Annals of Oncology Advance Access originally published online on May 3, 2006
Annals of Oncology 2006 17(6):909-913; doi:10.1093/annonc/mdl049
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© 2006 European Society for Medical Oncology
Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population
Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, USA
* Correspondence to: Dr A. D. Zelenetz, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. Tel: +1 212–639–2656; Fax: +1 212–717–3036; E-mail: a-zelenetz{at}ski.mskcc.org
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Abstract |
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Background: Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment.
Patients and methods: One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms.
Results: Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7–10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13).
Conclusion: These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.
Key words: lymphoma, relapse, surveillance imaging, follow-up
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Initial therapy of aggressive non-Hodgkin's lymphoma with anthracycline-containing chemotherapy regimens cures approximately 40% of patients. Consequently, up to 60% of patients are either refractory to initial therapy or relapse after achieving a complete remission [1
]. Although the addition of rituximab to initial anthracycline-based therapy has improved response rates and outcomes for diffuse large B-cell lymphoma (DLBCL) [2], primary refractory disease and relapse remain the major obstacle to cure. Consolidation therapy with high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is the most successful therapeutic approach for patients with DLBCL sensitive to second-line chemotherapy, resulting in 5-year event-free-survival (EFS) of 40% for those patients undergoing ASCT [3]. Based on intention to treat, about 30% of patients are cured with second-line chemotherapy followed by HDT/ASCT [4, 5]. We have previously reported that the age-adjusted international prognostic index determined at the start of second-line chemotherapy (sAAIPI), comprised of three risk factors: poor performance status, elevated LDH, and advanced stage, predicts outcome in relapsed and refractory DLBCL [6, 7]. This finding raises the question whether early detection of recurrent disease at a time of lower disease burden might be important in determining outcome.
Routine surveillance imaging following therapy is common practice in most oncology centers, employing a combination of chest x-ray, computer tomography (CT) scans and functional imaging evaluation with either gallium scanning or positron emission tomography (PET). During the initial two years, these studies are commonly performed every 3 to 6 months, and typically less frequently over the latter three years (every 6–12 months). After five years of durable remission, the risk of relapse is sufficiently low that surveillance imaging frequently ceases. The potential benefit of this strategy is the early detection of recurrent disease, although a survival benefit to such an approach has never been demonstrated in a rigorous fashion. Conversely, routine imaging is a source of patient anxiety, may be associated with false positive findings mandating invasive procedures, and it represents a significant cost in the post treatment setting. Only limited studies are available to evaluate its utility [8–10]. In this report, we seek to define the role of routine imaging in a database of uniformly treated and well characterized patients with relapsed aggressive NHL.
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patients and methods |
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patients
One hundred and eighteen patients with biopsy confirmed relapsed aggressive non-Hodgkin's lymphoma treated at Memorial Sloan-Kettering Cancer Center on sequential IRB approved clinical trials with ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy between 1993 and 2000 were retrospectively identified from an institutional database. With IRB permission, charts were obtained for all patients and reviewed for details of surveillance imaging: specifically, the imaging modality employed, interval between studies and study results were recorded. In addition, the presence or absence and type of symptoms or clinical signs at the time of relapse were identified. The remission duration was calculated from completion of first line therapy to confirmation of relapsed disease by biopsy. Ten patients were excluded because of incomplete information regarding the surveillance imaging studies or the presentation at relapse.
second-line age-adjusted IPI (sAAIPI)
The sIPI, assessed prior to the initiation of second-line chemotherapy, comprises five risk factors: age older than 60 years, extranodal sites more than 1, LDH more than upper limit of normal, stage III or IV disease, and Karnofsky performance status (KPS) less than 80% (equivalent to ECOG performance status 2–4). The sAAIPI, assessed prior to the initiation of second-line chemotherapy, comprises three of the IPI risk factors: LDH, stage, and KPS. These factors are identical to the age-adjusted prognostic index, described by Shipp et al. [11] in patients with de novo diffuse large cell lymphoma. The sAAIPI has previously been shown to predict outcome in relapsed DLBCL independent of age [7].
sAAIPI risk groups are determined as low risk (L) with zero factors, low-intermediate (LI) risk with one factor, high-intermediate risk (HI) with two factors, and high risk (H) with all three factors present.
statistical analysis
Overall survival was measured from the start of second-line chemotherapy until the time of last follow-up or death and calculated using the methods of Kaplan and Meier [12]. The log-rank test was used to compare the survival distributions for the sAAIPI groups and to compare the survival for patients whose relapse was identified by surveillance imaging versus workup that was initiated because of abnormal symptoms or physical findings [13]. On the basis of Kaplan-Meier curves for all four sAAIPI groups, the high intermediate and high risk sAAIPI as well as the low intermediate and low risk sAAIPI categories are not distinct and may be considered in aggregate, forming two risk categories: low risk (L/LI) and high risk (HI/H) [7]. The 
2-test was used to assess the correlation between the sAAIPI and presence or absence of symptoms and signs at the time of relapse.
