Standard Response Criteria In

The use of clinical response endpoints in trials in NHLs has been an intrinsic component of clinical trial design for many years. This is based largely on the observation that long-term disease-free and overall survival for patients in many clinical trials has been shown to correlate closely with the degree of clinical response. This observation holds true for first line therapy and for patients who receive second line regimens including the use of high-dose therapy and autologous stem cell transplantation (ASCT). Although a close correlation between response and event free and overall survival has been confirmed in multiple studies in aggressive NHL, results in studies in FLs and other indolent lymphomas have been less clear. Many studies have shown a correlation of clinical response with event- or failure-free survival in FLs, but in view of the indolent nature of these diseases, correlations with overall survival have been inconsistent. Additionally, in aggressive NHL, the persistence of residual masses after the completion of therapy, especially at sites of initial disease bulk, does not always indicate the presence of residual active disease. Inconsistencies in the assessment of response at sites such as the spleen and bone marrow have also added to uncertainty regarding the definition of response and comparability of results in different clinical trials.

An International Workshop to standardize response criteria for NHL was therefore developed in 1998 and published in 1999 in an attempt to provide uniform interpretation of clinical trial results across all studies.1 This included agreed definitions of response and appropriate endpoints and follow-up schedules for use in the trial setting. The definitions provided are based primarily on clinical, radiologic, and histopathologic criteria, and they have since been modified by the inclusion of functional imaging data. A formal update of the criteria is in progress and will incorporate other data including flow cytometric analysis and molecular studies.

A summary of the response criteria is shown in Table 66.1.

The specific definitions are given next.

Complete remission (CR)

• Complete resolution of all clinically and radio-logically detectable disease, all lymphoma-related symptoms, and all lymphoma-related biochemical abnormalities (such as elevated lac-tate dehydrogenase [LDH]).

• Lymph nodes and nodal masses must regress to normal size (defined as < 1.5 cm for lymph nodes initially >1.5 cm). Lymph nodes initially measuring 1.1-1.5 cm must regress to <1 cm in greatest transverse diameter, or by more than 75% of the sum of the perpendicular diameters (SPD).

• If the spleen is enlarged on CT scan prior to therapy, it must regress in size and not be palpable by physical examination. Normal splenic size was not defined. Any macroscopic nodules noted in the spleen by any imaging modality must be resolved. Similar criteria apply to other organs such as the liver and kidneys.

• In view of conflicting data regarding the use of unilateral and bilateral bone marrow biopsies at staging, the workshop defined an adequate marrow evaluation as one with a minimum total biopsy length of 20 mm. If the marrow is involved at diagnosis, CR requires complete clearing of the infiltrate on repeat biopsy, which must be from the same site and the same minimum length. At the time of the initial workshop publication, since the significance of flow cytometric, molecular and cytogenetic data were not clear, these have not, to date, been incorporated into the standardized criteria (see next).

CR Unconfirmed (CRu). The patients fulfill criteria for

CR, with the following exceptions:

• Residual lymph node masses more than 1.5 cm in maximum transverse diameter which have regressed by more than 75% of the SPD. Individual nodes which were previously confluent must regress by more than 75% of the SPD compared with the size of the original mass. Indeterminate bone marrow—defined as having increased number or size of lymphoid aggregates without cytologic or architectural atypia.

Partial remission (PR)

• In SPD of the six largest nodes or nodal masses, >50% decrease. Where possible, these masses should be from disparate lymph node regions, be readily measurable and include mediastinal and retroperitoneal masses if these are present.

• No increase in the size of other lymph nodes, liver, or spleen.

• Splenic and liver nodules must regress by at least 50% in the SPD.

• Involvement of other organs is considered assessable but not measurable.

• Bone marrow assessment is regarded as irrelevant because it is assessable but not measurable.

Stable disease (SD)

• Less than PR, but more than progressive disease (PD) (see next)

Progressive disease

• More or equal to 50% increase from the nadir in SPD of any previously identified abnormal node

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