Conclusions: These results suggest that PET and CT had sub-optimal diagnostic accuracy in the post-chemotherapy evaluation of liver lesions from colorectal cancer. Moreover, the combined use of the two imaging techniques does not significantly increase the sensitivity of CT. Further data are needed to evaluate the metabolic changes induced by chemotherapy which may be the cause for inaccurate PET findings. [Table: see text] No significant financial relationships to disclose.

3670 Background: Liver is the dominant site of metastases in patients (pts) with colorectal cancer (CRC). Intrahepatic arterial chemotherapy should deliver higher doses of drugs to the liver, but e...

3710 Background: Neoadjuvant chemotherapy has been successfully used in the treatment of patients (pts) affected by liver metastases from colorectal cancer unsuitable for surgery. We evaluated the ...

Exemestane (6-methylenandrosta-1.4-diene-3.17-dione) is a new type I aromarase inhibitor, which is active by the oral route. In a previous experience, we documented the drug's effectiveness in reducing serum oestrogen levels at daily doses ranging from 25 to 2.5 mg and, for this reason, we initiated this further study to determine the minimum effective dose. Exemestane was orally administered to 20 postmenopausal patients with metastatic breast cancer, at daily doses of 5, 2.5, 1 or 0.5 mg. The doses were randomly given under double-blind conditions (5 pts for each dose), and the changes in E1, E2, E1S, LH, FSH, SHGB and DHEAS serum levels were evaluated on days 0, 7, 14, 28 and 56. The pts were considered evaluable providing they had received at least two months of therapy. The hormone analysis is still ongoing, but here we report the data concerning clinical efficacy and tolerability. All of the pts had received previous hormonal therapy for metastatic disease (9 pts > 1 treatment) and 18 had also received chemotherapy (7 as adjuvant treatment and 11 for metastatic disease). The other characteristics of the pts were: median age 56 yrs (range 47–82); ER+/PgR+: 14 pts; DFI ≥ 2 yrs: 15 pts. Soft tissue involvement was documented in 7 pts, bone in 12 and viscera in 14. Irrespective of the dose, 2 PR were obtained on soft tissue and liver; SD with a median duration of 6 months (range 3–14) was observed in 14 pts. Exemestane was very well tolerated, with nausea and asthenia (grade 1 WHO) being reported in 3 and 2 pts respectively. The hormonal data will be provided at the Congress. Data management by I.T.M.O. (Italian Trials in Medical Oncology) Scientific Service.

Aims and background The incidence of malignant melanoma is rapidly increasing in many countries, and when this disease has reached advanced stages, standard therapies have little impact. Dacarbazine (DTIC) is the most effective chemotherapeutic agent with an overall response rate of 20-25%, but durable responses are uncommon. Interesting results with the use of cisplatin (CDDP) have been reported in DTIC-resistant melanoma. Moreover, malignant melanoma is an immunogenic tumor and a potential target for biological response modifier (BRM) therapies. The aim of the present study was to evaluate the efficacy and tolerability of a chemo-immunotherapeutic regimen including high-dose CDDP combined with glutathione (GSH) to limit platinum-related toxicity, and natural interferon-α (IFN-α) in patients with DTIC-resistant metastatic melanoma. Methods The treatment schedule included GSH 1,500 mg/m2 i.v. and CDDP 40 mg/m2 i.v. for 4 consecutive days every 3 weeks, with a maximum of 6 courses, and IFN-α 3 MIU i.m. 3 times a week, continuative for a maximum of 12 months. Results Twelve patients were enrolled in this phase II trial. Accrual was stopped due to treatment-related toxicity. Ten patients were evaluable for response; there were 2 partial responses, lasting 5+ and 9+ months, respectively, and 2 cases of stable disease, lasting 3+ and 8+ months. None of these patients completed the therapeutic program due to treatment-related side effects. Conclusions This regimen seems to be only partially active in DTIC-resistant metastatic melanoma. Hematologic and non-hema-tologic (nausea and vomiting, peripheral neurotoxicity, and asthenia) side effects are significant and GSH is not effective in limiting CDDP-related neurotoxicity in pretreated patients. Therefore, there is no indication to employ this regimen as second-line treatment in metastatic melanoma and these disappointing results highlight the urgent need for new therapeutic approaches.

