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CT era?
original article
Annals of Oncology 17: 117–122, 2006 doi:10.1093/annonc/mdj024 Published online 28 September 2005
Is CT scan still necessary for staging in Hodgkin and non-Hodgkin lymphoma patients in the PET/CT era? P. Raanani1,4*, Y. Shasha2,4, C. Perry3,4, U. Metser2,4, E. Naparstek3,4, S. Apter4,6, A. Nagler4,5, A. Polliack3, I. Ben-Bassat4,5 & E. Even-Sapir2,4 1
Rabin Medical Center, Department of Hematology; 2Tel-Aviv Sourasky Medical Center, Department of Nuclear Medicine; 3Department of Hematology; Tel-Aviv University, Sackler School of Medicine, Tel-Aviv; 5The Chaim Sheba Medical Center, Department of Hematology; 6Department of Radiology, Ramat-Gan, Israel 4
introduction Accurate staging is the basis for the selection of an appropriate therapeutic approach in patients with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Staging is necessary in order to prevent over or under treatment as well as to minimize morbidity related to the radio-chemotherapy regimens given. Quality of life during and after treatment may also be improved when therapy is tailored appropriately [1]. Despite differences in their biology and clinical behavior, the management of both NHL and HD follows well-established guidelines based on the initial staging assessment [2, 3]. Currently, computed tomography (CT) is the principal staging tool for patients with lymphoma. It is readily available, easy to perform, reliable and reproducible and there is evidence for its diagnostic and therapeutic impact in large series of patients [4]. However, this imaging modality also has several limitations since interpretation of nodal involvement by CT is based on *Correspondence to: Dr P. Raanani, Rabin Medical Center, Institute of Hematology, Campus Beilinson, Sackler School of Medicine, Tel-Aviv University, Petah-Tikva, 49100 Israel. Tel: +972-3-9378207; Fax: +972-3-6992463; E-mail: [email protected]
ª 2005 European Society for Medical Oncology
anatomic criteria of size and shape [5]. Early involvement of lymph nodes is not always associated with detectable anatomic changes and thus may be overlooked. On the other hand, benign lymph node enlargement as encountered in association with reactive changes, may be a cause for false-positive interpretation. Furthermore it is often impossible to reliably distinguish lymphoma lesions from benign CT abnormalities [6–9]. Moreover, extra-nodal sites of lymphoma in the liver, skin and skeleton are often notoriously difficult to assess by CT alone [10]. 2-[Fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), a functional imaging modality used for staging and monitoring response to treatment of a variety of human neoplasias, has a higher sensitivity and specificity than conventional anatomical imaging. FDG-PET has had a major impact on the staging and management of lymphoma, resulting in alterations of the clinical stage and therapy in a substantial number of patients. However, FDG-PET is a functional modality often requiring correlation with anatomical imaging modalities so as to localize the detected lesion more accurately [10].
original article
Background: The clinical impact of fused PET/CT data on staging and patient management of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) was assessed. Patients and methods: A total of 103 consecutive patients with newly diagnosed NHL (n = 68) and HD (n = 35) were assessed retrospectively. Three comparisons were carried out in an attempt to assess the added value of each modality. Results: For NHL patients, there were significant differences between staging by CT versus PET/CT (P = 0.0001). Disease was upstaged by PET/CT in 31% (mostly in stages I and II) and downstaged in only 1% of patients. In 25% of the patients, the treatment approach was changed according to CT versus PET/CT findings. For HD patients, disease was upstaged by PET/CT in 32% and downstaged by PET/CT in 15% (P = NS). As for NHL, upstaging by PET/CT versus CT was evident mostly for stages I and II. The treatment strategy was altered as determined by CT versus PET/CT in 45% of the patients. Conclusions: The addition of PET/CT to CT changed the management decisions in approximately a quarter of NHL and a third of HD patients, mostly in early disease stages. Thus, PET/CT performed as the initial staging procedure may well obviate the need for additional diagnostic CT in the majority of patients. Key words: PET/CT, Hodgkin disease, non-Hodgkin lymphoma, staging
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Received 15 July 2005; revised 19 August 2005; accepted 23 August 2005
original article
Annals of Oncology
patients and methods patients The study population included 103 consecutive unselected patients with newly diagnosed NHL and HD referred from two large hospitals in Israel, the Chaim Sheba Medical Center (SMC) and the Tel-Aviv Sourasky Medical Center (TASMC), for a baseline PET/CT scan at the department of Nuclear Medicine in TASMC between April 2002 and January 2004. For a retrospective analysis, our Institutional Review Boards do not require approval or informed consent to review patients’ records, files and images. Of the 103 patients, 52 were women and 51 men, with a mean age of 47 ± 17 years (range 20–81). Sixty-eight patients had NHL and 35 had HD (Table 1). Patients with biopsy-proven NHL and HD were enrolled for this study provided they had both CT and PET/CT studies performed prior to Table 1. Patients characteristics NHL n 68 M: F 35: 33 Age, mean 6 52 6 15 (range 20–81) SD (years) Pathological subtype Follicular, 19 Diffuse, 34 Other, 15: Anaplastic, 5; Mantle, 3; T cell, 2; marginal, 2; atypical, 1; Burkitt, 1; small lymphocytic, 1
HD 35 16: 19 38 6 17 (range 20–74)
Nodular sclerosis, 29 Mixed cellularity, 2 Lymphocyte predominant, 1
Unspecified, 3
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receiving therapy. PET/CT was performed within a mean of 24 days of the conventional diagnostic CT scan. Only nine patients had more than a 2-month interval between the two tests.
