Post-treatment surveillance imaging in lymphoma

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Post-Treatment Surveillance Imaging in Lymphoma Susan M. Hiniker, Richard T. Hoppe

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S0093-7754(17)30095-7 https://doi.org/10.1053/j.seminoncol.2018.01.008 YSONC52038

To appear in: Seminars in Oncology Cite this article as: Susan M. Hiniker and Richard T. Hoppe, Post-Treatment Surveillance Imaging in Lymphoma, Seminars in Oncology,doi:10.1053/j.seminoncol.2018.01.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Post-Treatment Surveillance Imaging in Lymphoma Susan M. Hiniker, M.D. 1, Richard T. Hoppe, M.D.1 1

Department of Radiation Oncology, Stanford University, Stanford, CA, U.S.A.

Conflicts of Interest: None Funding: None

To whom correspondence should be addressed: Susan M. Hiniker, M.D. Department of Radiation Oncology Stanford Cancer Center 875 Blake Wilbur Drive Stanford, CA 94305-5847 Phone: 650-725-2209 Fax: 650-725-8231 [email protected]

The authors have no actual or potential conflicts of interest or financial disclosures relating to this work.

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ABSTRACT Appropriate post-treatment management of patients with lymphoma has been controversial, with imaging frequently performed as post-treatment surveillance. The goal of post-treatment imaging is to identify relapse prior to clinical symptoms, when the burden of disease is lower and the possibility of effective salvage therapy and cure greater. However, little data exist to support the performance of surveillance imaging after completion of treatment, with the vast majority of studies suggesting there is no clinical benefit to surveillance imaging in asymptomatic patients. Ongoing efforts seek to identify a subset of patients with a higher risk of relapse who might benefit from surveillance imaging, though the financial and other costs associated with imaging are non-negligible and must be considered. Here we summarize the current data regarding post-treatment surveillance imaging in lymphoma.

PROGNOSTIC IMPLICATIONS OF MID- AND END-OF-TREATMENT IMAGING IN NON-HODGKIN AND HODGKIN LYMPHOMA Imaging, both anatomic and functional, plays a critical role in the staging and response evaluation of patients with non-Hodgkin lymphoma and Hodgkin lymphoma. Multiple studies have indicated that initial staging with positron emission tomographycomputed tomography (PET-CT) is more accurate than computed tomography (CT) alone (1-3). Interim PET-CT is useful in identifying those patients with Hodgkin lymphoma who have had a suboptimal response to treatment and may benefit from a change in therapy, or those who have had a good response and may benefit from de-

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escalation of the planned therapy, and end-of-treatment imaging has also proven prognostic in overall outcomes in non-Hodgkin and Hodgkin lymphoma (4) (5-7). The importance of PET-CT in the initial staging, assessment of treatment response, and end-of-treatment imaging in lymphoma has been well-established. However, the appropriate strategy for surveillance imaging (PET-CT or CT) in lymphoma is less clear. The goal of surveillance imaging is to detect disease relapse at an earlier time point when the burden of disease is less and treatment options greater, potentially translating to a better chance of cure after relapse. However, the financial and non-financial costs associated with surveillance imaging must also be considered, including monetary cost, radiation exposure, patient anxiety, and unnecessary procedures performed following a false-positive scan. Here we review the current literature on the value of surveillance imaging following completion of treatment in nonHodgkin and Hodgkin lymphoma. POST-TREATMENT SURVEILLANCE, NON-HODGKIN LYMPHOMA Diffuse large B cell lymphoma Despite the lack of strong evidence supporting a benefit to surveillance imaging after completion of treatment for DLBCL, the majority of patients still undergo surveillance CT or PET-CT imaging following end of therapy (8). The benefits of surveillance imaging in the population of all patients who have completed treatment are questionable (summarized in Table 1). Multiple large studies, both population-based and institutional, have failed to show clinical benefit associated with surveillance imaging, either CT or PET-CT. For example, a study conducted with a large, prospectively-enrolled cohort of 552 patients with DLBCL who achieved remission after 3

induction therapy found that most relapses were suspected and detected before scheduled follow-up, and that surveillance imaging (CT or PET-CT) detected relapse in only 1.6% of patients. No survival advantage was found for imaging-detected relapse (9). The authors confirmed these results in an independent cohort of patients in France, with relapse detected by surveillance imaging (CT or PET-CT) in only 1.8% of patients without an impact on survival (9). In concordance with these findings, a DanishSwedish population-based study of over 1200 patients with DLBCL found that patients in Denmark, who underwent routine imaging (generally CT scans every 6 months for 2 years) did not experience better survival than patients in Sweden, who were followed with clinical exams only (10). Multiple other studies have shown a similar lack of benefit to surveillance imaging, including a series of 106 patients with DLBCL in whom only 3 had an asymptomatic relapse detected by surveillance imaging (CT and PET-CT), and with false positive findings on imaging leading to unnecessary additional tests (11). Furthermore, 125 scans needed to be performed in order to detect one asymptomatic relapse, results similar to those in other studies. A high rate of false-positive surveillance PET-CT scans has been reported in other studies with one report noting that patients with DLBCL receiving R-CHOP in the rituximab era had a higher falsepositive rate (77%, with PPV 23%) than patients treated with CHOP alone, with treatment with rituximab the strongest predictor for false-positive PET-CT (12). Other studies have shown similarly low rates of true-positive asymptomatic relapses, with rates as low as 6% of patients, and 86% of relapses associated with clinical findings (CT surveillance) (13). Importantly, even studies showing higher rates of asymptomatic

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relapses have generally not shown a survival benefit to detection of relapse by surveillance imaging (PET-CT and CT) (14). Though a lack of clinical benefit has been shown in the setting of surveillance imaging for all patients who complete treatment for non-Hodgkin lymphoma, efforts have been made to identify a high-risk group who might benefit from surveillance imaging. In some settings, early detection of relapse may allow for selection of therapies that would not be possible with a greater burden of disease (15). In one study of 108 patients with relapsed aggressive NHL, the authors reported that 20% of relapses had been identified by surveillance imaging, while 80% were detected by clinical findings. Surveillance imaging identified patients with a more favorable predicted outcome based on the age-adjusted international prognostic index determined at the start of second-line chemotherapy (sAAIPI), which incorporates performance status, LDH, and stage (16). Patients whose relapse was detected by surveillance imaging were over 4 times more likely to have low-risk disease by sAAIPI that was chemotherapy-responsive than those whose relapse were detected by clinical signs or symptoms. Still, as the authors acknowledged, it is possible sAAIPI identifies patients with a more favorable lymphoma biology rather than better outcomes resulting from earlier detection of the temporal progression of disease; additionally, lead time bias also potentially confounds these results (16). Importantly, despite improved response rates, no survival benefit was noted in this study. The only study reporting a potential survival advantage associated with surveillance imaging was a multicenter retrospective study of 258 patients with aggressive non-Hodgkin lymphoma and Hodgkin lymphoma, who were treated between 2002-2011 and relapsed after achieving a complete remission to

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first-line therapy. The authors found that relapse was more commonly detected due to patient-related symptoms versus surveillance imaging (64% versus 27%), but that those with imaging-detected relapse had significantly lower disease burden and lower risk of death after relapse on multivariate analysis (17). However, once patients with indolent histology and patients who relapsed before first scheduled surveillance imaging were excluded, no survival advantage was seen (17). While it is clear surveillance of the entire population of patients with non-Hodgkin lymphoma is not defensible, whether a subset at higher risk of relapse may be more likely to benefit from surveillance imaging remains unresolved. Hong et al. found improved positive predictive values for CT and PET-CT imaging among patients with an IPI score of ≥3 (11), a finding also noted by another group (18). Still, no survival benefit has been associated with surveillance imaging in this population of patients. One study reported an improvement in the positive predictive value of surveillance PET-CT by incorporating CT-based measurements (long axis ≥1.5 cm or short axis ≥1.0 cm) into the analysis of PET-positive sites, as well as selecting high-risk patients with high-risk factors including IPI ≥2, lack of rituximab therapy, and FDG uptake in a previously FDG avid area for surveillance imaging (19). While yet another study reported a benefit to fourth and subsequent PET-CT scans in patients with non-Hodgkin lymphoma, reporting these scans impacted treatment and management of these patients particularly in the case of patients with a previous suspicion of recurrence, though again no survival benefit is described (20).

