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Nuclear Medicine |
1 From the Department of Radiology, University of Southern California, 1200 N State St, GNH 3550, Los Angeles, CA 90033. From the 2005 RSNA Annual Meeting. Received April 2, 2006; revision requested June 5; revision received May 14, 2007; accepted June 13; final version accepted August 1. Address correspondence to G.A.U. (e-mail: ulaner{at}usc.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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Materials and Methods: This HIPAA-compliant study was performed with approval from the University of Southern California Institutional Review Board and with informed consent. Five men and five women (mean age, 52 years; range, 38–70 years) with relapsed or refractory non-Hodgkin lymphoma underwent FDG PET/CT imaging both 14–27 days before treatment with 90Y–ibritumomab tiuxetan and 4–6 months after treatment. Response after treatment was measured with CT imaging as complete response, partial response, or stable or progressive disease, as defined according to published criteria from a National Cancer Institute–sponsored international workshop. Response after treatment was measured with PET as complete response, partial response, or stable or progressive disease, as defined according to published criteria of the European Organization for Research and Treatment of Cancer. Responses were determined by three interpreters in consensus.
Results: Interpretation of CT images alone resulted in classification of eight (80%) of 10 patients as responders to treatment, with two patients (20%) classified as having complete response. At reevaluation with fused PET/CT images, two patients (20%) had residual lesions at CT that did not show evidence of FDG avidity. These two patients, classified as partial responders according to CT criteria alone, were classified as complete responders at PET/CT. Both of these patients were free of evident disease at 18 or more months of follow-up.
Conclusion: The use of combined FDG PET/CT may enable superior assessment of response to 90Y–ibritumomab tiuxetan treatment than the use of CT alone, at which one may underestimate 90Y–ibritumomab tiuxetan response by considering inactive residual CT masses to be residual disease.
© RSNA, 2008
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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Monoclonal antibody technology has led to the development of targeted immunotherapy of non-Hodgkin lymphoma (5,6). The anti-CD20 antibody rituximab (Rituxin; Genentech, South San Francisco, Calif) is B-cell specific and has been used alone and in combination with chemotherapy for improved non-Hodgkin lymphoma treatment response rates (7,8).
Because B-cell non-Hodgkin lymphomas are radiosensitive, antibodies targeting B-cells have been cross linked to radioisotopes to deliver lethal radiation doses to these lymphomas (9). Yttrium 90 (90Y)-ibritumomab tiuxetan (Zevalin; Biogen Idec, San Diego, Calif), the first radiolabeled antibody approved for therapy by the U.S. Food and Drug Administration, is composed of an anti-CD20 antibody (ibritumomab) linked to a chelator (tiuxetan) that provides high-affinity chelation to the β-emitting isotope 90Y. A report of a prospective trial of patients with histologically confirmed relapsed or refractory non-Hodgkin lymphoma (10) indicated overall and complete response rates, respectively, of 80% and 30% for 90Y–ibritumomab tiuxetan, compared with 56% and 16% for rituximab, thus showing the success of 90Y–ibritumomab tiuxetan treatment, even in patients whose disease was refractory to previous chemotherapy. Thus, while the use of 90Y–ibritumomab tiuxetan is currently uncommon, it is likely to increase substantially in the future (11,12).
Response rates to 90Y–ibritumomab tiuxetan in the Witzig et al trial (10), as well as in other, smaller trials, have been based on clinical data and findings at computed tomography (CT) of the neck, chest, abdomen, and pelvis. The determination of treatment response in patients with non-Hodgkin lymphoma is complicated, and multiple systems of classifying treatment response have been used. Criteria proposed by a National Cancer Institute–sponsored international workshop (13) are used as a standard system of classification. This system defines categories of complete response, complete response–unconfirmed, partial response, stable disease, and progressive disease. The classification system is complicated, and we refer readers to the original report for complete details. Briefly, complete response requires disappearance of all disease at physical examination, normalization of lactate dehydrogenase levels, and CT findings that show that all lymph nodes and nodal masses have regressed to normal size (<1.5 cm in greatest dimension for nodes > 1.5 cm before therapy, and <1 cm for nodes 1.1–1.5 cm before therapy). Partial response requires a greater than 50% decrease in mass size.
