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Objective Direct oral anticoagulants (DOACs) were developed to avoid the limitations of vitamin K antagonists (VKAs). DOACs are associated with a greater incidence of gastrointestinal bleeding and a smaller number of intracranial haemorrhages than VKAs. Therefore, it is important to deepen our knowledge of their safety profiles. The aim of this study was thus to analyse adverse drug reaction (ADR) reports on DOACs and VKAs using the Sicilian Spontaneous Reporting System (SRS) database. Methods All ADR reports with DOACs and VKAs as suspected drugs that were entered into the Sicilian SRS database during the period 2001-2019 were selected. In detail, all reports with the following single active substances were included: dabigatran etexilate, rivaroxaban, apixaban and edoxaban; acenocoumarol and warfarin were included as a comparator group. Descriptive statistical methodology was used to evaluate characteristics of the reported cases with a case-by-case assessment. Results and discussion Out of 521 reports related to anticoagulants, 444 (85.2%) and 77 (14.8%) involved DOACs and VKAs, respectively. DOAC-related reports were mainly of gastrointestinal disorders. In contrast, VKAs were mostly associated with blood and lymphatic system disorders, injury, investigations and vascular disorders. Many more cases of ADRs in the form of gastrointestinal disorders concerned dabigatran etexilate (n = 179, 73.7%) than the other DOACs, while ADRs in the form of blood disorders were mainly associated with acenocoumarol (n = 27, 57.4%). The most commonly reported Preferred Terms for DOACs were dyspepsia (n = 89, 17.1%), upper abdominal pain (n = 41, 9.2%) and pruritus (n = 26, 5.8%), whereas for VKAs, they were anaemia (n = 21, 27.3%) and hypocoagulable state (n = 18, 3.5%). Potentially interacting concomitant medications particularly included antithrombotic agents (n = 19, 4.3%) for DOACs and proton-pump inhibitors (PPIs) (n = 37, 48.1%) and antithrombotic agents (n = 13, 16.9%) for VKAs. Conclusion The ADRs most commonly associated with DOACs, especially dabigatran, were gastrointestinal disorders, particularly gastrointestinal bleeding. Our study also highlights the potential role of drug-drug interactions in the ADRs. The cases of gastrointestinal bleeding highlight the need for careful prescribing of DOACs and use of potentially interacting concomitant drugs.

The available fluoropyrimidines and oxaliplatin combinations for colorectal cancer patients have different safety profiles. The aim of this systematic review was to compare their toxicities. The eligible studies were classified as: no bolus; 5-FU single bolus; 5-FU double bolus; capecitabine. We calculated the incidence of "any-grade" and "severe" toxicity for haematological and non-haematological adverse events of each group. We identified 184 treatment groups; compared to 5-FU double bolus, except for high-grade anaemia, all the groups showed reduced risk of haematological toxicities, with the most relevant advantages for single bolus regimens. Concerning non-haematological toxicities, compared to double bolus, the single bolus group showed a statistically significant reduced risk for many gastrointestinal toxicities and for pheripheral neuropathy. This is the first systematic review of the toxicity profile of different 5-FU or capecitabine and oxaliplatin regimens. Single 5-FU bolus is associated with a definitely favourable toxicity profile, both for haematological and non-haematological toxicity.

Background Targeted capture sequencing can potentially facilitate precision medicine, but the feasibility of this approach in gastrointestinal (GI) malignancies is unknown. Patients and methods The FOrMAT (Feasibility of a Molecular Characterisation Approach to Treatment) study was a feasibility study enrolling patients with advanced GI malignancies from February 2014 to November 2015. Targeted capture sequencing (mainly using archival formalin-fixed paraffin-embedded diagnostic/resection samples) was carried out to detect mutations, copy number variations and translocations in up to 46 genes which had prognostic/predictive significance or were targets in current/upcoming clinical trials. Results Of the 222 patients recruited, 215 patients (96.8%) had available tissue samples, 125 patients (56.3%) had ≥16 genes successfully sequenced and 136 patients (61.2%) had ≥1 genes successfully sequenced. Sample characteristics influenced the proportion of successfully sequenced samples, e.g. tumour type (colorectal 70.9%, biliary 52.6%, oesophagogastric 50.7%, pancreas 27.3%, P = 0.002), tumour cellularity (high versus low: 78.3% versus 13.3%, P ≤ 0.001), tumour content (high versus low: 78.6% versus 27.3%, P = 0.001) and type of sample (resection versus biopsy: 82.4% versus 47.6%, P ≤ 0.001). Currently, actionable alterations were detected in 90 (40.5%) of the 222 patients recruited (66% of the 136 patients sequenced) and 2 patients subsequently received a targeted therapy. The most frequently detected currently actionable alterations were mutations in KRAS, BRAF, TP53 and PIK3CA. For the 205 patients with archival samples, the median time to obtain sequencing results was 18.9 weeks, including a median of 4.9 weeks for sample retrieval and 5.1 weeks for sequencing. Conclusions Targeted sequencing detected actionable alterations in formalin-fixed paraffin-embedded samples, but tissue characteristics are of critical importance in determining sequencing success. Routine molecular profiling of GI tumours outside of clinical trials is not an effective use of healthcare resources unless more targeted drugs become available. ClinicalTrials.gov identifier NCT02112357

