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© 1999 American Society for Clinical Oncology Decision Analysis on Alternative Treatment Strategies for Favorable-Prognosis, Early-Stage Hodgkin's DiseaseFrom the Joint Center for Radiation Therapy and Dana-Farber Cancer Institute, Harvard Medical School, and the Department of Health Policy and Management, Harvard School of Public Health, Boston, MA. Address reprint requests to Karen M. Kuntz, ScD, Center for Risk Analysis, Harvard School of Public Health, 718 Huntington Ave, Boston, MA 02115-5924; email kmk{at}hsph.harvard.edu
PURPOSE: To compare the therapeutic outcomes of various treatment strategies in early-stage, favorable-prognosis Hodgkin's disease (HD) using methods of decision analysis. METHODS: We constructed a decision-analytic model to determine the life expectancy and quality-adjusted life expectancy for a hypothetical cohort of clinically or pathologically staged 25-year-old patients with early-stage, favorable-prognosis HD treated with varying degrees of initial therapy. Markov models were used to simulate the lifetime clinical course of patients, and baseline probability estimates were derived from published study results. RESULTS: Among patients with pathologic stage (PS) I to II, mantle and para-aortic (MPA) radiotherapy was favored over combined-modality therapy (CMT), mantle radiotherapy, and chemotherapy by 1.18, 1.33, and 1.55 years, respectively. For patients with clinical stage (CS) I to II, the treatment options of MPA-splenic radiotherapy, CMT, and chemotherapy yielded similar survival outcomes. Sensitivity analysis showed that the decision between CMT and MPA-splenic radiotherapy was highly influenced by the precise values of the estimates of treatment efficacy and long-term morbidity, the quality-of-life value assigned to the postsplenic irradiation state, and the time discount value used in the model. Probabilistic sensitivity analysis demonstrated that even if future studies doubled the precision of the estimates of the treatment-related variables, it would be impossible to demonstrate the superiority of one treatment over the other. CONCLUSION: Our model predicted that on average, MPA radiotherapy was clearly the preferred treatment for PS I to II patients. For CS I to II patients the treatment decision is a toss-up between MPA-splenic radiotherapy and CMT, emphasizing the importance of patient preference exploration and shared decision making between patient and physician when choosing between treatments.
MULTIPLE TREATMENT options exist for early-stage Hodgkin's disease (HD), and the optimal initial therapeutic approach is controversial.1-4 Although different types and degrees of treatments result in different disease control rates, because of the excellent outcomes in patients who relapse, it is difficult to detect a difference in survival rates among the various treatment options. Supporters of radiation therapy as initial treatment argue that patients with early-stage disease can be spared the toxicities of chemotherapy, which can be reserved for salvage therapy if failure occurs after radiotherapy. On the other hand, although patients treated with combined-modality therapy (CMT) may have less success with salvage therapy and this therapy may lead to more long-term complications, CMT offers excellent disease control. Moreover, recent improvements in CMT regimens have reduced the extent of treatment and toxicity. Long-term treatment outcomes using the more limited CMT regimens are not yet available; however, short-term follow-up demonstrates excellent disease control rates,5-9 and the risks of long-term treatment-related morbidity should be lower. Finally, some advocate chemotherapy alone in early-stage HD patients, to avoid radiation therapy altogether.10-12The main rationale is to reduce the risk of secondary solid tumors, especially in light of the increasing findings of secondary breast cancer in women who undergo radiation therapy at a young age.13-16 In choosing between more extensive and less extensive initial treatment for early-stage HD, one needs to weigh the long-term benefit of better disease control with aggressive upfront treatment against the drawbacks of greater short- and long-term toxicities and decreased potential for successful salvage therapy. In a previous decision-analytic model,17 we compared the life expectancy and quality-adjusted life expectancy of favorable-prognosis, early-stage HD patients managed with and without staging laparotomy. Surgical staging resulted in a gain in 9 months of life expectancy or 7 months of quality-adjusted life expectancy, suggesting that there may remain a role for pathologic staging in early-stage HD. Incorporated in the model were various treatment options for early-stage HD patients. In this study, we performed a decision analysis on the alternative treatment strategies for pathologically staged and clinically staged patients who present with initial clinical stage (CS) I to IIA, favorable-prognosis HD. Our goal was to compare the life expectancy and quality-adjusted life expectancy of early-stage, pathologically or clinically staged HD patients treated with the various approaches.