TPS4159 Background: Tivantinibis a selective, non-ATP competitive, oral inhibitor of MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF). MET over-expression is associated with poor prognosis in HCC patients. A phase Ib study (Santoro et al, Br J Cancer, 2013) with tivantinib 360mg BID revealed no worsening of liver function in cirrhotic HCC pts. A randomized, placebo-controlled phase 2 study identified HCC patients with high tumor MET expression at immunohistochemistry (IHC) as the target population for tivantinib in second line (overall survival: 7.2 months on tivantinib, 3.8 months on placebo, HR: 0.38, p=0.01), and selected 240mg BID as the appropriate dose for HCC patients (Santoro et al, Lancet Oncol, 2013). Methods: Enrollment forthis phase III clinical trial (ARQ 197-A-U303, NCT01755767) has begun.Eligible pts must present with Child Pugh A; ECOG performance score

Aims and background Somatostatin receptor scintigraphy (SRS) is the standard method for the detection of somatostatin receptors (SSTRs). It is commonly used in gastroenteropancreatic neuroendocrine tumor (GEP-NET) staging, and represents the criterion of choice for treatment with somatostatin (SST) analogs. Immunohistochemistry (IHC) was reported as a reliable method for the detection of SSTRs with theoretically superior sensitivity over SRS. Methods and study design We retrospectively analyzed the sensitivity and specificity of IHC in the detection of SSTRs in a cohort of consecutive patients with GEP-NETs attending our Institute from 1997 to 2007. IHC analysis was restricted to SSTR2 and SSTR5, and the results were interpreted according to two different scoring systems. SRS was used as the gold standard. Results Forty-four patients were enrolled; 24 (55%) had foregut carcinoids, 9 (20%) midgut carcinoids, 2 (5%) hindgut carcinoids, and 9 (20%) had GEP-NETs of unknown primary sites. A high concordance rate between IHC and SRS was shown, irrespective of the IHC scoring system applied (73% and 70%). The sensitivity of IHC was 89.3% and 78.6% and the specificity 43.8% and 50%, depending on the scoring system used. Conclusions Although SSTR2 was shown to be expressed by IHC in up to 50% of tumors not visualized by SRS, SRS still remains the method of choice in the diagnostic and therapeutic management of GEP-NETs. More pathological and clinical data are needed to properly understand the clinical relevance of immunohistochemical detection of SSTR expression in the absence of tumor uptake at SRS.

4006 Background: Tivantinib (T) is a selective, oral inhibitor of c-Met, the tyrosine kinase receptor for hepatocyte growth factor involved in tumor cell migration, invasion, proliferation and angiogenesis. T has shown promising results in HCC in phase 1 studies as monotherapy and in combination with sorafenib. Methods: This multi-center RCT, enrolled pts with unresectable HCC, 1 failed systemic therapy, ECOG PS 50% of tumor at immunohistochemistry) pts, safety. Results: Characteristics of the 107 enrolled HCC pts (A= 38, B= 33, P= 36) in T/P: 58/28 male; median age 70/68; PS 0 41/21; VI 22/13; Met+ 22/15; Met- 27/13. Dose A was reduced to B in all pts due to G≥3 neutropenia (NEUT) rate. Major TTP, DCR and PFS benefits were obtained in Met+ pts, with preliminary OS trend favoring T (HR=0.47) and no detrimental effect in Met- pts. DCR (95% CI) in T/P was 44 (31-56) / 31(16-48)% for ITT and 50 (28-72) / 20 (4-48)% in Met+ pts. Most common AEs in T were asthenia (26.8%), NEUT (25.4%), low appetite (25.4%); most common drug-related AEs were NEUT (25.4%), anemia (15.5%). Most frequent drug-related serious AE was neutropenic sepsis (4.2%). Efficacy was similar in A / B with less frequent NEUT in B (21.1% / 6.1%). Final OS, PK, biomarker data will be presented. Conclusions: Compared to P, T significantly benefited second-line HCC pts, especially if Met+, with manageable safety profile at 240 mg BID. [Table: see text]

