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Long-Term Survival and Competing Causes of Death in Patients With Early-Stage Hodgkin’s Disease Treated at Age 50 or Younger

From the Departments of Radiation Oncology, Biostatistical Sciences, and Adult Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, and Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA.

Supported in part by the Suzanne L. Chute Lymphoma Clinical Research Program.Address reprint requests to Peter M. Mauch, MD, Department of Radiation Oncology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; email: pmauch{at}lroc.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To analyze the long-term survival and the pattern and timing of excess mortality in patients with early-stage Hodgkin’s disease.

PATIENTS AND METHODS: Between 1969 and 1997, 1,080 patients age 50 or younger were treated for clinical stage IA to IIB Hodgkin’s disease. Overall survival was determined, and prognostic factors were assessed. Relative risk and absolute excess risk (AR) of mortality were calculated for the entire cohort and by prognostic groups (on the basis of B symptoms, mediastinal status, and number of sites, modified from the European Organization for Research and Treatment of Cancer).

RESULTS: The median follow-up was 12 years. The 15- and 20-year Kaplan-Meier survival estimates were 84% and 78%, respectively. Cox proportional hazards models showed that number of involved sites (P = .006), mediastinal status (P = .02), and histology (P = .02) were independent predictors of death from all causes. The AR of mortality in patients with a favorable prognosis increased over time, whereas for those with an unfavorable prognosis, the AR peaked in the first 5 years, predominantly from Hodgkin’s disease. The relative risk of mortality from all causes, causes other than Hodgkin’s disease, second tumors, and cardiac disease remained significantly elevated more than 20 years after treatment.

CONCLUSION: Patients treated for early-stage Hodgkin’s disease have a sustained excess mortality risk despite good control of the disease. Treatment reduction efforts in patients with early-stage, favorable-prognosis disease should continue, but for patients with an unfavorable prognosis, modified treatment may not be advisable. The excess mortality noted beyond two decades underscores the importance of long-term follow-up care in patients treated for Hodgkin’s disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
OVER THE PAST 30 years, significant advances have been made in the work-up and treatment of Hodgkin’s disease, transforming it from a previously uniformly fatal malignancy to a highly curable one. Currently, over three quarters of all patients presenting with Hodgkin’s disease will be cured. The disease control rates in patients with early-stage, favorable-prognosis disease have been shown in some studies to be over 90%.^1-4 It is unlikely that these high cure rates can be further improved by enhancing or augmenting treatments. Instead, the largest potential for improving the survival in these patients is through reducing the excess risk of mortality from causes other than Hodgkin’s disease, which can occur after long latencies, and requires long follow-up for its assessment. A number of investigators have independently demonstrated that although the cumulative incidence of mortality from Hodgkin’s disease levels off with increasing follow-up time, excess mortality from causes other than Hodgkin’s disease continues to be elevated at least 15 to 20 years after initial diagnosis.^5-9 After 12 to 15 years, treatment-related mortality, including death from second malignancies, cardiovascular or pulmonary diseases, and infections, begins to exceed the mortality from Hodgkin’s disease in patients with initially early-stage disease. Whether this excess mortality risk persists throughout a patient’s lifetime has yet to be confirmed.

This study evaluates the impact of several prognostic factors on overall survival and examines the long-term competing mortality in patients who had been treated for early-stage Hodgkin’s disease. We have restricted the analysis to 1,080 patients who presented with Ann Arbor stages IA to IIB Hodgkin’s disease,^10,11 and who were age 50 or younger at the time of initial diagnosis. The patient population of early-stage disease and younger age at diagnosis typifies the classic presentation of Hodgkin’s disease. Because of the high cure rate, these patients are more likely to live long enough to experience late complications. Examination of the long-term prognostic factors for survival, causes of death, and pattern of excess mortality over time may therefore be of particular significance in this patient population, and may have an important role in developing targeted treatment and follow-up strategies to maximize survival.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Between April 1969 and December 1997, 1,080 patients age 50 or under were treated for clinical stage IA to IIB Hodgkin’s disease 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. Patients to be included in this study were selected on the basis of clinical staging results at initial presentation, rather than pathologic staging, because of the decreasing use of staging laparotomy in current practice. The use of clinical staging allowed a more uniform evaluation of all patients. The decision to exclude older patients from our study is because of the known strong negative impact of older age on overall survival in patients with Hodgkin’s disease, likely from a combination of limitation of life expectancy, presence of comorbid illnesses, inability to tolerate more aggressive treatments, and higher treatment complications in older patients.^12-16 Focusing on patients aged 50 or younger at presentation may therefore provide a cleaner assessment of factors that predict for survival, and of the magnitude and pattern of excess mortality over time in the typical, young patient who presents with Hodgkin’s disease. The choice of age 50 as cutoff is derived from the most recent European Organization for Research and Treatment of Cancer (EORTC) prognostic classification system, in which age over 50, instead of 40, is now used as one of the factors in defining unfavorable prognosis. Moreover, patients age 50 or younger represent the majority of patients (92%) with early-stage Hodgkin’s disease treated at our institution between 1969 and 1997.

