A phase II/III randomized clinical trial of CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative chemotherapy versus immediate resection in patIents with resecTable BiliarY Tract Cancers (BTC) at high risk for recurrence: PURITY study.

BACKGROUND: Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1-3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20-40% and recurrence rates are up to ~ 75%(4-6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4-6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8). METHODS: PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients' outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery. TRIAL REGISTRATION: PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023-503295-25-00).

Prognostic Value of Body Mass Index in Stage II/III Colon Cancer: Posthoc Analysis From the TOSCA Trial.

BACKGROUND: High body mass index (BMI) plays a key role in the development of colon cancer (CC). Our post-hoc analysis from the TOSCA trial analyzed the association between BMI and survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS) in stage II/III CC patients. PATIENTS AND METHODS: Patients enrolled in the TOSCA trial between 2007-2013 with BMI data entered the study. The prognostic impact of BMI on survival outcomes was investigated through uni- and multivariable Cox regression analyses. RESULTS: Overall, 1455 patients with stage II/III CC patients were included. The median follow-up was of 61.5 months; 16.1% of patients relapsed, 11.2% died and 19.5% patients relapsed or died. No impact of BMI on RFS was detected at univariate or multivariable analyses. By univariate analysis for OS, a significantly impact of a BMI > 30 kg/m2 was reported (HR [>30 vs <25] 1.57, 95% CI 1.00-2.47, p = 0.049; HR [>30 vs <30] 1.55, 95% CI 1.01-2.37, p = 0.045). Multivariable analyses did not confirm this data. In the subgroup of stage III patients, a negative survival impact of BMI was found in univariate and multivariable models both for RFS and for OS. CONCLUSIONS: In our study, obesity with BMI > 30 kg/m2 was an independent prognostic factor for RFS and OS in CC patients treated with adjuvant chemotherapy, regardless of its duration (3 or 6 months). However, the prognostic impact of adiposity and body composition measurement should be considered to better classify patients with high visceral fat and refine their risk assessment.

Hyperthermic intraperitoneal chemotherapy (HIPEC) as adjuvant and therapeutic options for patients with advanced gastric cancer at high risk of recurrence or established peritoneal metastases: a single-centre experience.

Peritoneal metastases from gastric cancer (PM-GC) have a detrimental prognostic impact on survival and there is a lack of consensus regarding treatment. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer a chance for prolonged survival as compared to standard chemotherapy. This study aims to present our experience in the management of GC with CRS and HIPEC. This is a single-centre retrospective study. Patients were divided into two groups: patients with GC at high risk for developing PM-GC (adjuvant HIPEC group) and patients with PM-GC or positive peritoneal cytology (therapeutic CRS and HIPEC group). Overall survival (OS) and disease-free survival (DFS) were considered as outcome measures. A total of 41 patients with a GC primary received surgery and HIPEC: 14 patients (34.1%) were in the adjuvant HIPEC group, while 27 patients (65.9%) were in the therapeutic CRS and HIPEC group. In the adjuvant HIPEC group, the 1- and 3-year OS were 85.7% and 71.4%, while 1- and 3-year DFS were 71.4% and 64.3%, respectively. In the therapeutic CRS and HIPEC group, OS was 60.3% and 35.1% at 1 and 3 years, whereas 1- and 3-year DFS were 38% and 32.6%, respectively. Univariate survival analysis of patients in the therapeutic CRS and HIPEC group showed that the presence of lymph node metastasis and signet ring cell histology predicted worse OS, while PCI > 12 and lymph node metastasis were associated with decreased DFS. Treatment of highly selected patients with GC at high risk of peritoneal recurrence or established PM with CRS and HIPEC showed satisfactory results in terms of OS and DFS.

A randomized phase III study of fractionated docetaxel, oxaliplatin, capecitabine (low-tox) vs epirubicin, oxaliplatin and capecitabine (eox) in patients with locally advanced unresectable or metastatic gastric cancer: the lega trial.

