Derek G. Power

Role of Adjuvant Therapy After Resection of Colorectal Cancer Liver Metastases

Liver resection is the goal of treatment strategies for liver-confined metastatic colorectal cancer. However, after resection the majority of patients will experience recurrence. Chemotherapy seems to improve outcomes compared with surgery alone. We reviewed the data of the role of adjuvant chemotherapy after resection of liver- confined metastatic colorectal cancer. Optimal regimens and sequencing of chemotherapies when liver resection is an option are unclear. Some suggest that resectable liver metastases, in the absence of high-risk features, should begin with surgery and consideration given to adjuvant chemotherapy after surgery. If high-risk features are present, most physicians prefer a short course of systemic preoperative chemotherapy. Perioperative therapy and regional therapy with hepatic arterial infusion (HAI) both increase disease-free survival (DFS) when compared with surgery alone. In unresectable disease, consideration should be given to systemic chemotherapy with or without a biologic agent or HAI with systemic therapy. If the disease becomes resectable, adjuvant treatment should follow surgery. Adjuvant chemotherapy is usually FOLFOX, but HAI combined with systemic chemotherapy is also an option. The role of adjuvant treatment post-liver resection should not be viewed in isolation but rather in the context of prior treatment, surgical preference, and individual patient characteristics. Perioperative therapy and regional therapy have both shown an increase in DFS. Conducting randomized trials examining the role of adjuvant chemotherapy has been difficult because of rapidly changing chemotherapies.

Endoscopic Ultrasound Can Improve the Selection for Laparoscopy in Patients with Localized Gastric Cancer

BACKGROUNDnThe majority of newly diagnosed patients with gastric cancer have disease that is not resectable because of local extension or metastatic (M1) disease. Laparoscopy is a recommended staging evaluation to identify occult peritoneal metastatic disease. We determined if endoscopic ultrasound (EUS) could improve the selection of patients for laparoscopy.nnnSTUDY DESIGNnGastric cancer patients being screened for a preoperative chemotherapy clinical trial were prospectively examined. Patients underwent standard preoperative assessment. Those without obvious metastatic disease were referred for EUS and laparoscopy. EUS divided patients into risk categories for metastatic disease: low risk (T1-2, N0) and high risk (T3-4, N+, or both). Laparoscopy categories were M1 and M0. The ability of EUS to predict subradiographic peritoneal metastatic disease was evaluated.nnnRESULTSnNinety-four patients were studied. The majority were EUS high risk (72%). Occult metastatic disease was identified in 19 patients, 18 of whom had high-risk EUS stage. The yields of identifying M1 disease by laparoscopy in EUS high- and low-risk patients were 25% (95% CI, 15% to 37%) and 4% (95% CI, 0.1% to 20%), respectively. The negative predictive value of low-risk EUS for laparoscopy and pathologic M0 was 96% (exact 95% CI, 80% to 100%).nnnCONCLUSIONSnThis study suggested that laparoscopy can be avoided in patients with EUS early-stage gastric cancer. Patients with more advanced disease are at higher risk of occult peritoneal disease and require laparoscopy. Validation with greater numbers is warranted, but, based on these data, we propose a new staging algorithm allowing EUS low-risk patients to proceed directly to resection.

Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma

BACKGROUNDnAngiogenesis has been attributed to be a well-recognized aspect of human cancer biology. As such, proteinase-activated receptor (PAR)-1, endostatin (ES) and interleukin-8 (IL-8) mediate the regulation of early-onset angiogenesis and in turn impact the process of tumor-growth and disease progression.nnnPATIENTS AND METHODSnFormalin-fixed paraffin-embedded tissues were obtained from 137 patients with localized gastric cancer at University of Southern California and Memorial Sloan-Kettering Cancer Center medical facilities. DNA was extracted and genotyping was carried out using PCR-restriction fragment length polymorphism-based protocols.nnnRESULTSnIn false discovery rate-adjusted univariate analysis, PAR-1 -506 ins/del (P < 0.001), ES +4349 G>A (P = 0.004), and IL-8 -251 T>A (P < 0.0001) were associated with time to tumor recurrence (TTR). Further, PAR-1 -506 ins/del and IL-8 -251 were associated with overall survival (OS). After adjusting for covariates, IL-8 remained significantly associated with TTR (adjusted P = 0.003) and OS (adjusted P = 0.049), whereas ES was significantly associated with TTR (adjusted P = 0.026).nnnCONCLUSIONSnPolymorphisms in PAR-1, ES, and IL-8 may serve as independent molecular prognostic markers in patients with localized gastric adenocarcinoma. The assessment of the patients individual risk on the basis of interindividual genotypes may therefore help to identify patient subgroups at high risk for poor clinical outcome.

