Annalisa Fontana

Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial

Background:Advanced biliary tract carcinoma has a very poor prognosis, with chemotherapy being the mainstay of treatment. Sorafenib, a multikinase inhibitor of VEGFR-2/-3, PDGFR-β, B-Raf, and C-Raf, has shown to be active in preclinical models of cholangiocarcinoma.Methods:We conducted a phase II trial of single-agent sorafenib in patients with advanced biliary tract carcinoma. Sorafenib was administered at a dose of 400 mg twice a day. The primary end point was the disease control rate at 12 weeks.Results:A total of 46 patients were treated. In all, 26 (56%) had received chemotherapy earlier, and 36 patients completed at least 45 days of treatment. In intention-to-treat analysis, the objective response was 2% and the disease control rate at 12 weeks was 32.6%. Progression-free survival (PFS) was 2.3 months (range: 0–12 months), and the median overall survival was 4.4 months (range: 0–22 months). Performance status was significantly related to PFS: median PFS values for ECOG 0 and 1 were 5.7 and 2.1 months, respectively (P=0.0002). The most common toxicities were skin rash (35%) and fatigue (33%), requiring a dose reduction in 22% of patients.Conclusions:Sorafenib as a single agent has a low activity in cholangiocarcinoma. Patients having a good performance status have a better PFS. The toxicity profile is manageable.

FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer

Background:In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS).Methods:In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment.Results:From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1%; complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001).Conclusions:FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.

Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy.

Background:Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear.Methods:We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworaks tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed.Results:Tumour regression grade 4 and TRG3–4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found.Conclusion:Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.

The somatic affairs of BRAF: tailored therapies for advanced malignant melanoma and orphan non-V600E (V600R-M) mutations

BRAF V600R-M-D are uncommon mutations, not included in the experimental protocols of BRAF selective inhibitors. We report the evaluation of correlations among different types of BRAF somatic mutations in melanoma and their management with BRAF inhibitors. 21 patients with BRAF mutated metastatic melanoma were enrolled in the protocol with BRAF inhibitors for compassionate use at the University of Modena. Hot spot V600E mutations were found in 19 patients. V600R mutation and double (V600E -V600M) mutation were identified in two melanomas. In one case, V600K mutation was found. Two screening failures were noted. Mean progression free survival at follow-up of to 8 weeks, was 7.6 months. Five patients had a very short follow-up and the experimental protocol is still ongoing, so we cannot provide complete follow-up data. However, all of them are still under treatment and disease progression free. An objective response with few side effects was observed in all patients. in vitro studies with the aim of testing drug sensitivity.

Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors

Purpose: The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs. Methods: Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples. Results: Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome. Conclusion: This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors.

Primary adrenal gland carcinosarcoma associated with metastatic rectal cancer: a hitherto unreported collision tumor

In this report we describe the case of a young woman with familial adenomatous polyposis who developed metastatic rectal cancer during pregnancy. At diagnosis, we decided to perform a transabdominal laparoscopic adrenalectomy, because of the high risk of bowel obstruction, and to define the origin of the adrenal gland lesion, suspected to be primary on the basis of imaging results. The histological specimen showed a collision tumor between an adrenal metastasis of a rectal tumor and a primary adrenal gland carcinosarcoma. The peculiarity of the case is due not only to its clinical presentation during pregnancy, but also to the presence of this uncommon adrenal collision tumor. A particular challenge for the clinician is to define the priority between these two tumors: the presence of two distinct and colliding aggressive neoplasms poses a problem in the choice of the best therapeutic approach, also given the impossibility to biopsy all metastatic sites. However, we decided to treat the patient as having a metastatic rectal cancer, because we had a solid histological confirmation of metastases.

Impressive Response to Dose-Dense Chemotherapy in a Patient with NUT Midline Carcinoma.

Patient: Male, 21 Final Diagnosis: NUT midline carcinoma Symptoms: Fatigue • fever • pain Medication: Romidepsin Clinical Procedure: Chemotherapy Specialty: Oncology Objective: Rare disease Background: NUT midline carcinoma (NMC) is a rare, highly lethal malignancy that results from a chromosome translocation and mostly arises in the midline organs. To date, no treatment has been established. Most patients receive combinations of chemotherapy regimens and radiation, and occasionally subsequent resection; nevertheless, patients have an average survival hardly exceeding 7 months. Case Report: A 21-year-old patient was admitted to our division with a large mediastinal mass with lung nodules, multiple vertebral metastases, and massive nodal involvement. In a few days, the patient developed a superior vena cava syndrome and an acute respiratory failure. Due to the rapid course of the disease, based on preliminary histology of poorly differentiated carcinoma, a dose-dense biweekly chemotherapy with paclitaxel, ifosfamide, and cisplatin was started. In the meantime, the diagnosis of NMC was confirmed. A surprising clinical benefit was obtained after the first cycle of chemotherapy, and after 6 cycles a PET-CT scan showed a very good response. At this point, radiotherapy was started but the disease progressed outside of the radiation field. The patient entered into a compassionate use protocol with Romidepsin, but a PET/CT scan after the first course showed disease progression with peritoneal and retroperitoneal carcinosis. A treatment with Pemetrexed was then started but the patient eventually died with rapid progressive disease. Conclusions: Our case history adds some interesting findings to available knowledge: NMC can be chemosensitive and radiosensitive. This opens the possibility to study more aggressive treatments, including high-dose consolidation chemotherapy and to evaluate the role of biological agents as maintenance treatments.

