Supradiaphragmatic Radiotherapy Research Articles

Review of the Welsh mammographic screening programme for women who underwent mantle irradiation for Hodgkin lymphoma

There is evidence that women who received supra-diaphragmatic radiotherapy (sRT) for Hodgkin lymphoma at a young age are at increased risk of developing breast cancer. This study reports the implementation and results of the breast screening programme for such women in South Wales, which offers screening to women eight or more years following treatment.

Breast Cancer Risk After Supradiaphragmatic Radiotherapy for Hodgkin's Lymphoma in England and Wales: A National Cohort Study

To investigate breast cancer risk after supradiaphragmatic radiotherapy administered to young women with Hodgkin's lymphoma (HL) in a much larger cohort than previously to provide data for patient follow-up and screening individualized according to treatment type, age, and time point during follow-up. Breast cancer risk was assessed in 5,002 women in England and Wales treated for HL with supradiaphragmatic radiotherapy at age < 36 years from 1956 to 2003, who underwent follow-up with 97% completeness until December 31, 2008. Breast cancer or ductal carcinoma in situ developed in 373 patients, with a standardized incidence ratio (SIR) of 5.0 (95% CI, 4.5 to 5.5). SIRs were greatest for those treated at age 14 years (47.2; 95% CI, 28.0 to 79.8) and continued to remain high for at least 40 years. The maximum absolute excess risk was at attained ages 50 to 59 years. Alkylating chemotherapy or pelvic radiotherapy diminished the risk, but only for women treated at age ≥ 20 years, not for those treated when younger. Cumulative risks were tabulated in detail; for 40-year follow-up, the risk for patients receiving ≥ 40 Gy mantle radiotherapy at young ages was 48%. This article provides individualized risk estimates based on large numbers for patients with HL undergoing follow-up after radiotherapy at young ages. Follow-up of such women needs to continue for 40 years or longer and may require more-intensive screening regimens than those in national general population programs. Special consideration is needed of potential measures to reduce breast cancer risk for girls treated with supradiaphragmatic radiotherapy at pubertal ages.

Toward Risk-Based Breast Cancer Screening and Prevention Strategies for Survivors of Hodgkin's Lymphoma: One Step Closer?

Toward Risk-Based Breast Cancer Screening and Prevention Strategies for Survivors of Hodgkin's Lymphoma: One Step Closer?

FGFR2 genotype and risk of radiation-associated breast cancer in Hodgkin lymphoma

AbstractWomen treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P = .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk.

Barrett Esophagus in Long-term Survivors of Childhood Solid Tumors

We report on 2 cases of long-term survivors of childhood solid tumors, who developed Barrett esophagus (BE) after treatment for neuroblastoma and Hodgkin lymphoma, respectively. Case 1: A stage 3 neuroblastoma was treated with surgery, carboplatin/etoposide chemotherapy, and supradiaphragmatic radiotherapy (30 Gy). Twelve years later, based on endoscopic and histologic findings, BE was diagnosed on the middle segment. Case 2: A stage IIIB Hodgkin lymphoma received mechloretamine, oncovin, procarbazine, prednisone/adriamycin, bleomycin, vinblastine, dacarbazine chemotherapy and supra/subdiaphragmatic radiotherapy (25 Gy). Nineteen years later, BE was diagnosed associated with an esophageal stricture. In long-term survivors of childhood tumors who had received chest/neck radiotherapy and chemotherapy, the risk of BE may be increased, therefore the diagnosis should be considered in the presence of gastroesophageal symptoms.

Locoregional Treatment for Breast Carcinoma after Hodgkin's Lymphoma: The Breast Conservation Option

Locoregional Treatment for Breast Carcinoma after Hodgkin's Lymphoma: The Breast Conservation Option

SU‐DD‐A2‐01: Mechanistic Model of Radiation Induced Cancer after Fractionated Radiotherapy: Fit to Breast Cancer Risk after Radiation Therapy for Hodgkin's Disease