Safety and efficacy of panitumumab following cetuximab: retrospective review of the Memorial Sloan-Kettering experience

SummaryThere are two highly selective antibodies to the epidermal growth factor receptor (EGFR) now available for use in metastatic colorectal cancer (mCRC). In KRAS wild type patients, cetuximab (Cmab)-an IgG1 chimeric molecule—has activity alone and in combination with chemotherapy for the first, second and third-line settings. Panitumumab (Pmab)-a fully humanized IgG2 molecule-has activity as a single agent in chemorefractory mCRC and shows promising activity in combination with chemotherapy. It remains unclear which antibody to use. This retrospective review of our experience with Pmab in 13 EGFR antibody-naive patients and in 22 patients previously treated with Cmab for mCRC highlights a lack of hypersensitivity reactions (HSR) with Pmab, even in patients who experienced HSR to Cmab. In patients who received Cmab, 22% developed grade 3–4 HSR. There were no HSR on subsequent treatment with Pmab. We demonstrate similar activity in 95% of cases, between Cmab and Pmab both alone and in combination with chemotherapy in the treatment of mCRC. In one case we report unique sensitivity to Pmab after progression with Cmab.

Chemotherapy for the conversion of unresectable colorectal cancer liver metastases to resection.

Resection of colorectal liver metastases (CLM) is the ultimate aim of treatment strategies in most patients with liver-confined metastatic colorectal cancer. Long-term survival is possible in selected patients with initially resectable or unresectable CLM. As a majority of patients have unresectable liver disease at the outset, there is a clear role for chemotherapy to downstage liver disease making resection possible. Studies of systemic chemotherapy with or without biologic therapy in patients with unresectable CLM have resulted in increased response rates, liver resection rates and survival. A sound physiologic rationale exists for the use of hepatic arterial infusion (HAI) therapy. Studies have shown that HAI with floxuridine combined with systemic chemotherapy increases response rates and liver resection rates in those patients with initially unresectable CLM. Toxicity from preoperative chemotherapy, biologic therapy and HAI therapy may adversely affect hepatic resection but can be kept minimal with appropriate monitoring. All conversion strategies should be decided by a multidisciplinary team.

Clinical Genetics of Hereditary Colorectal Cancer

Colorectal cancer (CRC) is a common disease, and approximately 25% of patients have a familial component. High-penetrance singlegene germline mutations conferring a true hereditary susceptibility account for around 5% to 6% of all cases. Lynch syndrome is the most common hereditary form of colorectal cancer. Much of the hereditary component in the remaining familial cases of CRC is likely polygenic, and many of the genetic changes involved are as yet unidentified. This article addresses the most clinically important CRC genetic syndromes.

Regional Chemotherapy for Liver-Limited Metastatic Colorectal Cancer

This review examines the development of hepatic arterial infusion (HAI) of chemotherapy over the past 40 years. Liver metastases are mainly supplied by the hepatic artery, and high levels of intratumoral drug delivery are achievable with the use of HAI. Floxuridine, 5-fluorodeoxyuridine is commonly used, but intra-arterial oxaliplatin and mitomycin- C also have advantages. The dramatic responses observed with HAI plus systemic therapy offer the possibility of resection and cure in select patients. Resectability of liver-limited colorectal cancer metastases should be considered as an endpoint for all patients. Hepatic arterial infusion may be used in palliative, neoadjuvant, and adjuvant settings. Herein, combinations of systemic chemotherapy with HAI are discussed, along with the role of newer cytotoxic and biologic agents. The first-pass extraction of some drugs given by regional perfusion in the liver limits systemic side effects. Toxicity includes catheter-related complications and biliary and gastrointestinal ulcers. The role of HAI therapy for the treatment of unresectable and resectable disease, as well as the use of other regional strategies such as embolization and ablation, are discussed.

