Interim FDG-PET Imaging in Lymphoma

ARTICLE IN PRESS

Interim FDG-PET Imaging in Lymphoma Andrea Gallamini, PhD,* and Colette Zwarthoed, PhD† In the present article, the authors reviewed the rationale of FDG-PET/CT performed at an interim time point during therapy (iPET), focusing on the transition from standard, anatomical assessment of tumor shrinkage with CT to document a chemotherapy response, to the use of functional imaging with PET to assess chemosensitivity of the individual tumor. The prognostic or predictive role of iPET in different lymphoma subsets has been reviewed, with particular emphasis on early and advanced-stage Hodgkin lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, extranodal natural killer/T-cell lymphoma, and primary mediastinal B-cell lymphoma. A large body of evidence exists in most lymphoma subtypes stressing the role of iPET for early chemotherapy response during first-line chemotherapy treatment, but an increased number of reports have recently been published focusing on the role of iPET in relapsed or refractory lymphoma to predict treatment outcome. Varying patterns of FDG uptake was observed across various lymphoma entities; hence, interpretation of FDG-PET scans should be in the context of the tumor architecture and the prevalence of cellular population, in particular, neoplastic vs non-neoplastic inflammatory cells present in tissue microenvironment. In the second part of the article, the authors reviewed the iPET–response adapted clinical trials and the clinical benefits of this strategy compared to standard non–PET adapted therapy. In particular, the authors extrapolated the reproducibility of FDG-PET image interpretation and the feasibility of a timely treatment adaptation based on FDGPET results in daily clinical practice. This is essential for the reader, as the iPET-adapted strategy has become the standard of care in both early- and advanced-stage Hodgkin lymphoma, and, in the future, probably this strategy will be expanded to primary mediastinal B-cell lymphoma, follicular lymphoma, and peripheral T-cell lymphoma. Semin Nucl Med ■■:■■–■■ © 2017 Elsevier Inc. All rights reserved.

Chemosensitivity as a Predictive Biological Marker in Lymphoma

I

n clinical oncology, the effectiveness of antineoplastic treatment is measured by an improvement in survival. Because the disease relapse or progression invariably heralds death, the currently used surrogate end points used in clinical practice for survival include such measures as time to tumor progression and progression-free survival (PFS). Because cancers typically grow before causing death, dimensional parameters provide readouts of tumor growth. Thus radiological, static imaging has been extensively used to assess therapeutic effects early during treatment or immediately after with the socalled Response Evaluation Criteria In Solid Tumors (RECIST) criteria.1 Predictably, as tumor shrinkage after therapy indicates a better prognosis than an unchanged or an increasing

*Research, Innovation and Statistic Department, A. Lacassagne Cancer Centre, Nice, France. †Nuclear Medicine Department, A. Lacassagne Cancer Centre, Nice, France. Address reprint requests to Andrea Gallamini, PhD, A. Lacassagne Cancer Centre, 33, Rue de Valombrose, 16129 Nice, France. E-mail: [email protected], [email protected]

https://doi.org/10.1053/j.semnuclmed.2017.09.002 0001-2998/© 2017 Elsevier Inc. All rights reserved.

tumor size, these anatomical metrics are predictive of survival in most cancers.2 However, the kinetics of tumor shrinkage and regrowth are not linear; thus, these measures may be misleading. Moreover the high interobserver variability in tumor size assessment by traditional radiological means by CT undermines the reproducibility of these measures.3 The progress in the knowledge of neoplastic cell metabolism and the availability of biological tracers able to track specific tumor metabolic pathways such as tumor glycolysis with FDG has paved the way for the use of functional imaging with PET in tumor staging and restaging. FDG-PET has been proven to be a valuable tool to assess the effect of cytostatic treatment on tumor cell metabolism objectively and quantitatively.4,5 Because metabolic silencing is immediately visible after chemotherapy, preceding tumor shrinkage,6 response assessment with FDGPET could be performed anytime during lymphoma treatment, as early after one7 or two6,8,9 cycles of chemotherapy. Tumor selective avidity of FDG has been allegedly attributed to the “Warburg effect,”10 translating to a several-fold (>200) increased glycolytic activity combined with a glucose-6phosphate trapping within the neoplastic cell. However, more recently, new data have emerged showing that several other 1

