Annals of Oncology Advance Access originally published online on October 3, 2006
Annals of Oncology 2006 17(11):1693-1697; doi:10.1093/annonc/mdl288
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© 2006 European Society for Medical Oncology
hematologic malignancies |
Long-term results of a prospective trial of mantle irradiation alone for early-stage Hodgkin's disease
1 Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute
2 Department of Biostatistical Sciences
3 Department of Adult Oncology, Dana-Farber Cancer Institute
4 Department of Radiation Oncology, The Children's Hospital
5 Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, USA
* Correspondence to: Dr P. M. Mauch, 75 Francis St., ASB1-L2, Boston MA 02115, USA; Tel: 617-732-6310; Fax 617-732-7347; E-mail: pmauch{at}lroc.harvard.edu
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Abstract |
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Background: To determine the long-term treatment outcome and late effects of mantle irradiation alone in selected patients with early-stage Hodgkin's disease.
Methods: Between 1988 and 2000, 87 patients with pathologic stage (Ann Arbor) I–IIA or clinical stage IA Hodgkin's disease were entered on to a prospective trial of mantle irradiation alone. Patients with B symptoms, large mediastinal adenopathy, or subcarinal or hilar involvement were excluded. The median doses to the mantle field and mediastinum were 36 Gy (range 30.3–40) and 38.6 Gy (range 30.6–44), respectively. The actuarial freedom from treatment failure (FFTF) and overall survival (OS) rates were calculated using the Kaplan–Meier technique.
Results: The median follow-up was 107 months (range 23–192). Thirteen of 87 patients (15%) relapsed at a median of 30 months (range 5–62). The 5- and 10-year actuarial FFTF rates were 86% and 84.7%, respectively. All 13 patients who relapsed are alive without evidence of disease at a median of 84 months (range 30–156) post-salvage therapy. Five patients developed a second malignancy at a median of 93 months (range 27–131). The 10-year actuarial risk of a second malignancy was 4.5%. There have been two deaths to date, both due to second malignancies. The 10-year OS rate was 98.2%.
Conclusion: In selected patients with early-stage Hodgkin's disease, mantle irradiation alone has an excellent long-term survival rate, comparing favorably with the previous standard treatment of extended-field radiation therapy and the current standard of combined modality therapy.
Key words: Hodgkin's disease, radiation therapy, late effects
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introduction |
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The treatment of early-stage, favorable prognosis Hodgkin's disease has evolved over the years. Historically, subtotal nodal irradiation was the standard of treatment in patients with pathologically confirmed early-stage disease, with disease-free survival (DFS) rates ranging from 70% to 85%, and overall survival (OS) of >90% [1–4].
In 1988, we initiated a prospective single-armed trial evaluating the efficacy of mantle radiation therapy alone in patients who had a negative staging laparotomy. Compared with extended-field radiation therapy, this treatment approach is associated with fewer acute side-effects, shorter treatment time, and reduced likelihood of such late effects as bowel complications and second malignancies, specifically, malignancies arising below the diaphragm. Around the time of the initiation of this trial, results of the European Organization for Research and Treatment of Cancer (EORTC) H5F study comparing mantle and paraaortic irradiation versus mantle alone in pathologic stage (PS) I–II patients had become available, showing no significant difference in DFS and OS rates between the two arms [5]. In the EORTC H5F study, however, the 9-year DFS of the mantle-alone arm was somewhat disappointing at only 69%. Our hypothesis was that better treatment outcome could be achieved in the setting of a single-institution trial in which selected experienced surgeons were available to carry out the pathologic staging, and the radiation therapy was delivered by a limited number of physicians under strict treatment guidelines. Preliminary results of this trial have previously been reported, showing an excellent 5-year freedom from treatment failure (FFTF) rate of 86% and OS of 100% [6]. We now report on the long-term treatment outcome of this trial, focusing on relapses, salvage outcome, and late complications.
