Cetuximab Combined with Oxaliplatin-Based Chemotherapy May Not Be Effective First-Line Treatment for Metastatic Colorectal Cancer

Cetuximab Combined with Oxaliplatin-Based Chemotherapy May Not Be Effective First-Line Treatment for Metastatic Colorectal Cancer Summary In a randomized proviso III trial, a serve of a targeted therapy cetuximab to oxaliplatin and fluoropyrimidine chemotherapy did not lengthen presence or time to illness course of patients with modernized colorectal cancer. In contrariety to before studies, even … Continue reading “Cetuximab Combined with Oxaliplatin-Based Chemotherapy May Not Be Effective First-Line Treatment for Metastatic Colorectal Cancer”

Cetuximab Combined with Oxaliplatin-Based Chemotherapy May Not Be Effective First-Line Treatment for Metastatic Colorectal Cancer

Summary

In a randomized proviso III trial, a serve of a targeted therapy cetuximab to oxaliplatin and fluoropyrimidine chemotherapy did not lengthen presence or time to illness course of patients with modernized colorectal cancer. In contrariety to before studies, even patients whose tumors voiced a normal chronicle of a KRAS gene gifted no alleviation with cetuximab.

Source

The Lancet, published online Jun 5, 2011 (see a biography abstract).

Background

Until 10 years ago diagnosis for metastatic colorectal cancer was singular to a singular combination: 5-fluorouracil (5FU) and leucovorin (LV).  In a early 2000s, researchers identified several new drugs that were active in treating modernized colorectal cancer. These embody a chemotherapy agents irinotecan, oxaliplatin, and capecitabine and a targeted therapies bevacizumab and cetuximab. The best approach to use these novel agents to provide metastatic colorectal cancer, however, is not clear.

To residence this issue, researchers have instituted countless clinical trials contrast a drugs simply and in several combinations in patients whose illness had progressed on before therapy or who had not been treated previously. Two of these trials, referred to as CRYSTAL and OPUS, demonstrated that adding cetuximab, a monoclonal antibody that targets a EGFR, to a multiple chemotherapy regimens FOLFIRI or FOLFOX, respectively, as a first-line diagnosis increasing a response rate and a time to cancer course compared to diagnosis with chemotherapy alone.

However, usually patients retrospectively identified as carrying a wild-type, or normal, KRAS gene, whose product is a member of a EGFR signaling pathway, were found to advantage from cetuximab. This was approaching since mutant forms of KRAS send a expansion vigilance possibly or not EGFR has activated a pathway; therefore, predicament of EGFR signaling would be approaching to have an outcome usually in patients with wild-type KRAS. Other studies of cetuximab and chemotherapy as a second-line diagnosis have had identical findings.

The Study

To establish possibly a advantage from a serve of cetuximab to chemotherapy in patients with metastatic colorectal cancer that has not been treated formerly would reason adult in a incomparable studious population, researchers incidentally reserved 1,630 patients to accept oxaliplatin and a fluoropyrimidine (either capecitabine or 5FU and LV, as dynamic by a patient’s oncologist) with or but cetuximab. Treatment continued until a patient’s illness worsened or a side effects became unacceptable. The patients’ tumors were monitored by CT prove before a start of diagnosis and each 12 weeks until a finish of treatment.

Tumor biopsy samples from 1,065 patients were suitable to be examined by immunohistochemistry to establish EGFR expression. DNA removed from 1,316 growth samples was sequenced to brand probable mutations in a KRAS, BRAF, and NRAS genes. Like KRAS, BRAF and NRAS are famous to attend in signaling pathways associated to EGFR.

The investigate was led by Timothy S. Maughan, M.D., of a Cardiff University School of Medicine in Wales.

Results

The serve of cetuximab to chemotherapy did not urge altogether presence in patients whose tumors voiced wild-type KRAS. The median presence time was 17.9 months in those treated with chemotherapy alone and 17.0 months in those treated with cetuximab and chemotherapy. In patients whose tumors had a KRAS mutation, a median presence time was 14.8 months for those treated with chemotherapy alone and 13.6 months for those treated with cetuximab and chemotherapy. The serve of cetuximab to chemotherapy also did not urge a time to illness course in patients with wild-type KRAS (median time to cancer course was 8.6 months for both groups).