Purpose: The strongly elevated risk of breast cancer after radiotherapy for Hodgkin's lymphoma has become a major concern for female survivors of this disease. The risk of breast cancer after Hodgkin's lymphoma has been mainly attributed to supradiaphragmatic radiotherapy. Women treated with mantle field radiation experience up to 30‐fold increased risks for breast cancer compared with their peers in the general population. As a consequence radiation volumes and dose prescription for the treatment of Hodgkin's lymphoma have been reduced. The aim of this study is to develop a dose‐response model for breast cancer using risk data from epidemiological studies Hodgkin's disease patients treated with radiation therapy. Materials and Methods: The linear‐quadratic model of cell kill is applied to normal tissues which are unintentionally irradiated during a cancer treatment with radiotherapy. Tumor induction is modeled such that each transformation process results in a tumor cell. The microscopic transformation parameter was chosen such that in the limit of low dose and acute exposure the parameters of the linear‐no‐threshold model for tumor induction were approached. Results: The differential equations describing carcinoma and sarcoma induction were solved analytically. Cancer induction in this model is a function of treatment dose, the cell kill parameters (a, b), the tumor induction variable (μ) and the repopulation parameter (R). The dose‐response relationship for breast cancer was derived based on (i) the cancer risk model described above, (i) the analysis of breast cancer induction after Hodgkin's disease, and (iii) the reconstruction of mantle field treatment plans for Hodgkin's patients treated with radiotherapy. The fitted model parameters for an a/b=3 Gy were a=0.067Gy‐1 and R=0.62. Conclusions: The developed model can be used to further optimize involved field radiotherapy for Hodgkin's lymphoma with regard to second cancer induction.

The UK national breast cancer screening programme for survivors of Hodgkin lymphoma detects breast cancer at an early stage

Background:Supradiaphragmatic radiotherapy (SRT) to treat Hodgkin's lymphoma (HL) at a young age increases the risk of breast cancer (BC). A national notification risk assessment and screening programme (NRASP) for women who were treated with SRT before the age of 36 years was instituted in the United Kingdom in 2003. In this study, we report the implementation and screening results from the largest English Cancer Network.Methods:A total of 417 eligible women were identified through cancer registry/hospital databases and from follow-up (FU) clinics. Screening results were collated retrospectively, and registry searches were used to capture BC cases.Results:Of the 417 women invited for clinical review, 243 (58%) attended. Of these 417 women, 23 (5.5%) have been diagnosed with BC, a standardised incidence ratio of 2.9 compared with the age-matched general population. Of five invasive BCs diagnosed within the NRASP, none involved axillary lymph nodes compared with 7 of 13 (54%) diagnosed outside the programme (P<0.10). The mean latency for BC cases was 19.5±8.35 years and the mean FU duration for those unaffected by BC was 14.6±9.11 years (P<0.01), suggesting that those unaffected by BC remain at high risk. Recall and negative biopsy rates were acceptable (10.5 and 0.8%, respectively).Conclusions:The NRASP appears to detect BC at an early stage with acceptable biopsy rates, although numbers are small. Determination of NRASP results on a national basis is required for the accurate evaluation of screening efficacy in women previously treated with SRT.

Derby results and practical experience of breast imaging in women following supradiaphragmatic irradiation for Hodgkin's disease

The national recall programme for women who had supradiaphragmatic irradiation for Hodgkin's disease under the age of 30 years began in late 2003. In Derby, from an initial identified group of 56 women, 36 attended for a 1-hour consultation with a consultant oncologist. From these 36 women, 33 have attended for surveillance. In the group offered imaging surveillance, all 33 women took up the invitation. When magnetic resonance imaging (MRI) is indicated, it is done first; then the woman attends for mammography, MRI results and any focused ultrasound needed the following day. See Table ​Table11 for results. Five of the six MRI recalls were from a first screen, and the other from a second screen. One ductal carcinoma in situ was diagnosed in a lady with breast implants. Table 1 From the 56 eligible women, there were four with breast cancer: one woman diagnosed as above, two women from the National Health Service Breast Screening Programme and one woman symptomatically in 2007. The radiology and pathology of these cases will be presented. We commence family history screening with MRI soon and plan to apply this method, which works very well and within tight time limits.

Breast Cancer After Treatment of Hodgkin's Lymphoma: Risk Factors That Really Matter

To evaluate the risk of breast cancer (BC) and the contributing risk factors in women after supradiaphragmatic irradiation (SDI) for Hodgkin's lymphoma (HL). Medical records of 248 women 60 years of age or less who received SDI for stage I/II HL between 1964 and 2001 at Massachusetts General Hospital were retrospectively reviewed. The median age at SDI was 26 years (range, 5.7-59.3). The median follow-up was 15.2 years (range, 0.1-41.3). In 36 patients, BC developed (bilaterally in 11 patients) at a median interval of 18.4 years (range, 4.3-33.8) after SDI. Based on data from the National Cancer Institute Surveillance, Epidemiology, and End Results program, the standardized morbidity ratio (SMR) for the first BC after SDI was 9.78 (95% confidence interval [CI], 4.64-18.11, p < 0.0001). The SMR of patients who received radiation before age of 30 years was 19.05 (95% CI, 12.33-28.13) compared with 4.64 (95% CI, 2.31-8.30) for patients aged 30 years or more at the time of treatment (p < 0.00003). Risk for BC was significantly higher 15 years or more after SDI compared with the risk during the first 15 years (p = 0.0026). None of HL characteristics or treatment details was associated with higher risk of BC after adjusting for age and calendar time. Age at irradiation and time since therapy appear to be the only significant risk factors for development of BC after treatment of HL. The risk is significantly higher 15 years or more after radiation and for women treated before age 30 years. Long-term surveillance strategies are indicated for women at risk.

