New response criteria for lymphomas in clinical trials.

Standardized staging and response assessment are critical to the successful conduct of clinical trials. In turn, clinical trials are essential to the development of new and more effective therapy for patients with lymphomas. In the absence of effective agents, response criteria are almost irrelevant. However, with the increasing number of effective therapies, standardized criteria are necessary to reliably assess and compare results of studies. Variability in how patients were evaluated led to an International Working Group (IWG) that developed guidelines to standardize normal lymph node size, when and how responses are assessed, and definitions for response categories and endpoints [1]. These recommendations were widely adopted by clinical trials groups and regulatory agencies. However, with their application over time, it became clear that revisions were indicated. For example, the IWG criteria relied on physical examination, with its marked interand intraobserver variability, CT scans and SPECT gallium scans, the latter no longer being widely used. A major problem with the original IWG criteria was the misinterpretation of the term complete remission/unconfirmed (CRu). CRu was originally proposed to designate patients with curable histologies, such as Hodgkin’s lymphoma or diffuse large B-cell lymphoma, with a large mass prior to therapy for whom treatment eradicated all detectable tumor except for persistence of the single mass, which had decreased by at least 75% on CT scan, recognizing that these lesions are scar tissue or fibrosis in >90% of cases [2, 3]. Instead, CRu was often applied to situations in which the sum of the product of the diameters (SPD) of multiple nodes decreased by at least 75%, which would more appropriately designated partial response (PR). A second type of CRu indicated patients who fulfilled all of the conditions for a CR following therapy except that the bone marrow was considered morphologically indeterminate. Instead, the term was also assigned to patients who did not undergo a repeat biopsy to confirm response. FDG-PET has resulted in a major shift in lymphoma patient management. PET is not useful for diagnosis because it lacks specificity. However, it has been considered for staging, prognosis, directing therapy, restaging and post-treatment surveillance. The strongest evidence for the usefulness of PET is in post-treatment restaging [4–27]. The Ann Arbor system most commonly used was based on physical examination and bone marrow assessment, with CT scans subsequently incorporated. PET is highly sensitive in detecting nodal and extranodal involvement by most histologic subtypes of lymphoma and may provide complementary information to the Ann Arbor staging system [4, 8, 10, 11, 16, 21, 28–38]. Most common lymphoma histologies are routinely FDG avid with a sensitivity and specificity that is superior to CT [28, 29, 32, 38]. Whereas PET and CT are 80–90% concordant in staging of diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma [10, 32], PET results in upstaging by identifying additional sites of disease. Concordance of PET and CT is lower in Hodgkin’s lymphoma [4, 8, 16, 21, 34–36]. PET can detect bone or bone marrow involvement in lymphoma patients with a negative iliac crest bone marrow biopsy [39–41], although being more sensitive with diffuse disease and less reliable with limited involvement [41]. Thus, PET cannot substitute for bone marrow biopsy in lymphoma staging. PET is currently not part of standard lymphoma staging primarily because of its expense and the generally small percentage of patients ( 15–20%) where PET modifies clinical stage, with a change in management in only 10–15% [11, 32, 42]. Thus, at present PET alone should not replace CT for staging [4, 8, 16, 35]. PET/CT offers important advantages compared with contrast-enhanced, full-dose diagnostic CT or PET alone [37, 43, 44]. The CT portion of the PET/CT exam for initial staging using i.v. contrast may permit a more accurate assessment of liver and spleen compared with unenhanced CT [25]. PET/ CT may be valuable in patients with clinical stage I or II disease who are being considered for local radiation therapy. Numerous studies have demonstrated that PET scans performed after one or more cycles of chemotherapy predict progression-free and overall survival [5–7, 20, 21, 23, 24, 45–47]. Unfortunately, no available data demonstrate that altering treatment on the basis of PET results improves patient outcome. This critically important issue is currently being addressed in a number of clinical trials.