Background The potential of chemotherapy as salvage treatment after failure of neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC) has never been explored. We conducted a single-center, retrospective analysis to address this question. Patients and methods Patients with newly diagnosed LARC who were inoperable or candidates for extensive (i.e., beyond total mesorectal excision [TME]) surgery after long-course chemoradiotherapy and who received salvage chemotherapy were included. The primary objective was to estimate the proportion of patients who became suitable for TME after chemotherapy. Results Forty-five patients were eligible (39 candidates for extensive surgery and 6 unresectable). Previous radiotherapy was given concurrently with chemotherapy in 43 cases (median dose: 54.0 Gy). Oxaliplatin- and irinotecan-based salvage chemotherapy was administered in 40 (88.9%) and 5 (11.1%) cases, respectively. Eight patients (17.8%) became suitable for TME after chemotherapy, 10 (22.2%) ultimately underwent TME with clear margins, and 2 (4.4%) were managed with a watch and wait approach. Additionally, 13 patients had extensive surgery with curative intent. Three-year progression-free survival and 5-year overall survival in the entire population were 30.0% (95% confidence interval [CI]: 15.0-46.0) and 44.0% (95% CI: 26.0-61.0), respectively. For the curatively resected and "watch and wait" patients, these figures were 52.0% (95% CI: 27.0-73.0) and 67.0% (95% CI: 40.0-84.0), respectively. Conclusion Systemic chemotherapy may be an effective salvage strategy for LARC patients who fail to respond to chemoradiotherapy and are inoperable or candidates for beyond TME surgery. According to our study, one out of five patients may become resectable or be spared from an extensive surgery after systemic chemotherapy. Implications for practice High-quality evidence to inform the optimal management of rectal cancer patients who are inoperable or candidates for beyond total mesorectal excision surgery following standard chemoradiotherapy is lacking. We show for the first time that systemic chemotherapy may be beneficial and result in one out of five poor prognosis patients becoming resectable or being spared from an extensive surgical approach. Although mores studies are needed to confirm these data, administering salvage systemic chemotherapy in this setting may have the potential to minimize morbidity associated with extensive surgical procedures and improve long-term oncological outcome.

e24014 Background: PROs are the gold standard to describe subjective symptoms. In order to improve clinical management of outpatients receiving active anti-cancer treatment at Medical Oncology, Mauriziano Hospital, Turin, Italy, in January 2018 we introduced in routine clinical practice an assessment of patient-reported symptoms and toxicities. We demonstrated that use of PROs in clinical practice was associated with a significant QoL improvement, compared to the traditional visit (Baratelli, Support Care Cancer 2019). In this secondary analysis, we show the results obtained in older pts ( > 70yrs). Methods: Eligible pts were receiving an active anti-cancer treatment, as outpatients. Pts treated in 2017 underwent “usual” visits (group A), while pts treated in 2018 before each visit received a paper questionnaire by a dedicated nurse, in order to provide information about symptoms and toxicities to be discussed during visit (group B). Primary objective was the comparison of QoL changes, measured by EORTC QLQ-C30. Results: Out of 211 pts, 88 were older than 70 yrs (47 group A, 41 group B). Median age was 76 (70-84 yrs). Most common tumors were colorectal (25.0%), lung (22.7%) and pancreatic (17.0%). 68.2% were receiving first-line treatment. Tumors and setting were similar between group A and B. Younger and older pts had comparable baseline QoL scores: mean global QoL score was 59.96 in younger pts vs. 57.39 in older pts. After 1 month, global QoL of older pts was significantly improved in group B compared to group A: mean change from baseline was -0.89 group A vs. +4.47 group B (p = 0.006, effect size 0.23). There were statistically significant differences in mean changes from baseline, in favor of group B, for role functioning (-5.67 group A and -0.81 group B, p = 0.034, effect size 0.20) and emotional functioning (-2.30 group A and +3.25 group B, p = 0.014, effect size 0.36). Mean changes from baseline for pain were significantly better for group B (-3.25) than group A (+6.03, p = 0.01, effect size 0.43). There were no significant differences between the 2 groups in terms of other functional scales or symptoms. There was no significant heterogeneity in the proportion of QoL responders between younger and older pts (p = 0.60). The proportion of older pts obtaining a clinically significant improvement in global QoL was numerically higher in group B (36.6%) compared to group A (19.1%, p = 0.09). Odds Ratio of obtaining an improvement in global QoL for group B vs group A was 1.73 (95%CI 0.75 – 3.99) in younger pts and 2.44 (95%CI 0.93 – 6.40) in older pts. Conclusions: This secondary analysis shows that the use of PROs in clinical practice, thanks to an active role of nurses and discussion of symptoms with physicians during the visit, is associated, also in older patients receiving active anticancer treatment, with a significant improvement in global QoL.