Model Structure As described elsewhere,17 we constructed a decision-analytic model for a hypothetical cohort of 25-year-old patients presenting with early-stage, favorable-prognosis HD, managed with or without pathologic staging. Favorable prognosis was defined as lack of large mediastinal adenopathy and B symptoms. If surgical staging was performed and disease was confined to above the diaphragm, the treatment alternatives for the patients with pathologic stage (PS) I to IIA included mantle and para-aortic (MPA) radiation therapy, mantle radiation therapy alone, chemotherapy alone, and CMT. For patients in whom staging laparotomy was not performed, the treatment options for the patients with CS I to IIA included MPA-splenic radiation therapy, CMT, and chemotherapy alone. The structure of the decision tree is shown in Fig 1.
Markov models were used to simulate the lifetime clinical course of patients,18 whose prognosis depended on the actual PS and the type of treatment received. The model accounted for refractory disease, HD relapse, and long-term treatment-related side effects, such as development of second malignancies and cardiac deaths. Outcomes for the baseline analysis were life expectancy and quality-adjusted life expectancy, with or without discounting of the value of future years of life relative to the present at 3% per year. Threshold and sensitivity analyses were performed using the discounted, quality-adjusted model. In general, the ranges in the analysis were such that the lower and upper bounds were within clinically plausible ranges. Probabilistic sensitivity analyses of the treatment decision for clinically staged patients (Monte Carlo simulation) were performed using different ranges for key model estimates.19 We first conducted the Monte Carlo simulation by assigning a triangular distribution to uncertain parameters in the analysis, with the minimum and maximum values reflecting the ranges reported in the literature. The ranges of the uncertain parameters were then narrowed by 50% and the Monte Carlo simulation was repeated to determine the impact of reducing the uncertainty in key model estimates on the robustness of the analysis. We used the DATA software package (TreeAge Software, Inc, Williamstown, MA) to construct the model and perform the analyses.
Key Assumptions Patients who relapsed after initial radiotherapy and patients with limited relapse after chemotherapy alone underwent salvage therapy with conventional-dose CMT. Patients with extensive relapse after chemotherapy alone, after CMT, or with refractory disease who underwent salvage therapy consisting of either bone marrow transplantation or conventional-dose chemotherapy alone.23 (We assumed one quarter of the patients would be deemed ineligible for transplant for medical reasons and would thus receive salvage therapy consisting of chemotherapy alone.) In addition, we assumed that measures of long-term quality of life of patients in remission after MPA radiation therapy, mantle radiation therapy, MPA-splenic radiation therapy, CMT, and chemotherapy alone were identical, an assumption that was tested in sensitivity analysis.
Baseline Estimates
Most of the studies for which long-term follow-up is available after CMT or chemotherapy alone used mechlorethemine, vincristine, prednisone, and procarbazine (MOPP) chemotherapy,4,32,33,37 which has largely been replaced by doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy in current practice. Some of these studies also involved larger radiation fields as part of CMT than are currently used. The uncertainty of the treatment outcomes for CMT and chemotherapy in the modern era was examined by extensively exploring these variables in sensitivity analyses. Quality-of-life adjustment was performed by multiplying the time spent in each health state or an intervention by a quality-of-life weight, or utility, where a weight of 0 is equal to death and a weight of 1 is equal to complete remission without relapse or treatment complications. The utilities assigned to each of the short-term and long-term health states were based on expert opinions. The quality-of-life adjustment for the long-term health states remains as long as the patient stays in the particular health state. In contrast, for the short-term health states, the quality-of-life adjustments were made for only a finite period of time. The utility values were subjected to extensive sensitivity analysis to determine their influence on the optimal treatment decision.
