Interim positron emission tomography in early stage Hodgkin lymphoma: is there evidence for its prognostic and predictive value in patients treated with standard combined modality treatment?

An early interim positron emission tomography (PET) scan has proved highly predictive of outcome in patients with advanced Hodgkin lymphoma (HL) treated with the standard ABVD (adriamycin, bleomycin, vinblastine, DTIC [dimethyl triazeno imidazole carboxamide]) regimen [1]. However, for patients with early stage disease receiving standard treatment with 2–4 cycles of ABVD followed by limited radiotherapy to 20–30 Gy, the predictive value of an early interim PET scan after 1–2 cycles of ABVD is less impressive, as documented in the study by Filippi et al. in this issue [2]. In most studies of the prognostic significance of an early interim PET scan all stages were included, and because of the relatively few events in the early stage patients, results were dominated by the results in advanced disease [3]. Analyses of early stage patients alone generally find a low sensitivity and positive predictive value of an early interim PET scan [3–5].

The specificity and negative predictive value of an early interim PET scan in early stage disease is very high (over 80%) [4,5], which is not surprising in a disease where the large majority of patients are cured. This is seen after combined modality treatment, but we have few data to enable us to extrapolate to patients treated with chemotherapy alone for early stage disease. However, it seems plausible that an early PET scan is a good predictor of outcome after chemotherapy alone in early stage disease as well as in advanced disease.

Based largely on the results of studies of the predictive value of an early interim PET scan in advanced disease, recent trials have tested a strategy of chemotherapy alone in early stage patients who are PET negative after two cycles of ABVD. Final results of these trials are eagerly awaited. However, the European Organisation for Research and Treatment of Cancer/Groupe d’Etude des Lymphomes de L’Adulte/Intergruppo Italiano dei Linfomi (EORTC/GELA/ILL) H10 protocol had to be stopped prematurely because of the number of recurrences in PET negative patients in the experimental arm treated with chemotherapy alone, casting some doubt on the early interim PET scan as the basis for treatment modification. Indications are that there will be some more recurrences in patients treated without radiotherapy. Some of these recurrences will be cured by salvage treatment with high dose chemotherapy and stem cell transplant. However, this treatment is highly intensive, and associated with significant long-term complications.

Much of the research into treatment modification in early stage disease based on the result of an early interim PET scan has focused on ways to avoid radiotherapy. This is based on the data on long-term complications of extended field radiotherapy of the past, which have indeed proved to be serious. However, extended field radiotherapy, encompassing large volumes of normal tissue in the treatment fields, was abandoned 10–15 years ago. Modern radiotherapy for early stage HL encompasses only the initially involved site with narrow margins, leading to drastic reductions in the volume of normal tissue being irradiated. Moreover, radiation doses have been reduced from 40 Gy, or even more, down to 30 or even 20 Gy. It has not yet been determined whether the reduced risk of long-term complications after modern, limited radiotherapy to all early stage patients will in the end prove less detrimental compared to the risk of long-term complications after the intensive salvage therapy to the group of patients relapsing after a chemotherapy alone strategy [6,7].

The positive predictive value of an early interim PET scan in early stage disease is quite low. There is a high rate of false positive results (30–50%), and biopsies may be necessary for verification. Nevertheless, treatment decisions based on a positive early interim PET scan are increasingly being made. However, the data presented by Filippi et al. in this issue of Leukemia and Lymphoma [2], and data from other studies, indicate that radiotherapy may achieve durable complete remission in most of these patients [8]. Hence, most of these patients will be cured by standard limited radiotherapy, without the need for high dose chemotherapy and stem cell transplant.

The prognostic value of PET is dependent on treatment. PET seems to be a good predictor of outcome after chemotherapy, although dependent on the regimen used. However, radiotherapy seems to be able to eradicate residual PET positive disease after chemotherapy. In early stage HL, where all initial disease can be included in the irradiated volume, cure is likely to be achieved with a combined modality strategy, even in patients with a positive interim PET scan.

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