Background Generic anticancer drugs represent an opportunity in terms of cost savings but there are some concerns about their tolerability. The safety profiles of generic versus branded oxaliplatin formulations have never been studied in detail. Patients and methods We tested in vitro concentrations, stability and efficacy of branded versus generic oxaliplatin formulations, then we retrospectively collected data about hypersensitivity reactions (HSR) of 427 colorectal cancer patients treated with oxaliplatin-based regimens. Results No significant difference in oxaliplatin concentration or time-dependent antiproliferative activity between branded and generic oxaliplatin was detected. The incidence of HSR was 12.1% (33/273 patients) in those treated with branded and 9.8% (15/154 patients) in those treated with generic oxaliplatin (p=0.46). The occurrence of grade III-IV HSRs and severe HSRs leading to oxaliplatin discontinuation were comparable. Conclusion No difference between generic and branded formulations of oxaliplatin were demonstrated in preclinical nor in clinical settings. Generic oxaliplatin can be considered a safe alternative to branded formulation.

Background:\ud \ud Chemotherapy is the mainstay treatment for advanced biliary cancer (ABC). Best supportive care and clinical trials are currently alternative options. The identification of a prognostic score that can be widely applied to daily practice has the potential to better inform clinical management of ABC patients.\ud Methods:\ud \ud A cohort of 123 ABC patients undergoing first-line chemotherapy was used as an exploratory cohort to define the prognostic value of laboratory tests routinely performed in clinical practice. Kaplan–Meier analysis was used to investigate the association between the variables and overall survival (OS). Those variables that were statistically significant at the multivariate analysis were combined in a multiplex score. Performance of the novel prognostic score was confirmed in a validation cohort of 60 ABC patients.\ud Results:\ud \ud Baseline actual neutrophil count, lymphocytes-monocytes ratio, neutrophil-lymphocytes ratio and albumin (A.L.A.N.) correlated with OS at the multivariate analysis in the exploratory cohort. When combined in the multiplex, A.L.A.N. score was able to identify three classes of ABC patients with significantly different OS (high-risk: median OS, 5 months; intermediate-risk: median OS, 12 months and low-risk: median OS, 22 months; p

Patient-reported outcomes (PROs) are the gold standard to describe subjective symptoms. Nurses can be successfully involved in collecting symptom information, because of their direct relationship with the patient. In order to improve clinical management of outpatients receiving active anti-cancer treatment, we introduced in routine clinical practice an assessment of patient-reported symptoms and toxicities, starting from January 2018. Our hypothesis was that this could help to better control symptoms, improving patients’ quality of life (QoL). Eligible patients were receiving an active anti-cancer treatment, as outpatients. Patients included in the control group (treated in 2017) underwent “usual” visits (group A), while patients treated in 2018, before each visit received a questionnaire by a dedicated nurse, in order to provide information about symptoms and toxicities (group B). Primary objective was the comparison of QoL changes, measured by EORTC QLQ-C30. A total of 211 patients have been analyzed (119 group A; 92 group B). After 1 month, mean change from baseline of global QoL was − 1.68 in group A and + 2.54 in group B (p = 0.004, effect size 0.20). Group B showed significantly better mean changes for fatigue, pain, and appetite loss. Proportion of patients obtaining a clinically significant improvement in global QoL score was higher in group B (32.6%) compared to group A (19.3%, p = 0.04). Patients’ satisfaction with questionnaire was high. Introduction of PROs in clinical practice, thanks to an active role of nurses, was feasible, produced high patients’ satisfaction and a significant QoL improvement, compared to the traditional modality of visit.

This report summarizes the clinical features and the indications for treating HCV infection in immunocompromised and transplanted patients in the Direct Acting Antiviral drugs era.

