Clinical course of thoracic cancers in Hodgkin's disease survivors

P. Das1,*, A. K. Ng2, M. A. Stevenson3 and P. M. Mauch2

1 Department of Radiation Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX; 2 Departments of Radiation Oncology, Dana Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 3 Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

* Correspondence to: Dr P. Das, Department of Radiation Oncology, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 97, Houston, TX 77 030, USA. Tel: +1-713-563-2300; Fax: +1-713-563-2366; Email: prajdas{at}mdanderson.org


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:: Hodgkin's disease survivors have a high risk of subsequently developing thoracic cancers. Our goal was to evaluate the prognosis and treatment outcomes of thoracic cancers after Hodgkin's disease.

Patients and methods:: Thirty-three patients treated for Hodgkin's disease at Harvard-affiliated hospitals subsequently developed small-cell lung carcinoma, non-small-cell lung carcinoma (NSCLC) or mesothelioma. Information was obtained from medical records about the initial treatment for Hodgkin's disease, any salvage therapy, smoking history, and the stage, histology, treatment and survival for thoracic cancers.

Results:: Of the 33 patients, 29 (88%) had a history of radiotherapy to the thorax, 17 (52%) had received alkylating chemotherapy, and 24 (73%) had a known history of smoking. The median time between diagnosis of Hodgkin's disease and diagnosis of thoracic cancer was 17.3 years (range 1.2–27.9 years). Among patients with NSCLC and a known stage, 85% presented with stage III or stage IV disease. Among patients whose treatment details were available, 40% underwent surgery, 40% received radiotherapy and 65% received chemotherapy. The median survival was 9 months (range 1–47 months).

Conclusions:: Most patients with thoracic cancers after Hodgkin's disease have a history of exposure to risk factors and present at an advanced stage. Patients with thoracic cancers after Hodgkin's disease have a poor survival.

Key words: Hodgkin's disease, lung cancer, risk factors, second malignancy, survival, thoracic neoplasm


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Advances in the work-up and treatment of Hodgkin's disease have made it a highly curable malignancy. Patients with early-stage, favorable-prognosis Hodgkin's disease have disease control rates over 90% [1Go–4Go]. However, survivors of Hodgkin's disease face increased mortality from second malignancies, cardiovascular diseases, pulmonary diseases and infections [5Go–10Go]. Second malignancies represent the leading cause of excess mortality in these patients [5Go–9Go].

Many studies have shown that lung cancer is one of the two most common solid tumors after Hodgkin's disease [11Go–16Go]. Prior radiation therapy, prior alkylating chemotherapy and smoking history increase the risk of developing lung cancer [17Go–21Go]. Smoking appears to multiply the risks from treatment with radiotherapy or alkylating chemotherapy [21Go]. In addition to lung cancers, malignant mesotheliomas have also been reported in Hodgkin's disease survivors [22Go, 23Go].

We investigated the clinical course of thoracic cancers in Hodgkin's disease survivors. Understanding the outcomes of thoracic cancers in these patients will help in ascertaining their prognosis. Furthermore, a knowledge of the stage distribution and clinical course in these patients will help determine whether these patients will benefit from early detection, such as through annual low-dose computed tomography (CT) screening [24Go–26Go]. Hence, we evaluated exposure to risk factors, stage distribution, treatment and survival from thoracic cancers in 33 patients who were treated for Hodgkin's disease at Harvard-affiliated hospitals.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between April 1969 and December 1997, 1319 patients with clinical stage IA–IVB Hodgkin's disease were treated at one of the following Harvard-affiliated hospitals: Brigham and Women's Hospital, Dana-Farber Cancer Institute, Children's Hospital, or Beth Israel Deaconess Medical Center. Of these, 33 were known to subsequently develop small-cell lung cancer, non-small-cell lung cancer (NSCLC) or mesothelioma. The characteristics of these patients are shown in Table 1. The median age at presentation of Hodgkin's disease was 35 years. Sixty-four per cent of the patients were male. Histologic classification for all patients was confirmed by hematopathologists at the treating hospital. All patients underwent clinical staging with history and physical examination, chest radiography, complete blood counts and chemistry. Eighty-two per cent of the patients presented with clinical stage I–II disease. Initial treatment choices evolved over time, with earlier patients treated predominantly with radiation therapy alone (20 patients), some patients treated with chemotherapy alone (five patients) and more recent patients treated with combined modality therapy (eight patients). Initial radiation fields included total nodal irradiation in seven patients, mantle and para-aortic in 17 patients, mantle alone in two patients, and pelvic and para-aortic in two patients, one of whom was also treated to the left supraclavicular region. Initial chemotherapy included mechlorethamine, vincristine, procarbazine and prednisone (MOPP) in 10 patients, MOPP/doxorubicin, bleomycin, vinblastine and dacarbazine (MOPP/ABVD) in two patients, and cyclophosphamide, vinblastine, procarbazine and prednisone (COPP) in one patient. Ten patients (30%) developed a relapse and received further salvage therapy, including MOPP in three patients, ABVD in three patients, MOPP/ABVD in two patients, combined modality therapy in one patient and radiation therapy alone in one patient.