methods The clinical stage of the patients was assessed according to the modified Ann Arbor classification [19]. For the purpose of analysis three detailed data sheets were generated including a clinical data sheet and a separate data sheet for each of the imaging techniques, i.e. diagnostic CT and PET/CT report. A physician (YS) uninvolved in the imaging or in the clinical interpretation of data was responsible for the patients’ records and data sheets. These were passed on to an experienced team of hematologists, in three sequential steps at least 1 month apart. Patients’ names were removed from all data and the order of the patients investigated was altered at each step. clinical data sheet. This contained the physical examination, established prognostic factors according to the IPI prognostic scores for HD [20] and NHL [21], and data comprising complete blood counts, erythrocyte sedimentation rate (ESR) and biochemistry levels and bone marrow biopsy findings. diagnostic CT scan data sheet. This contained reports of CT scans done at diagnosis. Diagnostic contrast enhanced CT scans were performed in a variety of radiological institutes as both hospitals serve as tertiary centers. CT scans were performed using the appropriate protocol and guidelines for lymphoma staging. Each CT scan was reported initially by the scanning radiologist and were usually reviewed by a second radiologist specializing in tumor imaging in each of the two participating centers (UM and SA). Standard CT size criteria for individual lymph node groups were used to determine the enlarged lymph nodes. PET/CT scan data sheet. This contained a report of the PET/CT scan done at the time of diagnosis. All PET/CT scans were performed at the same nuclear medicine department (TASMC) and interpreted by the same team of specialists (EES and UM) in a consensus reading. For PET/CT imaging the patients fasted at least 4 h prior to the intravenous (i.v.) injection of 370–666 MBq (10–18 mCi) 18F-FDG. Administration of oral contrast was added for better discrimination between physiologic bowel activity and abdominal tumor sites. A PET/CT study was performed only when blood glucose levels did not exceed 150 mg/dl. Scanning from the base of the skull through the mid thigh was performed using the Discovery LS PET/CT system (GE Medical Systems, Milwaukee, WI). Low-dose CT acquisition was performed first with 140 kV, 80 mA, 0.8 s per CT rotation, a pitch of 6 and a table speed of 22.5 mm/s, without any specific breath-holding instructions. A PET emission scan was carried out immediately following acquisition of the CT, without changing the patient’s position. Five to eight bed positions were performed with an acquisition time of 5 min for each one. PET images were reconstructed using an OSEM algorithm. CT data were used for attenuation correction. PET/CT interpretation were performed on the eNTEGRA or the Xeleris workstations (ELGEMS, Haifa, Israel) equipped with fusion software, which enables the display of PET images (with and without attenuation correction), CT images and fused data of both modalities. Any site of increased uptake that was not due to physiological or benign uptake was considered a possible lymphoma site [22]. PET/CTs were visually interpreted and standardized uptake value (SUV) analysis was not used in this retrospective study to differentiate between reactive and involved lymph nodes. Involvement according to PET/CT was reported only when it was clear cut, according to the combination of morphology by the CT portion (size and shape of nodes and the presence of retained hilum) and by the uptake and location of the FDG-PET part. In the case of nodal involvement, any increased uptake other than the hilar region, regardless of the lymph node size was considered pathologic.
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It has been suggested for some time now, that complementary functional and anatomic imaging allows for improved diagnosis and, subsequently, to better patient-care in clinical oncology [11]. Recently, PET/CT systems, which enable acquisition of PET and CT data at the same setting without changing the patients’ positioning, have been introduced into clinical practice [12–15]. The molecular information provided by FDG-PET identifies the functional content of the anatomic findings and helps to categorize their nature as malignant or benign. On the other hand, the CT data obtained in the same setting provides anatomical localization of the FDG-PET data while also improving the FDG-PET image quality as it is utilized for attenuation correction [16, 17]. Thus, PET/CT offers several advantages including shorter image acquisition time, improved lesion localization and identification and more accurate tumor staging [10, 11]. Preliminary data, mostly in abstract form, or a few peer-reviewed studies examining the incremental value of PET/CT over FDG-PET alone for staging and restaging of cancer, have suggested that there is improved diagnostic and staging accuracy as well as a reduction in false-positive/negative rates and an improved confidence in FDG-PET interpretation [2, 18]. The purpose of the current study was to assess the clinical impact of fused PET/CT data on the staging and management of patients with HD and NHL.
original article
Annals of Oncology
Sites that were equivocal were reported on the data sheets as such. Since reactive lymph nodes may be associated with increased FDG uptake in the hilar region, positive diagnosis of lymphoma was only given if additional ‘hot’ nodes were detected above the diaphragm.
data analysis
treatment protocols The treatment protocols for stage I NHL consisted of abbreviated (three to four courses) chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) ± rituximab followed by involved field radiation for aggressive NHL and radiotherapy alone for indolent NHL. Treatment protocol for stages II–IV NHL consisted of a full chemotherapy regimen depending on the histopathology report, e.g. either six to eight courses of CHOP, COP, FMC or the MACOP-B, VACOP-B, HYPER C-VAD and GMALL 2000 regimens ± rituximab. In HD, treatment for stages I and II consisted of three to four courses of ABVD followed by involved field irradiation while the therapeutic regimens for advanced stage disease (stages III/IV) were either six cycles of ABVD or two cycles of escalated BEACOPP followed by four cycles of ABVD.
statistical analysis For continuous variables, ranges, means and standard errors were computed. The mean values were analyzed and compared with two-sample t-test for differences in means. For categorical variables, frequencies and relative frequencies were calculated. The chi-squared test of independence was used to compare the relative frequencies of the categorical variables. For small numbers of observations the Fisher–Irwin exact test was used. The Wilcoxon matched-pairs ranks test was used to test the equality of matched pairs of observations.
results Results for NHL and HD patients were analyzed separately. The staging and therapeutic recommendations of the clinical panel are given below.
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treatment approach. The suggested treatment strategy based on CT versus PET/CT was different in 17 patients (25%). The suggested treatment strategy based on CT versus CT plus PET/CT was different in 18 patients (26%). The suggested treatment strategy based on PET/CT versus CT plus PET/CT was different in six of 68 patients (9%).
hodgkin disease staging. Based on the modified Ann Arbor staging system there were differences between the staging based on CT versus PET/CT but these were not statistically significant (P = 0.16) (Table 3). In 16 patients (45%) staging based on diagnostic CT versus PET/CT was discordant. Disease was upstaged by Table 2. Comparison of staging algorithms based on CT or PET/CT in 68 NHL patients PET/CT
CT
I II III IV NE
I 9 1 2 7 –
II – 13 5 3 –
III – – 9 3 –
IV – – 1 14 –
NE – – – 1 –
Table 3. Comparison of staging algorithms based on CT or PET/CT in 35 patients with HD PET/CT
CT
I II III IV NE
I – 1 – – –
II 2 14 5 3 1
III – 1 2 2 –
IV – 2 – 2 –
NE – – – – –
doi:10.1093/annonc/mdj024 | 119
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Establishing the clinical stage of the disease and the proposed therapy was determined three times for each of the 103 study patients and for each decision the clinical data sheet was used. For the first decision, diagnostic CT was used as the only imaging modality (the conventional algorithm). The second decision algorithm was based on PET/CT findings alone, while the third decision was made after reviewing both the diagnostic CT and PET/CT scans. The clinical interpretation and decision making was made by experienced hematologists who determined the staging according to consensus and then suggested a plan for treatment. Three modes of comparison were carried out. The first compared the conventional staging algorithm based on physical examination, laboratory assessment and diagnostic CT results to the same staging algorithm replacing the CT modality with PET/CT. The second comparison was intended to assess the added value of PET/CT by comparing the stage of disease and the suggested management as determined by diagnostic CT alone to that of diagnostic CT plus PET/CT. In order to determine the added value and whether a diagnostic CT is really necessary in the era of PET/CT, a third comparison was performed in which staging by PET/CT alone was compared with that obtained after PET/CT plus diagnostic CT. Staging was classified as concordant or discordant. Concordant results were considered when there were no differences between the three decision algorithms. Since the ultimate goal of accurate staging is the selection of the appropriate clinical approach, a panel of clinicians was asked to decide how to treat each patient, based on the different staging algorithms used. The subsequent changes in the suggested therapy were assessed independently.