Baseline Analysis Results of the baseline analysis and the gain in life expectancy of the preferred treatment over other treatments are summarized in Table 2.
Pathologically staged patients. Considering life expectancy as the outcome, the treatment of choice for PS I to II patients was MPA radiation therapy, which resulted in a gain of 1.18 years compared with the next best option, CMT. The 20-year survival curves of patients treated with each of the four therapeutic approaches are shown in Fig 2 With adjustment for quality of life, MPA radiation therapy remained the treatment of choice for PS I to II patients. Mantle radiotherapy alone, which had lower acute toxicities and a shorter treatment time, became the next most favored treatment option. MPA radiation therapy led to a gain in quality-adjusted life expectancy of 1.30 quality-adjusted life years (QALYs) compared with mantle radiotherapy alone.
With discounting and adjustment for quality of life, the order of preference of treatment strategies for PS I to II patients remained the same, with MPA radiation therapy being the optimal choice, followed by mantle radiotherapy alone, CMT, and chemotherapy alone (the least-favored strategy). Clinically staged patients. Without discounting or quality-of-life adjustment, the treatment of choice for the clinically staged patients was CMT, favored over chemotherapy alone by 0.31 years. Figure 3 shows the 20-year actuarial survival of CS I to II patients treated with CMT, MPA-splenic radiation therapy, and chemotherapy alone, as predicted by the model. With adjustment for quality of life, the difference between CMT and chemotherapy alone decreased to 0.16 QALYs, although CMT continued to be the optimal treatment strategy. With discounting of QALYs, however, MPA-splenic radiation therapy became the optimal treatment choice, with a gain in discounted, quality-adjusted life expectancy of 0.15 QALYs compared with CMT. The late benefit associated with CMT with time discounting is valued less than the early benefit associated with MPA-splenic radiotherapy. The finding that the discounted results favored MPA-splenic radiotherapy is shown by Fig 3 Note that the survival curve for MPA-splenic radiotherapy is above that for CMT in the first 18 years, after which it falls below the CMT survival curve. This suggests that the high relapse risks in the 25% of the CS I to II patients, who in fact had PS III1A and PS III2 to IVA disease (7-year relapse rates of 61% and 85%, respectively), had a greater effect on the long-term mortality of patients treated with MPA than did the higher second malignancy risks of patients treated with CMT.
Sensitivity Analysis The issue of solid tumor risk often dominates discussion regarding optimization of treatment in early-stage HD, and there has been increasing interest in the use of chemotherapy alone in early-stage HD patients. It is noteworthy that the absolute risk for solid tumor after irradiation in PS I to II patients needs to be above 124.9/10,000 person-years before chemotherapy alone becomes favored over MPA radiation therapy. However, this rather high risk of solid tumor after radiation therapy is well beyond the range of 36.5 to 96/10,000 person-years reported in the literature. Alternatively, the absolute risk for solid tumor after chemotherapy alone in PS I to II patients needs to be below 19.2/10,000 person-years before chemotherapy alone becomes the treatment of choice. Again, this low risk of solid tumor after chemotherapy alone is outside of the range of 51 to 86/10,000 person-years reported in the literature. Treatment decision for CS I to IIA: CMT versus MPA radiation therapy. Results of the baseline analysis, performed with and without time discounting, indicated that the optimal treatment decision for CS I to IIA patients depended on whether future years of life were discounted. Without discounting, CMT was the preferred treatment; with discounting, MPA-splenic radiation therapy became the treatment of choice. In addition, the optimal treatment strategy was highly sensitive to a number of other variables (Table 3). For patients with clinical prognostic factors that were suggestive of risks of upstaging of more than 30%, CMT was the optimal treatment choice. For lower-risk patients, MPA radiation therapy was preferred. The analysis was also sensitive to several treatment-related factors, including relapse rates, second malignancy risks, and salvage rates after radiation therapy or CMT. In addition, the quality of life associated with the long-term health state of postsplenic irradiation as part of MPA-splenic radiotherapy in the clinically staged patients substantially influenced the optimal treatment decision. In contrast, the utility values of the remaining short- and long-term health states had little or no effect on the treatment decision between MPA radiotherapy and CMT for CS I to IIA patients.
