For Children with Neuroblastoma, Trial Results Highlight Continued Evolution of Treatment

For many
children with advanced forms of neuroblastoma, receiving two separate stem cell
transplants as part of their treatment is more beneficial than receiving one.
That’s according to the results of an NCI-supported clinical trial conducted by
the Children’s Oncology Group (COG).

Study published
in JAMA

Children in
the trial had high-risk neuroblastoma, meaning that their tumors had features
that make the cancer particularly aggressive and difficult to treat. Children
who received two transplants separated by several weeks lived substantially
longer without their cancer progressing or developing any other cancer-related
problems, an outcome known as event-free survival, than children who underwent
a single transplant, reported Julie Park, M.D., of Seattle Children’s Hospital,
and her colleagues August 27 in JAMA.

However,
undergoing two transplants—called a tandem transplant—is more intensive, and
the children who received tandem transplants had longer hospital stays, the
researchers reported. However, they did not have worse side effects.

The trial’s
results were initially presented more than 3 years ago at the American Society
of Clinical Oncology annual meeting. Since that time, a tandem transplant—with
the same initial (or induction) and pretransplant (or conditioning)
chemotherapy regimen used in the trial—has become the standard treatment for
most children in the United States with high-risk neuroblastoma, explained Nita
Seibel, M.D., head of Pediatric Solid Tumor Therapeutics in NCI’s Cancer
Therapy and Evaluation Program.

Further
advances or treatment options are likely to emerge, Dr. Seibel continued. Other
treatment approaches have also shown promise in children with high-risk
neuroblastoma, she said, and NCI is supporting COG-led trials testing some of
these approaches.

“So, while
tandem transplant is the current standard, we’ll have additional information on
whether alternative approaches can further improve outcomes for these
children,” Dr. Seibel said.

Continued
Movement Toward More Intense Treatment

About 800
children are diagnosed with neuroblastoma each year in the United States. It is
the most common non-brain solid tumor diagnosed in children. The cancer
originates in immature nerve cells, and neuroblastoma tumors often form in and
near the abdomen and in the chest or neck region along the spine.

About half
of kids diagnosed with neuroblastoma are considered to have high-risk
disease. Different characteristics can make the cancer high risk, such as
whether the cancer is widespread or has a specific genetic alteration.

Treatment of
patients with high-risk neuroblastoma begins with induction therapy, which
involves multi-drug chemotherapy regimens and, when possible, surgical removal
of the primary tumor. That is followed by consolidation therapy, which involves
administration of very high-dose chemotherapy and infusion of the patient’s own
stored blood stem cells, known as an autologous transplant. Radiation therapy
to the primary tumor sites, and sometimes sites of metastases, follows. And,
finally, there is post-consolidation therapy, which typically is the immunotherapy
drug dinutuximab (Unituxin) along with isotretinoin.

For many
years, high-risk neuroblastoma was considered to be nearly incurable.
Because it is so aggressive and can rapidly prove fatal, developing treatments
that can prevent or delay relapse has been a high priority, Dr. Seibel said.
And over time, that has meant that the treatments used have grown in complexity
and intensity, pushing cure rates to greater than 50%.

Neuroblastoma
treatment

“The
treatment is definitely complicated,” Dr. Seibel said. “It’s always a careful
balance between trying to avoid too much toxicity while trying to provide a
cure.” neuroblastoma

Creating
Better Opportunity for Immunotherapy Success?

After some
small clinical trials showed promise for tandem transplants in patients
with high-risk more than a decade ago, COG launched the large trial intended to
find out for certain whether the tandem approach was better than a single
transplant.

All of the
trial participants received the same induction chemotherapy regimen and
surgery. Children whose cancer did not progress after induction were then
randomly assigned to receive either a single autologous stem cell transplant or
a tandem transplant.

More than
650 children enrolled in the trial between 2007 and 2012. However, only 355
were randomly assigned to the single or double transplant. In some cases, this
was because a child’s cancer progressed or a child was no longer healthy enough
to receive a stem cell transplant. More often, children who initially enrolled
left the study, their families deciding against being randomly assigned to one
of the two treatment groups.

That’s not
unexpected, said Lisa Diller, M.D., of Dana-Farber Cancer Institute, the senior
investigator on the trial. “This is a big decision that families are making
about a life-threatening disease,” she said. And particularly as treatments
have become more intensive, “it’s a very hard decision to make.”