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methods |
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eligibility
Between October 1988 and June 2000, 87 patients were entered on to the single-arm prospective trial. Initially, entrance criteria included: laparotomy-staged (PS) IA to IIA Hodgkin's disease, nodular sclerosing (NS) or lymphocyte predominant (LP) histology, no B symptoms, absence of large mediastinal adenopathy (defined as more than one-third the maximum thoracic diameter on a standing posterior–anterior chest radiograph), and negative radiographic staging of the abdomen by computed tomographic (CT) scanning or lymphangiography. Thoracic CT and gallium scans were required to document the extent of Hodgkin's disease above the diaphragm. Patients with subcarinal or hilar lymph node disease were excluded. In 1995, several modifications were made to the entrance criteria. The trial became open to patients with PS IA mixed cellularity (MC) Hodgkin's disease. In addition, all patients with clinical stage (CS) IA LP and female patients with CS IA NS Hodgkin's disease became eligible for the trial without a staging laparotomy. This study was an institutional review board-approved protocol and informed consent was obtained from all enrolled patients. Characteristics of all enrolled patients are listed in Table 1.
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treatment
The standard lower border of the mantle field was modified according to the presence or absence of mediastinal disease. For patients without mediastinal involvement, the mantle field included the hilar and subcarinal regions and excluded most of the heart (bottom border at T8–T9). For patients with upper mediastinal disease, the field was extended to include the low central cardiac nodes (bottom border at T10–T11). The total prescribed dose varied depending on the initial sites of involvement. The dose to the mantle field ranged between 3060 and 4000 cGy, and the total dose to the mediastinum was between 3060 and 4400 cGy. At 3000 cGy, a subcarinal block was inserted to protect the lower heart.
follow-up data
Upon completion of treatment, patients were followed every 3 months for the first 2 years, every 4 months in the third year, twice a year in the fourth and fifth years, and once a year thereafter. At each follow-up visit, a history and physical examination, complete blood count, thyroid function tests, and chest radiography were obtained. Gallium and/or abdominal pelvic CT scans were obtained every 6–12 months for the first 5 years. Relapses, salvage treatment, second malignancies, major cardiac events, and other late complications were recorded.
statistical methods
The actuarial freedom from first relapse and survival from the end of mantle irradiation were calculated using the Kaplan–Meier technique. FFTF was calculated scoring only initial relapses as events. Survival was calculated scoring death from all causes as events. Comparisons between curves were made using a two-tailed log-rank test. P values 
0.05 were considered statistically significant. The actuarial risk of second malignancies was estimated using Gray's method [7]. Follow-up information was obtained by chart review and contact of physicians following the patients. All adverse events including second malignancies and cardiac disease were confirmed by reviewing the documentation on medical records. The median follow-up time was 107 months.
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results |
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relapses
The 5- and 10-year actuarial FFTF rates were 86% and 84.7%, respectively (Figure 1). Thirteen of 87 patients relapsed at a median of 30 months (range 5–62). A majority of the relapses (10 of 13 or 76%) occurred in the first 3 years after treatment. Ten relapses were exclusively out-of-field, one exclusively in-field, and two both in- and out-of-field. The 10-year FFTF rates in patients with stage I and stage II disease were 89% and 80%, respectively (P = 0.22). The 10-year FFTF rates in patients with and without mediastinal involvement at presentation were 84% and 85%, respectively (P = 0.86). There were no relapses among the 15 patients with LP histology, whereas the 10-year FFTF among the remaining patients with NS, MC, or unclassified histology was 81%. The differences in treatment outcome by histology, however, did not reach statistical significance (P = 0.08).
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salvage therapy
Twelve of the 13 relapses were successfully salvaged with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) with or without radiation therapy and had no further relapses. One patient, initially salvaged with combined modality therapy, had a second relapse after 8 months. The patient underwent autologous stem-cell transplantation, and is disease-free 84 months later. The time to relapse, sites of relapse, salvage therapy, and salvage outcome of the 13 patients with relapsed disease are summarized in Table 2. All 13 patients who relapsed are currently alive without evidence of Hodgkin's disease at a median of 84 months (range 30–156) post-salvage therapy.
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late effects
Five patients developed a second malignancy at a median of 93 months (range 27–131). The 10-year actuarial risk of a second malignancy was 4.5%. Localized invasive breast cancer developed in two patients who were aged 28 and 36 years, respectively, at the time of Hodgkin's disease therapy, after a latency of 8 and 2 years, respectively. Both patients were successfully treated with mastectomy and chemotherapy. One patient, aged 31 years at the time of Hodgkin's disease therapy, developed ductal carcinoma in situ 10 years after treatment, and underwent a mastectomy. She was placed on tamoxifen postoperatively and is currently disease-free while on tamoxifen. These three cases of breast cancer all developed within the prior radiation treatment field. Two additional patients had metastatic disease at the time when the second malignancies were discovered, one from breast cancer and the other from papillary serous carcinoma of the uterus. It was presumed that in the patient who had metastatic breast cancer, her primary disease arose within the prior mantle field. For the patient who was diagnosed with metastatic uterine cancer, her primary disease was outside of the previous radiation treatment field. Both patients died shortly after the diagnosis. Details of the five cases of second malignancies are summarized in Table 3.
