Elderly patients with metastatic colon cancer are generally excluded from randomized clinical trials, but were included in the OPTIMOX1 trial, led by Dr. Arie Figer of Beth Sourasky Medical Center in Tel Aviv, Israel. OPTIMOX1 was an evaluation of FOLFOX7, a simplified leucovorin (LV) and 5-fluorouracil (5FU) regimen (sLV5FU2) with high-dose oxaliplatin, in a new oxaliplatin stop-and-go strategy.

The study included 620 previously untreated patients between 76 and 80 years of age with metastatic colon cancer who were randomized to one of two arms of treatment.

One group received FOLFOX4, consisting of leucovorin followed by a bolus of 5-fluorouracil (5FU) and a 22-hour infusion of 5FU and oxaliplatin on day 1 every 2 weeks, which was given until disease progression occurred.

The other group received FOLFOX7 for six cycles, followed by 12 cycles of oxaliplatin and then reintroduction of FOLFOX7. FOLFOX7 consisted of leucovorin, followed by a 46-hour infusion of 5FU and oxaliplatin started on day 1 every 2 weeks.

Dr. Figer and colleagues report in the December 15 issue of Cancer that “the overall response rate was 59.4%, comparable to younger patients (59%).”

“Median progression-free survival was 9.0 months and median overall survival was 20.7 months. These results did not differ from that in patients 75 years and younger in the OPTIMOX1 study,” the investigators report.

The older patients had more grade 3/4 toxicity than younger patients, at 65% and 48%, respectively. This consisted primarily of more neutropenia, occurring in 41% of older patients and 24% of younger patients, and neurotoxicity, occurring in 22% of older patients compared with 11% of younger patients.

“Tolerability, however, was manageable and no toxic death occurred in this elderly population,” the investigators report.

They assert that “performance status and geriatric assessment are surely better criteria than age to predict the efficacy and toxicity of chemotherapy.” In older patients deemed able to tolerate FOLFOX, this stop-and-go oxaliplatin management plan can be offered.

“Our findings show a systematic change in microRNA expression in colon tumors, suggesting a role for microRNAs in this process,” Drs. Schetter and Harris, at the National Cancer Institute in Bethesda, Maryland, said. “High miR-21 expression has also been found in 11 other cancer types, indicating that these findings may be relevant to other cancers.”

Using microarray analysis, the researchers compared microRNA expression in pairs of primary colon tumor and adjacent nontumorous tissues from 84 US patients. Five microRNAs with increased expression were associated with poor cancer survival.

Expression patterns for these 5 microRNAs accurately distinguished tumor from benign tissue in a validation cohort of 113 Hong Kong patients. Increased expression of miR-21 was associated with poor prognosis in both cohorts.

The authors found that in adenomas as well, miR-21 expression was elevated but to a lesser degree than in adenocarcinomas, and that more advanced malignancies expressed higher levels than less advanced tumors.

According to Dr. Schetter and Dr. Harris, this dose-response relationship indicates that “high miR-21 expression may be an early event in colon cancer initiation and progression.”

In multivariate analyses, high miR-21 expression in tumors was associated with poor survival independent of tumor staging in the US cohort (hazard ratio 2.7, p = .008) and in the Chinese cohort (HR 2.4, p = .002). Among 56 patients treated with fluorouracil-based chemotherapy, high miR-21 expression was associated with a worse response to therapy.

“We are currently planning in vitro and in vivo experiments to determine if miR-21 is the cause for the poor survival outcomes,” the researchers noted.

If that proves to be true, they added, “Work will also have to be done to find the most effective way of targeting miR-21, to determine how toxic these therapeutics may be, and how they can possibly be used along with current chemotherapy protocols to more effectively treat colon cancer.”

“The results of our study provide additional evidence that colorectal cancer survivors benefit from surveillance with colonoscopy,” lead investigator Dr. Stephen J. Rulyak said.

Dr. Rulyak of the University of Washington, Seattle and colleagues note that the utility of colonoscopy in the follow-up of colorectal cancer survivors is uncertain, and findings of surveillance colonoscopy are not well-characterized.

In order to help do so, the researchers studied data on 1002 patients with colorectal cancer who had undergone surgical resection.

Five-year survival was higher (76.8%) for patients who had at least one follow-up exam than was the case for patients who did not undergo follow-up (52.2%).