ARTICLE IN PRESS A. Gallamini and C. Zwarthoed

2 mechanisms regulate the uptake of FDG by the neoplastic cell, including an m-TOR-mediated increase of transmembrane GLUT-1 protein,11 a direct FDG uptake by microenvironment (ME) cells such as CD8+ tumor-infiltrating lymphocytes and PD1-positive lymphocytes.12 Thus, the heterogeneity of cellular populations present in lymphoma, all of which are characterized by a very high FDG avidity, could increase the complexity of FDG-PET signal interpretation, thus accounting for its variability in outcome prediction. This is particularly evident in lymphoma subtypes showing a different ratio of neoplastic to ME reactive cells: very low in Hodgkin lymphoma (HL) and very high in diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma (PTCL).13,14 Despite its high overall accuracy in predicting treatment outcome, both during15 and after completion of treatment,16 FDG-PET performed at an interim time point during therapy (iPET) cannot discriminate between the presence of residual viable neoplastic tissue and a nonspecific inflammatory host response.17 In fact, in 8%-10% of HL18,19 and up to 15% of patients with DLBCL20, a nonspecific FDG uptake, presumably due to tissue inflammation in response to chemotherapy, accounts for false-positive results on iPET scans. This observation was provisionally coined as minimal residual uptake,18 which later led to the final definition of a complete metabolic response in the current response guidelines. A persistent moderate-degree residual FDG uptake with an intensity equal to that measured over the liver is now considered compatible with a metabolic complete response.21,22

Interim FDG-PET in HL A summary table reports published studies on the predictive value of interim FDG-PET in HL (Table 1).

Advanced-stage HL A multitude of publications consistently and unanimously stressed the role of iPET in predicting long-term outcome after standard treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in advanced-stage HL.6,9,18,27,28,31

iPET performed as early as after one7,30 and more frequently after two6,9,18,27,28,31 cycles of chemotherapy was able to identify a relatively small percentage of patients (18%-20%) with a dismal prognosis, with a 3-year PFS lower than 25%, compared with a 3-year PFS ranging from 85% to 95% in the majority of patients maintained on the original ABVD treatment. In a comprehensive meta-analysis of 13 iPET studies with 360 patients with advanced-stage HL, Terasawa et al showed a sensitivity of 81% and a specificity of 97%, and positive and a negative likelihood ratios of 81% (95% confidence interval [CI] 0.72-0.89), 97% (95% CI 0.94-0.99), 28.4% (95% CI 14.2-56.7), and 0.19% (95% CI 0.12-0.30), respectively.15 Several factors could explain this high performance, which is uncommon for a diagnostic test: ME cells in HL have a very high glucose metabolism, thus FDG avidity,12,32 but are also activated by direct contact with Hodgkin and ReedSternberg cells (HRSC),33 and conversely, their metabolic activity is abruptly shut off by a chemotherapy-induced HRSC kill.34 In other words, ME cells in HL behave as a “power amplifier” of the detection power of persisting viable neoplastic tissues by interim FDG-PET scan.34 The predictive value of iPET on ABVD treatment outcome superseded all other prognostic factors, including the International Prognostic Score.9 Scarce data are available on the predictive role of iPET in advanced-stage HL treated with the more toxic treatment, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). In the pioneer study by Markova et al, in a small cohort of 50 patients treated with escalated BEACOPP (eBEACOPP) and enrolled in the German Hodgkin Study Group (GHSG) HD 15 trial,35 an iPET imaging was performed after four cycles of eBEACOPP (PET-4).26 Fourteen of 50 patients retrospectively included in the study had a positive iPET. After a mean follow-up of 12 months, none of the 36 PET-4-negative patients and only 2 of PET-4-positive patients had a treatment failure; the 1-year PFS was 100% for PET-4-negative patients and 73% for PET-4-positive patients. The negative predictive value (NPV) and positive predictive value (PPV) of PET-4 were 97% and 14%, respectively. The disappointingly low PPV can be attributed to (1) the effectiveness of

Table 1 Published Studies Reporting the Predictive Value of Interim FDG-PET in HL Study Reference

Country

Data Acquisition

Pts. No.

Stage

iPET Interpretation

IPS: 0-2/≥3

Treatment

Gallamini et al 201423 Hutchings et al 20147 Rossi et al 201424

International (IVS) International France

Retrospective Prospective Retrospective

260 126 59

IIA-IVB I-IVB I-IV

5-PS 5-PS ΔSUVmax

189/71 NA 23/36

Filippi et al 201325 Markova et al 200926 Zinzani et al 201227 Cerci et al 201028 Straus et al 201129 Kostakoglu 200630 Gallamini et al 20079

Italy Czech Republic Italy Brazil USA USA Italy and Denmark

Retrospective Retrospective Retrospective Prospective Prospective Prospective Prospective

80 69 304 104 99 23 260

I-IIA IIB-IVA IA-IVB I-IVB IA-IIB NA IIA-IVB

5P-S IHP IHP Mod. IHP IHP Background Mod IHP

NA 44/25 NA 62/42 NA 17/7 195/65

ABVD ± consolidation RT ABVD, BEACOPP, IFRT Anthracycline-based regimen + IFRT ABVD + IFRT BEACOPP ABVD ABVD ± consolidation RT AVG ABVD ABVD ± consolidation RT

BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; IHP, International Harmonization Project criteria; Mod.IHP, modified International Harmonization Project criteria; NA, not available; pts., patients.; RT, radiation therapy.