non-Hodgkin lymphoma staging. Significant differences were found between staging based on CT versus PET/CT (P = 0.0001) (Table 2). Discordant staging by diagnostic CT and by PET/CT was found in 22 patients (32%). Disease was upstaged by PET/CT in 31% of patients and downstaged in 1%. Upstaging by PET/CT was mainly for the early stages I and II. Lesions diagnosed on PET/CT and overlooked on CT, included increased FDG uptake in small-sized lymph nodes or extranodal involvement in the liver, spleen, bones or skin. Significant differences were also found between staging based on CT alone and staging based on CT and PET/CT (P = 0.0001) (data not shown). Twenty-nine cases (42%) were discordant. Disease was upstaged by CT plus PET/CT in 41% of patients and downstaged only in 1%. Although the difference between the staging algorithms based on PET/CT alone versus CT and PET/CT reached statistical significance (P = 0.005), discordance was found in only eight patients (12%). All were upstaged by the addition of CT to PET/CT (data not shown).
original article
Annals of Oncology
PET/CT in 32% of patients and downstaged in 15%. Upstaging by PET/CT compared with CT was evident mostly for stages I and II. The cases upstaged by PET/CT included the detection of increased FDG uptake in small-sized lymph nodes, spleen, liver, thymus, cortical bone, bone marrow, lung and pleura. A statistically significant difference was found between staging based on CT alone or CT plus PET/CT (P = 0.0023) (data not shown). In 15 patients (43%) staging was discordant. Disease was upstaged by CT plus PET/CT in 34% of patients and downstaged only in 9%. No statistically significant difference was found between staging based on PET/CT alone or CT plus PET/CT (P = 0.31) (data not shown). Four cases (11.5%) were discordant: three upstaged and one downstaged by the addition of CT to PET/CT.
the effect of the interval between the performance of CT and PET/CT The mean interval between diagnostic CT and PET/CT was 24 days but nine patients had an interval greater than 2 months between the two tests. This raises the question whether disease progression occurred in the interval thereby contributing to upstaging of disease by the PET/CT. In four of the nine patients there was no change in stage between the two modalities, while in five patients disease was upstaged by PET/CT: one patient with HD was upstaged from IIA to IVA, two patients with diffuse large cell were upstaged from IA or IIA to IIIA, one patient with anaplastic lymphoma was upstaged from IIA to IVA, while one patient with follicular lymphoma was upstaged from IIA to IVA. In order to exclude the possibility of disease progression in patients with an interval greater than the mean of 24 days between performing the CT and PET/CT, we compared the cases with an interval of more or less than the mean. While there was a change in stage in 57% of the cases with an interval of less than 24 days, stage changed in only 45% of the cases with the longer interval. Table 4. Differences in the suggested treatment based on the various imaging algorithms in patients with NHL and HD Staging according to
NHL Change in treatment (%)
HD Change in treatment (%)
CT versus PET/CT CT versus CT+PET/CT PET/CT versus CT+PET/CT
25 26
45 32
9
9
120 | Raanani et al.
discussion Data assessing the true clinical impact of PET/CT imaging on diagnostic accuracy and patient management is still being accumulated and its role in the staging of lymphoma is under study. Bar-Shalom et al. [12] found PET/CT to be of additional value over CT or PET alone in 49% of patients with different neoplasias, including 36% of patients with lymphoma. Recently, Schaefer et al. [23] compared PET/CT findings with those of contrast CT in 60 patients with NHL or HD and concluded that PET/CT (although performed with non-enhanced CT) is more sensitive and specific for the evaluation of lymph node and organ involvement (mainly by excluding disease) than contrast enhanced CT. Until recently, staging algorithms of NHL and HD were based solely on diagnostic CT, which was mostly contrast-enhanced. With the introduction of FDG-PET and even more recently of PET/CT systems as part of the routine practice in lymphoma, it seems to have become important to choose the most appropriate staging algorithm for this patient population. Basically, this poses the question of comparing the use of diagnostic CT alone, PET/CT alone or both modalities. Even if PET/CT alone is used, one has to decide which acquisition protocol should be applied for the CT part of the PET/CT study; particularly whether to perform a full-dose or reduced-dose whole body CT, as well as whether to administer contrast-media intravenously. Since all our patients had already had a diagnostic CT performed, we used a reduced mAs CT protocol in our PET/CT acquisition protocol. The latter is associated with only 20% of the radiation exposure of a diagnostic CT. Our data suggested that in the majority of patients, PET/CT performed with lowdose CT and without i.v. contrast media was satisfactory for staging of most patients with lymphoma, as already shown by Schaefer et al. [23]. Only in 12% of our patients did the addition of a full-dose diagnostic CT to the PET/CT study contribute further information, probably due to the administration of i.v. contrast. A reasonable approach would be to omit the standard CT scanning from the initial staging and use a full-dose CT protocol in the PET/CT study. The issue of i.v. contrast administration in the CT portion of PET/CT is still open for further assessment. It is of interest to note that PET/CT mostly upstaged disease when compared with CT alone and this was observed mostly for stages I and II for both NHL and HD. On the basis of these results, it seems to us that PET/CT appears to be beneficial for patients in the early stages of the two groups of lymphoma. In the more advanced stages III and IV, PET/CT may not have any added value if the disease was already defined as advanced by a diagnostic CT alone [7]. These results suggest that in centers performing a diagnostic CT as the initial step of staging, PET/CT should only be added in patients defined as early stage disease by CT alone.
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treatment approach The suggested treatment strategy was different based on CT versus PET/CT in 16 patients (45%). The suggested treatment strategy was different based on CT versus CT and PET/CT in 13 of the 35 patients (32%). The suggested treatment strategy was different based on PET/CT versus CT plus PET/CT in only three of 35 patients (9%). Table 4 summarizes the differences in the therapy given based on the different algorithms for all patients in the cohort. Results are shown separately for NHL and for HD. The change in treatment was less frequent for NHL than for HD patients.
