Does interim PET increase the value of ABVD in advanced-stage Hodgkin lymphoma?

In the present issue of the journal, Ganesan et al. reported the results of a prospective, open-label single-centre phase II study on the role of PET response-adapted strategy in a small cohort of 50 patients affected by advanced-stage (IIB–IVB) Hodgkin lymphoma (HL) [1]. Briefly, the treatment started with two courses of ABVD chemotherapy, followed by an interim PET (PET-2). Subsequently, the treatment of PET-2 positive patients was switched to escalated BEACOPP (EB), following the same schedule as in the HD 9 trial [2], while PET-2 negative patients were kept on ABVD treatment to complete a total of six courses. After a median follow-up of 24.7 months, 47 patients were assessable for event-free survival (EFS) and 50 for overall survival (OS). The 2-year EFS and OS in the entire cohort were 76% [95% confidence interval (CI) 68–83] and 88% (95% CI 82–94), respectively. The authors concluded that, despite the failure to reach the primary end point of the trial (85% 2-year EFS for the entire cohort), the study results had the merit of improving the outcome of the PET-2-positive cohort when compared with historical data and to spare the toxicity of EB in 83% of the patients. This study readdresses a heated historical debate, which has been ongoing since the early 1990s for over two decades, on the following questions: in advanced disease, HL should a more effective treatment such as EB, be indiscriminately given to all patients at disease onset or it could be delivered only to those with relapsing or refractory disease, with the intent of sparing undue toxicity? A similar question was also raised in limited stage disease: should a combined chemoradiation protocol be applied invariably to all patients or radiotherapy could be omitted in some cases? While some data exist to provide answers to the latter question [3, 4], the former is yet to be answered. Despite the proven superiority of EB over standard ABVD as originally described by Bonadonna et al. [5], and later reported in four randomized clinical trials [2, 6–9], a large meta-analysis conducted on 2868 patients with advanced-stage HL concluded that there was no significant difference in OS between respective groups receiving ABVD and EB regimens [10]. Hence, ABVD with a minimum of six cycles and maximum eight cycles still remains the standard first-line choice for advanced-stage HL in most countries. The aforementioned questions are in line with the historical dilemma regarding the ideal end point in trials aimed at assessing the effectiveness of a given anti-cancer treatment, if progression-free survival (PFS) should be the preferred (surrogate) end point over a more definitive proof of disease cure, i.e. OS, which may be prolonged and impractical to achieve in a trial setting. However, the most compelling argument for a tailored therapy approach based on the actual risk of chemo-resistance in an individual patient, remained the unwarranted treatment-related morbidity. In early-stage HL, for instance, the disease itself no longer represents the main cause of death 5 years beyond the end of treatment, but rather patients die of secondary neoplasms and cardiovascular events [11]. Therefore, it is not a surprise that the search of reliable markers for tumour response prediction in an individual basis is very attractive in the context of a highly curable neoplasm, where the rate and magnitude of treatmentrelated morbidity or mortality supersedes the rate of diseaserelated death. Oncologic imaging plays a crucial role as a surrogate of response, particularly in an adapted, individualized treatment setting, which is increasingly becoming the standard approach. Surrogate end points for tumour response prediction should provide earlier, objective and hopefully correct answers about the efficacy of treatment: definition of an adequate response using an imaging technique relies on the adequacy of the test for the tumour response assessment during treatment. The Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 and 1.1 [12, 13] were proposed with great enthusiasm for the assessment of response to treatment, but the limitations of these metrics, in terms of reproducibility and reliance on merely anatomical information, became apparent over time with the realization that tumour size change lags behind early biological and molecular modifications during therapy [13]. The functional imaging modality, based on PET/CT with F-fluoro-D-deoxyglucose (FDG), has been used as a surrogate for response at early time points during ongoing therapy, tracing the early alterations in tumour metabolism which could not be detected by traditional radiological means. In HL, FDG-PET allows for assessment of metabolic changes occurring during the induction treatment as early as after the first [14], second [15], or the third [4] cycle of chemotherapy, predicting long-term treatment outcome in ABVD-treated advanced-stage HL patients [16]. PET-positive and PET-negative patients after two cycles of chemotherapy (PET-2) have a 3-year progression-free survival of 12%–30% and 90%–95%, respectively [16]. The high predictive value of interim PET scans is mainly on the account of high chemosensitivity associated with HL, which is reflected by the immediate decrease of metabolic signal in responding patients [17]. Practical and reproducible interpretation rules for interim PET scans, so-called Deauville 5-point score, have been proposed and retrospectively validated in a large cohort of ABVD-treated, advanced-stage HL patients by a panel of international experts [18, 19]. This study also confirmed a high inter-reader agreement (Cohen’s k: 0.69–0.84; Krippendorf α = 0.76) [18]. Several prospective trials are awaiting long-term results at this writing, aiming at assessing the role of an interim PET-adapted strategy both in early and advanced HL, with a twofold aim: (i) sparing toxicity by reducing treatment or even omitting radiotherapy in interim PET-negative patients; (ii) escalating treatment in interim PET-positive patients after two cycles of (standard) chemotherapy treatment [20]. In advanced-stage lymphoma, three international multicentre clinical trials with a similar design are now closed to patient enrolment: the UK NCRI RATHL study [21], the SWOG-CALG-B S016 [22], and the Italian GITIL/FIL HD0607 study [23]. The shared backbone Annals of Oncology editorials