Impact of [18F] Fluorodeoxyglucose Positron Emission Tomography on Staging and Management of Early-Stage Follicular Non-Hodgkin Lymphoma

Int. J. Radiation Oncology Biol. Phys., Vol. 71, No. 1, pp. 213–219, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter

doi:10.1016/j.ijrobp.2007.09.051

CLINICAL INVESTIGATION

Lymphoma

IMPACT OF [18F] FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY ON STAGING AND MANAGEMENT OF EARLY-STAGE FOLLICULAR NON-HODGKIN LYMPHOMA ANDREW WIRTH, M.B.B.S.,* MARCUS FOO, M.B.B.S.,* JOHN F. SEYMOUR, PH.D.,yx MICHAEL P. MACMANUS, M.D.,* AND RODNEY J. HICKS, M.D.z Departments of *Radiation Oncology, y Hematology, z Metabolic Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia; and x Department of Medicine, University of Melbourne, Melbourne, Australia Purpose: Accurate staging is critical to select patients with early-stage (I–II) follicular lymphoma (ESFL) suitable for involved-field radiotherapy (IFRT) and to define the radiotherapy portal. We evaluated the impact of fluorodeoxyglucose (FDG) PET on staging, treatment, and outcome for patients with ESFL on conventional staging. Methods and Materials: Forty-two patients with untreated ESFL (World Health Organization Grade I–IIIa, or ‘‘low grade’’) following a minimum of physical examination, computerized tomography, and bone marrow examination (conventional assessment) and who had staging PET from June 1997 to June 2006 were studied retrospectively. Stage allocation was based on routine imaging reports. Disease sites, stage, and management plan were recorded based on conventional assessment or conventional assessment plus PET. Results: FDG avidity was demonstrated in 97% of patients in whom disease was evident on conventional assessment after biopsy. PET findings suggested a change of stage or management in 19 patients: 13 (31%) who were upstaged to Stage III–IV, altering ideal management from IFRT to systemic therapy, and 6 (14%) who had the involved field enlarged, including 4 upstaged from Stage I to II. Of these 19 cases, PET findings were considered true positive in 8 patients, indeterminate in 10, and false positive in only 1 patient. Conclusions: Our data confirm that ESFL is usually FDG-avid. In routine practice, PET has the potential to upstage and thereby alter management in a high proportion of patients with apparent ESFL. Ó 2008 Elsevier Inc. PET staging, Follicular lymphoma.

INTRODUCTION

METHODS AND MATERIALS

Approximately 10–20% of patients with follicular nonHodgkin lymphoma present with early-stage (I–II) disease (ESFL) on the basis of standard staging investigations including physical examination, computerized tomography from neck to inguinal region, and bone marrow examination (1). Several large studies have reported that 30%–50% of such patients experience durable remissions and possible cure after treatment with involved field radiotherapy (IFRT) (2–6). Almost all treatment failures occur outside the radiotherapy field, likely representing undetected disease present at the time of initial therapy (7). Hence, accurate staging is crucial for selection of patients for radiotherapy and determination of the field to be irradiated. Increasingly, [18F] fluorodeoxyglucose positron emission tomography (PET) has been shown to be of value for lymphoma staging (8–12). This study assesses the impact of PET on disease localization, stage, and management for patients with ESFL on conventional assessment.

