Who Shall Live and Who Shall Die?

Presented at the annual meeting of the American Society of Bioethics and Humanities. Special thanks to my brother Yoram Unguru, Donna Ludwinski, Carie Carter, Pat Lacey and most of all to John London, who started it all with his heartwrenching words and compelling argument.

Who Shall Live and Who Shall Die?

It's a provocative question, one with Old Testament roots and an attendant seriousness. It's a question with wide application in ethical discourse.
And although it may be uncomfortable and perhaps sensationalistic, it is a question that we cannot ignore. Certainly in the world of pediatric cancer, "who shall live and who shall die" has very real meaning. For me, since my son Toby was diagnosed with stage IV neuroblastoma, the question "who shall live and who shall die" has become a constant backdrop to daily life.

Neuroblastoma is the most common solid tumor cancer in infants. The median age at diagnosis is 2 years old. At diagnosis, more than half of neuroblastoma patients have disease that has already metastasized to other parts of the body. Children with high-risk disease undergo aggressive high-dose chemotherapy, radiation, surgery, stem cell transplant, differentiation therapy, and antibody therapy. Even after this intense treatment, only 30% survive. If a patient relapses or stops responding to therapy, neuroblastoma is usually viewed as a terminal illness with less than a 10% chance of survival. For those that do survive, the late effects are significant: hearing loss, neurocognitive problems, sterility and secondary cancers.

Since my son was diagnosed in 2007 I have watched helplessly as child after child has died an often agonizing and prolonged death. Neuroblastoma parents describe the death of their children like this: "I’m literally seeing disease erupt all over his body, extraordinarily painful bone mets, fractured bones from disease, organ failure, breathing difficulty, seizures, paralysis, blindness.“ These families face the unthinkable.

In the blink of an eye, we have said goodbye to Liam and Evan, to Lucas, Penelope, Max, Erik, Sam, Erin and so many others that I could burn through my allotted time by reading their names. I think about these children every day. I try not to question their deaths, out of fear that I won’t be able to find my way back to sanity. So instead I remember their vibrancy, their beauty, their quintessential child-ness.

But in the dark hours, I ask why did Liam die? Why does Toby live? It is a terrible question. The randomness howls. And the world spins madly on.

*****

In March 2009, the Children's Oncology Group released a statement halting the phase 3 trial of ANBL0032, a randomized study of chimeric antibody 14.18 in high risk neuroblastoma. Preliminary results of the phase 3 trial showed a significant increase in survival among those patients who received the antibody, as compared with those who didn't. Not only was the trial stopped prematurely, but COG also stated that ch14.18 immunotherapy should become a standard part of upfront nb treatment.

The neuroblastoma world is not used to hearing good news. As a reminder, children diagnosed with high-risk disease have a 2 in 3 chance of DYING. So a trial that shows a 20% increase in survival is almost beyond belief.

This is what Dr. John Maris, Chief of the Oncology Division at Children’s Hospital of Philadelphia said about ANBL0032: “ The last clinical trial that showed a new treatment improving outcome in neuroblastoma was published in 1999, which means the study ended in about 1996. That was the one that showed that transplant helped and that Accutane helped, so it’s been a long time.”

But elation quickly turned to unease, as it became clear that ANBL0032
was a randomized trial that started accruing patients almost 8 years earlier, in October 2001. By the time of its halting, over 200 children had been accrued, ½ randomized to receive the antibody and the other ½ not.

Toby was not part of this trial. As a patient at Memorial Sloan-Kettering he, like every child treated there for the last 20 years, received a mouse-derived antibody as part of upfront treatment.

Before I go any further, I want to point out that I am a believer in research. Research has allowed my child to receive the best available treatment and it is important to understand that most neuroblastoma families gratefully sign their children up for trials, because the prognosis otherwise is so poor. In fact, virtually all children treated for neuroblastoma, both high and low-risk, are enrolled on a clinical trial. The cancer is ruthless and research offers a chance at new agents and therapies. I cannot relay how many times parents confess that they just need to keep their children alive until the next trial opens. String together enough trials and maybe you can buy another year or two for your child.

