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• CT Scans and Radiation: How Should We Approach Imaging in Our Patients with Lymphoma?
• The Complexities of Physician Interactions with Pharmaceutical Companies

CT Scans and Radiation: How Should We Approach Imaging in Our Patients with Lymphoma?

By Rebecca Elstrom, MD, and John Leonard, MD

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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The Complexities of Physician Interactions with Pharmaceutical Companies

Dr. Schiffer is Professor of Medicine and Oncology at the Karmanos Cancer Institute, Wayne State University School of Medicine.

In what in retrospect seems historically quaint, when I graduated from medical school in the late 60s, there were major disagreements among class members about the appropriateness of accepting stethoscopes and doctors' bags from pharmaceutical companies. Shortly thereafter, during my initial years in oncology, there were relatively few drugs, little attention to where they came from, and virtually no interactions with drug companies and their representatives.

Contrast this with the current situation in which private practitioners and academic physicians are inundated with contacts from pharmaceutical representatives in their offices, at educational/promotional dinners and trips, at company supported "in service" lectures for the doctors' staff (often with the company representative as the speaker), at lunch conferences at community and university hospitals, at regional or national "consulting" meetings coordinated by marketing groups, and at the annual meetings of their research societies. In exchange for a free lunch or fine dinner, companies are able to promote their products to physicians and staff, gather information about the usage of competitors' products as well as gather some information about patient volumes and demographics, and generate good will. Indeed, current trainees and junior physicians have been "raised" in this environment and consider this business as usual. Although physicians are wont to maintain that they are "above" such influences, the multi-million-dollar marketing investment by pharmaceutical companies, which in turn is incorporated into the cost of drugs, is based on data which strongly support the effectiveness of such approaches.

Interdependence has developed between the pharmaceutical industry and all levels of hematologic/oncologic activities, including those of the academic societies. The latter benefit from the revenue derived from journal advertising, the acres of exhibits at the national meetings, the fees for "Super Friday" corporate-sponsored symposia, and grants in support of travel and fellowship awards, as well as the considerable boost in meeting registrations provided by corporate support of travel and expenses for participants from overseas. ASH and ASCO are scrupulous in their review of these contacts, with guidelines assuring independence in the use of these funds, but the potential for "gray" areas abound.

Pharmaceutical-Company-Sponsored Clinical Research

In addition to these concerns related to clinical practice, and of particular relevance to research societies and academic centers, are issues arising during the conduct of pharmaceutical-company-sponsored clinical trials. Because pharmaceutical companies are the major source of novel and interesting therapeutic compounds, it is of critical importance to efficiently and collegially conduct pre-clinical and clinical research in collaboration with these companies. Drug-company-sponsored trials have become a key source of clinical research submissions to the ASH and ASCO annual meetings. For example, I analyzed that approximately a third of the oral presentations in the hematologic malignancies sessions at ASH's annual meeting in 2006 were sponsored by a pharmaceutical company or had co-authors from companies. Similarly, 44 percent of 332 clinical trials published in the Journal of Clinical Oncology in 2005 reported funding by pharmaceutical companies.¹

A number of issues can complicate these collaborations:

• It can be difficult to distinguish the presentation of new information at the annual meeting from marketing. It is common to see multiple presentations from the same company rehashing or "updating" older data, frequently focusing on subgroup or interim analyses, often with essentially the same information presented at ASCO the following spring. Judging by the similarities in format, these are often (usually?) prepared by the company, and, not infrequently, the abstracts/slides/posters are sent to the authors with short notice without the opportunity to review the primary data or have substantive input into the content. At the other end of the spectrum are submissions containing data that are too preliminary for meaningful interpretation, and company executives have acknowledged to me that such presentations are sometimes aimed more at investors than the scientific audience.
  
  
• Abstracts/manuscripts are often written by investigators from companies or by writers hired by the companies, a point which is sometimes, but not usually, acknowledged in the publication. Although this is not necessarily "bad," the authors of the abstract/paper have the critical responsibility for careful review of the data and the language used to describe the conclusions, particularly given the recent report that evaluated articles published in the Journal of Clinical Oncology and concluded that "conflicts of interest are associated with highly positive conclusions that use superlatives to promote the experimental arm."² It has been suggested that investigators and companies adhere to recently proposed AAMC Guidelines for Protecting Integrity in the Conduct and Reporting of Clinical Trials to help provide consistency and transparency in the conduct and reporting of such trials.
  
  
• There has been considerable interest in the lay press and academic journals about the effects of financial conflicts of interest (COI) posed by consultancies and stock ownership, with some articles documenting excessive honoraria to physicians for unbalanced presentations of clinical data. Of perhaps greater importance than what hopefully represents outliers, are other more subtle influences, including the potential effect on investigator objectivity of a career-advancing association with "positive" studies. This can result in the traditional rewards of publication, academic promotion, subsequent grant funding, and the ability to direct/attract the next major trial to one's institution, but it can also provide opportunities for remunerative consulting and extensive travel for lectures at restaurants and other non-academic venues around the country, often using slides prepared by the burgeoning industry of medical education companies. Few can claim indifference to these side benefits, although the temptations might be less if younger academics were paid more competitive wages. Professional societies, regulatory agencies, and universities have guidelines governing these interactions in place, although it remains unclear whether these are really realistic and functional and capture the impact (if indeed there is an impact) of these less obvious COI.
  
  
• There are also issues about interactions with clinical research organizations, including the emphasis on the excessive amount of data collected on industry-sponsored trials and the large number of frequently meaningless data queries, which decrease the efficiency of the conduct of trials, consume the time of data managers, and, thereby, reduce the number of trials that institutions can open. This is an area requiring more attention and new methodological research focused on whether data minimization might be sufficient for most clinical trials.

Conclusion

It is always easier to harp on the more negative and polarizing aspects of contentious issues such as this. However, pharmaceutical companies have and will continue to contribute enormously to the improved care of our patients, and these interactions are therefore likely to increase. Whatever new regulations may be forthcoming, in the end, the ultimate responsibility will reside with the individual physician and investigator who will, at times, have to react to some of the situations described above. Most will continue to respond with intelligence and integrity, although certainly they should maintain a questioning and critical attitude about these relationships.

Dr. Schiffer consults for Novartis, Celgene, Roche, Amgen, and Pharmion and receives research funding from Novartis, Bristol-Myers Squibb, and Celgene. He participates in speakers' bureaus for Novartis, Celgene, and MGI Pharma and is a member of scientific advisory committees for Kanisa and Celgene.

1. Riechelmann RP, Wang L, O'Carroll A, et al. Disclosure of conflicts of interest by authors of clinical trials and editorials in oncology. J Clin Oncol. 2007;29:4642-7.

2. Riechelmann RP, Dounaevskaia V, Taback N, et al. Source of funding, conflict of interest (COI), and the interpretation of cancer clinical trials. Proc ASCO. 2007;25:6530.

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