Columbus, OH - May 2016
The toxic mortality rate for young children undergoing intensive curative chemotherapy for malignant central nervous system tumors has dropped dramatically — from 6.4 percent to 2.1 percent to 0.8 percent — over the course of the first three “Head Start” clinical trials begun in 1991.
At the same time, morbidity rates for such side effects as infections and mouth and throat sores have similarly fallen.
"We believe this reflects the fact that all the participating institutions — there's a learning curve — gained a comfort level and experience managing these things," says Jonathan Finlay, MB, ChB, FRCP, director of Neuro-Oncology at Nationwide Children's Hospital and principal investigator for the trials. "There is no question that the switch from rescuing patients with cells collected from their marrow to cells collected from their peripheral blood gave us a better-quality product and speeded blood count recovery."
Importantly, data from 226 children over nearly two decades show that use of the autologous hematopoietic progenitor cells to restore marrow is a safe component of the treatment.
Nearly 85 percent of patients were younger than 6 years old when they received the treatment. Long-term follow-up studies show that “Head Start” preserves intellectual function and "we have not seen a single second malignancy due to this treatment without radiotherapy," Finlay says.
“Head Start” is a three-step protocol designed to wipe out a child's tumor and residual cancer. Dr. Finlay began the “Head Start” trials in 1991 while on the faculty at Memorial Sloan-Kettering Cancer Center. He led the second “Head Start” study at New York University and the third at Children’s Hospital of Los Angeles. Each lasted six to seven years.
The new ”Head Start 4” study is coordinated and hosted by Nationwide Children’s National Experimental Therapeutics (NEXT) Consortium.
The treatment process for a patient begins with what is called induction: five cycles of short but intensive chemotherapy over four to five months, followed by a single cycle of marrow-destructive chemotherapy. That is followed by transplantation of the patients' own hematopoietic progenitor cells, now almost uniformly collected from the blood. The cells restore new marrow to the child.
The regimen is designed to provide a cure and prevent, or at least delay, the use of radiation therapy. Radiation therapy is known to cause significant and irreversible intellectual and psychosocial deficits and, down the road, cancers.
Finlay began “Head Start” after seeing babies with malignant central nervous system tumors die shortly after completing traditional low-dose, 18-month-long chemotherapy.
"Supported by the literature at the time, most of the children relapsed and died with traditional chemotherapy," Finlay said. "On average, their cancers usually progressed in 9 to 12 months from diagnosis. Clearly the battle is lost or won very, very early."
Finlay was working with colleagues in France, finding success in treating children with recurrent cancer with shorter, more intense chemotherapy and marrow ablation.
In “Head Start I,” more than 20 other institutions achieved a 6.4 percent mortality rate during the transplant phase. “Head Start II,” with more than 30 institutions, saw the mortality rate drop by a third. During “Head Start III,” with more than 40 institutions, the rate dropped to less than 1 percent.
While many co-morbidity rates have dropped, permanent hearing loss has remained the most significant long-term side effect. The loss is usually manageable with older children who have already acquired speech but a greater challenge to young children who have not yet fully developed speech, Finlay says.
Platinum compounds used in induction and marrow ablation are the problem, Finlay says. "Together they produce the toxic effect. Hearing loss is the consequence."
To try to further reduce the mortality rate and co-morbidities, Finlay has begun “Head Start 4” at Nationwide Children's, with more than 60 institutions worldwide. Funding is provided by Worthington Industries and the McConnell Family Foundation, which helped establish the NEXT Consortium last year.
“Head Start 4” includes molecular studies to divide medulloblastoma in children into risk groups - those needing less intensive and those needing more intensive therapy.
After three cycles of chemotherapy, high- and low-risk children who show no signs of residual cancer will go directly into marrow ablation and transplantation.
High-risk children who have undergone either three or five cycles during induction will be randomly assigned to the traditional single ablation cycle or three cycles using two-thirds the dosage of the single cycle each time.
"Our hypothesis is that for the higher risk group of children, the dose intensification is going to produce an improved cure rate without increasing toxicities," Finlay says. "If proven, it would produce quite a paradigm shift in the treatment approach."
Altshuler C, Haley K, Vasquez L, Gardner SL, Stanek J, Finlay, JL for the 'Head Start' Consortium. Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the 'Head Start' trials, 1991-2009. Bone Marrow Transplantation.2016 March 7. [Epub ahead of print]
Cohen BH, Geyer JR, Miller DC, Curran JG, Zhou T, Holmes E, Ingles SA, Dunkel IJ, Hilden J, Packer RJ, Pollack IF, Gajjar A, Finlay JL; Children's Oncology Group. Pilot study of intensive chemotherapy with peripheral hematopoietic cell support for children less than 3 years of age with malignant brain tumors, the CCG-99703 phase I/II Study. A report from the Children's Oncology Group. Pediatric Neurology. 2015 Jul; 53(1) 31-46.
Saha A, Salley CG, Saigal P, Rolnitzky L, Goldberg J, Scott S, Olshefski R, Hukin J, Sands SA, Finlay J, Gardner SL. Late effects in survivors of childhood CNS tumors treated on Head Start I and II protocols. Pediatric Blood& Cancer. 2014 Sep; 61(9):1653-1672.