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Originally published as JCO Early Release 10.1200/JCO.2007.15.5507 on September 22 2008 © 2008 American Society of Clinical Oncology. Long-Term Effects of High-Dose Chemotherapy and Radiation for Relapsed and Refractory Hodgkin's Lymphoma
From the Departments of Radiation Oncology and Epidemiology and Biostatistics, and the Department of Medicine, Lymphoma Service, Memorial Sloan-Kettering Cancer Center; and the Department of Medicine, Weill Cornell Medical College, New York, NY Corresponding author: Karyn A. Goodman, MD, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: goodmank{at}mskcc.org
Purpose To evaluate the risk of late morbidity and mortality, and to assess long-term health-related quality of life (QOL) among patients with relapsed/refractory Hodgkin's lymphoma (HL) after high-dose chemoradiotherapy (HDT) and autologous stem-cell rescue (ASCR).
Patients and Methods From 1985 to 1998, 218 patients with HL were treated on HDT with ASCR salvage protocols. Of these 218, 153 (70%) who survived Results Median follow-up after ASCR was 11.5 years. Among 153 patients, there were 53 deaths; 33 from HL and 20 from other causes. Thirteen deaths were caused by SM, with median time from ASCR to SM diagnosis of 9 years (range, 3 to 18 years). The RR of SM was 6.5 (95% CI, 3.6 to 10.7) when compared with the general population, but 2.4 (95% CI, 1.4 to 4.05) when compared with patients with HL. Global QOL of ASCR survivors was comparable with the general population, but for specific domains, respondents’ scores indicated reduced functioning and worse symptoms. Conclusion HL accounts for most deaths among patients surviving HDT and ASCR. Survivors of ASCR had an elevated risk of SM compared with the cancer risk in the general population, but when compared with patients with HL in SEER, the risk was less pronounced.
Salvage high-dose therapy (HDT) followed by autologous bone marrow transplant or peripheral stem cell rescue (ASCR) has become standard treatment for patients with relapsed or refractory Hodgkin's lymphoma (HL).1-3 Survival rates have risen dramatically with the introduction of techniques that support patients through the complications of therapy. As salvage therapies and support measures have matured, fewer patients succumb to acute complications, but survivors risk late complications from both initial treatment and the sequelae of HDT followed by ASCR.4 Late complications among HL survivors are of particular concern. Excess rates of second cancers, heart disease, pulmonary fibrosis, and infections have been documented.5-12 Indeed, after 10 to 15 years of follow-up, mortality from HL among early-stage patients is exceeded by mortality from late complications.7,13 The recognition of these risks has resulted in modification of chemotherapy regimens and of radiation fields and doses.14,15 Health-related quality of life (QOL) among long-term survivors of ASCR is also affected by late sequelae of treatment, but specific data for the HL population are limited.16-22 Few studies identify predictors of post-transplant long-term QOL specifically for patients with HL, who have higher rates of treatment-related late morbidity and mortality than patients with other cancer diagnoses.23 In this study, we examined long-term medical outcomes and QOL among surviving patients with HL who underwent salvage therapy with HDT/ASCR at Memorial Sloan-Kettering Cancer Center. We evaluated late morbidity and mortality related to this intensive therapy, and identified risk factors associated with reduced QOL and mortality from non-HL causes. To determine if HDT/ASCR elevated the risk of a second malignancy (SM) over conventional HL therapy, we compared our cohort with patients with HL registered in the Surveillance Epidemiology and End Results (SEER) database.
Patient Characteristics Between 1985 and 1998, 218 patients with primary relapsed and refractory HL were treated on one of three institutional review board–approved HDT/ASCR salvage protocols at Memorial Sloan-Kettering Cancer Center.24-26 All patients had biopsy-confirmed relapsed or refractory HL and normal baseline cardiopulmonary function.
