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Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

e15506 Background: Adult granulosa cell tumour (AGCT) is a rare disease that develops in the testis, composed of sex cord cells, accounting for less than 0.5% of all sex cord-stromal neoplasias (WHO 2016). To our knowledge, 48 cases of AGCT of the testis have been published up to date reporting follow-up (Table 1). Infrequently, these tumors can metastasize, usually to retroperitoneal lymph nodes, but also liver, lungs and bones. Methods: In 2015 a 60-year-old Caucasian male with unilateral, painless slowly growing mass underwent to orchioectomy. A diagnosis of malignant ADTC was rendered. After 19 months metestatic spread to lung was hystologically confirmed. After cytotoxic treatment a compassionate use of pazopanib was sterted and the was in complete response today. Results: The patient is still on pazopanib treatment with complete response that is well tolerated and has improved quality of life 55 months after the initial AGCT diagnosis. Conclusions: Our case report could offer an important source of information for clinicians who are currently facing this rare entity. In summary in case of tumor larger than 4-5 cm adjuvant treatment may be considered and, more importantly, systemic treatments, including pazopanib, could be suggested as a treatment apporach to a metastatic AGCT patient. In the future, other reports containg long-term follow up will be of vital importance to understand the best management of patient with AGCT.

209 Background: Prostate cancer affects mainly elderly patients (pts) that have different comorbidities. AA is a selective androgen synthesis inhibitor that showed the efficacy in either chemotherapy (CT) naive pts or those pretreated with docetaxel. Its oral administration and good tolerability make it a manegeable treatment for elderly mCRPC pts. Methods: We collected retrospectively data regarding mCRPC pts aged ≥75 years treated with AA in 13 Italian Centers since April 2013. The median age was 79 years (r. 75-90) with 48% of pts being octagerians. Post CT pts had more extensive disease, higher baseline PSA and ECOG PS. Nearly all the pts had comorbidities, the most frequent being hypertension present in 146 pts (58%), 43 pts (17%) had diabetes type II. We evaluated duration of the AA treatment, overall response rate (ORR), 50% PSA decline, time to progression (TTP) and overall survival (OS). We reported all toxicities observed. Results: A total of 252 pts ,147 pre treated with docetaxel and 105 chemo naive, were included. Median duration of treatment with AA was 8,6 months in post CT and 11,5 in CT naive pts. ORR was 35,3% in pre docetaxel and 27,4% in post docetaxel group. 64 pts (65%) and 51 pts (46%) obtained 50% PSA reduction in pre and post docetaxel group, respectively. Median TTP was 8,6 in post docetaxel and 11,9 in CT naive pts. We observed a median OS of 13,8 months in post CT group while for CT naive pts data were not yet mature. AA was well tolerated with only 8 pts (3,2%) who discontinued treatment due to toxicity, while in 4 pts (1,6%) temporary dose reductions were performed. The most frequent G3 toxicities were hypertension and liver toxicity with 4 pts (1,6%) and 5 pts (2%), respectively. After progressing on AA, 85 pts (34%) received at least one subsequent treatment. 40 pts (15,9%) are still on treatment with AA. Conclusions: Even if almost all the pts reported comorbidities at AA start and 72 pts (28,6%) had PS ECOG 2, only a small proportion of them discontinued the treatment due to toxicity confirming that AA is well tolerated and efficient treatment also for elderly patients.

AIM: To assess how many patients with benign "difficult" colorectal lesions (DCRLs) referred to surgical resection, may be treated with endoscopic resection (ER) rather than surgical resection. METHODS: The prospectively collected colonoscopy database of our Endoscopic Unit was reviewed to identify all consecutive patients who, between July 2011 and August 2013, underwent an endoscopic re-evaluation before surgical resection due to the presence of DCRLs with a histological confirmation of benignancy on forceps biopsy. ER was attempted when the lesion did not have definite features of deeply invasive cancer. The "nonlifting sign" excluded ER only in naive lesions without a prior attempted resection. Lesions were classified, using the Kyoto-Paris classification for mucosal neoplasia. For sessile and non-polypoid lesions the "inject and cut" resection technique was used. Pedunculated and semi-pedunculated lesions were transected at the stalk just below the polyps head and before or after resection, metal clips or a loop were applied on the stalk to prevent bleeding. The lesions were histologically classified according to the Vienna criteria and for the pedunculated lesions the Haggitt classification was used. RESULTS: Eighty-two patients (42 females, mean age 62 years) with 82 lesions (mean size 37 mm) were included in the study. Sixty-nine (84%) lesions were endoscopically resected, while 13 underwent surgical resection since ER was deemed unsuitable. On histology, cancer was found in 21/69 lesions (14 intra-mucosal, 7 sub-mucosal) and was associated with the size (P < 0.001) and with type 0-IIa +Is (P = 0.011) and 0-IIa + IIc (P < 0.001) lesions. All patients with sub-mucosal cancer, underwent surgical resection. Complications occurred in 11/69 patients (7 bleedings, 2 transmural burn syndromes, 2 perforations), all managed endoscopically or conservatively, and were associated with presence of invasive cancer (P = 0.021). During follow-up recurrence/residual tissue was found in 14/51 sessile or non-polypoid lesions (13 treated endoscopically, 1 underwent surgical resection) and was associated with type 0-IIa + Is lesions (P = 0.001), piecemeal resections (P = 0.01) and with lesion size (P = 0.004). Overall, 74% of patients avoided surgery. Surgical resection was significantly associated with type 0-IIa + Is (P = 0.01) and 0-IIa + IIc (P = 0.001) lesions, with sub-mucosal invasion on histology (P < 0.001), with presence of the "nonlifting sign" (P < 0.001), and related to the dimension of the lesions (P = 0.001). In the logistic regression analysis, the only independent predictor for surgical resection was the dimension of the lesions (P = 0.002). CONCLUSION: Before submitting patients to surgical resection for a benign DCRL, a second opinion by an experienced endoscopist is mandatory to avoid unnecessary surgery.