ARTICLE IN PRESS Interim FDG-PET imaging eBEACOPP to rescue PET-4-positive patients; (2) a high number of false-positive FDG-PET scans due to the criteria used for interpretation; that is, the background FDG uptake was used as a threshold for a positive scan; and (3) the absence of a baseline PET scan to compare the residual activity with that of PET-4. Nonetheless, similar results were published 8 years later as a preliminary result of the PET-positive arm of the HD 18 GHSG trial.36 Four hundred forty out of 1100 (40%) enrolled patients had a positive iPET after two eBEACOPP cycles, upon adoption of a sensitive positive iPET definition with the threshold set as a Deauville score of ≥3. The patients who were iPET-2-positive were then randomized to receive six more courses of eBEACOPP or eBEACOPP supplemented with rituximab. After a median follow-up of 33 months, patients treated with chemotherapy alone or with chemotherapy and immunotherapy had a 3-year PFS of 91.4 (95% CI 87.0-95.7) and 93.0 (95% CI 89.4-96.6), respectively (P = 0.99). This treatment outcome was equivalent or even superior to that of standard eBEACOPP treatment. Again, false-positive results could have accounted for the exceedingly high percentage of iPET-2-positive patients for the same reasons of the Markova study.

Early-stage HL The standard treatment of early-stage favorable and unfavorable HLs is ABVD × 2 or four cycles, followed by involvedfield radiotherapy (IFRT) or involved-node radiotherapy, with delivering doses of 20 or 30 Gy, respectively.37 In both cases, radiotherapy is an essential part, along with chemotherapy of combined-modality treatment (CMT). Increasing concern exists, however, regarding the late and serious effects of radiotherapy, accounting for the main reason of treatmentrelated mortality (TRM) beyond 5 years of follow-up as a result of acute cardiovascular accidents or secondary cancers.38 The latter shows a prevalence that starts to increase 5 years and peaks 40 years after CMT, with a standardized incidence ratio compared to age-matched controls of 4.5%, and a cumulative risk of 48% after 40 years of follow-up.39 Therefore, an unmet need still exists to maintain the highest treatment effectiveness while sparing the toxicity of the CMT strategy. Due to the late incidence of TRM, prospective randomized clinical trials comparing CMT with chemotherapy (CT) alone require a very long follow-up to be published. Moreover, they were based on an updated and relatively obsolete modality of radiotherapy, with extensive fields of radiation and high dose of RT, both of which are no longer used at this writing. On the other hand, patients irradiated with a modern radiotherapy (RT) technology, with dose reduction from 40 to 2030 Gy, extension reduction of irradiated area from extended or involved field to involved nodal and adopting a threedimensional modeling do not have a sufficiently long followup to be compared to the long-term outcome of chemotherapy alone. In adults, the largest study directly comparing CT alone with CMT was the intergroup HD.6 study (NCIC), designed with the aim of comparing chemotherapy alone (4-6 ABVD cycles) to RT only or with two ABVD cycles (according to risk groups), with a subtotal nodal irradiation of 35 Gy.40 After a median follow-up of 11.3 years, the overall survival

3 (OS) rates for CT alone (N = 196) and CMT (N = 203) were 94% and 87%, respectively, whereas the 12-year freedom from progression rates were 87% and 92%, respectively. The results of these studies raised an important debate in the scientific community on the most appropriate treatment for early HL. A patient-based meta-analysis was recently undertaken to compare CMT and CT alone in the GHSG HD10,41 HD11,42 and HD6 trials. On 406 patients who fulfilled the eligibility criteria, CMT was shown to yield better time to progression (hazard ratio [HR] = 0.44); PFS was superior without reaching statistical significance, and the OS was not different.43 Due to the similarity in the long-term results of these different therapeutic strategies, an earlier superiority of CMT was offset by a higher TRM compared with CT alone; hence, omitting RT is still questionable. The optimal treatment option between CMT and CT is particularly difficult in young females with a bulky mediastinal mass because of the associated high risk of secondary breast cancer developing after exposure to RT. Furthermore, iPET proved useful in the prediction of treatment outcome in early-stage HL, albeit with a lower specificity and PPV.37 Although a number of phase 3 studies have recently explored the role of iPET in comparing the longterm treatment outcome of CMT vs CT alone in low-risk, iPETnegative patients (see further), no definite conclusions could be drawn to change current strategies of treatment planning in early-stage HL.37 The results of iPET should be reviewed in the context of other prognostic factors at baseline and the long-term risk of RT and treatment escalation or de-escalation.

