Late Mortality in Childhood Cancer: Time to Count Our Chips

Abstract

Sources: (1) Mertens AC,Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. Clin Oncol. 2001;19:3163–3172. (2) Möller TR, Garwicz S, Barlow L, et al. Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries. J Clin Oncol. 2001;19:3173–3181.Survivors of childhood and adolescent cancer remain at risk for a shortened life span because of the possible long-term sequelae of cancer therapy and recurrence of the primary malignancy. These 2 excellent reports, a multi-institutional study from The Childhood Cancer Survivor Study (CCSS) in the US, and a population-based study in 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden), are the largest studies to date evaluating long-term survivors of childhood cancer. The purpose of both retrospective studies was to assess the risk of death among childhood and adolescent cancer survivors.The CCSS was a retrospectivecohort study initiated in 1994 and designed to study late effects among long-term survivors of childhood cancer. The study population consisted of a cohort of 20,227 patients who were less than 21 years of age when diagnosed with cancer between 1970 and 1986 and who survived at least 5 years beyond the date of diagnosis. Standardized mortality ratios (SMRs) were calculated based on 208,947 person-years of follow-up in this population. The cumulative mortality was 6.4% at 10 years from diagnosis, 9.3% at 15 years, 11.4% at 20 years, and 14.0% at 25 years: a 10.8-fold increase in mortality rate when compared to the general population. Female gender, diagnosis before 5 years of age, and the diagnosis of leukemia or brain tumor were associated with a statistically significant higher mortality. Causes of death, in order of frequency, included recurrence of original disease accounting for 67% of deaths, treatment-related second malignancies (SMR 19.4), organ toxicity (such as cardiac [SMR 8.2], pulmonary [SMR 9.2], etc.) and others (SMR 3.3). As noted above, there was a 19-fold increased risk of death secondary to treatment-related second malignancy in this population relative to the risk of malignancy in the general population. No excess mortality was observed for non-cancer-related causes (motor vehicle accidents, suicide, or AIDS). Patients with a diagnosis of kidney tumor and neuroblastoma had the best overall survival, while those with CNS tumors had the poorest.The population-based Nordic study included data from the nationwide cancer registries of 5 countries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20years between 1960 and 1989 and who survived at least 5 years from diagnosis. The estimated overall mortality for the 5-year survivors was .10 at 15 years after diagnosis (expected mortality rate .01) and .14at 25 years after diagnosis (expected mortality rate .02). Unlike the CCSS study, higher mortality rates were observed among males and patients diagnosed after the first 5 years of life. The overall SMRs for validated causes of death based on 156,046 patient-years at risk, however, were identical to the CCSS figure of 10.8, and due largely to increased death from the primary cancer. The SMR for second cancer was 4.9 and was 3.1 for non-cancer death when compared to the general population. Late mortality was significantly lower in patients treated between 1980 and 1989 when compared to those treated between 1960 and 1979.In the United States, more than 12,000 children and adolescents less than 20 years of age are diagnosed with cancer each year. The 5-year survival rate for these patients was 80% according to the 1998 Surveillance, Epidemiology and End Results Program. That is an incredible achievement. Unfortunately, cancer remains the leading cause of disease-related death among this population and there are many late sequelae due to cancer treatment that haunt survivors of childhood cancer. As increasing numbers of these patients reach adulthood and form a growing segment of society, it becomes imperative to familiarize ourselves with the information presented in these studies. The whole medical community needs to be educated, including pediatricians, family practitioners, obstetricians/gynecologists, internists, and geriatricians. Surprisingly, fewer than half of US medical institutions have a mechanism for following up adult survivors, and only 15% have established a formal database for such individuals. In the Nordic countries, there is no general policy for the long-term follow-up of adult survivors of childhood cancer. Now we have the statistics on 33,938 patients followed for 364,993 patient-years at risk, forcing us to further reexamine our current cancer therapies and reevaluate our presently inadequate follow-up procedures.Dr. Joseph Simone, a well-known pediatric oncologist who has been an active researcher and witness to cancer therapy of children over the past several decades, has written an excellent commentary that put the volumes of data reported in these 2 extremely important studies into proper perspective. He was there when the glass was far less than half empty, and now relishes the fact that the glass has become “far more than half full.”1Although there have been previous studies dealing with the late mortality of childhood cancer, none have encompassed as many patients as the 2 studies cited above and, therefore, it is not necessary to ask for future, large-scale surveys to substantiate the conclusion that a problem exists. It has been estimated that in the not-too-distant future, perhaps as many as 1 in 20 adults will be a survivor of childhood cancer. In my view, all childhood cancer survivors need to be followed by pediatric oncologists in specialized clinics exclusively set up to deal with treatment-related problems because it is they who have administered the treatment and are fully acquainted with the short- and long-term side effects. Furthermore, they intimately know the patient and family and are able to offer not only medical, but psychological help when necessary. Such patients still need to be seen by their primary care physicians who should work in close cooperation with the oncologists.These long-term cancer patients may develop various problems, many of which are non-fatal, deserving close attention. We have significantly modified therapy in recent years to lessen the risk of possible side effects. However, many patients still exist who were placed on old protocols and, therefore, may develop more significant problems than might be expected from current therapy. Radiation therapy can cause cognitive disorders, sterility, pituitary problems including stunted growth, cataracts, thyroid cancer, hypothyroidism, bone and soft tissue sarcomas, breast cancer, lung cancer, scoliosis, and slipped capital femoral epiphysis. Chemotherapy can cause sterility, leukemia (usually AML), non-Hodgkin lymphoma, pulmonary problems, cataracts, osteopenia, hepatic disorders and cardiac difficulties (especially during pregnancy when the blood volume is increased by 40%, thereby putting a strain on a possibly already damaged heart). This is not an all-inclusive list.Until all pediatric cancer survivors are enrolled in specialized clinics as described above, the primary care physician will need to be keenly aware of the possible long-term effects of childhood cancer treatment so that monitoring is ongoing and intervention, when necessary, is rendered.