Kevin C. Oeffinger, MD Debra A. Eshelman, RN, MSN, CPNP Gail E. Tomlinson, MD, PhD Michael Tolle, MD Gregory W. Schneider, MD Dallas, Texas Submitted, revised, August 27, 2000. From the Department of Family Practice and Community Medicine (K.C.O., M.T., G.W.S.), the Center for Cancer and Blood Disorders (D.A.E.), and the Department of Pediatrics, Division of Hematology-Oncology (G.E.T.), the University of Texas Southwestern Medical Center at Dallas, and Children’s Medical Center of Dallas, the After the Cancer Experience (ACE) Young Adult Program. Reprint requests should be addressed to Kevin C. Oeffinger, MD, the University of Texas Southwestern Medical Center at Dallas, Department of Family Practice and Community Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390-9067. E-mail: kevin.oeffinger@email.swmed.edu.
Primary care physicians will be providing longitudinal health care for long-term survivors of childhood acute lymphoblastic leukemia (ALL) with increasing frequency. Late effects (sequelae) secondary to treatment with radiation or chemotherapeutic agents are frequent and may be serious. Depending on treatment exposures, this at-risk population may experience life-threatening late effects, such as cirrhosis secondary to hepatitis C or late-onset anthracycline-induced cardiomyopathy, or life-changing late effects, such as cognitive dysfunction. Many survivors of childhood ALL will develop problems such as obesity and osteopenia at a young age, which will significantly affect their risk for serious health outcomes as they grow older.
The goal of our review is to assist primary care physicians in providing longitudinal health care for long-term survivors of childhood ALL. We also highlight areas needing further investigation, including the prevalence of different late effects, determination of risk factors associated with a late effect, a better understanding of the potential impact of late effects on the premature development of common adult health problems, and the value and timing of different tests for screening asymptomatic survivors.
References
Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, accounts for almost one fourth of childhood cancers.1 The incidence of ALL has shown a moderate increase in the past 20 years. It is generally considered a cancer of younger children, with a peak incidence between the ages of 2 and 5 years. It is approximately 30% more common in boys than girls and approximately twice as common in white children as in black children. Improvements in ALL treatment during the past 20 years have increased the overall survival rate to approximately 80%. Thus, success in “curing” this childhood disease has resulted in a growing population of long-term survivors.
Since it is anticipated that the majority of long-term survivors of childhood ALL will seek health care from primary care physicians, it is important to understand the potential health problems that these patients may experience secondary to their cancer treatment.2-4 However, there are no articles in peer-reviewed family practice journals concerning the long-term follow-up of survivors of childhood ALL. Our clinical review briefly describes the evolution of the treatment for ALL, potential late effects of treatment, and recommendations for screening asymptomatic long-term survivors. Because this field of investigation is rapidly advancing and much of the available information is from cross-sectional and small cohort studies, these recommendations should not be viewed as a set of guidelines. Instead, our review is intended to contribute a foundation for primary care physicians providing longitudinal health care for ALL survivors while highlighting the areas needing further investigation. Also, because of the evolving changes in treatment protocols—and thus in potential late effects—it is essential to frequently communicate with our colleagues who specialize in the treatment of children with cancer.
Evolution of treatment for childhood all
During the 1940s childhood leukemias had a uniformly rapid fatal course over a short period of time, thus the designation of the term “acute.”5 In the late 1940s, Farber and colleagues6 found that aminopterin (a folic acid antagonist) could induce temporary remissions in leukemia. This discovery opened the era of clinical investigation into the uses of combined chemotherapy in treating childhood ALL Figure 1. The use of antimetabolite therapy for prolonged periods started in the late 1950s and early 1960s and suggested that it was possible for children to have an extended period of remission and possibly be cured. The addition of anthracyclines such as daunorubicin in the 1970s and the discovery that the enzyme L-asparaginase was useful in ALL therapy for depleting cells of the essential amino acid L-asparagine further boosted the ability to induce and sustain remission.7
A significant factor in morbidity and mortality from childhood ALL was the development of leukemia within the central nervous system (CNS). Left untreated, more than half the children with ALL developed leukemia in the CNS, even when bone marrow remission was sustained. In most patients, CNS relapse was followed by bone marrow relapse. Prophylactic radiation to the head and spine, introduced in the early 1970s, significantly decreased the incidence of CNS leukemia and resulted in significant advancement in long-term survival. However, in the early 1980s—as a consequence of the appreciation of neurodevelopmental delays and cognitive dysfunction secondary to relatively higher-dose (24 Gy) cranial irradiation (CRT), different methods of CNS treatment and prophylaxis evolved, either using lower-dose CRT (18 Gy), intensification of systemic methotrexate (MTX) dosaging, or intrathecal medications.8-11
Current treatment regimens divide therapy into remission induction, consolidation and CNS prophylaxis, and maintenance or continuous treatment. Induction chemotherapy (aimed at an initial reduction in blast cell percentage in the bone marrow to 5% or lower) consists of a 1-month schedule of vincristine, prednisone, and L-asparaginase alone or with other agents. Following induction, a consolidation phase consisting of an intensified period of treatment combines the use of antimetabolites and other agents with intrathecal chemotherapy for CNS prophylaxis. Maintenance therapy continues for a period of approximately 2 years and relies heavily on the use of methotrexate and 6-mercaptopurine. During the past 2 decades, recognized differences in the phenotype of the leukemic cells have resulted in protocol modifications to improve outcome and reduce toxicity. Increasingly, the T-cell phenotype of childhood ALL has been treated more effectively with intensified regimens that include cyclophosphamide, cytarabine, and anthracylines.12,13
Late effects of treatment for childhood all
A late effect is defined as any chronic or late occurring physical or psychosocial outcome persisting or developing more than 5 years after diagnosis of the cancer. In this section we describe potential late effects in order from more common or serious health problems to less common or serious ones Table 1. Many of these late effects may have long asymptomatic intervals before end-stage disease or serious health outcomes, such as survivors with hepatitis C who develop cirrhosis or those with a late-onset cardiomyopathy who present in congestive heart failure. Included in each section is a discussion about the screening tests commonly used in long-term follow-up programs that include asymptomatic survivors4Table 2. It should be stressed that the value of most of these tests has not been studied in this population in a prospective or a well-designed retrospective manner with adequate sample sizes, which limits the strength of the recommendations. Clinicians should be selective in ordering tests and providing preventive services and should actively incorporate the patient’s concerns and fears when arriving at an individualized decision on whether to perform a test. Figure 2 is a compilation of information pertinent to the follow-up of a survivor of childhood ALL, provided as a single-page template for clinical use.