Relapsed Refractory HL The standard treatment for relapsed, refractory HL (r/rHL) is high-dose chemotherapy followed by an autologous stemcell transplant (ASCT).44,45 In a recent international prognostic multivariable modeling study (RISPACT study) involving 656 patients with r/rHL undergoing ASCT between 1993 and 2013, Brockelmann et al reviewed the impact of 23 potential risk factors on long-term treatment outcome. The multivariate analysis identified stage IV disease at relapse, a time to relapse of <3 months, an Eastern Cancer Operative Group (ECOG) performance status of >1, a nodal bulk mass of >5 m, and an inadequate response to salvage chemotherapy by CT or FDG-PET as the only factors significantly associated with a lower OS46.46 The iPET performed immediately before ASCT was found to be an accurate tool to predict treatment outcome. In a pooled analysis by Poulou et al in a series of 386 patients with r/r HL or NHL, the HR for a positive vs a negative PET before ASCT for the time to event heralding disease progression was 3.83 (95% CI 2.14-4.87). When the analysis was restricted to six studies providing information on OS, the results also favor a higher risk of death in patients with a positive PET with an HR of 4.53 (95% CI 2.50-8.22).47 These observations underpinned a number of PET–response adapted therapeutic approaches in r/r HL undergoing ASCT for salvage treatment: in a phase 2 pilot study on 46 patients with r/rHL, Moskowitz et al administered four doses of brentuximabvedotin at a dose of 1.8 mg/kg and assessed patient chemosensitiveness immediately after with iPET: 12 patients were PET-negative and processed immediately to

ARTICLE IN PRESS A. Gallamini and C. Zwarthoed

4 ASCT, 33 were PET positive, and 1 withdrew the consent. PET-positive patients were treated with two cycles of augmented-ICE (ifosfamide, carboplatin, and etoposide) and a second iPET performed afterward: 22 had a negative FDGPET scan and 11 a positive FDG-PET scan. Overall, 74% achieved a negative pre-ASCT PET. The 2-year event-free survival (EFS) rates of PET-negative and PET-positive patients before ASCT were 95% and 46% (P = 0.007)48 (Fig. 1).

Interim FDG-PET in DLBCL A summary of studies on the predictive role of interim FDGPET scan in DLBCL is shown in Table 2. The interest for early chemosensitivity assessment in DLBCL started in the same time frame as the HL studies with the seminal article of Haioun et al. The predictive value of the treatment outcome of iPET after two cycles of chemotherapy was studied in a cohort of 90 patients with DLBCL treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or with a CHOP-like regimen with or without rituximab.8 At the end of the treatment, 83% of the iPET-negative and 58% of the iPET-positive patients reached a complete remission, with a 2-year estimate of PFS of 82% and 43%, respectively (P < 0.001) and a 2-year OS of 90% and 61%, respectively (P = 0.006). Since then, several studies have been published focusing on the role of iPET in PFS or OS prediction, with conflicting results. Nonetheless, the NPV of iPET was unanimously reported greater than 80%, while the PPV proved as low as 15%.58 (Fig. 2). Several factors could explain these contradictory results: (1) Phenotypic and genotypic heterogeneity of DLBCL: At least three separate entities have been considered in the broad DLBCL category: germinal B center, activated B cell, and

primary mediastinal B-cell lymphoma (PMBCL); these three subtypes show different chemosensitivities, different kinetics of cell cycle, and different sensitivities to new agents such as lenalidomide or ibrutinib. (2) Timing of interim scanning: The iPET imaging in DLBCL was performed as early as after one cycle30 or as late as after four cycles in the interim setting.59 Although the decrease in tumor glucose metabolism with treatment may be a surrogate marker of treatment efficiency,60 the latter is a continuous, nonlinear process, and the signal generated on PET is the sum of inflammatory changes due to chemotherapy effects and FDG uptake by the tumor regrowth.61 (3) Time between chemotherapy and iPET: An iPET should not be performed earlier than 10 days after CT, to avoid the “stunning” effect of therapy on tumor cells62 and not earlier than 13-14 days after last CT cycle to avoid a nonspecific FDG uptake due to CT-induced inflammation.63 (4) Interpretation criteria: Visual criteria adopting the fivepoint Deauville scale (5-PS) were first proposed for iPET interpretation in DLBCL,21 but different reference values for a positive scan were adopted. The degree of CTinduced inflammation in DLBCL was significantly variable, thus different reference values were proposed to define a positive scan.8,21,64 As a result, the overall accuracy in predicting the treatment outcome upon adopting visual criteria was disappointingly low, mainly due to a PPV as low as 13%.50 5-PS defined a positive scan with a cutoff score of >3, identical to that proposed for HL. However, upon adoption of this threshold, the PPV was found to be exceedingly low, ranging between 13% and 34%.50,65 After resetting the positivity threshold between scores 4 and 5, the PPV improved from 34.9% to 71.4%. 65 Semiquantitative methods based on direct

Table 2 Published Studies Reporting the Predictive Value of Interim FDG-PET in DLBCL Study Reference

Country

Data Acquisition

Pts. No.