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Primary central nervous system (CNS) lymphoma Another high-risk group in which the potential benefit of surveillance imaging has been explored is that of primary central nervous system (CNS) lymphoma, where physical exam may have greater difficulty eliciting evidence of relapse and surveillance imaging may prove beneficial, especially since the pre-test probability of relapse is higher in this setting. Still, even in this setting, most patients had their relapse diagnosed after clinical signs/symptoms prompted workup, and only 10% of relapses were diagnosed on surveillance imaging, many of which were MRI scans. There was no difference in overall survival between symptomatic and asymptomatic relapses, perhaps due to the lack of effective salvage regimens (21). Similarly in an analysis of 93 patients with relapsed CNS lymphoma in the French oculocerebral network (LOC), detection of relapse by imaging in the absence of symptoms was associated with better survival on univariate analysis, but as the authors noted, performance status at relapse was a major independent prognostic factor, potentially confounding the results. On multivariate analysis, asymptomatic relapse versus symptomatic relapse was no longer a significant predictor of outcome (hazard ratio 1.04, p=0.91) (22). When performed, imaging in CNS lymphoma can be difficult to interpret both at baseline and posttreatment, with a recent study of MRI characteristics indicating that initially nonenhancing T2-FLAIR lesions distant from the primary tumor were a common site of relapse among patients (23).

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Indolent Lymphomas The value of surveillance imaging in indolent lymphomas is also unclear (Table 2). In an early study of 257 patients with follicular lymphoma, most recurrences occurred in symptomatic patients and most patients did not derive clinical benefit from the use of surveillance imaging (24). Another study of patients with follicular lymphoma in remission after autologous stem cell transplantation found recurrences in approximately 50% of patients, half detected by signs/symptoms, and half by imaging alone. Median time to next treatment was longer in patients with recurrence detected by imaging (7 years) versus in those detected by clinical findings (4 years), but no difference in survival was found (25). Among 55 patients with transformed indolent lymphoma, surveillance scans were also found to be of limited clinical benefit, with all DLBCL relapses associated with clinical symptoms, and all asymptomatic relapses detected on surveillance imaging were of low-grade histology (26). Lymphomas in the pediatric population Among pediatric patients with Burkitt’s lymphoma and DLBCL, the value of surveillance scans has also been questioned. Many pediatric patients are enrolled and treated on protocols, on which follow-up imaging interval is standardized. In the only report to date of surveillance imaging in pediatric non-Hodgkin lymphoma, Eissa et al. reported on the Texas Children’s Cancer Center experience since 2000, with 44 patients followed after treatment for B-cell non-Hodgkin lymphoma. Only 3 of 44 patients relapsed, and no relapses were detected by CT or PET-CT scans. The median effective ionizing radiation dose per patient was 40.3 millisieverts (mSv) (range 0-276 mSv). Given the lack of impact of surveillance imaging on detection of relapse and 8

outcomes, as well as risks including radiation exposure in children and cost, the authors argue against routine surveillance CT or PET-CT in this patient population (27). Given the consistent results showing a lack of clinical benefit to post-treatment surveillance imaging, especially an impact on overall survival, consensus guidelines in recent years have moved away from recommending routine surveillance imaging after the end of treatment. National Comprehensive Cancer Network (NCCN) guidelines [Text Box 1] state that for limited-stage diffuse large B-cell lymphoma (DLBCL), surveillance imaging is recommended only as clinically indicated (28). For advancedstage DLBCL, imaging should be performed no more than every 6 months for 2 years, and then as clinically indicated. In the setting of follicular lymphoma, it is acceptable to obtain CT scans every 6 months for the first 2 years after treatment, then annually thereafter (28). The European Society for Medical Oncology (ESMO) [Text Box 2] states that for DLBCL scans are commonly performed at 6, 12, and 24 months, but there is no evidence that this provides a benefit to patients (29). For follicular lymphoma [Text Box 3], a minimal adequate radiological or ultrasound examination should be performed every 6 months for 2 years, and annually thereafter (30). The Lugano Classification [Text Box 4] recommendations discourage surveillance imaging without clinical suspicion in both Hodgkin and non-Hodgkin lymphoma (31). The British Committee for Standards in Hematology [Text Box 5] also recommends against surveillance imaging in Hodgkin lymphoma and DLBCL (32, 33). The American Society of Hematology (ASH) “Choosing Wisely” campaign recommends “limiting surveillance CT scans in asymptomatic patients who have after curative-intent therapy for aggressive lymphoma,” (34) For patients enrolled in clinical trials, the International

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Primary CNS Lymphoma Collaborative Group guidelines recommend follow-up with physical exam and T1-weighted MRI scan every 3 months for 2 years, then every 6 months for an additional 3 years, then yearly for an additional 5 years, though these recommendations were made in 2005 and importantly were designed for patients enrolled in trials, on which follow-up must be standardized to allow interpretation of results (35). POST-TREATMENT SURVEILLANCE, HODGKIN LYMPHOMA Among the earliest studies of surveillance in lymphoma, Torrey et al. reported relapse detection of 69% by history/clinical exam and 30% by imaging in 709 patients treated for stage I-II Hodgkin lymphoma, with no difference in OS An early European study of PET-CT as surveillance imaging after treatment in Hodgkin lymphoma showed that surveillance imaging detected asymptomatic relapses (36). Among 94 patients with relapsed Hodgkin lymphoma treated at Memorial Sloan-Kettering, 38% of relapses were detected preclinically on surveillance imaging, and 62% were diagnosed clinically. No differences were found in failure-free survival or overall survival between manner of relapse detection (37). Zinzani et al. reported on 343 patients with lymphoma (Hodgkin and aggressive and indolent non-Hodgkin lymphoma) and found that 10% of patients had asymptomatic relapse detected by PET-CT within the first 18 months after treatment. In this series, PET-CT had a higher PPV than noted in other series; still, no survival benefit was found (38). Another large study of surveillance imaging in Hodgkin lymphoma showed no survival benefit in patients who underwent surveillance imaging with PET-CT or CT (39). In a population-based Danish-Swedish observational study, no survival benefit was found to be associated with routine surveillance imaging for 10

Hodgkin lymphoma in first remission (40). Multiple other studies have also demonstrated a lack of survival benefit associated with surveillance imaging after first remission in Hodgkin lymphoma (41, 42). When surveillance imaging is performed, the best imaging modality is under debate. Among patients with advanced-stage Hodgkin lymphoma with complete response to induction therapy, Picardi et al. performed a prospective randomized study randomizing patients to either PET-CT or ultrasound/chest x-ray, every 4 months for the first 2 years, then every 6 months for the third year, then yearly. There was no difference between relapse detection rate between the two arms, and US/chest x-ray showed greater specificity and PPV than did PET-CT. US/chest x-ray also had significantly lower radiation exposure than PET-CT (0.1 mSv vs 14.5 mSv), and lower cost (approximately 10% cost of PET-CT) (43). Similarly low value of surveillance imaging has been reported in pediatric patients with Hodgkin lymphoma. Among 402 children with Hodgkin lymphoma treated on multiinstitutional consortium protocols between 1990 and 2006, 64 relapsed, the majority of which were detected at a routine visit (60%). Imaging findings detected relapse in 36%, and method of detection of relapse did not affect survival (44). In a report from the multicenter Pediatric Oncology Group 9425, 25 of 216 patients relapsed, and 76% of relapses were detected based on clinical findings, with two detected by imaging in the first year after treatment, and four detected by imaging after the first year after treatment. Detection of late relapse did not affect survival, and the authors argue against use of surveillance imaging after the first year off treatment (45). In another study, Rathore et al report that relapsed disease in 99 children treated for Hodgkin 11

lymphoma was detected in 17 of a total of 1358 scans (1.3%), with mean radiation doses of 32-51 mSv delivered depending on stage (46). American College of Radiology (ACR) Appropriateness Criteria (2014) [Text Box 6] for post-treatment surveillance of Hodgkin lymphoma notes that a majority of recurrences can be detected clinically rather than through the use of imaging or blood tests, and that routine surveillance CT scans can detect an additional proportion of recurrences, though the value of this detection is unclear. PET-CT surveillance is not recommended because of low positive predictive value (PPV), high false-positive rate, and high cost (47). Current NCCN guidelines [Text Box 7] advise that it is acceptable to obtain CT imaging at 6, 12, and 24 months after completion of treatment, or as clinically indicated (48) Surveillance PET-CT is discouraged due to high rate of false positive scans. ESMO Clinical Practice Guidelines [Text Box 8] recommend that imaging be performed once to confirm remission status, but is not indicated thereafter in the absence of clinical symptoms (49). The Lugano Classification [Text Box 4] recommendations discourage surveillance imaging without clinical suspicion in both Hodgkin and non-Hodgkin lymphoma (31), and as previously noted, the ASH “Choosing Wisely” campaign and the British Committee for Standards in Hematology [Text Box 9] both advise against surveillance imaging in Hodgkin and aggressive non-Hodgkin lymphoma (32-34).

