PET-CT is a non-invasive examination technique with three-dimensional imaging and metabolic imaging, which can reflect the physiopathological condition of organs and tissues and the anatomical structure of lesions, and has obvious advantages over traditional imaging techniques such as CT and magnetic resonance imaging (MRI), and has been widely used in the staging, efficacy evaluation and prognosis assessment of various tumors.
PET-CT is more sensitive and specific in detecting lymphoma lesions and evaluating their efficacy, especially in distinguishing necrosis, fibrous tissue or tumor, than CT or MRI.
Because of this, PET-CT has gained great attention in the field of lymphoma since its introduction, and has been partially introduced into the staging of lymphoma in clinical guidelines such as NCCN, and the criteria for efficacy assessment have been revised accordingly. For more than a decade, the actual clinical application of PET-CT in lymphoma has remained controversial, despite the large number of studies reported.
I. Application of PET-CT in lymphoma staging
The value of PET-CT in lymphoma staging is reflected in.
①Does it help to stage more accurately?
(ii) Is more accurate staging necessary?
(iii) whether it can change the treatment strategy and thus affect the patient’s prognosis.
The reported findings generally suggest that the sensitivity of PET-CT (95%-100%) is better than that of conventional CT (77%-90%), and the sensitivity of PET-CT and enhanced CT for extra-nodal lesions is 88% and 50%, respectively, and the specificity is 100% and 90%, respectively. For determining invasion of lymph nodes, spleen, lungs and bones, PET-CT is more advantageous due to its low false-positive rate.
However, it should be noted that only follicular lymphoma (FL) has some uptake activity for 18 fluoro-2-deoxy-D-glucose (18F-FDG) among inert lymphomas, while small B-cell lymphoma and marginal zone lymphoma (MZL) have very low uptake activity, and T-cell lymphoma has a large variation in uptake activity. Therefore, the application of PET-CT in these types of lymphomas is still limited.
At the 2013 Lugano International Lymphoma Conference, in the initial report of the AnnArbor Staging Revision Work Plan for Lymphoma, it was concluded that PET-CT could replace bone marrow aspiration biopsy in Hodgkin’s lymphoma (HL), and that if PET-CT showed positive bone marrow, it could be determined to be bone marrow invasion without the need for bone marrow invasion. Bone marrow invasion was determined and a bone marrow aspiration biopsy was not necessary.
In diffuse large B-cell lymphoma (DLBCL), unless PET-CT clearly shows bone marrow invasion, bone marrow aspiration biopsy should be performed to exclude mild bone marrow invasion. For other types of lymphoma, PET-CT cannot yet be used to evaluate bone marrow invasion.
Because Ann Arbor staging of lymphoma is a relatively “rough” staging with the lymph node area and extra-nodal organs as the invasion unit and the diaphragm as the main staging boundary, the rate of clinical staging change is not high despite the higher sensitivity of PET-CT, for example, the up-regulation rate for HL and DLBCL is <20% and the down-regulation rate is <10%. The down-regulation rate was <10% for HL and DLBCL. < p="">
Because treatment options do not differ significantly between stages I and II and between stages III and IV in many lymphomas, even if the high sensitivity of PET-CT changes the clinical stage, less than 15% of patients will require adjustment of the treatment plan, and most of them will only have a revised number of treatment cycles and radiotherapy sites.
Thus, the advantages of PET-CT in improving clinical staging and prognosis have not been fully demonstrated. However, at least in HL and DLBCL, the value of PET-CT in staging has been confirmed.
II. Advantages of PET-CT in the evaluation of efficacy and its limitations
The greatest value of PET-CT in lymphoma is mainly in the evaluation of efficacy. PET-CT has better discrimination ability than ordinary CT because it can show the metabolic activity of the lesion.
The value of PET-CT in the mid- and post-treatment evaluation of DLBCL and HL is relatively well established, with a negative predictive value (NPV) of 85-90% and a very low positive predictive value (PPV), i.e., a low false positive rate.
Studies have shown that the accuracy of PET-CT for HL restaging is as high as 95.9%, and the efficacy ratio is very high, accounting for only about 1% of the total cost of HL treatment. The results of the German HD15 study showed that the use of post-treatment PET-CT allowed some patients to avoid radiotherapy for residual foci. However, there are many unanswered questions.
1. At which time point is it more appropriate to perform the efficacy assessment examination? Since inflammatory reactions after radiotherapy or chemotherapy can lead to false positive PET-CT results, the “2007 Revised Cheson Criteria for Efficacy Assessment” stipulate the time points for mid-term and post-treatment PET-CT examinations, but there is still the problem of post-treatment inflammatory reactions affecting the results.
2. How many treatment cycles should be set for the so-called intermediate PET-CT? Some studies suggest that PET-CT after 2 cycles (PET2) is sufficient to reflect the treatment effect and assess the prognosis, but there are also studies with opposite results, especially for DLBCL, where changing the treatment plan because of a positive PET2 could lead to more patients receiving second-line treatment options with less efficacy.