Background Adenocarcinomas of the oral cavity are rare neoplasms, and only four cases of primary colonic adenocarcinoma of the tongue have ever been described in literature. Very few information about chemotherapy sensitiveness of this type of neoplasia is available, with only one regimen that showed some activity in a metastatic patient. Case presentation We describe the case of a patient bearing a metastatic colonic adenocarcinoma of the tongue submitted to a first-line chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX regimen). After chemotherapy the patient obtained the complete disappearance of the primitive neoplasia located in the body of the tongue, and a tumor size reduction > 50% of liver and lung metastases. Conclusions This case demonstrated the activity of the combination of oxaliplatin and 5-fluorouracil in this very rare neoplasia. The FOLFOX regimen might be considered either in advanced and especially in the neoadjuvant setting, when the reduction of the primary tumor is highly needed.

The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate. We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression. We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis. The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described.

Background: While the management of nonmetastatic and oligometastatic rectal cancer has rapidly evolved over the last few decades, many grey areas and highly debated topics remain that foster significant variation in clinical practice. We aimed to identify controversial points and evidence gaps in this disease setting by systematically comparing recommendations from national and international clinical guidelines. Methods: Twenty-six clinical questions reflecting practical challenges in the routine management of nonmetastatic and oligometastatic rectal cancer patients were selected. Recommendations from the ESMO, NCCN, JSCCR, Australian and Ontario guidelines were extrapolated and compared using a 4-tier classification system (i.e. identical/very similar, similar, slightly different, different). Overall agreement between guidelines (i.e. substantial/complete disagreement, partial disagreement, partial agreement, substantial/complete agreement) was assessed for each clinical question and compared against the highest level of available evidence by using the χ2 statistic test. Results: Guidelines were in substantial/complete agreement, partial agreement, partial disagreement, and substantial/complete disagreement for 8 (30.8%), 2 (7.7%), 7 (26.9%), and 9 (34.6%) clinical questions, respectively. High level of evidence supported clinical recommendations in 3/10 cases (30%) where guidelines were in agreement and in 10/16 cases (62.5%) where guidelines were in disagreement (χ2 = 2.6, p = 0.106). Agreement was frequently reached for questions regarding diagnosis, staging, and radiology/pathology pro-forma reporting, while disagreement characterised most of the treatment-related topics. Conclusions: Substantial variation exists across clinical guidelines in the recommendations for the management of nonmetastatic and oligometastatic rectal cancer. This variation is only partly explained by the lack of supporting, high-level evidence., SCOPUS: re.j, info:eu-repo/semantics/published

Background Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies. Patients and methods We conducted this multicentre, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed. Results Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P

Background The optimal therapeutic strategy for metastatic colorectal cancer patients is still a matter of debate. There are no prognostic variables indicating how many lines individual patients ought to receive, and whether later lines could be effective even when earlier ones were not. Patients and Methods We retrospectively collected data from 420 consecutive patients with metastatic colorectal cancer at our institution, describing the proportion of patients who received second or later lines of therapy and the chance of a line of treatment being active when the previous line was not. For each line of treatment, we defined clinical benefit as the probability of not having had evidence of disease progression 6 months after the start of chemotherapy. Results Of the 373 patients with disease progression after first-line chemotherapy (1L), 277 received a second line (2L) (probability of being submitted to a 2L (P(2L)) = 74.3%): 143 (63.3%) of 226 received a 3L (P(3L)), and 56 (45.9%) of 122 were submitted to a 4L (P(4L)). Joint probabilities were: 2L 74.3%, 3L 47.0%, and 4L 21.6%. A total of 298 (71.5%) of 417 patients had a clinical benefit with 1L; 134 (48.6%) of 276 with 2L; 50 (35.2%) of 142 with 3L; and 12 (25.0%) of 48 with 4L. Taking all these data together, 31% of the patients who experienced early progression at 1L had the chance to have a clinical benefit with any further lines. Conclusion Our study demonstrated that of 4 patients submitted to a 1L, about 3 will receive a 2L, about 2 a 3L, and nearly 1 a 4L. Later lines could be beneficial even though earlier ones were not.