This was a retrospective single-center study of patients presenting from June 1997 to June 2006 with previously untreated, biopsyproved follicular lymphoma (World Health Organization [WHO] follicular Grade I–IIIa, or ‘‘low grade,’’ follicular lymphoma when WHO nomenclature was not used); Stage I or II on conventional staging (clinical examination, computerised tomography (CT) of at least chest and abdomen and bone marrow aspirate and trephine); PET staging; and no intercurrent malignancy (13). Positron emission tomography scans at the Peter MacCallum Cancer Center were performed on a dedicated three-dimensional scanner (PENN-PET 300H, UGM Medical Systems, Philadelphia, PA), with a spatial resolution of approximately 6 mm from 1997 to 2001 or a combined PET-CT (Discovery LS or STE, GE Healthcare, Milwaukee, WI) from 2002-–2006. Whole-body acquisition included the neck, thorax, abdomen, and pelvis. Transmission or CT attenuation-correction was performed in all patients undergoing routine scanning from base of skull to pelvis and who did not need extended scanning to include suspicious sites in the lower limbs. PET scans were reported by nuclear medicine physicians in

Reprint requests to Andrew Wirth, M.B.B.S., Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia. Tel: (+61) 3-9656-1111; Fax: (+61) 3-9656-1424; E-mail: [email protected] This material consists of original work that was presented in part

at the Annual Scientific Meeting of the Royal Australia and New Zealand College of Radiology, Sydney, Australia, 2005. Conflict of interest: none. Received July 31, 2007, and in revised form Sept 18, 2007. Accepted for publication Sept 18, 2007. 213

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light of available clinical and imaging results. CT scans at our institute were performed on a helical scanner, and CT and PET scans at other centers were performed and reported according to their routine practice. Clinical details and scan results were abstracted from patient records by clinicians experienced in the management of lymphoma, and data were entered into study-specific data forms. To reflect the impact of PET in routine care, the analysis of CT and PET was based on scan reports issued at the time of management. When CT images were reviewed in light of PET findings, the results of the review were noted, but the analysis was based on original reports. Staging was based on the Ann Arbor system (14). Lymph nodes >1 cm in diameter on CT were scored as definitely involved (15, 16). If only qualitative descriptions were given in an imaging report, any node or organ described as clearly abnormal was scored as involved unless there was an unequivocally demonstrable benign cause. If there was a discrepancy between clinical examination and CT, the CT result was accepted, providing the region of interest was adequately imaged by CT. Any nodes #1 cm in diameter that were specifically noted or described as being of uncertain significance on CT were coded as equivocal. PET results were based on reports reflecting visual inspection of images with regions of interest compared with mediastinal blood pool or liver levels. Sites were classified as normal, equivocal, or definitely abnormal on the basis of the descriptions in PET reports. Sites of increased radiotracer uptake on PET were coded as uninvolved when uptake was considered to reflect intercurrent pathology, physiological uptake, symmetrical minor uptake in hilar nodes, or postoperative change. Bone marrow involvement was classified on the basis of morphology alone. Each patient was allocated a stage according to all evaluations apart from PET (conventional assessment) and all evaluations including PET (PET assessment). For the PET assessment, discrepancies between CT and PET were synthesized as follows: a normal site on conventional assessment was scored according to the PET findings at that site—that is, definite or equivocal abnormality on PET led to an overall score of definite or equivocal involvement at that site. An equivocal site on conventional assessment was scored as negative if PET was negative but as positive if PET was equivocal (reflecting partial volume) or positive. A site that was involved on conventional assessment but negative on PET was scored as equivocal on the overall PET assessment but scored as positive if PET was equivocal or positive. Stage allocation was based on definite sites only. For example, a patient with definite axillary nodes and equivocal abnormality in inguinal nodes would be scored as definite Stage I and equivocal Stage III. Minor bone marrow abnormalities (small lymphoid aggregates of uncertain significance or abnormal molecular or flow cytometric analysis) were scored as equivocal and did not lead to classification as definite Stage IV in accordance with consensus guidelines (16). The impact of PET on stage, treatment strategy (i.e., radiotherapy vs. chemotherapy or watch and wait) and radiotherapy fields was recorded. The analysis of the impact of PET was based on ‘‘ideal’’ management rather than treatment actually given (because treatment philosophy varied between clinicians). For this analysis, ideal management for Stage I–II was involved field radiotherapy (with or without chemotherapy), encompassing definite and contiguous equivocal sites; for Stage III–IV, management was chemotherapy or a watch and wait approach. Discrepant results between conventional and PET assessments were evaluable in some patients by biopsy, review of the conventional imaging looking for previously overlooked abnormalities, or examining the pattern of failure on follow-up.