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THE COSTS OF IMAGING The downsides associated with surveillance imaging after completion of treatment in lymphoma have been well-characterized. These include radiation exposure, anxiety, scan cost, and risks related to invasive procedures resulting from indeterminate scan findings. Anxiety and reduced quality of life related to surveillance scans have been wellreported. Thompson et al. found a high rate of fear of recurrence and increased anxiety around the time of surveillance imaging, with 37% of patients found to meet criteria for clinically significant anxiety (50). In a study of patients with early-stage Hodgkin lymphoma, routine surveillance imaging was associated with worsened quality of life and reduced quality-adjusted life expectancy (51). There is also the potential for falsepositive surveillance imaging to lead to invasive procedures which are associated with risk, including biopsy. In a study examining the clinical significance of post-treatment FDG uptake in cervical lymph nodes in patients with DLBCL, only 9% of FDG avid nodes were ultimately found to be malignant, and most patients therefore underwent biopsy for benign findings (52) Multiple studies have shown a lack of cost-effectiveness of surveillance imaging (51) (53), and even in a surveillance strategy incorporating biannual imaging for only the first year after treatment, the cost per imaging-detected relapse was $95,195 for Hodgkin lymphoma, and $46,125 for DLBCL (17). A model of quality-adjusted life-years (QALY) found incremental cost-effectiveness ratios associated with imaging surveillance versus clinical follow-up to be $164,960/QALY for two years of routine CT scans, and $168,750/QALY for two years of surveillance PET-CT scans (54). 13

Reports of risk of secondary cancers in lymphoma patients have shown a correlation between number of scans received and risk of secondary cancers (55) (56). This is particularly of concern in pediatric patients where secondary malignancy risks are higher (57) (46). In a retrospective cohort study, Pearce et al. found that children exposed to at least 30 mSv of radiation from CT scans were 3 times more likely to develop leukemia (58). FUTURE SURVEILLANCE STRATEGIES Given the lack of evidence supporting surveillance imaging after completion of treatment for lymphoma, as well as the noted cost, anxiety, and risks associated with imaging, other strategies for assessment of disease status after treatment are of interest. Efforts at using non-imaging-related surveillance strategies have to date met with mixed results. Absolute lymphocyte count (ALC) has been examined with one study showing lower ALC at 3 months after treatment predictive of relapse (59), and others showing decrease in ALC predictive of relapse after immunochemotherapy and after autologous stem cell transplantation (60, 61). Elevation of lactate dehydrogenase (LDH) has been examined as a predictor of relapse in asymptomatic patients, but most series have not found it to be predictive of relapse (14) (62) (63). Next generation surveillance strategies include evaluation for detection of minimal residual disease as has proved useful in leukemia and molecular monitoring. Current techniques being studied include PCR for recurrent translocations or patientspecific immunoglobulin genes, as well as next-generation sequencing of immunoglobulin loci and circulating tumor DNA (64) (65). The results of circulating tumor DNA in patients with DLBCL after induction therapy have recently been reported, 14

with high PPV for relapse due to high inherent specificity of these tests (66, 67). Further study of the clinical implementation of these new technologies may prove molecular monitoring to be the future of disease assessment following the completion of therapy, either alone or as an adjunct to imaging. CONCLUSION Despite the excellent survival outcomes among patients treated for lymphoma in the modern era, a sizable percentage of patients experience relapse after completion of therapy. Many patients can be cured with salvage therapy after relapse, leading to a desire to identify relapse as early as possible with the theory that this may increase likelihood of cure. However, the vast majority of evidence to this point shows no clinical benefit to surveillance imaging in Hodgkin or non-Hodgkin lymphoma. Further studies are needed to optimize potential non-imaging-based surveillance strategies for monitoring disease, and to potentially use these strategies to identify a group of patients who might benefit from selected use of post-treatment imaging. AUTHOR DECLARATION We wish to confirm that there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of the authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions, and final 15

approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author. Sincerely, Susan M. Hiniker, MD Richard T. Hoppe, MD

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25. Gerlinger M, Rohatiner AZ, Matthews J, Davies A, Lister TA, Montoto S. Surveillance investigations after high-dose therapy with stem cell rescue for recurrent follicular lymphoma have no impact on management. Haematologica. 2010;95(7):1130-5. 26. Cheah CY, Dickinson M, Hofman MS, George A, Ritchie DS, Prince HM, et al. Limited clinical benefit for surveillance PET-CT scanning in patients with histologically transformed lymphoma in complete metabolic remission following primary therapy. Ann Hematol. 2014;93(7):1193-200. 27. Eissa HM, Allen CE, Kamdar K, Simko S, Goradia P, Dreyer Z, et al. Pediatric Burkitt's lymphoma and diffuse B-cell lymphoma: are surveillance scans required? Pediatr Hematol Oncol. 2014;31(3):253-7. 28. Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, et al. NonHodgkin's lymphomas, version 4.2014. J Natl Compr Canc Netw. 2014;12(9):1282-303. 29. Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v116-25. 30. Dreyling M, Ghielmini M, Rule S, Salles G, Vitolo U, Ladetto M, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v83-v90. 31. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and nonHodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-68. 32. Chaganti S, Illidge T, Barrington S, McKay P, Linton K, Cwynarski K, et al. Guidelines for the management of diffuse large B-cell lymphoma. Br J Haematol. 2016;174(1):43-56. 33. Follows GA, Ardeshna KM, Barrington SF, Culligan DJ, Hoskin PJ, Linch D, et al. Guidelines for the first line management of classical Hodgkin lymphoma. Br J Haematol. 2014;166(1):34-49. 34. Hicks LK, Bering H, Carson KR, Kleinerman J, Kukreti V, Ma A, et al. The ASH Choosing Wisely(R) campaign: five hematologic tests and treatments to question. Blood. 2013;122(24):3879-83. 35. Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M, Pulczynski EJ, Zucca E, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):5034-43. 36. Jerusalem G, Beguin Y, Fassotte MF, Belhocine T, Hustinx R, Rigo P, et al. Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease. Ann Oncol. 2003;14(1):123-30. 37. Basciano BA, Moskowitz, C., and Zelenetz, A.D. Impact of routine surveillance imaging on the outcome of patients with relapsed Hodgkin lymphoma. ASH Annual Meeting Abstracts. 2009(114):1558. 38. Zinzani PL, Stefoni V, Tani M, Fanti S, Musuraca G, Castellucci P, et al. Role of [18F]fluorodeoxyglucose positron emission tomography scan in the follow-up of lymphoma. J Clin Oncol. 2009;27(11):1781-7. 39. El-Galaly TC, Mylam KJ, Brown P, Specht L, Christiansen I, Munksgaard L, et al. Positron emission tomography/computed tomography surveillance in patients with Hodgkin lymphoma 18

in first remission has a low positive predictive value and high costs. Haematologica. 2012;97(6):931-6. 40. Jakobsen LH, Hutchings M, de Nully Brown P, Linderoth J, Mylam KJ, Molin D, et al. No survival benefit associated with routine surveillance imaging for Hodgkin lymphoma in first remission: a Danish-Swedish population-based observational study. Br J Haematol. 2016;173(2):236-44. 41. Dann EJ, Berkahn L, Mashiach T, Frumer M, Agur A, McDiarmid B, et al. Hodgkin lymphoma patients in first remission: routine positron emission tomography/computerized tomography imaging is not superior to clinical follow-up for patients with no residual mass. Br J Haematol. 2014;164(5):694-700. 42. Tome A, Costa F, Schuh J, Monteiro L, Monteiro A, Botelho de Sousa A. No benefit of routine surveillance imaging in Hodgkin lymphoma. Br J Haematol. 2015;168(4):613-4. 43. Picardi M, Pugliese N, Cirillo M, Zeppa P, Cozzolino I, Ciancia G, et al. Advanced-stage Hodgkin lymphoma: US/chest radiography for detection of relapse in patients in first complete remission--a randomized trial of routine surveillance imaging procedures. Radiology. 2014;272(1):262-74. 44. Friedmann AM, Wolfson JA, Hudson MM, Weinstein HJ, Link MP, Billett A, et al. Relapse after treatment of pediatric Hodgkin lymphoma: outcome and role of surveillance after end of therapy. Pediatr Blood Cancer. 2013;60(9):1458-63. 45. Voss SD, Chen L, Constine LS, Chauvenet A, Fitzgerald TJ, Kaste SC, et al. Surveillance computed tomography imaging and detection of relapse in intermediate- and advanced-stage pediatric Hodgkin's lymphoma: a report from the Children's Oncology Group. J Clin Oncol. 2012;30(21):2635-40. 46. Rathore N, Eissa HM, Margolin JF, Liu H, Wu MF, Horton T, et al. Pediatric Hodgkin lymphoma: are we over-scanning our patients? Pediatr Hematol Oncol. 2012;29(5):415-23. 47. Ha CS, Hodgson DC, Advani R, Dabaja BS, Dhakal S, Flowers CR, et al. ACR appropriateness criteria follow-up of Hodgkin lymphoma. J Am Coll Radiol. 2014;11(11):1026-33 e3. 48. Hoppe RT, Advani RH, Ai WZ, Ambinder RF, Aoun P, Bello CM, et al. Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15(5):608-38. 49. Eichenauer DA, Engert A, Andre M, Federico M, Illidge T, Hutchings M, et al. Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii70-5. 50. Thompson CA, Charlson ME, Schenkein E, Wells MT, Furman RR, Elstrom R, et al. Surveillance CT scans are a source of anxiety and fear of recurrence in long-term lymphoma survivors. Ann Oncol. 2010;21(11):2262-6. 51. Guadagnolo BA, Punglia RS, Kuntz KM, Mauch PM, Ng AK. Cost-effectiveness analysis of computerized tomography in the routine follow-up of patients after primary treatment for Hodgkin's disease. J Clin Oncol. 2006;24(25):4116-22. 52. An YS, Yoon JK, Lee SJ, Jeong SH, Lee HW. Clinical significance of post-treatment 18Ffluorodeoxyglucose uptake in cervical lymph nodes in patients with diffuse large B-cell lymphoma. Eur Radiol. 2016;26(12):4632-9. 19