Furthermore, we compared the mean time interval between CT and PET/CT studies in the group of patients whose stage was changed and in those whose stage was not altered and found that it was 28.5 versus 21.7 days, respectively (P = NS). Thus, it seems that the longer interval did not contribute to the change of stage as determined by PET/CT.
original article
Annals of Oncology
Volume 17 | No. 1 | January 2006
acquisition was performed at different institutions before the PET/CT was done. On the other hand, the majority of CT scans were reviewed again by our team. The possibility that the group of patients who had a longer interval between performing the two modalities had progression of their disease related to the delay in performing their PET/CT, was basically ruled out as we have shown that the longer interval involved did not influence the change of stage recorded. However, the major limitation of this study relates to the absence of histological evaluation of the concordant and some of the discordant lesions. This is due to the fact that biopsy is not yet performed as a standard procedure for all lesions in lymphoma patients. This limitation is also inherent in other previously published studies [24, 29]. In summary, it seems that the combined functional and anatomical data available from PET/CT makes it an appropriate staging imaging technique for both NHL and HD patients. When added to CT scan done alone it can change the therapeutic approach in 20%–30% of the patients with HD and NHL and mostly those with early stages of disease [30]. Accordingly we recommend that it is best added for patients defined as early stage disease in centers performing a diagnostic CT. On the other hand, adding CT to PET/CT changed the therapeutic approach in only 9% of NHL and HD patients. Thus it seems to us that performing PET/CT as the initial staging modality obviates the need to use an additional diagnostic CT in the majority of patients with NHL and HD. As for the CT aspect of the PET/CT scan, reduced mAs CT with low radiation exposure may be satisfactory in the majority of patients. If the results of future larger studies confirm our own results, integrated PET/CT may become the new staging imaging modality for lymphoma at diagnosis, reserving an additional diagnostic CT only for selected patients.
references 1. Friedberg JW, Chengazi V. PET scans in the staging of lymphoma: current status. Oncologist 2003; 8: 438–447. 2. Hoskin PJ. PET in lymphoma: what are the oncologist’s needs? Eur J Nucl Med Mol Imaging 2003; 30 (Suppl 1): S37–S41. 3. Israel O, Keidar Z, Bar-Shalom R. Positron emission tomography in the evaluation of lymphoma. Semin Nucl Med 2004; 34: 166–179. 4. Vinnicombe SJ, Reznek RH. Computerised tomography in the staging of Hodgkin’s disease and non-Hodgkin’s lymphoma. Eur J Nucl Med Mol Imaging 2003; 30 (Suppl 1): S42–S55. 5. Carrington B. Lymph nodes. In: Husband JE, Reznek RH (eds): Imaging in Oncology. Oxford, UK: Isis Medical Media Ltd 1998; 729–748. 6. Menzel C, Dobert N, Mitrou P et al. Positron emission tomography for the staging of Hodgkin’s lymphoma–increasing the body of evidence in favor of the method. Acta Oncol 2002; 41: 430–436. 7. Naumann R, Beuthien-Baumann B, Reiss A et al. Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin’s lymphoma. Br J Cancer 2004; 90: 620–625. 8. Partridge S, Timothy A, O’Doherty MJ et al. 2-Fluorine-18-fluoro-2-deoxy-D glucose positron emission tomography in the pretreatment staging of Hodgkin’s disease: influence on patient management in a single institution. Ann Oncol 2000; 11: 1273–1279. 9. Delbeke D, Martin WH, Morgan DS et al. 2-deoxy-2-[F-18]fluoro-D-glucose imaging with positron emission tomography for initial staging of Hodgkin’s disease and lymphoma. Mol Imaging Biol 2002; 4: 105–114.
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Upstaging by PET/CT for both NHL and HD included the detection of increased FDG uptake in normal-sized lymph nodes (usually less than 1 cm) as well as in extra-nodal sites, most commonly the liver, spleen, cortical bone, bone marrow and skin, previously missed by diagnostic CT but nevertheless FDG avid. In a few cases, paraspinal and pulmonary lesions interpreted as benign by the CT scan were read as involved according to the PET/CT. The latter findings are in keeping with the results of other studies, reporting an improved sensitivity for FDG-PET compared with conventional imaging methods for detecting extra-nodal disease, both in the bone marrow and other organs [23, 24]. The explanation for this discrepancy may either be the higher sensitivity of PET/CT or alternatively a higher rate of false positivity using this method. Since the only way to solve this issue is by obtaining biopsies from discordant sites we cannot confirm or refute either hypothesis. Another key issue in lymphoma relates to whether a change in clinical staging indeed affects the type of therapy given. An interesting finding in our study relates to the fact that the impact of PET/CT on the subsequent change of therapeutic approach in patients with NHL, was much less pronounced than on the alteration in clinical stage This was at least partially due to the fact that most patients with early stage disease received ‘advanced stage treatment’ anyway. The lower impact on treatment found for PET/CT compared with its impact on disease stage may reflect the limited therapeutic options used at a given center. In general, HD patients with good-risk localized disease (stage I and II) are treated with an abbreviated course of chemotherapy and involved field radiation, whereas more advanced disease is treated with more cycles and a fuller course of combination chemotherapy. It should be noted, however, that many centers use the same therapy for all stages of histological aggressive NHL (with the possible exception of patients with stage I disease who have no adverse risk factors). The influence of FDG-PET or PET/CT on treatment strategy varies markedly in different studies and because of this the actual impact on patient management and outcome still remains to be determined [25]. In our study, the addition of PET/CT to the staging algorithm affected the treatment approach in approximately one-quarter of the 68 NHL patients and in a third of the 35 HD patients, while the addition of CT to the algorithm changed the suggested general treatment in only approximately 10% of NHL and HD patients. Recently, Schaefer et al. [23] showed that treatment was changed in 16% patients with HD or high grade NHL, on the basis of PET/CT staging, while on the basis of contrast-enhanced CT findings, it was changed in only about 5% of the patients. Other studies compared FDG-PET with CT, mainly for HD. The range of change in treatment strategy according to FDG-PET compared with CT for primary staging of HD was wide and varied between 3% and 25% [7, 8, 24, 26–28]. Our study has several shortcomings and its retrospective nature may have introduced a bias in the results. In addition, the patient population was heterogeneous, composed of smaller subgroups of indolent NHL lymphomas, different aggressive NHL as well as HD patients. Furthermore, the technique of contrast-enhanced CT was not standardized, since data
original article
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21. A predictive model for aggressive non-Hodgkin’s lymphoma. The International NonHodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987–994. 22. Kostakoglu L, Hardoff R, Mirtcheva R et al. PET-CT fusion imaging in differentiating physiologic from pathologic FDG uptake. Radiographics 2004; 24: 1411–1431. 23. 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: 823–829. 24. Hutchings M, Eigtved AI, Specht L. FDG-PET in the clinical management of Hodgkin lymphoma. Crit Rev Oncol Hematol 2004; 52: 19–32. 25. Kumar R, Maillard I, Schuster SJ et al. Utility of fluorodeoxyglucose-PET imaging in the management of patients with Hodgkin’s and non-Hodgkin’s lymphomas. Radiol Clin North Am 2004; 42: 1083–1100. 26. Bangerter M, Moog F, Buchmann I et al. Whole-body 2-[18F]-fluoro-2-deoxy-Dglucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin’s disease. Ann Oncol 1998; 9: 1117–1122. 27. Jerusalem G, Beguin Y, Fassotte MF et al. Whole-body positron emission tomography using 18F-fluorodeoxyglucose for post treatment evaluation in Hodgkin’s disease and non-Hodgkin’s lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging. Blood 1999; 94: 429–433. 28. Weihrauch MR, Re D, Bischoff S et al. Whole-body positron emission tomography using 18F-fluorodeoxyglucose for initial staging of patients with Hodgkin’s disease. Ann Hematol 2002; 81: 20–25. 29. Schiepers C, Filmont JE, Czernin J. PET for staging of Hodgkin’s disease and non-Hodgkin’s lymphoma. Eur J Nucl Med Mol Imaging 2003; 30 (Suppl 1): S82–S88. 30. Ho CL. Clinical PET imaging–an Asian perspective. Ann Acad Med Singapore 2004; 33: 155–165.
