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Originally published as JCO Early Release 10.1200/JCO.2008.20.1665 on March 9 2009 © 2009 American Society of Clinical Oncology.
The Case Against Heavy PETingDepartment of Hematology/Oncology, Georgetown University Hospital, Washington, DC "Do you know the difference between education and experience? Education is what you get when you read the fine print; experience is what you get when you don't." — Pete Seeger Rarely have such major changes in practice been based on so much published data with so little in the way of guidance as to how to actually apply those data, as with the use of positron emission tomography (PET). Hundreds of publications suggest that the availability of 18-fluorodeoxyglucose (FDG) PET scans has revolutionized the management and improved the outcome of patients with lymphomas and other cancers.1 FDG-PET has also been proposed as a replacement for current methods of lymphoma staging and response assessment and as a guide to modifying management during and after therapy.2 A positive scan after one or more cycles of therapy seems to be the strongest predictor of poor patient outcome.3,4 However, we need to examine the fine print before adopting the widespread use of PET. In lymphoma, computed tomography–PET (CT-PET) scans clearly identify more lesions than other imaging studies; however, stage is changed in only 10% to 30% of patients, and treatment is altered in even fewer patients, with no data to suggest that prognosis is improved based on this information. PET scans are imperfect with many false-negative and false-positive results. The reasons for false-negative PET scans include technical problems, uncontrolled diabetes, and variability of FDG avidity among lymphoma subtypes. The lengthy list of causes of false positives, which may occur in one quarter of patients, includes inflammation, infection, tumor necrosis, and scanning too soon after chemotherapy or radiotherapy.5 Fortunately, the problem of standardization has been resolved, for now, by the International Harmonization Project in Lymphoma; its recommendations for the conduct of scans and the definition of a positive scan were incorporated into the revised International Response Criteria.6,7 Two articles in this issue of Journal of Clinical Oncology support the judicious use of FDG-PET in lymphoma. Zinzani et al8 performed serial FDG-PET scans on patients with diffuse large B-cell lymphoma, Hodgkin's lymphoma, or follicular lymphoma in first complete remission at 6, 12, 18, and 24 months and annually thereafter. Scans were interpreted as positive, negative, or inconclusive. The patients with inconclusive scans underwent biopsy, particularly when there was a sufficient index of suspicion, such as if a scan remained positive 1 to 2 months later or if there were other signs suggesting active disease with additional follow-up; the likelihood of a positive biopsy also correlated with the pretreatment risk group. Their conclusion that FDG-PET was useful for follow-up is the large print version. However, the likelihood of relapse became insignificant after 12 months for Hodgkin's lymphoma and after 18 months for diffuse large B-cell lymphoma, although there was the expected continuous risk for relapse with a follicular histology. Importantly, patient risk before treatment correlated with systemic relapse. Only one third of patients with an inconclusive PET had a suspicious CT scan with a biopsy-proven 33% false-positive rate. For patients with a positive PET and a negative CT, the false-positive rate was 42%. FDG-PET identified unsuspected early relapse in only 10% of patients with Hodgkin's lymphoma, which was assisted by clinical risk and CT findings. What cannot be determined from these data are the cost effectiveness of the PET scan, compared with repeating CT scans a few months later, and whether identifying unsuspected relapses a few months earlier made a difference in clinical outcome. Indeed, it is the patient or the physician who suggests the possibility of relapse on clinical grounds 80% of the time, before it is detected by routine imaging studies.9–12 Certainly, routine scanning in the indolent histologies is not justified. FDG-PET scans are also being overused for interim assessment during treatment; however, the limited available data do not support that changing therapy on the basis of such information impacts favorably on patient outcome.13 The second article in this issue by Terasawa et al14 reports a systematic review of 13 studies that included 360 patients with advanced-stage Hodgkin's lymphoma and 311 patients with diffuse large B-cell lymphoma. The generalizability of the data is questionable because only 10% of Hodgkin's patients were in an unfavorable risk group, and patients with diffuse large B-cell lymphoma were heterogeneous with respect to risk of treatment failure and therapeutic interventions; in addition, there was variability in the number of chemotherapy cycles after which the PET was performed, when during the cycle the PET scan was performed, and equipment; some studies had methodologic problems; and a relatively small number of case series often from the same investigators were included. The authors appropriately conclude that the evidence does not support interim