Breast Cancer After Supradiaphragmatic Irradiation for Hodgkin's Disease; Risk Analysis and Possible Surveillance Strategies

Reviewer: Charles B. Simone, II, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 31, 2007

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Presenter: M. A. Alm El-Dina, MD
Presenter's Affiliation: Massachusetts General Hospital
Type of Session: Scientific

Background

  • Radiation therapy imparts an antitumor effect through the formation of free radiations. Radiation can also have effects on normal tissues.  It can also induce cancer in long-term cancer survivors, particularly those treated in childhood.  Such secondary malignancies generally present at least five (hematologic cancers) to 10 (solid tumors) years following irradiation. Risks of developing radiation-induced malignancies are higher when patients also received chemotherapy, particularly alkylating agents.
  • Hodgkin’s disease is one of the first malignancies that was found to be curable with radiation therapy. However, published reports have since suggested that long-term survivors are at an increased risk of treatment toxicities and secondary malignancies. Prior investigators have noted an increased risk of radiation-induced malignancies among females Hodgkin’s patients who received irradiation when compared to male patients.
  • This study was conducted to assess the risk of breast cancer following supradiaphragmatic irradiation (SDI) for Hodgkin’s disease and to recommend appropriate breast cancer surveillance measures in these women.

Materials and Methods

  • Medical records were retrospectively reviewed and analyzed for 249 women younger than 60 years of age who were treated for clinical or pathologic Stage I or II Hodgkin’s disease at Massachusetts General Hospital between 1964 and 2001. 
  • Patient and treatment characteristics were analyzed to evaluate for an effect on the development of secondary breast cancers.

Results

  • Among study participants at a median follow-up of 15.2 years, SDI was administered at a median age of 26.1 years, with a range from 5.7 to 59.3 years.  
  • 36 patients developed breast cancer, 11 of whom had bilateral disease. The median age at the diagnosis of breast cancer was 43.7 years (range 22.2 to 66.2 years).
  • The median interval of breast cancer development after SDI was 18.4 years. The earliest case of breast cancer that was likely attributable to prior radiation therapy occurred 6.4 years following treatment. 
  • The standardized morbidity ratio (SMR) for the first breast cancer after SDI, which is the number of observed breast cancer cases in the study cohort divided by the number of expected breast cancer cases among the study population, was calculated and standardized using SEER data. SMR among all participants was found to be 8.62.
  • According to age at SDI, the SMR was 68.8 for women younger than 20 years, 9.2 for women 20–29 years, and 4.0 for patients 30 years or older (p<0.0001).
  • There was a significantly higher risk of developing breast cancer 15 years after SDI when compared to the risk within 15 years of SDI (p=0.005). For this study population, 75% of events occurred between 10 and 20 years following SDI. 
  • No significant correlation was seen between the development of breast cancer and the dose of radiation therapy, radiation field arrangement, administration of chemotherapy, use of alkylating agents, history of splenectomy, or a mediastinal mass.
  • 19 of the 36 patients who developed breast cancer were treated at the investigative institution and accounted for 28 cases. Patients developed ductal carcinoma in-situ (9/28), invasive ductal carcinoma (17/28), mixed ductal and lobular features (1/28), and unknown pathology (1/28).
  • Cases of breast cancer were detected via mammography (55.6%), self-examination (25.9%), pathologic evaluation following elective mastectomy (11.1%), and clinical examination (7.4%). Most cases were located laterally.

Author's Conclusions

  • Although an increased risk of developing breast cancer is noted by 10 years following radiation therapy for Hodgkin’s disease, the risk is significantly higher 15 years after SDI.
  • Risk of breast cancer was found to be inversely related to age at SDI.
  • Patients should be counseling regarding primary and secondary prevention due to their increased risk of developing breast cancer.
  • Since these patients are more likely to developed bilateral breast cancers, patients should be counseled regarding bilateral prophylactic mastectomy.
  • By 10 years following SDI for Hodgkin’s disease, breast MRI, chemoprevention, and intensive screening should be strongly considered in all patients.

Clinical/Scientific Implications

With an increasing population of long-term cancer survivors, late treatment effects, particularly radiation-induced malignancies, are becoming more frequently documented. Secondary malignancies are becoming more frequently encountered among Hodgkin’s disease patients, as these patients are generally young at diagnosis and achieve high cure rates. As a result, current therapeutic strategies for patients with Hodgkin’s disease are attempting to minimize irradiation doses and treatment volumes. However, little data exists quantitating the rates of breast cancer among Hodgkin’s disease survivors, and appropriate surveillance recommendations are lacking. Previous investigators have found that the development of secondary malignancies following radiation therapy is dependent on age at irradiation, time since radiation administration, radiation dose, field arrangement and radiation technique, the administration of chemotherapy and alkylating agents, and mediastinal radiation. In this investigation, only age at irradiation and time since radiation therapy were found to contribute significantly towards the development of radiation-induced breast cancer. Due to the high risk of secondary breast cancers 10 years after SDI, this study demonstrates a need for vigorous surveillance and screening in survivors of Hodgkin’s disease who received irradiation. 

Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.


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