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10. Freudenberg LS, Antoch G, Schutt P et al. FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging 2004; 31: 325–329. 11. Beyer T, Antoch G, Muller S et al. Acquisition protocol considerations for combined PET/CT imaging. J Nucl Med 2004; 45 (Suppl 1): 25S–35S. 12. Bar-Shalom R, Yefremov N, Guralnik L et al. Clinical performance of PET/CT in evaluation of cancer: additional value for diagnostic imaging and patient management. J Nucl Med 2003; 44: 1200–1209. 13. Antoch G, Freudenberg LS, Beyer T et al. To enhance or not to enhance? 18F-FDG and CT contrast agents in dual-modality 18F-FDG PET/CT. J Nucl Med 2004; 45 (Suppl 1): 56S–65S. 14. Miller E, Lerman H, Gutman M et al. The clinical impact of camera-based positron emission tomography imaging in patients with recurrent colorectal cancer. Invest Radiol 2004; 39: 8–12. 15. Ratib O. PET/CT image navigation and communication. J Nucl Med 2004; 45 (Suppl 1): 46S–55S. 16. Townsend DW, Carney JP, Yap JT et al. PET/CT today and tomorrow. J Nucl Med 2004; 45 (Suppl 1): 4S–14S. 17. Kapoor V, McCook BM, Torok FS. An introduction to PET-CT imaging. Radiographics 2004; 24: 523–543. 18. Schoder H, Larson SM, Yeung HW. PET/CT in oncology: integration into clinical management of lymphoma, melanoma, and gastrointestinal malignancies. J Nucl Med 2004; 45 (Suppl 1): 72S–81S. 19. Lister TA, Crowther D, Sutcliffe SB et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 1989; 7: 1630–1636. 20. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 1998; 339: 1506–1514.
Annals of Oncology
Annals of Oncology 17: 117–122, 2006 doi:10.1093/annonc/mdj024 Published online 28 September 2005
Is CT scan still necessary for staging in Hodgkin and non-Hodgkin lymphoma patients in the PET/CT era? P. Raanani1,4*, Y. Shasha2,4, C. Perry3,4, U. Metser2,4, E. Naparstek3,4, S. Apter4,6, A. Nagler4,5, A. Polliack3, I. Ben-Bassat4,5 & E. Even-Sapir2,4 1
Rabin Medical Center, Department of Hematology; 2Tel-Aviv Sourasky Medical Center, Department of Nuclear Medicine; 3Department of Hematology; Tel-Aviv University, Sackler School of Medicine, Tel-Aviv; 5The Chaim Sheba Medical Center, Department of Hematology; 6Department of Radiology, Ramat-Gan, Israel 4
introduction Accurate staging is the basis for the selection of an appropriate therapeutic approach in patients with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Staging is necessary in order to prevent over or under treatment as well as to minimize morbidity related to the radio-chemotherapy regimens given. Quality of life during and after treatment may also be improved when therapy is tailored appropriately [1]. Despite differences in their biology and clinical behavior, the management of both NHL and HD follows well-established guidelines based on the initial staging assessment [2, 3]. Currently, computed tomography (CT) is the principal staging tool for patients with lymphoma. It is readily available, easy to perform, reliable and reproducible and there is evidence for its diagnostic and therapeutic impact in large series of patients [4]. However, this imaging modality also has several limitations since interpretation of nodal involvement by CT is based on *Correspondence to: Dr P. Raanani, Rabin Medical Center, Institute of Hematology, Campus Beilinson, Sackler School of Medicine, Tel-Aviv University, Petah-Tikva, 49100 Israel. Tel: +972-3-9378207; Fax: +972-3-6992463; E-mail: [email protected]
ª 2005 European Society for Medical Oncology
anatomic criteria of size and shape [5]. Early involvement of lymph nodes is not always associated with detectable anatomic changes and thus may be overlooked. On the other hand, benign lymph node enlargement as encountered in association with reactive changes, may be a cause for false-positive interpretation. Furthermore it is often impossible to reliably distinguish lymphoma lesions from benign CT abnormalities [6–9]. Moreover, extra-nodal sites of lymphoma in the liver, skin and skeleton are often notoriously difficult to assess by CT alone [10]. 2-[Fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), a functional imaging modality used for staging and monitoring response to treatment of a variety of human neoplasias, has a higher sensitivity and specificity than conventional anatomical imaging. FDG-PET has had a major impact on the staging and management of lymphoma, resulting in alterations of the clinical stage and therapy in a substantial number of patients. However, FDG-PET is a functional modality often requiring correlation with anatomical imaging modalities so as to localize the detected lesion more accurately [10].