53. Dryver ET, Jernstrom H, Tompkins K, Buckstein R, Imrie KR. Follow-up of patients with Hodgkin's disease following curative treatment: the routine CT scan is of little value. Br J Cancer. 2003;89(3):482-6. 54. Huntington SF, Svoboda J, Doshi JA. Cost-effectiveness analysis of routine surveillance imaging of patients with diffuse large B-cell lymphoma in first remission. J Clin Oncol. 2015;33(13):1467-74. 55. Chien SH, Liu CJ, Hu YW, Hong YC, Teng CJ, Yeh CM, et al. Frequency of surveillance computed tomography in non-Hodgkin lymphoma and the risk of secondary primary malignancies: A nationwide population-based study. Int J Cancer. 2015;137(3):658-65. 56. Berrington de Gonzalez A, Mahesh M, Kim KP, Bhargavan M, Lewis R, Mettler F, et al. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med. 2009;169(22):2071-7. 57. Miglioretti DL, Johnson E, Williams A, Greenlee RT, Weinmann S, Solberg LI, et al. The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk. JAMA Pediatr. 2013;167(8):700-7. 58. Pearce MS, Salotti JA, Little MP, McHugh K, Lee C, Kim KP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet. 2012;380(9840):499-505. 59. Aoki T, Nishiyama T, Imahashi N, Kitamura K. Lymphopenia following the completion of first-line therapy predicts early relapse in patients with diffuse large B cell lymphoma. Ann Hematol. 2012;91(3):375-82. 60. Porrata LF, Rsitow K, Inwards DJ, Ansell SM, Micallef IN, Johnston PB, et al. Lymphopenia assessed during routine follow-up after immunochemotherapy (R-CHOP) is a risk factor for predicting relapse in patients with diffuse large B-cell lymphoma. Leukemia. 2010;24(7):1343-9. 61. Porrata LF, Inwards DJ, Ansell SM, Micallef IN, Johnston PB, Hogan WJ, et al. New-onset lymphopenia assessed during routine follow-up is a risk factor for relapse postautologous peripheral blood hematopoietic stem cell transplantation in patients with diffuse large B-cell lymphoma. Biol Blood Marrow Transplant. 2010;16(3):376-83. 62. El-Sharkawi D, Basu S, Ocampo C, Qian W, D'Sa S, Hoskin PJ, et al. Elevated lactate dehydrogenase levels detected during routine follow-up do not predict relapse in patients with diffuse large B-cell lymphoma who achieve complete remission after primary treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone-like immunochemotherapy. Leuk Lymphoma. 2012;53(10):1949-52. 63. William BM, Bongu NR, Bast M, Bociek RG, Bierman PJ, Vose JM, et al. The utility of lactate dehydrogenase in the follow up of patients with diffuse large B-cell lymphoma. Rev Bras Hematol Hemoter. 2013;35(3):189-91. 64. Cohen JB, Kurtz DM, Staton AD, Flowers CR. Next-generation surveillance strategies for patients with lymphoma. Future Oncol. 2015;11(13):1977-91. 65. Scherer F, Kurtz DM, Newman AM, Stehr H, Craig AF, Esfahani MS, et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci Transl Med. 2016;8(364):364ra155. 66. Kurtz DM, Green MR, Bratman SV, Scherer F, Liu CL, Kunder CA, et al. Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood. 2015;125(24):3679-87. 20

67. Roschewski M, Dunleavy K, Pittaluga S, Moorhead M, Pepin F, Kong K, et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol. 2015;16(5):541-9. Table 1. Post-Treatment Surveillance, Non-Hodgkin Lymphoma: Diffuse Large B-cell Lymphomas (DLBCL) Reference Patient population Results Comment Thompson  Prospectively-enrolled cohort of MER Cohort:  Majority of DLBCL et al, 2014 552 patients with DLBCL treated relapses detected  112/552 (20%) suffered a [9] with anthracycline-based relapse - 93 DLBCL; 19 other outside of planned immunochemotherapy who lymphoma follow-up achieved remission after induction  74% of relapses occurred in  No survival advantage therapy [Source: Molecular first 24 months of surveillance for imaging-detected Epidemiology Resource (MER) of relapse  67/104 (64%) of relapses the University of Iowa/Mayo Clinic identified before scheduled  Authors concluded: Lymphoma Specialized Program of follow-up visit “These data do not Research Excellence] support the use of  9/552 (1.6%) of relapses  Confirmed results in an routine surveillance detected before clinical independent cohort of 222 patients imaging for follow-up manifestations from France [Source: Léon Bérard of DLBCL”  Across all 104 patients at Cancer Center, Lyon, France] relapse, 67% symptoms; 45%  Surveillance strategy (MER) = CT abnormal PE; 46% elevated or PET-CT, per discretion of LDH; 88% ≥ one of these treating physician features  Surveillance strategy (Lyon) = CT Lyon cohort: scan at 6 mo and at 1 yr, with  55/222 (25%) suffered frequency of scans adapted to initial lymphoma relapse - 46 DLBCL; stage and prognostic score 9 other  34/222 (62%) of relapses identified before scheduled follow-up visit  4/222 (1.8%) of relapses detected before clinical manifestations Overall Survival: MER p=0.56 / Lyon p=0.25  Median OS (mos) for relapse detected at a scheduled visit:  MER [n=22]: 21; 95% CI, 11-57  Lyon [n=21]: 19 95% CI, 382  Median OS (mos) for relapse detected before next scheduled visit  MER [n=63]: 15; 95% CI, 826  Lyon [n=34]: 12, 95% CI, 322 El-Galaly  Retrospective analysis  [Danish] Relapses after end of  Calculated 10-year et al, 2015  Population-based study ages18-65 treatment: survival probability [10] 0.815 for imaging from Danish [n=525] and Swedish  <24 months = 69% group vs. 0.810 for the [n=696] lymphoma registries with  24 to <36 months = 15% non-imaging group. newly diagnosed DLBCL from  ≥36 months = 16%

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2007 to 2012, and CR after RCHOP/CHOP-like regimens  Swedish surveillance strategy: Symptom assessment, PE, blood tests every 3-4 mos X 2 yrs, with longer intervals later. Imaging only when relapse clinically suspected  Danish surveillance strategy: Similar + CT every 6 mos X 2 yrs

Hong et al, 2014 [11]

Avivi et al, 2013 [12]

 Cumulative 2-year progression rates >CR  [Danish] IPI ≤2 = 6% (95%CI, 4-9)  [Danish] IPI >2 = 21% (95%CI, 13-28) for  Age >60 years = HR 2.3 (95%CI, 1.6-3.4)  Elevated LDH = HR 2.3 (95%CI, 1.4-3.8)  B symptoms = HR 1.7 (95%CI, 1.1-2.5)  ECOG PS ≥2 = HR 1.8 (95%CI, 1.0-3.0)





 Retrospective analysis  106 patients ≥ 20 years with diagnosis of DLBCL according to the 2008 WHO criteria who achieved CR by FDG-PET/CT according to 2007 Revised Criteria after receiving R-CHOP immunochemotherapy with or without consolidative therapies  Surveillance strategy: H&P every 2-3 months for 2 years, with longer intervals later. Routine CT or PETCT per discretion of treating physician

 15/106 experienced relapse  3-year-EFS and OS 86.4% and 93.6%, respectively  856 OPD visits; 501/322 visits with/without routine imaging; 33/856 visits (3.9%) unplanned early visits due to abnormal symptoms  Only 3/106 found to have asymptomatic relapse by surveillance imaging (CT and PET-CT)  False positive imaging findings led to unnecessary additional tests



 Retrospective analysis  Compare performance of surveillance PET in DLBCL patients receiving CHOP (n=35) alone versus CHOP-R (n=84)  Surveillance strategy: PET-CTs with 3-6 month interval for 1 year, 6 month interval in 2nd year, and yearly over next 5 years

 423 follow-up PETs analyzed  31 patients relapsed -17/35 (CHOP) vs. 14/84 (CHOP-R) p=0.02  PET detected all relapses, with no FN studies.  High rate of FP surveillance PET-CT scans  Higher FP (p<0.001) with lower PPV (p<0.0001) with R-CHOP (77%, 23%) than CHOP (26%, 74%)  FP-rate remained persistently high up to 3 years post-therapy.