Bone metabolism marker evaluation is expected to play an auxiliary role in the diagnosis and follow-up of bone metastases in patients affected by different types of neoplasms. In this study we have evaluated osteoblastic and osteoclastic markers in 18 patients with bone metastases from breast cancer at diagnosis and for 1 year of follow-up during treatment with the aromatase inhibitor formestane. Osteoblastic markers include the carboxy-terminal propeptide of type I procollagen, the bone-specific alkaline phosphatase and the bone GLA protein. The carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) was evaluated as a marker of osteoclastic activity. The patients were classified into three groups according to clinical response. A good correlation between marker level modifications and clinical evolution of skeletal metastases was observed for all the examined markers. Patients with progressive disease showed increasing levels of all markers, whereas patients in regression showed a reduction compared to the basal levels; patients with stable disease fell in between these two categories. We also found that basal ICTP values have prognostic significance: in the stable and progressive disease group they were higher than in the partial response group.

665 Background: Not all the patients with resectable colorectal liver metastases (CLM) benefit from liver resection (LR). To date, patients with disease progression during chemotherapy are excluded from surgery. The present study aims to elucidate if the CLM behavior in the interval between the end of chemotherapy and LR (stable disease vs. progression) impacts prognosis. Methods: All the consecutive patients undergoing LR for CLM between 2004 and 2014 after a tumor response or stabilization during chemotherapy were considered. The patients having received two separate imaging modalities after chemotherapy (one at the end of chemotherapy and one before LR) with an interval between the two > 3 weeks were included. Any variation of CLM size was registered. Tumor progression was defined according to the RECIST criteria. Results: Overall, 130 patients were analyzed. One fourth of the patients with partial response or stable disease during chemotherapy had a disease progression after the end of chemotherapy before LR, 16% if the interval chemotherapy-surgery was < 8 weeks. The risk of progression was not associated with the response to chemotherapy. Patients with progression after the end of chemotherapy had lower survival than patients with stable disease (5-year overall survival (OS) 19.0% vs. 27.6%; three-year recurrence-free survival (RFS) 6.7% vs. 21.3%, p < 0.001 for both). Survival was extremely poor in case of early progression ( < 8 weeks) (0% two-year RFS and OS). Progression was an independent prognostic factor of OS and RFS (HR = 3.243 and HR = 2.874, p < 0.0001). Eleven patients had a complete radiologic response to chemotherapy and underwent LR at disease reappearance without further chemotherapy after a median delay of 8.7 months. They had excellent survival (five-year OS 39.0%, three-year RFS 36.4%). Conclusions: Early disease progression between the end of chemotherapy and LR occurs in ~15% of patients. It is associated with extremely poor survival and should be considered a contraindication to surgery. Patients with a complete radiologic response can be resected upfront at recurrence without further chemotherapy.

Purpose: To assess the efficacy of stereotactic body radiotherapy in patients with unresectable locally advanced pancreatic cancer. Materials and Methods: All patients received a prescription dose of 45 Gy in 6 fractions. Primary end point was freedom from local progression. Secondary end points were overall survival, progression-free survival, and toxicity. Actuarial survival analysis and univariate or multivariate analysis were investigated. Results: Forty-five patients were enrolled in a phase 2 trial. Median follow-up was 13.5 months. Freedom from local progression was 90% at 2 years. On univariate ( P < .03) and multivariate analyses ( P < .001), lesion size was statistically significant for freedom from local progression. Median progression-free survival and overall survival were 8 and 13 months, respectively. On multivariate analysis, tumor size ( P < .001) and freedom from local progression ( P < .002) were significantly correlated with overall survival. Thirty-two (71%) patients with locally advanced pancreatic cancer received chemotherapy before stereotactic body radiotherapy. Median overall survival from diagnosis was 19 months. Multivariate analysis showed that freedom from local progression ( P < .035), tumor diameter ( P < .002), and computed tomography before stereotactic body radiotherapy ( P < .001) were significantly correlated with overall survival from diagnosis. Conclusion: Stereotactic body radiotherapy is a safe and effective treatment for patients with locally advanced pancreatic cancer with no G3 toxicity or greater and could be a promising therapeutic option in multimodality treatment regimen.

