Role of Hematotoxicity and Sex in Patients With Hodgkin's Lymphoma: An Analysis From the German Hodgkin Study Group
http://www.100md.com
《临床肿瘤学》
the First Department of Internal Medicine, Department of Radiation Oncology, Coordination Center for Clinical Trials
the German Hodgkin Study Group, University Hospital Cologne, Germany
ABSTRACT
PURPOSE: Several scores have described sex as a prognostic factor in patients with Hodgkin's lymphoma (HL). However, little is known how sex-specific factors influence treatment outcome. We systematically investigated sex differences with regard to pretreatment characteristics and therapy-related variables, and examined their influence on the outcome of HL patients.
PATIENTS AND METHODS: This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed.
RESULTS: Male and female patients had similar prognostic factors. There was more acute chemotherapy-related hematotoxicity in women, especially more severe leucopenia (WHO grade 3/4, 69.9% female and 55.2% male; P < .0001). Importantly, this did not translate into more infections. Female patients had similar response rates but fewer relapses and deaths, leading to a significantly better freedom from treatment failure (FFTF; at 66 months, 81% female [95% CI, 79% to 82%] and 74% male [95% CI, 72% to 76%]). Severe leucopenia during chemotherapy was strongly associated with better FFTF, both for males and females. In addition, when only those patients who developed severe leucopenia within the first two cycles of chemotherapy were included, the factor maintained its protective role.
CONCLUSION: The protective role of severe leucopenia suggests the testing of a more individualized therapy. In future trials, this therapy may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.
INTRODUCTION
Because of the substantial progress in recent years, Hodgkin's lymphoma (HL) has one of the best cure rates of all adult malignancies. According to stage and risk factors, patients with HL are usually assigned to early-stage favorable, early-stage unfavorable, and advanced-stage risk groups.[1] The freedom from treatment failure (FFTF) after 5 years ranges from approximately 90% for patients in early favorable stages[2] to 80% to 85% for those in early unfavorable and advanced stages.[3,4] Thus, an additional intensification of treatment does not seem possible without overtreating a substantial proportion of patients. Consequently, ongoing studies aim at reducing treatment-related toxicity,[5] including organ damage, infertility, and secondary malignancies such as acute myeloid leukemia,[6] non-Hodgkin's lymphoma (NHL),[7] and solid tumors.[8-11]
Despite recent progress, a small proportion of HL patients experience relapse or have primary refractory disease. Thus far, specific markers are missing that predict unfavorable outcome or excessive toxicity during first-line treatment. Furthermore, little is known about the impact of patient-related factors and drug metabolism on disease outcome. Different enzyme status and slower drug clearance in women, resulting in higher systemic toxicity, suggest that sex-specific aspects become increasingly important.[12]
In accordance with higher mortality rates, male sex has been identified as an adverse prognostic factor for HL patients.[13-15] In the International Prognostic Score (IPS), male sex is an independent unfavorable factor for advanced stages.[13] A prognostic index for pediatric HL identified male sex as one of five pretreatment factors correlating with inferior disease-free survival, although male patients had significant advantages in several prognostic categories before therapy.[14] A comparison of different prognostic models in patients with advanced HL identified age, stage of disease, lymphocyte count, and sex as factors with the highest impact.[15] However, none of these scores allows an identification of individual risk profiles or therapy-related risk profiles during treatment. In addition, the seven factors of the IPS were detected before the introduction of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen. The advent of this more effective treatment, particularly for patients in advanced stages, has rendered some of the older prognostic models such as the IPS void.[16]
Epidemiologic studies suggest an increase in the incidence of HL in young males age 10 to 24 and females age 10 to 29 years.[17] Simultaneously, a decrease was recorded for elderly patients that is at least in part related to more precise reference histology that excludes many diagnoses in elderly patients as non-Hodgkin's lymphoma.[18] So far, little is known on sex-specific differences in HL. One small analysis performed between 1969 and 1987 found that female sex was correlated with an inferior disease-free survival. However, only 163 patients were included and treatment was heterogeneous.[19] Another more recent study with 273 patients suggests that a positive Epstein-Barr virus status may be associated with better failure-free survival, particularly for males and younger adults with advanced HL.[20]
Taken together, data on sex- and patient-related factors are scarce, particularly in lymphoma patients. To fill this gap, we undertook a large retrospective analysis from the German Hodgkin Study Group (GHSG) database to explore systematically sex-specific characteristics of HL patients and their influence on the treatment outcome. We hypothesize that the superior outcome of female HL patients described in the present analysis is at least in part related to a different metabolism and thus better systemic dosing of cytostatic treatment compared with that in male HL patients.
PATIENTS AND METHODS
Patient Eligibility
Between 1988 and 1998, the GSHG conducted two trial generations for early favorable, early unfavorable, and advanced-stage HL (HD4 to HD6 and HD7 to HD9). To be eligible for these trials, patients had to be between 15 and 75 years of age. The present analysis includes only patients with a clear histopathology diagnosis performed by a pathologist. In addition, 72% of the patient cases were not only diagnosed by the initial pathologists but were also reviewed by a panel of lymphoma expert pathologists to confirm the diagnosis for the purpose of quality assurance.
Exclusion criteria before study entry were concomitant or prior malignancy, pregnancy, a positive HIV test, severe concurrent infection, cerebral dysfunction, Karnofsky performance score of 60 or inadequate organ function as defined by a creatinine clearance less than 60 mL/min, serum aminotransferases more than 100 U/L, serum bilirubin more than 2 mg/dL, left ventricular ejection fraction less than 0.45, forced expiratory volume in first second or diffusion capacity of carbon monoxide less than 60% of predicted, WBC counts less than 3,000/μL, hemoglobin less than 8 g/dL, and platelets less than 100,000/μL. Each patient signed an informed-consent form, which was based on institutional review board guidelines.