22

 



117,797 patients would be needed in each arm to detect this marginal difference, with 5% significance level and power of 80%. Imaging-based followup strategy had no impact on survival, neither for all patients nor for IPI-specific subgroups. Authors concluded: “DLBCL relapse after first CR is infrequent, and the widespread use of routine imaging did not translate into better survival” Small number of patients, precludes determining whether routine imaging can improve OS of patients with DLBCL who suffered a relapse 125 scans to detect one asymptomatic relapse Routine imaging unsatisfactory PPV due to frequent FP, and FP underwent unnecessary biopsies or additional scans. Compared with planned OPD visits, unplanned early visits were highly related to relapse FDG PET/CT highly sensitive for detecting relapse in both patient groups. However, less than third of recurrences were detected at an asymptomatic stage. Authors concluded: “routine surveillance FDG-PET is not recommended in DLBCL treated with rituximab; strict

Guppy et al, 2003 [13]

Hiniker et al, 2015 [14]

 Retrospective analysis  117 patients with DLBCL who achieved CR at the Royal Marsden Hospital between 1/1992 1/2000 using first line combination CTX: (1) CHOP; (2) PMitCEBO/M or (3) PACEBO/M. RT in 20 patients  Surveillance strategy: Symptom assessment, PE every 3 mos X 1 yr, every 6 months during 2nd year, then yearly. No routine blood tests. CT scans 3 and 12 months after completion of therapy  Retrospective analysis  162 stage I to II DLBCL treated with chemotherapy ± rituximab, radiation, or combined modality therapy between 2000-2013  Evaluated CT, PET-CT and LDH  Surveillance strategy: H&P every 3 months x 2 years, then every 4-6 months until year 5, then yearly. Surveillance imaging (CT, PETCT) at discretion of treating physician  Therapy:  160/162 (99%) CTX  Median CTX cycles = 6  110/162 (68%) ≥1 R-CHOP  12/162 (7%) R-CEOP  19/162 (12%) alternative R-CTX  16/162 (10%) CHOP without R  118/162 (73%) RT consolidation  2/162 (1%) RT alone

 Treatment with rituximab strongest predictor for FP PETCT  119 patients / 423 PET scans; 340/423 (80%) interpreted as negative; 83/423 (20%) interpreted as positive, including 31 (37%) eventually determined as TP and 52 (63%) as FP  Sensitivity, accuracy and NPV similar with CHOP-R (100%, 85%, and 100%) and CHOP alone (100%, 95%, 100%).  16/22 patients with relapses diagnosed clinically, remained alive (73%), compared with 8/9 (89%) of those diagnosed while being asymptomatic (P  =  NS)  35/117 suffered relapse  86% = relapse associated with development of new symptoms and/or signs  5.7% = relapses detected in asymptomatic patients using surveillance CT scans.

 5-year OS rate = 81.2%; 5-year FFP rate = 80.8%  124/162 patients (77%) ≥1 surveillance PET scan beyond end-of-treatment scans  94/124 (76%) CMR on PET after CTX  CMR on PET after CTX associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3)  18/162 suffered relapse; 13/18 received successful salvage CTX  9/18 relapses detected by surveillance imaging (8 PET, 1 CT)  9/18 relapses suspected clinically  No relapses detected by surveillance LDH  Median duration from initiation

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criteria identifying patients in whom FUPET is beneficial are required”

 Authors concluded: “Routine surveillance CT scans are of limited value in detecting asymptomatic early relapse”

 Shows that even studies showing higher rates of asymptomatic relapses have generally not shown a survival benefit to detection of relapse by surveillance imaging (PET-CT and CT)  Authors concluded: “Our results argue for limiting the use of post-treatment surveillance in patients with limitedstage DLBCL”



Lambert et al, 2010 [15]

Liedtke et al, [16]

 Prospective study  80 consecutive patients with lymphoma who received a reducedintensity allogeneic SCT  Surveillance strategy: CT and PETCT at 3, 6, 9, 15, 24, and 36 months after SCT



 108 patients with relapsed aggressive NHL treated with ICEbased second-line CTX. Relapses were categorized as detected by imaging, examination, or patientreported symptoms.  All previously received an anthracycline-containing first-line regimen [CHOP (50%), CHOPlike (24%) or NHL-15 (24%)]; o patient received rituximab  Most common subtypes: (1) DLBCL, 75%: (2) PTCL, 11%; and (3) MCL, 7%  Surveillance strategy: per treating physician discretion



  

 









of treatment to relapse = 14.3 months for relapses suspected by imaging and 59.8 months for relapses suspected clinically (P=.077) No significant difference in OS from date of first therapy or OS after relapse between relapse suspected by imaging versus clinically 42 patients with positive PETbefore transplantation Pre-transplantation PET status no impact on relapse rate or OS 17/34 relapses positive on PETwith a normal CT 14/26 donor lymphocyte infusion (DLI) guided by PET alone 24/108 (22.2%) relapses identified by surveillance imaging 84/108 (77.8%) relapses detected by symptoms or PE Most common patient-reported symptoms: lymphadenopathy/palpable mass (47.4%); pain (44.9%); Bsymptoms (5.2%); and others (2.5%). Likelihood of low risk disease: 4.1 X (95% CI 1.7-10.2) higher if relapse diagnosed by routine imaging than by symptoms or PE Likelihood disease chemosensitive: 4.0 X (95% CI 0.58-27.6) higher if relapse diagnosed by routine imaging than by symptoms or PE Median 5-year median OS: Relapse diagnosed by routine imaging = 54%; relapse diagnosed by symptoms or PE = 43% (P = 0.13) Surveillance imaging identified patients with a more favorable predicted outcome based on the age-adjusted international prognostic index determined at the start of second-line chemotherapy (sAAIPI), which incorporates performance status, LDH, and stage

24

 Post-transplantation surveillance by PET detected relapse before CT in half of episodes, often allowing earlier administration of DLI in patients  Authors concluded: “results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.  Not surprising more indolent disease that grows slower before symptomatic detected by imaging. Authors acknowledged possibility sAAIPI identifies patients with a more favorable lymphoma biology not that earlier detection of a gradual progression affects outcomes; additionally lead time bias potentially confounds results  Despite improved response rates, no survival benefit was noted in this study.

El-Galaly et al, 2014 [17]

 Retrospective analysis  258 patients with aggressive NHL ((nodal T-cell and diffuse large Bcell lymphomas)) and HL, treated between 2002-2011 who relapsed after complete remission to firstline therapy  All diagnosed 2002-2011 and relapsed after achieving CR on first-line therapy  Surveillance strategy: H&P every 3 months for first 2 years, every 6 months for years 3-5. CT scan every 6 months for first 2 years, then some continued yearly CT scans for years 3-5.

Cheah et al, [18]

 Retrospective analysis  116 patients with de novo DLBCL who underwent surveillance PETCT > CMR following primary therapy between 2002 and 2009  Initial immunochemotherapy was R-CHOP in 110/116 (95%), while 6/116 (5%) received R-HyperCVAD alternating with high-dose methotrexate and cytarabine  Surveillance strategy: PET-CT every 6 months for first 2 years, then yearly for years 3-5.

