The current paradigm of therapy in both classic Hodgkin lymphoma (HD) and diffuse large cell lymphoma (DLCL) is a risk-adapted approach, based primarily on established pretreatment prognostic factors. Recent advances in dynamic imaging technology have motivated attempts to determine an individual's risk early during therapy, thereby allowing development of a patient response-based therapeutic management strategy.1
With current treatment regimens, at least 80% of patients with HD can be cured by the use of single or combined modality therapies.2 DLCL is a biologically heterogeneous lymphoproliferative malignancy with inconsistent response to therapy, hence the existing therapeutic approach is successful in only 50% to 70% of patients.3, 4 Prognostic models, based on clinical and biological parameters (International Prognostic Index [IPI] for DLCL and international prognostic score [IPS] for HD),4, 5 provide risk stratification to predict outcome. Nonetheless, there is some variability in outcome within the individual IPI and IPS risk groups as these models do not identify the true genetic makeup of these diseases. Hence, there is a risk of treating low-risk patients more intensively than needed with potential unnecessary adverse effects.4 Alternatively, a substantial proportion of patients who are falsely stratified in the low-risk category may theoretically be undertreated. This issue is particularly problematic with DLCL, because of the significant overlap with the intermediate-risk category. Although microarray techniques have further refined the prognostic groups identified by the IPI, their routine use is limited by the requirement for fresh, cryopreserved samples and high cost.6
There is convincing evidence that imaging with fluorodeoxyglucose positron emission tomography (FDG-PET) can provide timely information about response when used early during therapy.7–12 The metabolic information obtained from FDG-PET may lead to improved patient management by determining rapid response, which could theoretically be used as a basis for therapy changes.
The purpose of the current study was to use FDG-PET as an early indicator of therapy response after 1 cycle of chemotherapy to determine its prognostic value in patients with previously untreated classic HD and DLCL.
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- MATERIALS AND METHODS
Increasing success of lymphoma therapy has now placed the prevention of long-term toxicities at the forefront of clinical management. In this context, a risk-adapted, individually tailored treatment for patients with DLCL and HD may provide an effective strategy for prevention of major late complications.
FDG-PET, as an indicator of treatment efficacy, has demonstrated encouraging results when used during or after chemotherapy, often despite contrary clinical or biochemical evidence of disease.15–21 In this study, we found a NPV (100%) and PPV (87.5%) for early FDG-PET obtained after 1 cycle of chemotherapy in both DLCL and HD. The vast majority of relapses occur within the first 2 years after therapy. In our group, the follow-up was >20 months in more than 85% of the patients in the early PET-negative group. Thus, our findings suggest that FDG-PET after 1 cycle offers a robust means for defining a patient population who is likely to benefit from treatment.
The results of this current study are in congruity with previous studies that were designed to predict therapy outcome early during chemotherapy.8–12 However, compared with prior studies, our study is unique in its design for evaluating response early after 1 cycle, whereas other studies were performed after 2 or more cycles of chemotherapy. The timing of treatment assessment may be critical, particularly, for patients who prove refractory to first-line therapy or relapse at a later time. These patients may benefit from early alternative therapy avoiding the complications of continued ineffective therapy. Likewise, the identification of patients who are likely to be cured by the first-line therapy may offer the potential of shortening the duration or intensity of treatment. Spaepen et al. reported that in 70 patients with aggressive non-Hodgkin lymphoma (NHL), FDG-PET at midtreatment was correlated with PFS and overall survival.9 None of the patients with persistent FDG uptake achieved a durable complete response (CR), whereas 84% of PET-negative patients remained in CR with a median follow-up of 37 months. In our study, the results were slightly different from this prior study as our data yielded no false-negative results. This difference may be due to the superior resolution of the PET scanner, the attenuation correction applied, and the higher specificity added by the integrated PET-CT system.
A clear definition of positive and negative lesions is crucial to obtain consistent results with less observer variability when using imaging probes as surrogate markers. In this regard, the present study offers a more finely tuned and strict set up definitions of the qualitative end points compared with other comparable studies in the literature.8–12 Mikhaeel et al. has recently reported that early interim FDG-PET after 2–3 cycles of therapy is an independent predictor of PFS in aggressive NHL.10 The estimated 5-year PFSs were 89%, 59% and 16% for the PET-negative group, the minimal residual uptake group, and the PET-positive groups, respectively. However, minimal residual uptake is a vague definition and is highly conducive to subjectivity. Likewise, other studies have not defined a sharp interpretation criteria in their study design.11, 12, 15 In our study, we used a dichotomous and well defined reading scale to avoid inconsistent readings.