Data Selection
Data analysis used collected data of 2,050 female and 2,576 male patients, which were recorded in the GHSG trial database and assessable for the final analysis of the corresponding trials HD4, HD5, HD6, HD7, HD8, and HD9.[2-4,21-23] Depending on the year of randomization, patients were allocated to the second (HD4 to HD6) or third (HD7 to HD9) generation of GHSG trials ([Table 1]). Generally, patients in clinical stage I or II without risk factors (early favorable stages) were enrolled onto HD4 or HD7, and those with one or more risk factors (early unfavorable stages) were enrolled onto HD5 or HD8. Patients with stage III or IV (advanced stages) qualified for HD6 or HD9. One group of HD5 patients (332 patients) in stage IIB or IIIA with certain risk factors was excluded from the analysis for reasons of comparability, given that they would have been considered as having advanced-stage disease according to the criteria of the subsequent trial generation HD6 to HD9. All 4,626 patients in trials HD4 to HD7 were included in the descriptive analyses. However, 686 patients in early favorable stages did not receive chemotherapy (HD4, 375 patients; HD7 arm A, 311 patients). For 93 patients, data on chemotherapy were missing or too incomplete for evaluation. In 22 patients, data on leucopenia were not assessable. Thus, 3,825 patients were assessable for chemotherapy and toxicity analyses.
The median observation time for all patients was 5.5 years. Trial design, number of patients, chemotherapy regimen used, and radiotherapy given in these studies are listed in [Table 1].
Statistical Analysis
Demographics and patient characteristics were summarized using descriptive statistics from SPSS 10.0 for Windows (SPSS Inc, Chicago, IL). Patient characteristics and survival data from trials HD4 to HD9 were assessed separately for males and females. Freedom from treatment failure (FFTF) and overall survival (OS) rates were estimated according to the Kaplan-Meier method.[24] FFTF was defined from date of random assignment to treatment to one of the following events: progression during therapy, lack of complete remission at the end of protocol treatment, relapse, or death as a result of any cause. OS was defined as the time from date of randomization until death as a result of any cause. Response criteria (complete remission, partial remission, no change, and progressive disease) were used as described previously.[3]
Univariate analyses were performed to evaluate the influence of sex (and all other variables differing between males and females) on the outcome of HL. Subsequently, multivariate analysis was executed. A Cox proportional hazards regression model was used to assess the influence of prognostic factors.[25] All variables found to have a P value of less than .05 were considered significant. All survival-related statistical analyses were performed with SAS, Version 8.2 (SAS Institute, Cary, NC).
RESULTS
Patient Characteristics
Patient characteristics are listed in [Table 2]. A total of 4,626 patients from the GHSG trials HD4 to HD9 were included. There were 2,050 female and 2,576 male patients. The median age at diagnosis was 31 years for female and 33.5 years for male patients (range, 15 to 75 years). Most patients had a good Karnofsky performance status. Review histology revealed the following frequency of occurrence for the different HL subtypes: nodular sclerosis more than mixed cellularity more than lymphocyte predominant or lymphocyte rich classical more than lymphocyte depleted. Staging procedures before therapy determined early-stage favorable disease in 19.3% females and 23.5% males, early-stage unfavorable disease in 43.6% females and 34.3% males, and advanced-stage disease in 37.1% females and 42.2% males. "B" symptoms were present more often in men at diagnosis. The distribution of clinical risk factors and prognostic factors was mostly similar between females and males; however, more women presented with a large mediastinal mass and more men with stage IV disease ([Table 2]).
Acute Toxicity From Chemotherapy
Acute toxicity from chemotherapy, recorded in 3,825 patients, was more pronounced in females, with 81.2% experiencing grade 3 or 4 toxicity from chemotherapy in at least one cycle compared with 71.0% of males ([Table 3]). Most toxicities were evenly distributed, except for hematotoxicity: women showed more pronounced anemia and, in particular, leucopenia. More female patients presented with WHO grade 3/4 leucopenia (69.9% females compared with 55.2% males; P < .0001), although there was a higher percentage of men receiving more intense therapy ([Table 2]). However, the rate of infection did not differ between the two collectives (P = .8293), with 23.3% females and 22.5% males developing grade 1/2 infections and 6.5% females and 6.4% males developing grade 3/4 infections. Other recorded toxicities mainly included transient disorders such as alopecia or nausea. No specific preference for either sex was observed for serious organ-related toxicity.
Application of Chemotherapy: Cycles and Drug Dosage
Those patients undergoing chemotherapy received an average of 94.2% of the scheduled dose (the average over all drugs). Most patients (94.1%) obtained the designated number of cycles (98.6% in early favorable, 98.7% in early unfavorable, and 88.9% in advanced stages). A total of 89.1% patients received chemotherapy per protocol, which was defined as 100% (the scheduled dose) ± 15% deviation as the average over all drugs (94.2% in early, 95.7% in early unfavorable, and 82% in advanced stages). Chemotherapy per protocol was applied equally in both sexes, with 89.6% in females and 88.8% in males (data not shown).
Acute Toxicity From Radiotherapy
A smaller proportion of patients experienced acute toxicity grade 3/4 from radiotherapy (12.0% females and 10.5% males). Grade 3/4 leucopenia during radiotherapy was more pronounced in females (5.1%) than males (3.6%). Other toxicities observed in more than 1% ofpatients comprise nausea, thrombocytopenia, and toxicities of the skin, the pharynx, and the esophagus (data not shown).
