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Originally published as JCO Early Release 10.1200/JCO.2003.07.131 on July 28 2003 © 2003 American Society for Clinical Oncology Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease
From the Department of Radiotherapy, and the Department of Epidemiology, the Netherlands Cancer Institute, Amsterdam; and the Department of Hematology, the Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands. Address reprint requests to Flora E. van Leeuwen, PhD, Department of Epidemiology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: f.v.leeuwen{at}nki.nl.
Purpose: To assess long-term cause-specific mortality of young Hodgkin’s disease (HD) patients. Patients and Methods: The study population consisted of 1,261 patients treated for HD before age 41 between 1965 and 1987. Follow-up was complete until October 2000. For 95% of deaths, the cause was known. Long-term cause-specific mortality was compared with general population rates to assess relative risk (RR) and absolute excess risk (AER) of death. Results: After a median follow-up of 17.8 years, 534 patients had died (55% of HD). The RR of death from all causes other than HD was 6.8 times that of the general population, and still amounted to 5.1 after more than 30 years. RRs of death resulting from solid tumors (STs) and cardiovascular disease (CVD) were increased overall (RR = 6.6 and 6.3, respectively), but especially in patients treated before age 21 (RR = 14.8 and 13.6, respectively). When these patients grew older, this elevated mortality decreased. The overall AER of death from causes other than HD increased throughout follow-up. Patients receiving salvage chemotherapy had a significantly increased RR of death from STs, compared to patients receiving initial therapy only. Conclusion: The main cause of death among HD patients was lymphoma, but after 20 years, HD mortality was negligible. The RRs and AERs of death from second primary cancers (SCs) and CVDs continued to increase after 10 years. Even more than 30 years after diagnosis, HD patients experienced elevated risk of death from all causes other than HD. Increased risk of death from SCs and CVDs was found especially in patients treated before age 21, but these risks seemed to abate with age.
DURING THE past few decades, the survival of patients treated for Hodgkin’s disease (HD) has improved dramatically1–9 as a result of the development of multiagent chemotherapy (CT), more accurate radiotherapy (RT), and enhanced possibilities to treat complications during and after treatment. Unfortunately, the improved prognosis of HD has been accompanied by elevated risks of second primary cancers (SC), cardiovascular disease (CVD), and infections.10–16 Treatments are currently being adapted based on increased knowledge of treatment-related morbidity and mortality. Only a few studies have examined excess mortality for major disease categories in large cohorts of HD patients.5,10,17–20 To our knowledge, there are no reports describing mortality with a median follow-up of more than 15 years. The purpose of this study was to examine cause-specific mortality and absolute excess mortality (compared to population rates) in a cohort of HD patients treated from the 1960s through the 1980s. We focused on patients diagnosed with HD before reaching 41 years of age, because such patients have a greater life expectancy if they are cured.
Data Collection Procedures Our cohort consists of 1,261 patients with HD as the first malignancy, who were no older than 40 years when diagnosed and treated for HD. Patients were treated between 1965 and 1987 in the Netherlands Cancer Institute or the Dr Daniel den Hoed Cancer Center. The selection of patients and methods of data collection have been described in detail in two reports on the incidence of second malignancies in this cohort.15,21 Originally, all patients were identified through the hospital-based cancer registries of both hospitals. Data were collected on each patient’s date of birth, sex, date of diagnosis of HD, splenectomy and date of splenectomy, treatment, relapse and date of relapse, date of diagnosis and topography site of second primary tumors, date of last medical information or date of death, vital status, and primary cause of death, according to International Classification of Diseases (9th revision; ICD-9). For this study we collected the most recent follow-up data from both hospital-based tumor registries. The data for 776 patients who were alive (n = 737) or had emigrated (n = 39), according to our most recent information, were linked with the Central Office of Genealogy (CBG). This register, containing information on date of death for all persons in the Netherlands who have died since 1938, has been computerized since 1994 and is complete until October 1, 2000. For all patients who had died, the medical record was reviewed to register the primary cause of death. If a patient had died after the date of last medical information in the records, a general practitioner and/or other treating physician was sent a questionnaire to obtain the cause of death.