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Two patients developed a myocardial infarction at 40 and 154 months, and one patient who received ABVD as salvage therapy developed cardiomyopathy at 34 months after that therapy. No infectious complications related to staging laparotomy were observed.
There have been two deaths to date, both due to second malignancies. The actuarial 10-year OS rate was 98.2%.
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discussion |
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We reported on the long-term outcome of a prospective trial of mantle irradiation alone in patients with early-stage, favorable prognosis Hodgkin's disease, most of whom were staged pathologically. At a median follow-up of 107 months, the 10-year actuarial FFTF and OS rates were 84.7% and 98.2%, respectively. Salvage after relapse, mostly utilizing conventional-dose therapy, was highly successful, with no deaths from Hodgkin's disease documented to date. The overall results are comparable to those achieved with the previous standard treatment of extended-field radiation therapy and the current standard of combined modality therapy, in which long-term relapse-free, and OS rates are
85% and >95%, respectively. Liao et al. [8] reviewed 145 patients with PS I or II Hodgkin's disease treated with mantle irradiation therapy alone at MD Anderson Cancer Center. At a median follow-up of 146 months, the 10-year progression-free and OS rates were 75.3% and 87.6%, respectively. The less favorable results from the MD Anderson series are likely due to their inclusion of patients with bulky disease, four or more sites of disease and/or constitutional symptoms, and 15% were aged 40 or older. Among the 54 patients without any of these adverse prognostic factors, an excellent 10-year progression-free survival rate of 96.3% was reported. Their findings highlight the importance of careful patient selection for this treatment approach.
Results from our trial were also more favorable than those of the EORTC H5F trial [5], which consisted of patients with similar characteristics, and in which the DFS at 9 years was only 69% in the mantle-radiation-therapy-alone arm. The differences in outcome between the two trials may reflect challenges in standardizing surgical techniques, radiation therapy delivery, and follow-up care of patients in a multi-institutional setting, whereas quality control can be more readily accomplished within a single institution. Quality assurance in radiation delivery may be especially important when radiation therapy is given as the sole treatment modality. The importance of uniform quality of radiation treatment techniques has been recognized by European Cooperative Groups, and in the more recent trials, centralized quality control programs have been put into place [9–13].
One main limitation of the current report is that the trial was conducted and the results were derived from an era when staging laparotomy was routinely carried out, a procedure which is no longer used. The number of clinically staged patients in our trial is too small for any conclusions regarding the effectiveness of mantle radiation therapy alone in these patients. Others, however, have demonstrated that this may be feasible in carefully selected subgroups of clinically staged patients. Investigators from Princess Margaret Hospital reported on the results of 521 CS I–II patients treated with radiation therapy alone [14]. In a selected group of patients aged <50, with LP or NS histology, erythrocyte sedimentation rate <40, and the absence of constitutional symptoms, large mediastinal mass, or extranodal lesions, the 5-year relapse-free rate with mantle radiation therapy alone was 84.9%; this was comparable to the 87.1% rate achieved with extended-field radiation therapy. Wirth et al. [15] evaluated mantle radiation therapy alone in 261 patients with CS I–II disease. Using the same prognostic criteria as were used in the Princess Margaret Hospital study, 68 patients were identified to have favorable disease; the 5-year progression-free and OS rates in this subgroup were 80% and 100%, respectively. Less encouraging results were reported in the EORTC H7 trial, in which clinically staged patients with ‘very favorable’ disease (women, age <40, CS IA, LP, or NS histology, and an erythrocyte sedimentation rate (ESR) <50 mm) were treated with mantle irradiation alone [16]. The 6-year relapse-free survival rate was only 73%, leading to closure of the trial. Despite the strict selection criteria in the EORTC trial, the poorer than expected treatment results may again reflect difficulties with ensuring uniform quality of staging and treatment when multiple institutions are involved. The inferior relapse-free survival observed in these clinically staged patients, compared with patients in our study, also reflects the limitations of clinical staging in detecting occult abdominal disease. It is noteworthy, however, that in these studies, modern radiographic staging techniques were not routinely used. In recent years, functional imaging has been increasingly incorporated into the management of Hodgkin's disease. Positron emission tomography (PET) scans have been shown to be more sensitive than computed tomography and gallium scans in identifying nodal disease and detecting splenic involvement [17–20]. Results of PET scan findings, in combination with pretreatment clinical factors, may better identify appropriate candidates for the more limited-field radiation therapy.
