Maligne lymfomen: stadiëring en response evaluatie algemeen

Datum laatste herziening: 16-10-2009

Stadiumindeling (volgens Ann Arbor met Cotswolds aanbeveling)

Onderverdeling van alle stadia in A en B (aan te geven als suffix):

Definities

Positieve milt bij maligne lymfoom: onmiskenbare palpabele splenomegalie, of twijfelachtige splenomegalie met op de CT scan of echo multipele focale defecten die niet op cysten of vaatafwijkingen berusten en PET positief zijn indien het lymfoom FDG avide is (zie verder bij FDG-PET) Een vergrote milt op de echo of CT alleen is onvoldoende voor de diagnose positieve milt.

Leveraantasting: multipele focale defecten die niet op cysten of vaatafwijkinge berusten, vastgelegd m.b.v. ten minste 2 imaging technieken en/of PET positief indien het lymfoom FDG avide is(zie bij PET scan). Hepatomegalie alléén of leverfunctiestoornissen alléén zijn onvoldoende voor de diagnose lever-involvement. In dat geval: leverbiopt doen.

Botaantasting: botscan/CT/MRI scans waar mogelijk bevestigd door FDG-PET.

Tot het lymfatisch apparaat behoren: lymfklieren, milt, thymus, ring van Waldeyer, plaques van Peyer, appendix.

Lokalisaties: Cervicaal en supraclaviculair aan één zijde geldt als één lokalisatie. Idem axillair en infraclaviculair aan één zijde. Mediastinum + hili gelden als één lokalisatie. Doorgroei in longweefsel vanuit een hilair- of mediastinaal klierpakket, dus per continuitatem, geldt als extranodale lokalisatie en niet als stadium IV.

Bulky disease (≥ 10 cm tumor diameter; > 0,35 Mediastinum/Thorax (MT) ratio) wordt met subscript 'X' aangegeven.

Extranodal disease met subscript 'E'.

Definities overleving

Progression Free Survival (PFS) is the time interval between the date of start therapy, or date of first (or second) randomisation and the date of disease progression or death, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow up examination.

Overall Survival (OS) is the time interval between the date of start therapy, or date of first randomisation and the date of death. Patients who were still alive when last traced are censored at the date of the last follow up.

The response groups are:

• Complete remission (CR);
• Complete remission/unconfirmed (CRu);
• Partial remission (PR);
• Stable disease (SD);
• Progressive disease/Relapse (PD).

Response criteria

Hieronder volgt de tekst van de zogenaamde Cheson criteria, zoals gehanteerd door de HOVON Werkgroep Maligne Lymfomen. Het is belangrijk de nieuwe plaats van PET en de rol van flowcytometrie en immunohistochemie van beenmerganalyses te registreren.

Cheson’s criteria

Response to treatment will be evaluated after the end of chemotherapy and at relapse. Evaluation of response will be done according to the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma (Cheson et al., 2007).

The following criteria are considered anatomic definitions (Table 1). PET is strongly commended before treatment for patients with routinely FDG-avid, potentially curable lymphomas. PET is essential for the post-treatment assessment of DLBCL and Hodgkin lymphoma. One has to be aware of false-positive PET results related to rebound thymic hyperplasia, infections, inflammation, sarcoidosis, or brown fat. Diffusely increased BM uptake is often seen after G-CSF. False-negative results are related to the resolution of the equipment, technique and variability of FDG avidity among histologic subtypes.

1. CR requires the following:
   1. Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalisation of those biochemical abnormalities (e.g. lactate dehydrogenase [LDH]) definitely assignable to NHL.
   2. PET evaluation:
      • Typically FDG-avid lymphomas: in patients with no pretreatment PET scan or when the PET scan was positive before treatment, a post-treatment residual mass of any size is permitted as long as it is PET negative.
      • Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT as defined below.
   3. All lymph nodes and nodal masses must have regressed to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long axis and > 1.0 cm in their short axis before treatment must have decreased to ≤ 1 cm in their short axis after treatment.
   4. The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination. However, no normal size can be specified because of the difficulties in accurately evaluating splenic and hepatic size. For instance, spleens thought to be of normal size may contain lymphoma, whereas an enlarged spleen may not necessarily reflect the presence of lymphoma but variations in anatomy, blood volume, the use of hematopoietic growth factors, or other causes. Any macroscopic nodules in any organs detectable on imaging techniques should no longer be present. Similarly, other organs considered to be enlarged before therapy due to involvement by lymphoma, such as liver and kidneys, must have decreased in size.

   If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow aspirate and biopsy of the same site. The sample on which this determination is made must be adequate (> 20 mm biopsy core). If the sample is indeterminate by morphology, it should be negative by immunohistochemistry. A sample that is negative by immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow cytometrie will be considered a CR until data become available demonstrating a clear difference in patient outcome.