BACKGROUND: EOX (epirubicin, oxaliplatin, and capecitabine) is one of the standard regimens for metastatic or locally advanced gastric cancer (GC). A new combination based on fractional docetaxel (low-TOX) has been developed in an attempt to increase the efficacy of EOX and reduce the heavy toxicity of classical docetaxel regimens. METHODS: Overall, 169 previously untreated GC patients were randomized between EOX (arm A) and low-TOX (arm B). The primary endpoint was progression-free survival (PFS), while secondary ones were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and tolerability. The study was designed to detect a 35% (80% power at a two-sided 5% significance level) PFS increase with low-TOX and an interim analysis for futility was planned after the first 127 events. RESULTS: At the cut-off date of interim analysis, median PFS was 6.3 months [95% confidence interval (CI) 5.0-8.1] in arm A vs 6.3 months (95% CI 5.0-7.8) in arm B, without statistical difference. OS was comparable in the two arms: 12.4 in arm A (95% CI 9.1-19.2) vs 11.5 months in arm B (95% CI 8.6-15.0). ORR was 33% and 24%, while DCR was 68% and 67%, respectively. Treatment modification (91% vs 78%, P = 0.017) and number of patients with CTC grade ≥ 3 adverse events (42 vs 35) were higher in arm B. CONCLUSIONS: A triplet regimen based on the fractional dose of docetaxel achieves no improvement over EOX which remains a potential standard treatment in many patients with inoperable, locally advanced or metastatic GC.

Randomized phase II trial of avelumab alone or in combination with cetuximab for patients with previously treated, locally advanced, or metastatic squamous cell anal carcinoma: the CARACAS study.

BACKGROUND: No standard therapies beyond first line are established for advanced squamous cell anal carcinoma (aSCAC). Earlier preliminary data suggest activity of epidermal growth factor receptor (EGFR) inhibition and programmed cell death ligand (PD-(L))1 blockade in patients with previously treated disease. Aim of this study was to explore activity and safety of avelumab with/without cetuximab in patients with aSCAC. METHODS: In this open-label, non-comparative, 'pick the winner', multicenter randomized phase II trial (NCT03944252), patients with aSCAC progressing after one or more lines of treatment were randomized 1:1 to the anti-PD-L1 agent avelumab alone (arm A) or combined with cetuximab (arm B). Overall response rate (ORR) was the primary endpoint. With one-sided α error set at 0.05 and power of 80%, at least 4 responses out of 27 patients per arm had to be observed to declare the study positive. Secondary endpoints were progression free survival (PFS), overall survival (OS), and safety. RESULTS: Thirty patients per arm were enrolled. Three patients in arm A and five in arm B achieved partial response: primary endpoint was reached in combination arm. ORR was 10% (95% CI 2.1 to 26.5) and 17% (95% CI 5.6 to 34.7) in arms A and B; disease control rate was 50% (95% CI 31.3 to 68.7) in arm A and 57 (95% CI 37.4-74.5) in arm B. At a median follow-up of 26.7 months (IQR 26.5-26.9), median PFS was 2.0 months (95% CI 1.8 to 4.0) in arm A and 3.9 (95% CI 2.1 to 5.6) in arm B. Median OS was 13.9 months (95% CI 7.7 to 19.4) in arm A and 7.8 (95% CI 6.2 to 11.2) in arm B. Acceptable safety profile was observed in both arms. CONCLUSIONS: CARACAS study met its primary endpoint in arm B, documenting promising activity of dual EGFR and PD-L1 blockade in aSCAC.

Nab-paclitaxel/gemcitabine combination is more effective than gemcitabine alone in locally advanced, unresectable pancreatic cancer - A GISCAD phase II randomized trial.

BACKGROUND: The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials. METHODS: This phase II trial tested the efficacy of Nab-paclitaxel (NAB-P)/Gemcitabine (G) versus G alone. Patients were randomized, 1:1 to G 1000 mg/m2 on days 1, 8 and 15 every 28 days versus NAB-P 125 mg/m2 on days 1, 8 and 15 every 28 days plus G 1000 mg/m2 on days 1, 8 and 15 every 28 days. Disease progression rate after three cycles of chemotherapy was the primary end-point. Progression-free survival (PFS), overall survival (OS) and response rate were secondary end-points. FINDINGS: A total of124 patients were enrolled. The study showed a reduction of a progressive disease from 45.6% with G to 25.4% with NAB-P/G (P = 0.01) at 3 months. Noteworthy, at 6 months in the G arm, 35.6% of patients present a metastatic spread versus 20.8% in the NAB/G arm. The response rate was 5.3% in the G arm and 27% in the NAB/G arm. Median PFS was 4 months for the G arm and 7 months for the NAB-P/G arm. Median OS was 10.6 in the G arm and 12.7 months in the NAB-P/G arm. One patient died during treatment with G due to a stroke. INTERPRETATION: NAB-P/G reduced the rate of LAPC patients progressing after three cycles of chemotherapy compared with G, especially in terms of distant relapses. It positively affects PFS. To the best of our knowledge, this is the first randomized trial providing evidence that combination chemotherapy is superior to gemcitabine alone in this setting. CLINICALTRIALS. GOV IDENTIFIER: NCT02043730.