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results |
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patient characteristics
One hundred eight (n = 108) patients with relapsed aggressive NHL were analyzed; patient characteristics at the time of relapse are listed in Table 1. All patients had previously received an anthracycline-containing first-line regimen, most commonly CHOP (50%), CHOP-like (24%) or NHL-15 (24%). Of note, none of the patients received rituximab as part of their initial treatment. The most common subtype was DLBCL (75%), followed by PTCL (11%) and MCL (7%). The median age was 49 years (range, 18–71 years). The median duration of follow-up for surviving patients is 5 years. Twenty percent of patients had bone marrow involvement prior to second-line chemotherapy, and 75% had advanced (stage III or IV) disease. Serum lactate dehydrogenase was elevated in 48% of patients.
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All 108 patients received ICE second-line chemotherapy. Ninety-two patients responded to second-line chemotherapy: 41 complete responses and 51 partial responses were observed. Eighty-eight of the 92 patients with chemosensitive disease underwent ASCT. The reasons for not proceeding to transplant include three patients with progressive disease post-ICE (pre-ASCT) and one patient with radiation toxicity.
symptoms and signs at relapse
Of the 108 patients, 24 relapses (22.2%) were detected by routine imaging at a time when the patients had no symptoms and an unremarkable physical exam (group 1). In contrast, 84 patients (77.8%) underwent unscheduled imaging to evaluate reported symptoms at the time of relapse or abnormal findings on exam (group 2); of these, recurrent disease was detected by imaging in 73 cases (87%). Of all patients, 78 patients (72.2%) self-reported symptoms or new physical findings and six patients (5.6%) were found to have abnormal findings on routine exam. The most common patient-reported symptoms leading to the diagnosis of recurrent disease were: lymphadenopathy/palpable mass (47.4%); pain (44.9%); B-symptoms (5.2%); and others (2.5%). Other simultaneously reported symptoms in order of frequency included shortness of breath, cough, lymphedema, confusion and GI-bleeding. The relative frequency of the indication for imaging is shown in Figure 1. Patients whose relapse was detected by routine imaging surveillance underwent a median of 3.5 imaging studies (range 1–8) before their recurrence was diagnosed, while symptomatic patients underwent a median of only two imaging studies (range 1–11). The total number of studies performed in both groups was 345. The median time from the completion of initial therapy to relapse was eight months in both groups.
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correlation between sAAIPI and presence of symptoms/signs at relapse
We analyzed the sAAIPI risk group at relapse in comparison to the mode of relapse identification. The breakdown of the sAAIPI for group 1 patients was low risk (sAAIPI = 0/1) 79% and high risk (sAAIPI = 2/3) 21%, compared to group 2 in which the sAAIPI was low risk 39% and high risk 61% (P = 0.001 by Fisher's exact test). Patients were 4.1 times (95% CI: 1.7–10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those instances in which symptoms or physical findings identified the relapse (group 2). Similarly, patients whose relapse was identified by routine imaging were 4 times as likely to have chemosensitive disease (RR = 4; CI 0.58–27.6) compared to symptomatic patients and achieved a longer progression-free survival of 34 months (group 1) versus 11 months (group 2) (P = 0.12), although these results did not meet statistical significance. Median overall survival at 5 years for group 1 versus group 2 was 54% and 43% respectively (P = 0.13) (Figure 2). A summary of the comparison of groups 1 and 2 is shown in Table 2.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The aim of this study was to determine the role of routine surveillance imaging in detecting recurrent aggressive NHL and to elucidate its impact on subsequent survival following second-line chemotherapy and HDT/ASCT. Prognostic models predicting long-term responses for patients with relapsed NHL have demonstrated that prolonged survival is associated with factors reflecting low disease burden (i.e. early stage and normal LDH) suggesting that early detection of relapsed disease would improve outcome [7
, 14–16]. Despite the theoretical advantage of early detection by surveillance imaging, routine follow-up strategies are not universally agreed upon.