For this long-term follow-up study, patients who died within 2 years of HDT/ASCR were excluded in order to limit the analysis to patients more likely to have died of causes other than HL or immediate transplant-related toxicity. Of the original 218 patients, 153 (70%) who survived
Treatment Data Information on treatment at the time of initial diagnosis and any relapse before ASCR was obtained from Memorial Sloan-Kettering Cancer Center electronic records and from outside hospitals, including chemotherapy regimens, doses, number of cycles, and dates; radiotherapy fields, doses, and dates; and surgical procedures when available. Chemotherapy regimens were classified as MOPP-like (mechlorethamine, vincristine, procarbazine, and prednisone), ABVD-like (doxorubicin, bleomycin, vinblastine, and dacarbazine), and MOPP-ABV(D) (combination or hybrid). All patients received radiation therapy as part of initial therapy or accelerated fractionated total lymphoid irradiation (TLI) as part of the HDT regimen. Ninety-three patients (61%) also received IFRT boost to residual or bulky disease immediately before HDT with or without TLI. Data on HDT followed by ASCR were available from an Memorial Sloan-Kettering Cancer Center database. Patients treated from 1985 to 1993 received various reinduction chemotherapy regimens and pretransplant IFRT (15 Gy). Previously unirradiated patients also received accelerated hyperfractionated TLI (20 Gy; 4 days; 12 fractions). Patients then received high-dose etoposide and cyclophosphamide.25 Previously irradiated patients received carmustine (instead of TLI) in addition to etoposide and cyclophosphamide. This was followed by autologous bone marrow transplant in all patients.
The subsequent protocol (1994 to 1998) used a standard reinduction regimen with ifosfamide, carboplatin, and etoposide (ICE).24 Responders to ICE received IFRT (18 to 36 Gy) to nodal sites of residual disease or to sites
Assessment of Health Status and QOL To evaluate health-related QOL, patients also received the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) version 3.0, a 30-item QOL tool extensively validated for use with cancer patients of diverse cultural backgrounds.27 This self-administered questionnaire measures five multisystem domains: physical, role, emotional, cognitive, and social functioning, and an overall assessment of global health status. Higher scores signify better functioning. Three symptom scales measure fatigue, pain, nausea, and vomiting; and six single items assess dyspnea, sleep disturbance, appetite loss, constipation, and diarrhea. Higher scores on the symptom scales and single items represent more severe symptoms. Mean scale and items scores were transformed to a 0 to 100 scale. The reference population for normative data was the German general population.
Statistical Analysis Risk ratios were calculated to examine SM incidence in the ASCR population compared with the cancer incidence in the general population and the SM incidence in all HL survivors. Overall cancer incidence rates and SM incidence rates in HL patients were retrieved from SEER (National Cancer Institute SEER*Stat software version 6.3.5 [http://ser.cancer.gov/seerstat]). The risk of SM was estimated by compiling person-years (PY) of follow-up time by age (5-year intervals), sex, and calendar year from 2 years after ASCR until date of SM diagnosis, death, or last follow-up. The expected number of cancers was estimated by either multiplying the SEER cancer incidence rates for each age group, sex, and calendar year by the accumulated PY at risk, or by multiplying SEER SM incidence rates in patients with HL for each age group, sex, calendar year, and latency since initial HL diagnosis (3 groups: 2 to 5, 5 to 10, and > 10 years) by the accumulated PY at risk. The observed and expected numbers of SM were then separately summed, and the relative risk (RR) was expressed as the ratio of observed-to-expected cases. The absolute excess risk was calculated by dividing the difference between the observed and expected number of SM by the number of PY at risk. The number of excess cancers is expressed per 10,000 PYs. Statistical tests and 95% CI were based on the assumption that the observed number of second cancers was distributed as a Poisson variable. Calculations of the EORTC QLQ-C30 scale scores were performed using the EORTC scoring manual coding for SAS (SAS Institute Inc, Cary, NC).31,32 Using the Wilcoxon rank sum test, univariate analyses assessed associations among demographic and cancer-related variables with QOL measures. Mean scores were compared with normative data from the general population using a regression model to calculate the expected mean scores for each sex and age distribution.33 Ten-point differences were considered clinically relevant.
Survival and Cumulative Incidence of Death Rates With a median follow-up from ASCR of 11.5 years (range, 3 to 18 years), 53 deaths occurred—33 from HL and 20 from other causes. Thirteen deaths were from SM, including five acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), three non-HL (NHL), two non–small-cell lung cancer (NSCLC), two colon cancer, and one gastric cancer. There were seven non-SM deaths: heart disease (n = 4), infection, suicide, unknown cause (one each). Ten- and 15-year overall survival rates were 71% and 60%, respectively (Fig 1). The 5-, 10-, and 15-year cumulative incidence of death rates from HL were 15.2%, 21.3%, and 22.3%, respectively (Fig 2). For mortality from causes other than HL, the 10- and 20-year cumulative incidence of death rates were 8.0% and 17.5%. In particular, the 10- and 15-year cumulative incidence death rates from SM were 5.1% and 11.1%. By univariate analysis, increased risk of death from SM was associated only with higher age at initial diagnosis and at ASCR (P = .03, P = .01, respectively). Other clinical variables, including sex, stage at diagnosis and transplant, pretransplant chemotherapy (MOPP, ABVD, hybrid, or other), protocol era (1985 to 1993, 1994 to 1998), TLI, and mediastinal radiotherapy, were not associated with SM mortality.