All clinical stage IA to IIB patients were separated into prognostic groups as modified from the EORTC classification.¹⁷ In the most recent EORTC prognostic classification system for early-stage patients, favorable prognosis was defined as satisfaction of all of the following criteria: clinical stage IA to IIB, age 50, erythrocyte sedimentation rate (ESR) 50 mm/h in patients without B symptoms or 30 mm/h in patients with B symptoms, lack of large mediastinal adenopathy, and less than four sites of disease.^17,18 In our study, instead of using a combination of B symptoms and ESR as one of the criteria, we used B symptoms alone, as information on ESR was not routinely available. Unfavorable prognosis was defined as the presence of one or more adverse factors including B symptoms, large mediastinal adenopathy (defined as the width of the mediastinal mass more than one third of the maximum thoracic diameter), and four or more involved sites. Separation of early-stage patients into favorable and unfavorable prognostic groups is commonly performed in clinical trials exploring different treatment options. Therefore, it is of interest to evaluate the excess risk of mortality over time in patients with favorable versus unfavorable clinical stage IA to IIB disease, as it may provide insights into initial treatment strategies as well as follow-up care. In this study, patient and disease characteristics (Table 1) and long-term treatment outcome were reviewed.

Only 72 patients (7%) were enrolled on controlled protocols during this period of time. The initial treatment regimens (Table 2) included radiation therapy alone in 648 patients (63%), combined-modality therapy in 360 patients (33%), and chemotherapy alone in 36 patients (3%). All patients treated with radiation underwent simulation and received radiation therapy on 4- to 6-MV linear accelerators for mantle and pelvic fields and 6- to 15-MV linear accelerators for para-aortic irradiation. The median dose to the mantle field was 3,600 cGy. The prescribed radiation doses were normalized to the central axis. Because of reduced scattered dose from the lung blocks, the lower mediastinum typically received approximately 7% lower than the prescribed dose. We did not routinely boost the lower mediastinum to correct for the inhomogeneity. However, bulk disease was routinely boosted (total median dose, 4,000 cGy). Daily fractions ranged from 150 to 200 cGy, 5 d/wk. Technical factors included the use of individualized divergent blocks, equal treatment from anterior and posterior fields, the addition of a larynx block at 2,000 cGy, and the addition of a posterior cervical spine block at 3,000 cGy. Mechlorethamine, vincristine, procarbazine, and prednisone were used in earlier years of the study, and were replaced by adriamycin, bleomycin, vinblastine, and dacarbazine in later years. Among the 396 patients who received chemotherapy either alone or as part of combined-modality therapy, most were treated with either alkylating agent–based chemotherapy (55%) or adriamycin, bleomycin, vinblastine, and dacarbazine (29%). Details of the remaining chemotherapy regimens used are listed in Table 3.

We analyzed the effect of several prognostic factors on survival and on the pattern of excess mortality over time, in order to help in the design of future clinical trials and in the development of follow-up guidelines for patients. Staging and treatment exposures were not included in the analysis because of the retrospective nature of the study, with different lengths of follow-up in patients managed with different strategies. For instance, considerable differences were seen in the follow-up time for laparotomy-staged versus clinically staged patients (median follow-up of 14.2 years v 5.1 years, respectively), and for patients who received alkylating agent–based chemotherapy versus adriamycin, bleomycin, vinblastine, and dacarbazine (median follow-up of 15.3 years v 4 years, respectively), because of changes in management policies over time. These differences did not allow us to evaluate the long-term effect of staging and treatment on survival. In this study, the focus is on the influence of patient- and disease-related factors on mortality.