Although various studies demonstrated that qualitative evaluation is sufficient for differentiating responders from nonresponders,7–12, 15, 16, 19 we endeavored to perform a ROC analysis based on using post 1 cycle SUVmax as a discriminator of the recurrence from remission status. The optimal post 1 cycle SUVmax cut point was determined to be 1.75 yielding a sufficiently high sensitivity and specificity for discriminating responders from nonresponders. There are currently only limited data using SUVs as a means to evaluate therapy response.17, 22 It has been reported that a SUVmax cutoff of 2.5 yielded a sensitivity and a specificity of 86% and 100%, respectively in the differentiation of sterile masses from active lymphoma using integrated PET-CT.22 In another study, the corresponding values obtained with a SUVmean cutoff of 3.0 were 100% and 93%, respectively.17 These cutoff values, however, may be different depending on the patient population and therapy modality. In our set-up, not only were all FDG-PET studies obtained before radiation, but also only 1 patient received radiation therapy after chemotherapy. Thus, higher cutoff values may have decreased the specificity of FDG-PET in the prediction of outcome. Among the nonrecurring lesions, the majority of lesions that exceeded the cutoff value were in the mediastinum or hilum where the SUVmax is usually between 2.0 and 2.5.
Although there was excellent agreement between the findings of FDG-PET after 1 cycle and after completion of therapy, in those instances of discordance, imaging after 1 cycle proved more accurate than after completion. This finding was similar to our previous results obtained on a dual-head imaging system7 as well as to those reported by a recent study.12 Hutchings et al. evaluated 77 HD patients after 2 and 4 cycles and after completion of chemotherapy with a median follow-up of 23 months. In the prediction of PFS, FDG-PET after 2 cycles was as accurate as that obtained later. Our results demonstrated a slightly higher NPV after 1 cycle compared with after completion of therapy. The explanation for a more favorable NPV obtained with the early scan would be that rapidity of achieving a complete response implies chemosensitivity of the tumor. Because high chemosensitivity usually translates into higher CR, this finding is probably a harbinger of sustained CR.23–25 In a seminal study of DLCL, Armitage et al. reported when therapy was adjusted according to the response after 3 cycles in NHL, 73% of the patients achieved a CR.23 The durability of remission in the rapidly responding patients was significantly longer than those who required more cycles to achieve CR. Similarly in HD, the rapidity of response to initial few cycles of chemotherapy was found to serve as a surrogate for ultimate outcome, reflecting both tumor burden and activity.26 However, these prior studies were based on tumor volume reduction measurements determined by CT, which can underestimate response rates, especially early during therapy. In a recent article, the response accuracy using International Workshop Criteria (IWC) was enhanced by the integration of FDG-PET into the IWC in patients with aggressive NHL.21
In a regression analyses, early interim FDG-PET was found to be a stronger predictor than established prognostic factors.9, 12 Similarly, in our study, it appeared that FDG-PET predicted PFS better than IPI and IPS, although we could not compare the results statistically because of the 100% NPV. In the early PET-negative group, there were 9 patients whose disease was in the intermediate or high-risk lymphoma by IPS and IPI, respectively. Likewise in the PET-positive group, of 10 patients who were in the low-risk group, 8 had a relapse. A major drawback of the IPI is that approximately half of the patients can be allocated into the intermediate-risk category, the group in which the treatment selection is the most challenging. Furthermore, 30% of the patients fit into the low-risk category and 20% to 40% do not survive for more than 5 years.4, 27
Although the high negative value obtained in this study is compatible with prior studies,8–12 it is important to understand that FDG-PET cannot exclude minimal residual disease due to the finite resolution limits of the PET systems. It is possible a small number of patients can still develop relapse during a longer follow up notwithstanding a median of 28 month follow up in our study when most relapses occur.
Ideally DLCL and HD should be evaluated in separate groups as these are 2 different disease entities with different biologic behavior and response profiles. Both, however, share the potential for cure. In our study, when patients with DLCL were separated from those with HD, the prognostic impact of FDG-PET after 1 cycle on PFS remained the same.
An early assessment of response with FDG-PET could provide the basis for selection of patients for alternative therapeutic strategies. Even if we were able to predict early that patients with a positive FDG-PET are destined to fare poorly with first-line therapy, it is possible that early alternative treatments, such as transplantation, may not result in any survival benefit. Indeed, an early positive FDG-PET may simply be a sad harbinger of a dismal prognosis reflecting inherent drug resistance. Nevertheless, an early negative FDG-PET may provide the potential to shorten therapy for curable lymphomas. In addition, a negative FDG-PET may allow the avoidance of radiation in patients with bulky disease. Conceivably, FDG-PET scanning may ultimately prove to be the most robust means for altering current treatment paradigms. Only extensive randomized studies will confirm the true potential of dynamic FDG-PET scanning.