CT in Lymphoma: Current Overview and Future Directions

PET/CT in Lymphoma: Current Overview and Future Directions Bruce D. Cheson Over the past several decades, PET has emerged as critical to accurate staging and restaging of lymphomas. Nonetheless, a number of critical issues regarding its optimal use remain. Whereas risk-adapted strategies appear to improve the outcome of patients with Hodgkin lymphoma, results are less convincing in non-Hodgkin lymphoma. Assessment of metabolic tumor volume before treatment may permit novel induction strategies. New drugs that may induce an immune response may result in a false-positive FDG/PET scan, mandating modifications of current criteria to consider tumor flare reactions. Application of PET may be improved by integration of biomarker studies and a better understanding of the role of the microenvironment. Methods to improve the integration of FDG/PET enhance its role in the management of patients with lymphoma, leading to improved patient outcome. Semin Nucl Med 48:76–81 © 2017 Elsevier Inc. All rights reserved.

Background

I

maging in lymphoma has evolved greatly over the past several decades.1,2 Technology has improved from the obsolescent lymphangiogram to the intravenous pyelogram, ultrasound, liver-spleen radionuclide scan, computer tomography (CT), and magnetic resonance imaging. Gallium-67 (Ga-67) scintigraphy represented one of the first attempts at functional imaging; however, Ga-67 imaging was not highly reliable because of its nonspecific targeting of tumors and low sensitivity because of inferior spatial resolution of gamma camera imaging, as well as the concerns about exposure to high radiation absorbed doses. Importantly, the 2-day interval between Ga-67 injection and scanning was not clinically practical. Using the technology available at the time, the first widely adopted National Cancer Institute-sponsored Working Group response criteria were published in 1999.3 These guidelines standardized the definitions for complete (CR) and partial response (PR), stable, progressive, and relapsed disease (RD). In addition, they incorporated the category of complete remission unconfirmed, first introduced in the Cotswold Classification,4 to designate patients with a large tumor mass before treatment, with a persistent mass with size reduction following treatment which, particularly in patients with Georgetown University Hospital, Washington, DC. Address reprint requests to Bruce D. Cheson, MD, Georgetown University Hospital, 3800 Reservoir Rd, NW, Washington, DC 20007. E-mail: [email protected]

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https://doi.org/10.1053/j.semnuclmed.2017.09.007 0001-2998/© 2017 Elsevier Inc. All rights reserved.

Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL), was the result of tumor fibrosis, rather than residual, viable disease. The PET technology was first developed in 1973, the first whole-body PET scanner in 1977, and the integrated PET/ CT as a hybrid imaging modality was introduced in the early 1990s. PET scans were first applied to lymphoma assessment around 1990. Juweid et al5 were the first to incorporate FDG/PET into the then standard lymphoma response criteria. They noted that in patients with DLBCL, long-term outcome was similar regardless of whether the patient had a CR or PR based on CT criteria, as long as the mass was not FDG-avid. Thus, complete remission unconfirmed was eliminated as a response category. This observation, along with a large body of accumulating data, led to the development of the revised criteria for lymphoma assessment published in 2007.6 These criteria were the first to incorporate PET into response assessment because of its superior sensitivity and specificity compared with CT. The hope was that, using improved imaging, fewer patients would be either under- or overtreated. The 2007 International Working Group recommendations were primarily designed for HL and DLBCL, because, at the time, data using FDG/PET for other histologic subtypes were limited. Moreover, whereas FDG/PET was often performed before therapy, it had not yet been formally incorporated into staging because of the limited available data at that time. At the 11th International Conference on Malignant Lymphoma (Lugano, Switzerland) in 2011, a workshop was