Statistical Analysis To assess treatment effects on cause-specific mortality, we compared patients receiving initial RT only, patients receiving initial RT and chemotherapy only, and patients treated with all other treatments combined (usually salvage therapy). Patients receiving CT only were analyzed with the salvage group. Overall and cause-specific actuarial survival rates were estimated using the Kaplan-Meier method. The impact of SC and CVD on survival was estimated in an analysis in which all deaths from SC or CVD were treated as censored. The Cox proportional hazards model was used to quantify the effects of different treatments and several covariates (age at treatment, sex, and calendar period) on mortality (adjusting for different follow-up periods). Forward stepwise confounder selection, in which the effect of adding one confounder at a time is evaluated, was based on a more than 10% change in the risk estimate of the exposure variable of interest. Cox’s models were fitted with the use of SPSS statistical software (SPSS Inc, Chicago, IL).
Patient cases were evenly distributed over the different treatment periods (Table 1  ). Twenty-six percent of patients received initial RT only, 21% were treated with an initial RT and CT combined without subsequent treatment, 50% received initial and salvage treatment, and only 3% received initial CT alone. Salvage treatment consisted mostly of conventionally dosed chemotherapy, because high-dose chemotherapy with bone marrow transplant was not available then. One third of the patients underwent splenectomy. Median age at the start of treatment was 26 years; median follow-up time was 17.8 years for the whole cohort (a total of 21,290 person-years) and amounted to 21.5 years for patients still alive on October 1, 2000. Twenty-five years after start of treatment, 22% of patients were still alive. Median survival time according to the Kaplan-Meier method was 28.7 years.
Overall Risks of Death The exact causes of death were obtained for 95% of the 534 patients who had died. Two hundred ninety-one patients died of HD; 116 of second malignancies, including 76 of solid tumors (STs); 15 of leukemia (including 12 myeloid leukemias); and nine of MDS. Fifty patients died of CVD, including five of cerebrovascular accidents. Nine deaths due to infectious diseases were observed, including seven cases of septicemia. Six patients were known to have died of intercurrent disease, (precise cause of death unknown) and four of ill-defined diseases (Table 2 ). The 10- and 25-year actuarial risks of death were: for all causes of death, 25.5% and 44.0%, respectively; for HD, 20.4% and 24.2%, respectively; for all SCs, 2.3% and 13.5%, respectively; and for all CVDs, 1.2% and 6.9%, respectively (Fig 1).
Significantly elevated RRs were found for all causes other than HD (RR, 6.8), CVD (including cerebrovascular accidents) (RR, 6.3), cerebrovascular accidents (RR, 3.3; 95% CI, 1.1 to 7.8), infectious diseases (RR, 24.0), sepsis (RR, 92.3), STs (RR, 6.6), leukemia (RR, 28.9) and non-Hodgkin’s lymphoma (RR, 35.6; Fig 2 ). Because of the high background mortality of STs and CVD compared with the low background risk of death from leukemia, Non-Hodgkin’s lymphoma and infectious diseases in the general population, the AER was highest for death from ST (30.3 per 10,000 person-years), followed by cardiovascular death (17.8 per 10,000 person-years; Fig 2).
During the first 15 years after start of treatment, the overall AER of death diminished, due to decreasing mortality from HD. From 15 years after start of treatment, the AER increased again and continued to do so up to at least 30 years from the date of first treatment, because the AER of death from causes other than HD increased dramatically throughout follow-up time. From 20 years since the start of treatment, the overall excess mortality was completely attributable to the excess mortality from diseases other than HD (Fig 3 ). According to the Kaplan-Meier method, the 25-year overall survival rate was 56%. When treating all second malignancies or all CVDs as censored, the proportion of surviving patients at 25 years increased by 8.8% to 64.8% and by 4.2% to 60.2%, respectively.
As we expected, when the disease-specific survival for HD was evaluated over time, the 20-year actuarial survival estimates improved spectacularly, with rates of 65%, 77%, and 87% for the treatment periods 1965 to 1972, 1973 to 1979, and 1980 to 1987, respectively.
Death From STs
Death From Leukemia and MDS Patients aged 21 to 30 years at the start of treatment experienced the greatest risk of death from leukemia or MDS (RR, 57.7). The risk of death from leukemia or MDS was highest in patients younger than 35 years at the end of follow-up. The risk of death from leukemia or MDS was concentrated in the 5 to 10 years follow-up interval; after 10 years there were no more leukemia deaths, whereas six deaths from MDS occurred after 10 years. The RR of leukemia or MDS was lower for patients treated before 1973, but noticeably, the RR for most recently treated patients was approximately as high as that for patients treated in the 1970s. Both the RR and AER of leukemia and MDS were significantly higher among patients receiving salvage treatment than in patients receiving initial RT only (P = .004).