original article
Background: The clinical impact of fused PET/CT data on staging and patient management of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) was assessed. Patients and methods: A total of 103 consecutive patients with newly diagnosed NHL (n = 68) and HD (n = 35) were assessed retrospectively. Three comparisons were carried out in an attempt to assess the added value of each modality. Results: For NHL patients, there were significant differences between staging by CT versus PET/CT (P = 0.0001). Disease was upstaged by PET/CT in 31% (mostly in stages I and II) and downstaged in only 1% of patients. In 25% of the patients, the treatment approach was changed according to CT versus PET/CT findings. For HD patients, disease was upstaged by PET/CT in 32% and downstaged by PET/CT in 15% (P = NS). As for NHL, upstaging by PET/CT versus CT was evident mostly for stages I and II. The treatment strategy was altered as determined by CT versus PET/CT in 45% of the patients. Conclusions: The addition of PET/CT to CT changed the management decisions in approximately a quarter of NHL and a third of HD patients, mostly in early disease stages. Thus, PET/CT performed as the initial staging procedure may well obviate the need for additional diagnostic CT in the majority of patients. Key words: PET/CT, Hodgkin disease, non-Hodgkin lymphoma, staging
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Received 15 July 2005; revised 19 August 2005; accepted 23 August 2005
original article
Annals of Oncology
patients and methods patients The study population included 103 consecutive unselected patients with newly diagnosed NHL and HD referred from two large hospitals in Israel, the Chaim Sheba Medical Center (SMC) and the Tel-Aviv Sourasky Medical Center (TASMC), for a baseline PET/CT scan at the department of Nuclear Medicine in TASMC between April 2002 and January 2004. For a retrospective analysis, our Institutional Review Boards do not require approval or informed consent to review patients’ records, files and images. Of the 103 patients, 52 were women and 51 men, with a mean age of 47 ± 17 years (range 20–81). Sixty-eight patients had NHL and 35 had HD (Table 1). Patients with biopsy-proven NHL and HD were enrolled for this study provided they had both CT and PET/CT studies performed prior to Table 1. Patients characteristics NHL n 68 M: F 35: 33 Age, mean 6 52 6 15 (range 20–81) SD (years) Pathological subtype Follicular, 19 Diffuse, 34 Other, 15: Anaplastic, 5; Mantle, 3; T cell, 2; marginal, 2; atypical, 1; Burkitt, 1; small lymphocytic, 1
HD 35 16: 19 38 6 17 (range 20–74)
Nodular sclerosis, 29 Mixed cellularity, 2 Lymphocyte predominant, 1
Unspecified, 3
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receiving therapy. PET/CT was performed within a mean of 24 days of the conventional diagnostic CT scan. Only nine patients had more than a 2-month interval between the two tests.
methods The clinical stage of the patients was assessed according to the modified Ann Arbor classification [19]. For the purpose of analysis three detailed data sheets were generated including a clinical data sheet and a separate data sheet for each of the imaging techniques, i.e. diagnostic CT and PET/CT report. A physician (YS) uninvolved in the imaging or in the clinical interpretation of data was responsible for the patients’ records and data sheets. These were passed on to an experienced team of hematologists, in three sequential steps at least 1 month apart. Patients’ names were removed from all data and the order of the patients investigated was altered at each step. clinical data sheet. This contained the physical examination, established prognostic factors according to the IPI prognostic scores for HD [20] and NHL [21], and data comprising complete blood counts, erythrocyte sedimentation rate (ESR) and biochemistry levels and bone marrow biopsy findings. diagnostic CT scan data sheet. This contained reports of CT scans done at diagnosis. Diagnostic contrast enhanced CT scans were performed in a variety of radiological institutes as both hospitals serve as tertiary centers. CT scans were performed using the appropriate protocol and guidelines for lymphoma staging. Each CT scan was reported initially by the scanning radiologist and were usually reviewed by a second radiologist specializing in tumor imaging in each of the two participating centers (UM and SA). Standard CT size criteria for individual lymph node groups were used to determine the enlarged lymph nodes. PET/CT scan data sheet. This contained a report of the PET/CT scan done at the time of diagnosis. All PET/CT scans were performed at the same nuclear medicine department (TASMC) and interpreted by the same team of specialists (EES and UM) in a consensus reading. For PET/CT imaging the patients fasted at least 4 h prior to the intravenous (i.v.) injection of 370–666 MBq (10–18 mCi) 18F-FDG. Administration of oral contrast was added for better discrimination between physiologic bowel activity and abdominal tumor sites. A PET/CT study was performed only when blood glucose levels did not exceed 150 mg/dl. Scanning from the base of the skull through the mid thigh was performed using the Discovery LS PET/CT system (GE Medical Systems, Milwaukee, WI). Low-dose CT acquisition was performed first with 140 kV, 80 mA, 0.8 s per CT rotation, a pitch of 6 and a table speed of 22.5 mm/s, without any specific breath-holding instructions. A PET emission scan was carried out immediately following acquisition of the CT, without changing the patient’s position. Five to eight bed positions were performed with an acquisition time of 5 min for each one. PET images were reconstructed using an OSEM algorithm. CT data were used for attenuation correction. PET/CT interpretation were performed on the eNTEGRA or the Xeleris workstations (ELGEMS, Haifa, Israel) equipped with fusion software, which enables the display of PET images (with and without attenuation correction), CT images and fused data of both modalities. Any site of increased uptake that was not due to physiological or benign uptake was considered a possible lymphoma site [22]. PET/CTs were visually interpreted and standardized uptake value (SUV) analysis was not used in this retrospective study to differentiate between reactive and involved lymph nodes. Involvement according to PET/CT was reported only when it was clear cut, according to the combination of morphology by the CT portion (size and shape of nodes and the presence of retained hilum) and by the uptake and location of the FDG-PET part. In the case of nodal involvement, any increased uptake other than the hilar region, regardless of the lymph node size was considered pathologic.
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It has been suggested for some time now, that complementary functional and anatomic imaging allows for improved diagnosis and, subsequently, to better patient-care in clinical oncology [11]. Recently, PET/CT systems, which enable acquisition of PET and CT data at the same setting without changing the patients’ positioning, have been introduced into clinical practice [12–15]. The molecular information provided by FDG-PET identifies the functional content of the anatomic findings and helps to categorize their nature as malignant or benign. On the other hand, the CT data obtained in the same setting provides anatomical localization of the FDG-PET data while also improving the FDG-PET image quality as it is utilized for attenuation correction [16, 17]. Thus, PET/CT offers several advantages including shorter image acquisition time, improved lesion localization and identification and more accurate tumor staging [10, 11]. Preliminary data, mostly in abstract form, or a few peer-reviewed studies examining the incremental value of PET/CT over FDG-PET alone for staging and restaging of cancer, have suggested that there is improved diagnostic and staging accuracy as well as a reduction in false-positive/negative rates and an improved confidence in FDG-PET interpretation [2, 18]. The purpose of the current study was to assess the clinical impact of fused PET/CT data on the staging and management of patients with HD and NHL.
original article
Annals of Oncology
Sites that were equivocal were reported on the data sheets as such. Since reactive lymph nodes may be associated with increased FDG uptake in the hilar region, positive diagnosis of lymphoma was only given if additional ‘hot’ nodes were detected above the diaphragm.
data analysis
treatment protocols The treatment protocols for stage I NHL consisted of abbreviated (three to four courses) chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) ± rituximab followed by involved field radiation for aggressive NHL and radiotherapy alone for indolent NHL. Treatment protocol for stages II–IV NHL consisted of a full chemotherapy regimen depending on the histopathology report, e.g. either six to eight courses of CHOP, COP, FMC or the MACOP-B, VACOP-B, HYPER C-VAD and GMALL 2000 regimens ± rituximab. In HD, treatment for stages I and II consisted of three to four courses of ABVD followed by involved field irradiation while the therapeutic regimens for advanced stage disease (stages III/IV) were either six cycles of ABVD or two cycles of escalated BEACOPP followed by four cycles of ABVD.
statistical analysis For continuous variables, ranges, means and standard errors were computed. The mean values were analyzed and compared with two-sample t-test for differences in means. For categorical variables, frequencies and relative frequencies were calculated. The chi-squared test of independence was used to compare the relative frequencies of the categorical variables. For small numbers of observations the Fisher–Irwin exact test was used. The Wilcoxon matched-pairs ranks test was used to test the equality of matched pairs of observations.
results Results for NHL and HD patients were analyzed separately. The staging and therapeutic recommendations of the clinical panel are given below.