Background Research biopsies are an increasingly important component of clinical trials, but there are concerns that biopsies may deter patients from participating in research. Patients and Methods Patients participating in a single-center study investigating the feasibility of molecular profiling in advanced gastrointestinal cancers were asked to complete a questionnaire regarding their reasons for consenting/declining optional research biopsies and blood samples. These samples were mainly for exploratory translational research and were unlikely to influence patients' treatment. Results One hundred ninety-six (88%) of the 222 patients registered in the study completed the questionnaire. One hundred twenty-six patients (64%) stated they consented to a biopsy and 180 patients (92%) to blood sample collection. Male patients ( P = .033) and patients with a good performance status (PS) were more willing to consent to a biopsy (79% for PS 0, 63% for PS 1, 43% for PS 2; P = .012). Eighty-eight patients (70%) who consented to a biopsy gave an altruistic reason (eg, to help research and/or others) as a reason why they consented. Only 8 patients (6%) consented solely because they believed it might influence their treatment. Reasons for declining biopsies included a wish to avoid additional procedures (n = 18; 29%) and previous unpleasant biopsy experiences (n = 9; 15%). Conclusion Many patients with advanced gastrointestinal cancer appear willing to undergo biopsies for exploratory research purposes. In our study, patients who consented to a biopsy mainly did so for altruistic reasons and/or a wish to contribute to scientific research.

PURPOSE The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). MATERIALS AND METHODS A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R2). RESULTS Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R2=0.539, p < 0.001) and poor correlation (R=0.169, R2=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. CONCLUSION Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

Background Although treatment of localized anal cancer (AC) is well established, very little evidence is available to inform the management of advanced tumors, and the prognosis of these patients remains poor. We have analyzed treatment pathways and outcomes of a single-institution series of advanced AC patients in order to provide insight into the management of this rare condition. Materials and methods Inclusion criteria included epidermoid histology, inoperable locally recurrent or metastatic disease, and availability of full medical records. The primary objective was overall survival (OS). Prognostic factors were analyzed in univariate models. Results Sixty-four patients (1997-2014) were included: 16 (25.0%) with inoperable locally advanced and 48 (75.0%) with metastatic tumors. Fifty-one (79.7%) received at least one line of chemotherapy; of these, 37% underwent multimodality treatment. A combination of a platinum agent plus a fluoropyrimidine was the most common first-line regimen (74.5%), with an objective response rate (ORR) of 34.4% (95% confidence interval [CI], 18.6%-53.2%). Paclitaxel-based chemotherapy was used in 15 patients as front-line or salvage treatment, and the overall ORR was 53.3% (95% CI, 26.6%-78.7%). Median progression-free survival (PFS) after first- and second-line chemotherapy was 5.8 (interquartile range [IQR], 2.8-7.6) and 3.2 (IQR, 2.5-7.1) months, respectively. Five-year OS in the overall population was 15% (95% CI, 7.0%-25.0%). Age ≤65 years and liver metastases were predictive of better PFS (hazard ratio [HR], 0.39; 95% CI, 0.16-0.97; p = .04) and worse OS (HR, 2.25; 95% CI, 1.25-4.03; p = .01), respectively. Conclusion A platinum agent plus a fluoropyrimidine and paclitaxel-based chemotherapy are active regimens for advanced AC. Clinical trials are needed to standardize treatment pathways, investigate the potential of novel therapeutics, and improve the poor prognosis of this rare condition. The Oncologist 2017;22:402-408Implications for Practice: Because of the lack of randomized trials, the optimal management of advanced anal cancer is uncertain. Despite its retrospective analysis and relatively small sample size, this is the second largest study ever conducted in this setting, and, as such, it has the potential to serve as a valuable source of information for everyday clinical practice. These findings suggest that chemotherapy with a platinum agent plus a fluoropyrimidine or paclitaxel-containing regimens are reasonable treatment options for patients with inoperable locally recurrent or metastatic anal carcinoma.

Serum marker evaluation is an easily available prognostic indicator that may help clinicians to discriminate patients with an aggressive disease; there are few and small-sized studies exploring the prognostic role of baseline carcinoembryonic antigen (CEA) values and their variations during first-line therapy, and even fewer data are available for carbohydrate antigen 19-9 (CA 19-9). Our aim was to analyze the role of those prognostic markers to exploit them in daily clinical practice. Data of 892 patients with marker determination before and 3 and/or 6 months during therapy were extracted from two institutional databases. Patients were grouped according to single marker variation as always negative (G0), decreasing (G1), stable (G2), or increasing (G3). We evaluated the progression-free survival (PFS) and the overall survival (OS) of all the patents and correlated them with CEA and CA 19-9 values. A concordance between response to therapy and marker decrease was evident in 50.2% and in 34.4% of the patients for CEA and CA 19-9. Patients with low CEA or CA 19-9 baseline values had a longer PFS (15.1 vs. 10.5; 13.6 vs. 10.2 months) and OS (32.0 vs. 22.3; 30.5 vs. 20.1 months). The same results of PFS and OS were obtained by analyzing the data of the four different groups. Multivariate analyses confirmed the independent prognostic role of CEA and CA 19-9. Baseline CEA and CA 19-9 levels and their kinetics demonstrated to be independent prognostic factors. CA 19-9 dosage is not recommended; a possible role of CA 19-9 in patients with negative CEA could be worth further evaluation.