So back to ANBL0032: I, like many others, found myself asking if it was truly necessary to do a phase 3 randomized trial when the phase 1 and 2 data demonstrated that antibody was substantially better than anything we had seen before in the treatment of high-risk neuroblastoma.

More than 30 early phase studies on the efficacy of antibody treatment were published before ANBL0032 even started. If children were knowingly randomized to the non-antibody arm that was thought to be inferior, the trial was unethical. And more importantly, lives, children’s lives, were sacrificed.

Listen to John London, whose daughter Penelope was randomized to the non-antibody arm: “I have to say how unethical it is to have designed a trial where 1) the average age of diagnosis is 2; 2) the survival rate for high risk is around 30%; and 3) the survival rate for relapse is below 10% AND then take a potentially promising agent and DISALLOW 50% of these children to receive it. All in the name of "perfect science". My daughter was one of the children who was turned away. Would it have saved her? Who knows? But I sure would have liked the chance to see. Can you imagine if one of the scientists/researchers/clinicians/protocol designers for ANBL0032 had a child with high risk NB who was denied a potentially promising agent? Randomized studies in High Risk Stage 4 NB sacrifice too many children in the name of science and it needs to change.”

Not all trials need to be randomized. Many in the medical community say that randomization is necessary to determine the best treatment and that improved survival in pediatric cancer is due to randomized trials. I would counter that increased survival is due to researchers using strong early phase evidence in choosing new treatment to test against old treatment. They are really good at this. Furthermore, if randomization provides better outcomes, why have changes to induction, radiation therapy and use of growth factors NOT been tested in RCTs? And if RCTs supposedly provide “proof” that one treatment is better than another, why is Memorial Sloan-Kettering not doing transplants when this was supposedly proven by 3 separate RCTs? And why is COG not doing rapid induction, as recommended by the International Society of Paediatric Oncology in Europe?

Earlier this year, the New York Times published an acclaimed series of articles on clinical trials in the treatment of melanoma. Many clinicians and researchers have said that the science behind the new drugs has eclipsed the old rules, and ethics, of testing them.

Dr. Charles Sawyers, chairman of human oncology at MSK on melanoma: “With these drugs (in development) that have minimal side effects and dramatic response rates, where we understand the biology, I wonder, why do we have to be so rigorous? This could be one of those defining cases that says, “Look, our system has to change.’”

To that point, if the odds of NB are already so abysmal, why not allow a promising agent to be used for all children? A different trial design could have built on previous knowledge. Perhaps results could have been compared historically to other studies. Perhaps children could have been allowed to cross-over. Either way it is clear that children did not need to be sacrificed to show that antibody is an effective treatment.

Dr. Richard Pazdur, director of the cancer drug office at the FDA has said, “new drugs in development, especially for intractable cancers, might require individual evaluation: “This is an unprecendented situation that will, hopefully, be increasingly common, and it may require a regulatory flexibility and an open public discussion.”

The blunt truth is that we cannot control whether our child is diagnosed with cancer. WE do not determine when we live and when we die.
BUT we CAN control what treatment we provide. And where we have the opportunity to offer an increased chance at survival, we have the obligation to do so.

A society is defined by how it treats its most powerless and vulnerable members. We cannot turn a blind eye to injustice. As Abraham Joshua Heschel said, “To accept passively an unjust system is to cooperate with that system.” Yes, I say this to you as the parent of a child with cancer, but we are also fellow human beings. I urge you to search inside, locate our common humanity and give ALL our children a chance at life.

******

I am able to stand here today in large part thanks to the support and smarts of my brother, who is sitting right there. His care and advocacy during the past 4 years of treatment have been nothing short of incredible.

It’s not often that a brother and sister find themselves on the front lines of a cancer diagnosis, occupying opposite yet congruent sides of what some term the research/care divide. I believe that with Toby’s diagnosis, brother and sister have been able to transcend our respective boundaries. Certainly in the case of ANBL0032, I hope we are on the same side.