Treatment Outcome, Causes of Death, and Secondary Malignancies
The overall response rates were as follows: a complete remission (confirmed or unconfirmed) was recorded in 90.7% females and 89.7% males, partial remission was recorded in 2.0% females and 2.8% males, primary progressive disease was recorded in 5.0% females and 5.3% males, and relapse was recorded in 9.1% females and 11.8% males. In total, 10.3% of females and 14.6% of males died. The causes of deaths during study and follow-up were mainly related to HL (46.2% of deaths in females; 39.4% of deaths in males). Another proportion of patients died due to acute toxicity from first-line or salvage therapy (18.4% females and 15.4% males). Death from secondary malignancies accounted for 15.6% females and 17.6% males. Other mortality included cardiovascular disease, which was recorded twice as often in males than females (5.7% females; 10.6% males), and lung failure (0.9% females; 3.2% males).
A total of 195 secondary malignancies were registered, 76 in females and 119 in males. Most patients developed solid tumors (31 females and 48 males). Other secondary malignancies included acute myeloid leukemia/myelodysplastic syndrome (22 females; 20 males) and non-Hodgkin's lymphoma (16 females and 46 males; [Table 4]).
Sex-Specific Outcome
The influence of sex on the outcome of HL patients was assessed by univariate analysis: at a median observation time of 66 months, female patients showed significantly (P < .0001) better FFTF (81%; 95% CI, 79% to 82%) compared with male patients (74%; 95% CI, 72% to 76%; [Fig 1]). Superiority was also observed for overall survival with 90% (95% CI, 88% to 91%) for females and 86% (95% CI, 85% to 87%) for males (P < .0001; [Fig 2]).
Identification of Prognostic Factors
Additional analyses were performed to evaluate the independent prognostic role of sex and sex-related variables on the FFTF of patients with HL. All known risk factors as well as the patient characteristics differing between female and male patients were included. In addition to sex, the following factors had a significant influence on FFTF in univariate analyses: stage of disease (P < .0001), age (P < .0001), B symptoms (P < .0001), IPS (grouped; P < .0001), designated number of cycles (P < .0001), and chemotherapy per protocol (P < .0001; [Table 5]).
Multivariate analyses were performed using a Cox proportional hazards regression model to assess the influence of prognostic factors. Sex was not identified as an independent prognostic factor in this setting. However, the following variables, which were more frequent in women, were associated with better FFTF: lower stages of disease (P < .0001), younger age (P < .0001), more leucopenia grade 3/4 from chemotherapy (P < .0001), fewer B symptoms (P = .0204), and a favorable IPS group (P = .0118; [Tables 6] and [7]). Most of these factors contributing to a better outcome in females include favorable characteristics of the female patients included at diagnosis. However, the occurrence of more leukopenia grade 3/4 in females (with the same therapy) is a protective factor that might be susceptible to clinical influence and was therefore analyzed further.
Protective Role of Leucopenia
The higher prevalence of severe leucopenia (grade 3/4) during chemotherapy was correlated with better FFTF in women. Importantly, the smaller proportion of male patients experiencing severe leucopenia also had a better outcome than their counterparts without severe leucopenia: when calculating the multivariate analysis ([Table 6]) separately for male and female patients, severe leucopenia (grade 3/4) remained significant, with P = .0011 when only male patients were included (hazard ratio [HR] = 0.644; 95% CI, 0.495 to 0.838) and P = .0444 when only females were included (HR = 0.699; 95% CI, 0.493 to 0.991; data not shown). In an additional step, only those patients who developed leucopenia grade 3/4 in the first or second cycle of chemotherapy were included (not in any cycle of chemotherapy). These patients also had a highly significantly better FFTF (P = .0002) compared with all other patients ([Table 7]).
For patients with advanced HL who received treatment with BEACOPP in baseline or escalated dose (HD9 arms B + C), the presence of severe leucopenia (grade 3/4) during chemotherapy also contributed to a better outcome (P = .0074; [Table 8]). When those patients who experienced grade 3/4 leucopenia within the first two cycles of BEACOPP are considered, the factor maintained its protective role (P = .0205; [Table 9]).
DISCUSSION
To our knowledge, this large retrospective analysis including a total of 4,626 patients is the first to investigate sex-specific differences and their influence on treatment and outcome in HL. The following results emerge from this study.
First, more female patients experienced chemotherapy-induced hematotoxicity, particularly severe leucopenia (grade 3/4). However, there was no difference in the rate of severe infections between male and female patients. Second, women showed significantly better outcomes compared with men (FFTF, 81% v 74%; P < .0001; OS, 90% v 86%; P < .0001). The better prognosis is related to more favorable patient characteristics at diagnosis such as younger age, less stage III/IV disease, fewer B symptoms, and a better prognostic score in females. In addition, the occurrence of severe leucopenia is a protective factor for FFTF in the multivariate analysis. Third, all patients experiencing severe leucopenia at any time during chemotherapy fare better than other patients. This was also validated for the first two cycles of treatment and for advanced-stage HL patients undergoing BEACOPP therapy. Fourth, these analyses suggest the testing of a toxicity-adapted treatment strategy in future trials with a similar patient collective, using severe leucopenia within the first two cycles as the relevant parameter.
A small recent analysis from our group including 266 patients with advanced HL suggested that low acute hematologic toxicity might independently predict a worse disease control.[26] Although these findings might in part explain prognostic differences between a number of subgroups, no larger analysis has ever analyzed sex-specific factors systematically in this group of patients. Our data clearly point toward an undertreatment of a portion of male HL patients, particularly in advanced stages. Here, 29.0% male patients compared with 18.8% female patients had no or only grade 1/2 leucopenia.