Stage

iPET Key

IPI: 1-2/3-4

Treatment

Haioun et al 20058 Lin et al 200720 Itti et al 201049 Moskowitz et al 201050 Horning et al 201051 Pregno et al 201252 Safar et al 201253

France France France USA

Retrospective Retrospective Retrospective Prospective

90 92 92 98

IA-IVB I-IVB I-IV III-IV

37/53 38/54 23/36 21/78

CHOP or ACVBP ± rituximab CHOP or ACVBP ± rituximab CHOP or ACVBP ± rituximab R-CHOP

USA

Prospective

12

i-IV

NA

R-CHOP

Italy France

Prospective Prospective

88 112

I-IV II-IV

53/35 45/67

Itti et al 201354

Italy, France

Retrospective

114

III-IVA

3-PS ΔSUVmax 140% liver SUVmax Surrounding background ECOG criteria, London criteria 5-PS Background ΔSUVmax 5-PS ΔSUVmax

Carr et al 201455

International

Prospective

327

I-IVB

Mamot et al 201556

Switzerland

Prospective

138

I- IVB

216/ 111 78/40

Mikhaeel et al 201657

UK

Prospective

147

I-IVB

Negative-MRU Positive-mixed 5-PS ΔSUVmax 5-PS ΔSUVmax

R-CHOP R-CHOP R-ACVBP R-CHOP R-ACVBP R-CHOP

ACVBP, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone.

40/74

63/84

R-CHOP R-CHOP

Interim FDG-PET imaging

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Figure 1 PFS in DLBCL according to interim PET results.

5

ARTICLE IN PRESS A. Gallamini and C. Zwarthoed

6

Figure 2 Kaplan-Meier curve of event-free survival after second-line treatment in relapsed or refractory HL according to interim PET status. (Adapted with permission from Moskowitz et al.48)

maximum standardized uptake value measurement (SUVmax) and SUVmax variation (ΔSUVmax) showed a higher specificity and PPV based on a retrospective analysis.14,20,59 However, due to the lack of standardization of the technical aspects of PET image generation, the reproducibility was not high in prospective studies. In fact, in an international prospective trial, the FDG uptake time measured was longer than that reported in the Dicom header, with a delay ranging between 1 minute to 1 hour in 31% of the cases.66 Mamot et al recently published the results of a prospective multicenter trial, SAKK 38/07, aimed at assessing the prognostic predictive role of iPET in patients with DLBCL treated with R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab).56 One hundred thirtyeight patients were consecutively enrolled: iPET was performed after two (PET-2), four (PET-4), and six (PET-6) cycles of R-CHOP, and no treatment change was allowed based on the iPET results. FDG-PET images were centrally reviewed by visual assessment and semiquantitatively by using 5-PS and SUVmax, respectively. By central review, using the 5-PS criteria, the 2-year EFS was 41.4% (95% CI 28.7-53.6) for PET2-positive patients and 75.9% (95% CI 63.7-84.5) for PET-2-negative patients. The 2-year OS was statistically different only in the ΔSUVmax analysis, 73.7% for PET-2positive patients and 91.3% for PET-2-negative patients (P = 0.03). However, the predictive role of iPET-2 was superseded by PET-6, which was found to be the most powerful predictor of treatment outcome in the trial: the 2-year EFS for PET-6 positive and PET-6 negative cases were 24.0% and 71.5%, respectively (P < 0.001). The authors concluded that iPET

failed to yield a high NPV and PPV in DLBCL, and only end-of-treatment PET should be considered for treatment alteration decisions. In conclusion, despite a number of positive studies that consistently reported on the prognostic and predictive role of iPET on DLBCL treatment outcome, the overall predictive value was lower than that of HL. No trial has, thus far, demonstrated the superiority of the iPET-driven strategy over the conventional methodology in DLBCL.61

Interim FDG-PET in Other Lymphoma Entities PTCL is a heterogeneous group of lymphoma entity affecting primarily lymph nodes or extranodal organs or both characterized by a widespread presentation, an aggressive clinical course, a poor response to treatment, and an invariably dismal prognosis.67 More than one-third of patients are chemoresistant and do not respond to first-line treatment, whereas another third relapse or progress at the end of firstline (aggressive) treatment, and no more than 40% are cured.68 Thus an unmet need still exists for a tool able to identify patients who will experience a treatment failure. Conflicting results have been reported on the predictive value of iPET: in the Danish series, iPET was performed after two or three cycles using 5-PS; patients scored 1-3, and 4-5 had a 2-year PFS of 63%, and 64%, respectively.69 On the other hand, in a large, retrospective cooperative international experience on 140 nodal PTCLs, using the same criteria for PET reading and including also the Danish patients, Cottereau et al70 reported that iPET performed after two cycles (PET2) was able