PET/CT in lymphoma attended by representatives of the major international cooperative oncology groups and cancer centers that studied lymphoma, as well as pathologists, radiologists, radiation oncologists, and nuclear medicine physicians. The rationale was that, in the interim since the 2007 criteria were published, sufficient amount of additional information had been generated, including data supporting the role of FDG/PET in other histologies, notably follicular lymphoma (FL).7 Moreover, there was now consensus for the use of standardized criteria for interpretation of scans, that is, the Deauville 5-point scale (D5PS).8 Imaging and clinical subcommittees that were formed had extensive communication over the ensuing 2 years. The result was the Lugano Classification presented at the 12th ICML in Lugano in 20139 and published 1 year later.2,10 These universally adopted recommendations were designed to improve lymphoma patient evaluation by facilitating comparisons among studies, providing a reproducible platform for the evaluation of new therapies by regulatory agencies. The Lugano Classification regarded FDG PET/CT to be the standard for staging all FDG-avid histologies; those excluded because of their variable FDG avidity were chronic lymphocytic leukemia or small lymphocytic lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphomas, and mycosis fungoides. A modified version of the Ann Arbor staging system was developed, and the size of the spleen to be considered splenomegaly was standardized at 13 cm. Based on the superiority of CT scans of the chest, routine chest X-rays were no longer recommended. Moreover, several studies in HL and DLBCL showed improved sensitivity of FDG/PET scans over trephine bone marrow biopsies.11,12 Thus, this procedure was no longer considered essential in the routine staging of HL, and in most patients with DLBCL, unless in the latter, the FDG/PET was negative and it was important to determine if a discordant histology was present in the bone marrow. With respect to response assessment, the Lugano Classification recommended the D 5PS for interpretation of FDG/PET8 for treatment assessment, and included as a metabolic complete remission those patients with a persistent mass that was no longer FDG-avid. FDG/PET has long been considered for surveillance post treatment under the impression that it could detect recurrence earlier, leading to successful intervention with improvement in patient outcome. Unfortunately, the available data do not support this consideration. Firstly, more than 80% of the time, the patient or the doctor identifies recurrence before a scheduled imaging study. In addition, FDG/ PET in this setting is associated with false positives, increased radiation exposure, increased patient anxiety, and no evidence of benefit. Thompson et al13 reported on 680 patients treated with an anthracycline-based chemoimmunotherapy regimen for DLBCL. Of these, 81% achieved a CR and 20% relapsed. Almost two-thirds of relapses were detected before a scheduled visit. Indications of recurrence included diseaserelated symptoms in about 60%, an abnormal physical examination or an increased lactate dehydrogenase in 50%, and at least one of these manifestations in 90%. Surveillance imaging detected asymptomatic recurrence in 1.8% of patients with no impact on outcome. El-Galaly et al14 reported

77 registry data on 1221 Danish and Swedish patients, the Danish undergoing routine imaging, usually CT scans, the Swedish not. Overall outcomes were comparable. Thus, the Lugano Classification discourages surveillance scans in patients with a negative post-treatment FDG/PET, especially in patients with HL or DLBCL. Imaging should be used judiciously in other generally incurable histologies, notably in those patients with residual intra-abdominal, thoracic, or retroperitoneal disease.

Clinical Trials and Future Issues Despite the wide use of PET/CT, a number of issues remain regarding its application. Because FDG PET/CT scans predict outcome following completion of therapy, perhaps interim PET scans might provide guidance for a risk-adapted approach: to predict patients unlikely to do well, thus, requiring an alternative approach to improve efficacy, or those more likely to do well who might be spared a portion of the standard treatment, thus reducing toxicity.

Hodgkin Lymphoma Gallamini et al15 first reported, and subsequently confirmed in the International Validation Project,16 that a PET following 2 cycles of adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) for advanced HL using visual interpretation criteria is a better predictor of outcome than the International Performance Score: 85%-95% of those who are PET negative have prolonged disease-free survival, compared with 20%30% of those with a positive interim PET. Although most subsequent studies, particularly those that used the D 5PS, have confirmed this observation, the results have not been quite as dramatic.2,17,18 A number of risk-adapted studies have been conducted in patients with advanced HL. Johnson et al19 reported the Response-Adapted Therapy in Advanced Hodgkin Lymphoma trial in which 1214 patients with poor-risk stage II or stage III-IV disease received 2 cycles of ABVD. At PET2, 83.7% had a negative scan. PET-negative patients were randomized to ABVD or adriamycin vinblastine, dacarbazine (AVD) treatment, with no subsequent radiation. The 3-year progression free survival (PFS) for ABVD and AVD were 85.7% and 84.4%, respectively, with a similar overall survival of 97.2% and 97.6%, respectively. Importantly, there was significantly less toxicity in the AVD arm. In the Italian GITIL/FIL DH0607 trial,20 773 consecutively registered patients with advanced-stage disease were treated with ABVD; 89 were PET2 positive. They were randomized to 1 of 2 BEACOPP regimens, 1 containing rituximab. CR was achieved in 74.2%. The 4-year PFS and overall survival (OS) for this group were 62% and 86%, respectively, compared with 85% and 95% for the PET-negative group. In the German Hodgkin Study Group HD15 trial, patients were initially randomized to induction with 8 or 6 cycles of eBEACOPP or 8 cycles of BEACOPP-14.21 Patients with a negative post-treatment CT scan received no further treatment. A post-treatment FDG/PET scan was performed in those with a residual mass of ≥2.5 cm. If the scan was negative, there

