Camillo Aliberti

Effect of Angiosonography to Monitor Response During Imatinib Treatment in Patients with Metastatic Gastrointestinal Stromal Tumors

Purpose: Gastrointestinal stromal tumor (GIST) metastases are typically intra-abdominal and hypervascular. We assessed the effect of angiosonography with a second-generation contrast agent to monitor response during imatinib treatment in patients with metastatic KIT+ GIST. Experimental Design: Ten consecutive patients with known advanced KIT+ GIST were investigated with angiosonography and computerized tomography (CT). We also monitored the serum levels of the major angiogenic growth factor, vascular endothelial growth factor. Results: Angiosonography showed a reduction in tumor vascularization of liver metastases during imatinib treatment in all cases. We observed a reduction in tumor vascularization before a reduction in tumor size. The tumor perfusion appeared reduced in the central part of the liver metastases. With a median follow-up of 18 months (range 3-33), a reduction in tumor vascularization was initially observed in all patients, but progressive disease was documented in four patients following imatinib treatment. CT documented tumor response according to standardized criteria in six patients, stable disease in four, and progressive disease according to angiosonography. The reduction of tumor perfusion at angiosonography correlated with the pseudocystic appearance at CT. The “nodule(s) within a mass” pattern of recurrence occurred in two patients with no difference observed between angiosonography and CT. Early decreasing serum vascular endothelial growth factor levels were observed in the two cases with higher pretreatment levels. Conclusions: Imatinib could induce antiangiogenic and/or antivascular effects in GIST, and this effect could be easily monitored with angiosonography. Angiosonography might be a useful complement for monitoring the therapeutic effect of imatinib in these patients.

Onset of Male Gynaecomastia in a Patient Treated with Sunitinib for Metastatic Renal Cell Carcinoma

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor that has demonstrated substantial antitumour activity in patients with metastatic renal cell carcinoma. The more common grade 3 or 4 adverse effects of sunitinib include hypertension, fatigue, hand-foot syndrome, elevated lipase and lymphopenia. We report the case of a 69-year-old patient with metastatic renal clear-cell carcinoma, treated with nephrectomy and three lines of therapy (interleukin-2 plus interferon-α2a, vinorelbine plus gemcitabine, and capecitabine), who started a fourth-line therapy with oral sunitinib because of disease progression. At the end of his fifth cycle of sunitinib therapy, the patient complained of the development of abnormally large mammary glands associated with pain and peri-areolar erythema. After 2 weeks’ off therapy, a partial reduction in mammary gland enlargement, local pain and erythema was observed. However, re-initiation of sunitinib treatment was followed by bilateral breast enlargement again. The mechanism by which sunitinib induces gynaecomastia is thought to be associated with an unknown direct action on breast hormonal receptors. To the best of our knowledge, this is the first report of an association between sunitinib and gynaecomastia.

Complete response of colorectal liver metastases after intra-arterial chemotherapy

AIMS AND BACKGROUND We demonstrated that colorectal liver metastases considered in complete response after intra-arterial floxuridine-based chemotherapy had recurred in situ. METHODS AND STUDY DESIGN One hundred and six colorectal liver metastases disappeared after intra-arterial chemotherapy. Persistent macroscopic disease was observed at surgery at the site of 52 of 106 liver metastases, even though computerized tomography scan and ultrasound showed a complete response. The sites of 35 initial liver metastases that were not visible at surgery were resected. Pathologic examination of these sites, considered in complete response, showed viable cancer cells in 22 of 35 cases. RESULTS After 1 year of follow-up, 33 of 106 liver metastases considered in complete response had recurred in situ. After 2 years of follow-up, persistent macroscopic or microscopic residual disease or recurrence was observed in 86 (81%) of the 106 liver metastases. CONCLUSIONS Nevertheless, 19% of the patients had a long-lasting response. This means that floxuridine given as intra-arterial hepatic chemotherapy can still be considered an interesting option of cure in the treatment of colorectal liver metastases. When feasible, the site of the lesion that disappeared after intra-arterial chemotherapy should be resected at surgery. The best palliative cure of liver metastases should be the combination of local-regional strategies like intra-arterial chemotherapy, surgery or radiofrequency ablation with the systemic approach.

