Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is the most accurate tool for staging, treatment monitoring, and response evaluation in Hodgkin lymphoma (HL). Early determination of treatment sensitivity by FDG-PET is the best tool to guide individualized, response-adapted treatment. Several ongoing or recently completed trials have investigated the use of FDG-PET/CT for early response-adapted HL therapy. The results are encouraging, but the data are immature, and PET response–adapted HL therapy is discouraged outside the setting of clinical trials. PET/CT looks promising for selection of therapy in relapsed and refractory disease, but the role in this setting is still unclear.
Key points
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Fluorodeoxyglucose (FDG) positron emission tomography (PET) performed during or after chemotherapy is the strongest predictor of outcome in Hodgkin lymphoma.
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A large number of active trials have investigated the value of early PET response–adapted Hodgkin lymphoma therapy.
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Preliminary reports from recently completed trials are encouraging, but data are immature, and the use of PET response–adapted therapy is discouraged outside clinical trials.
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Postchemotherapy FDG-PET/computed tomography is a safe tool to identify advanced patients without the need for consolidation radiotherapy.
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Standardized image acquisition and image interpretation criteria are essential for the value and the use of interim FDG-PET.
Introduction
The Hodgkin Lymphoma Therapeutic Dilemma
The treatment of patients with Hodgkin lymphoma (HL) requires a delicate balance between high treatment efficacy and acceptable acute and late treatment-related toxicity. Overall long-term survival from HL exceeds 80% with modern therapy. These excellent cure rates are a result of the high chemosensitivity and radiosensitivity of the disease, of the evolution of cytotoxic drugs and radiotherapy techniques but also of important developments in staging accuracy, identification of prognostic factors, and optimization of treatment according to well-defined risk groups. However, the efficacy of treatment is hampered by serious long-term adverse effects, including heart and lung disease, and secondary malignancies. As a consequence of these acute and late toxicities, patients with HL have an excessive mortality. At 15 years following treatment, the risk of death from HL is overtaken by the risk of death from other causes. The most important goal of contemporary clinical HL research is to address this problem and to optimize the balance between efficacy and toxicity. In order to reduce the long-term effects of treatment, therapeutic strategies are becoming more tailored to the individual patient’s disease profile and other clinical characteristics. The aim is to maintain and improve the high cure rates while reducing therapy-related morbidity and mortality.
Patients with early-stage disease have a chance of cure that exceeds 90% when treated with combined-modality treatment (ie, chemotherapy followed by radiotherapy to the initially involved lymph nodes or lymph node regions). With such high cure rates, it is more than likely that a substantial proportion of patients could be treated with less therapy than is currently considered standard practice. In the light of the serious long-term morbidity and mortality attributed to radiotherapy, it is desirable to identify the patients who might be cured with less treatment burden, particularly without radiotherapy.
In advanced-stage disease, around two-thirds of patients can be cured with 6 to 8 cycles of the Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) combination. Patients who have primary refractory disease or who relapse after first remission may be cured by high-dose salvage regimens, but 20% to 25% of ABVD-treated advanced-stage patients still die of treatment-resistant or relapsed HL. In comparison, the more intensive and more toxic bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPPesc) regimen yields significantly higher cure rates. However, treating all patients with advanced-stage HL with BEACOPPesc means overtreatment of most patients, who would have been cured with ABVD.
However, the existing pretreatment prognostic scoring systems are not strongly predictive. There are therefore no pretreatment predictive markers to safely identify those patients who are more likely to be cured with less therapy on, and those patients who require more intensive treatment, both in early-stage and advanced-stage disease.
Fluorodeoxyglucose Positron Emission Tomography in HL
A more patient-tailored treatment may be achieved by more refined and risk-adapted selection of up-front therapy and by subsequent treatment modifications that reflect the individual patient’s treatment sensitivity and response. The optimal up-front therapy selection demands precise determination of the initial disease extent, and, for this purpose, staging positron emission tomography (PET)/computed tomography (CT) has been accepted as the gold standard method in HL. Over the last 15 years, positron PET using 2-[18]fluoro-2-deoxyglucose (FDG) has gained widespread use in most lymphoma subtypes. Stand-alone FDG-PET has largely been replaced by combined scanners, in which FDG-PET and CT are performed in 1 scanning session, resulting in fusion PET/CT displaying pathologic anatomy and tumor physiology/metabolism in combined images. The European Society of Medical Oncology clinical practice guidelines and the National Comprehensive Cancer Network guidelines recommend the use of PET/CT for primary staging and final response evaluation in patients with HL. Furthermore, it is generally agreed that the modern and highly conformal radiotherapy volumes that have become standard in HL are only safe when based on the most accurate baseline imaging (ie, PET/CT).
