• The Time is Now: Reducing the Toxicity of Cancer Treatment

    decreasing toxicity in cancer treatment

    Looking back over the last half a century—maybe not even that long—one can see how the conversation about treatment in pediatric oncology has evolved. It used to be that survival rate was the primary, maybe only, concern among pediatric oncologists. How can we help more children and achieve more cures?

    Fast forward to today. With experience and experiment has come greater knowledge of the biology underlying many solid, neurological and hematologic malignancies. That knowledge has, in turn, opened opportunities to reduce the long-term toxicity of cancer treatment and improve survivorship along with survival. How can we help more children survive, and survive better?

    “These discussions are no longer in the background. They’re right up front,” says Elizabeth Mullen, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center‘s Solid Tumor Center. “There’s much more focus on avoiding late toxicities because of the success rates that we see. It’s so much more of how we think now, even when we’re treating high-risk disease. It’s always part of the conversation.”

    Matching patients to therapies based on risk

    Take, for example, acute lymphoblastic leukemia (ALL), where overall survival for standard risk patients exceeds 90 percent. “In the treatment of ALL, there has been an ongoing focus on improving cure rates while at the same time minimizing the toxicity of therapy,” says Lynda Vrooman, MD, of Dana-Farber/Boston Children’s Hematologic Malignancy Center, who is interested in questions about long-term survivorship among patients with blood cancers. “An important factor in improving therapy has been providing the right treatment to the right patients based on risk.”

    Risk stratification has been the key. According to Vrooman, nearly every ALL protocol now draws on the primary concept of providing the appropriate therapy for a patient’s risk of recurrence.

    Whereas doctors used to assess that risk based only on features such as age and white blood cell count, “now we also assess risk by more sophisticated means, such as leukemia cytogenetics at the start of therapy and end induction minimal residual disease assessments,” she says.

    Over the course of several treatment protocols, clinicians have also reduced their use of therapies with potential long-term toxicities, such as anthracyclines (which can affect the heart) and cranial radiation. “Changes have been made in protocols here and elsewhere to minimize these particular exposures,” Vrooman notes.

    A similar approach to stratification also now drives the treatment of solid tumors like neuroblastomaand Wilms tumor (WT). But again, the question comes back to identifying the right patients.

    “We need to find better ways of identifying patients beyond saying to families, ‘Your child is two years old today, so he has to get chemotherapy. But if you had come in yesterday, we could put him on a less toxic regimen,'” says Mullen, who is studying an observation-only approach after surgery for very low-risk types of WT. “We have to rely more on biology and biologic markers related to relapse risk and less on things like age or tumor size. That would let us offer less toxic options to a larger group of children.”

    Reducing reliance on radiation

    Improvements in risk stratification and therapy are also driving change in the standard approaches to an expanding portfolio of brain tumors, particularly reductions in the use of radiation.

    “Radiation to the developing brain causes a lot of problems,” says Peter Manley, MD, a neuro-oncologist with Dana-Farber/Boston Children’s Brain Tumor Center and director of the Stop & Shop Family Pediatric Neuro-Oncology Outcomes Clinic. “With this understanding, we’re trying to move forward with ways by which we can reduce the use of radiation.”

    He cites low-grade gliomas (LGGs) as one tumor type where significant strides have already taken place in radiation reduction. The overall survival rate for LGGs, Manley explains, is quite high. A Pediatric Blood and Cancer (PBC) paper he and colleagues published in 2014 documented an 87 percent 20-year overall survival rate among LGG patients.

    But radiation used to be the standard of care for these tumors, leading to learning, behavioral and cognitive deficits that survivors carry with them for the rest of their lives. (And not just for brain tumors—ALL survivor studies have documented long-lasting cognitive effects linked to cranial radiation and intrathecal chemotherapy.)

    Radiation has also impacted brain tumor patients’ survival in ways we are only just starting to appreciate. In that same PBC paper, Manley’s team found that radiation treatment reduced LGG patients’ long-term survival.

    But here, too, research linking specific genetic changes with patient outcomes may help improve risk assessment and reduce treatment toxicity in patients with LGG and other tumors, such asmedulloblastoma. Manley and his colleagues developed a clinical trial studying the feasibility of treating Wnt-positive medulloblastoma—a molecular subtype of the tumor with a 95 percent survival rate—with surgery and chemotherapy alone, eliminating radiation altogether.

    While this approach may be risky, it has a saving grace: If the frontline therapy doesn’t work, generally oncologists can still fall back on radiation. “The salvage rate is still really good,” Manley says, “so that if the tumor does recur we still have treatments to cure the patient.”

    Relying more on biology and biologic markers and less on things like age or tumor size would let us offer less toxic options to a larger group of children.

    Mullen points out that radiation is still widely used for post-treatment surveillance. Current practice in WT and other tumors, such as Hodgkin lymphoma, is to bring survivors back for frequent CT scans to check for recurrence. Not only does this practice add to a child’s cumulative radiation dose (thereby making secondary cancers more likely), it also increases the risk of incidental or false positive findings—and may not actually be useful for detecting a relapse.

    “You’re doing scan after scan after scan for tumors where the cure rate is really high,” she explains. “For the huge majority of children you’re never going to find anything. So does the scan help you and the patient?”

    Balancing, and communicating, risks and benefits

    All this is not to say that reducing therapy now to minimize toxicities down the road is a risk-free proposition. For some brain tumors, for instance, the pendulum can swing too far over in favor of avoiding radiation.

    “There was a chemotherapy-only protocol for germ cell tumors, and the relapse rate was too high,” Manley says. “We recognize that for these tumors we have to use radiation.” He notes that a new germ cell tumor trial open now relies on chemotherapy first, and then radiation adjusted to the patient’s response.

    In addition, families’ perception of the risks and benefits of cancer treatment can cause them to shy away from less intensive therapy in favor of more aggressive therapies. “If families are given a choice of less therapy up front but with the possibility of more therapy should the child relapse, a lot will choose to receive more therapy up front,” says Mullen. “They’re very concerned about the possibility of relapse.”

    Sometimes the idea of receiving less therapy scares families. “We emphasize to families how rare pediatric cancers are, so they often feel they are likely to have other rare events happen,” Mullen says. “Even if their child is likely to be in the 90 percent that can be cured with less intense therapy, families understandably worry that their child will be in the 10 percent that will relapse.

    “They already feel like they’re the one that was struck by lightning the first time, ” she adds. “How do we know it won’t happen again?”

    Overall, though, Mullen advocates taking a thoughtful approach to protocol development and prescribing practices.

    “We have to think carefully about every single dose that we prescribe,” she says. “Even chemotherapy that we consider mild may have adverse effects that we don’t yet understand, and much of our therapy clearly does have known potential negative acute and long-term impact.

    “The emphasis now is on developing ways to feel confident about how much therapy each individual really needs to cure their cancer,” Mullen continues. “We do not want to give any child a drug or therapy that they don’t need.”

    This article originally appeared on the Boston Children's Hospital blog Notes.

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