FDG-PET for Early Response Assessment in Lymphomas: Part 1-Hodgkin Lymphoma

Interim positron emission tomography (PET)/CT has shown encouraging results when used as a prognostic tool early in the course of treatment of advanced Hodgkin lymphoma, allowing for a reduction in treatment for patients with favorable characteristics, while suggesting a benefit from changing therapy for those with a positive scan. For patients with limited disease, a negative scan allows for a decrease in treatment; however, the benefits for those patients whose scans are positive are less certain. Here we critically analyze the role of PET/CT in the early assessment of Hodgkin lymphoma. In Part 2, we will review the role of interim PET/CT in diffuse large B-cell lymphoma (DLBCL), and also explore the question of whether new approaches to quantitative assessment improve the prognostic value of interim PET scans in both Hodgkin lymphoma and DLBCL.

Introduction

Hodgkin lymphoma is one of the true success stories of modern hematology/oncology. The cure rate in patients with limited-stage disease is around 95%, and 80% for those with advanced-stage disease, although cure rates are somewhat lower for those with bulky disease at presentation. Nonetheless, the survival of patients with Hodgkin lymphoma is shorter than that of age-matched controls; this difference is due, in large part, to the remote effects of the curative therapy. The use of ¹⁸F fluorodeoxyglucose (FDG)–positron emission tomography (PET)/CT scans has markedly improved the accuracy of staging of patients with Hodgkin lymphoma, resulting in fewer patients being undertreated and fewer overtreated. PET/CT is also considered the gold standard for restaging patients following therapy. However, the increased risk of long-term sequelae from toxic therapy requires better identification of favorable patient subgroups who might be able to achieve prolonged survival with less therapy, while accurately selecting patients who would require alternate approaches for optimal outcome. Current prognostic models appear to fall short with regard to their ability to support a reliable risk-adapted therapeutic strategy.

Nonadapted Interim PET Studies

Interim PET has consistently been shown to be a strong predictor of progression-free survival (PFS) in the setting of standard doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) treatment, with a high negative predictive value (NPV) and a moderate positive predictive value (PPV), particularly in patients with advanced-stage Hodgkin lymphoma.[1-9] In earlier studies, interim PET was found to be superior to the International Prognostic Index (IPI) score in predicting patient outcomes.[1-4] In a meta-analysis of 13 studies involving 360 patients with advanced-stage Hodgkin lymphoma, Terasawa et al showed that the 3-year PFS rate of patients who were PET-positive after 2 courses of treatment (PET-2–positive) and those who were PET-negative after 2 courses of treatment (PET-2–negative) ranged between 12% and 30% and between 90% and 95%, respectively.[5] A positive likelihood ratio (LR) of 28.4 (95% CI, 14.2–56.7), and a negative LR of 0.19 (95% CI, 0.12–0.30) were strongly predictive of superior survival in the interim PET–negative group compared with the interim PET–positive group. However, because of the inadequate number of high-risk (IPI > 4) patients, this analysis may lack the required power to establish external validity in high-risk populations.

While the predictive value of interim PET in advanced-stage Hodgkin lymphoma is well established, its role in limited-stage Hodgkin lymphoma is unclear.[2,10-12] Relapses occur in only 20% to 30% of early-stage Hodgkin lymphoma patients who are interim PET–positive, while in advanced-stage patients the relapse rate is at least twice as high-at 50% to 100%.[1,3,4,6,7,9,13,14] In a recent meta-analysis comprising 1,389 Hodgkin lymphoma patients in 10 studies, Adams et al showed that the pooled sensitivity and specificity of interim PET during first-line chemotherapy were 71% (95% CI, 64.7%–76.4%) and 90% (95% CI, 88.0%–91.6%), respectively.[15] Thus, a negative interim PET result should be considered to be less reliable as a confirmation of treatment success than a positive interim PET result is for identifying treatment failure. These summary estimates of test performance are about 10% lower than the pooled sensitivity and specificity reported in the previous meta-analysis by Terasawa et al.[5] This discrepancy is probably a result of population differences, given that the more recent meta-analysis included both limited- and advanced-stage patients while the prior meta-analysis included only advanced-stage patients. Additionally, the more recent meta-analysis included only those studies that applied standardized reading criteria.[1,16,17] The reliability of a positive interim PET result as a basis for adapting therapies is called into question by the widely varying PPVs among the studies in these meta-analyses (0 to 86%).