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Patient demographics and disease characteristics were summarized using descriptive statistics and compared between groups using the Fisher’s exact test or c2 for categorical variables and the Mann-Whitney U test for numerical variables.

RESULTS Forty-two eligible patients with conventional Stage I–II follicular Grade I–IIIa NHL who had staging PET between June 1997 and June 2006 were identified from our institutional PET database and review of patients referred for radiotherapy for Stage I–II disease who had PET elsewhere (two cases). Sixteen had PET and 26 PET-CT. Forty PET scans were performed at the Peter MacCallum PET center. Sixteen CT scans were performed at our institution or other tertiary or teaching hospitals, 13 were performed at district or local hospitals, and 13 were performed in private radiology departments. Patient and disease characteristics are shown in Table 1. Thirty-seven of 42 cases demonstrated FDG avidity (88%). In five PET-negative cases, disease had either been completely excised (four cases) or consisted solely of a superficial scalp lesion. The case sensitivity of PET for disease evident on conventional assessment was thus 97% (37 of 38; 95% confidence interval [CI], 86%–100%). Of 70 involved sites on conventional evaluation, 17 had been removed at biopsy, leaving 53 for the evaluation of PET site sensitivity. PET was positive in 42 (79%) and equivocal in 4 (9%) sites. The seven negative sites were nodes measuring 12, 12, 15, 15, 16, and 22 mm on CT and the small scalp lesion. PET was positive in 8 of 13 definite sites measuring 1.1–1.5 cm on CT. There were 36 equivocal sites on conventional imaging. These were nodes measuring no more than 1cm, or subcentimeter nodes noted as being present. PET was positive in 11, equivocal in 1, and negative in 24 of these equivocal sites on CT. Seven patients had equivocal abnormalities in Table 1. Patient characteristics Age Sex Histology Follicular Grade I / FSC Follicular Grade II / FMC Follicular Grade IIIa Other Interval from CT to PET Conventional stage I II Equivocal stage* II (when definite Stage I) III No equivocal stage

Median 52 (22–77) 24 male/18 female 21 14 3 (+1 Grade 2–3) = 4 3 Median 16.5 days (–106 to 90) #21 days in 24 26 16 4 14 24

Abbreviations: FSC = follicular small cleaved; FMC = follicular mixed, other low-grade follicular,- not specified; PMCC = Peter MacCallum Cancer Centre. * Equivocal stage: stage if equivocal clinical and CT findings are counted as definite sites of disease.

PET staging for early-stage follicular lymphoma d A. WIRTH et al.

marrow, insufficient to establish marrow involvement and upstage to Stage IV (interstitial aggregates, four; paratrabecular aggregates, one; molecular or flow cytometric abnormalities, two). None of these patients had PET abnormalities suggestive of marrow involvement. Compared with conventional assessment, PET led to the identification of 41 additional sites (in 19 patients). Of these additional sites, 30 were in areas that were not reported to show an abnormality on conventional assessment, and 11 were in sites considered to be equivocal. Of these 19 patients with additional sites on PET assessment, 6 had corresponding abnormalities noted on retrospective targeted review of the original CT that were not previously noted. These abnormalities were either described as ‘‘small’’ or measured at <1.0, 1.3, and 1.5 cm. In four patients, the additional sites identified on PET may not have been adequately imaged on CT (neck node 3, inguinal 1), although these sites were amenable to physical examination. Of the 19 patients for whom PET demonstrated apparent additional sites of disease, confirmatory evidence of the PET findings consisted of a positive biopsy in three, pattern of failure consistent with PET abnormalities in three, and identification of missed abnormalities on existing radiology in two. One apparent false positive was bilateral symmetrical uptake in hilar nodes, which, although clinically reported as suspicious for disease, on review was thought more likely to be reactive. These abnormalities failed to progress over several years’ observation. In 10 cases, discrepancies could not be evaluated because all sites were treated (n = 6), there was insufficient follow-up time for definitive classification (n = 2, 8, and 12 months), or progression occurred but in other sites. For the evaluation of the impact of PET on stage and management, the one false-positive site described was not scored as upstaging the patient, to avoid knowingly overestimating the impact of PET. Overall, PET suggested alteration of stage or ideal management in 19 patients (45%; 95% CI, 30–61%). Table 2. Impact of PET staging