Radiofrequency ablation of liver malignancies: MRI for evaluation of response

Summary The aim of this study was to investigate the role of magnetic resonance imaging (MRI) in the evaluation of response to radiofrequency ablation (RFA) and detect residual or recurrent tumor. After RFA, the target lesion shows a hyperintensive signal without increased T1-weighted, low on T2-weighted, non enhancing in gadolinium-enhanced MRI. In the long term follow-up the successfully treated lesions decrease in size. Signs of recurrence include new enhancement areas, the lesion’s size increase, and development of T1-weighted hypointense and T2 weighted hyperintense areas. The MRI is a reliable method to evaluate the effectiveness of RFA and detect residual tumor.

Hepatic metastases of hemangiopericytoma: contrast-enhanced MRI, contrast-enhanced ultrasonography and angiography findings.

Hemangiopericytoma is a rare and characteristically hypervascular tumour. We report a case of hepatic metastases of hemangiopericytoma for which there was correlative imaging by ultrasonography, ultrasonography with second-generation contrast agent (BR1), computed tomography, gadolinium-enhanced, Gd-BOPTA-enhanced and ferumoxides-enhanced magnetic resonance, and angiography. To our knowledge, this is the first reported case in which all these modalities were used in the diagnostic evaluation.

Locoregional therapy and systemic cetuximab to treat colorectal liver metastases

AIM To investigate efficacy and safety of second-line treatment with irinotecan-loaded drug-eluting beads (DEBIRI) and cetuximab (DEBIRITUX) of unresectable colorectal liver metastases. METHODS Patients with the following characteristics were included in the study: unresectable hepatic metastases from colorectal carcinoma (CRC-LM), progression after first line chemotherapy (any type of chemotherapeutic drug and combination was allowed), second line treatment (mandatory), which included for each patient (unregarding the KRas status) two cycles of DEBIRI (using 100-300 μm beads loaded with irinotecan at a total dose 200 mg) followed by 12 cycles of cetuximab that was administered weekly at a first dose of 400 mg/m(2) and then 250 mg/m(2); good performance status (0-2) and liver functionality (alanine aminotransferase and gamma-glutamyl transferase not exceeding three times the upper limit of normal, total bilirubin not exceeding 2.5 mg/mL). Data were collected retrospectively and included: tumor response (evaluated monthly for 6 mo then every 3 mo), overall response rate (ORR), KRas status, type and intensity of adverse events (G according to the Common Terminology Criteria for Adverse Events v3.0, CTCAE), overall survival (OS) and progression free survival (PFS). RESULTS Forty consecutive cases of CRC hepatic metastases were included in the study. Median duration of DEBIRITUX was 4.4 mo (range, 4.0-6.5). Sixteen patients (40%) received the planned 2 cycles of DEBIRI and an average of 10 cetuximab cycles. ORR of the whole sample was 50%, in particular 4 patients were complete responders (10%) and 16 (40%) partial responders. The most observed side effects (G2) were: post-embolization syndrome (30%), diarrhea (25%), skin rushes (38%) and asthenia (35%). The retrospective evaluation of KRas status (24 wild type, 16 mutated) showed that the group of patients with wild type KRas had ORR significantly higher than mutant KRas. Median follow-up was 29 mo (8-48 range); median PFS was 9.8 mo and OS was 20.4 mo. Future randomized trials are required in this setting to establish a role for DEBIRITUX compared with systemic chemotherapy. CONCLUSION DEBIRITUX seems to be efficacious after first line chemotherapy for the treatment of unresectable CRC-LM.

Long-lasting response with metronomic capecitabine in advanced hepatocellular carcinoma.

Effective and safe systemic treatment for advanced hepatocellular carcinoma (HCC) with severe underlying cirrhosis is not yet available. Sorafenib, an oral multikinase inhibitor, has proved to be effective in the treatment of patients affected by HCC with Child-Pugh class A liver function. For patients with cirrhosis-associated HCC having Child-Pugh class B and C liver function, no systemic treatments of documented efficacy and safety exist. We report a case of metastatic HCC associated with Child-Pugh class B cirrhosis that was treated with low, “metronomic” doses of capecitabine (1000 mg/day continuously). This treatment was effective and well tolerated and the response was maintained for 18 months. Metronomic capecitabine may represent a possible alternative in the treatment of those patients with advanced cirrhosis-associated HCC who cannot be treated with sorafenib. Free full text available at www.tumorionline.it

Differences in Efficacy and Safety Between Capecitabine and Infusional 5-Fluorouracil When Combined With Irinotecan for the Treatment of Metastatic Colorectal Cancer