After initiation of chemotherapy, and in the absence of strong pretreatment predictive markers, an early assessment of treatment sensitivity may allow identification of patients with low treatment sensitivity who might benefit from escalation to more aggressive therapy, and also of patients with high treatment sensitivity who could be cured with less than standard therapy. After completion of chemotherapy, a reliable response assessment is crucial to guide further management, including consolidation radiotherapy, follow-up, and salvage therapy in cases of refractory or relapsed disease.
Numerous studies have shown that PET/CT provides the most reliable assessment of chemosensitivity and response during and after completion of HL therapy. As a result, the method plays an important role in current efforts to further optimize therapy. This article addresses the role of FDG-PET/CT for response-adapted HL therapy, both in the first-line setting and in relapsed disease.
Introduction
The Hodgkin Lymphoma Therapeutic Dilemma
The treatment of patients with Hodgkin lymphoma (HL) requires a delicate balance between high treatment efficacy and acceptable acute and late treatment-related toxicity. Overall long-term survival from HL exceeds 80% with modern therapy. These excellent cure rates are a result of the high chemosensitivity and radiosensitivity of the disease, of the evolution of cytotoxic drugs and radiotherapy techniques but also of important developments in staging accuracy, identification of prognostic factors, and optimization of treatment according to well-defined risk groups. However, the efficacy of treatment is hampered by serious long-term adverse effects, including heart and lung disease, and secondary malignancies. As a consequence of these acute and late toxicities, patients with HL have an excessive mortality. At 15 years following treatment, the risk of death from HL is overtaken by the risk of death from other causes. The most important goal of contemporary clinical HL research is to address this problem and to optimize the balance between efficacy and toxicity. In order to reduce the long-term effects of treatment, therapeutic strategies are becoming more tailored to the individual patient’s disease profile and other clinical characteristics. The aim is to maintain and improve the high cure rates while reducing therapy-related morbidity and mortality.
Patients with early-stage disease have a chance of cure that exceeds 90% when treated with combined-modality treatment (ie, chemotherapy followed by radiotherapy to the initially involved lymph nodes or lymph node regions). With such high cure rates, it is more than likely that a substantial proportion of patients could be treated with less therapy than is currently considered standard practice. In the light of the serious long-term morbidity and mortality attributed to radiotherapy, it is desirable to identify the patients who might be cured with less treatment burden, particularly without radiotherapy.
In advanced-stage disease, around two-thirds of patients can be cured with 6 to 8 cycles of the Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) combination. Patients who have primary refractory disease or who relapse after first remission may be cured by high-dose salvage regimens, but 20% to 25% of ABVD-treated advanced-stage patients still die of treatment-resistant or relapsed HL. In comparison, the more intensive and more toxic bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPPesc) regimen yields significantly higher cure rates. However, treating all patients with advanced-stage HL with BEACOPPesc means overtreatment of most patients, who would have been cured with ABVD.
However, the existing pretreatment prognostic scoring systems are not strongly predictive. There are therefore no pretreatment predictive markers to safely identify those patients who are more likely to be cured with less therapy on, and those patients who require more intensive treatment, both in early-stage and advanced-stage disease.