SM Fifteen patients were diagnosed with a SM; 13 have died (Table 2). Of the two surviving patients, one was alive with adenocarcinoma of unknown primary and the other was successfully treated for AML. Median age at diagnosis of SM was 46 years; median time from ASCR to SM was 9 years (range, 3 to 18 years). The 5-, 10-, and 15-year cumulative incidence of developing a SM were 2.0% (range, 0.7% to 6.2%), 5.8% (range, 3.0% to 11.5%), and 15.3% (range, 8.9% to 26.2%), respectively. Thirteen of 15 patients received alkylating agents as part of an initial chemotherapy regimen, including mechlorethamine, cyclophosphamide, and/or thiotepa. Those who developed AML or MDS received MOPP-based chemotherapy before HDT. Bone marrow cytogenetic analysis was only available for two of these six patients, and both had a deletion of 7q. One had a 5q deletion and a rearrangement at 11q23.
The RR of SM among patients receiving HDT/ASCR was elevated compared with the general population in the SEER registry (Table 3). The AER was 108 of 10,000 PYs. The RR was significantly elevated in each follow-up time interval. The RR of SM compared with only patients with HL in the SEER registry was not elevated at 2 to 5 years or 5 to 10 years after ASCR, but became significantly higher after 10 years. The overall RR of SM was 2.45 compared with patients with HL; the AER was 75 of 10,000 PYs.
Late Morbidity and Health-Related QOL Of 153 eligible patients surviving  2 years after ASCR, 107 survived by 2003. Sixty-nine patients participated in the QOL study, and 60 patients (56%) completed both self-administered questionnaires, including the health status questionnaire and the EORTC QLQ C-30 version 3. The disease and treatment characteristics of these 60 patients are comparable with the study group as a whole (Table 1). The remaining 38 patients were: living outside of the United States (n = 6); contacted but never submitted the questionnaire (n = 15); or lost to follow-up (n = 16). One patient died during that period. The median interval between ASCR and completion of the questionnaire was 12 years (range, 6 to 18 years). Of these 60, five have died—one of progressive HL and four from SM. Among respondents to the health status questionnaires, four had coronary artery disease resulting in myocardial infarction (n = 1), cardiac bypass surgery or angioplasty (n = 3). One patient developed chemotherapy-induced cardiomyopathy. Almost half (49%) of these patients reported subclinical hypothyroidism. Thirteen patients reported being diagnosed with breathing or lung problems. Of those, six reported lung fibrosis and six had chronic bronchitis. Other reported late effects included avascular necrosis of the hips (n = 2), stroke, esophageal stricture, renal failure, and small bowel obstruction (one each). Thirty-six respondents (57%) reported infertility; of those, 25 (40%) underwent work-up for infertility. Eight respondents reported major depression.
Mean values for most QOL scales were comparable with expected scores for the general population, including global QOL (Table 4).33 For specific domains including social and cognitive functioning, as well as symptom scales for fatigue, insomnia, and financial problems, scores were 10 points higher than mean scores for the general population. This suggests a clinically relevant difference for respondents in the degree to which their physical condition and medical treatment interfered with family life and social activities. Respondents also experienced difficulty concentrating and remembering, fatigue and insomnia, and concern about financial issues. Of the demographic and treatment-related variables, including sex, age at HL diagnosis (< 26.5 years,
This study confirms that patients with relapsed or refractory HL who undergo salvage HDT and ASCR are at highest risk of death from recurrent HL; however, among the increasing number of long-term survivors, late effects of therapy are also significant with a 15-year cumulative mortality from SM of 11%. Our study demonstrates that patients with HL receiving aggressive therapy with high-dose chemotherapy and large-field radiation therapy have slightly higher rates of SM than patients with HL as a whole. At 10 years from ASCR, the SM risk begins to exceed the risk observed in patients with HL from the SEER registry, the majority of whom received conventional therapy alone. These results differ from a British Columbia study in which an elevated risk of SM was not identified among 202 patients with HL who underwent ASCR as compared with patients with HL receiving conventional therapy alone. With a median follow-up of 9.8 years, they reported 12 SMs, resulting in a 15-year cumulative incidence of 8%.34 More than half the SM deaths in this study were from hematologic malignancies, with six AML/MDS and three NHL cases. This may not only be attributable to high-dose etoposide as part of the ASCR regimen, but also to the MOPP-based regimens for initial therapy or conventional salvage treatment as well as exposure to TLI