It can be hypothesized that the higher toxicity profile observed for female HL patients in this analysis may be related to a different enzyme status, drug metabolism, and poorer drug clearance. Genetic polymorphisms are known to produce intraindividual differences in drug toxicity, and their expression and activity are influenced by factors such as sex, smoking, or coadministration of other drugs.[27] Furthermore, individual differences in DNA sequences that alter the expression of proteins targeted by cytostatic drugs can contribute to variations in toxicity during treatment and outcome.[28] Results from patients with colorectal cancer suggest higher systemic drug levels in women, resulting in higher toxicity due to lower drug clearance.[29] Two phase III trials confirmed female sex and advanced age as independent predictors for fluorouracil (FU) toxicity.[30,12] Female sex predicts for increased severe hematologic and nonhematologic toxicity related to FU.[12] Severe toxicity and toxic deaths after treatment with FU were mainly associated with the first cycle.[31] These toxic effects may be related to sex-specific differences in dihydropyrimidine dehydrogenase. This rate-limiting enzyme in the catabolism of FU has shown deficiencies more frequently in women.[32]
For single anticancer drugs, pharmacokinetic models have been established, using therapeutic drug monitoring as a tool for controlling toxicity and at the same time improving efficacy. Examples include the continuous infusion of FU, where doses can be routinely adjusted posteriori on the basis of blood levels measured. An a priori model is used for carboplatin, which allows clinicians to calculate the dose to be given based on weight, age, sex, and creatinine clearance.[33]
In the treatment of malignant lymphoma, the development of pharmacokinetic models is challenging because of the complexity of multidrug regimen being used. Correlation between drug metabolism, clearance, and treatment outcome has just begun to attract scientific interest: an inadequate low clearance of cyclophosphamide to active metabolites was associated with increased risk of disease recurrence in 34 children with B-cell non-Hodgkin's lymphoma.[34] Another recent study retrospectively investigated 45 patients with CNS lymphoma treated with different high-dose methotrexate-based combinations. In that study, a high area under the curve of methotrexate and a slow creatinine clearance were favorable outcome-determining factors.[35]
With regard to the excellent cure rates of patients with HL using the modern combination regimen, response-adapted therapy (RAT) models might be warranted. This should help avoid overtreatment and reduce life-threatening toxicity for patients with higher sensitivity, and should enable escalation of dose or cycle numbers for patients with a reduced systemic dose and thus reduced disease control. Diagnostic approaches of RAT are currently being developed: early response to chemotherapy might represent a surrogate for final outcome and might result in less treatment given.[36] New diagnostic tools such as positron emission tomography may serve as better indicators for early response during chemotherapy and influence the decision on length and intensity of treatment.[37] In the future, new prognostic indices will need to incorporate prognostic biologic markers such as soluble CD30 and others, to identify patients with poor prognosis early to allow a more intense treatment.[38] In addition, gene expression profiling using cDNA microarrays may lead to better biologic characterization of lymphoid malignancies.[39] For diffuse large B-cell lymphoma, DNA microarrays were used to construct a gene-based independent prognostic predictor of risk and survival after chemotherapy.[40] This molecular classification was confirmed by immunohistochemistry using tissue microarrays.[41] However, for HL the search for specific biologic markers continues.
In the meantime, a more practical clinical approach of RAT based on the current analysis could use leucopenia as the relevant parameter to adjust dose-intensity. This might be an effective means to better fine-tune chemotherapy, at least for patients with comparable eligibility criteria (ie, good performance status and no severe comorbidity). Escalated BEACOPP therapy has been shown to substantially improve outcomes for advanced-stage HL.[4] Despite increased hematotoxicity, this regimen is safe for the majority of patients when granulocyte colony-stimulating factor and other supportive measures are used.[42] Mortality associated with escalated BEACOPP therapy ranges between 1.7% (GHSG HD9 trial, arm C) and 3.1% (GHSG HD12 trial).[43] These deaths were observed mainly within the first two cycles of escalated BEACOPP as well as in patients older than 50 years with a poor risk profile (IPS 3 to 7). As a consequence, the age for this regimen was restricted and preventive measures such as hospitalization for the first cycle and introduction of antibiotic prophylaxis. As listed in [Table 5], patients with severe complications and subsequent early termination of chemotherapy have a poorer outcome compared with those receiving chemotherapy per protocol.
In addition to the already established toxicity-based dose reduction, a stepwise dose escalation may improve outcome for certain advanced HL patients who do not experience hematotoxicity grade 3/4 during the first cycles of treatment. This hypothesis could be tested within a new pilot trial with the aim to improve FFTF for a subgroup of patients (especially young males) who might have lower disease control due to a different drug metabolism. Results from patients with aggressive NHL treated with dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone indicated that this approach is safe and at the same time might result in higher efficacy.[44] In this trial sponsored by the US National Cancer Institute, doses of the hematotoxic drugs etoposide, doxorubicin, and cyclophosphamide were adjusted by 20% each cycle to achieve an absolute neutrophil count below 0.5 x 109/L.
The present analysis demonstrates clearly the sex-specific differences in patients with HL. The protective role of severe leucopenia suggests a better dose-adapted treatment, not only for de-escalation but also for possible escalation. Future studies, particularly for patients with good performance status in advanced-stage HL, might use such a toxicity-tailored approach, adjusting therapy to individual leucopenia within the first cycles.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank all members and associated centers of the GHSG for enabling the conduct of the clinical trials HD4 to HD9, which provided a basis for this analysis.
NOTES
Supported in part by the German Cancer Aid (Deutsche Krebshilfe), the Competence Network Malignant Lymphoma (Kompetenznetz Maligne Lymphome), and the German Federal Ministry of Science and Education (Bundesministerium für Bildung und Forschung).