B.D. Cheson

78 Table Risk-adapted Studies in Patients With Hodgkin Lymphoma Study (Reference)

Stage

CALGB 5060425 I-II EORTC H1026 I-II RATHL19

GITIL HD060720

SWOG S081627 FIL HD080128

N, PET- Initial % iPET Positive Post-PET Therapy positive Therapy (D5PS if used) 14 361

2 ABVD 2 ABVD

9 19

II with adverse 182 features, III, IV II with adverse 98 features, III, IV III, IV 60 IIB-IV 103

2 ABVD

16 (4-5)

2 ABVD

20 (4-5)

2 ABVD 2 ABVD

18 (4-5) 20 (3-5)

Time to PFS % OS % Analysis

2 esc BEACOPP + IFRT 2.1 y 2 ABVD + INRT 5y 2 esc BEACOPP + INRT 4 esc BEACOPP or 6 3y BEACOPP-14

66 77 91 68

N/A 87 96 87

4 esc BEACOPP + 4 BEACOPP baseline ± rituximab 6 esc BEACOPP 4 IGEV + BEAM

2

66

N/A

2 2

64 76

N/A N/A

D5PS, Deauville 5-point scale; iPET, interim PET; N, number; OS, overall survival; PFS, progression-free survival.

was no further treatment. Those with a positive scan underwent involved field radiation therapy. The outcome was comparable for the 2 cohorts not treated with RT, with a 92% 4-year PFS. With the implementation of PET, the number of patients subjected to radiation therapy decreased from HD9 to HD12 trials,22,23 and now to the HD15 trial24 from 70% to 11%, with no decrease in the cure rate. For patients with a positive (Table) interim scan, several studies have explored intensification of treatment. Press et al27 reported the SWOG-led US intergroup study S0816 in which patients were initially treated with 2 cycles of ABVD followed by a FDG/PET scan, interpreted using the D 5PS. Those who were considered negative (scores of 1-3) received 4 more cycles of ABVD. The 18% who were positive received 6 additional cycles of eBEACOPP. The 2-year estimated PFS was 79% with an OS of 98% for the entire cohort. For those in the PET2 positive subset, the PFS of 64% was considered promising. In the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study, the 16% of patients with a positive interim PET scan were randomized to either 4 eBEACOPP or 6 BEACOPP-14. Results were similar between the arms with a 3-year PFS of 68%, and an OS of 87%. Benefit from a risk-adapted approach has been less consistent in patients with limited disease. Zinzani et al28 reported the final results of the Italian HD0801 study in which 103 of the 512 evaluable patients with a positive PET2 scan were treated with ifosfamide, gemcitabine, and vinorelbine, followed by autologous stem cell transplantation, with a 76% 2-year PFS, regardless of the salvage therapy they received, and despite the fact that about 20% did not receive all the planned therapy. These data were interpreted as supporting intensification in the PET2-positive patients. Straus et al25 from the Cancer and Leukemia Group B (CALGB, now Alliance) treated early-stage, non-bulky patients with 2 cycles of ABVD. Those who became PET2 negative were treated with an additional 2 cycles without radiation therapy. Those with a positive scan went on to receive 2 cycles of escalated BEACOPP, followed by involved field radiation therapy. The estimated 3-year PFS was 92% vs 66% for the negative and positive cohorts, respectively. Using a D5PS of 1-3 as negative (rather than 1-2) reduced the number of

