Second malignant neoplasms among survivors of pediatric Hodgkin disease treated with low-dose radiation (15-25.5 Gy) and chemotherapy

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2009

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Presenter: M.M. O'Brien
Presenter's Affiliation: Standford University
Type of Session: Scientific

Background

  • There has been a steady improvement in the survival rates of pediatric patients with Hodgkin's disease as more effective treatment and more accurate staging techniques have become available in the last few decades.
  • As the number of Hodgkin's disease (HD) survivors increases, we are seeing an increased number of late-term toxicities, including second malignant neoplasms (SMN), which are the most common cause of death in these patients.
  • It is well-known that the occurrence of second malignant neoplasms in these patients is associated with both chemotherapy and radiation.
  • Current published studies that have reported rates of second malignancies in pediatric patients with HD were treated with radiation 20-30 years ago with radiation doses often exceeding 40 Gy.
  • Modern protocols use much lower doses of radiation in children with HD, however these studies have been limited by short follow up (median f/up is approximately 10 years).
  • While it is theorized that lower radiation doses may be associated with lower SMN risk, long-term follow-up of children treated with low-dose radiation is lacking. Therefore, we do not have adequate data on second malignancy risk in these patients.
  • Pediatric HD patients at Standford University have been routinely on an in-house protocol where low dose RT (15-25.5 Gy) and chemotherapy are used. The main objectives of this protocol were to decrease the risk of complications from radiation for these patients and see a benefit in efficacy.
  • This retrospective cohort study was performed to examine the occurrence of SMNs among pediatric HD survivors treated at Stanford with chemotherapy and low-dose radiation from 1970 to 1990.
    • The hypothesis of the current study was that lower radiation doses would lower SMN incidence and provide a longer latency period the development of SMNs.

Materials and Methods

  • Pediatric HD patients at Standford were treated on the Ped HD1 protocol from 1970-1982, in which patients received 6 cycles of MOPP (mechlorethamine, vincristine, prednisone, procarbazine) with 15-25.5 Gy (dependent on bone age) radiation ± 10 Gy boost. Children on HD1 had to have a bone age< 15 years and radiation was given to a modified involved field. 
  • From 1982-1990, they were treated on the Ped HD2 protocol with 3 MOPP and 3 ABVD cycles (doxorubicin, bleomycin, vinblastine, dacarbazine) with 15 Gy radiation ± 10 Gy boost to bulky disease. These children had were age <19 and also received radiation to a modified involved field. 
  • Follow-up was obtained through 9/1/2007 by the form of questionnaires.
  • A thorough central review of pathology reports of secondary malignancies was performed.
  • Standardized incidence ratios (SIRs) and absolute excess risk (AER) for SMN were calculated using the SEER9 database (1973-2004).
  • Kaplan-Meier method was used to determine the cumulative SMN incidence.
  • Univariate associations were evaluated with the chi-square test or t-test, and multivariate analysis was performed with Cox proportional hazards regression using chronological age as the time scale.

Results

  • 110/112 patients achieved remission; median follow-up was 20.6 years.
  • In the Ped HD1 protocol, the median age was 10.5 years and the median mantle field radiation dose was 20 Gy. The median follow-up for this group was 25.4 years.
    • 4 patients in this group developed secondary leukemia, and 6 patients developed solid tumors (2 breast, 2 thyroid, and 2 other).
  • In the Ped HD 2 protocol, the median age was slightly higher at 12.4 years. The median mantle field radiation dose was 20 Gy and 90% of patients got below 25.5 Gy. Median f/up was 19 years.
    • No patients has secondary leukemias, 11 patients developed solid secondary malignancies (thyroid, breast and sarcoma).
    • The median time to development of SMN was 15.5 years.
  • In total, of all patients treated on these 2 protocols, fifteen patients developed 17 secondary solid tumors (5 thyroid carcinomas, 6 breast carcinomas, 4 sarcomas, 1 bladder paraganglioma, 1 melanoma) at a median of 15.4 years.
  • All solid tumors except the melanoma occurred within or at the margin of radiation fields, ranging in dose from 15-26.5 Gy.
  • There were no cases of lung, gastric, or colorectal carcinoma.
  • Cumulative incidence of any SMN is 17% (95%CI 10.5-26.7) at 20 years following HD diagnosis. For solid SMNs, the cumulative incidence was 14.3% at 20 years.
  • Overall, the SIR for any SMN is 22.9 (95%CI 14.2-35) with an AER of 93.7 cases per 10,000 person-years.
  • The analysis of risk factors for SMN development was limited by the small cohort size.
    • However, in univariate analysis, older age at HD diagnosis (>11 years) and female gender were associated with SMN (p<0.05).
    • In multivariate analysis, there were no statistically significant associations.

Author's Conclusions

  • The incidence of SMN in pediatric HD survivors continues to be elevated following treatment with chemotherapy and low-dose radiation.
  • Low-dose radiation does not prevent or delay the occurrence of solid SMNs.
  • The cumulative incidence rates and SIR estimates of sarcomas, breast, and thyroid carcinomas occurrence seen in this study were similar to cohort previously treated with high-dose radiation on trials like LESG, CCSS, and the Nordic trial.
  • Future work should involve:
    • Refinement of XRT techniques.
    • Radiation dose reduction or elimination.
    • Studies of genetic predisposition of patients to SMNs.

Clinical/Scientific Implications

  • As the treatment of Hodgkin’s disease improves, children are surviving longer due to higher rates of cure. This brings about a growing concern over the long-term toxicity of treatment that involves both radiation and chemotherapy.
  • One of the most worrisome and lethal late-term toxicities in these patients is the development of a second malignant neoplasm.
    • SMNs may be caused by chemotherapy or radiotherapy, as both can lead to tumor formation. They may also be due genetic predisposition.
  • The results of this retrospective study were negative, and show that despite using much lower doses of radiation, the incidence of SMN in pediatric HD survivors continues to be high following treatment with chemotherapy and radiation. Moreover, the rates seen in this study were similar to previous studies where larger doses of radiation were used.
  • The elevated risk of SMNs has largely been attributed to the effects of radiation by the authors of this study. However, we must remember that the chemotherapy agents used in these protocols are also carcinogenic and may be contributing in large part to the elevated risks of SMNs in these patients.
    • Furthermore, there are likely other contributing factors including an impaired immune system related to treatments or the disease itself and/or genetic susceptibility in some of the patients.
  • We must be cautious when trying to reduce radiation treatment doses for pediatric patients with HD because this may come at the expense of a higher relapse rate, which has been seen when chemotherapy is used alone.
    • Our foremost goal is improving the Hodgkin's disease cure rate, and therefore we must balance the need to reduce late toxicities such as SMNs with making sure we continue to deliver appropriate therapy for the patients’ initial HD.
  • One limitation of this retrospective study is that follow-up data is based on patient questionnaire and there is varying follow-up time of the different treatments as therapeutic approaches for Hodgkin's disease evolve over time.
  • Our goal in guiding practices to reduce the rate of SMNs should be to continue to identify other non-treatment risk factors for the development of second malignancy after Hodgkin's disease treatment.
    • Modifiable risk factors (e.g. tobacco use, sun exposure, dietary habits) should be identified as these patients become older.
    • Counseling and behavioral modification both at the time of Hodgkin's disease diagnosis and during follow-up may serve to lower the risk.
  • Patients should also be targeted for more vigilant follow-up and more intensive cancer screening.

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