June 24, 2009 — Prophylactic cranial radiation can be omitted without compromising survival in the treatment of childhood acute lymphoblastic leukemia (ALL) when personalized chemotherapy is used as the primary therapy, according to the authors of a new study.
The radiation is problematic because of a range of late-treatment effects, including second cancers, stunted growth, hormone imbalances, and cognitive deficits.
Use of the radiation has been a standard of care in patients with ALL who are at high risk for central nervous system (CNS) relapse, and is still used in up to 20% of all patients in clinical studies, write the authors in the June 25 issue of the New England Journal of Medicine.
However, a personalized chemotherapy approach without radiation produced a 5-year survival rate of 93.5% in 498 patients, which is superior to results of all other major studies reported to date, according to the study authors.
The study was performed at St. Jude Children's Research Hospital in Memphis, Tennessee, and at Cook Children's Medical Center in Fort Worth, Texas.
The success rate was partly dependent on St. Jude's ability to deliver highly personalized chemotherapy that used, among other things, unique risk-assessment tools, said lead author Ching-Hon Pui, MD, who is chair of the St. Jude Department of Oncology and an American Cancer Society Professor.
Nevertheless, other pediatric cancer centers should be able to safely omit cranial radiation as well, noted Dr. Pui. "Other centers still can forgo cranial irradiation as long as they provide effective systemic chemotherapy and, more importantly, optimal intrathecal therapy," Dr. Pui told Medscape Oncology.
The intrathecal therapy used in the study was a triple therapy of methotrexate, cytarabine, and hydrocortisone. "We used triple therapy, which proved to be more effective than intrathecal methotrexate for CNS control," write the authors.
Role for Radiation
Clinicians who are hesitant to adopt a chemotherapy-only approach should realize that cranial radiation still has a role to play in the treatment of ALL, Dr. Pui noted.
"For those who are still afraid to forgo irradiation, they should know that the problem for high-risk patients is bone marrow relapse — not CNS relapse — and isolated CNS relapse can be salvaged," he said. In their study, cranial radiation was used successfully as salvage therapy for CNS relapse in the study, he explained.
Indeed, in the study, all 11 of the patients with isolated CNS relapse were in second remission of varying lengths after 1 course of salvage radiation; "most were probably cured," the authors comment.
In effect, radiation can be omitted in most patients and used sparingly and effectively when needed, suggest the authors.
St. Jude has been at the forefront of the treatment of childhood ALL and this latest study is part of a history of research into the disease and its treatment, said one of the study coauthors, William Evans, MD, who is also the director and CEO of St. Jude.
"In a way, these findings represent coming full circle," said Dr. Evans in a statement. "St. Jude was the first to introduce cranial radiation as a treatment strategy that advanced the cure of childhood ALL to 50%. Now, St. Jude is the first to show that we can successfully eliminate irradiation by optimizing chemotherapy."
Chemotherapy vs. Prophylactic Radiation
In the study, 71 patients had a high enough risk for disease relapse to qualify for prophylactic radiation. However, those patients, like the other 427 patients in the study, received personalized chemotherapy alone.
To determine whether or not the omission of cranial radiation compromised survival in these high-risk patients, the investigators compared them with 56 historic controls.
The 71 patients had significantly longer continuous complete remission than the 56 historic controls (P = .04), report the authors.
In short, the chemotherapy-only approach was more effective and had the benefit of sparing the children the adverse effects of radiation, the authors note.
Despite intensive chemotherapy, the rate of death from toxic effects was only 1.4%, and no patients died from disseminated fungal infection or thrombosis, even though the rate for each was substantial, report the authors.
Furthermore, the novel approach produced an acceptable rate of CNS relapse among the 498 patients, they note.
"The rate of isolated CNS relapse was 2.7%, well within the 1.5% to 4.5% range in clinical trials that used prophylactic cranial irradiation," the authors write about the 5-year rate.
The 5-year rate of any CNS relapse (which was defined as isolated relapse plus bone marrow relapse) was 3.9%.
Factors in the Improved Outcome
A variety of chemotherapies were used in the study, starting with remission-induction therapy and carrying through to continuation therapy, which lasted 120 weeks in girls and 146 weeks in boys.
A key to personalizing therapy was the ability of the St. Jude researchers to refine risk assessment after induction therapy and to subsequently tailor treatment, explained Dr. Pui.
The risk for relapse was determined by measuring the residual leukemia cells, also known as minimal residual disease, that remain after initial treatment. This measurement was the most important prognostic indicator in these ALL patients, according to the authors.
"While most investigators agree that incorporation of response to remission induction in the final risk assessment is ideal for patient management, we are the only institution that is able to measure it in all patients with sensitive and specific methods," said Dr. Pui, referring to flow cytometry and PCR.
"Other centers use only morphology by microscope — a crude measure — to measure response to remission induction. Hence, St. Jude is unique in this regard," he added.
He also said that the few centers that can perform pharmacogenetic and pharmacodynamic studies do not do so for the sake of personalizing chemotherapy. "They consider those tests as research and do not use the results, as we do, for routine patient care. Hence, we are also unique in this respect," he said.
The study was supported by the National Institutes of Health, the American Cancer Society F.M. Kirby Clinical Research Professorship, and American Lebanese Syrian Associated Charities. Dr. Pui has received lecture fees from Enzon Pharmaceuticals. Other coauthors have disclosed no relevant financial relationships.
New Engl J Med. 2009;360:2730-2741.
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