Association of high TUBB3 with resistance to adjuvant docetaxel-based chemotherapy in gastric cancer: translational study of ITACA-S.

BACKGROUND: No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III ß-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported. METHODS: We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival. RESULTS: Patients with TUBB3 protein levels >750 and <750 amol/µg were 21.9% and 78.1%, respectively, and were well-balanced between treatment arms. TUBB3 protein levels were not prognostic. Whereas no survival differences according to the 2 arms were observed in the subgroup with low TUBB3 expression (5-year OS 47% vs 40%; p = 0.44), patients with high TUBB3 had a clinically meaningful poorer OS when receiving docetaxel-based versus 5-FU/LV chemotherapy (5-year OS 31% vs 54%; p = 0.09), with a statistically significant interaction between TUBB3 and treatment (p = 0.049). CONCLUSIONS: The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.

Prevalence and Clinical Impact of SARS-CoV-2 Silent Carriers Among Actively Treated Patients with Cancer During the COVID-19 Pandemic.

INTRODUCTION: In Europe, the SARS-CoV-2 pandemic had its first epicenter in Italy. Despite a significant mortality rate, the severity of most cases of COVID-19 infection ranges from asymptomatic to mildly symptomatic, and silent infection affects a still-unknown proportion of the general population. No information is available on the prevalence and clinical impact of SARS-CoV-2 silent infection among patients with cancer receiving anticancer treatment during the pandemic. MATERIALS AND METHODS: From April 1, 2020, to the end of the same month, 560 consecutive patients with cancer, asymptomatic for COVID-19 and on anticancer treatment at Papa Giovanni XXIII Hospital in Bergamo, were evaluated and tested for SARS-CoV-2. We implemented a two-step diagnostics, including the rapid serological immunoassay for anti-SARS-CoV-2 immunoglobulin (Ig) G/IgM and the nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) test in case of seropositivity to identify SARS-CoV-2 silent carriers. RESULTS: In 560 patients, 172 (31%) resulted positive for anti-SARS-CoV-2 IgM/IgG antibodies, regardless of different type of cancer, stage, and treatment. The Ig-seropositive patients were then tested with RT-PCR nasopharyngeal swabs, and 38% proved to be SARS-CoV-2 silent carriers. At an early follow-up, in the 97 SARS-CoV-2-seropositive/RT-PCR-negative patients who continued their anticancer therapies, only one developed symptomatic COVID-19 illness. CONCLUSION: Among patients with cancer, the two-step diagnostics is feasible and effective for SARS-CoV-2 silent carriers detection and might support optimal cancer treatment strategies at both the individual and the population level. The early safety profile of the different anticancer therapies, in patients previously exposed to SARS-CoV-2, supports the recommendation to continue the active treatment, at least in cases of RT-PCR-negative patients. IMPLICATIONS FOR PRACTICE: This is the first study evaluating the prevalence and clinical impact of SARS-CoV-2 silent infection in actively treated patients with cancer, during the epidemic peak in one of the worst areas of the COVID-19 pandemic. Lacking national and international recommendations for the detection of asymptomatic SARS-CoV-2 infection, a pragmatic and effective two-step diagnostics was implemented to ascertain SARS-CoV-2 silent carriers. In this series, consisting of consecutive and unselected patients with cancer, the prevalence of both SARS-CoV-2-seropositive patients and silent carriers is substantial (31% and 10%, respectively). The early safety profile of the different anticancer therapies, in patients previously exposed to SARS-CoV-2, supports the recommendation to continue the active treatment, at least in case of RT-PCR-negative patients.

Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer.