Confirming the results of prior studies, in a recent multicenter retrospective cohort of 257 patients with early-stage Hodgkin lymphoma who were treated initially with ABVD followed by involved-field radiation therapy (IFRT), the 5-year PFS rates for PET-2–negative and PET-2–positive patients with a Deauville five-point scale (5PS) score of > 3 were 98% and 84%, respectively, and in patients with a Deauville 5PS score of > 4, 5-year PFS rates were 98% and 79%, respectively (P = .0001).[18] Considering the high survival rates despite a high Deauville score in the PET-2–positive group, it is not convincing that PET-2 has an important prognostic role in early-stage Hodgkin lymphoma.

It is also crucial to realize that the relative efficacy of various treatment regimens has an impact on the performance of prognostic markers. For example, it is notable that in a prospective phase II Cancer and Leukemia Group B (CALGB) study of limited-stage nonbulky Hodgkin lymphoma treated with an experimental regimen of doxorubicin, vinblastine, and gemcitabine (AVG), the 2-year PFS rate was only 88% in the PET-2–negative cohort.[19,20] The lower NPV, as compared with previously mentioned studies, was probably due in part to the lower complete remission (CR) rate achieved with AVG (81%) compared with ABVD (94%).[21] The use of consolidative IFRT as an effective treatment leading to durable CR in the majority of PET-2–positive patients[22] should also be considered when interpreting interim PET results.

The findings of the observational studies just summarized confirm that a positive interim PET result in early-stage Hodgkin lymphoma is unlikely to justify treatment intensification. Also, it is questionable whether assignment of patients to less intensive treatment schemes based on negative interim PET results leads to similar survival rates compared with rates in patients treated with standard therapies. Discussion of the impact on these questions of the results of recently completed randomized trials of interim PET–adapted therapy may be found in the following section.

Combination of Interim PET Results With Other Predictors

Combinatory analysis of interim PET results together with other prognostic variables may improve the predictive value of a positive interim PET result for defining groups possibly at risk for treatment failure. In 88 patients with stage I/II nonbulky Hodgkin lymphoma in the CALGB 50203 trial, Kostakoglu et al reported that when the PET-2 results were combined with tumor size change after 2 cycles of AVG chemotherapy (dCT2), a negative dCT2 (> 65% decrease) in the PET-2–positive group increased PFS by about 30%.[20] The results overall suggested better predictive values when the results of PET-2 and dCT2 were either both positive or both negative. However, some confidence intervals were large because of small sample sizes. Similarly, in a subgroup analysis of PET-positive patients in the HD15 trial of the German Hodgkin Study Group (GHSG), the overall rate of relapse or recurrence in the first year was 11%, but in those patients with the largest reduction in tumor size (> 40%), the rate was only 5%. In contrast, PET-positive patients in whom the tumor size was reduced by < 40% had a relapse rate of 23%, corresponding to a difference in risk of 18 percentage points.[23]

More recently, in a multicenter retrospective study combining PET-2 and end-of-therapy PET results in patients with early-stage Hodgkin lymphoma treated with combined-modality therapy, Ciammella et al found 5-year PFS rates of 97%, 100%, and 82% in the negative/negative, positive/negative, and positive/positive PET groups, respectively.[24] However, in this setting, a treatment change early in the course of therapy would not be possible.