Toby has been the beneficiary of the dedication and care of a team of incredible doctors and nurses at multiple institutions. As a parent, I cope with one child who has cancer. Our doctors and NPs cope with the pain of hundreds of children every day. I want to thank them. They have chosen to face death, yet they engage with life. They care enough about our children to embrace hope, and through their work they affirm that people can change.

Thank you for giving me the opportunity to share my thoughts. I am grateful to be here in your company. I would also like to thank Donna Ludwinski, mother to Erik. She is the force behind my words. Her vast knowledge, pinpoint clarity and graceful support to the neuroblastoma community deserve unending recognition.

Thank you.

Good-night, sweet Prince

I loved Liam before I ever met him.

In April 2007, after Toby was diagnosed with stage IV neuroblastoma, after we saw the scans of his body filled with metastatic cancer, and after our doctor told us that Toby might die from the baseball-sized tumor in his abdomen, a parent from Toby's preschool sent me a clipping from Cookie magazine. "Maybe you've seen this," she wrote. "This boy has cancer too."

I had not seen the article, but started carrying it in my bag, searching everywhere for Liam and his parents. I desperately needed to connect with another family experiencing the same terror and pain. Eleven days after Toby's diagnosis I posted a comment to Liam's blog, and received a meltingly lovely voicemail from Liam's father Larry the next day. Our paths finally crossed a few weeks later.

Toby already had tubes implanted in his chest and had been through two devastating cycles of chemotherapy. His hair was gone, his mouth was lined with oozing sores, and his days were spent in a blur of treatment. This particular morning he had to have blood drawn via a "fingerstick," a routine but painful procedure that involves pinning down the child, lancing a finger and squeezing out enough blood to perform a battery of tests. Toby began screaming immediately and was inconsolable for an hour. After everything he had already been through I didn't expect such a strong reaction.

A beautiful woman with startling blue eyes touched my shoulder, looked at Toby and said, "Don't ever let them tell you that he needs a fingerstick when they can access his port instead. It won't hurt him as much." This was my introduction to Gretchen. I followed her advice for 3 years.

Liam, our beacon and guide, the beautiful boy whose nickname was "Mr. Inquisitive" died on Monday.

On their first "playdate" in the hospital pediatric wing, as both were attached to blinking, beeping IV poles, Liam and Toby fingerpainted. Toby was tentative, unsure whether he liked the sensation of the paint on his fingertips. Liam stuck all five fingers into the paint pots, scooping out the oily pigment and brandishing it against the paper, swooping again and again into an orgy of beautiful color and energy. He chattered the whole time, laughed, described his masterpiece, tore into life with joyful abandon. And then he raced off to the next thing: to investigate the pneumatic blood tube delivery system or visit with his buddy, the custodian who mopped the floors, or a long conversation with the cafeteria workers.

I wanted to live like Liam. Each time he had surgery, he was up and walking within absurdly short periods of time -- a day, 12 hours, immediately. He loved science and magnatiles, he played with his little sister Ella with a sweetness that I've never seen before or since. He took comfort in his paci and clan of stuffed lovies. He was a child who always wanted to "go faster, daddy." He deserved to become a doctor, an astronaut, an adult.

Today is my birthday. Today I have lived 40 years longer than Liam.

Imagine if Liam was your child. Imagine administering agonizing treatment that makes your child whimper with pain. Imagine your child with no hair, hearing loss, sterility. Imagine your child not having the energy to play. And imagine this scenario replaying itself day after day for almost 4 years. The thing is, Liam's story is not singular. Every day (every day!) 46 children are diagnosed with cancer. Every day we face the fact that there is less than a 5% survival rate for relapsed neuroblastoma. And every day we are reminded that there is a "near absence" of research into pediatric cancer drugs. The reality: most children will be dead long before government funding is secured for pediatric cancer. Please don't turn away.

Give 3 friends a box of cookies from www.cookiesforkidscancer.org/ and count it as your charitable contribution for the month. Or have a bake sale at your office and find out if your employer has a matching program. If you are in the NYC area, please walk with us in Central Park on May 7 to help raise funds for research and treatment. Or find out more about neuroblastoma and donate at www.bandofparents.org

Please remember Liam and all the children who fight.

Thank you.

Love,
mooki