scanning outside of a clinical trial. Although patients often request interim scans, a negative scan does not guarantee a positive clinical outcome, and a positive scan does not ensure ultimate doom but clearly engenders anxiety in the patient and caregivers. So how does the clinician navigate the numerous articles published on FDG-PET and apply the information to daily practice? First, limit generalizations; not all lymphomas are FDG avid. Just because the test is more sensitive than other available technologies, such as CT or magnetic resonance imaging scans, does not mean that it provides information that should be acted on, and acting on such information does not necessarily translate into improved patient outcome. Most importantly, it is mandatory to incorporate clinical information in scan interpretation and decision making; a PET scan does not replace a biopsy. Where FDG-PET scans will be most useful is in risk-adapted therapy, by reducing the amount of treatment for patients with responsive disease without compromising efficacy or by improving the outcome of patients with resistant disease by the earlier detection of treatment failure. Numerous studies are now addressing these issues. In a Cancer and Leukemia Group B study, patients with early-stage disease will receive two cycles of doxorubicin, bleomycin, dacarbazine, and vinblastine (ABVD); those who become PET negative will receive only two more cycles, rather than the standard six additional cycles. Patients who remain PET positive will be treated with aggressive escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine for two cycles followed by involved-field irradiation. The same investigators will be conducting a trial to determine whether PET can be used to reduce the number of patients with bulky tumors who require radiation therapy. A US Intergroup study will soon be activating a trial in which patients with advanced Hodgkin's lymphoma will receive two cycles of ABVD followed by a PET scan. Patients who are PET negative will complete six cycles of ABVD. Patients with a positive PET scan will be treated with the escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine regimen. The Risk Adapted Therapy for Hodgkin's Lymphoma trial is addressing a similar question in the United Kingdom for PET-positive patients; in this trial, patients who are PET negative are randomly assigned to four cycles of AVD or ABVD to determine whether de-escalation of therapy is possible. Thus, at present, FDG-PET should be reserved for restaging curable lymphomas, sparing other patients expense and radiation exposure until clinical trials validate the role of this technology in other settings. We have been gaining extensive experience with FGD-PET; it is time we learn what to do with it. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Juweid M, Cheson BD: Positron emission tomography (PET) in post-therapy assessment of cancer. N Engl J Med 354:496–507, 2006. 2. Seam P, Juweid ME, Cheson BD: The role of FDG-PET scans in patients with lymphoma. Blood 110:3507–3516, 2007. 3. Haioun C, Itti E, Rahmouni A, et al: [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: An early prognostic tool for predicting patient outcome. Blood 106:1376–1381, 2005. 4. Gallamini A, Hutchings M, Rigacci L, et al: Early interim 2-[18F]fluoro-2-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: A report from a joint Italian-Danish study. J Clin Oncol 25:3746–3752, 2007. 5. Castellucci P, Nanni C, Farsad M, et al: Potential pitfalls of 18F-FDG PET in a large series of patients treated for malignant lymphoma: Prevalence and scan interpretation. Nucl Med Commun 26:689–694, 2005.[CrossRef][Medline] 6. Juweid ME, Stroobants S, Hoekstra OS, et al: Use of positron emission tomography for response assessment of lymphoma: Consensus recommendations of the Imaging Subcommittee of the International Harmonization Project in Lymphoma. J Clin Oncol 25:571–578, 2007. 7. Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586, 2007. 8. Zinzani PL, Stefoni V, Tani M, et al: Role of [18F]fluorodeoxyglucose positron emission tomography scan in the follow-up of lymphoma. J Clin Oncol 27:1781–1787, 2009. 9. Weeks JC, Yeap BY, Canellos GP, et al: Value of follow-up procedures in patients with large-cell lymphoma who achieve a complete remission. J Clin Oncol 9:1196–1203, 1991.[Abstract] 10. Oh YK, Ha CS, Samuels BI, et al: Stages I-III follicular lymphoma: Role of CT of the abdomen and pelvis in follow-up studies. Radiology 210:483–486, 1999. 11. Foltz LM, Song KW, Connors JM: Who actually detects relapse in Hodgkin lymphoma: Patient or physician. Blood 104:853a–854a, 2004 abstr 3124. 12. 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 17:909–913, 2006. 13. Moskowitz C, Hamlin PA, Horwitz SM, et al: Phase II trial of dose-dense R-CHOP followed by risk-adapted consolidation with either ICE or ICE and ASCT, based upon the results of biopsy confirmed abnormal interim restaging PET scan, improves outcome in patients with advanced stage DLBCL. Blood 108:161a; 2006 abstr 532. 14. Terasawa T, Lau J, Bardet S, et al: Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: A systematic review. J Clin Oncol 27:1906–1914, 2009.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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