Less aggressive treatment of primary cancer in childhood, together with careful screening to detect the late effects of cancer therapy, have essentially halved the risk for all-cause late mortality over 3 decades in children who survive their cancer for more than 5 years, an analysis of the Childhood Cancer Survivor Study (CCSS) indicates.
The study was published online January 13 in the New England Journal of Medicine.
"The reason we've lowered therapy along the way is that we've discovered that some children were at low risk for relapse and they needed less therapy," principal investigator Greg Armstrong, MD, from St. Jude Children's Research Hospital in Memphis, Tennessee, told Medscape Medical News.
The classic story would be acute lymphoblastic leukemia, he added.
"In the 1970s, we were using cranial radiation and we learned that cranial radiation wasn't needed, so by the 1990s, less than one in five children were getting that radiation," he said. "Reduction in that therapy also reduced the risk of late effects, plus, at the back end of their lives, it extended children's lives so they're not getting second cancers."
The decline in late mortality was not seen in every type of cancer. "For children with high-risk cancers or those with metastatic disease and in many of our children with brain tumors, therapies are just as intensive today because we haven't been able to back off on some of these treatments," Dr Armstrong explained.
"But for children with some of the common cancers, like acute lymphoblastic leukemia and Hodgkin's lymphoma, it's important for parents to realize that therapies today are not nearly as intensive as they were before," he added. "It drives the fact that we need to continue to identify low-risk patients in whom we can reduce therapy. For children who are being treated now and in the more recent eras, it's a bright future for our more modern survivors.
Study Details
An earlier analysis of the same cohort revealed that reductions in the overall use of radiation and chemotherapy, along with dose modifications, significantly reduced the risk of dying from the late effects of cancer treatment, as reported by Medscape Medical News.
The CCSS involved 34,033 patients diagnosed before the age of 21, all of whom survived at least 5 years. The median follow-up was 21 years (range, 5 - 38 years), and initial treatment was received from January 1970 to December 1999.
"Overall, 57% of the cohort received radiotherapy," Dr Armstrong reported. However, more of the survivors were treated in the 1970s than in the 1990s (77% vs 41%).
In contrast, more survivors received chemotherapy — including anthracyclines and alkylating agents — in the 1990s than in the 1970s, but the mean cumulative dose of chemotherapeutic agents used declined steadily over time.
Table 1. Mean Cumulative Dose of Anthracycline Chemotherapy
| Diagnosis | 1970s, mg/m² | 1980s, mg/m² | 1990s, mg/m² |
| Acute lymphoblastic leukemia | 289 | 217 | 158 |
| Hodgkin's lymphoma | 295 | 212 | 193 |
| Wilms' tumor | 267 | 244 | 179 |
Fifteen years after diagnosis, the cumulative incidence of death from any cause in children who survived their cancers was higher in those diagnosed in the 1970s than in those diagnosed the 1980s and 1990s (10.7% vs 7.9% vs 5.8%; P < .001).
"Across these decades, the cumulative incidence of death from recurrence or progression of a primary cancer decreased as well" — from 7.1% in the 1970s to 4.9% in the 1980s and 3.4% in the 1990s (P < .001), the investigators report.
In parallel, death from "health-related causes" — which included deaths from the late effects of cancer therapy — decreased from 3.1% in the 1970s to 2.4% in the 1980s to 1.9% in the 1990s (P < .001).
For these health-related causes of death, there were significant reductions in death from malignant neoplasms and from cardiac and pulmonary-related events, Dr Armstrong added.
Table 2. Cumulative Incidence of Death at 15 Years in 5-Year Survivors After a Primary Cancer Diagnosis
| Cause of Death | 1970–1974 | 1975–1979 | 1980–1984 | 1985–1989 | 1990–1994 | P Value |
| Any | 12.4 | 12.4 | 8.8 | 6.9 | 6.0 | <.001 |
| Recurrence or progression | 8.4 | 6.2 | 5.5 | 4.2 | 3.6 | <.001 |
| Subsequent neoplasm | 1.8 | 1.5 | 1.3 | 1.3 | 1.0 | <.001 |
| Cardiac-related event | 0.5 | 0.4 | 0.3 | 0.1 | 0.1 | .001 |
| Pulmonary-related event | 0.5 | 0.2 | 0.3 | 0.1 | 0.1 | 0.04 |
Specific Cancers
There were also significant reductions in deaths from health-related causes over the 3 decades, according to analyses of specific cancers, including acute lymphoblastic leukemia — from 3.2% in the early 1970s to 2.1% in the 1990s (P < .001).
The same was true for Hodgkin's lymphoma, where death rates dropped from 5.3% in the 1970s to 2.6% in the 1990s (P = .006); Wilms' tumor, where death rates dropped from 2.6% in the 1970s to 0.4% in the 1990s (P = .005); and astrocytoma, where death rates dropped from 4.7% in the 1970s to 1.8% in the 1990s (P = .020).
There were also significant reductions in cardiac mortality over the 3 decades for each of these cancers, reflecting reductions in the mean cumulative dose of anthracycline chemotherapy used over time.
Reductions in the use of radiotherapy for each of these four cancers over the time have also been dramatic.
Table 3. Percentage of Patients Receiving Radiotherapy for Specific Cancers Over 3 Decades
| Cancer | Radiotherapy Site | 1970s, % | 1980s, % | 1990s, % |
| Acute lymphoblastic leukemia | cranial | 85% | 51% | 19% |
| Hodgkin's lymphoma | chest | 87% | 79% | 61% |
| Wilms' tumor | abdominal | 78% | 53% | 43% |
| Astrocytoma | cranial | 55% | 50% | 24% |
The investigators point out, however, that reductions in treatment exposure for children with Hodgkin's lymphoma and astrocytoma might not fully explain the reductions in health-related mortality seen over the 3 decades. At least part of the explanation lies with the increased use and accuracy of screening methods, which would be expected to favorably influence outcomes.
This study was funded by the National Cancer Institute and by the American-Lebanese-Syrian Associated Charities.
N Engl J Med. Published online January 13, 2016. Abstract
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Cite this: Late Mortality in Pediatric Cancers Halved in Recent Decades - Medscape - Jan 18, 2016.
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