Seasonal variation of baseline diagnosis (or clinical suspect) of stage I-III colorectal cancer patients has been repeatedly reported as an independent variable influencing overall survival. However, data are conflicting and no information is available about such a rhythm in advanced stage patients. To test whether a circannual rhythm of efficacy outcomes can be detected in this setting, we collected data about response rate (RR), progression-free survival (PFS), and overall survival (OS) to first-line chemotherapy of 1610 newly diagnosed metastatic patients treated at four independent centers. Responses to first-line chemotherapy were available for 1495 patients. A strong circannual rhythm in RR was evident, with the higher proportion of responding patients in the subgroup diagnosed in January (acrophase). At the time of data cutoff, 1322 patients progressed and 986 died, with median PFS and OS of 11 and 25.6 months, respectively. A circannual rhythmicity of the proportion of patients progressing at 6 months and surviving at 1 year was demonstrated, with acrophases located both in winter (February and January, respectively), similar to what reported for RR. Several interpretations about the genesis of this cyclic variation could be claimed: the rhythm in sunlight exposure and, as a consequence, of vitamin D serum levels and folate degradation, the variability in toxic effect intensity of chemotherapy, and the rhythm in the biological behavior of tumor cells. This observation is worth of further investigation both in preclinical and in clinical settings in order to better elucidate the underlying mechanisms.

Patients with RAS and BRAF wt mCRC are regarded as the best candidates to receive anti-EGFRs. Nevertheless, almost half of these patients do not achieve response, so that a deeper refinement of candidates’ selection would be highly desirable. Different molecular alterations, supported by a strong and sound biologic rationale, have been suggested as predictors of primary resistance to anti-EGFRs, but up today their potential impact has been suggested only in preclinical experiences and retrospective series, and their low frequency makes difficult the validation of each single marker. The present case-control study was conducted to prospectively demonstrate the negative predictive impact of HER-2 amplification or mutations, MET amplification, NTRK/ROS1/ALK/RET rearrangements, and mutations activating MAPKs or PI3K/Akt axis. Patients with RAS and BRAF wt mCRC clearly resistant (cases) vs. clearly sensitive (controls) to single-agent anti-EGFRs were selected, their archival tissue samples were collected and the prevalence of above-mentioned alterations was prospectively assessed. HER-2 status was evaluated by immunohistochemistry (IHC) and silver in-situ hybridization (SISH); MET amplification was studied by SISH; gene rearrangements were screened by IHC followed by RNA-based NGS confirmation. Other candidate mutations were investigated by NGS (Hotspot Cancer Panel v2, Ion Torrent Personal Genome platform (Life Technologies®). Hypothesizing a prevalence of candidate alterations of 0% and 15% among controls and cases, respectively, we needed to include 47 cases and 47 controls to be able to reject the null hypothesis that the prevalence of alterations is equal, with α-error 0.05 and β-error 0.20. Moreover, we evaluated the predictive impact of microsatellite instability, since hypermutated tumors may hardly rely on a single pathway (i.e. EGFR) for their growth. Forty-six cases and 47 controls were included. The primary endpoint was met: above-mentioned alterations were reported in 19 (41.3%) cases and 1 (2.1%) control (p This is the first prospective demonstration that the combined assessment of these rare alterations allows to better select patients for treatment with anti-EGFRs, while opening the way to properly tailored therapies. Molecular alterationCases (Resistant patients)Controls (Sensitive patients)N=46N=47HER-2 amplification7*0HER-2 mutations1 (G776V, exon 20)0MET amplification5*0NTRK rearrangements2 (SCYL3-NTRK1 and TPM3-NTRK1)0ALK rearrangements00ROS1 rearrangements00RET rearrangements1 (CCDC6-RET)0PIK3CA mutations (exon 20)1 (A1035V, exon 20)1 (H1047R, exon 20)PTEN mutations3 (L247S, R233stop and del P248, exon 7)0Total n. of patients with candidate alterations191Microsatellite instability (MSI-high)60RAS mutations at low allele fraction **2 (KRAS G12V, exon 2, 6%; NRAS Q61R, exon 3, 10%)0New RAS mutations3 (2 KRAS L19F, exon 2; KRAS T50I, exon 3)0* in 1 case HER-2 and MET co-amplification was found** previously defined as wt by pyrosequencing Citation Format: Chiara Cremolini, Rosa Berenato, Federica Morano, Roberto Moretto, Federica Perrone, Elena Tamborini, Daniele Rossini, Annunziata Gloghini, Adele Busico, Giovanni Fucà, Chiara Baratelli, Emiliano Tamburini, Iolanda Capone, Chiara Costanza Volpi, Massimo Milione, Massimo Di Maio, Gabriella Fontanini, Filippo De Braud, Alfredo Falcone, Filippo Pietrantonio. Dissecting primary resistance to anti-EGFR monoclonal antibodies (anti-EGFRs) in RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-238. doi:10.1158/1538-7445.AM2017-LB-238

