The CancerWeb Report, What's New In Cancer: October, 1996
Childhood Cancers

• Long-term adverse effects of cancer therapy in children - Several articles in the October, 1996 issue of the Journal of Clinical Oncology included information on the long-term side-effects of cancer treatment in children. Since chemotherapy and multimodal therapy of many childhood cancers has been significantly more successful than for cancer in adults, there is a burgeoning population of patients cured of their original childhood cancers, but facing the late complications of their treatment. Identification of components responsible for specific side-effects will help in the design of treatment schedules that provide substitutes for the offending agent. However, it may not always be possible to reduce the problem of long-term effects while preserving high survival rates intact, and we should keep in mind that these patients would not have survived for this length of time without treatment.
  1. Secondary Leukemia - Researchers at Southwestern Medical Center in Dallas treated children with acute lymphoblastic leukemia by intensive divided-dose methotrexate during the first 16 months of therapy with 6-mercaptopurine and asparaginase (initially also with etoposide and cytarabine), followed by 30 months of weekly methotrexate. Event-free survival at 4 years was 73% for standard-risk and 60% for high-risk patients. Whereas high-risk patients tended to have relapses in the central nervous system (16 of 93 patients), the 150 standard risk patients had secondary acute myelocytic leukemia (AML; 12 cases) as the most common side-effect. AML is associated with use of etoposide; methotrexate could conceivably enhance the amount of DNA damage. Mexican-American patients were most prone to developing AML with 7 cases out of 51 versus 9 of 192 for other patients. This may be connected with the higher incidence of abnormalities on chromosome number 11 noted in US Hispanic children with leukemia (Winick, J Clin Oncol 14:2803, 1996). It is interesting that etoposide has been implicated in second tumors in patients treated for other cancers. For example, an article in the October, 1996 issue of the Journal of Clinical Oncology implicates etoposide as a factor in second tumors in women treated for gestational trophoblastic tumors (Rustin, J Clin Oncol 14:2769, 1996).

  2. Secondary Sarcoma - The incidence of secondary sarcomas in patients successfully treated for Ewing's sarcoma approaches 22% after 20 years, with the dose of radiation implicated as the major causative factor. Researchers from St. Jude's Hospital in Memphis, the National Cancer Institue and the University of Florida, Gainesville, reviewed information on Ewing's sarcoma patients followed up for between 3 and 30 years. The overall rate for secondary sarcomas was 6.5% (9.2% for all second malignancies), but no sarcomas developed in those given less than 48 Gy of radiotherapy. (Kuttesch, J Clin Oncol 14:2818, 1996)

  3. Neuropsychologic Effects - A group at the M.D. Anderson Cancer Center in Houston carried out a prospective study of 99 children with malignant tumors, of whom 51 had received intrathecal chemotherapy, 48 had chemotherapy, and none had irradiation of the head. On a wide range of tests, all the treated patients showed a decline in perceptual-motor skills, but they remained within the normal range. Academic declines were more noticeable but the differences were not statistically significant. Effects were more pronounced at 5-11 than at 3 years after diagnosis. (Copeland, J Clin Oncol 14:2826, 1996)

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• Neuroblastoma, bone marrow purging can be carried out in vivo - The problem overhanging bone marrow transplantation where the treated patient is donating marrow to his or herself (autologous transplantation) is that tumor cells may be lurking in the marrow preparation. Reinfusing the marrow into the patient would then seed the patient with tumor after treatment had eradicated it. In the September, 1996 issue of CancerWeb Report, we described European work in lymphoma patients (See CancerWeb Report Volume 2 Number 9, "Further information on the marrow purging controversy" under Hematologic Malignancies) which suggested that purging of marrow removed from the patient, so called ex vivo purging, is unnecessary. However, abandoning purging is not likely to be entirely acceptable so an alternative is desirable. Finnish doctors claim in an article appearing in the October, 1996 issue of the Journal of Clinical Oncology, that conventional chemotherapy prior to harvesting the bone marrow can satisfactorily purge (in vivo purging) the bone marrow in patients with poor-risk neuroblastoma. An immunological-based fluorescence test was used to monitor how well the marrow had been cleared of neuroblastoma cells. Marrows were eventually purged in 19 of 23 children, and the overall 4-year disease-free survival was 53% after surgery with or without radiation and marrow transplantation. Survival reached 100% in those who were perfectly purged with only 2 courses of chemotherapy. (Saarinen, J Clin Oncol 14:2791, 1996)

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• Retinoblastoma, use of cyclosporin to avoid the damaging effects of radiation - Chemotherapy alone is not able to control intraocular retinoblastomas, tumors within the eye. In those patients with large or moderate sized tumor "seeds"in the central or anterior part of the eye especially, there is need for external-beam irradiation rather than laser, cryotherapy, or the more localized focal radiotherapy that are effective for small tumors. Unfortunately, it is children who develop these tumors, and the long expected life-span of those who are cured means that over the course of 30 years, radiation-beam treatment carries the risk of long-term effects such as a 35% risk of melanomas or of second tumors in the bone or brain, and a 90% risk of deformity of the orbit. The September, 1996 issue of Clinical Cancer Research included a multi-institutional study from Canada, the UK and the US, which claimed superior results without the use of external irradiation, by adding cyclosporin to the chemotherapy regimen of vincristine, teniposide and carboplatin. Chemotherapy responses were consolidated by using focal therapy only. The researchers had previously found high levels of P-glycoprotein in retinoblastomas. P-glycoprotein confers drug resistance, and cyclosporin is known to block this type of resistance. The 21 children with bilateral genetic-linked disease, showed a relapse-free survival of 76% at 3.3 years, rising to 92% for those newly-diagnosed. This compared with 45% relapse-free survival at 2.6 years in similar patients given chemotherapy and irradiation without cyclosporin. Even in those who were treated previously and relapsed, the survival figure was 50%. (Chan, Clin Cancer Res 2:1499, 1996)