By Rebecca Elstrom, MD, and John Leonard, MD

2008-03-01

Dr. Elstrom is Assistant Professor of Medicine at Weill Cornell Medical College.

Dr. Leonard is The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College.

"I'm glad that my lymphoma is in remission, but do I need to get all of these scans? Will the radiation from the scans give me another cancer?"

If you take care of patients with lymphoma (and other cancers), chances are that you have heard the questions above many times, and a bit more often recently. Unfortunately, it is difficult to provide an evidence-based answer, and often the reply is something along the lines of "Don't worry about it." Perhaps we need to work a bit harder to get some real answers to these important questions.

Radiologic imaging has become an integral part of care for patients with lymphoma, but data regarding optimal use of imaging studies in routine clinical practice are lacking. While the potential advantage of imaging in carefully defining disease extent is clear, pitfalls also exist. The potential for false-positive results, suggesting the presence of active lymphoma in a place or at a time that it does not exist, is a recurring issue with all forms of imaging. Furthermore, radiologic studies, especially CT and PET scans, are expensive. This is a growing issue in this era of mounting health-care expenses. Recently, the risks of radiation exposure to patients have also received increased attention, with concerns raised about the long-term health effects of the repeated doses of radiation to which patients are subjected during the course of cancer treatment and follow-up. This is a particular issue in lymphoma, where patients frequently live for decades and might receive several scans per year over this time. In light of these issues, it is important that we carefully consider the role of imaging in our practice in order to optimize the care of patients with such procedures while being cost-effective.

Two areas in which the value of radiologic imaging is clear are in initial staging and in assessment of response to therapy. This is most evident in Hodgkin lymphoma and aggressive non-Hodgkin lymphomas (such as diffuse large B cell), where the objective of treatment is cure, and appropriate treatment planning and achievement of a complete remission (CR) are prerequisites to achieving that objective. However, the optimal choice of imaging modality is a critical issue. Many patients currently undergo both PET/CT and standard, diagnostic CT because of concerns that performing only one study will result in "missed" findings. A careful analysis of the data addressing this issue, however, reveals that, if the CT portion of the combined PET/CT study is adequately performed and reviewed, it is rare to detect additional clinically relevant information from a separate, standard CT.^{1, 2, 10} One could advocate that these findings argue against the cost and radiation exposure of duplicating studies.

The utility of radiologic imaging is most unclear in follow-up of patients previously known to have already achieved a CR. Most physicians perform serial scans, either CT or PET/CT, as surveillance at regular intervals over the course of a certain time period after CR. A common strategy is to perform CT scans every three months for two years, then every six to 12 months for a total of five years. The rationale for this practice is the hope that routine surveillance scans will identify relapse earlier than would reliance on patients' symptoms, physical examination, and laboratory findings, with the corollary that early detection and treatment will presumably lead to better outcome. While this rationale for routine surveillance seems compelling, the data to support it are less so. In order to make a convincing case for routine imaging surveillance, one would need to show that this strategy not only leads to earlier detection of recurrent lymphoma than a clinical evaluation without imaging, but that this early detection also leads to improved outcome for patients, including a better chance of successful second-line therapy and improved, or at least not compromised, quality of life. No prospective, randomized trial has been performed to appropriately compare the strategies of routine imaging surveillance (at any specific interval) versus non-imaging-based follow-up. However, several retrospective studies in patients with Hodgkin or aggressive non-Hodgkin lymphoma have reported that most relapses are associated with signs or symptoms of recurrent disease. The finding of recurrence in an asymptomatic patient with diffuse large B-cell lymphoma (DLBCL) based on CT imaging alone is uncommon, accounting for between 6 percent and 22 percent of recurrences.^3-5 Some might conclude that there is no need to obtain any follow-up scans in patients with aggressive lymphoma once they achieve CR as long as they are clinically well — a strategy that would be in contradistinction to current practice. However, one study reported improved outcome with second-line therapy for DLBCL patients in whom recurrent disease was detected based on routine imaging rather than signs or symptoms (median five-year overall survival of 54 percent vs. 43 percent). It was not possible, however, to determine whether these patients had better outcome because recurrence was detected early, or whether the lack of symptoms correlated with more favorable tumor biology.⁵ In other lymphoma histologies, such as follicular and mantle cell subtypes, where patients are generally not cured and often only observed at relapse, the arguments against frequent or routine imaging in the absence of symptoms seem even stronger.