Fluorodeoxyglucose Positron Emission Tomography in HL
A more patient-tailored treatment may be achieved by more refined and risk-adapted selection of up-front therapy and by subsequent treatment modifications that reflect the individual patient’s treatment sensitivity and response. The optimal up-front therapy selection demands precise determination of the initial disease extent, and, for this purpose, staging positron emission tomography (PET)/computed tomography (CT) has been accepted as the gold standard method in HL. Over the last 15 years, positron PET using 2-[18]fluoro-2-deoxyglucose (FDG) has gained widespread use in most lymphoma subtypes. Stand-alone FDG-PET has largely been replaced by combined scanners, in which FDG-PET and CT are performed in 1 scanning session, resulting in fusion PET/CT displaying pathologic anatomy and tumor physiology/metabolism in combined images. The European Society of Medical Oncology clinical practice guidelines and the National Comprehensive Cancer Network guidelines recommend the use of PET/CT for primary staging and final response evaluation in patients with HL. Furthermore, it is generally agreed that the modern and highly conformal radiotherapy volumes that have become standard in HL are only safe when based on the most accurate baseline imaging (ie, PET/CT).
After initiation of chemotherapy, and in the absence of strong pretreatment predictive markers, an early assessment of treatment sensitivity may allow identification of patients with low treatment sensitivity who might benefit from escalation to more aggressive therapy, and also of patients with high treatment sensitivity who could be cured with less than standard therapy. After completion of chemotherapy, a reliable response assessment is crucial to guide further management, including consolidation radiotherapy, follow-up, and salvage therapy in cases of refractory or relapsed disease.
Numerous studies have shown that PET/CT provides the most reliable assessment of chemosensitivity and response during and after completion of HL therapy. As a result, the method plays an important role in current efforts to further optimize therapy. This article addresses the role of FDG-PET/CT for response-adapted HL therapy, both in the first-line setting and in relapsed disease.
Early treatment monitoring with FDG-PET
Clinical stage and prognostic factors are used to determine the initial treatment strategy for patients with HL. However, the tumor response to induction treatment is strongly prognostic. A reliable and early prediction of response to therapy may identify good-risk patients who will be cured with conventional therapy or even less intensive and less toxic regimens, and poor-risk patients for whom an early switch to alternative, more aggressive treatment strategies could improve the chance of remission and cure. This concept, called risk-adapted therapy, is a potential way to maintain or improve the high cure rates without increasing, and perhaps even decreasing, the risk of treatment-related morbidity and mortality.
Conventional methods for treatment response monitoring are based on morphologic criteria, and a reduction in tumor size on CT is the most important determinant. However, size reduction is not necessarily an accurate predictor of outcome. In HL, the malignant cells make up only a small fraction of the tumor volume, which is dominated by reactive infiltrating cells not directly affected by antineoplastic therapy. Even more importantly, tumor shrinkage takes time and depends on several factors in the host. The rate of structural regression therefore cannot form the basis for therapy response assessment until late during treatment, at which point a treatment modification might be less useful.
As opposed to the morphologic changes of the lymphoma occurring later during therapy, functional imaging with FDG-PET enables early evaluation of the metabolic changes that take place early during the treatment induction. The rapid decrease in metabolic activity of cells in the tumor environment is highly predictive of the subsequent response and final outcome. Several studies of FDG-PET after 1 to 3 cycles of chemotherapy have shown that these early metabolic changes are highly predictive of final treatment response and progression-free survival (PFS). Most evidence is available for FDG-PET after 2 cycles of chemotherapy. However, there are data to suggest that the prognostic accuracy is already high after only 1 cycle of chemotherapy.
In 2005, a retrospective analysis of 88 patients scanned after 2 or 3 cycles of ABVD-like chemotherapy for HL showed a 5-year PFS of 39% in the PET-positive group compared with 92% in the PET-negative group. These results were later confirmed in several prospective studies, showing excellent outcomes for patients becoming PET negative after 2 cycles of chemotherapy (approximately 95% long-term PFS) and poor outcomes for early PET-positive patients. In patients with advanced disease, the high prognostic value of early FDG-PET seems to dilute the role of the widely accepted International Prognostic Index (IPS), which is based on pretherapeutic factors. The prognostic value of PET/CT in advanced HL was recently validated in an international study that showed 3-year failure-free survival of 28% and 95% for early PET-positive and early PET-negative patients, respectively. In this validation study, the interobserver agreement was high between 6 independent PET/CT reviewers using the Deauville criteria for interim PET, which have become widely recognized. Apart from giving reproducible results, the Deauville criteria are simple in use, thus it is hoped that their use in most of the recently opened PET response–adapted trials will enhance comparability between clinical trials and also enable a better translation of clinical trial results into clinical practice outside of trials. Recent data strongly suggest that the negative predictive value of FDG-PET may be even higher if the test is performed after 1 cycle of chemotherapy for HL.
