A Selfless Act

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Susan L. Cohn, MD

During my career, I have witnessed remarkable advances in the treatment of neuroblastoma and other pediatric cancers that resulted from randomized studies. For a parent, though, enrolling a son or daughter onto a randomized trial, truly, is a selfless act.

—Susan L. Cohn, MD

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Within minutes after opening the e-mail from ASCO on March 10, 2015, announcing the U.S. Food and Drug Administration (FDA) approval of dinutuximab (chimeric MAb ch14.18 or Unituxin), I contacted Amy’s mother (names have been changed). Amy was referred to our hospital in 2007, when she was 3 years old, after being diagnosed with high-risk neuroblastoma. She had developed a limp and leg pain, and an evaluation at another hospital revealed an adrenal mass and metastatic disease in multiple bones and the bone marrow. I met Amy and her parents in our clinic to discuss the diagnosis, prognosis, and treatment plan.

Although I have been caring for children with cancer for more than 30 years, I still find it difficult to break the news to a parent that his or her child has a potentially terminal illness. For children with some types of cancers, I am able to emphasize that the prognosis is excellent and that the treatment is well tolerated. This is not the case, however, for high-risk neuroblastoma. I told Amy’s parents that, with current treatments, approximately 40% of children are cured. I also stated, “Although this number may be difficult to hear, please remember it is just a statistic. Right now, I am only concerned about one patient, and my intention is to cure Amy.”

Planned Therapy

Because there were no open clinical trials at the time for patients with newly diagnosed neuroblastoma, I recommended treatment that was based on the best arm of a completed randomized, pediatric cooperative group clinical trial. I explained that this study showed better outcomes with myeloablative therapy followed by bone marrow transplantation than with chemotherapy.1 Amy’s parents had tears in their eyes as I reviewed the intensive, multimodal therapy and the expected toxicities. I also informed Amy’s parents that, even if their daughter had no evidence of disease after she completed the planned therapy, the neuroblastoma could return and that cure after relapse remains elusive.

Amy tolerated her induction chemotherapy well. However, she developed high fevers and severe mucositis during consolidation, and she remained in the hospital for weeks after the stem cell transplantation. Amy’s energy and appetite slowly returned. Two months after her stem cells were infused, Amy’s mom told me that Amy finally was beginning to act like the daughter she knew before the diagnosis of neuroblastoma. Amy received radiation after her stem cell transplantation; 7 months after her initial diagnosis, Amy was in remission.

Search for Better Treatments

I was thrilled that Amy’s tumor responded so well to treatment, but I knew that she was likely to have minimal residual disease. I reminded Amy’s parents that their daughter remained at significant risk for relapse. I informed them that a prior randomized, cooperative group clinical trial had shown that oral isotretinoin (cis-retinoic acid [RA]) given after consolidation improved the outcome for patients with high-risk neuroblastoma.1 On the basis of these results, RA is now considered part of the standard-of-care therapy for high-risk neuroblastoma. “However, we are always looking for better treatments,” I explained, “and your daughter is eligible for a randomized, Children’s Oncology Group clinical trial that is comparing RA alone with immunotherapy combined with RA.”

The expected toxicities of the two regimens on this study differed substantially. The immunotherapy regimen, which consisted of intravenous monoclonal antibody dinutuximab and cytokines, was administered during 4 days in the hospital, and patients required a morphine drip because of the antibody-induced peripheral nerve pain. Other toxicities include swelling caused by capillary leak; low blood pressure; hives; and more serious allergic reactions, including anaphylaxis. Conversely, the most common adverse effect of oral RA is dry skin. I stressed that, although we designed the study on the basis of the antineuroblastoma activity seen in patients with relapsed disease, we did not know if the immunotherapy combined with RA would lead to improved survival in patients who were in first remission. We needed to complete the randomized, clinical trial to answer this question.

Amy’s parents listened carefully. They were, understandably, concerned that Amy would again be in the hospital and separated from her sister if she was assigned to the immunotherapy arm. They also were worried about the pain and need for a morphine drip associated with the antibody therapy. After all, Amy was just beginning to feel better after being hospitalized for weeks because of the toxicities of high-dose therapy and stem cell transplantation.

As a physician desperate to find better treatments for my patients, I understand the potential impact that a randomized study can have for children worldwide who are diagnosed with neuroblastoma. During my career, I have witnessed remarkable advances in the treatment of neuroblastoma and other pediatric cancers that resulted from randomized, cooperative group studies. For a parent, though, enrolling a son or daughter onto a randomized trial, truly, is a selfless act. The decision to participate in this particular clinical trial was especially agonizing, because the treatment arms were so disparate. I suggested that Amy’s parents go home and take some time to think about whether or not they would like to enroll their daughter onto this study.

Helping Future Children

One week later, Amy’s mother and father met with me in clinic. “We have decided to do the clinical trial,” said Amy’s mom. “My daughter has benefited from families who enrolled their children onto previous clinical studies, and we want to help future children with this disease.”

Amy was enrolled onto the study a few days later and was randomly assigned to the immunotherapy arm. She developed many of the expected toxicities of immunotherapy, and I know that her mom asked herself if she made the right decision when she saw her daughter, swollen and miserable, on a morphine drip. However, Amy and her family persevered, and Amy completed the planned therapy. Eight years later, Amy remains in remission and is a healthy preteen who loves school, cheerleading, and Taylor Swift.

When I called Amy’s mom with the news about the FDA approval, I was the one with tears in my eyes. I informed her that the approval of dinutuximab was based on the demonstration of significantly improved survival with immunotherapy plus RA on the Children’s Oncology Group randomized clinical trial.2 Her selfless act would help children with neuroblastoma in the future. ■


1. Matthay KK, Villablanca JG, Seeger RC, et al. (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341:1165-1173, 1999.

2. Yu AL, Gilman AL, Ozkaynak MF, et al. (2010) Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363:1324-1334, 2010.