Conventional imaging Stage I (n = 26) Stage II (n = 16) Equivocal stage Stage II (n = 4) Stage III (n = 14) No equivocal Stage (n = 24)

PET upstage Increase in No change PET with upstage to to Stage radiotherapy PET (%)* Stage II (%) III–IV (%) field (%) 14 (54)

4 (15)

8 (31)

4 (15)

9 (56)

–

5 (31)

2 (12)

1 (25)

2 (50)

1 (25)

2 (50)

5 (36)

1 (7)

6 (43)

3 (21)

17 (71)

1 (4)

6 (25)

1 (4)

* Totals may not equal 100% because some patients had both a stage change and field change.

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Seventeen patients (40%) were upstaged. Thirteen were changed to Stage III (n = 12) or IV (n = 1), with consequent ideal management changed from IFRT to observation or systemic chemotherapy. Four patients were upstaged from Stage I to II, and 2 patients with Stage II had the number of involved sites increased, leading to changes in the irradiated field in 6 patients. Of 17 patients upstaged by PET, only 7 had equivocal abnormalities on conventional imaging that would have suggested the higher stage if accepted as representing disease. The impact of PET on stage is shown in Table 2, and details of patients whose management was altered by PET are shown in Table 3. PET-CT images of a patient upstaged by PET are shown in Fig 1. The likelihood of PET upstaging was not influenced by histology (Grade I vs. other), treatment year, sequence of or time interval between CT and PET, presence of equivocal marrow abnormalities, or definite stage (data not shown). Of 18 patients with equivocal evidence of higher stage on CT, 10 (56%) were upstaged by PET, whereas only 7 of 24 (29% , p = 0.085) without such equivocal abnormalities on CT were upstaged by PET. In three of these seven patients, a review of prior radiology revealed abnormalities that had been overlooked by the original reporting radiologist. If they were excluded, the rate of upstaging by PET would have been 17%. DISCUSSION There is accumulating evidence that PET scanning enhances accuracy of staging both Hodgkin and non-Hodgkin lymphoma, and there is increasing interest in integrating PET into the routine management of these conditions (8–12). We and others have shown that follicular lymphoma is almost always FDG-avid and that PET scanning may be of value in disease staging (17–23). This study is the first of which we are aware to focus solely on PET staging for patients with conventional Stage I–II follicular lymphoma. This is a group of patients for whom PET may have great impact because upstaging will alter the management strategy from one aimed at potential cure using radiotherapy to one aimed at disease control and survival prolongation, but without curative potential. This study confirms the high avidity rate of FDG-PET in follicular lymphoma, with 97% of cases and 79% of ‘‘definite’’ sites on conventional imaging being FDG-avid. The cases that were entirely PET-negative either had all disease removed at biopsy or had small-volume superficial disease. PET affected management in 45% of patients. Upstaging to Stage III–IV occurred in 31%, altering management from IFRT to systemic therapy and observation. No patients in this series were upstaged to Stage IV by virtue of identification of marrow positivity on PET. The potential for PET to identify marrow involvement in lymphoma has been reported for patients with Hodgkin lymphoma and aggressive NHL (24, 25). It may be that PET is less useful for identifying marrow involvement in patients with indolent lymphomas (26). In a further 14%, PET led to increase of radiotherapy field size by identifying additional disease sites. Previously in