PURPOSE: To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin, and fluorouracil (FOLFIRI) in patients with RAS-mutated, methyl-guanine methyltransferase (MGMT)-methylated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In this randomized, phase II trial, we enrolled patients with RAS-mutated, MGMT-methylated mCRC after failure of oxaliplatin-based regimen. Patients with centrally confirmed MGMT methylation were stratified by first-line progression-free survival (PFS) and prior bevacizumab and randomized to either capecitabine plus temozolomide (arm A, CAPTEM) or FOLFIRI (arm B). The primary endpoint was PFS analyzed on intention-to-treat basis, with 90% power and one-sided significance level of 0.05 to detect an increase of median time from 2 months in arm B to 4 months in arm A. RESULTS: Between November 2014 and May 2019, 86 patients were randomly assigned to arm A (n = 43) or arm B (n = 43). After a median follow-up of 30.5 months (interquartile range, 12.2-36.3), 79 disease progression or death events occurred. Superiority of arm A was not demonstrated (one-sided P = 0.223). Progression-free survival and overall survival were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) in arm A versus 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B [HR = 1.19 (0.82-1.72) and HR = 0.97 (0.58-1.61)], respectively. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. Patients with positive MGMT expression by IHC did not benefit from CAPTEM. CONCLUSIONS: Temozolomide-based therapy warrants further investigation in molecularly hyperselected subgroups.

Trifluridine/Tipiracil (TAS-102) in Refractory Metastatic Colorectal Cancer: A Multicenter Register in the Frame of the Italian Compassionate Use Program.

BACKGROUND: TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost-benefit ratio is crucial. The "ColonLife" nomogram allows an estimate of the 12-week life expectancy of patients with refractory mCRC. MATERIALS AND METHODS: We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS-102 and regorafenib, clinical outcomes of the two sequences were compared. RESULTS: This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression-free survival (PFS) was 2.4 months with an estimated 6-month PFS rate of 19%; the median overall survival (OS) was 6.2 months. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, normal lactate dehydrogenase (LDH), and a time from the diagnosis of metastatic disease of >18 months were independently associated with higher chances of a patient being progression free at 6 months. The discriminative ability of ColonLife was confirmed. Among 121 patients who received both regorafenib and TAS-102, no differences in first or second PFS or OS were reported between the two sequences. CONCLUSION: One out of five patients achieves clinical benefit with TAS-102. ECOG PS, LDH, and time from diagnosis of metastatic disease may help to identify these patients. Excluding patients with very short life expectancy appears a reasonable approach. IMPLICATIONS FOR PRACTICE: Improving the cost-efficacy ratio of TAS-102 in metastatic colorectal cancer is needed to spare useless toxicities in a definitely palliative setting. Eastern Cooperative Oncology Group performance status, lactate dehydrogenase levels, and time from the diagnosis of metastatic disease may help to identify patients more likely to achieve benefit. Properly designed prognostic tools (i.e., the "ColonLife" nomogram) may enable excluding from further treatments patients with very limited life expectancy.

Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial.