Statistical Analysis
Survival curves were calculated by the Kaplan-Meier method.¹⁹ Univariate and multivariate analyses were used to test for the association of several baseline characteristics with survival. The log-rank test was used to assess the significance of univariate associations,²⁰ and Cox proportional hazards models were used in the multivariate analysis.²¹

To adjust for expected mortality, univariate associations of excess mortality with prognostic factors were computed. Age- and sex-specific incidence rates from the National Center for Health Statistics were multiplied by corresponding person-years of observation to obtain expected numbers of events. Person-years of observation started at the end of treatment of Hodgkin’s disease and continued until death or the last day of follow-up evaluation. Relative risk (RR) was estimated on the basis of the assumption that the observed number of second cancers followed a Poisson distribution. Confidence intervals for relative risks (ratio of observed/expected number of cases) were calculated with exact Poisson probabilities. Absolute excess risk (AR) was calculated by dividing observed minus expected numbers of cases by the person-years at risk. The result was multiplied by 10,000 and expressed as the number of excess cases per 10,000 person-years. Dividing the AR by 100 gives the average percentage excess mortality per year per patient.

To account for competing risks, cumulative incidence functions were used to estimate the percentage of patients who died of each cause over time.²² Causes of mortality were determined and grouped into the following categories: Hodgkin’s disease, second malignant tumors, cardiovascular/pulmonary, infection, other, and unknown.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Characteristics of all 1,080 patients are listed in Table 1. The median age at diagnosis was 25 years (range, 3 to 50 years). The median follow-up time among survivors was 12 years, with 346 patients (38%) having more than 15 years and 179 patients (20%) more than 20 years of follow-up. Eight patients (0.7%) were lost to follow-up. The 15- and 20-year Kaplan-Meier survival estimates for all patients were 84% and 78%, respectively (Fig 1).

View larger version (15K): [in this window] [in a new window]   Fig 1. Overall survival.

The RR and AR of mortality from all causes and causes other than Hodgkin’s disease according to age at diagnosis are listed in Table 6. As expected, the RR of mortality was the highest among the younger patients because of the low background risk of death in the younger age group. The AR of mortality from all causes as well as causes other than Hodgkin’s disease, however, increased with increasing age at diagnosis. This observation is in agreement with the known negative prognostic impact of older age at diagnosis on survival in patients with Hodgkin’s disease.

To ascertain the impact of different causes of death on overall survival, we estimated the cumulative incidence curves for competing causes of death in the 1,080 patients age 50 or younger (Fig 2). Death from Hodgkin’s disease had the greatest impact on survival in the initial 15 years, but no deaths from Hodgkin’s disease were seen after that. At approximately 14 years, the cumulative incidence of death from all other causes exceeded that from Hodgkin’s disease, and at 18 years, the cumulative incidence of second-malignancy deaths exceed that of Hodgkin’s disease mortality. The 15- and 20-year cumulative rates of mortality from second malignancy were 5.1% (95% confidence interval [CI], 3.5% to 6.9%) and 9.8% (95% CI, 7.0% to 12.6%), respectively, and the corresponding rates for cardiac/pulmonary disease were 2.0% (95% CI, 0.9% to 3.1%) and 3.1% (95% CI, 1.5% to 4.7%), respectively.

View larger version (20K): [in this window] [in a new window]   Fig 2. Competing causes of death.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Limited data are available in the literature on excess mortality beyond 20 years after treatment for Hodgkin’s disease. In another study with long-term follow-up, Hoppe²³ examined the AR of death (excluding Hodgkin’s disease) at 5-year intervals in 812 early-stage patients treated between 1962 and 1980 and 653 early-stage patients treated between 1980 and 1996. In the earlier cohort of patients, the AR at 20 years and beyond was 296 per 10.000 person-years. Similarly, we found that although Hodgkin’s disease deaths abated with time, the AR of mortality from other causes remained elevated, and there did not appear to be any diminution of the excess risk beyond 20 years.