CT stage

Equivocal stage*

Equivocal sitesy

Interval PET to CT (days)

Stage change because of PET

Field change because of PET

III

0

No change

II

III

9

No change

I

III

I

–

I

II

I

Additional PET sites

to II

3

to II

PA, R ing

54

to II

II

L neck

20

to II

II I

III —

PA

0 2

to III to III

I

II

R neck, L ax, med

41

to III

n

I

–

18

to III

n

L ax, med, R ing L neck, med

II I

III III

L + R neck, L ax R + L neck

–1 29

to III to III

n n

L neck PA

I I

– III

L neck, L ing

22 29

to III to III

n n

I II

– II

13 55

to III to III

n n

II

III

R ax, PA , mes

13

to III

n

R ing R neck, L ax, PA, R iliac, L ing R ing L neck, R ax, med, R+L hila, PA L neck

I II

III –

PA

29 4

to III to IV

n

PA bone

L axil, PA, mes

PA, L iliac, L ing R neck

No—all sites treated

PA, L iliac

No—all sites treated

L neck, wald, med, L hilum

No—all sites treated

ing PA

Biopsy +ve r/v existing radiol +ve Biopsy +ve

Targeted review of region

Unconfirmed

Pattern of relapse +ve Relapse other sites r/v existing radiol +ve Biopsy +ve Relapse other sites

Small node seen PA node seen

PA node 1.5 cm seen Palpable on review

Unconfirmed no—all sites treated

1.3 cm on PET CT <1 cm PA node seen

No—all sites treated

Not seen on review CT

Relapse other sites Pattern of relapse +ve

Abbreviations: CT = computerized tomography, 1 on CT; L = left; R = right; PA = paraaortic nodes; ing = inguinal nodes; ax = axillary nodes; med = mediastinal nodes; Mes = mesenteric nodes; wald = waldeyer’s ring. * Equivocal stage is stage if all equivocal abnormalities on conventional assessment were scored as definite sites. y on Conventional assessment.

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–18

Add right deltoid region to epitrochlear and neck Enlarge involvedfield margins Ing enlarged to inverted Y Unilateral to bilateral neck Ing enlarged to inverted Y Unilateral neck enlarged to bilateral neck, mediastinum, and pharynx n n

Confirmation of PET findings

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II

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Table 3. Patients with management altered by PET

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Fig. 1. Illustration of Patient 5, Table 2. Disease (follicular Grade I) was clinically evident in neck. Positron emission tomography (PET) identified a small inguinal node, upstaging to Stage III: (a) initial PET (arrowed node 15 5 mm), (b) follow-up PET showing increasing node size and a new adjacent node. An inguinal node biopsy confirmed lymphoma.

such patients, strict application of involved-field radiotherapy may have led to a geographic miss of disease sites. These findings are in keeping with previous reports of PET upstaging in approximately 10–40% of patients and altering management in 10–30% of patients with a range of lymphoma types and stages (8, 27–32). The substantial impact of PET in our series can be explained by our focus on a homogeneous group of patients with early-stage follicular lymphoma, for whom identification or confirmation of additional disease sites will always have an impact on management. To estimate the minimum impact of PET, we evaluated a subset of patients with no equivocal abnormalities reported on CT and no abnormalities seen on targeted review of the CT in light of PET information. In this cohort, 17% were upstaged by PET. However, given known interobserver variation in reporting CT and the possibility of overlooking borderline lesions in routine CT reporting, our estimate of the overall impact of PET was much greater than this theoretical minimum (33). The International Workshop Criteria specify a 10-mm cutoff for normal lymph node size in the conventional staging of NHLs (15, 16). However, normal lymph node size has been reported to vary according to site, being up to 14 mm in diameter in the mediastinum and up to 15 mm in the pelvis (15, 34, 35). Varying the definition of ‘‘normal’’-sized lymph nodes has been shown to alter assessment of response rates in clinical trials and may similarly alter the detection rates of lymph nodes and lymphoma staging (36). In routine clinical practice, the identification of lymph nodes measuring 1.1–1.5 cm or clusters of nodes up to 1 cm may present diagnostic difficulty because it may be uncertain whether such ‘‘borderline’’ nodes harbor disease or are ‘‘false positives’’. Assuming that all such borderline lesions contain disease presents the risk of overstaging some patients, with conse-

