Risk-adapted therapies reduce long-term toxicity in pediatric Hodgkin lymphoma
The use of risk-adapted therapies for pediatric Hodgkin lymphoma has significantly reduced the incidence of serious long-term health problems among survivors, according to a study published in Journal of Clinical Oncology.
“Pediatric oncologists and radiation oncologists have worked diligently over the last few decades to improve cure rates for Hodgkin lymphoma while reducing the long-term toxicity of therapy,” Kevin C. Oeffinger, MD, family physician, professor in the department of medicine and director of the Duke Cancer Institute Supportive Care and Survivorship Center at Duke University School of Medicine, told Healio. “We hypothesized that outcomes would be better in the more recent era and our hypothesis was confirmed. Risk-adapted therapy is working.”
Oeffinger and colleagues analyzed data of 2,996 Hodgkin lymphoma survivors (mean age, 35.6 years; range, 12-58;47.4% female; 82.6% white) from the Childhood Cancer Survivor Study who were diagnosed between 1970 and 1999 and had survived at least 5 years. Forty-eight percent of the cohort had been diagnosed when aged 15 years to 20 years.
Researchers examined the cumulative incidence of self-reported grade 3 to grade 5 chronic conditions, medically confirmed subsequent malignant neoplasms and cause of death based on the National Death Index, comparing the survivors by decade of diagnosis (1970-1979, n = 1,097; 1980-1989, n = 1,057; 1990-1999, n = 842) and key treatment exposures.
Researchers focused on three common groups of morbidity among Hodgkin lymphoma survivors: cardiopulmonary disease, subsequent malignant neoplasms and endocrinopathies.
Overall, 9.9% of the cohort had progressive disease or relapse and had received salvage therapy or hematopoietic stem cell transplant, and 22% had died.
Results showed the cumulative incidence of any grade 3 to grade 5 condition by age 35 years was 31.4% (95% CI, 29.2-33.5), with a higher cumulative incidence among females than males (41.3% vs. 23.1%; HR = 2.1; 95% CI, 1.8-2.4).
These data suggest it is “imperative” that clinicians attend to symptoms reported by female survivors, using screening and surveillance strategies to detect problems early, Oeffinger said.
“Women have a greater risk for subsequent cancers due to the vulnerability of breast tissue to radiation,” he said. “Also, importantly, women have a similar risk for heart disease as men — this is much different than in the general population, where men tend to have heart disease at a younger age than women.”
Oeffinger and colleagues found that from the 1970s to the 1990s, there was a 20% reduction (HR = 0.8; 95% CI, 0.7-0.9) in decade-specific risk for a grade 3 to grade 5 condition, driven largely by a reduction in cumulative incidence at age 35 years of subsequent malignant neoplasms (10.9% in 1970s vs. 5.7% in 1990s).
Treatment modifications that led to the reduction in risk for subsequent malignant neoplasms included the use of high-dose (≥ 35 Gy) radiation fields confined to the chest and neck, compared with high-dose, extended-field radiotherapy (HR = 0.5; 95% CI, 0.3-0.8), although this did not appear associated with significant changes in overall grade 3 to grade 5 conditions.
Also, reduction of radiation doses to less than 35 Gy when combined with a hybrid regimen, including both an anthracycline and alkylator, reduced risk for grade 3 to grade 5 conditions by 30% (HR = 0.7; 95% CI, 0.5-0.9) compared with high-dose extended-field radiotherapy without chemotherapy.
"Hodgkin lymphoma was one of the early success stories in the war on cancer. Because the disease is often very radiation-sensitive, cures could be achieved back in the 1960s with wide fields of high-dose radiation,” Oeffinger said. “However, we learned that that cure was tempered by the risk for subsequent cancers and heart disease. Because the mediastinal lymph nodes are often involved in disease, irradiating the chest area is often necessary. Needless to say, that generally exposes the heart, lungs and breast tissue to radiation and thus leads to the later complications we see.
“Innovations introduced by our radiation oncologists and physicists have led to the use of smaller and smaller radiation fields and with newer techniques aimed at reducing radiation damage to the surrounding normal tissues,” Oeffinger added. “We anticipate that this will lead to improved outcomes as patients treated with contemporary therapy are followed over the next few decades.”
Survivors who had salvage therapy and/or HSCT for recurrence had a 4.7-fold (95% CI, 2.8-7.8) higher risk for a grade 3 to grade 5 condition compared with survivors who only received a hybrid chemotherapeutic regimen, a risk researchers noted was similar to that of survivors treated with high-dose, extended-field radiotherapy (HR = 1.2; 95% CI, 0.9-1.5).
Overall, researchers estimated that use of a contemporary regimen for low- to intermediate-risk Hodgkin lymphoma would lead to a 40% reduction in risk for a grade 3 to grade 5 condition compared with high-dose chest radiotherapy plus an anthracycline or alkylator (HR = 0.6; 95% CI, 0.4-0.8).
Oeffinger and colleagues noted the analysis does not “provide a full picture” of the trade-offs between therapeutic regimens because it was limited to 5-year survivors, and that it’s essential in balancing risks and benefits to remember that patients who relapse have a higher risk for serious late effects.
“There is a tenuous balance between our goal of reducing the intensity of upfront therapy and the risk for progressive or recurrent disease,” Oeffinger said.
For more information:
Kevin C. Oeffinger, MD, can be reached at Duke University/Duke Cancer Institute, 2424 Erwin Drive, Suite 601, Durham, NC 27705; email: kevin.oeffinger@duke.edu.
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