Anthracyclines are key agents in the treatment of DLBCL, and treatment with only 100 mg/m2 adriamycin may put some patients into the relapse-refractory category, necessitating more intense chemotherapy or even autologous hematopoietic stem cell transplantation.
At present, the value of PET2 for efficacy assessment of HL is generally recognized, but for other types of lymphoma, especially DLBCL, PET-CT after 3~4 cycles (PET3/PET4) is more recognized.
3. Can the treatment strategy be changed due to the mid-term PET-CT results? However, for DLBCL, there is limited evidence-based medical evidence and the US NCCN guidelines only recommend revising the next treatment strategy after 4 cycles of chemotherapy for stage III-IV DLBCL patients based on PET-CT results;
However, it is also recommended that biopsy should be performed before changing the treatment plan, and in the newly revised 2012 European Guidelines on Medical Oncology (ESMO) for DLBCL, it is recommended that follow-up treatment for elderly patients can be adjusted based on PET-CT results after 4 weeks of chemotherapy, and chemotherapy can be reduced to 6 cycles if it is negative.
4.How to accurately interpret PET-CT (especially mid-term) results? In a 2007 study, the value of PET2 in determining the prognosis of 92 DLBCL patients was evaluated by visual inspection and SUVmax reduction method (65.7% reduction threshold). The SUVmax reduction method was superior to the visual method.
However, analysis of PET4 results in 80 DLBCL patients 2 years later showed that the visual method and the SUVmax reduction method were similar in evaluating the prognostic value of PET4. There are several methods of PET-CT interpretation, but they are mainly applied after the end of treatment (e.g. Juweid criteria).
In recent years, the Deauville criteria (5-point scale) have been increasingly used in the interpretation of intermediate-term PET-CT, which theoretically provides a more realistic picture of the value and limitations of intermediate-term PET-CT, and was recognized in the 2013 Lugano International Lymphoma Conference in the “Revised Work Plan for the Evaluation of Lymphoma Efficacy “It was also recommended by the NCCN guidelines of HL 2013, but more studies are needed to confirm whether it can be widely accepted.
5. Is PET-CT applicable to the efficacy evaluation of all types of lymphoma? Similar to the problems encountered in lymphoma staging, PET-CT does not have efficacy evaluation value for all types of lymphomas, such as inert lymphomas like FL and borderline B-cell lymphoma, and mantle cell lymphoma (MCL), and conventional CT remains the first choice for efficacy evaluation of these lymphomas.
III. Whether PET-CT can assess the prognosis of lymphoma patients
PET-CT may be more advantageous for assessing the prognosis of lymphoma patients than the traditional International Prognostic Index (IPI) scoring system or gene expression profiling, which are based on the analysis of patient population data; and gene expression profiling, which reflects individual prognostic factors but, like IPI, are both static factors before treatment.
PET-CT, on the other hand, reflects the sensitivity and resistance of individual patients to chemotherapy regimens during the course of treatment, and is a dynamic monitor, and therefore more valuable for guiding individualized treatment. Most studies to date have also shown PET-CT to be a prognostic factor independent of IPI scores.
However, there are many problems in assessing patient prognosis with PET-CT, consistent with those that exist in its efficacy evaluation, i.e., the time point of the examination, how to interpret the results more accurately, and the type of lymphoma to which it applies. Can PET-CT before bone marrow transplantation predict outcome?
In a meta-analysis summarizing data from 12 studies (630 patients), including 187 with HL and 313 with DLBCL, the sensitivity and specificity of PET-CT for assessing prognosis were 69% and 81%, respectively, and PET-positive patients had significantly lower 3-year PFS or EFS (31%-41%) than PET-negative patients (75%-82%). 82%). It is generally accepted that PET-CT after salvage chemotherapy or before transplantation can be used as a means to assess prognosis.
IV. Can PET-CT be used for follow-up and monitoring of recurrence
The main purpose of follow-up is to monitor recurrence. However, data from multicenter studies in Europe and the United States show that more than 95% of lymphoma relapses are detected by patients or physicians through clinical presentation, routine physical examination and general laboratory tests, and imaging has a limited role in early detection of lymphoma relapses, and patients’ prognosis does not improve with early detection of relapses.
The high cost of PET-CT and radiation are also issues that have to be considered.
Some patients with low-grade malignant lymphoma and low-risk, aggressive lymphoma with low risk of recurrence have a low recurrence rate or long PFS, so PET-CT as a follow-up is clearly not a reasonable option. In patients with inert lymphoma with suspicious relapse on routine examination, PET-CT examination can help to detect hypermetabolically active lesions and guide biopsy when the clinical presentation suggests the possibility of transformation to large cells.
In summary, the basic consensus is that PET-CT is mainly recommended for DLBCL and HL as a routine staging and efficacy evaluation tool, with promising applications for other aggressive lymphoma types and limited value for certain inert lymphomas; for HL, mid-stage PET-CT has value in suggesting prognosis and guiding subsequent treatment, and the Deauville criteria are recommended For DLBCL, changes in treatment regimen based on mid-term PET-CT results need to be made with caution; PET-CT is not recommended as a routine follow-up test for any type of lymphoma.