BACKGROUND: Pancreatic ductal adenocarcinoma are known to metastasise early and a rationale exists for the investigation of preoperative chemotherapy in patients with resectable disease. We aimed to assess the role of combination chemotherapy in this setting in the PACT-15 trial. METHODS: We did this randomised, open-label, phase 2-3 trial in ten hospitals in Italy. We report the phase 2 part here. Patients aged 18-75 years who were previously untreated for pancreatic ductal adenocarcinoma, with Karnofsky performance status of more than 60, and pathologically confirmed stage I-II resectable disease were enrolled. Patients were randomly assigned (1:1:1), with a minimisation algorithm that stratified treatment allocation by centre and concentrations of carbohydrate antigen 19-9 (CA19-9 ≤5 × upper limit of normal [ULN] vs >5 × ULN), to receive surgery followed by adjuvant gemcitabine 1000 mg/m2 on days 1, 8, 15 every 4 weeks for six cycles (arm A), surgery followed by six cycles of adjuvant PEXG (cisplatin 30 mg/m2, epirubicin 30 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 every 4 weeks and capecitabine 1250 mg/m2 on days 1-28; arm B), or three cycles of PEXG before and three cycles after surgery (arm C). Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation. The primary endpoint was the proportion of patients who were event-free at 1 year. The primary endpoint was analysed in the per-protocol population. Safety analysis was done for all patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, number NCT01150630. FINDINGS: Between Oct 5, 2010, and May 30, 2015, 93 patients were randomly allocated to treatment. One centre was found to be non-compliant with the protocol, and all five patients at this centre were excluded from the study. Thus, 88 patients were included in the final study population: 26 in group A, 30 in group B, and 32 in group C. In the per-protocol population, six (23%, 95% CI 7-39) of 30 patients in group A were event-free at 1 year, as were 15 (50%, 32-68) of 30 in group B and 19 (66%, 49-83) of 29 in group C. The main grade 3 toxicities were neutropenia (five [28%] of 18 in group A, eight [38%] of 21 in group B, eight [28%] of 29 in group C before surgery, and ten [48%] of 21 in group C after surgery), anaemia (one [6%] in group A, four [19%] in group B, eight [28%] in group C before surgery, and five [24%] in group C after surgery), and fatigue (one [6%] in group A, three [14%] in group B, two [7%] in group C before surgery, and one [5%] in group C after surgery). The main grade 4 toxicity reported was neutropenia (two [11%] in group A, four [19%] in group B, none in group C). Febrile neutropenia was observed in one patient (3%) before surgery in group C. No treatment-related deaths were observed. INTERPRETATION: Our results provide evidence of the efficacy of neoadjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Since the trial began, the standard of care for adjuvant therapy has altered, and other chemotherapy regimens developed. Thus, we decided to not continue with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this approach with different chemotherapy regimens. FUNDING: PERLAVITA ONLUS and MyEverest ONLUS.

Cholangiocarcinoma.

Biliary tract cancer accounts for <1% of all cancers and affects chiefly an elderly population, with predominance in men. We distinguish cholangiocarcinoma (intrahepatic, hilar and distal) and gallbladder cancer, with different pathogenesis and prognosis. The treatment is based on surgery (whenever possible), radiotherapy in selected cases, and chemotherapy. The standard cytotoxic treatment for advanced/metastatic disease is represented by the combination of gemcitabine and cisplatin, whereas fluoropyrimidines are generally administered in second line setting. At the present time, no biologic drug demonstrated a clear efficacy in this cancer, although the molecular characterisation could provide a promising basis for experimental treatments. A good supportive care and an early palliative care are warranted in most patients and should be delivered as a part of a global approach.

Assessment of a HER2 scoring system for colorectal cancer: results from a validation study.

We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrollment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.

The value of lactate dehydrogenase serum levels as a prognostic and predictive factor for advanced pancreatic cancer patients receiving sorafenib.

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

Optimizing single agent panitumumab therapy in pre-treated advanced colorectal cancer.

PURPOSE: To improve the selection of advanced colorectal cancer patients to panitumumab by optimizing the assessment of RAS (KRAS-NRAS) mutations. EXPERIMENTAL DESIGN: Using a centralized pyrosequencing RAS assay, we analyzed the tumors of 94 patients, wild-type for KRAS mutations (codons 12 to 13) by Sanger sequencing (SS), treated with panitumumab. RESULTS: By SS analysis, 94 (62%) of 152 patients were wild-type and their objective response rate to panitumumab was 17%. We first optimized the KRAS test, by performing an accurate tissue-dissection step followed by pyrosequencing, a more sensitive method, and found further mutations in 12 (12.8%) cases. Secondly, tumors were subjected to RAS extension analysis (KRAS, exons 3 to 4; NRAS exons 2 to 4) by pyrosequencing that allowed to identify several rare mutations: KRAS codon 61, 5.3%; codon 146, 5.3%; NRAS, 9.5%. Overall, RAS mutation rate was 32.9%. All patients with additional RAS mutations had progressive or stable disease, except 3 patients with mutations at codon 61 of KRAS or NRAS who experienced partial (2 cases) or complete response. By excluding from the analysis 11 cases with mutations at codons 61, no patient was responsive to treatment (P=.021). RAS wild-type versus RAS mutated cases had a significantly better time to progression (P=.044), that resulted improved (p=.004) by excluding codon 61 mutations. CONCLUSION: This study shows that by optimizing the RAS test it is possible to significantly improve the identification of patients who do not gain benefit of panitumumab. Prospective studies are warranted to determine the clinical significance of rare mutations.

Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study.