Presented in part at American Society of Hematology, Orlando, FL, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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the German Hodgkin Study Group, University Hospital Cologne, Germany
ABSTRACT
PURPOSE: Several scores have described sex as a prognostic factor in patients with Hodgkin's lymphoma (HL). However, little is known how sex-specific factors influence treatment outcome. We systematically investigated sex differences with regard to pretreatment characteristics and therapy-related variables, and examined their influence on the outcome of HL patients.
PATIENTS AND METHODS: This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed.
RESULTS: Male and female patients had similar prognostic factors. There was more acute chemotherapy-related hematotoxicity in women, especially more severe leucopenia (WHO grade 3/4, 69.9% female and 55.2% male; P < .0001). Importantly, this did not translate into more infections. Female patients had similar response rates but fewer relapses and deaths, leading to a significantly better freedom from treatment failure (FFTF; at 66 months, 81% female [95% CI, 79% to 82%] and 74% male [95% CI, 72% to 76%]). Severe leucopenia during chemotherapy was strongly associated with better FFTF, both for males and females. In addition, when only those patients who developed severe leucopenia within the first two cycles of chemotherapy were included, the factor maintained its protective role.
CONCLUSION: The protective role of severe leucopenia suggests the testing of a more individualized therapy. In future trials, this therapy may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.
INTRODUCTION
Because of the substantial progress in recent years, Hodgkin's lymphoma (HL) has one of the best cure rates of all adult malignancies. According to stage and risk factors, patients with HL are usually assigned to early-stage favorable, early-stage unfavorable, and advanced-stage risk groups.[1] The freedom from treatment failure (FFTF) after 5 years ranges from approximately 90% for patients in early favorable stages[2] to 80% to 85% for those in early unfavorable and advanced stages.[3,4] Thus, an additional intensification of treatment does not seem possible without overtreating a substantial proportion of patients. Consequently, ongoing studies aim at reducing treatment-related toxicity,[5] including organ damage, infertility, and secondary malignancies such as acute myeloid leukemia,[6] non-Hodgkin's lymphoma (NHL),[7] and solid tumors.[8-11]
Despite recent progress, a small proportion of HL patients experience relapse or have primary refractory disease. Thus far, specific markers are missing that predict unfavorable outcome or excessive toxicity during first-line treatment. Furthermore, little is known about the impact of patient-related factors and drug metabolism on disease outcome. Different enzyme status and slower drug clearance in women, resulting in higher systemic toxicity, suggest that sex-specific aspects become increasingly important.[12]
In accordance with higher mortality rates, male sex has been identified as an adverse prognostic factor for HL patients.[13-15] In the International Prognostic Score (IPS), male sex is an independent unfavorable factor for advanced stages.[13] A prognostic index for pediatric HL identified male sex as one of five pretreatment factors correlating with inferior disease-free survival, although male patients had significant advantages in several prognostic categories before therapy.[14] A comparison of different prognostic models in patients with advanced HL identified age, stage of disease, lymphocyte count, and sex as factors with the highest impact.[15] However, none of these scores allows an identification of individual risk profiles or therapy-related risk profiles during treatment. In addition, the seven factors of the IPS were detected before the introduction of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen. The advent of this more effective treatment, particularly for patients in advanced stages, has rendered some of the older prognostic models such as the IPS void.[16]
Epidemiologic studies suggest an increase in the incidence of HL in young males age 10 to 24 and females age 10 to 29 years.[17] Simultaneously, a decrease was recorded for elderly patients that is at least in part related to more precise reference histology that excludes many diagnoses in elderly patients as non-Hodgkin's lymphoma.[18] So far, little is known on sex-specific differences in HL. One small analysis performed between 1969 and 1987 found that female sex was correlated with an inferior disease-free survival. However, only 163 patients were included and treatment was heterogeneous.[19] Another more recent study with 273 patients suggests that a positive Epstein-Barr virus status may be associated with better failure-free survival, particularly for males and younger adults with advanced HL.[20]
Taken together, data on sex- and patient-related factors are scarce, particularly in lymphoma patients. To fill this gap, we undertook a large retrospective analysis from the German Hodgkin Study Group (GHSG) database to explore systematically sex-specific characteristics of HL patients and their influence on the treatment outcome. We hypothesize that the superior outcome of female HL patients described in the present analysis is at least in part related to a different metabolism and thus better systemic dosing of cytostatic treatment compared with that in male HL patients.
PATIENTS AND METHODS
Patient Eligibility
Between 1988 and 1998, the GSHG conducted two trial generations for early favorable, early unfavorable, and advanced-stage HL (HD4 to HD6 and HD7 to HD9). To be eligible for these trials, patients had to be between 15 and 75 years of age. The present analysis includes only patients with a clear histopathology diagnosis performed by a pathologist. In addition, 72% of the patient cases were not only diagnosed by the initial pathologists but were also reviewed by a panel of lymphoma expert pathologists to confirm the diagnosis for the purpose of quality assurance.
Exclusion criteria before study entry were concomitant or prior malignancy, pregnancy, a positive HIV test, severe concurrent infection, cerebral dysfunction, Karnofsky performance score of 60 or inadequate organ function as defined by a creatinine clearance less than 60 mL/min, serum aminotransferases more than 100 U/L, serum bilirubin more than 2 mg/dL, left ventricular ejection fraction less than 0.45, forced expiratory volume in first second or diffusion capacity of carbon monoxide less than 60% of predicted, WBC counts less than 3,000/μL, hemoglobin less than 8 g/dL, and platelets less than 100,000/μL. Each patient signed an informed-consent form, which was based on institutional review board guidelines.