The estimated influence on survival was similar whether the initial examination took place within 18 months or at up to 60 months of diagnosis.

After adjustment, colon examination was a significant independent predictor of decreased overall mortality (hazard ratio, 0.58). Being female and receiving chemotherapy were also associated with reduced risk (hazard ratio, 0.50).

Following examination, 20 patients were diagnosed with a second colorectal cancer. Of these cancers, 9 were detected within 18 months of initial cancer diagnosis. Advanced neoplasia was more common in patients followed up at 36 to 60 months after diagnosis compared with those followed up within 18 months.

“Our results,” Dr. Rulyak concluded, “support recently published guidelines that recommend initial surveillance colonoscopy should be performed at one year after colon resection because of the significant risk of additional cancers and polyps found in these patients.”

Senior investigator Dr. Heidy Schmid-Alliana said that “our preliminary experiments performed in models of subcutaneous implantation of several tumor cell types, with intra-tumoral injections of fractalkine-coding plasmids, produced highly promising results with a marked reduction in tumor size.”

Dr. Schmid-Alliana, of INSERM U638, Nice, and colleagues note that the agent presents as both a secreted and a membrane-anchored form. Using murine models of skin tumors and liver and pulmonary metastasis, the researchers compared the extent of tumor development in C26 colon cancer cells expressing fractalkine in its molecular forms.

Native fractalkine reduced the tumor size by 93% in the skin and by 99% in the orthotopic models. Both soluble and membrane-bound fractalkine reduced tumor development in skin by 66%.

The soluble form reduced liver and lung metastases by 96%. However, the membrane-bound variant had a barely significant effect and promoted tumor growth in the lungs.

The researchers conclude that fractalkine “drastically reduces” metastatic potential in the two physiological target organs. “Both molecular forms contribute to its antitumour potential, but exhibit differential effects on tumour development depending on the target tissue,” they add.

Dr. Martina Brueckmann of the University of Heidelberg, Germany, author of an accompanying editorial, told Reuters Health that little is known about suitable techniques for immune therapy with fractalkine.

However, she concluded, the efficacy of this reported approach “deserves further research in experimental and especially in human clinical trials to improve immunological treatment modalities of metastatic colon cancer.”

“No minimum [number of nodes] can be determined based on this review, and that number may be elusive and may depend on other factors which are patient- and tumor-related,” Dr. George J. Chang from The University of Texas M. D. Anderson Cancer Center, Houston, Texas “Twelve as proposed, however, seems very achievable in nearly all cases.”

Dr. Chang and colleagues reviewed the evidence on the value of lymph node recovery and evaluation in colon cancer resection.

Two nested cohort studies found an improvement in overall survival among patients with stage II colon cancer as the number of recovered lymph nodes increased, the investigators report.

Among five population/registry-based cohort studies of patients with stage II disease, three showed improved survival with more than 12 lymph nodes evaluated, and two showed that survival increased linearly with the number of lymph nodes evaluated.

All but one of 10 single-institution retrospective cohort studies showed an improvement in overall survival for stage II cancers when greater numbers of lymph nodes were evaluated, the researchers note, but the smallest study showed a difference only in disease-free survival when dividing patients at a cutpoint of 9 lymph nodes.

“All physicians should consider the number of lymph nodes evaluated in the treatment of their patients with colon cancers,” Dr. Chang concluded.

He urged surgeons “to communicate with pathologists if an insufficient number are identified; pathologists to be attentive to communicate with surgeons regarding the specimen delivered to them; medical oncologists to include the number of lymph nodes evaluated when determining indications for adjuvant chemotherapy.”

In 2001, Medicare coverage for colon cancer screening expanded to include colonoscopy every 10 years for people at average risk. While prior studies have documented disparities in screening rates between different groups, very few have examined these disparities since the expanded coverage began.

As reported in the Archives of Internal Medicine for February 12, Dr. Joan M. Neuner, from the Medical College of Wisconsin in Milwaukee, and colleagues analyzed data from 596,470 Medicare beneficiaries who submitted a billing claim in New York, Florida, and Illinois in 2002 and 2003.

Approximately 18.3% of these subjects underwent a colon screening test during this period. The investigators found that nonwhite persons were 48% less likely to undergo colon cancer screening than their white counterparts. Specifically, “Blacks (9.7%) and Hispanics (8.1%) had lower rates of colon cancer screening compared with whites (19.3%).”

