Study Confirms Long-Term Risk of Secondary Cancers in Pediatric Hodgkin Lymphoma Survivors

Smita Bhatia, MD, MPH

The relative risk of developing a solid subsequent malignant neoplasm (sSMN) remained elevated in survivors of childhood Hodgkin lymphoma, according to extended follow-up of more than 25 years from the Late Effects Study Group (LESG) cohort published in Cancer.

“It’s important that clinicians and providers are aware of this risk and who it affects—cancer risk doesn’t disappear because people become a certain age or survive their first cancer,” lead investigator Smita Bhatia, MD, MPH, professor and vice chair of outcomes for pediatrics at the University of Alabama at Birmingham Comprehensive Cancer Center, said in a statement. “They need to be screened and treated accordingly.”

The multinational LESG cohort of children diagnosed with Hodgkin lymphoma between 1955 and 1979 at ≤16 years was established in 1979. In 1994, the cohort was expanded to include 1380 patients across 15 institutions, the first update was reported, and follow-up was extended to 11 years.

In 2001, the second analysis was reported, pushing the median length of follow-up to 17 years. A total of 11 LSEG institutions participated in the third study update, and provided investigators with evidence of clinical status of patients since 2001, with data pertaining to disease recurrence, vital status, and development of new solid malignancy.

Patients were separated into 3 groups based on the therapy they had received as part of their primary lymphoma treatment or as salvage therapy for disease recurrence: radiotherapy (RT) alone, chemotherapy alone, or radiotherapy and chemotherapy.

The relative risk of developing an sSMN was estimated with proportional subdistribution hazards regression, which used death as a competing risk and calendar time as the time scale. Explanatory variables, such as age at the time of diagnosis of Hodgkin lymphoma (0-9 years versus 10-16 years); sex; doxorubicin exposure; alkylating agent score (≥2 or <2); and localized radiotherapy to the chest, abdomen or pelvis, or neck, were assessed for their impact on developing an sSMN without statistical selection.

The analysis accounted for 1136 patients who were diagnosed with Hodgkin lymphoma between 1955 and 1986. The median age at the time of diagnosis for these patients was 11 years (range, birth—16 years) with 23,212 person-years of follow-up from the time of primary diagnosis. Sensitivity analyses were done to account for the 595 patients who had not experienced an event (sSMN or death).

A total of 162 patients developed a collective total of 196 sSMNs, which included breast cancer, thyroid cancer, colorectal cancer (CRC), lung cancer, basal cell carcinoma (BCC), or other/unspecified, resulting in a 26.4% cumulative incidence of any sSMN at 40 years after primary diagnosis (95% CI, 22.4%-30.5%). This translated to a 14-fold increase in the risk of developing an sSMN compared with the general population (standardized incidence ratio, 14.0; 95% CI, 12.0-16.3). Although BCC was identified as an sSMN, it was excluded from further analysis because it was not reported to the Surveillance, Epidemiology, and End Results Program database. By age 50 years, the cumulative incidence of breast cancer, lung cancer, colorectal cancer, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk.

Across all cohorts, a multivariable analysis indicated an increased risk of sSMN among females (HR, 1.8; 95% CI, 1.3-2.5) and those who received radiotherapy (HR, 4.8; 95% CI, 1.8-19.7).

“These findings support the need for continued surveillance of patients with Hodgkin lymphoma, regardless of the era in which they were treated,” wrote study investigators.

Of the 54 individuals who developed breast cancer, 42 were women. The median age at the time of their primary and subsequent diagnoses were 13 years (range, 6-15) and 37 years (range, 24-48), respectively, resulting in a median age of 25 years (range, 10-40 years) between diagnoses. Of the 42 women, 9 developed contralateral breast cancer after a median of 5.9 years (range, 1.6-10.5).

Overall, these patients had a 25.8-fold increased risk of developing breast cancer compared with the general population (95% CI, 19.3-fold—33.5-fold; P <.001). Patients who had been diagnosed with Hodgkin lymphoma between the ages of 10 and 16 were approximately 5 times as likely to develop a breast sSMN than patients <10 years relative to the general population (P = .004). However, exposure to a high-dose alkylating agent lowered the risk of developing breast cancer (HR, 0.5; 95% CI, 0.3-0.9).

After a median of 28 years following primary diagnosis (range, 12-34), 11 cases of subsequent lung cancer were reported; 10 patients were male, although all had received chest RT. The median age at the time of lung cancer diagnosis was 41 years (range, 22-46). Although the cumulative incidence of lung cancer was 2.3% by age 50, males were at a 26.7-fold increased risk of developing lung cancer compared with the general population (95% CI, 13.4-fold—16.7-fold). Further, those who had been treated with RT <10 years of age were at an increased risk of developing lung cancer. Conversely, females were at a 3.3-fold increase risk of developing lung cancer relative to the general population (95% CI, 0.2-fold–14.6-fold).

CRC was also identified in 15 patients after a median of 25 years (range, 15-45) after an initial diagnosis of Hodgkin lymphoma. Although the cumulative incidence was relatively low at 2.7% at 50 years, the group was at a 16.2-fold increased risk of developing the malignancy compared with the general population (95% CI, 9.3-fold—25.8-fold). Contrary to the subset of women who went on to develop breast cancer, a multivariable analysis revealed that exposure to high-dose alkylating agents was found to be a risk factor associated with subsequent CRC development (HR, 5.1; 95% CI, 1.3-33.6). Moreover, abdominal/pelvic RT was found to be another independent risk factor (HR, 3.6; 95% CI, 1.1-16.1).

The last identifiable malignancy that investigators included in their analysis was thyroid cancer. After a median follow-up of 27 years after a Hodgkin lymphoma diagnosis (range, 7-45 years), thyroid cancer was identified in 30 patients. The median age at the time of subsequent diagnosis was 34.5 years (range, 13-53 years). Compared with the general population, these patients harbored a 27.7-fold increase in the risk of developing thyroid cancer compared with the general population (95% CI, 18.9-fold—38.8-fold). In this cohort, women (HR, 2.1; 95% CI, 1.0-4.4) who had been treated <10 years (HR, 3.0; 95% CI, 1.4-6.7) held a higher risk of subsequent development of thyroid cancer. Treatment with neck RT <10 years compounded this risk.

The risk of secondary malignancy among childhood survivors of Hodgkin lymphoma has long been established, but the investigators wrote that this study confirmed the continual risk of future malignancy beyond 25 years after a diagnosis of Hodgkin lymphoma, underscoring the need for appropriate screening techniques for those individuals at highest risk.

“The results of the current study provide evidence for screening parameters in these high-risk subgroups, both with respect to a Hodgkin lymphoma diagnosis as well as the attained age of the survivor of Hodgkin lymphoma,” the investigators concluded.

Holmqvist A, Chen Y, The J, et al. Risk of solid subsequent malignant neoplasms after childhood hodgkin lymphoma—identification of high-risk populations to guide surveillance: a report from the late effects study group. [published online ahead of print December 17, 2018]. Cancer. doi: 10.1002/cncr.31807.