patients unnecessarily exposed to radiation by 16% while maintaining a 90% PFS. Whereas the data in the positive cohort fared better with respect to PFS than historical controls, the study did not achieve its primary end point when compared with the results in the negative group (HR 3.84). Radford et al29 reported on the RAPID trial that 602 patients with stage IA or IIA disease received 3 cycles of ABVD followed by an FDG/PET scan. Those who were negative were further randomized to involved field radiation therapy or no further therapy. The PET3-positive group received a fourth cycle and RT. The 3-year PFS was 94.6% in the irradiated group, compared with 90.8 in the group without RT. Whereas the study did not meet its modified noninferiority boundary, about 90% of patients were spared unnecessary radiation. André et al26 recently published the final results of the EORTC/LYSA/FIL H10 trial in patients with stage I and II favorable and unfavorable HL. In this randomized trial, 1925 patients underwent FDG/PET imaging after 2 cycles of ABVD, of which 18.8% were positive. In the standard arm of both cohorts, patients completed ABVD (1 additional cycle for the patients with favorable prognosis, 2 for the unfavorable), followed by involved nodal radiation therapy. The 5-year PFS with ABVD was 77.4%, where it improved to 90.6% with intensification with escalated BEACOPP plus involved nodal radiation. In the interim PET-negative group, those in the favorable group who received ABVD alone had a 5-year PFS of 87.1% compared with 99% for the control arm who also received radiation. Thus, noninferiority of ABVD alone could not be demonstrated. In the unfavorable group, the numbers were 92.1% vs 89.6%, respectively. The authors concluded that, in this subset, combined modality therapy was not necessarily superior, and chemotherapy alone was an acceptable alternative. For those patients who had a positive interim PET, the 5-year PFS improved from 77.4% to 90.6%, although with considerably more toxicity than observed in the control patients. Nevertheless, the long-term survival results were comparable (100% for ABVD plus radiation vs 99.6% for ABVD alone). Thus, the aggregate of data would support interim PET in HL to reduce the amount of therapy in interim PET-negative

PET/CT in lymphoma patients, and to modify treatment in those with residual tumor. Unfortunately, starting with or changing to BEACOPP is unattractive given its potential short- and long-term adverse effects. With the availability of highly effective and less toxic agents such as brentuximab vedotin 30 and checkpoint inhibitors,31 alternative approaches should be explored.

Diffuse Large B-Cell Lymphoma (DLBCL) Approximately 60% of patients with advanced-stage DLBCL are cured with standard chemotherapy such as R-CHOP. A small fraction of the remaining patients are stem cell transplant candidates, but only a proportion of those are cured. Early enthusiasm for interim PET in predicting outcome32,33 was tempered by considerable inconsistency in the results of subsequent studies, reflecting variability in patient populations, therapy, use of rituximab, equipment, and interpretation.34-37 Whereas the negative predictive value is high in most studies, the positive predictive value is disappointingly low as a result of false-positive results caused by inflammation and tumor necrosis.38 The larger issue is whether altering treatment on the basis of an interim PET can favorably impact outcome. Moskowitz et al38 treated patients with DLBCL with 4 cycles of intensified R-CHOP followed by a PET scan. Those patients with a negative scan received ifosfamide, carboplatin, and etoposide for 3 cycles followed by observation. Those patients with a positive PET scan underwent a biopsy. Patients with a negative biopsy were observed. Those with a positive biopsy underwent intensive chemotherapy followed by autologous stem cell transplantation. Of the 97 patients who underwent an interim PET, 59 were negative, and 51 of those remained progression free. Biopsy was positive in only 5 of the 38 with a positive PET result, and 3 of those remained progression free. Of the other 33 with a negative biopsy, 26 remained free of progression. Thus, the outcome of the biopsy-negative group was similar to that of the PET-negative group with an 81% false-positive rate. To date, data fail to support performing an interim PET scan in patients with DLBCL in clinical practice. Whereas the use of the D5PS has improved standardization of FDG/PET interpretation and comparability among studies, a number of substantive issues still remain. To improve on the discrimination of FDG PET/CT scans, a number of investigators have explored more quantitative methods of interpretation. Lin et al39 conducted a retrospective analysis of interim scans in patients treated on protocols for DLBCL. Their observations suggested that patients with an SUVΔ reduction of greater than two-thirds experienced a greater improvement in PFS than those with lesser decrease, in part resulting from a reduction in the number of false-positive studies associated with visual assessment. Casasnovas et al40 evaluated interim PET scans in patients with DLBCL, and concluded that the combination of the cycle 2 PET scan and the reduction in the SUVmax was preferable to simple visual interpretation alone. In HL, Kostakoglu et al demonstrated the benefit of combining FDG/PET with a reduction in the tumor size determined from contrast-enhanced CT studies.41 However, rather than waiting for treatment to fail, it would be preferable to be able to predict which patients are unlikely