In a recent study in 102 Hodgkin lymphoma patients treated with ABVD, interim PET, CD68+ cell counts, and the presence of B symptoms were independently associated with PFS. Therefore, the evaluation of CD68+ cell counts and B symptoms at diagnosis was suggested to help identify low-risk patients regardless of a positive interim PET result.[25]

Thus, the predictive value of interim PET results may be improved by using other prognostic variables that can potentially lead to better selection of those patients in the cohort with positive interim PET results who have an unfavorable prognosis. However, the preliminary nature and retrospective design of the studies just described warrant further prospective investigations with larger datasets.

The differences in the prognostic utility of interim PET in published studies, particularly in early-stage Hodgkin lymphoma, has stemmed in part from the variable criteria used in the interpretation of PET-based responses. The Deauville 5PS is now an internationally recommended set of criteria for evaluating FDG avidity of the majority of lymphoma subtypes.[17,26] The Deauville 5PS system has been adopted because of its proven reproducibility and improved prognostic value compared with other methods.[27,28]

In summary, interim PET has a demonstrated role in advanced-stage Hodgkin lymphoma, but less of a role in limited-stage disease-due in part to the invariable existence of an inflammatory process within the tumor and the low likelihood of relapse in early Hodgkin lymphoma. These factors lead to high false-positive rates for PET results despite high NPVs for the prediction of PFS.

PET-Adapted Treatment in Hodgkin Lymphoma

The toxicities of current therapies have given rise to interest in risk-adapted treatments in both limited- and advanced-stage disease; risk-adapted treatment would allow the amount of therapy to be reduced in responsive patients, and would facilitate administration of intensified therapy in those for whom treatment was failing. Because of the increased sensitivity and specificity of FDG-PET imaging compared with other imaging modalities, such as CT scans, researchers have focused on the use of FDG-PET to distinguish between more and less responsive patients.

The possibility of risk-adapted treatment spawned numerous clinical trials testing the concept, in limited- and advanced-stage patients (Table). Straus et al of CALGB (now Alliance) treated patients with early-stage, nonbulky disease with 2 cycles of ABVD.[29] Those who became PET-negative were treated with an additional 2 cycles without radiation therapy. Treatment for the PET-positive group was changed to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine (BEACOPP) for 2 cycles, followed by IFRT. The estimated 3-year PFS rate was 92% vs 66% for the negative and positive cohorts, respectively. Using a Deauville 5PS score 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 rate. However, while the data in the PET-positive cohort were better than historical controls, they did not achieve the primary endpoint-unlike the results in the PET-negative group (hazard ratio, 3.84). Radford et al recently published results of the RAPID trial,[30] in which 602 patients with stage IA or IIA disease received 3 cycles of ABVD and then were evaluated with a PET scan. Those who were PET-negative were further randomized to IFRT or no additional therapy. The PET-positive group received a fourth cycle of ABVD and radiation therapy. The 3-year PFS rate was 95% in the PET-negative irradiated group, compared with 91% in the group that did not receive radiation. Although the study did not meet its modified noninferiority boundary, a significant proportion of patients were spared unnecessary radiation. In the European Organisation for Research and Treatment of Cancer (EORTC)/Lymphoma Study Association (LYSA)/Fondazione Italiana Linfomi (FIL) HD10 trial,[31] patients with favorable or unfavorable pretreatment characteristics were randomized to either standard treatment with ABVD and involved-node radiation therapy (INRT), or PET-based treatment (patients with a negative PET scan after 2 cycles received 2 more cycles of ABVD alone [favorable] or 4 cycles [unfavorable], whereas those with a positive scan received BEACOPP plus INRT). After a median of only 1.1 years of follow-up, the PFS rate in the favorable population was higher in the INRT group (100% vs 94.9%); in the unfavorable group, the 1-year PFS rate was 97.3% vs 94.7%, again with the higher value in the group that received INRT. Unfortunately, based on these results, the study was terminated early for futility. Extrapolating from the study of Meyer et al,[32] it would be critical to observe the impact of late complications on overall results in both the RAPID and HD10 trials.