as part of initial therapy or as part of the ASCR protocol.11,35-37 Despite the elevated risk of breast cancer in female patients with HL who have received mantle irradiation,38,39 there were no breast cancers in this cohort. The breast cancer risk is most pronounced for patients younger than 30 at the time of irradiation.40 The median age of women at ASCR, when many received TLI, was 30 years; thus, they tended to be older, potentially reducing their risk. The exposure to alkylating agents as part of prior therapy may also have resulted in decreased ovarian function and early menopause, a finding consistent with data suggesting that hormone stimulation is critical for radiation-induced breast carcinogenesis.38,40-41 Most survivors of relapsed and refractory HL in our study enjoyed normal lives after transplant. Their global QOL score was comparable with the EORTC referent general population. However, late treatment-related morbidity was significant, with cardiac, pulmonary, and infertility issues. There were also complaints of fatigue, insomnia, and financial problems, corresponding to reports that survivors of bone marrow transplantation experience relatively good post-transplant global QOL, but encounter persistent deficits in specific psychosocial functions.16-22,42 In our study, only the number of recurrences was associated with reduced physical and social functioning, probably from exposure to additional therapy.
Small sample size is the principal limitation of this single-institution study. Changes in treatment protocols, supportive measures, and other types of cohort effects have taken place over the last 15 years. New radiation therapy technology has affected dose delivery and precision of treatment fields. These cohort effects were taken into account by analyzing time period of treatment. As a tertiary care center, Memorial Sloan-Kettering Cancer Center patients are often observed elsewhere. Despite attempts to track down patients, many were lost to follow-up. While there was no difference in demographic and treatment characteristics between the 60 respondents and the total cohort, it is possible that patients who responded to the QOL questionnaire may have been healthier than those lost to follow-up, resulting in an upward bias in QOL responses. Another limitation is that the median follow-up of 11.5 years may not be long enough to detect mortality associated with cardiovascular problems and other SMs that can manifest During the past 40 years, modifications in patient treatment and initial treatment have reduced late effects from conventional therapies. With the current combined-modality therapy using moderate doses of IFRT and fewer cycles of risk-adapted chemotherapy, cardiac complications and development of SMs should diminish. Expectations of long-term risks based on obsolete radical treatments may not pertain to patients treated today with combined-modality therapy.43 It is necessary to evaluate the effects of transplant in a newer cohort of patients to determine to what degree high-dose therapy increases the risk of late effects. Number of recurrences and thus more exposure to multiple rounds of chemotherapy was the only predictor of reduced QOL in this study. Although decreasing chemotherapy doses or radiation therapy fields in the salvage setting may not be entirely possible, modifications can be made to better adapt high-dose therapy to risk. Finally, surveillance mechanisms should be in place to follow patients after transplantation. Primary care physicians should institute interventions and screening mechanisms that reduce the risk of mortality from late cardiovascular events and second cancers in these patients.
The author(s) indicated no potential conflicts of interest.
Conception and design: Karyn A. Goodman, Joachim Yahalom Financial support: Karyn A. Goodman, Joachim Yahalom Administrative support: Victoria Serrano Provision of study materials or patients: Subhash Gulati, Craig H. Moskowitz, Joachim Yahalom Collection and assembly of data: Karyn A. Goodman, Victoria Serrano Data analysis and interpretation: Karyn A. Goodman, Elyn Riedel, Joachim Yahalom Manuscript writing: Karyn A. Goodman, Elyn Riedel, Joachim Yahalom Final approval of manuscript: Karyn A. Goodman, Craig H. Moskowitz, Joachim Yahalom
We thank Carol Pearce for assistance with manuscript preparation. We also thank the patients who were treated on the autologous stem-cell rescue protocols at Memorial Sloan-Kettering Cancer Center, many of whom participated in this long-term outcome study by answering questionnaires and responding to our requests for follow-up information.
published online ahead of print at www.jco.org on September 22, 2008. Supported by the Lymphoma Foundation. K.A.G. was a Dr Morton Lacher Lymphoma Fellow at Memorial Sloan-Kettering Cancer Center. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 statistic was used for categoric variables,
28 years, > 28 years), bone marrow or peripheral stem cell rescue, years between ASCR and questionnaire (