Because most non-Hodgkin lymphomas are fluorine 18 fluorodeoxyglucose (FDG) avid (14,15), FDG positron emission tomography (PET) can help distinguish viable lymphoma from postchemotherapy fibrotic change (16–18), and because FDG PET is superior to CT for the assessment of recurrent lymphoma after chemotherapy (19,20), we hypothesized that the use of combined FDG PET/CT would enable superior evaluation of 90Y–ibritumomab tiuxetan treatment response than that enabled by CT alone. Thus, the purpose of this study was to retrospectively compare fusion FDG PET/CT imaging with CT imaging alone in the evaluation of 90Y–ibritumomab tiuxetan radioimmunotherapy treatment.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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Our study included 10 patients—five men and five women ranging in age from 38 to 70 years (mean age, 52 years)—who were referred to the University of Southern California PET Center between November 2003 and February 2005 for 90Y–ibritumomab tiuxetan treatment of non-Hodgkin lymphoma that was refractory to chemotherapy and who had undergone PET/CT examinations before and after radioimmunotherapy as described below. Presence of refractory disease was suspected because of clinical, laboratory, or imaging findings and was confirmed with histologic findings from biopsy before 90Y–ibritumomab tiuxetan treatment.
Initial Clinical and Pathologic Data
The histologic and CD20 status of malignancies were determined with biopsy. The treatments patients received before 90Y–ibritumomab tiuxetan therapy were summarized from the patients' medical records.
Time Course of PET/CT Imaging and 90Y–Ibritumomab Tiuxetan Treatment
Patients with biopsy-proved refractory non-Hodgkin lymphoma underwent baseline PET/CT for staging of current disease. Patients then underwent preparation for 90Y–ibritumomab tiuxetan treatment, including an initial dose of rituximab (250 mg per square meter of body surface area) administered intravenously 1 week before treatment to optimize tumor targeting and determination of antibody biodistribution with 5-mCi (185-MBq) indium 111–ibritumomab tiuxetan imaging. Therapy, consisting of a dose of intravenous rituximab (250 mg/m2), followed by a single intravenous dose of 90Y–ibritumomab tiuxetan (0.3–0.4 mCi/kg [11.1–14.8 MBq/kg], up to 32 mCi [1184 MBq]), was performed 14–27 days (mean, 18 days) after the baseline PET/CT examination.
A PET/CT examination to evaluate response was performed 4–6 months (mean, 5.6 months) after 90Y–ibritumomab tiuxetan therapy, and its results were compared with those of the baseline imaging examination. No treatment other than 90Y–ibritumomab tiuxetan was administered between the baseline and follow-up PET/CT examinations.
Imaging
PET and CT were performed with a commercial combined PET/CT scanner (Biograph Duo LSO; Siemens, Erlangen, Germany). This scanner combines a septa-less three-dimensional PET scanner (ECAT LSO) with a helical CT scanner (Emotion Duo). PET/CT imaging was performed 1 hour after intravenous administration of 13–17 mCi (481–629 MBq) of FDG.
Helical CT (pitch, 1.0; 90–130 mAs; 130 kVp) was performed first, with oral but not intravenous contrast material. PET was subsequently performed with 3–7 minutes per bed position and six to eight bed positions per patient, depending on patient size. Raw CT data were reconstructed into transverse images with a 5-mm section thickness. Sagittal and coronal CT images were generated by reconstruction of transverse data. Raw PET data were reconstructed with and without attenuation correction into transverse, sagittal, and coronal images. Attenuation correction was based on the CT attenuation coefficients, which were determined by iterative reconstruction.
During the 4–6 hours prior to imaging, patients had fasted, except for water. All patients had a blood glucose level of less than 200 mg/dL (11.1 mmol/L) before FDG administration.
Image Interpretation
All images were reviewed at a workstation by using PET/CT fusion software (E-soft; Siemens). Each pair of baseline and follow-up PET/CT studies was interpreted by the three authors in consensus. G.A.U., P.M.C., and P.S.C. had 3, 4, and 5 years of experience in interpreting PET/CT studies, respectively. The examiners first evaluated the CT images alone. Mass sizes were measured by using vendor-provided software (Siemens). A lesion in the baseline study was defined as an identifiable mass or lymph node larger than 1 cm in minimum diameter with soft-tissue window settings. Response to treatment was assessed by comparing the baseline CT study with the follow-up CT study and was defined as no response, partial response, or complete response, as described by the published criteria of a National Cancer Institute–sponsored international workshop (13). After lesions had been classified with CT alone, the same pair of studies was evaluated with access to CT, PET, and fused PET/CT images. Maximum standardized uptake values (SUVs), or SUVmax values, were determined by using vendor-provided software (Siemens). Again, lesions were defined as showing no response, partial response, or complete response, as defined by published criteria of the European Organization for Research and Treatment of Cancer (21). The National Cancer Institute and European Organization for Research and Treatment of Cancer criteria are recognized as standards for CT and PET evaluation of non-Hodgkin lymphoma, respectively.
