Pediatric Cancer Guidelines Are a National Effort

FORT LAUDERDALE, Fla--The panel preparing pediatric cancer guidelinesfor the National Comprehensive Cancer Network (NCCN) faced a somewhatdifferent task than the adult cancer panels, since the developmentof pediatric guidelines is much more of a national undertaking.

"There is interest on the part of the leadership of the PediatricOncology Group (POG) and the Childrens Cancer Group (CCG) to tryto develop this as a national effort, and we at the NCCN are goingto cooperate in whatever way we can," said Richard O'Reilly,MD, chairman of the pediatric guidelines panel, in his presentationat the NCCN's first annual conference.

He noted that the NCCN guidelines effort is "particularlyexciting" because it will eventually include a system fortracking their utility, including outcomes, compliance, and resourceutilization by different centers.

At the NCCN conference, Dr. O'Reilly, of Memorial Sloan-KetteringCancer Center, and panel member Ching-Hon Pui, MD, of St. JudeChildren's Research Hospital, presented the preliminary guidelinesfor three pediatric cancers: acute lymphoblastic leukemia (ALL),osteogenic sarcoma, and neuroblastoma.

Genetic Testing

Genetic alteration underlies every case of leukemia, and for thatreason, the leukemia guideline stresses the importance of geneticstudies in the diagnosis, Dr. Pui said.

Virtually all of the NCCN centers are performing cytogeneticsstudies, he said. But the panel considers molecular studies evenmore important, because "cytogenetically seemingly identicallesions can be different at the molecular level, and also evenin the best hands, cytogenetic studies can be successfully performedin only 80% to 90% of patients." Moreover, Dr. Pui said,there are some very important abnormalities that can be identifiedonly by molecular studies.

"When we first began to develop the guideline, only about25% of childhood ALL patients had phenotype-specific genetic abnormalities,"Dr. Pui said. "More recently, with the identification ofthe TEL-AML1 fusion gene, up to 50% of childhood ALL cases havephenotype-specific genetic abnormalities, and, most importantly,every abnormality has prognostic and therapeutic implications."

He noted that if ploidy or DNA index is included, up to 70% ofchildhood ALL cases have prognostically important genetic abnormalities.

Many of these tests have not been incorporated into the pediatricguideline because the studies have not yet been confirmed, hesaid. "I think in the future, we will classify the patientaccording to genetic event, and I think I can see 5 years downthe road that the NCCN will recommend genetic classificationsto manage these patients."

Treatment of ALL

The pediatric guideline divides ALL patients into three prognosticgroups--low, intermediate, and high risk, with more intensivetherapy indicated for the latter two groups. If treated by NCCNstandards, 5-year event-free survival should be 80% or more inthe low-risk patients, 60% or more in the intermediate-risk patients,and about 30% for the high-risk group.

In fact, Dr. Pui pointed out, a study at one of the NCCN institutions,using the NCCN criteria, found 85% event-free survival at 5 yearsfor the low-risk patients, 65% for the intermediates, and 40%for the high-risk group. "Therefore, we have not only establishedthe prognostic guidelines, we have also set the standards,"he said.

Reinduction or consolidation therapy is recommended for all threegroups, since, even in low-risk patients, studies have shown thatit can improve outcome, Dr. Pui said.

Cranial radiation is not indicated for the low-risk group, hesaid, and is somewhat controversial for the intermediate-riskgroup.

"There are several studies showing that intermediate-riskpatients can have very good CNS control by using only intensiveintrathecal therapy," he said. At the moment, however, theguideline leaves the decision on cranial irradiation up to theindividual institution.

A selected group of high-risk patients should receive cranialirradiation, according to the guideline, but Dr. Pui pointed outthat this issue "is evolving. A few years down the road wemight limit cranial irradiation to even a smaller group."Patients with a particularly poor prognosis may be candidatesfor allogeneic hematopoietic stem cell transplantation, he said.

When Patients Relapse

For the 20% to 30% of patients who recur, "we think it isimportant to perform all of the workup again, to see if this representsa clonal evolution or development of a new or second malignancy,"Dr. Pui said.

Salvage treatment varies, depending on the timing and type ofthe relapse and the initial treatment, and may include transplantfor patients who have an early hematologic relapse or those whohad received intensive initial therapy.

For patients with CNS relapse, the issue of whether to give cranial-spinalirradiation remains somewhat controversial, he said. "Thereare several unpublished studies suggesting that one can cure CNSrelapse without giving irradiation, so again we leave that openfor the different institutions."

For patients in second relapse who have never had a transplant,transplant is the treatment of choice; for those with a previoustransplant, a second transplant using an alternative preparativeregimen can be considered. But, Dr. Pui said, for all others ingood clinical condition, "we think they should enter a phaseII trial, because phase II agents can put a number of them intogood clinical remissions and will also yield information to helpus develop the next treatment protocols." Patients in thirdor fourth relapse are candidates for phase I trials.

The development of guidelines for osteogenic sarcoma "istruly a national effort," Dr. O'Reilly said. The NCCN currentlyrecommends that osteogenic sarcoma patients at member institutionsbe enrolled in the joint trial being conducted by the POG andthe CCG.

Patients in this trial receive either regimen A or B, both ofwhich include high-dose methotrexate plus doxorubicin and cisplatin,Dr. O'Reilly said.

Regimen B is more prolonged (38 weeks) than regimen A (31 weeks)and includes ifosfamide (Ifex), while regimen A does not.

Use of MTP

Patients in both regimens are further randomized to receive MTPor not as a potential approach to augment the patient's immuneresponse to the cancer.

"We know from experience in large centers and large cooperativegroups that using the standards presented here today for thesecancers, we have achieved very real results," Dr. O'Reillyconcluded. "What we are saying with these guidelines is:If you want to treat patients for these diseases, you should beprepared to give this type of therapy so that these outcomes canbe achieved."