FOLLOW-UP OF SURVIVORS OF CHILDHOOD CANCER FREDERICK P. LI, MD

A registry has been established of survivors of childhood cancer treated at the Sidney Farber Cancer Institute, Boston. This resource provides opportunities for studies of physiologic, genetic, psychologic, and social sequelae of childhood neoplasia. Findings indicate potential in most patients for a high quality of extended life. Comprehensive long-term care may further reduce late morbid- ity and mortality.

Cancer 39:1776-1778, 1977.

PURPOSE OF THE CONFERENCE IS TO PRO- A mote interchange between clinicians and epidemiologists. This presentation explores po- tentials for collaborative follow-up studies of pa- tients with cancer.

The prognosis of patients with many forms of neoplasia has improved in recent years3 Mortal- ity of children with acute lymphocytic leukemia, for example, approached 100% in past decades; new treatments may now yield sustained remis- sion (> 5 years) in over 50% of case^.^^'^ In addition, Wilms’ tumor, Hodgkin’s disease, and other childhood neoplasia are presently curable in a high proportion of patients. Survival of adults with cancer has also improved, although at a slower rate.

Follow-up of patients with cancer should con- tinue after eradication of evident disease. How- ever, care at oncology centers may lapse for those who remain in continuous remission, re- quire no additional tumor therapy, and are likely cured. At some institutions, successfully treated patients are typically returned to the primary physician for further medical attention, and then are lost to study of late effects of neo- plasia. Long-term follow-up by cancer centers for statistical and other purposes is often made by a clerk, who merely determines whether a patient is free of disease, in relapse, or deceased. Data on quality of survival may not be system- atically collected and utilized in management of sequelae of cancer. These practices no longer seem desirable. Innovative approaches are now

Presented at the National Cancer Institute Conference on Cancer Epidemiology and the Clinician, Boston, Mass., Oc- tober 23-25, 1975.

From the Sidney Farber Institute, Boston. Massachusetts; and Clinical Studies Section, Clinical Epidemiology Branch, National Cancer Institute, Rethesda, Maryland.

Address for reprints. Frederick P. Li, MD, 35 Binney Street, Boston, M A 021 15.

Received for publication January 4, 1977.

needed to provide comprehensive continuing care of the survivors of neoplasia.

At the Sidney Farber Cancer Institute (SFCI) epidemiologists and oncologists have jointly de- veloped a registry of patients who were alive without relapse at 5 years after diagnosis of a cancer in childhood (< age 18 years). In 1973, 410 patients who had been treated at the In- stitute were enrolled in the registry (Table 1). Initial treatment of each child involved biopsy or more radical surgery. Two hundred eighty-four (69%) received radiation therapy (median dose, 2600 rads); 346 (84%) received chemotherapy with diverse drugs. The series constitutes a re- source for studies of physiologic, genetic, psy- chologic, and social sequelae of childhood can- cer.

Risk of Second Neoplasms Patients with cancer have increased risk of a

second primary neoplasm. Development of mul- tiple primaries may result from host susceptibil- ity, or carcinogens that act on several organs. Also, a second primary may arise because prior tumor therapy involved agents with an onco- genic potential, such as radiation.’

Study of the 410 registered patients in 1973 showed that 28 had developed second neoplasms between 6 and 21 years after a childhood cancer; 15 had second malignancies and 13 benign or other tumors.’* Nearly all the second lesions arose within sites of prior radiotherapy, and were considered radiation-induced. Host factors were also implicated in individual cases, but carcinogenic effects of cancer chemotherapy could not be demonstrated. Life-table analysis of the series showed a 12% cumulative probabil- ity of developing a new malignancy in a 20-year interval (5-24 years after initial diagnosis). T h e expected frequency of a new cancer in persons of comparable ages in the general population was less than 1% (Fig. 1).

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No. 4 SURVIVORS OF CHILDHOOD CANCER Li 1777

TABLE 1. Initial Diagnoses in 410 Survivors of Childhood Cancer, Sidney Farber Cancer Institute Series'

Type of tumor No. of patients

Wilms' tumor Neuroblastoma Lymphoma Soft-tissue sarcoma Bone tumor Hodgkin's disease Gonadal tumor Leukemia Other'

All types

115 73 49 44 43 34 11 11 30

410

* Excludes 4 patients who were treated elsewhere for the first of double primaries.

17 retinoblastomas, 6 neural tumors, 5 embryomas, 3 melanomas, 3 renal cell carcinomas, 2 adrenocortical carci- nomas, 2 hepatomas, and 2 parotid tumors.