Screening mammography for young women treated with supradiaphragmatic radiation for Hodgkin’s lymphoma

BackgroundFemale survivors of Hodgkin’s lymphoma (HL) treated with supradiaphragmatic radiation therapy (SRT) are at increased risk of breast cancer (BC), but there is little data on the optimal screening strategy. Patient and methodsWe report a prospective surveillance study of women treated for HL with SRT before age 30 participating in a high-risk screening clinic. Starting 8 years after treatment, women received annual mammography and clinical follow-up from 1997 to 2006. Method of detection and characteristics of BCs were identified. ResultsIn all, 115 female HL survivors attended at least one clinic; 100 participated in annual surveillance. The majority had mammography alone; adjunctive magnetic resonance imaging (MRI) was used more frequently in women with high breast density (P=0.025). Median age at first mammogram was 36 years and decreased with more recent year of diagnosis. Twelve of the 100 participating women (12%) were diagnosed with BC after a median of 5 years of surveillance (range, 1–9). Seven BCs presented as palpable masses [six invasive, one ductal carcinoma in situ (DCIS)], five were detected by mammography (one invasive, four DCIS). ConclusionsDespite earlier initiation of mammographic screening, most BCs were detected clinically and had unfavorable pathologic characteristics. Evaluation of more intensive screening and the contribution of MRI for earlier detection is warranted.

Gonadotropin-releasing hormone analog treatment for the prevention of treatment-related ovarian failure and infertility in women of reproductive age with Hodgkin lymphoma

We conducted a retrospective study on treatment-related ovarian failure in 61 women with Hodgkin lymphoma who were under treatment from 1994 to 2006. To minimize the risk of treatment-related gonadotoxicity, triptorelin (Decapeptyl®), a gonadotropin-releasing hormone analog (GnRHa), was administered monthly. All patients were treated with frontline polychemotherapy with or without radiotherapy. Seven refractory or relapsed patients received salvage treatment, and six of these patients further received peripheral blood stem cell transplantation. Fifty patients (82%) recovered regular menses, four patients (6%) reported menstrual abnormalities, and seven patients (12%) who were under salvage treatment became amenorrheic. We found a clear correlation between age at the time of treatment, advanced disease, cumulative therapeutic load and ovarian failure. After the completion of treatment, 13 patients who attempted conception conceived. GnRHa may preclude ovarian damage and infertility in young women receiving frontline polychemotherapy alone or in combination with supradiaphragmatic radiotherapy. In refractory or relapsed patients, GnRHa does not seem to be very effective, and further experimental approaches are required for fertility preservation.

Conventional and CT-based Volumes in IFRT for Supradiaphragmatic Malignant Lymphoma

Purpose: The study arose within the Stanford V Trial to assess differences between conventional and CT-based treatment volume and field definition in lymphoma patients undergoing involved-field supradiaphragmatic radiotherapy.

Myocardial Infarction Mortality Risk After Treatment for Hodgkin Disease: A Collaborative British Cohort Study

Myocardial infarction is a major cause of excess long-term mortality in survivors of Hodgkin disease, but limited information exists on the effects of specific chemotherapy regimens used to treat these patients on their risk of death from myocardial infarction. We followed a cohort of 7033 Hodgkin disease patients who were treated in Britain from November 1, 1967, through September 30, 2000, and compared their risk of myocardial infarction mortality with that in the general population of England and Wales. All statistical tests were two-sided. A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100,000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracyclines (SMR = 14.8, 95% CI = 4.8 to 34.5). The risk of death from myocardial infarction after treatment for Hodgkin disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.

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Breast Cancer in Young Women after Treatment with Irradiation for Hodgkin's Lymphoma.