79 to benefit from conventional therapies ahead of time. To this aim, several studies have suggested a strong predictive value for pretreatment metabolic tumor volume in primary mediastinal B-cell lymphoma, DLBCL,42,43 HL,44 and FL.45 This information could provide support for a risk-adapted approach, selecting initial treatment strategies on the basis of metabolic imaging. Over the past few years, a new issue has arisen, which mandated a reconsideration of the Lugano Classification for response assessment. Immune therapy, most notably checkpoint inhibitors, has demonstrated remarkable activity in a variety of solid tumors, and, more recently, in hematologic malignancies as well.31,46 An observation is that a flare reaction occurs in about 15% of patients, which may be confused with progressive disease, leading to premature discontinuation of potentially effective therapy. Immune cells in the microenvironment may be stimulated to create an immune or inflammatory reaction, which would be detected on an FDG/ PET scan. Immune response criteria were developed for solid tumors,47,48 but these may not be considered suitable for lymphomas, which often have disease that is not detectable on a CT scan (eg, bone and bone marrow infiltration, soft tissue involvement). Moreover, discordance in results between FDG/PET and CT may be encountered with a residual CT lesion (a PR by immune response criteria) that is no longer FDG-avid (CR by Lugano criteria). Such potential clinically significant problems led to a workshop co-sponsored by the Lymphoma Research Foundation and the Cancer Research Institute, which resulted in the Lymphoma Response to Immunomodulatory Therapy Criteria.49 These recommendations use a provisional term of indeterminate response to categorize the different types of flare reactions. Patients suspected of a flare reaction may remain on treatment until progressive disease is confirmed by biopsy or by continued growth, or evidence of deterioration. In the future, circulating DNA assays may also be useful in distinguishing flare reactions from progressive disease in Non-Hodgkin lymphoma patients on immunotherapeutic agents such as checkpoint inhibitors.50 However, these criteria are yet to be validated in large imaging data sets. Additional evidence supports an interaction between the microenvironment and the PET results. For example, whereas a PET after 2 cycles of therapy is a strong predictor of outcome in HL, 12% of patients still relapse. Agostinelli et al51 combined interim FDG/PET after 2 cycles (PET2) with a Classification and Regression Tree approach to distinguish PET2-negative patients into 3 distinct risk groups based on pretreatment microenvironment biomarkers. This observation warrants prospective validation. Currently, FDG PET/CT is considered the gold standard for response assessment. Nevertheless, 15%-20% of patients with DLBCL in a metabolic CR will relapse as will 10%15% of those with HL, and almost all of those with FL will exhibit disease recurrence. Thus, identifying companion response assessment strategies is warranted. Studies have shown a correlation between eradication of minimal residual disease in chronic lymphocytic leukemia or small lymphocytic lymphoma as well as FL52 and that FDG PET/CT and minimal

80 residual disease assessment may be complementary,53 but further investigation is necessary to prove this approach. There is growing interest in the use of next-generation sequencing techniques for detecting minimal residual disease and circulating tumor cell DNA for response assessment as well.50 FDG PET/CT imaging has revolutionized the management of patients with lymphoma. It is now considered essential for accurate staging, and has become the foundation of widely adopted response criteria.2,10 Integration of molecular genetic and biomarker studies have the potential to increase the sensitivity and specificity of FDG PET/CT, improve the negative and positive predictive values, and further enhance the contribution of this important imaging modality in the management of patients with lymphoma.

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45.

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