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treatment approach. The suggested treatment strategy based on CT versus PET/CT was different in 17 patients (25%). The suggested treatment strategy based on CT versus CT plus PET/CT was different in 18 patients (26%). The suggested treatment strategy based on PET/CT versus CT plus PET/CT was different in six of 68 patients (9%).
hodgkin disease staging. Based on the modified Ann Arbor staging system there were differences between the staging based on CT versus PET/CT but these were not statistically significant (P = 0.16) (Table 3). In 16 patients (45%) staging based on diagnostic CT versus PET/CT was discordant. Disease was upstaged by Table 2. Comparison of staging algorithms based on CT or PET/CT in 68 NHL patients PET/CT
CT
I II III IV NE
I 9 1 2 7 –
II – 13 5 3 –
III – – 9 3 –
IV – – 1 14 –
NE – – – 1 –
Table 3. Comparison of staging algorithms based on CT or PET/CT in 35 patients with HD PET/CT
CT
I II III IV NE
I – 1 – – –
II 2 14 5 3 1
III – 1 2 2 –
IV – 2 – 2 –
NE – – – – –
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Establishing the clinical stage of the disease and the proposed therapy was determined three times for each of the 103 study patients and for each decision the clinical data sheet was used. For the first decision, diagnostic CT was used as the only imaging modality (the conventional algorithm). The second decision algorithm was based on PET/CT findings alone, while the third decision was made after reviewing both the diagnostic CT and PET/CT scans. The clinical interpretation and decision making was made by experienced hematologists who determined the staging according to consensus and then suggested a plan for treatment. Three modes of comparison were carried out. The first compared the conventional staging algorithm based on physical examination, laboratory assessment and diagnostic CT results to the same staging algorithm replacing the CT modality with PET/CT. The second comparison was intended to assess the added value of PET/CT by comparing the stage of disease and the suggested management as determined by diagnostic CT alone to that of diagnostic CT plus PET/CT. In order to determine the added value and whether a diagnostic CT is really necessary in the era of PET/CT, a third comparison was performed in which staging by PET/CT alone was compared with that obtained after PET/CT plus diagnostic CT. Staging was classified as concordant or discordant. Concordant results were considered when there were no differences between the three decision algorithms. Since the ultimate goal of accurate staging is the selection of the appropriate clinical approach, a panel of clinicians was asked to decide how to treat each patient, based on the different staging algorithms used. The subsequent changes in the suggested therapy were assessed independently.
non-Hodgkin lymphoma staging. Significant differences were found between staging based on CT versus PET/CT (P = 0.0001) (Table 2). Discordant staging by diagnostic CT and by PET/CT was found in 22 patients (32%). Disease was upstaged by PET/CT in 31% of patients and downstaged in 1%. Upstaging by PET/CT was mainly for the early stages I and II. Lesions diagnosed on PET/CT and overlooked on CT, included increased FDG uptake in small-sized lymph nodes or extranodal involvement in the liver, spleen, bones or skin. Significant differences were also found between staging based on CT alone and staging based on CT and PET/CT (P = 0.0001) (data not shown). Twenty-nine cases (42%) were discordant. Disease was upstaged by CT plus PET/CT in 41% of patients and downstaged only in 1%. Although the difference between the staging algorithms based on PET/CT alone versus CT and PET/CT reached statistical significance (P = 0.005), discordance was found in only eight patients (12%). All were upstaged by the addition of CT to PET/CT (data not shown).
original article
Annals of Oncology
PET/CT in 32% of patients and downstaged in 15%. Upstaging by PET/CT compared with CT was evident mostly for stages I and II. The cases upstaged by PET/CT included the detection of increased FDG uptake in small-sized lymph nodes, spleen, liver, thymus, cortical bone, bone marrow, lung and pleura. A statistically significant difference was found between staging based on CT alone or CT plus PET/CT (P = 0.0023) (data not shown). In 15 patients (43%) staging was discordant. Disease was upstaged by CT plus PET/CT in 34% of patients and downstaged only in 9%. No statistically significant difference was found between staging based on PET/CT alone or CT plus PET/CT (P = 0.31) (data not shown). Four cases (11.5%) were discordant: three upstaged and one downstaged by the addition of CT to PET/CT.
the effect of the interval between the performance of CT and PET/CT The mean interval between diagnostic CT and PET/CT was 24 days but nine patients had an interval greater than 2 months between the two tests. This raises the question whether disease progression occurred in the interval thereby contributing to upstaging of disease by the PET/CT. In four of the nine patients there was no change in stage between the two modalities, while in five patients disease was upstaged by PET/CT: one patient with HD was upstaged from IIA to IVA, two patients with diffuse large cell were upstaged from IA or IIA to IIIA, one patient with anaplastic lymphoma was upstaged from IIA to IVA, while one patient with follicular lymphoma was upstaged from IIA to IVA. In order to exclude the possibility of disease progression in patients with an interval greater than the mean of 24 days between performing the CT and PET/CT, we compared the cases with an interval of more or less than the mean. While there was a change in stage in 57% of the cases with an interval of less than 24 days, stage changed in only 45% of the cases with the longer interval. Table 4. Differences in the suggested treatment based on the various imaging algorithms in patients with NHL and HD Staging according to
NHL Change in treatment (%)
HD Change in treatment (%)
CT versus PET/CT CT versus CT+PET/CT PET/CT versus CT+PET/CT
25 26
45 32
9
9
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discussion Data assessing the true clinical impact of PET/CT imaging on diagnostic accuracy and patient management is still being accumulated and its role in the staging of lymphoma is under study. Bar-Shalom et al. [12] found PET/CT to be of additional value over CT or PET alone in 49% of patients with different neoplasias, including 36% of patients with lymphoma. Recently, Schaefer et al. [23] compared PET/CT findings with those of contrast CT in 60 patients with NHL or HD and concluded that PET/CT (although performed with non-enhanced CT) is more sensitive and specific for the evaluation of lymph node and organ involvement (mainly by excluding disease) than contrast enhanced CT. Until recently, staging algorithms of NHL and HD were based solely on diagnostic CT, which was mostly contrast-enhanced. With the introduction of FDG-PET and even more recently of PET/CT systems as part of the routine practice in lymphoma, it seems to have become important to choose the most appropriate staging algorithm for this patient population. Basically, this poses the question of comparing the use of diagnostic CT alone, PET/CT alone or both modalities. Even if PET/CT alone is used, one has to decide which acquisition protocol should be applied for the CT part of the PET/CT study; particularly whether to perform a full-dose or reduced-dose whole body CT, as well as whether to administer contrast-media intravenously. Since all our patients had already had a diagnostic CT performed, we used a reduced mAs CT protocol in our PET/CT acquisition protocol. The latter is associated with only 20% of the radiation exposure of a diagnostic CT. Our data suggested that in the majority of patients, PET/CT performed with lowdose CT and without i.v. contrast media was satisfactory for staging of most patients with lymphoma, as already shown by Schaefer et al. [23]. Only in 12% of our patients did the addition of a full-dose diagnostic CT to the PET/CT study contribute further information, probably due to the administration of i.v. contrast. A reasonable approach would be to omit the standard CT scanning from the initial staging and use a full-dose CT protocol in the PET/CT study. The issue of i.v. contrast administration in the CT portion of PET/CT is still open for further assessment. It is of interest to note that PET/CT mostly upstaged disease when compared with CT alone and this was observed mostly for stages I and II for both NHL and HD. On the basis of these results, it seems to us that PET/CT appears to be beneficial for patients in the early stages of the two groups of lymphoma. In the more advanced stages III and IV, PET/CT may not have any added value if the disease was already defined as advanced by a diagnostic CT alone [7]. These results suggest that in centers performing a diagnostic CT as the initial step of staging, PET/CT should only be added in patients defined as early stage disease by CT alone.