Risk-adapted studies have also been conducted in patients with advanced disease. In the Response-Adapted Therapy in Hodgkin Lymphoma (RATHL) trial, Johnson et al treated 1,214 patients with poor-risk stage II or stage III/IV disease with 2 cycles of ABVD; of these patients, 83.7% had a negative interim PET scan.[33] The patients with negative PET scans were subsequently randomized to ABVD or to doxorubicin, vinblastine, and dacarbazine (AVD), with no subsequent radiation. The 3-year PFS rates for ABVD and AVD were 85.7% and 84.4%, respectively, with overall survival (OS) rates of 97.2% and 97.6%, respectively; there was less toxicity in the AVD-treated patients. In the Gruppo Italiano Terapie Innovative nei Linfomi (GITIL) trial,[34] patients with a negative PET scan after 2 cycles of ABVD were randomized to receive or omit consolidation IFRT to sites of initial bulky disease at the completion of 6 cycles of ABVD. Curiously, the NPV of a PET scan after 2 cycles was lower in the prospective trials than it was in the previously noted retrospective series, perhaps in part reflecting pretreatment factors.

In other studies, BEACOPP was used as the initial treatment. The GHSG conducted the HD15 trial, which involved an initial randomization to induction with escalated BEACOPP (eBEACOPP) or BEACOPP-14.[35] Patients with a negative posttreatment CT scan were observed without further treatment-notably, no radiation. Those with a residual mass of at least 2.5 cm underwent PET scanning; those with a negative scan were observed, while those with a positive scan underwent IFRT. The two cohorts not treated with radiation therapy had similar outcomes, with a 4-year PFS rate of 92%. The number of patients subjected to radiation therapy had thus been reduced from 70% in the HD9 trial to 12% in the HD15 trial, with no reduction in the cure rate. A de-escalation approach was evaluated by the LYSA group: following 2 cycles of eBEACOPP, patients were randomized on the basis of interim PET results to either 4 more cycles of that regimen, or to the less toxic ABVD, with similar outcomes (94% vs 92% 2-year PFS rate).[36]

The second approach taken has been to intensify treatment in those patients with a positive interim scan. Press et al recently reported the results of the Southwest Oncology Group–led US Intergroup study S0816.[37] Patients were treated with 2 cycles of ABVD followed by a PET scan. Those whose scans were negative (Deauville 5PS score of 1–3) received 4 more cycles of ABVD. The 18% whose scans were positive received 6 additional cycles of eBEACOPP. For the entire cohort, the 2-year estimated PFS rate was 79%, with an OS rate of 98%; in the PET-2–positive subset, the PFS rate was promising at 64%. In the RATHL study, the 16% of patients with a positive interim PET scan were randomized to either 4 cycles of eBEACOPP or 6 cycles of BEACOPP-14, with no difference in outcome but with a promising 3-year PFS rate of 68% and an OS rate of 87% across both interim PET–positive cohorts. In patients with limited disease, Raemaekers et al, in the HD10 trial,[38] treated the 19% of patients with a positive interim PET scan with either continued ABVD followed by IFRT or eBEACOPP followed by IFRT; the latter regimen resulted in an improvement in the estimated 5-year PFS rate from 77% to 91%. Zinzani et al recently reported the final results of the Italian HD0801 study,[39] in which 103 of the 512 evaluable patients with a positive PET scan were treated with ifosfamide, gemcitabine, and vinorelbine, followed by autologous stem cell transplantation, with a 76% 2-year PFS rate, regardless of the salvage therapy they received, and despite the fact that about 20% did not receive all planned therapy. These data were interpreted as supporting intensification in the PET-positive patients.

Although no randomized trials have been successfully performed, the aggregate of data would support interim scans in Hodgkin lymphoma to reduce the amount of therapy in patients with negative interim PET scans, and to modify treatment in those with residual tumor. Unfortunately, starting with or changing to BEACOPP is unattractive, given the short- and long-term potential adverse effects of this regimen. Moreover, the approximately 60% long-term PFS rate is still considered unsatisfactory. With the availability of newer, highly active, and less toxic agents, such as brentuximab vedotin[40] and checkpoint inhibitors,[41] alternative strategies should be explored.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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