National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 30, 2009 • Volume 6 / Number 13

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Cancer Research Highlights

For Children with Leukemia, Radiation May Be Unnecessary

Children with the most common form of leukemia can safely forego radiation therapy to prevent a relapse of the disease if they are treated with chemotherapy regimens tailored to their individual needs. This is the conclusion of a clinical trial involving 498 patients with acute lymphoblastic leukemia (ALL). Nearly 94 percent of the patients were still alive 5 years after treatment, a result that compares favorably with other ALL treatment studies.

The strategies and treatments employed in this trial could be adopted by other medical centers, said researchers from St. Jude Children’s Research Hospital in Memphis, who published their results in the June 25 New England Journal of Medicine.

Cranial irradiation has been used since the 1960s as a way to prevent a recurrence of cancer in the brain. First introduced by researchers at St. Jude, it was considered a breakthrough and improved survival rates in the disease to about 50 percent. Thanks to continued improvements in chemotherapy, today 90 percent of children with ALL are cured of their disease.

But with a growing population of survivors and clear evidence that radiation exposure can lead to second cancers and cognitive problems, many centers have limited its use to patients at risk of a relapse. In the trial, Dr. Ching-Hon Pui and his colleagues tailored chemotherapy regimens for each patient and used the latest techniques for delivering the drugs and monitoring their effectiveness. After several weeks, adjustments could be made if a patient had evidence of residual cancer cells.

Based in part on comparisons with historical data on patients with ALL, the researchers conclude that individualized chemotherapy regimens are preferred over treatments that include cranial irradiation. They even recommend against irradiation for patients considered at risk of relapse. If this group had received radiation therapy in the current study, the researchers explained, 90 percent of the patients would have received radiation unnecessarily.

“The introduction of radiation therapy in the 1960s put the word ‘cure’ into discussions of ALL,” said coauthor and director of St. Jude, Dr. William Evans. “The importance of the current study is that we’re now removing radiation from the therapy. And the reason we’re able to do this is that we’ve gotten smarter and better at using chemotherapy.”

Survivors of Hodgkin Lymphoma May Face Increased Risk of Stroke

Patients who receive radiation therapy for Hodgkin lymphoma may be at increased risk of a stroke or transient ischemic attack (TIA), also called a “mini stroke,” later in life, according to a report in the July 1 Journal of the National Cancer Institute. The risk is primarily associated with radiation to the neck and chest area, and it remains elevated for years after treatment.

The researchers, led by Dr. Flora E. van Leeuwen of the Netherlands Cancer Institute, tracked 2,201 survivors of Hodgkin lymphoma who were treated before the age of 51 between 1965 and 1995. At a median follow-up of almost 18 years, 96 survivors developed a stroke or TIA. The incidence of stroke among the survivors was 2.2 times that of the general population, while the incidence of TIA was 3.1 times that of the general population.

Overall, these events occurred at a relatively young age (the median age was 52 years, with a range from 24 to 80 years). For young survivors of Hodgkin lymphoma who are at especially increased risk of stroke and TIA, physicians should consider strategies to reduce the risk, such as treatment of hypertension and certain lifestyle changes, the researchers said.

The findings add to the overwhelming evidence that using radiation therapy in Hodgkin lymphoma is “shortsighted,” according to an accompanying editorial by Dr. Dan Longo of the National Institute on Aging. Even though treatments for this disease have included reduced doses of radiation since 1995, there is no evidence yet that this translates into fewer late effects for survivors, he cautioned.

“Unfortunately, given the lifelong increased risks of late effects that have been documented from the use of radiation therapy, we simply cannot keep exposing patients to risk without clear benefit while we wait for safety data to be produced,” Dr. Longo added.

Another Genetic Change Linked to Neuroblastoma: Missing DNA

A series of genome studies have, for the first time, revealed common genetic changes associated with neuroblastoma, a cancer that most often occurs in children. Building on this work, researchers have now expanded the scope of these surveys to include structural changes, such as gains and losses of DNA. As reported in the June 18 Nature, this strategy has revealed a region of chromosome 1 that is missing in some children with neuroblastoma and that may contribute to their disease.

Gains and losses of DNA, known as copy number variations or CNVs, have been linked to conditions such as autism and schizophrenia, but this study is the first to demonstrate their role in predisposing to cancer. Dr. John Maris of the Children’s Hospital of Philadelphia and his colleagues made the discovery by screening DNA from 1,600 children with and without the disease. The missing DNA on chromosome 1 was confirmed in two independent groups, and additional evidence for its role in neuroblastoma came from experiments in cells.

Neuroblastoma arises in children in the developing cells of the sympathetic nervous system. The unstable region of chromosome 1 is near a family of genes involved in the development of the central nervous system. In experiments with cells, the researchers learned that the CNV alters the activity of a previously unknown member of this gene family, which resides within the region. The presence of this CNV alone is not sufficient to cause neuroblastoma, the researchers noted.

Indeed, a variety of genetic alterations contribute to the disease, including, it now appears, CNVs. In their previous studies (here, here, and here), Dr. Maris and his colleagues in the Children’s Oncology Group implicated two other types of genetic changes—mutations and single nucleotide polymorphisms (SNPs), which are places in the genome where a single letter of DNA may vary from person to person.

“It has been widely thought that CNVs could play a role in cancer, but the evidence has been lacking,” said Dr. Sharon Diskin of the Children’s Hospital of Philadelphia, the first author of the new study. “We hope that our findings provide the evidence for the importance of expanding genome-wide association studies to include CNVs as well as SNPs in cancer.”

Immune Cells with Stem Cell-like Properties Destroy Tumors in Mice

Researchers from NCI’s Center for Cancer Research have shown that a cell signaling network called the Wnt-β-catenin pathway drives the development of a type of immune cell that may provide opportunities to enhance cancer immunotherapies. Immunotherapy techniques recruit the body’s immune system to attack cancer cells.

In a paper published online June 14 in Nature Medicine, the researchers found that when T cells—a type of white blood cell—were cultured with drugs that mimic components of the Wnt pathway, the T cells acquired stem-cell like properties. They were able to both regenerate themselves and produce daughter cells that differentiated into mature T cells, which can recognize and attack cancer cells.

These cells, called CD8+ memory stem cells, were tested as a treatment for large melanoma tumors (containing about one billion malignant cells) in mice. Relatively tiny numbers (about 40,000) of these T cells given in combination with a tumor vaccine and an immune system stimulant called interleukin 2 were able to trigger the destruction of the bulky tumors and improve survival. The memory stem cells that were transplanted multiplied 10 to 30 times more than other types of T cells tested in the mice.

“This new category of lymphocytes is superior to T cells used in earlier experiments because they have the enhanced ability to renew themselves, to proliferate, to differentiate and ultimately to kill tumor cells,” said lead author Dr. Nicholas Restifo in a statement.

Adoptive immunotherapy, the reinfusion of anti-tumor T cells after expansion outside the body, has shown promise as one of the few new therapies that may result in complete remission for patients with metastatic disease. This approach has previously relied on the transfer of large numbers of tumor-specific T cells generated and expanded in the laboratory, a time-consuming and expensive process. However, the use of smaller numbers of “stem-like” T cells may broaden the use of this treatment approach in patients with cancer, said Dr. Restifo. Further studies are needed to confirm the promising results from CD8+ memory stem cells in humans, concluded the authors.