Data Selection
Data analysis used collected data of 2,050 female and 2,576 male patients, which were recorded in the GHSG trial database and assessable for the final analysis of the corresponding trials HD4, HD5, HD6, HD7, HD8, and HD9.[2-4,21-23] Depending on the year of randomization, patients were allocated to the second (HD4 to HD6) or third (HD7 to HD9) generation of GHSG trials ([Table 1]). Generally, patients in clinical stage I or II without risk factors (early favorable stages) were enrolled onto HD4 or HD7, and those with one or more risk factors (early unfavorable stages) were enrolled onto HD5 or HD8. Patients with stage III or IV (advanced stages) qualified for HD6 or HD9. One group of HD5 patients (332 patients) in stage IIB or IIIA with certain risk factors was excluded from the analysis for reasons of comparability, given that they would have been considered as having advanced-stage disease according to the criteria of the subsequent trial generation HD6 to HD9. All 4,626 patients in trials HD4 to HD7 were included in the descriptive analyses. However, 686 patients in early favorable stages did not receive chemotherapy (HD4, 375 patients; HD7 arm A, 311 patients). For 93 patients, data on chemotherapy were missing or too incomplete for evaluation. In 22 patients, data on leucopenia were not assessable. Thus, 3,825 patients were assessable for chemotherapy and toxicity analyses.
The median observation time for all patients was 5.5 years. Trial design, number of patients, chemotherapy regimen used, and radiotherapy given in these studies are listed in [Table 1].
Statistical Analysis
Demographics and patient characteristics were summarized using descriptive statistics from SPSS 10.0 for Windows (SPSS Inc, Chicago, IL). Patient characteristics and survival data from trials HD4 to HD9 were assessed separately for males and females. Freedom from treatment failure (FFTF) and overall survival (OS) rates were estimated according to the Kaplan-Meier method.[24] FFTF was defined from date of random assignment to treatment to one of the following events: progression during therapy, lack of complete remission at the end of protocol treatment, relapse, or death as a result of any cause. OS was defined as the time from date of randomization until death as a result of any cause. Response criteria (complete remission, partial remission, no change, and progressive disease) were used as described previously.[3]
Univariate analyses were performed to evaluate the influence of sex (and all other variables differing between males and females) on the outcome of HL. Subsequently, multivariate analysis was executed. A Cox proportional hazards regression model was used to assess the influence of prognostic factors.[25] All variables found to have a P value of less than .05 were considered significant. All survival-related statistical analyses were performed with SAS, Version 8.2 (SAS Institute, Cary, NC).
RESULTS
Patient Characteristics
Patient characteristics are listed in [Table 2]. A total of 4,626 patients from the GHSG trials HD4 to HD9 were included. There were 2,050 female and 2,576 male patients. The median age at diagnosis was 31 years for female and 33.5 years for male patients (range, 15 to 75 years). Most patients had a good Karnofsky performance status. Review histology revealed the following frequency of occurrence for the different HL subtypes: nodular sclerosis more than mixed cellularity more than lymphocyte predominant or lymphocyte rich classical more than lymphocyte depleted. Staging procedures before therapy determined early-stage favorable disease in 19.3% females and 23.5% males, early-stage unfavorable disease in 43.6% females and 34.3% males, and advanced-stage disease in 37.1% females and 42.2% males. "B" symptoms were present more often in men at diagnosis. The distribution of clinical risk factors and prognostic factors was mostly similar between females and males; however, more women presented with a large mediastinal mass and more men with stage IV disease ([Table 2]).
Acute Toxicity From Chemotherapy
Acute toxicity from chemotherapy, recorded in 3,825 patients, was more pronounced in females, with 81.2% experiencing grade 3 or 4 toxicity from chemotherapy in at least one cycle compared with 71.0% of males ([Table 3]). Most toxicities were evenly distributed, except for hematotoxicity: women showed more pronounced anemia and, in particular, leucopenia. More female patients presented with WHO grade 3/4 leucopenia (69.9% females compared with 55.2% males; P < .0001), although there was a higher percentage of men receiving more intense therapy ([Table 2]). However, the rate of infection did not differ between the two collectives (P = .8293), with 23.3% females and 22.5% males developing grade 1/2 infections and 6.5% females and 6.4% males developing grade 3/4 infections. Other recorded toxicities mainly included transient disorders such as alopecia or nausea. No specific preference for either sex was observed for serious organ-related toxicity.
Application of Chemotherapy: Cycles and Drug Dosage
Those patients undergoing chemotherapy received an average of 94.2% of the scheduled dose (the average over all drugs). Most patients (94.1%) obtained the designated number of cycles (98.6% in early favorable, 98.7% in early unfavorable, and 88.9% in advanced stages). A total of 89.1% patients received chemotherapy per protocol, which was defined as 100% (the scheduled dose) ± 15% deviation as the average over all drugs (94.2% in early, 95.7% in early unfavorable, and 82% in advanced stages). Chemotherapy per protocol was applied equally in both sexes, with 89.6% in females and 88.8% in males (data not shown).
Acute Toxicity From Radiotherapy
A smaller proportion of patients experienced acute toxicity grade 3/4 from radiotherapy (12.0% females and 10.5% males). Grade 3/4 leucopenia during radiotherapy was more pronounced in females (5.1%) than males (3.6%). Other toxicities observed in more than 1% ofpatients comprise nausea, thrombocytopenia, and toxicities of the skin, the pharynx, and the esophagus (data not shown).