Germline polymorphisms in genes involved in the CD44 signaling pathway are associated with clinical outcome in localized gastric adenocarcinoma.

The cluster of differentiation 44 (CD44) signaling pathway is crucial in cancer‐cell growth, invasion, proliferation and metastasis. CD44 is a transmembrane receptor for hyaluronan and osteopontin, and has recently attracted attention as a gastric cancer stem cell marker. Previous studies showed that polymorphisms in the CD44 gene can influence both human cancer survival and determine cellular response to cytotoxic chemotherapeutics. In addition, CD44 protein overexpression has been associated with poor prognosis in gastric adenocarcinoma (GA). We tested the hypothesis whether polymorphisms involved in the CD44 pathway will predict clinical outcome in patients with localized GA. Either blood or formalin‐fixed paraffin‐embedded (FFPE) tissues were obtained from 137 patients with localized GA at University of Southern California and Memorial Sloan‐Kettering Cancer Center medical facilities. DNA was isolated and polymorphisms within the CD44 pathway were determined by PCR‐RFLP technique. In univariate analysis CD44 rs187116 and CD44 rs7116432 were significantly associated with time to tumor recurrence (TTR) and overall survival (OS). After adjusting for covariates, patients harboring at least one G allele of CD44 rs187116 remained significantly associated with TTR (adjusted p = 0.009) and OS (adjusted p = 0.045). Further, patients harboring CD44 T‐A haplotype were at the lowest risk of developing tumor recurrence (HR: 0.255; 95% CI: 0.11–0.591; adjusted p = 0.001) and death (HR 0.198; 95% CI: 0.07–0.563; adjusted p = 0.002). These results provide the first evidence that CD44 polymorphisms predict clinical outcome in patients with localized GA. This may help to identify localized GA patients at high risk for tumor recurrence.

GRP78 promoter polymorphism rs391957 as potential predictor for clinical outcome in gastric and colorectal cancer patients

BACKGROUNDnRecently, the analysis of gastric and colorectal tumor specimens determined that 78-kiloDalton glucose-regulated protein (GRP78), an endoplasmic reticulum chaperone, up-regulation serves as an efficient mechanism protecting cells against apoptosis and can confer drug resistance. We tested whether functional polymorphisms within the GRP78 gene are related to clinical outcome in gastric and colorectal cancer (CRC) patients.nnnPATIENTS AND METHODSnBlood samples of 234 stage II/III CRC patients at the University of Southern California (USC) and formalin-fixed paraffin-embedded tissues of 137 patients with localized gastric adenocarcinoma (GA) at USC and Memorial Sloan-Kettering Cancer Centers were obtained. GRP78 polymorphisms analyzed on germline DNA were correlated with clinical outcome using univariate and multivariate analyses.nnnRESULTSnGA patients with the combined GRP78 rs391957 C/T and T/T genotype were at higher risk for tumor recurrence and death [hazard ratio (HR) 2.61; Pu2009<u20090.001 and HR 3.17; Pu2009<u20090.001, respectively], than those with C/C. These findings were subsequently tested in a CRC cohort where patients with the homozygous T/T genotype were at highest risk for tumor recurrence (HR 2.61; Pu2009=u20090.015). The results remained significant after adjusting for clinicopathologic determinants.nnnCONCLUSIONnThese data provide the first evidence that the GRP78 rs391957 polymorphism can predict clinical outcome in localized GA and locally advanced CRC patients.

Chemotherapy for the Elderly Patient With Colorectal Cancer

Colorectal cancer is a common cancer in older patients with nearly 70% of all cases diagnosed in patients 65 years and older. Many chemotherapy clinical trials that have advanced the field in both localized and metastatic disease have not included patients from the age group most representative of the disease. Retrospective series and subset analyses show that older patients derive the same benefit from optimum multimodality strategies as their younger counterparts. Lack of prospective data and a generalization of increased toxicity rates seen in older patients with multiple comorbidities to the overall heterogenous population of older patients have lead to a reluctance to treat older patients with modern chemobiologic therapy. Despite increased comorbidities, decreased hepatic reserve, and an under-representation of older patients undergoing liver resection, the majority of published data does not support a negative correlation between poor outcome and increasing age. There is an urgent need to include older patients in clinical trials for colorectal cancer and to understand and use geriatric assessment scoring systems to identify those patients most likely to benefit from optimum treatment.