ARTICLE IN PRESS Interim FDG-PET imaging

7

to identify two cohorts of patients with an impressive statistically different PFS and OS. The 2-year PFS for iPETnegative and iPET-positive patients were 73% and 6% (P < 0.0001, HR 6.8), and 2-year OS rates were 84% and 22% (P < 0.0001, HR 6.6), respectively. Upon combining iPET with metabolic tumor volume at baseline, the authors were able to construct a prognostic model to identify patients with a 2-year PFS of 79%, 59%, 42%, and 0%. A separate group of investigators reported similar results, adopting visual assessment with 5-PS. Interestingly, the best cutoff was between scores 2 and 3 to predict PFS, and between scores 3 and 4 to predict OS.71 In PMBCL, the CMT, consisting on immunochemotherapy (R-CT) upfront followed by consolidation RT, has long been considered the gold standard therapeutic strategy. iPET between chemotherapy and RT is performed to assess the response to R-chemo, to predict treatment outcome, and even to avoid RT in favorable-risk patients.72 In the International Extranodal Lymphoma Study Group (IELSG)-26 study, 115 PMBCL patients underwent iPET after rituximab-supplemented CT and before RT: patients with scores 1-3 and scores 4-5 had a 5-year PFS of 99% and 68% (P < 0.001) and a 5-year OS of 100% vs 83% (P < 0.001), respectively.30 In a more recent study and in a smaller cohort 53 PMBCL patients treated with CMT, after a median follow up or 51 months, only six patients relapsed, and five of them had a DS score of 5 in the final, postRT PET. The authors concluded that a cutoff between scores 4 and 5 and a SUVmax of >5 identified patients with a poor outcome with a highly statistical difference (log-rank P < 0.001).73 Preliminary reports seem to suggest a predictive role on the treatment outcome of iPET in extranodal natural killer/ T-cell lymphoma, nasal type undergoing iPET after CMT, and before the second block of chemotherapy.74 Upon adoption of the 5-PS analysis and a threshold for a positive scan between

scores 3 and 4, the 2-year PFS for a positive and a negative iPET in a small cohort of 68 extranodal natural killer/T-cell lymphoma patients were 31.3% and 72.4%, respectively (P < 0.001). These data have been confirmed in an independent cohort of patients treated with L-asparaginase.75

Interim FDG-PET-guided Clinical Trials Hodgkin Lymphoma An overview of the published trials on iPET–response adapted therapy in HL is shown in Table 3. In the 50604 study, on behalf of the U.S. Alliance group, patients with early-stage, nonbulky HL were treated with two ABVD courses followed by iPET; patients with a negative iPET-2 (5-PS score of 1-3) continued with ABVD, patients with a positive iPET-2 switched to BEACOPP × 2 cycles followed by IFRT. With a primary end point of a 3-year PFS of ≥85% for iPET-2negative patients, the main objective of the trial was met, being the 3-year PFS of PET-2-negative patients of 92%; however, the difference in HR between iPET-2-negative and positive cohorts was 6.06, which was far beyond the maximum interval of HR allowed by the secondary end point: an HRΔ of ≤3.54.76 Recently, the final results of the U.K. RAPID trial have been published. Briefly, stage I-IIA nonbulky patients were treated with 3 ABVD courses and an iPET-3 was performed: iPET-3 negative were randomized to IFRT or no further treatment (NFT); iPET-3 positive continued with one more ABVD, followed by IFRT. With a statistical design on noninferiority of NFT vs IFRT arms, and with a noninferiority margin of 3-year PFS of −7% in the iPET-3 negative cohort, the 95% CI intervals of the NFT arm fell below the noninferiority margin and the study end point was not met,

Table 3 Interim PET Response-adapted Clinical Trials in HL Trial

Stage

PET2+ PET2+ PET2 Initial (n) (%) Key Therapy

CALGB 5604 EORTC H10 (exp.) EORTC 10 (St.) NCRI RATHL GITIL HD0607 SWOG S0816 FIL HD0801

I/II

14

9

5-PS

I/II

361

19

IHP

I/II

954

ABVD × 3 (F) − 4 (U) + INRT

II adv. 182 III-IV IIB-IVB 150

16

5-PS

19

5-PS

III-IV

60

18

5-PS

IIB-IVB 103

20

IHP

Treat. PET2+

Treat. PET2-

F-UP PFS PFS (y) PET2+ PET2− (%) (%)

ABVD × 2 BEACOPP × 2 + INRT

ABVD × 2

2.1

66

92

ABVD × 2 BEACOPP × 2 + INRT

ABVD × 2/4

5

90.6

5

77 67

87 (F), 90 (U) 99 (F), 92 (U) 85.7 84.4

60

87

64

79

74

81

ABVD × 2 BEACOPP × 4

ABVD × 4 3.4 AVD × 4 ABVD × 2 BEACOPP × 4 + 4bas. ABVD × 4 ± RT 3.6 ± rituximab ABVD × 2 BEACOPP × 6 ABVD × 4 + RT 2 ABVD × 2 IGEV × 4 + ASCT ± ASCT +Allo SCT

ABVD × 4 ± RT 2.1

Allo SCT, allogeneic stem cell transplantation; CALGB, Cancer and Acute Leukemia Group-B; EORTC, European Organization for Study and Treatment of Cancer; F, favorable; FIL, Italian Foundation on Lymphoma; F-UP, follow-up; GITIL, Gruppo Italiano Terapie Innovative nei Linfomi; IGEV, ifosfamide, gemcytabine, and vinorelbine; NCRI, National Cancer Research Institute; PET2 key, interpretation schema of interim PET scan; PET2−, negative interim PET after two chemotherapy cycles; PET2+, positive interim PET after two chemotherapy cycles; U, unfavorable.