11508 Background: Almost half of RAS and BRAFwt mCRC patients do not respond to anti-EGFRs. Different molecular alterations suggested as predictors of resistance have not been validated. Methods: We conducted a case-control study to prospectively demonstrate the negative predictive impact of HER-2 amplification or mutations (mut), MET amplification, NTRK/ROS1/ALK/RET rearrangements, and mut activating MAPKs or PI3K/Akt axis. Patients with RAS and BRAFwt mCRC clearly resistant (cases) or clearly sensitive (controls) to anti-EGFRs were selected. Hypothesizing a prevalence of candidate alterations of 0% and 15% among controls and cases, 47 cases and 47 controls were needed to be able to reject the null hypothesis of equally prevalent alterations, with a- and b- error 0.05 and 0.20. Since hypermutated tumors may hardly rely on a single pathway for their growth, we also evaluated the impact of microsatellite instability. Results: 47 cases and 47 controls were included. Primary endpoint was met: mentioned alterations were reported in 20 (42.6%) cases and 1 (2.1%) control (p

Summary Insulinoma is a rare form of insulin-secreting pancreatic islet cell neuroendocrine (NE) tumor. The medical treatment of the malignant NE disease of the pancreas deeply changed in the last years, thanks to the introduction of new target molecules, as everolimus. Even if the exact mechanism is not actually known, one of the side effects of everolimus, hyperglycemia, has been demonstrated to be useful to contrast the typical hypoglycemia of the insulinoma. We report the case of a patient with a metastatic malignant insulinoma treated with intermittent everolimus, obtaining an important improvement in the quality of life; this suggests the necessity of preclinical studies to analyze the cellular pathways involved in insulin-independent gluconeogenesis. Learning points Effect of somatostatin analogs is long-lasting in the control of functioning NE tumors. Persistent everolimus control of hypoglycemia despite serum insulin levels and disease progression. Open issue: are disease progression and the increase in serum markers the only valid criteria to reject a treatment?

Case Thrombocytopenic thrombotic purpura (TTP), a life-threatening event consisting of disseminated vascular thrombosis, has never been described before as a possible side effect of the anticancer drug pemetrexed. A 70 years old patient affected by a poorly differentiated non small cell lung cancer, subjected to his first pemetrexed administration, developed an acute thrombocytopenic thrombotic purpura, fatal in a few hours. Conclusions Pemetrexed can cause TTP. Clinicians have to be alert for the rapid onset and aggressiveness of this possible side effect. It is difficult to recognise the first signs and symptoms.

709 Background: International guidelines suggest that RT dose escalation, intraoperative RT or brachytherapy could be considered for LARC pts with positive resection margins, pT4 or unresectable tumours after standard neoadjuvant CRT. However, data to support these approaches are scarce. The potential of systemic CT as salvage treatment after failure of neoadjuvant CRT for LARC has never been explored. We conducted a single-centre, retrospective analysis to address this question. Methods: Pts with newly diagnosed rectal adenocarcinoma who were deemed inoperable or candidates for extensive (i.e. beyond total mesorectal excision, TME) surgery after completion of long-course RT and received salvage systemic CT were included. The primary objective was to estimate the proportion of pts who became potentially suitable for TME after CT. Secondary objectives included the proportion of pts who ultimately underwent TME and survival outcomes. Results: 45 pts (2001-2015) met the study inclusion criteria (39 candidates for extensive surgery and 6 with unresectable tumours). Previous RT was given concurrently with CT in 43 cases (median dose: 54.0 Gy; range: 34.0-55.8). Salvage oxaliplatin-based and irinotecan-based CT was administered in 40 (88.9%) and 5 (11.1%) cases, respectively. 8 pts (17.8%) became suitable for TME based on the MRI after CT, 10 (22.2%) ultimately underwent TME with clear margins and 2 (4.4%) were managed with a watch & wait approach following radiological clinical complete response. Additionally, 13 pts had a beyond-TME surgery with curative intent. 3-year progression-free survival and 5-year overall survival in the entire population were 30.0% (95% CI: 15.0-46.0) and 44.0% (95% CI: 26.0-61.0), respectively. For the curatively resected and watch & wait pts these figures were 52.0% (95% CI: 27.0-73.0) and 67.0% (95% CI: 40.0-84.0), respectively. Conclusions: Systemic CT may be an effective salvage strategy for LARC pts who fail to respond to long-course CRT and are inoperable or candidates for beyond-TME surgery. According to our study, 1 out of 4 pts may become resectable or being spared from an extensive surgery after systemic CT.