The positive predictive value of early FDG-PET may be lower in patients treated with the more dose-intensive regimens such as BEACOPPesc than in patients treated with ABVD. Also, the positive predictive value is lower in patients with early-stage HL, probably because of both the inherently better prognosis for this patient group and because of the subsequent radiotherapy, which may in many early-stage patients overcome an insufficient chemotherapy response. Table 1 provides an overview of the studies showing the prognostic value of early interim FDG-PET in HL.
| Investigators, Ref #, Year | Cycles of Chemotherapy Before Interim PET | Patients | PET Positive | PET Negative | Follow-up (mo) | ||
|---|---|---|---|---|---|---|---|
| Total | Treatment Failure, n (%) | Total | Treatment Failure, n (%) | ||||
| Hutchings et al, 2005 | 2–3 | 85 | 13 | 8 (62) | 72 | 4 (6) | 6–125 |
| Hutchings et al, 2006 P | 2 | 77 | 16 | 11 (69) | 61 | 3 (5) | 2–41 |
| Zinzani et al, 2006 P | 2 | 40 | 8 | 7 (88) | 32 | 1 (3) | 12–27 |
| Gallamini et al, 2006 P | 2 | 108 | 20 | 18 (90) | 88 | 3 (3) | 2–47 |
| Gallamini et al, 2007 P | 2 | 260 | 50 | 43 (86) | 210 | 10 (5) | 4–62 |
| Cerci et al, 2010 P | 2 | 104 | 30 | 16 (53) | 74 | 6 (8) | 32–40 |
| Zinzani et al, 2012 | 2 | 304 | 53 | 40 (75) | 251 | 20 (8) | 6–100 |
| Biggi et al, 2013 | 2 | 260 | 45 | 33 (73) | 215 | 12 (6) | 12–96 |
| Hutchings et al, 2013 P, U | 1 | 126 | 37 | 22 (59) | 89 | 5 (6) | 8–56 |
PET response–adapted HL therapy: early-stage disease
More than 90% of patients with early-stage HL are cured with standard therapy. However, the patients still have a greatly reduced life expectancy because of treatment-related illness including second cancers and cardiopulmonary disease. Patients with early-stage HL more often die from late effects of therapy than from the disease itself, which suggests that a substantial number of patients with early-stage HL are subject to some amount of overtreatment, and it is the background for an ongoing effort to reduce the treatment burden while still maintaining or improving cure rates.
Two or 4 cycles of ABVD chemotherapy followed by involved-field radiotherapy (IFRT) or involved-node radiotherapy (INRT) is widely regarded as standard of care for early-stage HL, although 6 cycles of ABVD seem to be comparable in safety and long-term cure rates. Before the PET era, several studies suggested that selected patients could be safely managed with even less treatment. The German H10 trial for patients with early-stage HL without risk factors showed that 2 cycles of ABVD followed by 20-Gy IFRT is as effective as, and less toxic than, 4 cycles of ABVD followed by 30-Gy IFRT. The National Cancer Institute of Canada (NCIC) and the Eastern Cooperative Oncology Group (ECOG) randomized 399 patients with early-stage HL to either combined-modality treatment or ABVD chemotherapy alone. In the chemotherapy-alone arm, patients who achieved a complete or unconfirmed complete remission after 2 cycles of ABVD received only 2 additional chemotherapy cycles. Despite this abbreviated chemotherapy, 95% of patients who received only 4 cycles of ABVD were free from progression after 5 years’ follow-up. These studies, among others, have inspired researchers to propose that some patients with early-stage HL may be treated with even less therapy. In contrast, and particularly among patients with risk factors, cure rates leave room for improvement because approximately 15% of patients experience treatment failure with 4 cycles of ABVD plus 30-Gy INRT. The German HD14 study showed that replacing 4 cycles of ABVD with 2 of BEACOPPesc followed by 2 of ABVD resulted in a small but significant 6 percentage-point benefit to PFS at 5 years. This finding did not translate into an improved overall survival (OS), and most colleagues find it undesirable to offer intensified treatment to all patients with early unfavorable HL in order to gain improved outcome for very few patients. However, these studies have shown that one size does not fit all in early-stage HL. The high prognostic accuracy of the early interim FDG-PET makes the method a likely tool to guide early response–adapted therapy, aiming to improve management by minimizing therapy in most early-stage patients, who respond well, and perhaps intensifying therapy in a high-risk, poor-responding minority.