ARTICLE IN PRESS 8 although the difference in PFS was not statistically different (P = 0.16).77 Similar results were reached by the French Lymphoma Study Association (LYSA) Italian Foundation on Lymphoma (FIL) European Organization for Radiotherapy and Treatment of Cancer (EORTC) Study H10, aimed to assess the role of escalating or de-escalating treatment based on iPET results after two ABVD courses compared with standard treatment, in both early favorable and early unfavorable HLs, according to EORTC criteria.78 While the superiority or the treatment intensification with BEACOPP escalated ×2 courses followed by IFRT (N = 169) was evident in the cohort of iPET2-positive patients (N = 361) compared with standard ABVD arm + IFRT (N = 192), with a PFS of 90.6% (95% CI 84.794.3) vs 77.4% (95% CI 70.4-82.9), P = 0.002, in the iPET2-negative the non-inferiority of radiation-free treatment could not be claimed for futility. However, in an intention-to-treat analysis, the long-term disease control of CMT vs CT only was not significantly different both in the favorable (N = 465) cohort, with 5-year PFS rates of 99.0% and 87.1%, respectively, and unfavorable (N = 594) cohort, with 5-year PFS rates of 92.1% and 89.6%, respectively.79 Taken together, these two large trials point toward a limited benefit of the CMT modality in iPET-2-negative patients, which is offset by an expected higher TRM 20 years and beyond the end of treatment. With a very high rescue rate of second-line treatment in early-stage HL,77,79 clinicians should be cognizant of the cost-effectiveness ratio of both therapeutic strategies. A similar scenario with the same tradeoff between effectiveness and toxicity held the stage for long in advancedstage HL, and iPET, superseding International Prognostic Index in predicting ABVD treatment outcome,9 offered new opportunities for treatment intensity adjustment. As a consequence, several PET-adapted clinical trials have been launched to assess the clinical effectiveness of this approach compared with standard ABVD treatment, to reduce the distance, in terms of PFS of ABVD vs eBEACOPP.34,35,80,81 Three prospective clinical trials explored the feasibility and effectiveness, in terms of 3-year PFS for the entire patient population of switching to BEACOPP escalated in case of a positive iPET after 2 ABVD cycles, while continuing with ABVD in iPET-negative patients: the U.K. RATHL study, the Southwest Oncology Group (SWOG)CALG-B S016, and the Italian GITIL/FIL HD0607.82-84 Overall, more than 2000 patients were enrolled and critical information from these trials is now available: (1) the 5-PS was confirmed to be reproducible and practical, as the percentage of iPET-2-positive patients was 16%, 18%, and 19%, respectively; (2) eBEACOPP was able to rescue iPET-2positive patients, resulting in a 3-year PFS of 67%, 64%, and 60%, respectively; (3) the overall long-term disease control proved superior to standard ABVD, in terms of 3-year PFS and OS for the entire cohort of patients, being 82.6%, 79%, and 82%, and 95.8%, 98%, and 96%, in the RATHL, SWOG S016, and HD0607 trials, respectively; and (4) treatment with standard ABVD in iPET-2-negative patients proved slightly inferior than expected (90%-95% in retrospective trials), with a 3-year PFS of 85.1%, 82%, and 87%, respectively. The feasibility and effectiveness of treatment de-escalation in iPETnegative patients after eBEACOPP upfront therapy have been

A. Gallamini and C. Zwarthoed the primary end point of two large cooperative trials on behalf of the GHSG and the LYSA groups: the HD 18 and the Advanced Hodgkin Lymphoma (AHL 2011) trials.36,85 In both trials, an iPET is performed after two BEACOPP escalated cycles: patients with a positive scan continue with standard BEACOPP escalated-21, patients with a negative iPET-2 are treated either with an abbreviated BEACOPP regimen (two more cycles only, in the GHSG 18 Trial) or switch to ABVD (LYSA AHL trial). In both cases, treatment outcome in the abbreviated treatment of i-PET-2 negative arm superimposable to the standard BEACOPP regimen, thus confirming that standard BEACOPP is indeed an overtreatment for iPET-2negative, standard-risk HL.

