Stefania Eufemia Lutrino

Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer

AIM To explore the prognostic value of extended mutational profiling for metastatic colorectal cancer (mCRC). MATERIALS & METHODS We retrospectively reviewed survival results of 194 mCRC patients that were assigned to four molecular subgroups: BRAF mutated; KRAS mutated codons 12-13 only; any of KRAS codons 61-146, PIK3CA or NRAS mutations and all wild-type. Point mutations were investigated by pyrosequencing. RESULTS BRAF (5.2%) and KRAS 12-13 (31.9%) mutations were associated with poorer survival (HR 2.8 and 1.76, respectively). Presenting with right-sided colon cancer, not resected primary tumor, WBC >10 × 10(9)/l, receiving less chemotherapy or no bevacizumab were all associated with inferior outcome. The all-wild-type subgroup (39.2%) reported the longest survival. CONCLUSION Extended mutational profile combined with clinical factors may impact on survival in mCRC.

Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight

Advanced gastric cancer ranks second as the global leading cause of cancer-related death and improvements in systemic chemotherapy have reached a plateau. Advanced molecular sequencing techniques help identifying patients more likely to respond to targeted agents; nevertheless we are still far from major breakthroughs. Although antiangiogenic drugs have produced notable advances, redundant pathways or mechanisms of resistance may limit their efficacy. Novel compounds have been recently developed to specifically target VEGF receptors, PlGF, FGF, MET, and angiopoietin. Ramucirumab, a monoclonal antibody specifically directed against the VEGFR-2, has emerged as a novel therapeutic opportunity. REGARD and RAINBOW were the first phase III studies to report the value of this strategy in gastric cancer patients, and other ongoing trials are testing novel antiangiogenic compounds. The aim of our review is to present the state-of-the-art of novel antiangiogenic compounds in advanced gastric cancer, underlying the biology, their mechanism of action, and their clinical results.

Oxaliplapin and Capecitabine (XELOX) Based Chemotherapy in the Treatment of Metastatic Colorectal Cancer: The Right Choice in Elderly Patients

PURPOSE Elderly patients with metastatic colorectal cancer (mCRC) differ from the general population and are underrepresented in clinical trials. We, retrospectively, analyzed the safety and efficacy of XELOX regimen in the treatment of elderly patients affected by mCRC. PATIENTS AND METHODS One-hundred-eleven consecutive patients, aged 70 years or older, were enrolled in the study. RESULTS All patients were evaluated for safety and efficacy (male/female, 63/48). Median age was 75 years (range 71-85 years). Median Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0 (range 0-2). Metastatic sites distribution is as follows: liver (44.1%), lung (13.5%), liver plus lung (12.6%) and other (29.7%). A total of 584 cycles were administered (median 6 cycles/patient, range 2-10). Median follow-up time was 14.5 months (range 1-41 months). In an intent-to-treat analysis, objective responses and stable disease were recorded in 41 (40.4%) and 29 (26.6%) patients, respectively. The median response duration was 5.9 months (range 0.5-28.8). The median progression free-survival (PFS) was 7.5 months (range 1-26 months). The median overall survival (OS) was 15 months (range 1-64 months). The grade 3 toxicities were: neutropenia (8.1%), diarrhea and neurotoxicity (5.4% respectively). Most adverse events were mild to moderate; the most common was acute sensory neuropathy (57.6%). CONCLUSION XELOX is a highly effective first-line treatment for mCRC elderly patients. Response rates, PFS and OS are similar to those observed with fluorouracil/leucovorin/oxaliplatin combinations. XELOX is a convenient regimen, likely to be preferred by both patient and healthcare providers.

Evidence-based appraisal of the upfront treatment for unresectable metastatic colorectal cancer patients.

Colorectal cancer (CRC) is a significant health problem, with around 1 million new cases and 500000 deaths every year worldwide. Over the last two decades, the use of novel therapies and more complex treatment strategies have contributed to progressively increase the median survival of patients with unresectable advanced CRC up to approximately 30 mo. The availability of additional therapeutic options, however, has created new challenges and generated more complicated treatment algorithms. Moreover, several clinically important points are still in debate in first-line, such as the optimal treatment intensity, the most appropriate maintenance strategy, the preferred biologic to be used upfront in patients with KRAS wild-type CRC, and the need for more detailed information on tumor biology. In this moving landscape, this review analyses why the first-line treatment decision is crucial and how the choice may impact on further treatment lines. In addition, it focuses on results of major phase III randomized trials.

MGMT promoter methylation status in brain metastases from colorectal cancer and corresponding primary tumors

BACKGROUND Brain metastases (BM) from colorectal cancer are usually associated with poor prognosis. The aim of this retrospective study is to evaluate MGMT promoter methylation in BM and their corresponding primary colorectal cancer tumors. MATERIALS & METHODS MGMT promoter methylation status was assessed by pyrosequencing in 53 consecutive patients resected for BM. A concordance analysis between BM and matched primary tumor was performed in 39 cases. RESULTS MGMT methylation was found in 34 (64.2%) BM and in 25 corresponding primary tumors (64.1%). Median survival after neurosurgery was independent from MGMT promoter methylation (163 days for those with methylated MGMT versus 193 days for the unmethylated). CONCLUSION Epigenetic MGMT promoter methylation was common and the concordance between primary and secondary lesions was high.

Timing and extent of response in colorectal cancer: critical review of current data and implication for future trials.