Metronomic Capecitabine Effectively Blocks Leptomeningeal Carcinomatosis From Breast Cancer: A Case Report and Literature Review

Patient: Female, 57 Final Diagnosis: Meningeal carcinomatosis from breast cancer Symptoms: Seizures Medication: — Clinical Procedure: — Specialty: Oncology Objective: Unusual clinical course Background: Meningeal carcinomatosis is a rare complication in breast cancer patients. At present, there are no defined guidelines for its management. The efficacy of systemic treatment seems to depend on its ability to cross the blood-brain-barrier and its interaction with tumor vasculature. Metronomic chemotherapy is a known modality of drug administration able to inhibit tumor angiogenesis. Case Report: We present a case of symptomatic leptomeningeal carcinomatosis from breast cancer successfully treated with capecitabine. Based on the hypothesis that angiogenesis contributes to neoplastic meningitis, the patient was treated with a metronomic schedule that provided long-term clinical benefit with a very low toxicity profile. Conclusions: To assess the real impact of metronomic chemotherapy in patients with meninges involvement, a phase II study will be starting soon in our institution. A review of the literature concerning the management of meningeal carcinomatosis is also presented.

Advanced gastric cancer: is there an optimal chemotherapy regimen?

ABSTRACT Introduction: Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide. For patients with advanced gastric cancer (AGC), systemic chemotherapy remains the standard of care, improving survival and quality of life (QoL); however prognosis remains poor. Areas covered: Several clinical trials have been evaluated the efficacy of different combination regimens in AGC patients. This review will underline existing literature on the role of chemotherapy in the management of AGC, discussing the key determinants of treatment decision aiming at identify the optimal chemotherapy regimen for individual patients and the role of addition of biological agents in these regimens. Expert commentary: Despite the progress in understanding of the molecular subtypes of GC, chemotherapy remains the backbone of treatment for all-line setting in well-selected AGC patients. Moreover, several trials have failed to demonstrate a benefit of targeted agents and to date only trastuzumab and ramucirumab and apatinib only in China are approved in the treatment of this disease. Therefore, an improved patient selection before and during therapy with a better definition of predictive biomarkers are really needed.

591PA PHASE IB STUDY OF EVEROLIMUS, 5-FLUOROURACIL (5-FU) AND PELVIC RADIOTHERAPY (RT) AS NEO-ADJUVANT TREATMENT FOR LOCALLY ADVANCED RECTAL CANCER (LARC)

ABSTRACT Aim: The addition of 5FU to preoperative RT increases clinical downsizing and pathological downstaging and optimizes local control but has no significant effect on survival (OS). New cytotoxic drugs (irinotecan and oxaliplatin, i.e.) and targeted agents (bevacizumab and cetuximab, i.e.) have been tested in combination with 5FU and RT, but with no benefit on pathological complete response (pCR) and OS. Primary aim of the present phase Ib study is to establish the maximum tolerated dose (MTD) of everolimus in combination with 5FU and RT in LARC. Secondary: Tumor regression grade (Dworak score); rates of pCR; evaluation of biological parameters of inhibition of target (tissue expression of phosphorilated S6 and mTOR) before, after 2 weeks of treatment (before concomitant treatment) and on surgical specimen. Methods: Between march 2011 and december 2013 12 patients with histologically confirmed diagnosis of LARC (T3-T4; N0-1; within 15 cm from anal rhyma) were enrolled at University Hospital of Modena. Pts have been sequentially assigned to one of the following 4 cohorts and have been administered with the following dose levels: everolimus at 2,5 mg; 5 mg; 7,5 mg; 10 mg daily per os starting from 14 days before 5FU and RT and for all the duration of the concomitant treatment. DLT was defined as every reported toxicity (haematological and non haematological) ≥ grade 3, as defined by CTC criteria 3.0. Grade 2 pneumonitis lasting more than 7 days or recurrent on the same cycle or grade > 3 of any duration. Results: Twelve pts have been treated and no DLT (as defined above) was recorded. The reported toxicities were: skin rash (observed in 3 cases: 2 G1 and 1 G2), asthenia (observed in 4 cases, G1), diarrhea (observed in 6 cases: 5 G1 and 1 G2), mucositis (observed in 1 case, G1) and urinary disfunction (observed in 4 cases, G1; probably related to pelvic radiotherapy). Only one pt underwent Miles surgical resection (8%). Dworak TRG was as follows: TRG 0-1-2 = 10/12 (83%); TRG 4 (pathological complete response) = 2/10 (17%). No TRG3 was recorded. Conclusions: Combination of everolimus, 5FU and RT is feasible. We observed ≥15% of patients with TRG 3-4; the combination will be considered for a phase II trial. Biological parameters evaluation is still ongoing. Disclosure: All authors have declared no conflicts of interest.