Diffuse Large B-cell Lymphoma Despite the demonstration that early chemo-sensitiveness assessment in DLBCL has a prognostic/predictive relevance,61 no convincing data exist, at this writing, that a iPET-driven strategy could improve the long term disease control in this lymphoma subset. Nonetheless, it is conceivable that a iPETdriven strategy would lead to an improvement in the longterm disease control in DLBCL.59 Two prospective studies have been published, which failed to show a clinical benefit for patients in a treatment intensifying treatment protocol, based on a positive iPET.86,87 In the PETAL trial, 779 out of 1072 aggressive CD20-positive patients with DLBCL were treated with two cycles of R-CHOP-14: iPET-2-positive patients (defined by a ΔSUVmax of <66%) were randomly assigned to continue with R-CHOP or to switch to an intensified treatment with an acute leukemia-like schedule of drugs. Although iPET-2 retained its prognostic meaning, with a 2-year TTF of 77% vs 40% for iPET negative or positive, respectively (P < 0.0001), the 2-year TTFs of patients treated with R-CHOP and acute leukemia (AL)-like were 36% and 22%, respectively.86 In a prospective multicenter Australian trial, 151 aggressive NHL, with an International Prognostic Index (IPI) score of 2-5 or IPI 0-1 with a bulky lesion of ≥7.5 cm were treated with R-CHOP-14 regimen for four cycles, followed by an iPET. Out of 42 iPET-positive patients, 39 were rescued with high-dose chemotherapy with ICE (Ifosfamide, Cisplatinum, and etoposide), followed by 90Y ibritumomab tiuxetan (Zevalin) and BEAM (carmustine, etoposide, ARAC, melphalan, and ASCT). Those patients who were negative on iPET were treated with two further R-CHOP courses and two rituximab consolidation doses. At a median follow-up of 35 months, the 2-year PFS of iPET-positive and iPETnegative patients were 67% and 74%, respectively (P = 0.11).87

Interim PET in Routine Clinical Practice The latest updated recommendations including interim and end-of-treatment PET interpretation are part of the socalled the Lugano criteria for response assessment in lymphoma.88 One of the crucial points of these criteria is the use of the 5-PS, recommended both in clinical trials and in daily clinical practice.

ARTICLE IN PRESS Interim FDG-PET imaging Historically, this scale has been proposed during the First International Workshop on iPET in Lymphoma held in Deauville, France, in 2009.89 Subsequently, 5-PS was introduced in clinical trials. The International Validation Study (IVS) retrospectively reconfirmed and validated its accuracy,90 and this effort provided further support to the design of PET-adapted prospective trials in HL.76,77,79,82-84 Due to the high concordance of results in the previously mentioned studies, iPET has been progressively adopted in clinical trials and in daily clinical practice. However, the use of 5-PS can still raise questions because of the possible risk of false positive results and the attendant risk of overtreatment.91 The potential subjective interpretation of these visual criteria is still debated. Biggi et al analyzed the interobserver reproducibility of the 5-PS in the IVS90; in this study, six nuclear medicine experts from five countries reviewed iPET after two courses of ABVD in 260 patients with HL. Independent agreement was reached in 97% of the patients. All six reviewers agreed in 82% of the cases. The discordant cases were due to difficulties to distinguish the physiological from the pathologic FDG uptake (cardiac, brown fat, gut), or due to the presence of parotid adenoma, pathologic fracture, or very low liver uptake reference. The Cohen κ for the agreement between pairs of reviewers ranged from 0.69 to 0.84 (“good and very good”). The overall agreement among reviewers was excellent (Krippendorff α of 0.76). After the final consensus session, the PPV and the NPV of iPET were 0.73 and 0.94, respectively. A more recent prospective PET-adapted trial in PMBCL92 showed the effect of training upon concordance reviewers rates: the review panel (six experienced nuclear physicians) used the 5-PS with a score of 3 as the cutoff for a complete metabolic response, with an overall interobserver agreement among the reviewers similar to the IVS study (Krippendorff α = 0.72.); this agreement, initially moderate, improved progressively from phases 1 to 4 of the study (Krippendorff α from 0.53 to 0.81, Cohen κ from 0.35-0.72 to 0.77-0.87), which indicates that a training exercise and practical rules help to improve iPET interpretation. Another tool for improving iPET reproducibility might be the quantitative analysis, with SUVmax or SUV-derived metrics such as ΔSUVmax, metabolic tumor volume, or total lesion glycolysis. As PET is an intrinsically quantitative method and visual assessment has shortcomings, quantitative assessment may overcome these problems.91 Several published studies showed that the PPV of iPET improved by using ΔSUVmax compared with standard visual assessment with 5-PS.24,54 The quantitative PET value introduced by the group of Leipzig, Germany, is another potential quantitative measurement: it is the quotient of the SUVpeak of the hottest residual uptake over the SUVmean of the liver.93 Some recent data also suggest that the combination of 5-PS with baseline total lesion glycolysis,94 or the use of a SUVmax-liverbased interpretation,95 could improve the iPET performance. However, at this time, the quantitative metrics to accurately determine the metabolic response are yet to be validated and optimized. The variability in PET scanner calibration procedures, image generation and acquisition protocols, image reconstruction algorithms, and timing and intensity of the given

9 treatment should be standardized for an improved quantitative assessment.

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