 Median time from response to relapse 8 months (10–90% percentile 2–43 months) but varied within the diagnostic subgroups  60% relapse in first year; 19% after the second year.  Relapse more commonly detected due to symptoms alone or in combination with abnormal blood tests or PE vs. surveillance imaging (64% versus 27%)  Patient-reported symptoms most common cause of relapse detection alone (41%) or with abnormal blood tests and/or PE (23%)  Imaging-detected relapse = lower disease burden (P=0.045) and reduced risk of death (HR=0.62, P=0.02 in multivariate analysis)  Unadjusted median OS for patients with imaging-detected relapse 90 vs. 38 months for non-imaging-detected relapse (P=0.0008)  Univariate HRs for death with imaging-detected relapse 0.52 (95%CI 0.35–0.76) for all patients, and 0.57 (95%CI 0.36–0.91) for DLBCL  116 patients; 450 scans  13/116 (11%) relapsed all within first 18 months  7/13 suspected clinically  6/13 subclinical  PET-CT high sensitivity 95% and specificity 97% for relapse: 13 true-positive, 6 false positives, no false negatives and 424 true negatives; PPV 68% and NPV 100%  PPV for baseline IPI <3 = 56%; PPI for baseline IPI ≥3 80%

25

 Estimated 91-255 routine scans per relapse depending on the lymphoma subtype  Patient-reported symptoms most common factor detecting relapse  High number of scans per relapse underscores need for improved surveillance criteria. However, imaging-detected relapse associated with lower disease burden and possible survival advantage.  The only study reporting a potential OS advantage with surveillance imaging. However, once patients with indolent histology and patients who relapsed before first scheduled surveillance imaging were excluded, no OS advantage was seen

 Confirms sensitive and specific of PET– CT for detection of relapsed DLBCL. NPV of 99–100% means with negative scans can reassure patient CMR truly reflects ongoing remission from DLBCL  No survival benefit associated with surveillance in this population (p=0.73)  Authors concluded “PET/CT surveillance is not useful for majority with DLBCL in CMR after primary therapy, possible exception baseline IPI

≥3 in the 18 months following completion of primary therapy” Lavi et al,  Retrospective analysis  70 scans; 53 patients  PPV of surveillance 2016 PET-CT may be  Investigate if specific CT  25/70 (36%) = TP [19] improved with measurements could improve the  45/70 (64%) = FP incorporation of CTPPV of surveillance FDG-PET/CT.  Multivariate analysis for based measurements  53 patients with DLBCL treated independent predictors of TP long axis ≥1.5 cm or with CHOP or R-CHOP who surveillance PET/CT: short axis ≥1.0 cm achieved CR. CT-derived features  Long or short axis measuring into analysis of PETof PET-positive sites, including ≥1.5 and ≥1.0 cm, positive sites long/short diameters, presence of respectively, in PET-positive  PPV of surveillance calcification and fatty hilum within sites [OR 5.4; p<0.05] PET-CT may be lymph nodes, assessed  IPI ≥ 2 [OR 6.89; p<0.05] improved with  Surveillance strategy: PET-CT  Lack of prior rituximab selection of high-risk every 6 months for first 2 years, therapy [OR 6.6; p<0.05] patients for then yearly for years 3-7  FDG uptake in previously surveillance imaging involved site [OR 4.9; with high-risk factors p<0.05] including IPI ≥2, lack of rituximab therapy, and FDG uptake in a previously FDG avid area Taghipour  Retrospective analysis  First three follow-up scans:  Authors concluded et al [20] “Fourth and  Biopsy-proven NHL patients who  Excluded clinical suspicion in subsequent follow-up had more than three follow-up 18.9%; changed management PET/CT scans add scans after completion of primary 32.4% same value as first treatment from 2000 to 2013  Identified recurrence in 13.4%; three. Impact on  77 patients with 208 fourth and changed management 7% management subsequent follow-up F-FDG [p<0.001 c/w excluded significantly greater if PET/CT scans included suspicion] there is clinical  Scans performed per physician  208 fourth and subsequent suspicion. Perform discretion follow-up PET/CT scans: only if clinical  Excluded clinical suspicion in suspicion or with 27.3%; changed management appropriate clinical 36.4% indication.”  Identified recurrence in 5.1%;  However, impact on changed management 9.2% survival not [p<0.001 c/w excluded demonstrated suspicion] Abbreviations: CHOP, Cyclophosphamide + Hydroxydaunorubicin hydrochloride + vincristine (Oncovin) + Prednisone; CHOP-R or R-CHOP, CHOP + Rituximab; CI, confidence interval; CMR, complete metabolic response; CR, complete remission; CTX, chemotherapy; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; EFS, event-free survival FFP, freedom from progression; FN, false negative; FP, false positive; HR, hazard ratio; ICE, ifosfamide, carboplatin, etoposide; IPI, International Prognostic Index; LDH, lactate dehydrogenase; OR, odds ratio; OS, overall survival; PACEBO/M, prednisolone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine ± methotrexate; PE, physical exam; PMitCEBO/M, prednisolone, mitoxantrone, cyclophosphamide, etoposide, bleomycin, vincristine ± methotrexate; PPV, positive predictive value; RCEOP, rituximab, cyclophosphamide, etoposide, vincristine, and prednisone; RHyper-CVAD, rituximab, hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone; RT, radiotherapy; TP, true positive; OPD, outpatient department.

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Table 2. Post-Treatment Surveillance, Non-Hodgkin Lymphoma: Indolent Lymphomas (FL, Follicular Lymphomas) Reference Patient population Results Comment Oh et al,  328 patients with previously  78/257 relapsed  Yield of routine 1999 untreated stages I, II, or III FL abdominal and pelvic CT  11/78 (14%) relapses detected [24] treated between 1978 and 1994 in follow-up appears low solely with abdominal and/or of whom 257 achieved a CR for stages I–III FL pelvic CT  Median follow up = 101  11/257 (4.3%) who achieved CR  Most patients did not months derive clinical benefit benefited from abdominal and from the use of  Surveillance strategy: H&P, pelvic CT surveillance imaging labs, CXR, KUB, CT A/P  Most recurrences occurred in every 3-6 months for first 5 symptomatic patients years, then yearly  Probabilities of relapse detection by each method during followup: 55/568 H&P; 1/534 CBC; 5/517 serum chemistry; 6/488 CXR; 13/190 KUB-LAG  29/259 abdominal CT; 19/242 pelvic CT, and 12/91 bone marrow biopsy and/or aspiration Gerlinger et  71 patients with diagnosis of  Progression in approximately  No difference in OS al, 2010 FL in remission after 50% of patients, half detected by found with annual [25] autologous stem cell signs and symptoms, and half by surveillance consisting transplantation imaging alone of CT and bone marrow biopsies in FL  Median follow up = 16 years  Progression documented by surveillance in 16/71 and  Surveillance strategy: H&P, clinically in 18/71, with median labs every 3 months x 3 years, response duration 2.4 and 2.3 every 6 months x 2 years, then years, respectively (P=NS). yearly. Annual CT scans and bone marrow biopsies  Median time to next treatment 7 years when progression detected by imaging versus 4 years when detected by clinical findings (P=0.03)  OS not significantly different between the two groups Cheah et al,  55 patients with transformed  All 7 “subclinical” (PET-CT  Surveillance PET-CT of 2014 FL who achieved complete detected relapses were low-grade limited clinical benefit in [26] metabolic remission (CMR) histology and occurred a median FL after primary therapy of 9.8 months after completion of  Reserve PET-CT for therapy  37/55 (67%) received evaluation of clinically consolidation ASCT following  All 9 nine relapses with DLBCL suspected relapse CIT were symptomatic and occurred a median of 17 months after  Median follow up = 34 months completion of therapy  Determine utility of  180 surveillance PET-CT scans: surveillance PET-CT 153 true negatives, 4 false  Surveillance strategy: PET-CT positives, 1 false negative, 7 every 6 months for first 2 years, indeterminate and 15 true then annually for next 3 years positives  Considering indeterminate scans as false positives, specificity of PETCT for detecting relapse was 94%, sensitivity was 83%, PPV was 63% and NPV 98%

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Abbreviations: ASCT, autologous stem cell transplantation CBC, complete blood count; CIT, chemoimmunotherapy; CR, complete response; DLBCL, diffuse large B cell lymphoma H&P, history and physical examination; NPV, negative predictive value OS, overall survival; PET-CT, positron emission tomographycomputed tomography; PPV, positive predictive value

Reference Torrey et al, 1997 [36]

Jerusalem et al, 2003 [37]

Basciano et al, 2009 [38]

Zinzani et al, 2009 [39]