The identification of new surrogate endpoints for advanced colorectal cancer is becoming crucial and, along with drug development, it represents a research field increasingly studied. Although overall survival (OS) remains the strongest trial endpoint available, it requires larger sample size and longer periods of time for an event to happen. Surrogate endpoints such as progression free survival (PFS) or response rate (RR) may overcome these issues but, as such, they need to be prospectively validated before replacing the real endpoints; moreover, they often bear many other limitations. In this narrative review we initially discuss the role of time-to-event endpoints, objective response and response rate as surrogates of OS in the advanced colorectal cancer setting, discussing also how such measures are influenced by the tumor assessment criteria currently employed. We then report recent data published about early tumor shrinkage and deepness of response, which have recently emerged as novel potential endpoint surrogates, discussing their strengths and weaknesses and providing a critical comment. Despite being very compelling, the role of such novel response measures is yet to be confirmed and their surrogacy with OS still needs to be further investigated within larger and well-designed trials.

Maintenance Therapy in Colorectal Cancer: Moving the Artillery Down While Keeping an Eye on the Enemy

The survival improvement in metastatic colorectal cancer, achieved with more intensive chemotherapy regimens, has recently led clinicians to question the optimal duration of therapies and to consider the role of maintenance. Indeed, patients whose disease is controlled after induction chemotherapy may benefit from continuing a less intensive regimen in order to reinforce the results achieved with up-front treatment. In addition, the more favorable toxicity profile of maintenance approaches would ensure a better quality of life. After discussing the rationale and the difference of pursuing a maintenance strategy with chemotherapeutic and/or biologic agents, we present significant available data from the literature and comment on the current implications and future directions of maintenance therapy. The current roles of depotentiated treatment schedules, antiangiogenic compounds, epidermal growth factor receptor inhibitors, and novel targeted therapies are also reviewed. Finally, we address elements that may foster clinical and social debate on this topic, suggesting potential aspects that need to be further investigated.

588PSAFETY AND EFFICACY OF PREOPERATIVE CHEMORADIOTHERAPY (CRT) IN LOCALLY ADVANCED RECTAL CANCERS (LARC): A RETROSPECTIVE ITALIAN SURVEY OF 389 ELDERLY PATIENTS

ABSTRACT Aim: Although CRT is considered the worldwide standard of treatment in LARC, this strategy in elderly patients (pts 370 years) is not often feasible due to morbidity, performance status and compliance. Methods: We reviewed clinical and pathological features of a large series of elderly pts with T3-T4 N0/N+ rectal carcinoma (within 12 cm from anal verge). All patients received CRT with fluoropyrimidines +/- oxaliplatin concomitant to pelvic radiation (45-50.4 Gy). Surgery was scheduled within 6-8 weeks after the end of CRT. Aim was to evaluate safety and outcome results in a retrospective series of elderly pts with LARC. Results: 389 pts from 7 centers were collected. Demographic characteristics were as follows: M/F 251/138, median age 74 (range 70-89); clinical stage was T3 in 321 (82%) and T4 in 52 (13%); 207 pts (53%) showed suspicious nodes, while in 12 pts (3%) stage was unknown. Comorbidities were present in 214 out of 294 pts on which the information was known (73%). Cardiovascular diseases, primarily hypertension, affected 132 out of 294 pts while metabolic and neurological disorders was present in 57 and 17 cases respectively. Continuous infusion of 5-FU was given to 208 pts (53%), capecitabine in 86 (22%) while 89 pts (22%) had oxaliplatin-based combination. Any grade toxicities were reported in 307 patients (78%): diarrhoea (48%), skin toxicity (17%) and dysuria (21%) were the most frequently side effects. Surgery was performed in 349 pts (89%): low anterior resection in 247 cases, Miles resection in 75, Hartmann resection in 7, local excision in 19, missing in 1. Pathologic report showed a complete remission in 59 cases (17%), ypT1-T2: 145, ypT3: 119, ypT4: 9, while 81 pts had ypN1-2 tumor. Downstaging rate was 60% and sphincter preserving surgery rate was 77%. At the time of analysis, 76 pts (22%) relapsed locally or at a distant site. Conclusions: Even though potential bias of selection, this retrospective study suggest that CRT is feasible in elderly patients with mild toxicities with results similar to those reported in younger pts. However prospective trials focusing on the older population are lacking. Disclosure: All authors have declared no conflicts of interest.

From trial highlights to clinical context: putting American Society of Clinical Oncology gastrointestinal news into practice

Celebrating its tenth anniversary, the Gastrointestinal Cancers Symposium is a world class, international conference focused on research and multidisciplinary management of digestive tract malignancies, co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the American Gastroenterological Association Institute and the Society of Surgical Oncology. This premium meeting was held from 24 to 26 January 2013 in San Francisco (CA, USA) and, in line with its principal mission, it sought to globally embrace prevention, screening, diagnostics, translational research and multimodal treatment, moving on three major anatomic tracks (upper gastrointestinal cancers, pancreatic/hepatobiliary tumors and colorectal malignancies). Over 2000 healthcare professionals gathered at this valuable 3day scientific event, which included plenary educational sessions and oral presentations of the top-rated abstracts, as well as the exposition of nearly 600 posters. This short article offers a summarized opinion-based overview of the most significant studies presented at the meeting that are likely to impact on clinical practice as well as new drug development, as best exemplified by the three most important messages of the whole meeting: the value of nanoparticle albumin-bound paclitaxel in metastatic pancreatic cancer; that of ramucirumab in second-line gastric cancer; and that of capecitabine and bevacizumab in elderly advanced colorectal cancer patients.