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treatment approach The suggested treatment strategy was different based on CT versus PET/CT in 16 patients (45%). The suggested treatment strategy was different based on CT versus CT and PET/CT in 13 of the 35 patients (32%). The suggested treatment strategy was different based on PET/CT versus CT plus PET/CT in only three of 35 patients (9%). Table 4 summarizes the differences in the therapy given based on the different algorithms for all patients in the cohort. Results are shown separately for NHL and for HD. The change in treatment was less frequent for NHL than for HD patients.
Furthermore, we compared the mean time interval between CT and PET/CT studies in the group of patients whose stage was changed and in those whose stage was not altered and found that it was 28.5 versus 21.7 days, respectively (P = NS). Thus, it seems that the longer interval did not contribute to the change of stage as determined by PET/CT.
original article
Annals of Oncology
Volume 17 | No. 1 | January 2006
acquisition was performed at different institutions before the PET/CT was done. On the other hand, the majority of CT scans were reviewed again by our team. The possibility that the group of patients who had a longer interval between performing the two modalities had progression of their disease related to the delay in performing their PET/CT, was basically ruled out as we have shown that the longer interval involved did not influence the change of stage recorded. However, the major limitation of this study relates to the absence of histological evaluation of the concordant and some of the discordant lesions. This is due to the fact that biopsy is not yet performed as a standard procedure for all lesions in lymphoma patients. This limitation is also inherent in other previously published studies [24, 29]. In summary, it seems that the combined functional and anatomical data available from PET/CT makes it an appropriate staging imaging technique for both NHL and HD patients. When added to CT scan done alone it can change the therapeutic approach in 20%–30% of the patients with HD and NHL and mostly those with early stages of disease [30]. Accordingly we recommend that it is best added for patients defined as early stage disease in centers performing a diagnostic CT. On the other hand, adding CT to PET/CT changed the therapeutic approach in only 9% of NHL and HD patients. Thus it seems to us that performing PET/CT as the initial staging modality obviates the need to use an additional diagnostic CT in the majority of patients with NHL and HD. As for the CT aspect of the PET/CT scan, reduced mAs CT with low radiation exposure may be satisfactory in the majority of patients. If the results of future larger studies confirm our own results, integrated PET/CT may become the new staging imaging modality for lymphoma at diagnosis, reserving an additional diagnostic CT only for selected patients.
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Upstaging by PET/CT for both NHL and HD included the detection of increased FDG uptake in normal-sized lymph nodes (usually less than 1 cm) as well as in extra-nodal sites, most commonly the liver, spleen, cortical bone, bone marrow and skin, previously missed by diagnostic CT but nevertheless FDG avid. In a few cases, paraspinal and pulmonary lesions interpreted as benign by the CT scan were read as involved according to the PET/CT. The latter findings are in keeping with the results of other studies, reporting an improved sensitivity for FDG-PET compared with conventional imaging methods for detecting extra-nodal disease, both in the bone marrow and other organs [23, 24]. The explanation for this discrepancy may either be the higher sensitivity of PET/CT or alternatively a higher rate of false positivity using this method. Since the only way to solve this issue is by obtaining biopsies from discordant sites we cannot confirm or refute either hypothesis. Another key issue in lymphoma relates to whether a change in clinical staging indeed affects the type of therapy given. An interesting finding in our study relates to the fact that the impact of PET/CT on the subsequent change of therapeutic approach in patients with NHL, was much less pronounced than on the alteration in clinical stage This was at least partially due to the fact that most patients with early stage disease received ‘advanced stage treatment’ anyway. The lower impact on treatment found for PET/CT compared with its impact on disease stage may reflect the limited therapeutic options used at a given center. In general, HD patients with good-risk localized disease (stage I and II) are treated with an abbreviated course of chemotherapy and involved field radiation, whereas more advanced disease is treated with more cycles and a fuller course of combination chemotherapy. It should be noted, however, that many centers use the same therapy for all stages of histological aggressive NHL (with the possible exception of patients with stage I disease who have no adverse risk factors). The influence of FDG-PET or PET/CT on treatment strategy varies markedly in different studies and because of this the actual impact on patient management and outcome still remains to be determined [25]. In our study, the addition of PET/CT to the staging algorithm affected the treatment approach in approximately one-quarter of the 68 NHL patients and in a third of the 35 HD patients, while the addition of CT to the algorithm changed the suggested general treatment in only approximately 10% of NHL and HD patients. Recently, Schaefer et al. [23] showed that treatment was changed in 16% patients with HD or high grade NHL, on the basis of PET/CT staging, while on the basis of contrast-enhanced CT findings, it was changed in only about 5% of the patients. Other studies compared FDG-PET with CT, mainly for HD. The range of change in treatment strategy according to FDG-PET compared with CT for primary staging of HD was wide and varied between 3% and 25% [7, 8, 24, 26–28]. Our study has several shortcomings and its retrospective nature may have introduced a bias in the results. In addition, the patient population was heterogeneous, composed of smaller subgroups of indolent NHL lymphomas, different aggressive NHL as well as HD patients. Furthermore, the technique of contrast-enhanced CT was not standardized, since data
original article
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Annals of Oncology