Several studies have suggested that surveillance imaging is of little value in the follow-up of patients with NHL who achieved a complete remission after first-line therapy. Weeks and colleagues reported that in patients with large cell lymphoma, the vast majority of relapses were detected at unscheduled visits for symptomatic disease [8]. Elis and colleagues confirmed these results in a retrospective analysis of 30 patients with relapsed intermediate- and high-grade lymphoma [9]. In addition, they found no correlation between the IPI at initial presentation and the method of relapse detection. However, the small number of patients enrolled in the study may have limited the power of the analysis. Based on their results, a follow-up strategy is suggested that consists of history and physical examination and reserves the use of laboratory or radiological studies for specific indications. In a prospective study, Guppy and colleagues followed 117 patients with DLBCL in remission after first line combination chemotherapy with surveillance CT scans at 3 and 12 months and found that only 5.7% of relapses were detected in asymptomatic patients [10]. They conclude that other approaches are required to identify relapsed disease at an early stage and suggest the use of PET scan should be considered for this purpose.
In the current study, we examined the role of imaging to detect recurrence in a large group of uniformly treated patients with aggressive lymphoma. Since we sought to determine the role of imaging in the diagnosis of recurrence, only patients who relapsed following a clinical complete remission to initial therapy were included. Our results indicate that planned surveillance imaging identified recurrence in approximately 20% of patients prior to the development of signs and symptoms. However, routine imaging identified a population of patients with a more favorable outcome based on the sAAIPI. The sAAIPI, when determined at the time of relapse, is predictive of overall survival and progression free survival independent of the sensitivity of the disease to second-line chemotherapy and is therefore a powerful tool in determining the prognosis of relapsed NHL. If recurrent disease was diagnosed by routine imaging, the patient was 4.1 times more likely to belong to the low risk disease category. Corresponding to this, treatment response, progression-free survival and overall survival of patients whose relapse was diagnosed by surveillance imaging compared favorably to those who presented with symptomatic disease or had abnormalities on physical exam. This observation, however, may in part be the result of lead time bias as well as length time bias. Faster growing tumors are less likely to be detected by surveillance imaging because they cause symptoms or physical findings earlier and they may have an inherently worse prognosis. In addition, it is possible that the sAAIPI represents a surrogate measure of the lymphoma biology and may not identify a time dependent progression that can be favorably changed by earlier diagnosis and treatment. It therefore remains important to determine if relapse identified by routine imaging represents early detection of disease at a more favorable time point or identification of a group of patients with a more favorable underlying biology.
As budget limitations are increasingly important in directing and prioritizing the provision of health care services, the cost of routine surveillance imaging also needs to be taken into consideration. To estimate the cost of detecting one asymptomatic relapse by surveillance imaging, we assume that the relapse free survival rate for patients who achieved a complete remission after initial treatment is 59% at 5 years and estimate that patients who remain in remission undergo a median of seven imaging studies during the initial 5-year follow-up period. Combined with our results for the median number of imaging studies per asymptomatic or symptomatic patient, approximately 57 imaging studies have to be performed over a 5-year period to diagnose recurrent disease in one asymptomatic patient. Assuming that the average cost of a CT scan is between $750 and $1500, between $42 750 and $85 500 would be spent to detect one asymptomatic relapse by surveillance using this imaging modality.
In addition to CT scanning, FDG PET imaging has been widely used in patients with lymphoma for initial staging, monitoring of treatment response [17] and restaging at the completion of therapy [18]. When relapse is suspected based on abnormal clinical or radiographic findings, PET is often employed to determine the extent of recurrence. Due to its ability to detect early asymptomatic disease, it has been suggested that PET scan may also be beneficial in routine surveillance and that its higher cost may be offset by a high degree of sensitivity and a high positive predictive value for relapse.
In summary, our study suggests that routine surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at the time of relapse.
Additional prospective randomized studies are indicated comparing routine surveillance imaging to functional imaging with FDG PET/CT and/or to observation alone to fully explore the impact of imaging on prognosis of recurrent disease. These studies would have important implications, as imaging is a major drive of health care cost after completion of treatment. [19]
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Acknowledgements |
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We thank Nicole Marshall and Letha Menon for excellent assistance. M.L. is supported by a fellowship from the Lymphoma Research Foundation.
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Notes |
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Current address: Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA. 
Received for publication October 24, 2005. Revision received February 6, 2006. Accepted for publication February 10, 2006.
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