Robert Pelley

Predictors of Survival After Radiofrequency Thermal Ablation of Colorectal Cancer Metastases to the Liver: A Prospective Study

PURPOSE The aim of this study was to determine the predictors of survival at the time of radiofrequency thermal ablation (RFA) in patients with colorectal liver metastasis. PATIENTS AND METHODS One hundred thirty-five patients with colorectal liver metastases who were not candidates for resection underwent laparoscopic RFA. RESULTS The median Kaplan-Meier survival for all patients was 28.9 months after RFA treatment. Patients with a carcinoembryonic antigen (CEA) less than 200 ng/mL had improved survival compared with those with a CEA more than 200 (34 v 16 months; P = .01). Patients with the dominant lesion less than 3 cm in diameter had a median survival of 38 v 34 months for lesions 3 to 5 cm, and 21 months for lesions greater than 5 cm (P = .03). Survival approached significance for patients with one to three tumors versus more than three tumors (29 v 22 months; P = .09). The presence of extrahepatic disease did not affect survival. Only the largest liver tumor size more than 5 cm was found to be a significant predictor of mortality by Cox proportional hazards model, with a 2.5-fold increased risk of death versus the largest liver tumor size less than 3 cm (P = .05). CONCLUSION This study determines which patients do best after RFA. Historical survival with chemotherapy alone is 11 to 14 months, suggesting RFA has a positive impact on overall survival. Limited amounts of extrahepatic disease do not appear to affect survival adversely. RFA is a useful adjunct to chemotherapy in those patients with liver-predominant disease.

Multidisciplinary management of colorectal brain metastases: A retrospective study

The incidence of brain metastases (BM) from colorectal cancer (CRC) is increasing, and the management of this previously rare complication at a single institution is reported.

TREATMENT OF COLON AND RECTAL CANCER

This article discusses multimodal treatment of noncomplicated colon and rectal cancer, considerations for specific types of colon cancer, considerations that may modify the extent and technique of surgery, the role of adjuvant chemotherapy for colon adenocarcinoma and rectal cancer, and surgical treatment of complicated colorectal cancer.

RECENT ADVANCES IN SYSTEMIC THERAPY FOR GASTROINTESTINAL NEUROENDOCRINE TUMORS

Neuroendocrine tumors of the gastrointestinal tract are rare tumors which can be classified as amine precursor uptake and decarboxylation tumors (APU-Domas). Although the majority of clinically apparent tumors are malignant, they are frequently slow growing. Despite this characteristic, they may generate disabling hormonal syndromes requiring aggressive treatment to achieve palliation. Recent advances in understanding the pathophysiology of these tumors has led to better medical therapy with chemotherapeutic agents, somatostatin analogues, and biologic therapies. This review will update the recent efforts in systemic therapies of the gastrointestinal neuroendocrine tumors.

Phase II Trial of Liposomal Doxorubicin (Doxil®) in Advanced Soft Tissue Sarcomas

AbstractPurpose: To assess the objective response rate, toxicityexperienced, progression-free survival, and overall survival ofpatients with previously untreated advanced soft tissue sarcomastreated with a liposomal doxorubicin formulation (Doxil). Methods: Patients with metastatic or recurrent soft tissuesarcoma who had received no prior chemotherapy for advanceddisease were treated with liposomal doxorubicin (Doxil) accordingto a two stage accrual design. Doxil was administered at 50mg/m2 every 4 weeks. A total of 15 patients were treated andare evaluable for response and toxicity. Results: The male/female ratio was 7/8, the median age was60 years (34–75) and the ECOG performance status was 0-1 in>90% of patients. Leiomyosarcoma (7/15) and malignant fibroushistiocytoma (2/15) were the most common histologic diagnoses.No objective responses were observed in the 15 evaluablepatients. No lethal toxicity occurred. Grade 3–4 leukopenia orneutropenia were reported in 3/15 (20%) patients. Grade 3mucositis or hand-foot syndrome occurred in 2/15 (13%) and 1/15(7%) patients respectively and seemed more severe in olderpatients. The median time to progression was 1.9 months (range0.9–6.2). Twelve patients have now died. The Kaplan-Meierestimate of median overall survival is 12.3 months. As called forin the study design, accrual was terminated because no responseswere obtained in the first 15 patients. Conclusion: Though well-tolerated, Doxil given accordingto this dose and schedule to patients with advanced soft tissuesarcoma had no significant therapeutic activity. A correlationbetween older age and skin/mucosal toxicity of Doxil is suggestedin this study but needs confirmation. Future investigations ofDoxil in soft tissue sarcomas should use a different schedule anddose.