BACKGROUND Capecitabine is an oral fluoropyrimidine that is shown to have similar efficacy to 5-fluorouracil (5-FU) when used both alone and in combination with oxaliplatin in the treatment of colorectal cancer (CRC). Capecitabine and irinotecan combinations (XELIRI) have been developed for the treatment of this disease but randomized comparisons with standard infusional 5-FU and irinotecan (FOLFIRI) showed conflicting results. PATIENTS AND METHODS We searched the literature for randomized controlled trials comparing XELIRI to FOLFIRI for the treatment of metastatic colorectal cancer. Odds ratios with 95% confidence intervals were used to analyze dichotomous variables. Hazard ratios for progression and death were combined with an inverse variance method based on logarithmic conversion. The fixed-effect model and Mantel-Haenszel method were used. Heterogeneity was investigated with the Q-test and I2. Sensitivity analyses were performed. RESULTS Only 3 studies were identified, involving a total of 450 patients. XELIRI was associated with significantly shorter progression-free survival (PFS) and increased grade 3/4 gastrointestinal toxicities such as nausea, vomiting, and diarrhea. Severe neutropenia, however, was significantly more frequent with FOLFIRI. No differences in responses and febrile neutropenia events were observed. CONCLUSION Our analysis suggest that the 2 regimens are not equivalent. XELIRI remains an option for the first-line treatment of metastatic CRC but FOLFIRI should be preferred as it confers more benefits in terms of PFS and induces fewer GI toxicities.

Multidisciplinary approach of colorectal cancer liver metastases

Large bowel cancer is a worldwide public health challenge. More than one third of patients present an advanced stage of disease at diagnosis and the liver is the most common site of metastases. Selection criteria for early diagnosis, chemotherapy and surgery have been recently expanded. The definition of resectability remains unclear. The presence of metastases is the most significant prognostic factor. For this reason the surgical resection of hepatic metastases is the leading treatment. The most appropriate resection approach remains to be defined. The two step and simultaneous resection processes of both primary and metastases have comparable survival long-term outcomes. The advent of targeted biological chemotherapeutic agents and the development of loco-regional therapies (chemoembolization, thermal ablation, arterial infusion chemotherapy) contribute to extend favorable results. Standardized evidence-based protocols are missing, hence optimal management of hepatic metastases should be single patient tailored and decided by a multidisciplinary team. This article reviews the outcomes of resection, systemic and loco-regional therapies of liver metastases originating from large bowel cancer.

Chemoembolization Adopting Polyethylene Glycol Drug-Eluting Embolics Loaded With Doxorubicin for the Treatment of Hepatocellular Carcinoma

OBJECTIVE The purpose of this study is to determine the efficacy and tolerability of transarterial chemoembolization (TACE) using polyethylene glycol (PEG) drug-elutable microspheres loaded with doxorubicin for treatment of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS Forty-two patients with unresectable HCC, as determined by a tumor board, were assigned to undergo TACE and were treated with PEG drug-elutable embolics loaded with doxorubicin. Patients were prospectively enrolled and included 32 (76%) men and 10 (24%) women. Their median age was 65 years (range, 42-83 years). Patients were treated with 50 mg of doxorubicin loaded in 2 mL of PEG embolics (mean [± SD] diameter, 100 ± 25 µm) that were infused via a chemoembolization method. Data collected included previous cancer therapy, tumor size, number of lesions, history of TACE, tumor response (at 1, 3, and 6 months), type and intensity of adverse events, and quality of life (QOL) analysis. RESULTS One month after TACE, the overall tumor response rate was 79% (50% complete response, 29% partial response, 17% stable disease, and 5% progressive disease). At 3 months, the rates were 48% for complete response, 24% for partial response, 24% for stable disease, and 3% for progressive disease. At 6 months, the rates were 43% for complete response, 19% for partial response, 29% for stable disease, and 10% for progressive disease. TACE was well tolerated by all patients, with no evidence of procedure-related complications or systemic drug-related adverse events. Fever (33%), increase in transaminase level (17%), and pain (33%) were the most frequent adverse events, and their intensity was mostly mild (grades 1 and 2). The QOL scores were 80 at 1 month, 81 at 3 months, and 82 at 6 months after TACE. CONCLUSION These data suggest that PEG embolics are efficacious and safe for the treatment of HCC, as indicated by their good tolerability, QOL scores, and high tumor response.