Advances in stents design have led to a substantial increase in the use of stents for a variety of digestive diseases. Initially developed as a non-surgical treatment for palliation of esophageal cancer, the stents now have an emerging role in the management of malignant and benign conditions as well as in all segments of the gastrointestinal tract. In this review, relevant literature search and expert opinions have been used to evaluate the key-role of stenting in gastrointestinal benign and malignant diseases.

From February 1996 to December 1998, 95 patients affected with colorectal liver metastases underwent the positioning of an intraarterial hepatic catheter by a transcutaneous subclavian access, under local anesthesia. All patients were evaluated for catheter implantation complications. Moreover, 61 patients of 95 treated at our center were retrospectively evaluated for results of chemotherapy performed with two different schedules of hepatic artery infusion (HAI) combined with systemic chemotherapy (SC). Eleven patients (group A) were treated with combined SC (5-fluorouracil continuous infusion) and HAI (floxuridine). A subsequent 50 patients underwent HAI (floxuridine, 4 cycles) followed, if a response or stable disease were observed, by combined SC and HAI (group B). Three cases of aneurysm of subclavian artery occurred, which were treated by the positioning of a radiologic arterial stent and the reimplantation of the catheter by a femoral access. Thrombosis of the hepatic artery was registered in four cases. We observed 10.5% occurrence of dislocation of the catheter, which was always moved again in the hepatic artery. In group A, with 45% clinical objective response rate and 10% stable disease rate, median survival time and median time to extrahepatic progression were 9 and 6 months, respectively. In group B, we observed 44% clinical objective responses and 26% stable disease after HAI. Patients without disease progression and therefore submitted to sequential SC and HAI had a median survival time of 21 months and a median time to extrahepatic progression of 16 months. The development of the mini-invasive technique of implantation of an arterial port can avoid laparotomy for HAI. Percutaneous implantation of an arterial port has a low rate of technical complications. HAI followed by combined systemic and regional chemotherapy has good results in terms of survival and time to extrahepatic progression.

Hepatic arteriovenous shunting in the metastatic liver reduces the advantages of intraarterial infusion of chemotherapeutic agents because of the passage of drugs into the systemic circulation. The aim of this study was to quantitatively assess spontaneous functional hepatic arteriovenous shunting in patients with liver metastases and to determine its implication in the increase in systemic toxic effects of intra-arterial infusion chemotherapy with floxuridine.Twenty-five patients who underwent implantation of arterial ports for regional chemotherapy of liver metastases were studied. Functional hepatic arterio-venous shunting was evaluated through the bioavailability of intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic features make its hepatic clearance flow dependent. In addition, D-sorbitol hepatic clearance (a parameter reflecting functional liver blood flow) and common liver function tests were evaluated for each studied patient. Patients were then grouped with respect to the percentage of medically-assessed liver occupation by metastases and with respect to systemic toxicity of the chemotherapeutic treatment. Both univariate and multivariate analyses by Student's t-test and stepwise logistic regression, respectively, were performed in both groups for each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic clearance and arterial bioavailability).Arterial bioavailability of D-sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients with more than 50% liver occupation (0.39+/-0.19) compared with those with minor liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with those with low-grade toxicity (0.16+/-0.11; p0.001). Multivariate analysis showed that arterial bioavailability of D-sorbitol was the only parameter among those evaluated which was able to predict systemic toxicity of this kind of chemotherapy.Our results show that, in the metastatic liver, arterial bioavailability of D-sorbitol, an index of functional arteriovenous shunting, varies widely, is significantly greater in patients with massive liver occupation and it is a good predictor of systemic toxicity of intra-arterial regional chemotherapy with floxuridine.

Background. The role of surgery for lung metastases (LM) secondary to colorectal cancer (CRC) remains controversial. The bulk of evidence is derived from single surgical series, hampering any definitive conclusions. The aim of this study was to compare the outcomes of CRC patients with LM submitted to surgery with those who were not. Patients and Methods. Data from 409 patients with LM as the first evidence of advanced disease were extracted from a database of 1,411 patients. Patients were divided into three groups: G1, comprised of 155 patients with pulmonary and extrapulmonary metastases; G2, comprised of 104 patients with LM only and no surgery; G3, comprised of 50 patients with LM only and submitted to surgery. Results. No difference in response rates emerged between G1 and G2. Median progression-free survival (PFS) times were: 10.3 months, 10.5 months, and 26.2 months for G1, G2, and G3, respectively. No difference in PFS times was observed between G1 and G2, whereas there was a statistically significant difference between G2 and G3. Median overall survival times were 24.2 months, 31.5 months, and 72.4 months, respectively. Survival times were longer in resected patients: 17 survived >5 years and three survived >10 years. In patients with LM only and no surgery, four survived for 5 years and none survived >10 years. Conclusions. Even though patients with resectable LM are more likely to be those with a better outcome, our study provides evidence suggesting an active role of surgery in improving survival outcomes in this patient subset.

3732 Background: Colorectal cancer is one of the most important malignant tumours in adults and the median survival of patients with advanced disease is lower than 24 months. This study was conduct...

15039 Background: Resection of liver mts has been repeatedly shown to prolong survival of pts with metastatic colorectal cancer (mCRC). While in some published data resection of lung mts (RLM) seem...