Death From CVD
RRs of cardiovascular death overall and of death from MI were nearly constant throughout follow-up. Risk of cardiovascular death did not vary significantly across treatment groups and appeared to level off after 25 years. When treatment-specific risks were categorized according to treatment period, RRs did not decrease with more recent treatment periods.
Death From Infectious Diseases
Comparisons Within the Study Cohort: Cox Model Analysis
Most late-effect studies have focused on the morbidity of potentially treatment-related disorders, which has the advantage that the risk of such complications is fully assessed, independent of their severity. Mortality studies, on the other hand, address the risk of fatal complications that affect life expectancy. Mortality is not only influenced by the incidence but also by the severity and the treatment possibilities of certain diseases. Complete follow-up and valid ascertainment of cause of death are critical aspects in studies assessing the impact of treatment-related mortality. In our study, follow-up regarding vital status was complete until October 2000, and cause of death was obtained for 95% of patients who had died. Since we assessed the primary cause of death, as opposed to the direct cause of death, it is unlikely that our estimates of RR and AER are overestimated. In several other mortality reports, follow-up was incomplete for patients lost to follow-up in the original treatment center, which may cause overestimation of treatment related risks.23 Generally, the survival of our cohort, with a 10-year overall survival of 75%, is comparable to survival in the literature, given that this cohort consists of patients treated in the period between 1966 and 1986 and includes patients with advanced disease.1,3–6,8,24 Our study, which, to our knowledge, has the longest median follow-up of all mortality reports on HD patients,10,11,18,20,25–29 shows that in the first 10 years following HD, the excess mortality rate is largely due to the primary disease, while after 10 years, causes other than HD contribute most to excess mortality. Unfortunately, even after 30 years of follow-up, there was no evidence of a decline in the RR of death from causes other than HD; however, the number of person-years in this follow-up interval was still rather small. In 30-year survivors of HD, the annual excess mortality rate from all causes other than HD was nearly three per 100 patients. Solid tumors, especially from the digestive and respiratory tract, contributed most to this excess risk, followed by cardiovascular disease. Nearly all studies report that the incidence of STs increases over time and that excess is particularly seen more than 10 years after RT.3,5,14,15,21,30–35 The manifestation of increased death from STs only after a certain follow-up interval is generally assumed to be a result of a (long) induction period but may also be an effect of the patients’ attaining a specific age (the age range in which cancer mortality normally occurs). As we expected from our previous studies,15,21 we found that not only the incidence but also the mortality of STs was most strongly increased in patients treated before the age of 21. The RR of death from STs was highest in patients treated before age 21, with an RR of 15, as compared to RRs of 9 and 4 for patients first treated in their twenties and thirties, respectively. Lee et al 13 observed a similar trend, although the absolute values of the RR estimates differ considerably. Hypothetically, these young patients might be at greater risk for side effects, because immature tissues and organs are more vulnerable to the effects of ionizing radiation, or because these individuals might have genetic alterations also influencing their susceptibility to develop malignancies at an early age. In recent studies, chemotherapy also appears to increase the risk of STs resulting from RT.15,34,36,37 This is particularly important because combined modality is given more often now. We also observed a significantly increased mortality from STs comparing treatment containing chemotherapy with RT alone (P = .04). The excess risk of death from STs after radiation treatment may also be influenced by behavior of the patient: Smokers experience greater risk of lung cancer attributable to RT than do nonsmokers.24,37 An elevated risk in incidence of a malignancy does not always result in an equally elevated risk of mortality. Previously, we described an RR of 5.2 (95% CI; range, 3.4 to 7.6) for breast cancer in one-year survivors from our cohort.15 As a result of early detection and good treatment options for breast cancer, an RR of 2.5 for death from breast cancer was observed in this study.38–40 Strikingly, in our study, 15 of 20 patients who died of a second malignancy before the age of 35 years died of leukemia. The risk of secondary acute leukemia is strongly associated with the use of alkylating chemotherapy and in the treatment of HD is especially associated with the use of mechlorethamine in the regimen of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP).41 Survival after secondary leukemia is usually poor.12,42,43 Since the decreasing use of MOPP, the risk of secondary acute leukemia has been reported to diminish.35,41,43–45 It is important to realize that in our cohort, many patients have still received MOPP chemotherapy (often more than six cycles), whereas now, patients are usually treated with chemotherapy regimens containing less mechlorethamine or none. The increased