Patient Follow-up
Evaluation of baseline and follow-up CT studies and collection of data for this study began in February 2005. The baseline and follow-up PET/CT studies were reviewed retrospectively. Clinical follow-up then continued prospectively.
Of the 10 patients, two died during follow up. The remaining eight patients were followed up for 12–21 months after 90Y–ibritumomab tiuxetan therapy (mean, 17.5 months; median, 18 months). During follow-up, the status of disease was determined in consultation with the referring clinicians by using the most recent clinical data and imaging results. Side effects from 90Y–ibritumomab tiuxetan therapy were also determined in consultation with the referring clinicians by using laboratory data and the patient's medical records. The additional treatments patients received after 90Y–ibritumomab tiuxetan therapy were summarized from the patients' medical records. Lactate dehydrogenase levels were obtained from a review of the patients' medical records.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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In the remaining two patients (patients 9 and 10), CT and fused PET/CT interpretations were discordant (Fig 3). On CT images, residual masses remained in areas of previous lymphoma after 90Y–ibritumomab tiuxetan treatment. These masses were interpreted as being residual lymphomatous disease, and thus, according to CT criteria alone, the studies were classified as evidence for partial response to therapy. Subsequent evaluation with fused PET/CT images revealed that these masses were no longer FDG avid, with SUVs equivalent to background. Thus, according to PET criteria, these masses were attributed as benign posttherapy residual fibrosis, and both patients were classified as complete responders. Patient 9 underwent two subsequent PET/CT examinations at which the residual masses were stable in size and lacked FDG avidity; hence, the patient was regarded as being without evidence of disease 21 months after 90Y–ibritumomab tiuxetan treatment. Patient 10 underwent one subsequent PET/CT examination and then two additional CT studies, at which the residual mass (Fig 3) was stable in size; hence, this patient was regarded as being without evidence of disease 18 months after 90Y–ibritumomab tiuxetan treatment. Neither patient 9 nor patient 10 received additional treatment after 90Y–ibritumomab tiuxetan therapy.
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Side Effects of 90Y–Ibritumomab Tiuxetan Treatment
The side effects of 90Y–ibritumomab tiuxetan therapy seen in this study were similar to those seen in previous studies (10,22), with patients experiencing transient reductions in leukocytes, erythrocytes, and platelets. Patients 3 and 7 required platelet transfusions for platelet levels of less than 20 x 103 cells per cubic millimeter. Patients 1 and 8 received epoetin, and patient 3 received darbepoetin for hematocrit levels of less than 28%. Patient 1 received filgrastim, patient 2 received granulocyte colony-stimulating factor, and patients 3 and 10 received pegfilgrastim for leukocyte levels of less than 2 x 103 cells per cubic millimeter.
Serum Tumor Marker Levels during Treatment
Lactate dehydrogenase levels were obtained as a serum tumor marker; however, this had little effect on detection of lymphomatous disease. Lactate dehydrogenase levels in all patients remained between 119 and 256 U/L, with our laboratory's normal range being 100–250 U/L.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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Subsequent evaluation with fused PET/CT altered the classification for two patients. In both patients, residual masses at CT, which were originally considered evidence of residual lymphoma, were found to have SUVs at PET that were equivalent to background. This changed the classification from partial to complete response for both patients. Thus, by using PET/CT images for evaluation of response, the complete response rate increased to 40% (four of 10 patients), while the overall response rate remained 80% (eight of 10 patients). Because both patients who were reclassified as complete responders with fused PET/CT data were free of evident disease without additional therapy by at least 18 months of follow-up, we hypothesize that fused PET/CT is superior to CT alone for evaluating the degree of response to 90Y–ibritumomab tiuxetan therapy.