Second malignancy and cardiac disease are the two most significant late effects in survivors of Hodgkin's disease. The relatively small number of patients in this trial does not allow us to meaningfully compare the differences in the incidence of late effects with other series using either larger-field radiation therapy or combined modality therapy. Breast cancer has been identified as one of the most common second cancers after Hodgkin's disease therapy. Its development is associated with a long latency of 10–15 years and the risk is especially high in women irradiated at a young age. In our study, at a median follow-up time of 9 years, four cases of breast cancer were observed (one case occurred after a latency of only 2 years and is unlikely to be related to her therapy). The peak of the breast cancer risk has yet to be reached, and it is important that women continue to be closely followed and screened for breast cancer on a regular basis. Lung cancer is another common second malignancy, typically presenting after a latency of 5–10 years. While there have not been any cases of lung cancer thus far in our cohort, because of the multiplicative effect of smoking on lung cancer risk in patients who have received either chest radiation therapy and/or alkylating agent chemotherapy for the Hodgkin's disease, counseling on smoking cessation is imperative in those who continue to be smokers. The role of routine chest CT screening for lung cancer is unclear at this time, but should be considered in patients at high risk on the basis of their prior treatment and tobacco history. Coronary heart disease after mediastinal irradiation for Hodgkin's disease has a typical latency of at least 5–10 years. There have been two cases of non-fatal myocardial infarction in our cohort thus far, and continued long-term follow-up with special attention to controlling or eliminating traditional cardiac risk factors may have an important role in reducing cardiac-related complications in this population.
The current standard therapy for early-stage Hodgkin's disease, combined modality therapy, has been associated with better DFS, although not OS, when compared with radiation therapy alone, on the basis of several multi-institutional randomized studies [16, 21–24]. In addition to the superior DFS compared with radiation therapy alone, combined modality therapy allows the use of smaller radiation fields and lower radiation dose, and should therefore remain the preferred treatment choice in patients with early-stage Hodgkin's disease. However, the successful long-term survival results reported in this trial suggest that with careful patient selection and rigorous staging and radiation treatment techniques, mantle radiation therapy is a viable option in selected patients, especially in those who may benefit from being spared chemotherapy-related toxicity. Although there may be a higher relapse rate with radiation therapy alone, the salvage rate with conventional-dose chemotherapy appears to be excellent. There are specific patient populations in which mantle radiation therapy alone is not recommended, however. These include young female patients and patients with a significant tobacco history, because of risks of breast cancer and lung cancer, respectively, with the use of a full mantle field. In addition, patients with pre-existing cardiac risk factors may not be ideal candidates for mantle radiation therapy alone, because the standard inferior border of a mantle field is typically lower than that of an involved-field given as part of combined modality therapy, thereby exposing a larger volume of heart to the radiation treatment.
This trial, which started >10 years ago, was initially designed with the purpose of reducing treatment from the then standard of extended-field radiation therapy in patients with early-stage, favorable prognosis disease. As treatment of Hodgkin's disease continues to evolve over time with an emphasis on treatment reduction among favorable patients, trials with long follow-up time, inevitably will have the inherent predicament of consisting of patients managed with approaches that are no longer considered standard. Currently, in most combined modality therapy studies, the radiation field sizes are more limited and the doses are lower than those that were used in this trial. In order to learn whether efforts to reduce treatment will translate into reduced late effects, it is imperative that patients on these trials continued to be followed and that long-term results are reported.
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Presented in part at the 47th American Society of Therapeutic Radiology and Oncology Meeting, Denver, CO, 2005.
The authors wish to acknowledge Ronald Takvorian and Kendall Backstrand for their contribution to the original publication of this trial.
Received for publication March 29, 2006. Revision received June 26, 2006. Accepted for publication June 30, 2006.
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