e16116 Background: IRI is widely used in the treatment of gastrointestinal cancers. Consistent with current guidelines, UGT1A1 genotyping may drive IRI dose reductions, but the usefulness of this approach is still unclear. We assessed potential clinical variables that may predict grade ≥3 neutropenia and more specifically the upfront genotyping of UGT1A1 polymorphisms associated with IRI toxicity, according to predefined IRI dose reductions. Methods: We genotyped UGT1A1*28 polymorphisms in 247 patients with metastic colorectal, gastric and pancreatic cancers who received second or third-line IRI-based chemotherapy in clinical practice at a single academic center. Concomitant DPYD sequencing was undertaken in 179 patients receiving also fluoropyrimidines. We compared the incidence of severe neutropenia with full-dose IRI in UGT1A1 6/6 and 6/7 carriers, and in UGT1A1 7/7 carriers who underwent initial IRI dose reductions by at least 30%. Results: The incidence of UGT1A1 7/7, 6/7, 6/6 genotypes was 11.3%, 51.4%, and 37.2%, respectively. IRI dose reductions were significantly more frequent with UGT1A 7/7 and 6/7 genotypes (odds ratio [OR] = 9.5; 95% confidence interval [CI]: 4.3-21.7), and combination chemotherapy (OR = 3.8; 95%CI: 1.3 – 11.1). Other clinical parameters, including sex, cancer type, baseline neutrophils levels, performance status were not significantly associated with IRI dose reductions. Despite initial IRI reductions driven by the UGT1A1 panel, patients with UGT1A1 7/7 genotype had an increased, albeit non-significant, risk of grade ≥3 neutropenia, compared to patients with UGT1A1 6/6 and 6/7 genotypes who received full dose IRI (incidence: 39% versus 21%; OR = 2.4; 95%CI: 0.85 – 7.03). Conclusions: UGT1A1 testing is a determinant of IRI dose reductions, however this strategy does not reduce the burden of grade ≥3 neutropenia in UGT1A1 7/7 carriers. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the increased risk of neutropenia in patients candidate to IRI-based chemotherapy.

Background & Aims Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population. Methods Multicentre retrospective, cross-sectional, international study of liver cancer patients with SARS-CoV-2 infection registered between February and December 2020. Clinical data at SARS-CoV-2 diagnosis and outcomes were registered. Results Two hundred fifty patients from 38 centres were included, 218 with hepatocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at SARS-CoV-2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow-up of 7.20 (IQR: 1.84–11.24) months, 100 (40%) patients have died, 48% of the deaths were SARS-CoV-2-related. Forty (18.4%) HCC patients died within 30-days. The death rate increase was significantly different according to the BCLC stage (6.10% [95% CI 2.24–12.74], 11.76% [95% CI 4.73–22.30], 20.69% [95% CI 11.35–31.96] and 34.52% [95% CI 17.03–52.78] for BCLC 0/A, B, C and D, respectively; p = .0017). The hazard ratio was 1.45 (95% CI 0.49–4.31; p = .5032) in BCLC-B versus 0/A, and 3.13 (95% CI 1.29–7.62; p = .0118) in BCLC-C versus 0/A in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, and 12 deaths were related to SARS-CoV-2 infection. Conclusions This is the largest cohort of liver cancer patients infected with SARS-CoV-2. It characterizes the 30-day mortality risk of SARS-CoV-2 infected patients with HCC during this period., Spanish Health Ministry; Ricerca Corrente, Grant/Award Number: RC2019/105-01, RC2018/105-01 and RC2017/105-01; European Association for the Study of the Liver (Andrew Burroughs Fellowship); Cancer Treatment and Research Trust (CTRT); Wellcome Trust Strategic Fund, Grant/Award Number: PS3416; Cancer Research UK (CR UK) centre, Grant/Award Number: C9380/A26813, C18342/A23390 and C9380/A18084; Instituto de Salud Carlos III, Grant/Award Number: PI18/0358, PI15/00145, CD18/00126, PI19/00819, FI19/00222, 16-0026, PI044031, PI18/00768, PI18/00542 and PI13/01229; Bristol Myers Squibb and Celgene; Cancer Research UK, Grant/Award Number: RCCPDB-Nov21/100008