Treatment Outcome, Causes of Death, and Secondary Malignancies
The overall response rates were as follows: a complete remission (confirmed or unconfirmed) was recorded in 90.7% females and 89.7% males, partial remission was recorded in 2.0% females and 2.8% males, primary progressive disease was recorded in 5.0% females and 5.3% males, and relapse was recorded in 9.1% females and 11.8% males. In total, 10.3% of females and 14.6% of males died. The causes of deaths during study and follow-up were mainly related to HL (46.2% of deaths in females; 39.4% of deaths in males). Another proportion of patients died due to acute toxicity from first-line or salvage therapy (18.4% females and 15.4% males). Death from secondary malignancies accounted for 15.6% females and 17.6% males. Other mortality included cardiovascular disease, which was recorded twice as often in males than females (5.7% females; 10.6% males), and lung failure (0.9% females; 3.2% males).
A total of 195 secondary malignancies were registered, 76 in females and 119 in males. Most patients developed solid tumors (31 females and 48 males). Other secondary malignancies included acute myeloid leukemia/myelodysplastic syndrome (22 females; 20 males) and non-Hodgkin's lymphoma (16 females and 46 males; [Table 4]).
Sex-Specific Outcome
The influence of sex on the outcome of HL patients was assessed by univariate analysis: at a median observation time of 66 months, female patients showed significantly (P < .0001) better FFTF (81%; 95% CI, 79% to 82%) compared with male patients (74%; 95% CI, 72% to 76%; [Fig 1]). Superiority was also observed for overall survival with 90% (95% CI, 88% to 91%) for females and 86% (95% CI, 85% to 87%) for males (P < .0001; [Fig 2]).
Identification of Prognostic Factors
Additional analyses were performed to evaluate the independent prognostic role of sex and sex-related variables on the FFTF of patients with HL. All known risk factors as well as the patient characteristics differing between female and male patients were included. In addition to sex, the following factors had a significant influence on FFTF in univariate analyses: stage of disease (P < .0001), age (P < .0001), B symptoms (P < .0001), IPS (grouped; P < .0001), designated number of cycles (P < .0001), and chemotherapy per protocol (P < .0001; [Table 5]).
Multivariate analyses were performed using a Cox proportional hazards regression model to assess the influence of prognostic factors. Sex was not identified as an independent prognostic factor in this setting. However, the following variables, which were more frequent in women, were associated with better FFTF: lower stages of disease (P < .0001), younger age (P < .0001), more leucopenia grade 3/4 from chemotherapy (P < .0001), fewer B symptoms (P = .0204), and a favorable IPS group (P = .0118; [Tables 6] and [7]). Most of these factors contributing to a better outcome in females include favorable characteristics of the female patients included at diagnosis. However, the occurrence of more leukopenia grade 3/4 in females (with the same therapy) is a protective factor that might be susceptible to clinical influence and was therefore analyzed further.
Protective Role of Leucopenia
The higher prevalence of severe leucopenia (grade 3/4) during chemotherapy was correlated with better FFTF in women. Importantly, the smaller proportion of male patients experiencing severe leucopenia also had a better outcome than their counterparts without severe leucopenia: when calculating the multivariate analysis ([Table 6]) separately for male and female patients, severe leucopenia (grade 3/4) remained significant, with P = .0011 when only male patients were included (hazard ratio [HR] = 0.644; 95% CI, 0.495 to 0.838) and P = .0444 when only females were included (HR = 0.699; 95% CI, 0.493 to 0.991; data not shown). In an additional step, only those patients who developed leucopenia grade 3/4 in the first or second cycle of chemotherapy were included (not in any cycle of chemotherapy). These patients also had a highly significantly better FFTF (P = .0002) compared with all other patients ([Table 7]).
For patients with advanced HL who received treatment with BEACOPP in baseline or escalated dose (HD9 arms B + C), the presence of severe leucopenia (grade 3/4) during chemotherapy also contributed to a better outcome (P = .0074; [Table 8]). When those patients who experienced grade 3/4 leucopenia within the first two cycles of BEACOPP are considered, the factor maintained its protective role (P = .0205; [Table 9]).
DISCUSSION
To our knowledge, this large retrospective analysis including a total of 4,626 patients is the first to investigate sex-specific differences and their influence on treatment and outcome in HL. The following results emerge from this study.
First, more female patients experienced chemotherapy-induced hematotoxicity, particularly severe leucopenia (grade 3/4). However, there was no difference in the rate of severe infections between male and female patients. Second, women showed significantly better outcomes compared with men (FFTF, 81% v 74%; P < .0001; OS, 90% v 86%; P < .0001). The better prognosis is related to more favorable patient characteristics at diagnosis such as younger age, less stage III/IV disease, fewer B symptoms, and a better prognostic score in females. In addition, the occurrence of severe leucopenia is a protective factor for FFTF in the multivariate analysis. Third, all patients experiencing severe leucopenia at any time during chemotherapy fare better than other patients. This was also validated for the first two cycles of treatment and for advanced-stage HL patients undergoing BEACOPP therapy. Fourth, these analyses suggest the testing of a toxicity-adapted treatment strategy in future trials with a similar patient collective, using severe leucopenia within the first two cycles as the relevant parameter.
A small recent analysis from our group including 266 patients with advanced HL suggested that low acute hematologic toxicity might independently predict a worse disease control.[26] Although these findings might in part explain prognostic differences between a number of subgroups, no larger analysis has ever analyzed sex-specific factors systematically in this group of patients. Our data clearly point toward an undertreatment of a portion of male HL patients, particularly in advanced stages. Here, 29.0% male patients compared with 18.8% female patients had no or only grade 1/2 leucopenia.