Among the
children who were randomly assigned to a treatment group, event-free survival
was 61.1% in the tandem transplant group and 48.4% in the single-transplant
group at a median of 3 years of follow-up.

There was no
improvement in how long patients lived overall, although the trial wasn’t designed
to look for an improvement in that outcome. That’s due in part, the research
team wrote, because when a relapse is detected, children quickly move on to new
treatments, and trying to disentangle the effect of a new therapy on survival
from the initial treatment can be problematic.

Most
children in the trial went on to receive dinutuximab, which emerged as
an effective therapy for children with high-risk neuroblastoma during the
trial. Children in the trial who received immunotherapy with dinutuximab, in
fact, received the drug as part of other COG studies that led the Food and Drug
Administration to approve the drug in children with high-risk disease.

Dr. Park and
her colleagues decided to look specifically at survival among trial
participants who were also treated with dinutuximab. Three years after
receiving the immunotherapy, children who had undergone a tandem transplant had
substantially better event-free (73.3% versus 54.7%) and overall (84% versus
73.5%) survival than children who received a single transplant. Although,
again, this analysis was not a planned part of the trial.

The improved
survival after dinutuximab treatment in the tandem transplant group
could be the result of several factors, the trial investigators noted. For
instance, by reducing the extent of cancer in the body more than a single
transplant, a tandem transplant might be creating an opening for immunotherapy
to better control the disease, they wrote.

In other
words, Dr. Diller said, “you’re asking the [immunotherapy] to do less.” But she
cautioned that there “could be other explanations,” and that more research is
needed to better understand what might be happening.

Continued
Push for Greater Survival, Fewer Side Effects

Overall, the
trial’s findings show that “even in the era of precision medicine,” a tandem
autologous stem cell transplant should be used “in most patients with high-risk
neuroblastoma,” wrote Rochelle Bagatell, M.D., of the Children’s Hospital of
Philadelphia, and Meredith Irwin, M.D., of the Hospital for Sick Children in
Toronto, in an accompanying editorial in JAMA.

But, they
cautioned, the greater efficacy of a tandem transplant has to be considered “in
the context of the induction and post-consolidation therapies administered” in
the trial. Other treatment approaches may prove to be more effective and/or
less toxic, they wrote.

In Europe,
for example, many clinicians currently treat children with high-risk
neuroblastoma using only a single stem cell transplant, but with different
induction and pretransplant conditioning regimens than were used in the COG
trial. In a large international clinical trial, children who received the
European induction regimen followed by a single transplant had substantially
better event-free survival than children who got the European induction
followed by the single transplant conditioning regimen used in the COG trial.

COG, in
fact, has launched a phase 3 clinical trial for children newly diagnosed with
high-risk neuroblastoma that includes 5 treatment groups, including one that
will receive the conditioning regimen used in Europe.

The trial
also includes another drug, I 131 MIBG (Azedra), that is already being tested
in clinical trials in children with neuroblastoma that has come back after
earlier treatment. In the current COG trial, I 131 MIBG—which delivers
radiation directly to cancer cells—is being tested as part of induction
therapy. The trial is also testing the use of the targeted therapy crizotinib
(Xalkori) in children whose tumors express a specific genetic alteration.

A smaller,
early-phase COG trial is testing the addition of dinutuximab to standard
induction chemotherapy.

Even with
these trials, there is an important area where progress needs to be made, Drs.
Bagatell and Irwin wrote. “At present, it is not clear whether all high-risk
patients benefit equally from intensification” with a tandem transplant, they
stressed.

So a major
point of emphasis going forward, Dr. Diller said, is using the data and
analyses of tumor and other tissue specimens from completed and ongoing trials
to “gain a better biological understanding of what’s going on in individual
patients’ tumors and individual differences in tumor response to therapy.”

Doing so may
allow researchers to identify biomarkers and subgroups of patients with
high-risk disease who may or may not need more intensive therapy or would be
more likely to respond to a specific treatment.

“But that will require more patients, more studies, and definitely international collaboration,” she said.

“For Children with Neuroblastoma, Trial Results Highlight Continued Evolution of Treatment was originally published by the National Cancer Institute.”

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