Audrey Andrews, Freelance Medical Writer

Orlando, FL—In metastatic colorectal cancer, mutations in the 

 gene are emerging as prognostic indicators of worse outcomes. The latest evidence comes from an updated analysis of the CRYSTAL study, in which patients who had wild-type (normal) 

 had a poor prognosis in spite of treatment with cetuximab, reported Eric Van Cutsem, MD, of University Hospital Gasthuisberg, Leuven, Belgium, 

at the 2010 Gastrointestinal Cancers Symposium.

 typically respond to inhibitors of epidermal growth factor receptor (EGFR).

At the 2009 ESMO/ECCO meeting in Berlin, Dr Van Cutsem presented the main results of the phase III CRYSTAL trial of 1198 patients with metastatic colorectal cancer, in which treatment with cetuximab and FOLFIRI was associated with a 30% reduction in progression (

 = 0.0012) and a 20% reduction in mortality (

 = 0.0093), versus FOLFIRI alone, in the 

At the GI Cancers Symposium, Dr Van Cutsem presented updated data on the wild-type 

cohort, 83% of whom had tissue samples tested for 

 status. Of these, 6% showed mutations. The 

mutation was present in 9% of all patients with 

 wild-type population of 666 patients was dependent upon 

In the FOLFIRI plus cetuximab arm, median overall survival was 23.5 months for all 

 wild-type patients, but just 14.1 months for 

 mutation patients. PFS was, respectively, 9.9 months, 10.9 months, and 8.0 months. 

mutation, cetuximab had no benefit over FOLFIRI alone, as the differences between the experimental and control arms in this wild-type population were not statistically significant. 

“This final analysis confirms KRAS tumor mutation status to be a predictive factor across all efficacy endpoints examined for cetuximab in combination with FOLFIRI,” Dr Van Cutsem said. “And it suggests that BRAF tumor mutations are a poor prognostic factor in first-line metastatic colorectal cancer.” 

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Colorectal cancer patients who had wild-type (normal) KRAS gene status, but mutations in the BRAF, had a poor prognosis in spite of treatment with cetuximab.

BRAF Mutation Emerging as Prognostic in KRAS Wild-Type CRC Patients

Orlando, FL—Individuals with the highest intake of dietary polyamines&mdash;common in orange juice, corn, red meat, peas and nuts&mdash;had larger colorectal adenomas and more advanced adenomas on colonoscopy screening, according to research presented at the 2010 Gastrointestinal Cancers Symposium.

The study was a follow-up to an earlier phase III study by the same researchers that found a polyamine-inhibitory regimen of difluoromethylornithine (DFMO) plus the COX inhibitor sulindac reduced the incidence of metachronous colorectal cancer by 70% and advanced adenomas by 90%.

The current study, presented by Kavitha P. Raj, MD, of the University of California, Irvine, evaluated the role of dietary polyamines in the occurrence of sporadic adenomas, and their effects on treatment with DFMO plus sulindac in preventing adenoma recurrences.

Increased polyamine synthesis and inflammation have been associated with colon carcinogenesis in both preclinical models and humans. It is possible that by decreasing polyamines, one might slow the cancer process, Dr Raj said.

The study subjects had a history of at least one resected adenoma within the past year, but no history of invasive cancer or hereditary colon cancer syndromes. Patient data were obtained from the previous multicenter colon adenoma prevention trial, and a self-administered food frequency questionnaire was collected.

Polyamine values for individual foods were calculated and reported. Of the different polyamines, dietary putrescine was the major contributor. Total dietary polyamine content was derived by adding putrescine, spermine, and spermidine, and patients were categorized into a highest quartile (75-100%), and a lower quartile group that included all three lowest quartiles (0-12%, 25-50%, 50-75%).

Tissue polyamine content was also evaluated from rectal mucosal biopsy specimens and compared with the dietary intake.

Baseline information was available for 222 of the initial 375 study participants, and for 188 patients who completed the study.  

At baseline, adenomas > 1 cm were found in 43.6% of subjects in the highest dietary polyamine group compared with 26.4% in the lowest quartile (

 = 0.01); advanced adenomas were identified in 52.7% versus 35.9% (

 = 0.03) and high-grade adenomas in 32.7% versus 20.4%, respectively (

Tissue levels of spermine and spermidine were both significantly elevated in the higher dietary group, versus the lowest quartile.

“We found, in the baseline characteristics, that there was a strong association between dietary and tissue polyamine levels,” Dr Raj said, “and higher dietary polyamines were associated with larger and more advanced adenomas.”

Risk of recurrence was significantly reduced in patients in the lower quartile group, with an 81% reduction in risk that was highly significant (

 < 0.0001). Patients with lower intakes also had an 89% reduction in adenomas > 1 cm, a 91% reduction in high-grade adenomas, and a 94% reduction in advanced adenomas (adjusted for aspirin intake). All were statistically significant and “striking,” Dr Raj said.

Finally, dietary polyamine intake was found to alter the risk reduction of recurrent adenoma formation by DFMO plus sulindac, Dr Raj said. “The benefit we observed with DFMO plus sulindac in the trial was seen only in the lower dietary polyamine group, and there was no clear benefit of this regimen in the higher dietary polyamine group.”

Patients with high intake of polyamines found in orange juice, corn, red meat, peas and nuts had larger, more advanced adenomas on colonoscopy screening.

