No Plateau for Secondary Cancer Risk After Leukemia

MEMPHIS, Tenn., March 20 -- Children and adolescents who survive acute lymphoblastic leukemia (ALL) need a lifetime of follow-up because of an elevated risk of secondary neoplasms that continues to climb through adulthood.

The cumulative incidence of secondary malignancy was 4.17% following 15 years of complete remission but continued to rise to 5.37% at 20 years and 10.85% at 30 years, according to a retrospective single-center study.

Even excluding late "low grade" neoplasms--meningioma and basal cell carcinoma--survivors were at 13.5-fold higher risk than the general population, said Nobuko Hijiya, M.D., of St. Jude Children's Research Hospital here, and colleagues.

"These results suggest that lifelong follow-up of acute lymphoblastic leukemia survivors is needed to ascertain the full impact of treatment and other leukemia-related factors on secondary neoplasm development," they wrote in the March 21 issue of the Journal of the American Medical Association.

Because newer treatment regimens for ALL have achieved 80% survival rates, long-term follow-up has taken on new importance, they said.

Previous studies had shown increased secondary neoplasm risk as long as 10 or 15 year after remission, but it was not known whether the risk would plateau at that point or continue to rise.

The researchers looked at medical records of 2,169 consecutive patients who achieved complete remission after being treated for acute lymphoblastic leukemia by age 21 at the hospital from 1962 to 1998.

After diagnosis, patients were examined at least annually for 10 years or until they reached 18 years of age. Thereafter, they were followed with mailed questionnaires.

After a median follow-up of 18.7 years (range 2.4 to 41.3), 879 had relapse as a first event, of whom 5.1% subsequently developed a secondary neoplasm, and 68 (5.3%) died in complete remission.

Another 123 (9.5%) developed a secondary neoplasm as their first event. These were comprised of 46 myeloid malignancies (37 acute myeloid leukemias), three lymphomas, 14 basal cell carcinomas (11.4%), 16 other carcinomas (13.0%), six sarcomas, 16 meningiomas (13.0%), and 22 other brain tumors (17.9%).

The cumulative incidence rates at 30 years were:

• 6.27% (SE 0.83%) overall excluding meningiomas and basal cell carcinomas.
• 2.19% (SE 0.32%) for myeloid malignancy.
• 0.17% (SE 0.10%) for lymphoma.
• 3.00% (SE 0.59%) for brain tumor.
• 4.91% (SE 1.04%) for carcinoma.
• 0.57% (SE 0.37%) for sarcoma.

The relatively rapid increase in incidence from 5.37% at 20 years to 10.85% at 30 years appeared to be largely due to late meningiomas and basal cell carcinomas. When they were excluded, the incidence of central nervous system tumors plateaued at 15 years at 1.17% and carcinoma incidence slowed from a 4.4% increase from 15 to 30 years to only a 1.77% increase.

"However, even with exclusion of basal cell carcinomas, there remains an impressive increase in carcinoma incidence between 25 and 30 years after induction, reflecting cases of more aggressive malignant neoplasms," the researchers wrote.

Forty one patients developed secondary neoplasms beyond 15 years of follow-up (median 23.7). Of these neoplasms, 15 were meningioma and 12 basal cell carcinoma. Fourteen were histologically aggressive tumors. All but one had received cranial or craniospinal irradiation.

When the entire cohort was stratified by cranial or craniospinal irradiation treatment, those who had received it were significantly more likely to have certain tumor types than the general population, based on Surveillance, Epidemiology, and End Results (SEER) data. The standardized incidence ratios (observed over expected) were:

• Overall, 13.6 (95% CI 10.5 to 17.1) with irradiation and 13.3 (95% CI 7.9 to 21.0) without.
• For central nervous system tumors, 45.8 (95% CI 26.0 to 64.2) with irradiation and 4.3 (95% CI 0.1 to 24.0) without.
• For other solid tumors, 5.1 (95% CI 3.1 to 8.0) with irradiation and 2.5 (95% CI 0.3 to 9.0) without.
• No different for lymphomas or myeloid malignancies with irradiation than without (3.0 and 150.9 overall, respectively).

The risk of solid tumor development 20 years after diagnosis was 2.4-fold higher than in the age- and sex-matched general population

No risk factors were related to cumulative incidence at 20 years, but at 30 years there was a trend for more risk of secondary neoplasms for women (8.51% versus 4.53% incidence for men, P=0.06) and for treatment with an alkylating agent (4.41% versus 1.43% without, P=0.08).

At 30 years, there was a cumulative incidence of 18 cases of a third malignant neoplasm.

Because the current treatment protocol for ALL at their hospital no longer calls for prophylactic cranial or craniospinal irradiation, the long-term risk of secondary neoplasms is expected to decrease, Dr. Hijiya and colleagues said.

Nonetheless, they concluded that all patients who experienced childhood acute lymphoblastic leukemia are at risk throughout their life and so require continued careful follow-up.

"Although the majority of these late-occurring secondary neoplasms are low-grade tumors such as meningioma and basal cell carcinoma, the health care issues they raise may be critical," they wrote.

"The risk for high grade tumors, especially carcinomas, significantly exceeds the risk in the general population, underscoring the need for continued careful follow-up of acute lymphoblastic leukemia survivors," they continued.

They cautioned that the study did not address the impact of transplantation or salvage therapies.