Improving outcome after positive interim PET in advanced Hodgkin’s disease: reality vs expectation

Excerpt

The initial enthusiasm regarding the high predictive value of FDG-PET scan in re-staging Hodgkin’s disease (HD) has been partially hampered by emerging and challenging dilemmas, including how to treat patients with residual uptake and no evidence of disease progression based on conventional criteria and how to tailor treatment according to mid-treatment PET studies. For the former, Poulou et al. and Jabbour et al. demonstrated that patients with positive scans and no measurable disease on conventional re-staging are expected to share similar progression-free survival rates (PFS) with those being in complete remission with negative PET scans [1, 2]. For the latter question, Mac Manus et al. and Seam et al., in their fine reviews on FDG-PET in lymphoma, state that, to date, no clinical trials have demonstrated clinical benefit from altering therapy on the basis of interim PET results. Thus, mid-treatment PET scans should be reserved for clinical trials addressing this important question [3, 4]. Current studies in HD indicate that FDG-PET scanning after two to three cycles of chemotherapy provides valuable prognostic information at a time when changes could be made in the first-line treatment protocol. This information appears to be as reliable as or more reliable than definitive response assessment at the end of therapy. Gallamini et al. have more recently reported the results of a study of 108 patients with newly diagnosed HD who had stage IIA with adverse prognostic factors or stage IIB–IVB and were re-staged with FDG-PET after two cycles of ABVD chemotherapy [5]. Interim PET was positive in 20 patients of whom 17 progressed during therapy, one relapsed and two remained in complete remission. By contrast, 85/88 (97%) patients with a negative PET remained in complete remission; three progressed or relapsed early after the end of chemotherapy. The 2-year PFS for PET-negative and for PET-positive patients was 95% and 12.8%, respectively. Hutchings et al. investigated the prognostic significance of early PET response assessment after two cycles of chemotherapy (principally ABVD). Forty-six patients belonged to the advanced stage group (stage IIB–IV). After two cycles, 35/46 patients had negative PET scans and 11/46 patients had positive scans. The 2-year PFS was 93% and 0%, respectively [6]. Pooled data show that 20.1% (31/154) are expected to have positive interim scans. Clinical trials may be justified for such patients to investigate the effects of early intensification of therapy in an effort to improve their relatively poor outcomes with current treatment strategies. Certainly, the incremental efficacy of dose intensification was established in the HD9 study and also serves as the basis for treating recurring HD with myeloablative chemotherapy and stem cell transplantation. Dose adjustment could be approached by starting with dose-intense therapy (i.e. escalated BEACOPP) and then de-escalating based on PET-2 or, alternately, escalating to dose-intense treatment based on PET-2. Dann et al. studied the former approach in 108 patients with HD dichotomised as intermediate risk (n = 69, IPS 0–2) or high risk (n = 39, IPS 3–7), yielding an 84% PFS for the cohort of 69 patients. Although the sample size is small, this interesting study suggests that risk-adapted treatment is feasible and effective [7]. However, de-escalation does not protect patients from the higher risks of intensive treatment, whereas escalation may not fully recapture the benefit of more intensive treatment. The ability to successfully treat PET-positive patients with a second-line or cross-over treatment has not been established. Whether it is essential to treat patients with HD with aggressive therapy from the time of diagnosis remains an unanswered question. Furthermore, it is likely that patients with PET-2-positive studies after ABVD are also patients at greatest risk for failing escalated therapies, as has been established before dose-intense therapy and auto-transplantation. Of course, risk-adapted approaches do not address the most challenging population, the elderly. Finally, risk-adaption based on early PET may not reveal cases that relapse later after treatment, as seen in the approximately 10% of PET-2-negative patients who progressed in the study of Dann et al. [8]. In fact, within the limits of clinical practice, standard ABVD protocols with adjuvant radiotherapy in advanced HL confer a 2-year PFS of 90% [9]. In an intention-to-treat all patients with positive scans (Fig. 1), any intensified protocol should achieve a 2-year PFS >75% at baseline and at least 54% on best-case scenarios (Table 1). Data on autologous stem cell transplantation (ASCT) for relapsed/refractory HD hardly approximate the predicted cut-off values [10, 11]. ASCT as an option in carefully designed prospective studies remains hypothetical. Long-term sequelae such as secondary neoplasms and non-relapse mortality should be estimated in any intensified protocols [12]. These data suggest that ABVD appears outdated for poor risk HD when interim PET is used for prognostic stratification. It is unlikely though that any alternative strategy would combine both favourable long-term results and safety profile; not at least in the near future.

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