Prognosis Lymphoma is one of the common malignant tumors in China. The survival rate of lymphoma patients has been greatly improved due to their sensitivity to both radiotherapy and chemotherapy. Conforming line single photon emission computed tomography (SPECT, also known as SPECT/PET) is widely used in clinical oncology, which uses 18F-fluorodeoxyglucose (18F-FDG) as a positron imaging agent and is a functional imaging technique at the molecular level. SPECT/PET is more sensitive, accurate, and comprehensive than conventional ultrasound, CT, and MRI, and has shown superiority over conventional imaging tests in judging the efficacy of lymphoma, guiding treatment, and estimating prognosis, and has received more and more attention. In this paper, we reviewed 83 SPECT/PET examinations in 70 lymphoma patients in our hospital to analyze its role in the evaluation of the efficacy of lymphoma patients in the early stage of treatment and after treatment.
Materials and methods
1. Clinical data
From May 1998 to November 2008, a total of 83 SPECT/PET examinations were performed in 70 patients with lymphoma confirmed by surgery or histopathology through puncture biopsy in our hospital. The patients were 38 males and 32 females, with a median age of 49 (17-81) years. There were 57 patients with non-Hodgkin’s lymphoma (NHL) and 13 patients with Hodgkin’s lymphoma (HL). There were 11 cases of Ann Arbor stage I-II and 59 cases of stage III-IV before treatment; 46 cases in group A and 24 cases in group B.
2. Methods
Metabolic imaging was performed with VertexPlusEPIC MCD/AC SPECT/PET from ADAC, USA. 18F-FDG was provided by the Institute of Nuclear Science of the Chinese Academy of Atomic Energy, with radiochemical purity >95%. 18F-FDG was injected with fasting glucose <7.9 mmol/L for at least 4 hours before injection. Rest quietly for 15 minutes before injection of the imaging agent. After intravenous injection of 18F-FDG 129.5 to 168.5 Mbq, rest for 1 hour and urinate for imaging.SPECT/PET acquisition for imaging, each bed acquisition included emission acquisition and transmission acquisition. Each bed was overlapped by 30% to 50%. The images were processed and reconstructed by the 2-iteration method and attenuation corrected (AC) and non-attenuation corrected (NOAC) images were obtained, showing transverse, sagittal, coronal and 3D stereoscopic images.
3.Judgment of examination results
The examination results are analyzed qualitatively and quantitatively. Qualitative analysis, also called visual inspection, means that all images, including X-ray films, computerized fluoroscopic 2D and 3D stereo reconstructed images, are read by at least two experienced nuclear medicine physicians at the same time to determine whether there is abnormal 18F-FDG uptake. The presence of abnormal 18F-FDG uptake outside of normal sites (brain, heart, gastrointestinal tract, kidneys, bladder, etc.) is determined to be a malignant lesion. Quantitative analysis, also called the ratio method, refers to the calculation of the ratio of radioactive counts (T/NT) between tumor and normal tissue. In other words, on the processed 18F-FDG image, the computerized region of interest (ROI) technique is used to outline the ROI at the site of the suspected tumor lesion and the corresponding or adjacent normal tissue site on the opposite side, and the uptake ratio (T/NT) of the suspected tumor tissue to its opposite or adjacent normal tissue (background) is calculated. lesion.
4. Diagnostic and staging criteria
The pathological diagnosis of all patients was made by the Department of Pathology of Peking University First Hospital with reference to the WHO 2001 diagnostic criteria for hematologic lymphoma. Clinical staging was based on the Ann Arbor staging criteria.
5.Efficacy evaluation criteria
Progression-free Survival (PFS) and Overall Survival (OS) were used as follow-up indexes to evaluate the efficacy of treatment, PFS was defined as the time from diagnosis to disease progression, relapse or disease-related death, OS was defined as the time from diagnosis to disease-related death.
6. Statistical methods
SPSS 13.0 software was applied for statistical processing and analysis. Univariate analysis of prognostic factors was performed using the Kaplan-Meier method of survival analysis; Log rank test was used for comparison between groups. Statistical significance of differences was considered at P < 0.05.