Because of the exquisite sensitivity of the analysis comparing CMT and MPA radiation therapy in CS I to IIA patients with a considerable number of variables, we performed additional analyses to assess whether reducing uncertainty in the model estimates of treatment-related variables would permit identification of an optimal treatment strategy. Using probabilistic sensitivity analysis (Monte Carlo methods),19 we first ran the model 1,000 times, selecting values for the key variables at random from ranges reflecting what has been reported in the literature. We found that 90% of the time, the model generated estimates of the difference between MPA radiotherapy and CMT from -0.52 to 0.70 QALYs. We then reduced the width of the variable ranges by 50% and repeated the procedure. With the narrower ranges, 90% of the time, the results fell between -0.19 and 0.46 QALYs, thus still including zero. In other words, even when the uncertainties of the treatment-related variables were reduced by one half, there was still no clear superiority of one treatment over the other. CS I to II: Chemotherapy alone versus MPA radiation therapy. Since the baseline estimates of treatment outcomes for chemotherapy alone were derived from studies in which mainly MOPP chemotherapy was used, the secondary leukemia risks were probably overestimated in the model. However, even when the secondary leukemia risk after chemotherapy alone was set to zero, chemotherapy alone remained inferior to MPA radiation therapy. Chemotherapy alone became the optimal treatment choice only when the relapse rate after chemotherapy alone was less than 15.3% (baseline, 20%) or when the secondary solid tumor risk was less than 58/10,000 person-years (baseline, 69/10,000 person-years).
Our decision-analytic model on alternative treatment strategies for early-stage, favorable-prognosis HD revealed that the treatment of choice for PS I to IIA patients was MPA radiation therapy, and results of the analysis were robust. In contrast, for CS I to IIA patients, our model indicated that the choice between MPA radiation therapy and CMT was essentially a toss-up. Both strategies yielded similar life expectancies, and even minor changes in a number of variables could change the results with respect to which strategy led to slightly better outcomes. Our findings on the preferred therapeutic options for patients with favorable-prognosis HD with a negative laparotomy are consistent with current patterns of care. We found that the outcomes of MPA radiation therapy alone are superior to chemotherapy alone or CMT, which were never optimal, even when their relapse rates and treatment complication rates were at their most optimistic values. Because of concern for secondary solid tumors after irradiation, especially in young patients, some have regarded chemotherapy alone as an attractive option in early-stage HD patients.10-12 Our analysis showed MPA radiation therapy to be superior for the pathologically staged, early-stage HD patients because patients treated with chemotherapy alone have less success with salvage therapy.30 Two randomized trials comparing MPA radiation therapy with MOPP chemotherapy in PS I to II patients had conflicting results.10,30 However, the trial showing a higher survival rate in patients treated with MOPP chemotherapy compared with radiation therapy excluded patients with PS IA disease and included patients with PS IIIA disease and was thus not comparable to our analysis.10 In comparing MPA radiation therapy with mantle radiotherapy alone for PS I to IIA patients, we found that the relapse rate after mantle radiation therapy needed to be lowered to close to the relapse rate after MPA radiation therapy for it to be the preferred treatment. Although the threshold relapse rate is outside of the reported ranges in the literature, whether this value is within a clinically plausible range is unclear, as there are limited data on the long-term treatment outcome of mantle radiotherapy. According to the results of the European Organizaion for the Research and Treatment of Cancer (EORTC) H5F study, the only randomized trial thus far comparing MPA with mantle radiation therapy, the relapse rates and overall survival rates were the same between the two arms at 15 years of follow-up.3 It is important to note, however, that the baseline relapse rate after mantle radiation therapy used in our model may well be an overestimate, since it is heavily weighted by the results of the EORTC H5F study, in which the overall disease control rates were inferior to results in some single-institutional studies. Furthermore, as shown in our sensitivity analysis, if longer follow-up of patients treated with mantle radiotherapy alone demonstrates that rates of secondary solid tumors are significantly lower than after MPA radiotherapy, mantle radiotherapy alone could emerge as the preferred treatment option