Background The management of advanced colorectal cancer patients differs among cancer centers. International guidelines recommend offering all the recognized active regimens in order to obtain survival advantage, but little information is given about the sequence and combination in which such regimens should be administered. Case report We report the case of a man with multiple liver metastasis from colorectal cancer followed for more than 78 months at our Institution. Repeated response to the same oxaliplatin, 5-fluorouracil and folinic acid chemotherapy schedule was achieved, and repeated radiofrequency ablation of liver metastases was performed until progression of lung and brain disease at 50 and 72 months, respectively, after the diagnosis of advanced disease. Although the tumor became oxaliplatin and chemo-resistant after the onset of extra-hepatic disease, a more aggressive chemotherapy regimen, including a doublet with a biological, halted tumor growth. Conclusions The patient survived for more than 78 months without experiencing a major impact on his quality of life. This case reflects the importance of following tumor biology in the therapeutic decision-making process, reintroducing oxaliplatin whenever possible, and adopting a more aggressive strategy when the tumor becomes oxaliplatin-resistant.

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.

470 Background: Outcomes of pts treated with three TTs for mRCC have not been well characterized. Survival data as well as existing prognostic criteria in this population were evaluated. Methods: Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was send to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type, and length of first-, second-, and third-lines were collected. Values of serum Hb, PLT, neutrophils, LDH and Ca, ECOG-PS, previous RT and number of metastatic sites >2 before the start of third-line were evaluated. Cleveland Clinic, French, Heng, and MSKCC scores and relative survival were calculated. Results: Following the screening of 1,905 pts, 252 (13%) with 3 TTs were identified. The median age was 60 yrs (range 52-68), 73% were male, 96% had nephrectomy and 38% were metastatic at diagnosis. At first-line, the Motzer class was good, intermediate, and poor in 48%, 47%, and 5% of pts, respectively. The median OS from the start of third-line was 14.3 mos (95%CI, 10.1–18.6). Rate and survival by prognostic group according to each classification are reported in table below. When prognostic factors were considered separately, at the univariate analysis ECOG-PS≥2, Hb1.5ULN, Ca>ULN; PLT>ULN; Neu>ULN, and sites of disease >2 had negative prognostic role. Multivariate analysis shows an independent prognostic role only for ECOG-PS≥2 (HR: 1.8; 95%CI: 1.1–2.8), HbULN (HR: 2.1; 95%CI: 1.2–3.8). Pts were stratified in 3 groups according to the presence of none, 1 or ≥2 prognostic factors. The median OS was 20.3, 13.6 and 7.8 months, respectively (p

74 Background: While the management of nonmetastatic and oligometastatic rectal cancer has rapidly evolved over the last few decades, many grey areas and highly debated topics remain that foster significant variation in clinical practice. We aimed to identify controversial points and evidence gaps in this disease setting by systematically comparing recommendations from national and international clinical guidelines. Methods: Twenty-six clinical questions reflecting practical challenges in the routine management of nonmetastatic and oligometastatic rectal cancer patients were selected. Recommendations from the ESMO, NCCN, JSCCR, Australian and Ontario guidelines were extrapolated and compared using a 4-tier classification system (i.e., identical/very similar, similar, slightly different, different). Overall agreement between guidelines (i.e., substantial/complete disagreement, partial disagreement, partial agreement, substantial/complete agreement) was assessed for each clinical question and compared against the highest level of available evidence according to the Oxford CEBM Levels of Evidence guidelines by using the χ2 statistic test. Results: Guidelines were in substantial/complete agreement, partial agreement, partial disagreement, and substantial/complete disagreement for 8 (30.8%), 2 (7.7%), 7 (26.9%), and 9 (34.6%) clinical questions, respectively. High level of evidence supported clinical recommendations in 2/10 cases (20%) where guidelines were in agreement and in 10/16 cases (62.5%) where guidelines were in disagreement (χ2 = 4.4726, p = 0.034). Agreement was frequently reached for questions regarding diagnosis, staging, and radiology/pathology pro-forma reporting, while disagreement characterised most of the treatment-related topics. Conclusions: Substantial variation exists across national and international clinical guidelines in the recommendations for the management of nonmetastatic and oligometastatic rectal cancer. This variation is only partly explained by the lack of supporting, high-level evidence.