Follow-Up for Hodgkin's Disease

Interpretation of a decision-analytic model has revealed that routine computed tomography scanning is not a necessary part of follow-up for Hodgkin's disease patients who have a complete response to treatment. The study appeared in the September 1 issue of the Journal of Clinical Oncology (2006;24:4116–4122) and included an analysis of cost effectiveness as well as clinical benefit. First author Beverly A. Guadagnolo, MD, MPH, Assistant Professor of Radiation Oncology at the University of Texas M. D. Anderson Cancer Center, noted in an interview that 10% to 15% of patients with early-stage Hodgkin's disease will have a relapse, as will 35% to 40% of those with advanced disease. “Close follow-up allows for relapses to be detected early, but it involves considerable expense and the possibility of false-positive test results,” she said, adding that no one knows the best combination of follow-up modalities. Analytic Method Before the advent of CT, the majority of relapses were detected the old-fashioned way: with a history and physical. Does adding a CT scan to the mix improve the likelihood of detecting relapse early? Not according to a study at the University of Toronto, which found that only 9% of relapses were detected by CT—and they represented almost one third of the cost of routine follow-up. To test whether CT is really needed, the authors developed a Markov decision-analytic model to estimate clinical benefit and cost effectiveness. This characterizes the prognosis of a cohort of patients by assigning them to a fixed number of health states (in this case, evidence of disease, early-stage relapse, advanced-stage relapse, high-dose chemotherapy with autologous bone marrow transplant salvage, evidence of disease after salvage, refractory disease, and death) and modeling transitions among the states. “The annual probabilities of transition from one state to another depended on clinical stage at initial treatment, relapse stage, and the time interval since initial treatment,” Dr. Guadagnolo said. The model was run until all patients died. The authors set up two hypothetical cohorts of 25-year-old patients who had a complete response to primary treatment for Hodgkin's disease—one with Stage I-II and the other with Stage III-IV. Three strategies for follow-up were evaluated: annual CT for 10 years; annual CT for five years; and non-CT modalities only. The incremental cost-effectiveness ratio also was calculated for each strategy. Baseline estimates for probabilities of change in status were derived from published studies or from expert opinion when there were no published data, the researchers explained. The risk of relapse was highest in the first two years, and 90% of relapses occurred by five years after primary treatment. Other Findings Other findings were as follows: Relapses missed by non-CT modalities were detected by CT scan 80% of the time. Patients with undetected early-stage relapse had a 50% probability of transforming to advance-stage relapse in one year. Fifty-five percent of patients with early-stage and 45% advanced-stage disease would relapse. All relapsing patients with advanced-stage disease would receive high-dose chemotherapy. For early-stage relapse, 90% of patients would go directly to high-dose chemotherapy and autologous bone marrow transplant, and 10% would have a trial of conventional-dose salvage therapy. How accurate is the Markov model in terms of predictability? OT Editorial Board member Richard T. Hoppe, MD, Professor and Chairman of the Department of Radiation Oncology at Stanford University, was asked for his opinion. “Given that I'm not a statistician, the Markov can make a point, but it's only as good as the accuracy of the probabilities that you factor into it in the first place,” he said. Dr. Guadagnolo acknowledged the same thing: “Any model is only as good as the data you use for it, and we had very good data for this study,” she said. “It's possible to do sensitivity analyses, and ours showed that this was a pretty robust model.” Costs Costs were derived from the 2005 Medicare fee schedule and included an office visit and blood tests four times a year. Costs assigned to a false-positive CT included needle biopsy, pathology processing, and other procedures. The costs of relapse were based on treatment received. In terms of bias, “we structured the model so that it would be biased in favor of the CT follow-up strategies, thus increasing the chance of detecting a relapse,” Dr. Guadagnolo and her coauthors wrote. Results Routine CT scanning for asymptomatic patients for five years increased the cost of follow-up from $14,000 to $19,000, which included costs associated with a false-positive result—for a 0.01 year gain in life expectancy. Ten-year CT follow-up increased the cost from $14,000 to $24,000. Non-CT follow-up resulted in better life expectancy at less cost. For patients with advanced-stage disease, the use of annual CT for five years increased cost from $23,000 to $27,8000, with a 0.03 year gain in life expectancy. This was well above what is considered cost effective for medical interventions, she said. “Use of CT in follow-up of HD patients should be limited to investigation of symptoms or signs and avoided as a routine surveillance modality.” Didn't Address Role of PET or PET-CT Dr. Guadagnolo acknowledged that the model used in this study did not address the role or PET or PET-CT in following HD patients. She said that PET is used increasingly in managing patients with lymphoma, mostly for initial staging and predicting outcome during and immediately after chemotherapy. “It is not possible to reliably determine the sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV] in detecting relapse,” she said. What about conducting a “real” 10-year survival study comparing CT vs non-CT in relapse of Hodgkin's disease? Dr. Hoppe said it was neither feasible nor practical. “First, you wouldn't need a full 10 years, because most relapses occur in three to five years,” he said. “Second, and more important, oncologists want to use CT scans [and now PET scans] in addition to assessment of symptoms and physical examination—all available technology.” Dr. Guadagnolo said there have been no such studies and never will be—“Anyway, models are the big thing now in situations where you can't do a randomized trial.” NCCN & ACR Guidelines This study, the first of its kind and relatively new, probably won't have an effect on established clinical practice guidelines because it is not Category 1 evidence. The National Comprehensive Cancer Network (NCCN) recommends the following regarding follow-up after completion of treatment for Hodgkin's disease: Chest x-ray (Category 2A) or CT (Category 2B) every three to six months during the first three or three years, and then annually thereafter, depending on the clinical circumstances. Abdominal/pelvic CT (Category 2B) every three to 12 months for the first two to three years, and then annually to five years. For late effects, chest x-ray (Category 2A) or CT (2B) annually, depending on clinical circumstances. The American College of Radiology recommends (Rating of 9) history and physical examination every two to four months for two years, then every six months for three years, and then annually for life. The ACR also recommends (Rating of 8) chest/abdomen/pelvic CT every six months for two years, then yearly for three years. The College does not recommend chest CT for lung cancer screening. Dr. Hoppe is Chair of the NCCN Practice Guidelines in Hodgkin's disease. Will a reassessment be prompted by this study? “There is very diverse opinion about the best way to follow up HD, and we debate it often,” he said. “We look at all the available studies, of which this will be one, and come to a consensus. Since there is a total lack of evidence of what's correct in HD follow-up, and since there will not be, because it cannot be, a randomized clinical trial, we debate long and hard. So the answer is that we will look at this study along with everything else. The problem is that there isn't much of anything to look at.” PET Scans Several studies have evaluated the use of gallium and PET scans in predicting HD relapse: The positive predictive value and negative predictive value of gallium scans were very good. Sensitivity, specificity, PPV, and NPV of the PET scans were 100%; CT and ultrasound tests were far less reliable. Despite comparisons in favor of PET, there are no data available on how frequently nuclear imaging studies, compared with other methods, detect recurrence of disease over the course of follow-up. Dr. Hoppe said he has mixed feelings about PET in this situation: “It may show things that aren't there— or rather things that have nothing to do with HD, and patients may be subjected to unnecessary biopsies.” On the other hand, it reveals more than a CT scan, and if something very small is there, you're more likely to see it and catch it early with PET. “Therefore, the biggest debates we have over NCCN guidelines aren't whether to do CT or not, but rather when to use PET.”

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