Age was also a factor in screening rates. “Almost 22% of individuals aged 65 to 69 years had undergone a screening test, compared with only 11.7% in the population older than 80 years.”

In addition, a gender-based disparity in colon cancer screening was noted. For example, in subjects 80 years of age and older in the highest income tertile, women were 36% less likely to be screened than men.

A higher income level increased the odds of screening in white patients, but had no significant effect in nonwhite patients, the report indicates.

“Further research is needed to determine the basis for the observed ongoing disparities to develop interventions to reduce and eliminate these differences,” the authors state. “Policy initiatives are necessary to increase the awareness of colorectal cancer screening, especially in women and in racial/ethnic minorities, and to increase physician awareness about screening.”

The authors of the report, in the American Journal of Clinical Nutrition for February, note that prebiotics are nondigestable food ingredients that promote the growth of beneficial resident bacteria. Probiotics are living organisms thought to have a beneficial effect on health. Findings from animal studies have supported an anti-tumor effect for both types of agents, but confirmatory data from human studies is lacking.

Dr. Jan Van Loo, from ORAFTI in Tienin, Belgium, and colleagues assessed various colorectal cancer biomarkers in 37 colon cancer patients and 43 polypectomized patients who were randomized to receive a synbiotic preparation or placebo for 12 weeks.

The synbiotic preparation included the prebiotic oligofructose-enriched inulin (BeneoSynergy1, ORAFTI) and the probiotics Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12. Fecal and blood testing was performed before, during, and after treatment, and colon biopsy specimens were obtained before and after treatment.

A rise in Bifidobacterium and Lactobacillus was noted in fecal specimens from the active treatment group, whereas levels of Clostridium perfringens fell.

Consumption of the synbiotic preparation was also associated with a reduction in colorectal proliferation, an improvement in epithelial barrier function, and with a drop in the DNA damaging effects of fecal water.

The synbiotic preparation had apparently beneficial effects on levels of interleukin-2 and interferon gamma, the report indicates.

“Our results offer valuable corroboration of the wealth of animal data in the field and suggest that synbiotics of the type studied in the present study may represent a feasible means of chemoprevention of colon cancer in humans,” the researchers conclude.

Using a genetic fingerprint, a U.S. team traced back a so-called founder genetic mutation to the couple found among two large families currently living in Utah and New York.

Cancer researchers at the Huntsman Cancer Institute in Utah did not name the families but said thousands of people across the country may have the mutation that spread widely as the couple’s descendants branched apart over many generations.

“The fact that this mutation can be traced so far back in time suggests it could be carried by many more families in the United States than is currently known,” said Deb Neklason, who led the study. “In fact, this founder mutation might be related to many colon cancer cases in the United States.”

Colorectal cancer is the third-leading cause of cancer death in the United States. It will affect 153,000 Americans in 2008, according to the American Cancer Society, and will kill 52,000.

Family history, smoking and diet are all linked with colorectal cancer but experts are still struggling to identify the causes that underlie most cases.

An estimated less than 1 percent of these cases are due to this particular genetic mutation, according to the study published in Clinical Gastroenterology and Hepatology.

Mutation increases risk
The U.S. team first focused on the Utah branch of the family — numbering about 5,000 people today — 14 years ago because its members had an unusually high risk of colon cancer.

Because the family was Mormon, the researchers were able to mine a wealth of genealogical information taken from detailed church records over the years that is now part of a large genetics database in Utah, Neklason said.

While most of the records in the study related to the Utah part of the family, the researchers eventually identified the New York branch as well.

“We just know about these two branches of the family,” Neklason said. “The significance of it going so far back is there are probably many branches of the family out there that aren’t aware of the mutation.”

In the study, the team identified the mutation that causes a condition called attenuated familial adenomatous polyposis (AFAP), which makes people more prone to developing polyps that can cause colon cancer.

Without proper treatment, people with this mutation have a greater than 2 in 3 risk of developing colon cancer by age 80, compared to about 1 in 24 for the general population. Early treatment, however, can just about eliminate this risk.

“This study highlights that you need to pay attention to your family history,” Neklason said. “With intervention to remove the polyps, the risk goes to near nothing.”