BACKGROUND: The RAF-MEK-ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations. A phase II randomized trial was designed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer. METHODS: Locally advanced or metastatic pancreatic adenocarcinoma patients were randomized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400mg bid (arm A) or without sorafenib (arm B). RESULTS: One hundred and fourteen patients were enrolled; of these, 43 (74.6%) patients progressed in arm A and 44 (82.4%) in arm B. Median progression-free survival was 4.3 months (95% CI: 2.7-6.5) and 4.5 months (95% CI: 2.5-5.2), respectively (HR=0.92; 95% CI: 0.62-1.35). Median overall survival was 7.5 (95% CI: 5.6-9.7) and 8.3 months (95% CI: 6.2-8.7), respectively (HR=0.95; 95% CI: 0.62-1.48). Response rates were 3.4% in arm A and 3.6% in arm B. CONCLUSIONS: Sorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients, and therefore should not be assessed in phase III trials.

Colon cancer.

Colon cancer is one of the leading tumours in the world and it is considered among the big killers, together with lung, prostate and breast cancer. In the recent years very important advances occurred in the field of treatment of this frequent disease: adjuvant chemotherapy was demonstrated to be effective, chiefly in stage III patients, and surgery was optimized in order to achieve the best results with a low morbidity. Several new target-oriented drugs are under evaluation and some of them (cetuximab and bevacizumab) have already exhibited a good activity/efficacy, mainly in combination with chemotherapy. The development of updated recommendations for the best management of these patients is crucial in order to obtain the best results, not only in clinical research but also in every-day practice. This report summarizes the most important achievements in this field and provides the readers useful suggestions for their professional practice.

Cholangiocarcinoma.

Cholangiocarcinoma is an uncommon adenocarcinoma with poor prognosis. Although the 1-year survival has increased over time, the 5-year survival has not shown any significant change (less than 5%). Cure can only be expected from surgical resection of early stage tumours but most patients initially present with advanced disease. Cancer cachexia, liver failure, and recurrent sepsis due to biliary obstruction are among the main causes of mortality. Patients' prognosis is strongly related to radical surgery and complete resection is the most effective therapy; the location within the biliary tree (proximal versus distal) has no impact on survival when a complete resection is achieved despite the fact the rate of resectability is up to 70% in case of distal cancer and 15-20% for high bile ducts tumours. Prognosis of cholangiocarcinoma remains poor even with aggressive surgical therapy because of the high incidence of local or regional recurrence and distant metastasis. Based on these data many questions need an answer: is there a role for adjuvant chemotherapy or radiotherapy? Neoadjuvant treatments provide best results? There is a standard therapy in unresectable or metastatic cholangiocarcinoma? This report tries to answer to frequently asked questions that the readers are faced with their patients every day (from diagnostic procedures to palliative treatment) and tries to suggest useful information for their professional practice.

Incidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: the 'GISCAD-alternating schedule' study findings.

AIM OF THE STUDY: To investigate the incidence and clinical implications of venous thromboembolism (VTE) in advanced colorectal cancer (ACC) patients treated and followed-up through a prospective randomised trial, comparing FOLFIRI chemotherapy given as an intermittent or as a continuous schedule. PATIENTS, MATERIALS AND METHODS: A total of 266 patients were randomised by 15 experimental centres: 168 (63.2%) were males, median age: 64.6 years, age range: 37-76 years. Almost all (95.5%) patients had metastatic disease, while the remainder were classified with locally advanced irresectable disease. For 138 (51.9%) of the patients, the chemotherapy treatment was intermittent FOLFIRI and the remaining patients received continuous treatment. All toxicities, including VTE, were prospectively collected. RESULTS: During the study protocol, the central data management gathered two cases of VTE. Our analysis retrieved 27 (10.2%) patients who developed a VTE, almost all (89%) during the course of chemotherapy treatment: 20 out of 27 during FOLFIRI, the remaining 7 during following lines or follow-up. VTE was the most frequent grade 3/4 toxicity. The incidence of VTE was significantly increased in the patients receiving continuous rather than intermittent treatment (HR 2.67, 95% CI 1.17-6.10; p<0.02). CONCLUSION: VTE is a common complication among advanced colorectal cancer patients and yet this type of toxicity is widely underestimated. In this randomised trial, VTE was the most frequent grade 3/4 toxicity. Use of an intermittent schedule is associated with a reduced risk of developing VTE.