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Table 1. Patient characteristics

 
Data on smoking history, performance status and latency from Hodgkin's disease were obtained througha review of medical records. Data on the stage, histology, treatment and survival for thoracic cancers were also obtained through review of medical records. The survival curve for thoracic cancers was calculated by the Kaplan–Meier method [27Go]. Follow-up was until death for all patients.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Exposure to risk factors
Of the 33 patients with thoracic cancers, 29 (88%) had a history of radiation therapy to the thorax, during either initial treatment or salvage therapy for Hodgkin's disease (Table 2). Among patients receiving thoracic radiation, the median dose to the mantle field was 3800 cGy (range 3060–4200 cGy) with a boost to bulk disease to a median total dose of 4000 cGy (range 3600–5400 cGy). Seventeen of the 33 patients (52%) had received alkylating chemotherapy during initial treatment or salvage therapy. Only three (9%) patients had no history of smoking, four (12%) had a smoking history <10 pack-years, and 20 (61%) had a smoking history of ≥10 pack-years. Smoking status was unknown in the remaining six (18%) patients. No patient had a history of exposure to asbestos. All 33 patients had at least one of the three risk factors: thoracic radiotherapy, alkylating chemotherapy and smoking. Twenty-seven patients (82%) had at least two of these risk factors and 10 (30%) had all three risk factors.


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Table 2. Risk factors for thoracic cancers

 
Clinical course
The median time between diagnosis of Hodgkin's disease and diagnosis of thoracic cancer was 17.3 years (range 1.2–27.9 years; Table 3). Of the 33 patients, one had mesothelioma, 23 had NSCLC, and three had small-cell lung carcinoma. Six other patients had lung carcinoma, but the histology (small-cell or non-small-cell) was unknown. Among patients with NSCLC and a known American Joint Committee on Cancer (AJCC) stage, one (5%) presented with stage I, two (10%) presented with stage II, six (30%) presented with stage III and 11 (55%) presented with stage IV disease. The AJCC stage was unknown in the remaining three patients with NSCLC. At the time of diagnosis of the thoracic cancer, two patients had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 13 had ECOG PS 1, two had ECOG PS 2 and one had ECOG PS 3. ECOG PS was unknown in 15 patients.


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Table 3. Clinical course of thoracic cancers after Hodgkin's disease

 
Six patients underwent thoracic surgery, including lobectomy in three patients, pneumonectomy in one patient, resection of Pancoast tumor in one patient and resection of pleural mass in one patient. Two patients underwent surgery at other sites; specifically, one had resection of a cerebellar metastasis and one had radical neck dissection for a neck mass that was subsequently found to be metastatic lung cancer. Three patients were treated with radiation therapy to the thorax. The first of these had not received any thoracic radiation for Hodgkin's disease and was treated with definitive radiotherapy for lung cancer. The second patient received intra-operative brachytherapy and post-operative external beam radiation therapy after resection of a Pancoast tumor, and the third received radiation to a subcarinal mass following lobectomy. Five other patients were treated with palliative radiotherapy to other sites, including the brain in one patient and the pelvis or sacrum in four patients. Thirteen patients were treated with chemotherapy. Details about the treatment for thoracic cancers were not available for 13 patients.

The median survival from diagnosis of thoracic cancer was 9 months (range 1–47 months). Figure 1 shows the Kaplan–Meier curve for survival from thoracic cancers.