quent inappropriate treatment selection. PET may be useful in interpreting such lesions, especially where a confirmatory biopsy is difficult or hazardous. For example, in our series, PET was negative in 29 of 49 ‘‘borderline’’ nodes on conventional assessment: 69% of equivocal abnormalities up to 1 cm and 38% of nodes measuring 1.1–1.5cm were PET negative. It remains to be determined whether negative PET in borderline nodes has useful negative predictive value. Several factors may have influenced our estimate of the impact of PET. Initially PET may have been used more selectively for cases with suspicious or equivocal findings on CT, which may have enriched the population in whom additional abnormalities were identified on PET. However, we found no difference in the rate of PET upstaging between the early and latter parts of the study period, nor was there an impact of the time interval between CT and PET scans or their sequencing. Some patients had CT performed in community radiology departments, and the standard of reporting may have varied between departments, whereas all but two PET scans took place within an academic center with expertise in PET. Furthermore, our analysis was based on radiological reports rather than rigorous review of original images. However, it was intended that this study reflect the impact of PET in routine care. In an attempt to identify the minimum potential impact of PET, we looked at a subgroup excluding patients with equivocal abnormalities on CT or any abnormalities seen on review of original images in light of PET findings. In this population, 17% were still upstaged by PET. Discrepant results between conventional and PET assessments could not always be evaluated because biopsy of all discrepant sites was neither feasible nor ethical, and treatment limited the value of follow-up assessment for evaluating sites. Hence, as in many studies of functional imaging for

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lymphoma staging, it was not possible to establish a ‘‘gold standard’’ for determining the true status of most sites (28). In eight cases in which assessment of discrepancies could be made by biopsy, further imaging, or follow-up of untreated sites, we found PET to be true positive. There was one case of FDG uptake in bilateral hilar nodes that was classified as a false positive, and there were 10 sites that could not be evaluated. The occurrence of false-positive results on functional imaging studies is well recognized. False positives may occur in sites of infection or inflammation, following surgery (such as healing biopsy scars), in granulomatous change (for example in pulmonary hilae), in areas of brown fat, and in rebound thymic hyperplasia or reactive marrow after chemotherapy (37–39). Experienced nuclear physicians, with appropriate attention to the clinical context, can often correctly identify abnormalities on PET due to intercurrent processes (40). The use of combined PET-CT may further assist in the evaluation of potential false positives (41). Clinicians managing patients with lymphoma

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need to be aware of common pitfalls in the interpretation of PET scans (37, 40). Our data indicate that the vast majority of cases of follicular lymphoma are FDG-avid and that PET has the potential to alter stage and management in a substantial proportion of cases in routine clinical practice. Patients upstaged to Stage III–IV by PET may be spared unnecessary IFRT, and PET may also assist in more accurately defining the involved field. The published long-term results of radiotherapy (with or without chemotherapy) for Stage I–II follicular lymphoma, with 30–50% freedom from progression rates, of necessity reflect the selection of patients using imaging available approximately 20 years ago (2–4, 6, 42). It is reasonable to hypothesize that the more accurate anatomic definition of disease extent using PET, by excluding patients with previously unrecognized Stage III–IV, may contribute to improved results following radiotherapy. The results of RT in PET-staged patients with ESFL warrant assessment in larger cohorts with longer follow-up to evaluate this hypothesis.

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