mortality from CVD that we observed is in agreement with other reports in the literature.3,10,11,13,18,26,46,47 In our study, the majority of the patients were treated with a mantle field including part of the coronary arteries and the heart itself. According to treatment protocols used in the 1960s and 1970s, patients were treated with one field per day, causing an unfavorable, inhomogeneous dose distribution. Shielding of the heart below the carina for part of the treatment was introduced in the 1980s. We did not observe a decrease of the RR of cardiovascular death with more recent treatment periods, probably because of the limited number of patients treated with more recent RT techniques. Hancock et al,46 however, showed that shielding part of the heart did not decrease the risk of death from MI but did decrease the risk of dying from other cardiovascular diseases from an RR of 5.3 (95% CI, 3.1 to 7.5) to 1.4 (95% CI, 0.6 to 2.9). Contrary to our expectations, the RRs of cardiovascular mortality overall and of dying from an MI were already increased within a follow-up of 5 years. Whether this was related to specific treatment factors could not be evaluated, because we did not collect detailed data on radiation dose, radiation technique, chemotherapeutic agents, or CVD risk factors. Few studies have examined whether CT adds to the increased risk of cardiovascular death from RT.48,49 Furthermore, in other studies, patients without cardiovascular risk factors, such as smoking, hypertension, obesity, hypercholesterolemia, or diabetes mellitus, had a low risk of CVD after conventionally fractionated radiation to a dose between 30 and 40 Gy.3 Consistent with the results of Hancock et al,46 we observed a declining trend of RR of death from CVD with advancing age. Among patients treated before age 21, 14-fold increased RRs of death from CVD were observed, whereas RRs of 7 and 5 were found in patients first treated at ages 21 to 30 and 31 to 40 years, respectively. Information on the effect of age at first treatment on mortality of causes other than HD is limited.50 Our study is the first in which RRs and AERs of death from SCs or CVD are given by age at first treatment and attained age, rendering it possible to disentangle the contributions of these variables. Within each category of age at first treatment, the RR of death from SC and the RR and AER of death from CVD decreased with advancing age. The decrease of RRs with increasing age may be due to the strong increase in baseline risk with advancing age in the general population, but the reduction in AER indicates that the burden of CVD is declining when patients grow older. As did other authors,10 we observed in our HD survivor population a strongly increased risk of death from infections (RR = 24). The AER, however, was low, with 4 per 10,000 person-years. Splenectomy did not increase the risk of death from an infectious disease. One could hypothesize that this is due to a vaccine against pneumococcal infections usually administered immediately after splenectomy and instructions about potential risks of infections. Long-term immunosuppression has been observed after treatment with splenectomy, RT, and CT.51–53 In conclusion, our study shows that in patients with HD, their primary disease remained the most important cause of death until 10 years after primary treatment. After 10 years, the main causes of death are, similar to the general population, malignancies and cardiovascular disease. In our population of long-term survivors after HD, however, excess mortality of second cancers and cardiovascular diseases was observed especially in patients treated before age 21. Achieving control of Hodgkin’s disease with first-line treatment is of the utmost importance, in that salvage treatment may cause more late effects. Because of the increased risks of ST after RT,5,14,15 clinical trials are ongoing; some have recently been performed to decrease the extent of the radiation fields54,55and thereby lower the radiation dose in patients with a complete remission after chemotherapy,4,8,56,57 without compromising control of HD. Improved knowledge about the morbidity and mortality after treatment may influence treatment strategies for patients with malignancies as well as follow-up guidelines for long-term survivors. During follow-up it is important to pay attention to possible signs of malignancies—especially of the digestive and respiratory tract and especially in patients treated at young ages. For women who have been irradiated before age 30, screening is urged because of the highly elevated relative risk of developing breast cancer.38–40 Pneumococcal vaccination and instructions on the use of antibiotics are recommended after splenectomy to prevent death from infections. Patients treated for HD should be strongly advised to refrain from smoking, because smoking acts synergistically with radiation in the development of lung cancer24 and, potentially, cardiovascular disease. Finally, timely intervention in other risk factors of CVD (eg, hypertension) may help to reduce the high absolute excess risk of CVD in survivors of HD.
The authors indicated no potential conflicts of interest.
Supported by Dutch Cancer Society grant NKI 98-1833.
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57. Nachman JB, Sposto R, Herzog P, et al: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. J Clin Oncol 20:3765–3771, 2002 Submitted July 22, 2002; accepted April 25, 2003. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