Anatomic and Physiologic Disorders Vital organs are susceptible to permanent

damage by both the tumor and tumor therapy. Severity of the injury is determined chiefly by stage and site of the neoplasm, and intensity of treatments with surgery, radiotherapy and chemotherapy. Disorders associated with radi- cal surgery are immediate and obvious, and re- ceive attention in many rehabilitation programs. Radiation effects can be more subtle and appear years later, particularly in patients treated in childhood." Radiation of bones in young chil- dren, for example, can retard growth and pro- duce scoliosis and other deformities in later life; l6 comparable treatment in adult patients would have fewer skeletal effects. With chemo- therapy, common toxic effects such as myelo- suppression, gastrointestinal dysfunction, and dermatitis are usually transient. However, indi- viduals have been reported with drug-associated irreversible failure of kidneys, heart, lungs, liver, and reproductive and other organs.' In this series, several patients died with failure of a vital organ years after treatment of an advanced can- cer with multiple modalities.

Genetic Effects Certain cancers show a strong hereditary ten-

dency. '' Children and young adults who survive the inherited form of a cancer can transmit the condition to their progeny. Moreover, systemic chemotherapeutic agents and gonadal irradia- tion have shown mutagenic properties in labora- tory systems, though not directly in the offspring of exposed persons. Among 107 pregnancies in- volving patients in the present series, no excess of fetal losses, major birth defects, tumors, or

other serious chronic diseases were detected. l1

However, the available studies are too small to fully evaluate genetic effects.61'

Psychological and Social Effects Cancer can have profound psychological and

social impacts on patients, Deleterious effects have been reported in association with cancer diagnosis, therapy, and terminal i l l nes~ . '~~ For patients who remain in continuous long-term remission, actual or perceived threats to health and survival may persist.21 O n the other hand, several reports have concluded that most patients can make adequate adjustments to re- sidual effects of

Recently, a questionnaire study was made of the education, occupation, and health care utili- zation of 142 patients in the registry now ages 18 years and over.13 The majority in the series have attended college. Many are presently employed as professionals or managers, and are raising a family. In other studies, patients who were suc- cessfully treated for cancer at an older age have also shown satisfactory work performance at home and on the job.

Retrospective data on medical care of the 142 patients showed that follow-up examinations at the SFCI clinic focused on possible tumor recur- rence and gross abnormalities at treated sites. Little mention was made in the records of sec- ondary psycho-social effects. Also, nearly 40% of the series has not returned to the clinic for eval- uation in the last 2 years.

Comments Data from available studies suggest potential

for high quality of survival of most forms of cancer. Nevertheless, successfully treated

$ w o Q 10 I

5 10 15 20 25 30 35 YEARS

FIG. 1. Observed and expected probabilities of a second malignancy in the 2 decades of study (5-24 years after diagnosis of a childhood cancer).

1778 CANCER April Supplement 1977 Val. 39

patients are at high risk of diverse late effects of neoplasia, and should be followed for life. How- ever, patients in the present series often changed physicians on reaching adulthood, entering col- lege, or moving to a new place of residence; individual practitioners may also move or retire during a period of many years. In addition, patients may develop complex medical problems that require treatment by medical oncologists, surgeons, rehabilitation physicians, and other consultants.

Cancer centers can assist individual oncolo- gists and other practitioners in providing the continuity and range of services required during follow-up for a lifetime. The registry of survivors was established at the Sidney Farber Cancer Institute to help improve care of our patients. The registry is used to maintain closer contact with patients and their primary physicians, and to arrange for regular return visits to the clinic. For purposes of clinical research, the registry is

a repository for data on sequelae of cancer, in- cluding disorders associated with newer forms of tumor therapy, e.g., encephalopathy after irra- diation and chemotherapy for central nervous system leukemia.I7 In addition, it provides a means for assessment of availability and utiliza- tion of health care, and for planning additional services. To date, medical records files have been reviewed to identify survivors of childhood cancer. Data on diagnosis, treatment, and late effects have been abstracted, coded, and com- puterized for easy retrieval.

Development of the registry of survivors has fostered a close working relationship between epidemiologists who maintain the data files, and clinicians who evaluate the consequences of childhood neoplasia. This collaboration has yielded new findings on sequelae of curative tu- mor therapy in man, and presents new opportu- nities for prevention and early treatment of mor- bid effects of cancer therapy.

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