for pathologically staged, early-stage HD. For patients who have not undergone staging laparotomy, we found that the optimal treatment decision for the clinically staged patients was highly dependent on the precise values of a number of factors. Even when the uncertainties of the treatment-related variables were reduced by 50%, the choice between MPA-splenic radiation therapy and CMT remained equivocal. Therefore even if long-term treatment outcomes become available in the future, thereby reducing the uncertainties of these estimates, it is unlikely that a clear-cut overall survival advantage for one treatment approach will emerge. But our analysis highlights the fact that these options do differ in other ways. First, we found that CMT was the preferred treatment when no time discounting was considered, whereas MPA-splenic radiation therapy was preferred with time discounting, because patients treated with CMT were exposed to greater acute toxicities and longer treatment time but enjoyed higher long-term disease control rates. This suggests that the more a patient values present time relative to future time, the more attractive MPA-splenic radiation therapy will seem compared with CMT. A patient with a young family, for example, may prefer to incur early toxicity and thereby to maximize the probability of being there for his/her family in the long run. For this type of patient, CMT may be the treatment of choice. In contrast, a patient who no longer has important family obligations may prefer to maximize his or her health in the near term, with the result that MPA radiation therapy is the optimal choice. Second, we found that the quality of life after splenic irradiation only needed to be minimally affected for CMT to be preferred over MPA-splenic radiation therapy. It is therefore important that patients understand the infection risks and inconvenience associated with life after splenic irradiation64 and that their views about quality of life after such treatment be carefully explored when choosing between the treatment options. One of the advantages in using methods of decision analysis to compare different management strategies is that it allows reporting of survival in terms of years (or QALYs) gained or lost, thereby allowing a different perspective to comparisons between various interventions.65 However, inherent to this type of analysis are limitations, including difficulty in adjusting for the heterogeneous patient characteristics in the studies used in the model, limited available data in the literature on specific baseline estimates, and outdated treatment approaches used in some of the studies. For instance, one may argue that the estimates for chemotherapy and CMT were from studies in which predominantly alkylating chemotherapy regimens were used and may partly explain the slight superiority of MPA radiation therapy over CMT and chemotherapy in the baseline analysis. However, although death from leukemia has decreased with the diminishing use of alkylating chemotherapy, pulmonary toxicity is an emerging cause of mortality in patients treated with ABVD chemotherapy.5,7,39 We did not include pulmonary complications as a cause of death in patients treated with chemotherapy/CMT because of the limited data available. Therefore the survival rate of patients treated with CMT may be overestimated in this regard. The results of our analysis have a number of clinical implications. First, in deciding the treatment approach for patients with pathologically staged, early-stage HD, the superiority of MPA radiation therapy over chemotherapy alone or CMT is fairly certain. However, if future studies establish that mantle radiotherapy alone results in comparable disease control and lower long-term complication rates than MPA radiation therapy, it could emerge as the treatment of choice. Efforts should therefore be directed at determining the long-term efficacy and treatment-related complications of mantle radiotherapy alone. Second, our results suggest that the choice between MPA-splenic radiotherapy and CMT for favorable-prognosis, CS I to IIA patients is essentially a toss-up. More important, our probabilistic sensitivity analyses suggest that additional data on long-term outcomes after MPA radiotherapy and CMT for CS I to IIA HD are unlikely to change the indecision and may therefore be of limited value. Third, in deciding between the treatment choices for the clinically staged patients, emphasis should be placed on how patients weigh the greater immediate toxicity of CMT against the higher chance of relapse in the long run, as well as the increased infection risks with MPA-splenic radiation therapy. Future research on how to tailor treatment for the clinically staged, early-stage HD patients based on their values and preferences may be warranted.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
, Decision node; 
, chance node.