Polyamines in the Diet Related to High-Risk Adenomas

	Orlando, FL—For patients with advanced pancreatic cancer, a novel inhibitor of the insulin-like growth factor (IGF) receptor led to response rates or stable disease in a majority of patients, according to a study reported at the 2010 Gastrointestinal Cancers Symposium.

	“We observed sustained partial responses with two different regimens of this agent,” said Milind Javle, MD, professor of oncology at MD Anderson Cancer Center in Houston.

	Activation of the IGF-1 receptor is associated with aggressive disease and acquired resistance to drugs that target the epidermal growth factor receptor (EGFR). Preclinical studies have shown that synergy can be obtained when an IGF-1 receptor antagonist and an EGFR antagonist are combined, Dr Javle said.

	The novel agent is a humanized monoclonal antibody that binds to the IGF-1 receptor and blocks its interaction with IFG-1 and IGF-2 ligands. It enhances gemcitabine-induced apoptosis and inhibits multiple actions along the signaling pathway, he explained.

	The phase I/II study enrolled 28 individuals with stage IV pancreatic adenocarcioma 6 months or more after completion of chemotherapy. MK-0646 was given in combination with gemcitabine (weekly gemcitabine plus weekly MK-0646 at 5 mg/kg or 10 mg/kg) or gemcitabine plus the EGFR inhibitor cetuximab. Along with determining maximum tolerated dose, the study assessed progression-free survival (PFS) of the two combination arms.

	Of 24 evaluable patients, 6 (25%) had a partial response and 8 (33%) experienced stable disease. The response duration ranged from 14 to 44  weeks, but time to progression did not differ between the arms (

	“What is important is that we believe these responses are sustained,” he commented. He said the responses occurred equally in the arms containing erlotinib, versus those with only gemcitabine.

	Of the 28 patients, 23 (82%) required dose reductions of gemcitabine, and 7 required reductions in erlotinib. Five patients discontinued erlotinib because of toxicity but no patients withdrew from the study completely because of adverse events, he said. Hyperglycemia and fatigue were the most frequent toxicities, while elevated liver enzymes and hypermagnesemia also occurred. Grade 3-4 neutropenia was observed in about half the patients, but there were no cases of febrile neutropenia.

	The investigators are moving into a randomized phase 2 study of 80 patients, “which should provide further stop-or-go information for a phase 3 trial,” he said. He added that biomarker studies are also being conducted, which might determine which patients will benefit from this compound.

	Philip A. Philip, MD, of the Karmanos Cancer Center, Detroit, Michigan, said in a formal discussion of the study that the study has a strong “scientific rationale” and the findings demonstrate “some activity” of the agent, although “it is too early to make much of this.”

	Other anti-IGF receptor agents are also in development and entering trials, he added, but suggested, “We need more data before designing phase III studies of anti-IGFR agents.”

For patients with pancreatic cancer, an inhibitor of the insulin-like growth factor receptor led to response rates or stable disease in a majority of patients.

IGF Receptor Antagonist Shows Activity in Advanced Pancreatic Cancer

ORLANDO, FL—The TN category of disease has a significant impact on survival, relapse, and colostomy failure in patients with anal cancer treated with concurrent chemoradiation (CCRT), according to an analysis of the US GI Intergroup RTOG 98-11 study reported at the 2010 Gastrointestinal Cancers Symposium by L.L. Gunderson, MD, of the 

In particular, the TN was found to be associated with significant outcomes in overall survival (OS), disease-free survival (DFS), local-regional failure (LRF), distant metastases (DM), and colostomy failure (CF).

RTOG 98-11 evaluated CCRT with 5-FU plus mitomycin versus 5-FU plus cisplatin, and found that colostomy-free survival was improved with the 5-FU plus mitomycin regimen. The current analysis aimed to determine the impact of TN category on numerous clinical outcomes.

Investigators evaluated 6 TN categories for their association with outcomes in 615 patients. According to Gunderson, “All endpoints showed significant differences between TN categories of disease.” OS, DFS, LRF, and DM were not statistically different for T2N0 and T3N0, but they were worse for the other TN categories.

The poorest OS, DFS, and LRF were observed in T3-4N  patients. Outcomes were similar for T2N  patients and T4N0 patients. In the node-negative group, OS at 5 years was 81% for T2, 75% for T3, and 59% for T4, and DFS was 69%, 63%, and 40%, respectively. In the node-positive group (1-3 nodes), OS at 5 years was 66% for T2, 44% for T3, and 48% for T4. DFS was 50%, 33%, and 14%, respectively, reported Gunderson.

At 5 years, distant metastases occurred in 12% of T2N0 patients compared with 31% of T2N  patients. Colostomy failure at 3 years was not affected by TN category in patients receiving 5-FU plus mitomycin, ranging from 2% to 20%, but on the 5-FU plus cisplatin regimen it was significantly greater in the T4N0 (37%) and T3N  (28%) categories. 

“Significant challenges remain for patients with T4N0 disease and patient with node-positive disease,” Gunderson said. “Potential strategies to improve outcomes include treatment intensification and molecular-based individualized treatment.” 

The TN category of disease significantly impacts survival, relapse, and colostomy failure in patients with anal cancer treated with concurrent chemoradiation.

Audrey Andrews, Freelance Medical Writer

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