Safety and efficacy of sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation.

Recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT) carries a poor prognosis. The aim of our study was to assess the safety and efficacy of sorafenib in patients with recurrent HCC following LT.

Prospective Clinical Study of Precision Oncology in Solid Tumors

Systematic studies evaluating clinical benefit of tumor genomic profiling are lacking. We conducted a prospective study in 250 patients with select solid tumors at the Cleveland Clinic. Eligibility required histopathologic diagnosis, age of 18 years or older, Eastern Cooperative Oncology Group performance status 0-2, and written informed consent. Tumors were sequenced using FoundationOne (Cambridge, MA). Results were reviewed at the Cleveland Clinic Genomics Tumor Board. Outcomes included feasibility and clinical impact. Colorectal (25%), breast (18%), lung (13%), and pancreatobiliary (13%) cancers were the most common diagnoses. Median time from consent to result was 25 days (range = 3-140). Of 223 evaluable samples, 49% (n = 109) of patients were recommended a specific therapy, but only 11% (n = 24) received such therapy: 12 on clinical trials, nine off-label, three on-label. Lack of clinical trial access (n = 49) and clinical deterioration (n = 29) were the most common reasons for nonrecommendation/nonreceipt of genomics-driven therapy.

A Phase I Study of EKB-569 in Combination with Capecitabine in Patients with Advanced Colorectal Cancer

Purpose: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer. Experimental Design: Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m2 twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle. Results: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m2 capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321 ± 151 ng*h/mL) than for capecitabine alone (176 ± 62 ng*hours/mL; P = 0.0037). Conclusion: In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m2 capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.

Predicting early mortality in resectable pancreatic adenocarcinoma: A cohort study

Survival after surgical resection for pancreatic cancer remains poor. A subgroup of patients die early (<6 months), and understanding factors associated with early mortality may help to identify high‐risk patients. The Khorana score has been shown to be associated with early mortality for patients with solid tumors. In the current study, the authors evaluated the role of this score and other prognostic variables in this setting.

Modulation of erbB kinase activity and oncogenic potential by single point mutations in the glycine loop of the catalytic domain.

Avian c-erbB is activated to a leukemia oncogene following truncation of its amino-terminal ligand-binding domain by retroviral insertion. The insertionally activated transcripts encode protein products which have constitutive tyrosine kinase activity and can induce erythroleukemia but not sarcomas. We have previously found that a valine-to-isoleucine point mutation at position 157 (V157I mutant) within the tyrosine kinase domain of this truncated erbB can dramatically activate the sarcomagenic potential of the oncogene and increase the kinase activity of this oncoprotein. This mutation lies at position 157 of the insertionally activated c-erbB product, affecting a highly conserved valine residue of the glycine loop involved in ATP binding and phosphate transfer. To investigate the functional importance of this residue in the catalytic activity of kinases, we have introduced at this position, by site-directed mutagenesis, codons representing the remaining 18 amino acid residues. Most of the mutants have diminished activity, with six of them completely devoid of kinase activity, indicating the sensitivity of this region to conformational changes. Some of these mutants displayed increased kinase activity and greater transforming potential in comparison with IA c-erbB, but none had levels as high as those of the V157I mutant. In general, the sarcomagenic potential of the various erbB mutants correlated with their autophosphorylation state and their ability to cause phosphorylation of MAP kinase. However, there are important exceptions such as the V157G mutant, which lacks enhanced autophosphorylation but is highly sarcomagenic. Studies of this and other autophosphorylation site mutants point to the existence of an autophosphorylation-independent pathway in sarcomagenesis. The requirement for leukemogenic potential is much less stringent and correlates with positivity of kinase activity. When the valine-to-isoleucine substitution was put in context of the full-length erbB protein, the mutation relaxed the ligand dependence and had a positive effect on the transforming potential of the full-length c-erbB.