BACKGROUND: Women who are survivors of Hodgkin's Lymphoma (HL) are at increased risk of developing breast cancer (BCa) as a long-term complication due to the use of extended field (mantle) irradiation (RT) of disease above the diaphragm. Many young women are at significantly increased risk of BCa prior to the age at which routine screening mammography is recommended for the general population. The sensitivity of mammography is lower in these women, in part due to increased breast tissue density characteristic of young pre-menopausal women. Currently, there is a paucity of information on the optimal screening modality and surveillance frequency for these women.METHODS: We reviewed the current BCa screening strategies used for this high risk group at our centre and described the incidence, method of detection, and characteristics of secondary BCas in a cohort of 115 women who received supradiaphragmatic RT for HL before age 30 between 1965 and 2000 at Princess Margaret Hospital (PMH) and who subsequently accepted long-term follow-up in a high-risk screening clinic.RESULTS: Median age at treatment was 22 (range 9–30). Radiation fields were mantle in 106 women, modified mantle in 6, and involved field in 3 (median dose delivered: 35 Gy, range 15–60). RT alone was used for 44 patients while 71 received combined modality therapy, of which 45 (65%) received MOPP. Treatment induced amenorrhea occurred in 15 women (median age 38); hormone replacement therapy was subsequently used by 9. Of the 107 women who participated in annual radiographic BCa screening, 95 were screened with mammogram alone, 1 with breast MRI alone, 8 with mammogram and MRI, and 3 with mammogram and ultrasound. Median age at first mammogram was 36; however, median age decreased with more recent year of HL diagnosis (age 40 for women diagnosed before 1985 compared to age 33 for women diagnosed after 1985, p<0.0001). Women with high breast density received MRI screening more often (p=0.02); however, breast density was not significantly associated with previous breast radiation dose or age at last follow-up. Twelve women were diagnosed with BCa in this cohort, following active breast surveillance for a median of 5 years (representing 584 person-years). The 20-year cumulative incidence of breast cancer was 10.9% (95% CI 5.3–18.8%) in this group of women. This was comparable to the 20-year cumulative incidence of breast cancer of 12% (95% CI 8–17%) in all 448 women with HL treated with supradiaphragmatic radiation before age 30 at PMH during the same time period. BCa occurred after a median of 17 years after treatment for HL (range 13–28). Median age at BCa diagnosis was 40 (range 31–51). Seven cancers were detected by physical exam (6 node-positive invasive BCas, 1 in-situ BCa) and 5 were detected on annual mammograms (1 node-positive invasive BCa, 4 in-situ BCas).CONCLUSIONS: Although women in the more recent treatment cohort are receiving their first mammogram at a younger age, the majority of BCas were still detected clinically, and these BCas had less favorable pathological characteristics. More frequent breast imaging should be considered in women who have had supradiaphragmatic RT for HL. Prospective evaluation of breast MRI as a screening strategy for HL survivors has been initiated at PMH in an effort to detect BCa at an earlier stage.

Risk of breast cancer in female survivors of childhood Hodgkin's disease in Britain: A population‐based study

There is now widespread evidence that female survivors of Hodgkin's disease who have been treated with supradiaphragmatic radiotherapy are at an increased risk of breast cancer. Mantle irradiation, which includes irradiation of the mediastinum, conveys a particularly high risk. Previously published studies have found a wide variation in risk. To provide British estimates of risk to inform surveillance programmes, we carried out the first British population-based cohort study of breast cancer in female survivors of childhood Hodgkin's disease. From the underlying cohort of the British Childhood Cancer Survivor Study, a cohort of 18,123 British 5-year survivors of childhood cancer diagnosed between 1940 and 1991, there were in total 383 female 5-year survivors of childhood Hodgkin's disease. Sixteen of these 383 survivors went on to develop invasive breast cancer subsequent to 5-year survival (standardised incidence ratio, 11.5; 95% confidence interval (95% CI), 6.6-18.6) and all of these 16 survivors had been treated with supradiaphragmatic irradiation as treatment for childhood Hodgkin's disease. The cumulative risk of breast cancer by 25 years of follow up was 9.9% (95% CI, 3.3-16.6) for all patients and 12.2% (95% CI, 4.3-20.1) for those treated with supradiaphragmatic radiotherapy. The cumulative risk of breast cancer in female survivors of childhood Hodgkin's disease in Britain is at the lower end of previous estimates. We hope that our data may provide a basis for future surveillance and for counselling survivors as to their likely risk of breast cancer.