Several trials have assessed such PET response–adapted therapy for early-stage HL ( Table 2 ). In the National Cancer Research Institute (NCRI) Lymphoma Group RAPID trial, patients who were PET negative after 3 cycles of ABVD were randomized to radiotherapy or no further treatment. The German HD16 trial for early-stage patients without risk factors uses up-front randomization, between a standard combined-modality arm and a PET-driven experimental arm, in which patients who are PET negative after 2 cycles of ABVD receive no further treatment. The experimental arms of the European Organisation for Research and Treatment of Cancer (EORTC)/Groupe des Etudes des Lymphomes de l’Adulte (GELA)/Fondazione Italiana Linfomi (FIL) H10 protocol also omitted radiotherapy to early PET-negative patients while escalating to BEACOPPesc followed by radiotherapy in PET-positive patients. This trial tested the noninferiority of a less toxic treatment to good-risk patients, and at the same time attempted treatment intensification for patients regarded as having a high risk of failure based on a positive interim PET/CT. The German HD16 trial is still recruiting patients, but results from the RAPID (Response-Adapted PET trial In early-stage Hodgkin’s Disease) trial and the H10 trial were presented at the 2013 annual meeting of the American Society of Hematology. The results are summarized in Table 3 . The results from the RAPID trial were based on a mature analysis with a median follow-up of 46 months, whereas the H10 results were based on an interim analysis after a median follow-up of 13 months. Apart from this, the results were similar. Early PET-negative patients who, according to randomization, did or did not receive radiotherapy showed differences in PFS rates that were within the predefined margin of noninferiority (7% for RAPID, 10% for H10). Nevertheless, the conclusions from the two studies were the opposite of one another. The RAPID trial is considered a positive trial, because mature results show what is considered noninferiority of the experimental arm. In contrast, the experimental arms for early PET-negative patients in the H10 trial were closed after a futility analysis of the presented interim data rendered it unlikely that noninferiority of the chemotherapy-only treatment could be shown in a mature analysis, compared with the combined-modality standard arms. This analysis used the assumption that the hazard ratio for recurrences in each arm is unchanged during the observation period. This assumption is not correct, because most recurrences in HL occur within the first 2 years, and because it is likely that patients not receiving radiotherapy will relapse earlier than those relapsing after combined-modality treatment.
| Study Title | Reference # | Patients | Design | Study Type |
|---|---|---|---|---|
| GHSG HD16 | Early-stage HL no risk factors | No radiotherapy in experimental arm if PET-negative after 2 × ABVD | Phase III | |
| EORTC/GELA/FIL H10 (completed) | Early-stage HL | Experimental arm: no radiotherapy if PET negative after 2 × ABVD BEACOPPesc + radiotherapy if PET positive after 2 × ABVD | Phase III | |
| UK NCRI RAPID (completed) | Early-stage HL | If PET negative after 3 × ABVD, randomization to RT vs no RT | Phase III | |
| CALGB 50604 | Early-stage HL, nonbulky | Additional ABVD × 2 and no RT if PET negative after 2 × ABVD BEACOPPesc + radiotherapy if PET positive after 2 × ABVD | Phase II | |
| CALGB 50801 | Early-stage HL, bulky | Additional ABVD × 4 and no RT if PET negative after 2 × ABVD BEACOPPesc + radiotherapy if PET positive after 2 × ABVD | Phase II | |
| ECOG 2410 | Early-stage HL, bulky | 4 × BEACOPPesc + RT if PET positive after 2 × ABVD | Phase II |
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FDG-PET Response–adapted Therapy
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