Table 3. Post-Treatment Surveillance, Hodgkin Lymphoma [HL] Patient population Results Comment  Examine costs and benefits  Relapse detected primarily  Perfomed in the pre-CT, pre-PET of routine follow-up studies by history (22%), physical era including history and exam (14%), CXR (23%),  Most relapses occurred within 5 physical, laboratories, and KUB (7%), laboratory years of treatment and identified surveillance imaging (CXR studies (1%) by H&P and KUB) for the detection  10-year actuarial survival  Projected charges per relapse of relapse in stage I-II HL rate was 65% overall, no were $11,000 by H&P, $68,000  709 patients treated for stage difference by method of by CXR, $142,000 by KUB I-II HL, 157 patients with detection relapsed HL  Surveillance strategy: per physician discretion  Examine value of PET for  1 residual tumor and 4  Showed that 18F-FDG PET the detection of preclinical relapses during a followsurveillance can detect relapse in HL up of 5–24 months asymptomatic relapses correctly identified early  Prospectively evaluated  But numbers and length of follow by 18F-FDG PET up both small  Surveillance strategy: 36 18  Compliance to undergo patients underwent F-FDG  Argument that help identify clinical follow-up visits was PET at end of treatment and patients requiring salvage  good with median number every 4–6 months for 2–3 chemotherapy at the time of of visits in the first and years minimal disease rather than at the second years = number of time of clinically overt relapse  Abnormal 18F-FDG PET visits recommended lacks published support and confirmed 4–6 weeks later  Compliance to undergo PET authors acknowledge need for less good with 119/180 further studies planned studies performed  Cost–benefit analysis necessary  94 patients with relapsed HL  38% of relapses detected  No differences in FFS or OS treated at Memorial Sloanpre-clinically with between manner of relapse Kettering surveillance; 62% detection diagnosed clinically.  Surveillance did not identify

 421 patients (160 HL 183 aggressive NHL, and 78 indolent follicular NHL)  Prospectively evaluated

 Outcome correlated with low (L) vs. intermediate / high (I/H) prognostic risk group validating applicability in this patient cohort: FFS at 5 years was 64.8% in L and 49.4% in H, p=0.045  Within a given risk group (L or I/H) outcome with surveillance not superior to clinically indicated scanning

patients with a more favorable risk profile according the MSKCC prognostic model nor led to improved outcomes

 Asymptomatic relapse detected in 10% of patients by PET-CT within first 18

 Still, no survival benefit found  The trend in NHL reflects trend in HL with true-positive decreasing

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 Surveillance strategy: FDG-PET scans at 6, 12, 18, and 24, months, then annually

El-Galaly et al, 2012 [40]

 211 routine and 88 clinically indicated PET-CT performed in 161 patients  Median follow-up = 34 months  Surveillance strategy: PET-CT per physician discretion

Jakobsen et al, 2016 [41]

 Population-based DanishSwedish observational study of post-remission survival  Denmark: Follow-up in included routine imaging, usually CT scan every 6 mo for a minimum of 2 years, Sweden: Clinical follow-up without routine imaging standard  317 Danish and 454 Swedish comparable HL patients aged 18– 65 years, diagnosed between 2007– 2012 having achieved CR following ABVD)/BEACOPP therapy  Retrospective study of HL in two Israeli (N = 291) and one New Zealand academic center (N = 77)  Compared active surveillance (AS) vs clinically guided imaging  All patients followed clinically every 3-4 months during first 3 years, then every 6 months for years 4-5  Active surveillance strategy: CT or PET-CT every 6 months for 2 years, then once in 3rd year

Dann et al, 2014 [42]

months after treatment  Overall, 1,789 PET scans were performed  PET-CT had a higher PPV than in other series  PET enabled documentation of relapse in 41, 30, 26 10 and 11 cases at 6, 12, 18 and 24 and 36 months, respectively  24/36 (66%) patients had lymphoma relapse documented on biopsy  22 recurrences; 10/22 by surveillance  True positive rates of routine and clinically indicated imaging were 5% and 13%, respectively  (P=0.02).  The overall PPV and NPV of PET-CT were 28% and 100%, respectively

and true-negative increasing over time  Relapse frequency decreased between 12-18 months for HL (10% to 4%) and between 18 and 24 months for aggressive NHL (11% to 2%)

 Cumulative progression rates in first 2 years were 4% (95% CI, 1– 7) for patients with stage I– II disease vs. 12% (95% CI 6– 18) for patients with stage III– IV disease

 Relapse of HL patients with CR is infrequent and surveillance imaging does not improve postremission survival.

 Five-year OS 94% and median TTR 8.6 months for both AS and clinically guided imaging; relapse rates 13% and 9%, respectively.  During first 3 years of follow-up, 47.5 and 4.7 studies performed per detected relapse in AS vs clinically guided imaging

 Lack of PFS or OS benefit associated with AS imaging after first remission in HL  The cost was 10 times higher for routine imaging.

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 No OS benefit in patients with

HL with surveillance PET-CT  Estimated cost per routine imaging diagnosed relapse was US$ 50,778  Low PPV

 Median time of first CR =  Lack of survival benefit 17 months (range 2–192). associated with AS after first remission in HL  42/58 (72%) relapses detected on basis of  Surveillance CT scans should be clinical symptoms or discouraged in asymptomatic signs; 16 /58 (28%) patients in CR from HL due to: detected by AS (1) lack of impact on CR2 or on survival from relapse; (2)  Only 4/25 (16%) of financial costs; (3) anxiety relapses occurring in first provoked; and (4) measurable risk year after therapy detected of second cancers linked to by AS radiation exposure in young  CR2 rate = 82% and 5patients with a highly curable year post-relapse survival lymphoma = 62%, regardless of the mode of relapse detection Picardi et  Prospective randomized  40/40 relapses identified  No difference between relapse al, 2014 study comparing PET-CT vs. with FDG PET/CT (100%) detection rate between the two [44] US/CXR, every 4 months for with 39/40 identified with arms the first 2 years, then every 6 US/chest radiography  US/chest x-ray: (1) greater months for the third year, (97.5%; P = .0001 for the specificity and PPV than did then yearly equivalence test) PET-CT; (2) significantly lower  Single center 2001-2009  Compared to PET/CT, radiation exposure than PET-CT US/CXR had significantly (0.1 mSv vs 14.5 mSv); and (3)  300 patients with advancedhigher specificity (96% lower cost (approximately 10% stage HL with CR after first[106/110] vs 86% cost of PET-CT) line [95/110], respectively; P = .02; and higher PPV (91% [39/43] vs 73% [40/55], respectively; P = .01) Abbreviations: ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; AS, active surveillance; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; 18F-FDG PET, 2[fluorine-18] fluoro-2-deoxy-D-glucose positron emission tomography; FFS, failure-free survival; HL, Hodgkin’s lymphoma; NHL, non-Hodgkin’s lymphoma; OS, overall survival; PPV, positive predictive value; TTR, time to relapse/recurrence; US, ultrasound; H&P, history and physical; CXR, chest x-ray; KUB, abdominal x-ray Tome et al, 2015 [43]

 58 first relapses of HL treated between 1998-2012  Patients had been followed with active surveillance (AS) CT scans every 6–12 months for the first 2 years

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TEXT BOX 1

NCCN: Diffuse Large B-Cell Lymphoma Version 1.2016 [Reference 28] End of Treatment Response Assessment for Stage I-II After end of treatment restaging, follow-up at regular intervals (every 3 to 6 months for 5 years and then annually or as clinically indicated thereafter) is recommended for patients with CR. In these patients, follow-up CT scans are recommended only if clinically indicated. End of Treatment Response Assessment for Stage III-IV After end of treatment restaging, observation is preferred for patients with CR. RT to initially bulky disease (category 2B) or first-line consolidation with HDT/ASCR can be considered in selected patients at high risk (category 2B). TEXT BOX 2

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. [Reference 29] 

Patients with DLBCL who are event-free at 2 years have an identical OS to that of the general population, emphasizing the need to only specifically monitor the disease in this early period.  Careful history and physical examination every 3 months for 1 year, every 6 months for 2 more years and then once a year with attention to development of secondary tumors or other long-term side effects of chemotherapy is recommended [V, D].  Blood count should be carried out at 3, 6, 12 and 24 months, then only as needed for evaluation of suspicious symptoms or clinical findings in those patients suitable for further therapy [V, C].  Minimal radiological examinations at 6, 12 and 24 months after end of treatment by CT scan are common practice, but there is no definitive evidence that routine imaging in patients in complete remission provides any outcome advantage, and it may increase the incidence of secondary malignancies [V, D] [61, 62]. Routine surveillance with PET scan is not recommended [V, E]. High-risk patients with curative options may potentially mandate more frequent evaluation. Note: Follow-up of patients in second response is the same as for first response. Levels of Evidence: V = Studies without control group, case reports, experts opinions

C = Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, …), optional D = Moderate evidence against efficacy or for adverse outcome, generally not recommended E = Strong evidence against efficacy or for adverse outcome, never recommended

TEXT BOX 3

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. [Reference 30] Note: The following minimal recommendations are based on consensus rather than on evidence  After local radiotherapy: history and physical examination every 6 months for 2 years, subsequently once a year if clinically indicated.  After (during continuous) systemic treatment: history and physical examination every 3–4 months for 2 years, every 6 months for 3 additional years, and subsequently once a year [V, D].  Blood count and routine chemistry every 6 months for 2 years, then only as needed for evaluation of suspicious symptoms.  Evaluation of thyroid function in patients with irradiation of the neck at 1, 2 and 5 years.  Minimal adequate radiological or ultrasound examinations every 6 months for 2 years and optionally annually up to 5 years. Regular CT scans are not mandatory outside of clinical trials, especially if abdominal ultrasound is applicable. PET–CT should be not used for surveillance.  MRD screening may be carried out in clinical studies but should not guide therapeutic strategies. Levels of Evidence: V = Studies without control group, case reports, experts opinions D = Moderate evidence against efficacy or for adverse outcome, generally not recommended