Our study also provides further evidence of the success of 90Y–ibritumomab tiuxetan therapy and the prognostic importance of 90Y–ibritumomab tiuxetan therapy failure. Four patients had complete response to 90Y–ibritumomab tiuxetan therapy, as measured with PET/CT, despite the failure of multiple previous treatments, including rituximab. All four of these patients had no evidence of disease at follow-up 18–21 months after treatment. Conversely, both of the two patients who showed no response to 90Y–ibritumomab tiuxetan therapy died of disease shortly thereafter. Of the patients with a partial treatment response, two (patients 4 and 6) had not been treated with nonradioactive CD20 antibody (rituximab) before 90Y–ibritumomab tiuxetan treatment. For these two patients, treatment response may have been due to the introduction of rituximab, and not just to 90Y–ibritumomab tiuxetan.
In our study, all patients had FDG-avid tumors. Even the relatively lower SUVmax values seen in patient 3 were substantially higher than background blood pool activity. Of course, FDG PET would not be of benefit to patients with non–FDG-avid tumors.
All patients had histologic verification of refractory lymphomatous disease before 90Y–ibritumomab tiuxetan treatment, which is a strength of our study. There was no histologic verification of disease after 90Y–ibritumomab tiuxetan treatment. Residual posttreatment disease was evaluated with imaging and clinical findings.
The CT examinations performed in our study were not enhanced with contrast material, and PET/CT at our institution is performed without contrast material. This limits the comparison of combined PET/CT with CT performed with intravenous contrast material. However, because the published criteria for CT evaluation of non-Hodgkin lymphoma treatment response are based on mass size and do not consider mass enhancement (13), the addition of intravenous contrast material would not have altered our interpretation of treatment response.
Recently, revised criteria for assessment of lymphoma treatment response were published (23,24). These criteria were not available during the course of our study. Use of the revised criteria would not have altered the interpretation of treatment response in the 10 patients presented in our study.
Limitations of this study included the retrospective examination of images, the small number of patients, and the limited number of imaging examinations for each patient. The retrospective examination of images allows the biases that are inherent in a retrospective study. The small number of patients included in our study was a result of the small number of patients with non-Hodgkin lymphoma currently being treated with 90Y–ibritumomab tiuxetan rather than with conventional chemotherapy. However, as clinical experience with 90Y–ibritumomab tiuxetan grows, the use of this promising radioimmunotherapy is likely to expand substantially. This is especially true in light of attempts to investigate radioimmunotherapy as a first-line treatment for non-Hodgkin lymphoma (25).
The restricted number of time points examined for each patient was another limiting factor of our study. Investigations of CT for monitoring therapy response often include multiple studies beginning only 1 month after treatment (10). Others have imaged with PET/CT after 3 months (26,27). When this protocol began, we were unsure as to whether radioimmunotherapy would produce inflammatory responses early after treatment that would display FDG avidity. Thus, our posttreatment evaluations began at 4–6 months. We did not encounter FDG-avid inflammatory responses in our follow-up studies 4–6 months after treatment, and we anticipate that in the future, evaluation of patients after 90Y–ibritumomab tiuxetan treatment can be performed earlier.
Currently, CT alone is the standard for imaging 90Y–ibritumomab tiuxetan treatment response. To our knowledge, no previous investigation has compared CT with PET/CT in the evaluation of 90Y–ibritumomab tiuxetan treatment response. We believe that fused FDG PET/CT is superior to CT alone for evaluating response to 90Y–ibritumomab tiuxetan therapy, because the use of CT alone may lead to underestimation of response. If improved classification of treatment response can be obtained by using PET or PET/CT, substantial improvements in patient care may be realized. A PET/CT examination demonstrating complete response, which may have been mistaken as partial response at CT alone, would save a patient from the toxicity and costs of additional treatment. We believe the potential of PET/CT to improve the care of patients with non-Hodgkin lymphoma receiving 90Y–ibritumomab tiuxetan therapy warrants additional investigation.
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ADVANCE IN KNOWLEDGE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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IMPLICATION FOR PATIENT CARE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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FOOTNOTES |
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Abbreviations: FDG = fluorine 18 fluorodeoxyglucose • SUV = standardized uptake value
Author contributions: Guarantor of integrity of entire study, G.A.U.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, G.A.U.; clinical studies, all authors; and manuscript editing, all authors.
Authors stated no financial relationship to disclose.
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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This article has been cited by other articles:
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  H. A. Jacene, R. Filice, W. Kasecamp, and R. L. Wahl 18F-FDG PET/CT for Monitoring the Response of Lymphoma to Radioimmunotherapy J. Nucl. Med., January 1, 2009; 50(1): 8 - 17. [Abstract] [Full Text] [PDF]
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