Adverse effects after radiotherapy for early stage (I,IIa,IIb) seminoma

Background and purposeThe evaluation of adverse effects after radiotherapy for early stage (I,IIa,IIb) seminoma. Patients and methodsA retrospective analysis of 164 patients with stage I, IIa, IIb seminoma treated with post-orchidectomy irradiation, between 1974 and 1990 was performed. Patients had been treated with infradiaphragmatic radiotherapy only (IDRT) in 48%, and prophylactic mediastinal and left supraclavicular irradiation (supradiaphragmatic radiotherapy, SDRT) was performed additionally in the remaining 52% of patients. Median follow-up was 12 years. The incidence of late morbidity was evaluated with respect to treatment-related factors like: PTV, number of fields irradiated each day, beam energy, total dose and dose per fraction. Afterwards, the dose distribution in normal tissues-based on dose per fraction at 3cm depth and total dose at 3cm depth, was evaluated in relation to late morbidity. ResultsOverall 5-year and 10-year survival was 92 and 86%. For IDRT, dose per fraction at midline and dose per fraction from AP field at 3cm depth were not significantly associated with Gastro-Intestinal morbidity. For SDRT, dose per fraction at 3cm depth from AP field was significantly associated with cardiac morbidity (mean-1.98Gy in patients without and 2.27Gy in patients with cardiac morbidity P=0.006), however total dose at 3cm was not significantly associated with cardiac morbidity. Dose per fraction at 3cm depth from AP field significantly (P=0.047) influenced cardiac morbidity probability in multivariate logistic regression, which included patients' age, smoking habits and total dose at 3cm. ConclusionsExcessive dose maximum in normal tissues from each fraction to anterior mediastinum is associated with increased cardiac morbidity.

Is the Treatment of Hodgkin’s Disease Detrimental to the Parathyroid Gland?

The thyroid gland is often injured by supradiaphragmatic irradiation for Hodgkin’s lymphoma. The aim of the present study was to examine whether the parathyroid gland gets injured by the treatment for Hodgkin’s disease. Calcium, phosphorus and parathormone levels of 143 patients with primary treatment for Hodgkin’s disease and in complete remission for 2 years were measured as well as the presence of antiparathyroid antibody in patients having antithyroid antibody. Out of the 143 patients studied, 104 received neck irradiation (with or without chemotherapy); among them laboratory alterations were observed in 7 cases. 39 patients received only chemotherapy; 3 of them had alterations. In contrast to the injury of the thyroid gland, no damage to the parathyroid glands associated with the treatment for Hodgkin’s disease was noted. It has been concluded that the use of high-dose external radiotherapy does not mean a higher risk as regards the parathyroid gland but further follow-up studies of the patients may result in the revelation of the development of parathyroid lesions.

Risk of Breast Cancer and Breast Cancer Characteristics in Women Treated With Supradiaphragmatic Radiation for Hodgkin Lymphoma: Mayo Clinic Experience

To evaluate the overall risk of breast cancer and breast cancer characteristics in women given supradiaphragmatic radiation therapy for Hodgkin lymphoma. Medical records of 653 female patients who received supradiaphragmatic radiation therapy for Hodgkin lymphoma at the Mayo Clinic in Rochester, Minn, between 1950 and 1993 were abstracted, and follow-up questionnaires were mailed. In 4 patients, breast cancer was diagnosed before Hodgkin lymphoma was discovered. The median age of 649 patients at supradiaphragmatic radiation therapy was 31.8 years (range, 2.6-86.5 years). The median duration of follow-up was 8.7 years (range, < 1-47.9 years). In 30 patients, breast cancer developed (bilaterally in 4 patients) after supradiaphragmatic radiation therapy; the median interval was 19.9 years (range, 0.7-423 years). The median age at breast cancer diagnosis was 44.4 years (range, 27.5-70.8 years). The standardized morbidity ratio for breast cancer after supradiaphragmatic radiation therapy was 2.9 (95 % confidence interval [CI], 2.0-4.2) (P < .001). Breast cancer risk significantly increased 15 to 30 years after patients received supradiaphragmatic radiation therapy, and risk was inversely related to age at supradiaphragmatic radiation therapy until age 30 years. The standardized morbidity ratio for patients younger than 30 years at supradiaphragmatic radiation was 8.5 (95% CI, 53-13.1) vs 1.2 (95% CI, 0.5-2.2) for those aged 30 years or older (P < .001). Splenectomy increased breast cancer risk (P = .01). Breast cancer detection was by self-examination in 15 cancers, by mammography in 13, and by clinical examination in 4; in 2 cancers, the mode of detection was unknown. Modified radical mastectomy was used to treat breast cancer. The increased risk of breast cancer in survivors of Hodgkin lymphoma given supradiaphragmatic radiation therapy appears to be limited to patients who are younger than 30 years at radiation therapy or to those who have undergone splenectomy.