With the progressive improvement in the survival of children with acute lymphocytic leukemia, the question of late effects of therapy on normal tissue becomes a more significant problem. In a review of a large number of children who have received long-term treatment with chemotherapy, especially methotrexate, a significant increase in the serious effects on hepatic, pulmonary, and skeletal tissue was noted. A review of the methotrexate-induced acute and chronic changes seen in these tissues is the basis for this report.
Late effects of therapy were evaluated in 50 children surviving orbital rhabdomyosarcoma following treatment on Intergroup Rhabdomyosarcoma Study I. All patients had microscopic or gross tumor present following surgery and subsequently received radiotherapy and various combinations of chemotherapeutic agents. Problems in the eye included infections and functional and structural changes. Decreased vision in the treated eye was the most common functional problem and in most patients related to cataract formation, which occurred in 90% of eyes. Changes in the cornea and retina were also seen. Bony hypoplasia of the orbit and facial asymmetry were present in one half of the children. Gonadal development was normal. Statural growth was retarded in 61% of the patients. All children were in school, with five having learning or behavioral problems. One child developed acute myeloblastic leukemia. The excellent survival in patients with orbital rhabdomyosarcoma provides support for treatment programs that use multiple-agent chemotherapy and radiotherapy and do not include orbital exenteration initially.
A recent experience made us aware of a potential hazard from equipment used in the care of newborn infants. A newborn boy who weighed 1,585 gm after 36 weeks' gestation and thus was small for date, was cared for in an Air-Shields C-86 Isolette, Intensive Care Model. He became very active and was able to change position inside the incubator. On several occasions he was seen with his head or feet pressed against the sides of the incubator.
Peripheral blood lymphocyte size distribution curves in normal children and adults revealed a very constant pattern with a modal class size of 9.5μ to 10.4μ and a curve slightly skewed to the right. In acute infections characterized by abnormal lymphocytes an irregular alteration in the size distribution curve was seen. This pattern returned to normal following recovery. In children with immunologic defects abnormal distribution curves were seen. These abnormalities were unrelated to absolute lymphocyte count or to the clinical condition at the time measurements were determined. Patients with combined immunodeficiency states showed a biphasic abnormality with two distinct peaks at 13μ and 15μ. This was most pronounced in ten patients with the Wiskott-Aldrich syndrome. In one of these patients the curve became normal following successful bone marrow transplantation.
The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment.Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (<1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (> or =3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group.The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively.Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.
In 1977, a program of early, wide-field radiation therapy (RT) to the central nervous system and repeated lumbar intrathecal (IT) medications along with systemic chemotherapy was begun by the Intergroup Rhabdomyosarcoma Study (IRS) for patients younger than 21 years of age with cranial parameningeal sarcoma and a high risk of meningeal extension. From 1977 until 1987, 149 eligible patients with high-risk cranial parameningeal sarcoma were enrolled in IRS trials. None had evidence of lower extremity or sphincter impairment at diagnosis. Five of the 149 (3.4%) had ascending myelitis at 5.5 to 9 months after the initiation of therapy, with loss of sphincter control and inability to walk; this progressed to severe flaccid quadriparesis and necessitated longterm ventilatory support in 4. All five had received vincristine, dactinomycin, cyclophosphamide, and doxorubicin; four also had received cisplatin and three also had received etoposide. All patients received 4770 to 5500 cGy to the primary tumor, and four patients received 3000 cGy of cranial RT. Three patients received cervical RT and two received spinal RT. The patients also received four to seven courses of IT methotrexate, hydrocortisone, and cytosine arabinoside. Three patients died: one after local tumor recurrence with central nervous system extension and two without known recurrence. In one of the latter patients, the results of an autopsy showed necrosis of the cervical spinal cord and caudal medulla. Although the exact cause of this complication is unclear, no additional cases have been reported to the IRS since the protocol was revised in 1987 to reduce the doses of the IT drugs and to limit them to four courses each. Cancer 1992; 69:1498-1506.
A recent experience made us aware of a potential hazard from equipment used in the care of newborn infants. A newborn boy who weighed 1,585 gm after 36 weeks9 gestation and thus was small for date, was cared for in an Air-Shields C-86 Isolette, Intensive Care Model. He became very active and was able to change position inside the incubator. On several occasions he was seen with his head or feet pressed against the sides of the incubator.