DNA sequencing research suggested mutations in KRAS, BRAF, and NRAS in 43 percent, 8 percent, and 4 percent of tumors, respectively. No patients had mutations in both BRAF and NRAS or BRAF and KRAS. Eleven patients, however, had mutations in both a KRAS and NRAS genes.

Regardless of treatment, a scientists found that altogether presence sundry depending on a mutations benefaction in a patient’s tumor. Median presence time for patients with tumors expressing a deteriorated BRAF gene was 8.8 months, for those whose cancers had NRAS mutations was 13.8 months, and for those with KRAS deteriorated tumors was 14.4 months. Patients but any of these mutations in their tumors survived for a median of 20.1 months.

Treating patients with a multiple of cetuximab and oxaliplatin-based chemotherapy increasing a skin irritations and gastrointestinal side effects of a chemotherapy drugs but improving studious survival. Some of these poisonous effects were specific to a fluoropyrimidine used. For example, patients who perceived capecitabine and cetuximab had some-more diarrhea and insensibility and pain in their extremities than patients who perceived 5FU and cetuximab.

Comments

The anticipating from this proviso III hearing that there was no advantage from adding cetuximab to oxaliplatin-based chemotherapy was a warn given that a OPUS investigate had shown that mixing FOLFOX and cetuximab was profitable in patients whose tumors voiced wild-type KRAS. The authors lift a probability that a specific drugs that are total with cetuximab have critical effects on studious survival. If so, a miss of advantage in a stream hearing could be due to a use of capecitabine rather than 5FU and LV to provide a infancy of a patients.

Whatever a reason for a manifold results, a authors state that “the use of cetuximab in multiple with oxaliplatin and capecitabine in first-line chemotherapy…cannot be recommended.” Likewise, in an concomitant editorial, Madeleine Hewish, M.R.C.P., and David Cunningham, M.D., from a Royal Marsden Hospitals in London and Surrey, United Kingdom, introduce that oxaliplatin might “not be a best chemotherapy drug for cetuximab.” They advise that mixing cetuximab with irinotecan, 5FU, and LV might urge growth response and studious presence formed on a formula of a CRYSTAL study, observant that serve trials comparing a efficacies of these combinations are needed.

According to Jack Welch, M.D., Ph.D., of NCI’s Division of Cancer Treatment and Diagnosis, this hearing also supposing discernment into some of a critical biomarkers (KRAS, BRAF, and NRAS) that could be used as premonitory indicators in patients with metastatic colorectal cancer. He combined that destiny clinical trials in patients with modernized illness will expected stratify patients by pivotal specific biomarkers.

Finally, a presence times for a patients in this hearing are shorter than in those published previously, including a OPUS study. The authors prove that this might be due to differences in a investigate populations and to a theatre of their illness during a time of diagnosis. Patients with some-more modernized illness mostly have shorter presence times.

Modeling disparities may help with cervical cancer prevention

ScienceDaily (Sep. 6, 2011) — Researchers reported that explicit inclusion of disparities in cost-effectiveness analysis, would allow policy makers to identify strategies that would reduce overall cancer risk, reduce disparities between racial ethnic subgroups, and be cost-effective, according to a study published online September 6 in the Journal of the National Cancer Institute.

Disease simulation models can be used to identify effective and cost-effective strategies for reducing overall cancer incidence and mortality, but are sometimes criticized for not considering how the benefits are distributed within the population. Advances in computer-based modeling, together with the availability of better data, allows details to now be included that account for inequalities between different population subgroups.

To provide a framework for how health inequities could be more explicitly considered in model-based cost-effectiveness analysis, Sue J. Goldie, MD, MPH, and Norman Daniels, Ph.D., of the Harvard School of Public Health, devised a typology of cancer disparities among black, white, and Hispanic populations in the United States that differentiated inequalities resulting from different factors, such as access and quality of treatment and prevention. They used this typology to guide an evaluation of different cervical cancer screening and vaccination strategies in which the health and economic outcomes were calculated for the average population, and also for the three racial subgroups separately.