TEXT BOX 4

Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification [Reference 31]      

PET-CT should be used for response assessment in FDG-avid histologies, using the 5-point scale; CT is preferred for low or variable FDG avidity. A complete metabolic response even with a persistent mass is considered a complete remission. A PR requires a decrease by more than 50% in the sum of the product of the perpendicular diameters of up to six representative nodes or extranodal lesions. Progressive disease by CT criteria only requires an increase in the PPDs of a single node by ≥50%. Surveillance scans after remission are discouraged, especially for DLBCL and HL, although a repeat study may be considered after an equivocal finding after treatment. Judicious use of follow-up scans may be considered in indolent lymphomas with residual intra-abdominal or retroperitoneal disease. TEXT BOX 5

British Committee for Standards in Hematology: Guidelines for the management of diffuse large B-cell lymphoma [Reference 32]    

Patients who achieve a CR following treatment should be followed up on a 3–4 monthly basis for up to 2 years Outside a clinical trial, there is no role for routine surveillance scans during post-treatment follow-up and patients should be assessed clinically The risk of relapse beyond 2 years is <10%. It is therefore reasonable to discharge patients back to their primary care physician at that stage with advice and support.

TEXT BOX 6

American College of Radiology Appropriateness Criteria Follow-up of Hodgkin Lymphoma [Reference 47]  The main focus of follow-up is recurrent disease in the first 5 years, as the majority of relapses occur in this time period. However, the focus shifts to late side effects beyond this time period.  In general, a majority of recurrences can be detected initially by history and physical examination rather than by routine imaging studies or blood tests such as erythrocyte sedimentation rate, complete blood count, and chemistry panel.  Routine surveillance CT scans can detect a proportion of recurrent diseases not detected by history and physical examination. However, their exact value in terms of life expectancy and cost-effectiveness is unclear. Some investigators believe that surveillance CT scans are currently overused.  PET scan is a useful tool in defining a subset of patients who require additional therapy after completion of the initial therapy. However, the routine use of PET for surveillance is not recommended in general because of its low PPV, high false-positive rate, and lack of costeffectiveness. TEXT BOX 7

NCCN Guidelines: Follow-up after completion of treatment and monitoring for late effects [Reference 48]  CR should be documented including reversion of PET to "negative" within 3 months following completion of therapy.  It is recommended that the patient be provided with a treatment summary at the completion of his/her therapy, including details of radiation therapy, organs at risk, and cumulative anthracycline dosage given.  Follow-up with an oncologist is recommended, especially during the fi st 5 years after treatment to detect recurrence, and then annually due to the risk of late complications including second cancers and cardiovascular disease. Late relapse or transformation to large cell lymphoma may occur in NLPHL.  The frequency and types of tests may vary depending on clinical circumstances: age and stage at diagnosis, social habits, treatment modality, etc. There are few data to support specific recommendations; these represent the range of practice at NCCN Member Institutions. Follow-up After Completion of Treatment up to 5 Years

  

Interim H&P: Every 3–6 months for 1–2 y, then every 6–12 months until year 3, then annually Annual influenza vaccine Laboratory studies:

  

 CBC, platelets, ESR (if elevated at time of initial diagnosis), chemistry profile as clinically indicated  Thyroid-stimulating hormone (TSH) at least annually if RT to neck. Acceptable to obtain a neck/chest/abdomen/pelvis CT scan with contrast, at 6, 12, and 24 mo following completion of therapy, or as clinically indicated. PET/CT only if last PET was Deauville 4-5, to confirm complete response. Counseling: Reproduction, health habits, psychosocial, cardiovascular, breast self-exam, skin cancer risk, end-of treatment discussion. Surveillance PET should not be done routinely due to risk for false positives. Management decisions should not be based on PET scan alone; clinical or pathologic correlation is needed.

Follow-up and Monitoring After 5 Years  Interim H&P: Annually  Annual blood pressure, aggressive management of cardiovascular risk factors  Pneumococcal, meningococcal, and H-flu revaccination after 5–7 years, if patient treated with splenic RT or previous splenectomy (according to CDC recommendations)  Annual influenza vaccine  Cardiovascular symptoms may emerge at a young age.  Consider stress test/echocardiogram at 10-year intervals after treatment is completed.  Consider carotid ultrasound at 10-year intervals if neck irradiation.  Laboratory studies:  CBC, platelets, chemistry profile annually  TSH at least annually if RT to neck  Biannual lipids  Annual fasting glucose  Annual breast screening: Initiate 8–10 year post-therapy, or at age 40, whichever comes first, if chest or axillary radiation. The NCCN Hodgkin Lymphoma Guidelines Panel recommends breast MRI in addition to mammography for women who received irradiation to the chest between ages 10–30 years, which is consistent with the American Cancer Society (ACS) Guidelines. Consider referral to a breast specialist.  Perform other routine surveillance tests for cervical, colorectal, endometrial, lung, and prostate cancer as per the ACS Cancer Screening Guidelines.  Counseling: Reproduction, health habits, psychosocial, cardiovascular, breast self-exam, and skin cancer risk.  Treatment summary and consideration of transfer to PCP.  Consider a referral to a survivorship clinic.

TEXT BOX 8

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [Reference 49] 

History, physical examination and laboratory analysis including full blood cell count, ESR and blood chemistry should be carried out every three months for the first half year, every 6 months until the fourth year and once per year thereafter [V, B].  Additional evaluation of thyroid function (thyroid-stimulating hormone) after irradiation of the neck at one, two and at least five years is recommended. Furthermore, testosterone and estrogen levels should be monitored, particularly in younger patients who had intensive chemotherapy.  CT scans and previously pathologic radiographic tests must be carried out once to confirm the remission status. Thereafter, surveillance scans are not indicated unless clinical symptoms occur [IV, B].  Patients should be asked for symptoms indicating the existence of long-term toxicity, particularly of heart and lung.  Cancer screening should be conducted regularly due to the increased risk of hematological and solid secondary malignancies after HL treatment. Levels of evidence: IV = Retrospective cohort studies or case–control studies V = Studies without control group, case reports, experts opinions B = Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended

TEXT BOX 9

Guidelines for the first line management of classical Hodgkin lymphoma KEY recommendations for follow-up, late effects and survivorship [Reference 33]    

Patients are usually followed with intermittent outpatient clinical review for 2–5 years following first line therapy (2C). There is no proven role for routine surveillance CT or PET/CT imaging in patients who are otherwise well following first line therapy (2B). HL patients should be made aware that they are at an increased lifetime risk of second neoplasms, cardiovascular and pulmonary disease and infertility (1A). Apart from the current breast cancer-screening programme, there are no national cancer screening programmes tailored for HL survivors. Women treated with mediastinal RT before the age of 35 years should be offered entry into the breast cancer National Notification Risk Assessment and Screening programme (NRASP) (1A).





Regular lifestyle advice should be offered to reduce secondary neoplasms and cardiovascular risk. There should be complete avoidance of smoking and careful management of cardiovascular risks such as hypertension, diabetes mellitus and hyperlipidaemia (1B). Patients who have had RT to the neck and upper mediastinum should have regular thyroid function checks. Hypothyroidism can occur up to 30 years after RT (1A). Patients should receive irradiated blood products for life (1B).

 Strength of recommendations Strong (grade 1): Strong recommendations (grade 1) are made when there is confidence that the benefits do or do not outweigh harm and burden. Grade 1 recommendations can be applied uniformly to most patients. Regard as ‘recommend’. Weak (grade 2): Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation is made. Grade 2 recommendations require judicious application to individual patients. Regard as ‘suggest’. Quality of evidence The quality of evidence is graded as high (A), moderate (B) or low (C). To put this in context it is useful to consider the uncertainty of knowledge and whether further research could change what we know or our certainty. A. High: Further research is very unlikely to change confidence in the estimate of effect. Current evidence derived from randomised clinical trials without important limitations. B. Moderate: Further research may well have an important impact on confidence in the estimate of effect and may change the estimate. Current evidence derived from randomised clinical trials with important limitations (e.g. inconsistent results, imprecision – wide confidence intervals or methodological flaws – e.g. lack of blinding, large losses to follow up, failure to adhere to intention to treat analysis), or very strong evidence from observational studies or case series (e.g. large or very large and consistent estimates of the magnitude of a treatment effect or demonstration of a dose-response gradient).