   B. Unconfirmed (CRu). This entity can be eliminated.

    

2. PR requires the following:
   1. 50% decrease in SPD of the six largest dominant nodes or nodal masses. These nodes or masses should be selected according to the following features:
      1. they should be clearly measurable in at least two perpendicular dimensions,
      2. they should be from as completed disparate regions of the body as possible, and
      3. they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
   2. No increase in the size of the other nodes, liver, or spleen.
   3. Splenic and hepatic nodules must regress by at least 50% in the SPD.
   4. With the exception of splenic and hepatic nodules, involvement of other organs is considered assessable and not measurable disease.
   5. Bone marrow assessment is irrelevant for determination of a PR because it is assessable and not measurable disease; however, if positive, the cell type should be specified in the report and preferably confirmed by immunohistochemistry.
   6. No new sites of disease.
   7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET scan was positive before therapy, the post-treatment PET should be positive in at least one previously involved site.
   8. Variably FDG-avid lymphomas/FDG-avidity unkown: for patients without a pretreatment PET scan, or if a pretreatment PET scan was negative, CT criteria should be used.
   9. In patients with follicular lymphoma or mantle cell lymphoma, a PET scan is only indicated with one or at most two residual masses that have regressed by more than 50% on CT; those with more than two residual lesions are unlikely to be PET negative and shoul be considered partial responders.
3. Stable disease/No change is defined as less than a PR (see above) but is not progressive disease (see below). Typically FDG-avid lymphomas: the PET should be positive at prior sites of disease with no new areas of involvement on the post-treatment CT or PET. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan or if the pretreatment PET was negative, there must be no change in the size of the previous lesions on the post-treatment CT.
4. Relapsed disease (after CR)/Progressive disease requires the following:
   1. Appearance of any new lesion or increase by (≥ 50%) in the size of previously involved sites.
   2. ≥ 50% increase in greatest diameter of any previously identified node greater than 1.5 cm in its short axis or in the SPD of more than one node.
   3. Appearance of any new lesion during or at the end of therapy,even if other lesions are decreasing.
   4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesions was PET positive before therapy unless the lesion is too small to be detected with current PET systems (<1.5 cm in its long axis by CT).
   5. NB: Increased FDG uptake in a previousy unaffected site should only be considered relapsed or progressive disease after confirmation with other modalities.
   6. In patients with no prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly benign.

Response assessment

1. CT scans remain the standard for evaluation of nodal disease. Thoracic, abdominal, and pelvic CT scans are recommended even if those areas were not initially involved because of the unpredictable pattern of recurrence in NHL. Studies should be performed no later than 4 weeks after the end of treatment to assess response.
2. The role of FDG-PET scans needs to be assessed depending on the type of lymphoma, the presence of pretreatment data and the quality of the center. See above.
3. A bone marrow aspirate and biopsy should only be performed to confirm a CR if they were initially positive or if it is clinically indicated by new abnormalities in the peripheral blood counts or blood smear. A histologically normal bone marrow with a small (<2%) clonal B cell population detected by flow cytometrie should be considered normal. It is strongly advised that additional immunohistochemistry is applied for specific subtypes of NHL. The use of rituximab can cause false-negative results, however, and other B cell markers than CD20 should be applied in those cases.

Table 1. Response Criteria for Non-Hodgkin's Lymphoma

In case of relapse after initial complete remission the following information will be registered:

• Date of relapse.
• Site of relapse.
• Whether there is histological or cytological confirmation of the relapse.

FDG-PET scanning

In de nieuwe CHESON guidelines 2007 is de rol van de FDG-PET scan nu zorgvuldig gedefinieerd voor het evalueren van responsen na therapie. De komende jaren zal in de nieuwe studies (EORTC (Hodgkin) H10 studie, meerdere HOVON NHL studies) de PET scan gebruikt gaan worden bij de response meting tijdens therapie. Bij het Hodgkin lymfoom en recidief agressief NHL wordt inmiddels aangenomen dat een positieve scan halverwege (re-)inductietherapie voorspellend is voor een slechte prognose (Schot et al., 2003; Gallamini et al., 2007). Meerdere groepen hebben dezelfde ervaring wanneer PET wordt toegepast bij de initiële therapie halverwege R-CHOP (-like) bij het agressieve NHL (Juweid et al., 2005; Juweid en Cheson, 2005). Echter, deze data zijn nog onvoldoende uitgekristalliseerd voor PET-geleide sturing van de behandeling buiten studie verband.

PET lijkt zeer bruikbaar om bij evaluatie van tumorrespons onderscheid te maken tussen CR en PR wanneer sprake is van residuale massa’s na afloop van chemotherapie en radiotherapie, rekening houdend met het type lymfoom en pre-treatment PET gegevens (zie hierboven). Belangrijk is daarbij rekening te houden met vals-positieve uptake in het geval van rebound thymus hyperplasie, of ontstekingsprocessen. Wanneer G-CSF is gebruikt, zal de beenmerguptake sterk toenemen, hetgeen wel eens abusievelijk als lymfoomactiviteit is geïnterpreteerd. Na radiotherapie kan de PET het beste 6-8 weken na de bestraling worden gemaakt.

Zie ook Profylaxe en behandeling van meningeale leukemie en lymfoom.

Literatuur

• Cheson BD, Pfistner B, Juweid ME et al. Revised Response Criteria for Malignant Lymphoma. J Clin Oncol 2007;25:579-586.
• Gallamini A, Hutchings M, Rigacci L et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 2007;25:3746-3752.
• Juweid ME, Cheson BD. Role of Positron Emission Tomography in Lymphoma. J Clin Oncol 2005; 23.
• Schot B, Van Imhoff G, Pruim J et al. Predictive value of early 18F-fluoro-deoxyglucose positron emission tomography in chemosensitive relapsed lymphoma. Br J Haematol 2003; 123:282-287.