The researchers identified strategies that reduced the overall risk of cervical cancer from 60% to 74.5%, and that improved cancer outcomes in all racial subgroups. However, they also found that the benefits were unequally distributed; for example, while current screening patterns would resulted in a 60% reduction in overall cancer incidence, reductions ranged from 54.8% for Hispanic women to 62.5% for white women.

The researchers found that screening strategies that directly targeted racial subgroups bearing the greatest inequalities, when combined with vaccination, provided a more equitable distribution of benefits. For example, reduction in cervical cancer incidence was 69.7% in white women versus 70.1% in Hispanic women. These strategies were also more effective and less costly than current screening patterns.

The authors conclude that modeling disparities in cancer prevention can identify strategies that will improve overall population health, distribute health benefits fairly, and utilize health care resources efficiently. They write, “These points of convergence are ‘win-win’ in the sense that they have the biggest positive impact in worst-off groups as well as on population health overall.

Our claim is that such win-win strategies are most desirable from the perspective of both goals of health policy, population health improvement, and health equity.”

In an accompanying editorial, Kevin A. Ault, M.D., of the Department of Gynecology and Obstetrics at Emory University School of Medicine writes that the introduction of the HPV vaccines into the world of medicine has made cervical cancer prevention a reality. Ault agrees with the study’s conclusions on the utility of modeling, particularly that, “modeling of racial and ethnic subgroups at increased risk identifies strategies that can reduce cancer burden among these groups.” Ault adds that since recent research has identified HPV vaccination and diagnostic testing as potential improvements to the Pap smear in cervical cancer prevention, these strategies should be made available to all women.

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Metabolic state of brain cancer stem cells significantly different than the cancer cells they create

ScienceDaily (Sep. 6, 2011) — The metabolic state of glioma stem cells, which give rise to deadly glioblastomas, is significantly different from that of the brain cancer cells to which they give birth, a factor which helps those stem cells avoid treatment and cause recurrence later.

Researchers with the UCLA Department of Radiation Oncology at UCLA’s Jonsson Comprehensive Cancer Center also found for the first time that these glioma stem cells can change their metabolic state at will, from glycolysis, which uses glucose, to oxidative phosphorylation, which uses oxygen.

The glioma stem cells’ ability to change their metabolic state at will also allow these stem cells that seed new cancer growth to evade treatment and remain alive, said Dr. Frank Pajonk, an associate professor of radiation oncology and senior author of the study.

“We found these cancer stem cells are substantially different in their metabolic states than the differentiated cancer cells they create, and since they act differently, they can’t be killed in the same way,” Pajonk said. “And as yet, we don’t have anything to target these glioma stem cells specifically.”

The study is published this week in the early online edition of the journal Proceedings of the National Academy of Sciences.

Cancer cells take up large amounts of glucose, which fuels their grow and spread and allows them to be differentiated from normal cells under Positron Emission Tomography (PET) scanning, which captures metabolic activity. Pajonk and his team found that the glioma stem cells took up much less glucose, which makes them difficult to detect with PET.

Targeting cancer metabolic pathways as a treatment has gained new interest in recent years. However, these cancer stem cells that take up less glucose could evade those treatments by utilizing glucose more efficiently through oxidative phosphorylation, which would not be targeted by such drugs.

“If glioma stem cells are indeed important for tumor control, knowledge of the metabolic state of glioma stem cells is needed,” the study states.

Using a unique imaging system Pajonk and his team developed for glioma stem cells that relies on low enzymatic activity of the proteasome in cancer stem cells, they were able to assess them for metabolic function, including oxygen consumption rates, glucose uptake and other markers. They also found that the glioma stem cells were resistant to radiation, another roadblock to targeting these cells with conventional treatments.

Pajonk and his team concluded that glioma stem cells rely mainly on oxidative phosphorylation for energy. But they found if the stem cells were challenged, they could switch on additional metabolic pathways.

The study also shows for the first time that low expression of proteasome sub-units, an indicator of large numbers of glioma stem cells in the tumor, predicts unfavorable treatment outcomes for those patients.

“What I think is really exciting is we have here for the first time a novel cancer stem cell marker in glioma, which gives us an additional tool to look for these cells and come up with therapies that target them,” said Pajonk, who also is a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

This study was funded by the National Cancer Institute.

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