It can be hypothesized that the higher toxicity profile observed for female HL patients in this analysis may be related to a different enzyme status, drug metabolism, and poorer drug clearance. Genetic polymorphisms are known to produce intraindividual differences in drug toxicity, and their expression and activity are influenced by factors such as sex, smoking, or coadministration of other drugs.[27] Furthermore, individual differences in DNA sequences that alter the expression of proteins targeted by cytostatic drugs can contribute to variations in toxicity during treatment and outcome.[28] Results from patients with colorectal cancer suggest higher systemic drug levels in women, resulting in higher toxicity due to lower drug clearance.[29] Two phase III trials confirmed female sex and advanced age as independent predictors for fluorouracil (FU) toxicity.[30,12] Female sex predicts for increased severe hematologic and nonhematologic toxicity related to FU.[12] Severe toxicity and toxic deaths after treatment with FU were mainly associated with the first cycle.[31] These toxic effects may be related to sex-specific differences in dihydropyrimidine dehydrogenase. This rate-limiting enzyme in the catabolism of FU has shown deficiencies more frequently in women.[32]
For single anticancer drugs, pharmacokinetic models have been established, using therapeutic drug monitoring as a tool for controlling toxicity and at the same time improving efficacy. Examples include the continuous infusion of FU, where doses can be routinely adjusted posteriori on the basis of blood levels measured. An a priori model is used for carboplatin, which allows clinicians to calculate the dose to be given based on weight, age, sex, and creatinine clearance.[33]
In the treatment of malignant lymphoma, the development of pharmacokinetic models is challenging because of the complexity of multidrug regimen being used. Correlation between drug metabolism, clearance, and treatment outcome has just begun to attract scientific interest: an inadequate low clearance of cyclophosphamide to active metabolites was associated with increased risk of disease recurrence in 34 children with B-cell non-Hodgkin's lymphoma.[34] Another recent study retrospectively investigated 45 patients with CNS lymphoma treated with different high-dose methotrexate-based combinations. In that study, a high area under the curve of methotrexate and a slow creatinine clearance were favorable outcome-determining factors.[35]
With regard to the excellent cure rates of patients with HL using the modern combination regimen, response-adapted therapy (RAT) models might be warranted. This should help avoid overtreatment and reduce life-threatening toxicity for patients with higher sensitivity, and should enable escalation of dose or cycle numbers for patients with a reduced systemic dose and thus reduced disease control. Diagnostic approaches of RAT are currently being developed: early response to chemotherapy might represent a surrogate for final outcome and might result in less treatment given.[36] New diagnostic tools such as positron emission tomography may serve as better indicators for early response during chemotherapy and influence the decision on length and intensity of treatment.[37] In the future, new prognostic indices will need to incorporate prognostic biologic markers such as soluble CD30 and others, to identify patients with poor prognosis early to allow a more intense treatment.[38] In addition, gene expression profiling using cDNA microarrays may lead to better biologic characterization of lymphoid malignancies.[39] For diffuse large B-cell lymphoma, DNA microarrays were used to construct a gene-based independent prognostic predictor of risk and survival after chemotherapy.[40] This molecular classification was confirmed by immunohistochemistry using tissue microarrays.[41] However, for HL the search for specific biologic markers continues.
In the meantime, a more practical clinical approach of RAT based on the current analysis could use leucopenia as the relevant parameter to adjust dose-intensity. This might be an effective means to better fine-tune chemotherapy, at least for patients with comparable eligibility criteria (ie, good performance status and no severe comorbidity). Escalated BEACOPP therapy has been shown to substantially improve outcomes for advanced-stage HL.[4] Despite increased hematotoxicity, this regimen is safe for the majority of patients when granulocyte colony-stimulating factor and other supportive measures are used.[42] Mortality associated with escalated BEACOPP therapy ranges between 1.7% (GHSG HD9 trial, arm C) and 3.1% (GHSG HD12 trial).[43] These deaths were observed mainly within the first two cycles of escalated BEACOPP as well as in patients older than 50 years with a poor risk profile (IPS 3 to 7). As a consequence, the age for this regimen was restricted and preventive measures such as hospitalization for the first cycle and introduction of antibiotic prophylaxis. As listed in [Table 5], patients with severe complications and subsequent early termination of chemotherapy have a poorer outcome compared with those receiving chemotherapy per protocol.
In addition to the already established toxicity-based dose reduction, a stepwise dose escalation may improve outcome for certain advanced HL patients who do not experience hematotoxicity grade 3/4 during the first cycles of treatment. This hypothesis could be tested within a new pilot trial with the aim to improve FFTF for a subgroup of patients (especially young males) who might have lower disease control due to a different drug metabolism. Results from patients with aggressive NHL treated with dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone indicated that this approach is safe and at the same time might result in higher efficacy.[44] In this trial sponsored by the US National Cancer Institute, doses of the hematotoxic drugs etoposide, doxorubicin, and cyclophosphamide were adjusted by 20% each cycle to achieve an absolute neutrophil count below 0.5 x 109/L.
The present analysis demonstrates clearly the sex-specific differences in patients with HL. The protective role of severe leucopenia suggests a better dose-adapted treatment, not only for de-escalation but also for possible escalation. Future studies, particularly for patients with good performance status in advanced-stage HL, might use such a toxicity-tailored approach, adjusting therapy to individual leucopenia within the first cycles.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank all members and associated centers of the GHSG for enabling the conduct of the clinical trials HD4 to HD9, which provided a basis for this analysis.
NOTES
Supported in part by the German Cancer Aid (Deutsche Krebshilfe), the Competence Network Malignant Lymphoma (Kompetenznetz Maligne Lymphome), and the German Federal Ministry of Science and Education (Bundesministerium für Bildung und Forschung).
Presented in part at American Society of Hematology, Orlando, FL, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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