There is a growing body of evidence that the gain in Hodgkin’s disease–specific survival associated with aggressive initial treatment may eventually be offset by excessive deaths from other causes.^25,26 In our study, significantly more patients in the unfavorable prognostic group received combined-modality therapy compared with patients in the favorable prognostic group (64% v 14%, P < .0001). Despite the more aggressive initial treatment, there were still more Hodgkin’s disease deaths in the unfavorable prognosis group. Patients with an unfavorable prognosis were also at higher risk of mortality from causes other than Hodgkin’s disease, even though they were more likely to die of Hodgkin’s disease early on and would therefore be no longer at risk for mortality from other causes. This may be because of a combination of the more aggressive initial treatment, as well as salvage therapy for relapsed disease. The higher overall treatment exposure in this group of patients likely contributes to the increased risk of mortality from causes other than Hodgkin’s disease.

We also noted a contrasting pattern of excess mortality over time between the two groups. In patients with favorable-prognosis disease, the excess mortality increased over time, predominantly from causes other than Hodgkin’s disease. Conversely, in the unfavorable prognosis group, excess mortality from all causes was greatest in the first 5 years after diagnosis, predominantly from Hodgkin’s disease. These observations suggest that in the favorable-prognosis group, efforts to explore less intensive treatments to minimize toxicities should be continued. However, in patients with unfavorable-prognosis disease, although some treatment reductions have been shown to be feasible,^4,27,28 other trials have found high recurrence rates with the use of modified regimens.^29,30 The finding that initial patient and disease characteristics that have been used for prognostic stratification remain prognostic for Hodgkin’s disease deaths strongly suggests that the priority in the management of patients with an unfavorable prognosis should continue to be optimizing tumor control, and that modified regimens should be used in these patients only in the setting of carefully controlled trials.

One inherent obstacle in the study of late complications after cancer therapy is that as treatment approaches evolve over time, the relevance of the long-term effects of outdated treatments to patients receiving modern therapy becomes questionable. However, the fact is that even with 20 years of follow-up, the average Hodgkin’s disease survivor would be barely entering middle age. A large number of long-term survivors who have received treatments that are now considered outdated, such as large-field radiation therapy alone, or mechlorethamine, vincristine, procarbazine, and prednisone–based chemotherapy, still exist. Clinicians are faced with the obligation to help these patients in receiving proper follow-up care. In current practice, patients are typically followed only once a year after they are 5 years or more past treatment. However, the observation that the risk of mortality remained significantly elevated at four to five times that of expected even beyond 20 years past treatment raises the question of whether these patients should in fact be followed more closely as they get further away from initial diagnosis. Education of both patients and primary care physicians, who often are the main health care professionals following the patients years after their cure, about the increased excess risk of mortality with increasing time is crucial. Another key message brought out by the findings of the significantly increased excess mortality long after cure of the Hodgkin’s disease is that a long follow-up time is needed before the late ramifications of Hodgkin’s disease therapy are fully revealed. Because trials are currently underway exploring treatment reductions in patients with early-stage Hodgkin’s disease, it is important to allow for adequate follow-up time before the long-term safety of the new regimens can be established. This point is further illustrated by the finding that with only a few additional years of follow-up, the RR of mortality from second malignancies of 11.2 in the present study was almost double that of the RR of 6.8 found in our previous report.⁶

Results of this study provide a sense of how long after initial treatment the excess deaths from causes other than Hodgkin’s disease begin to occur. However, challenges remain in establishing the optimal time to begin screening for potential late complications and in developing better surveillance guidelines. Further work is also needed to identify risk factors that may predict for specific late effects. Those who are recognized to be at the highest risk may be targeted for more rigorous follow-up, risk-reduction programs, or other active preventative measures. Consideration may also be given to altering the initial therapeutic approach in high-risk patients. Further studies are needed to determine whether risk-reduction strategies and early detection of late complications will improve the long-term survival in these patients.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted March 6, 2001; accepted January 7, 2002.

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