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Figure 1. Kaplan–Meier estimates of overall survival in patients with thoracic cancers after Hodgkin's disease.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Previous studies have reported that Hodgkin's disease survivors have an increased risk of lung cancers and that radiation therapy, alkylating chemotherapy and smoking increase the risk of lung cancer in these patients [11Go–21Go]. However, limited information exists about the prognosis and treatment outcomes of thoracic cancers after Hodgkin's disease. Our goal was to characterize the clinical course of thoracic cancers following Hodgkin's disease. All patients in this study had a history of at least one risk factor (radiotherapy, alkylating chemotherapy or smoking) and 82% had a history of at least two of these risk factors. The median time between diagnosis of Hodgkin's disease and diagnosis of thoracic cancer was 17.3 years. Most patients presented at an advanced stage, with 85% having either stage III or stage IV disease. Although 40% of the patients underwent surgery, 40% received radiotherapy and 65% received chemotherapy, the prognosis was poor with a median survival of only 9 months.

Our findings are similar to those reported for 19 patients with non-small-cell lung carcinoma after Hodgkin's disease [28Go]. In that study, 14 of the 19 patients presented with stage III or IV disease, and the median survival was 5.1 months. Our study included a larger number of patients and different histologies, i.e. small-cell lung cancer, NSCLC and mesothelioma. We also found that most patients presented with an advanced stage and had poor survival.

There has been increasing interest in the role of screening in patients at high risk for lung cancers. Randomized studies have shown that screening with chest X-rays produces no differences in mortality compared with unscreened patients [29Go, 30Go]. However, prospective studies on annual CT screening for lung cancer have shown early, promising results [24Go–26Go]. We previously reported a decision-analytic model indicating that annual CT screening for lung cancer may increase survival and quality-adjusted survival among Hodgkin's disease survivors and that screening appears to be cost-effective, at least for smokers [31Go]. A screening program can be successful only if unscreened patients present at advanced stages, and screening causes a stage-shift towards earlier stages. This study has shown that most patients with lung cancer after Hodgkin's disease present with advanced disease, while other studies have reported that CT screening causes a stage-shift towards earlier stages in subjects at high risk for lung cancer [24Go–26Go]. Thus, the results of the present study help support the hypothesis that screening may help improve survival for lung cancer after Hodgkin's disease. Furthermore, in this study, thoracic cancers arose only in patients exposed to one or more risk factors and 82% of thoracic cancers arose in those exposed to at least two risk factors. This finding suggests that screening programs should be targeted towards those with multiple risk factors.

Many of the patients in this study were treated with extended-field radiation therapy or alkylating chemotherapy. The risk and natural history for thoracic cancers may be different for Hodgkin's disease patients treated in the current era with involved-field radiation therapy and non-alkylating chemotherapy regimens. Nevertheless, the results of this study are applicable to thoracic cancers in Hodgkin's disease patients who were first treated 10–15 years ago. Since there is a long latency between Hodgkin's disease and thoracic cancers, the findings of this study are relevant for many thoracic cancers being diagnosed now in Hodgkin's disease survivors.

The patients in this study were all evaluated in the radiation oncology departments of Harvard-affiliated hospitals when they initially presented with Hodgkin's disease, and there may be a selection bias for patients being exposed to radiotherapy. However, the goal of this study was not to define risk factors, but to depict the clinical course of thoracic cancers after Hodgkin's disease. Other limitations of this study include incomplete information on the smoking history histology, stage and treatment in some patients. We were unable to obtain complete information on all patients since there was a long interval between Hodgkin's disease and thoracic cancers in many cases and since some patients were treated for thoracic cancers at other institutions.

Since thoracic malignancies are one of the most common secondary cancers after Hodgkin's disease, it is important to understand the risk factors, prognosis and treatment outcomes of thoracic cancers in Hodgkin's disease survivors. We found that patients with thoracic cancers after Hodgkin's disease had a history of exposure to risk factors, presented at advanced stages and had poor survival. Screening programs aimed at those with a history of risk factors may lead to the early detection of thoracic cancers and may improve survival in these patients.

Received for publication October 20, 2004. Revision received January 3, 2005. Accepted for publication January 5, 2005.


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 Patients and methods
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 Discussion
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