When considering the potential benefits of routine imaging surveillance, it is also appropriate to consider the costs. Using the strategy of CT scans every three months for two years, then every six to 12 months for a total of five years, the additional cost per patient over clinical follow-up without routine imaging has been estimated to be in the range of $15,000 to $50,000.⁶ Regarding radiation exposure, the same series of CT scans would confer excess exposure in the range of 250 to 350 mSv (25 to 35 rad).⁷ This is well above levels of exposure found to be associated with an increased risk of cancer observed in atomic bomb survivors and radiation workers (5 to 150 mSv). While the risk of a secondary malignancy due to this amount of radiation is likely to be modest and must be weighed against potential benefits in a high-risk population, this range has been associated with increased risk, particularly in younger patients.

Data regarding the use of PET/CT scans in routine follow-up are emerging. While some investigators have reported utility of this modality in detecting asymptomatic relapses,¹⁰ others have suggested that its use is associated with a prohibitively high rate of false-positive findings,^8,11 leading to unnecessary biopsies and psychological distress for patients. Again, the clinical benefit for patients in whom recurrences are detected early remains unclear.

Another important consideration regarding routine follow-up imaging involves the impact on patient well-being. One could theorize both positive and negative effects. While some patients may find comfort in the close monitoring and the results of a negative CT scan, others find CT scans an unwelcome reminder of their illness, with the peri-scan time period associated with high levels of stress. Data regarding these effects of routine follow-up scans are needed, and we look forward to well-designed, quality-of-life studies to assess this topic.

In the absence of clear data to guide our practice, how should we approach this issue? It seems that many patients undergo more scans than are beneficial, resulting in excessive monetary cost, further testing, radiation exposure, and, for some, psychological distress. Common sense would argue, then, that physicians should consider changing practice in the face of these negative factors, and performing imaging when there is a reason, rather than as a default. Any emphasis on imaging should be primarily toward patients with aggressive lymphoma, patients with a high risk of recurrence and likely indications for intervention, patients with a new sign or symptom that needs to be investigated, or patients for whom routine surveillance scans will calm, rather than exacerbate, disease-related stress. In addition, now is the time for development of well-designed, prospective studies to answer these issues more definitively.

1. Schaefer NG, Hany TF, Taverna C, et al. Non-Hodgkin lymphoma and Hodgkin disease: coregistered FDG PET and CT at staging and restaging--do we need contrast-enhanced CT? Radiology. 2004;232:823-9.

2. Gollub MJ, Hong R, Sarasohn DM, et al. Limitations of CT during PET/CT. J Nucl Med. 2007;48:1583-91.

3. Guppy AE, Tebbutt NC, Norman A, et al. The role of surveillance CT scans in patients with diffuse large B-cell non-Hodgkin's lymphoma. Leuk Lymphoma. 2003;44:123-5.

4. Elis A, Blickstein D, Klein O, et al. Detection of relapse in non-Hodgkin's lymphoma: role of routine follow-up studies. Am J Hematol. 2002;69:41-4.

5. Liedtke M, Hamlin PA, Moskowitz CH, et al. Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population. Ann Oncol. 2006;17:909-13.

6. Armitage JO, Loberiza FR. Is there a place for routine imaging for patients in complete remission from aggressive lymphoma? Ann Oncol. 2006;17:883-4.

7. Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. N Engl J Med. 2007;357:2277-84.

8. Jerusalem G, Beguin Y, Fassotte MF, et al. Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease. Ann Oncol. 2003;14:123-30.

9. Elstrom RL, Brown RJK. Does FDG-PET/CT obviate the need for standard diagnostic contrast-enhanced CT in patients with lymphoma? Blood (Annual Meeting Abstracts). 2007;110:689a.

10. Zinzani PL, Stefoni V, Ambrosini V, et al. FDG-PET in the serial assessment of patients with lymphoma in complete remission. Blood (Annual Meeting Abstracts). 2007;110:71a.
    
    
11. Zuckerman D, Lacasce A, Jacobsen E, et al. High false positive rate with the use of CT and FDG-PET in post-remission surveillance for Hodgkin lymphoma. Blood (Annual Meeting Abstracts). 2007;110:688a.

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