Results
1, SPECT/PET metabolic imaging for early efficacy evaluation of chemotherapy A total of 40 patients underwent SPECT/PET examination after 2-4 cycles of chemotherapy, including 5 cases after 2 cycles of chemotherapy, 2 cases after 3 cycles of chemotherapy, and 33 cases after 4 cycles of chemotherapy. Fourteen patients had positive results, of which 10 patients had disease progression or recurrence at 1-15 months (median time 3 months) and 6 patients had death at 6-35 months (median time 16 months). 26 patients had negative results. 26 patients had negative test results, of which 4 patients had disease progression or recurrence at 11-25 months (median time 15 months) and 1 patient died at 12 months follow-up.
Figure 1 Progression-free survival curve of SPECT/PET results after 2-4 chemotherapy sessions
The median progression-free survival was 5.5 months and 15.5 months for those with positive and negative SPECT/PET results after 2-4 chemotherapy sessions, respectively, and the progression-free survival rates were 25%/12.5% and 88.2%/66.8% at 1 year/2 years, respectively, with statistically significant differences between the two groups (P<0.001) (Figure 1).
Figure 2 Overall survival curve of SPECT/PET findings after 2-4 chemotherapy sessions
The median overall survival of those with positive and negative SPECT/PET findings after 2-4 chemotherapy sessions was 12.5 and 17 months, respectively, and the 1-year overall survival rates were 28.8% and 94.1%, respectively, with a statistically significant difference between the two groups (P = 0.003) (Figure 2).
2. Evaluation of the efficacy of SPECT/PET metabolic imaging at the end of chemotherapy
A total of 43 patients underwent SPECT/PET examination at the end of all treatments (including chemotherapy, radiotherapy and bone marrow transplantation). Ten patients had positive results, seven of whom had disease progression or relapse at 2-27 months (median time 10 months) and five of whom died at 8-42 months (median time 19 months). 33 patients had negative results, five of whom had disease progression or relapse at 2-27 months (median time 10 months) and five of whom had death at 8-42 months (median time 19 months). patients had negative test results, of which 5 patients had disease progression or recurrence at 13-48 months follow-up (median time 32 months) and 2 patients died at 33-35 months follow-up (median time 34 months).
Figure 3 Progression-free survival curve of SPECT/PET results at the end of treatment
The median progression-free survival for those with positive and negative SPECT/PET results at the end of treatment was 10 months and 23 months, respectively, and the progression-free survival rates at 1 year/2 years were 46.7%/23.3% and 92.4%/83.2%, respectively, with statistically significant differences between the two groups (P<0.001) (Figure 3).
Figure 4 Overall survival curve of SPECT/PET findings at the end of treatment
The median overall survival for those who had positive and negative SPECT/PET results at the end of treatment was 17 and 27 months, respectively, and the overall survival rates at 1 year/2 years/3 years were 90.0%/60.0%/40.0% and 100%/100%/82.5%, respectively, with a statistically significant difference between the two groups (P = 0.001) (Figure 4).
Discussion
Lymphoma is a malignant tumor of the hematologic system with a trend of increasing incidence year by year, with more than 4.5 million patients worldwide. Currently, CT and ultrasound, as conventional imaging methods for lymphoma staging and follow-up, have a low detection rate for small and early limited lesions [2], and have limitations in the identification and restaging of residual tumor foci, scar tissue, and tumor recurrence after treatment [3]. 18F-FDG, the tracer of SPECT/PET, is a glucose analogue that is taken up by the cell membrane transporter protein and phosphorylated intracellularly by hexokinase action to generate 6-phosphate deoxyglucose, but cannot continue down the glucose metabolic pathway. At the same time, due to the negative charge of deoxyglucose 6-phosphate, it cannot pass through the cell membrane freely, and the glucose-6-phosphatase catalyzed dephosphorylation of deoxyglucose 6-phosphate in cardiac muscle, brain and tumor cells is weak, therefore, the 18F -SPECT/PET reflects the local metabolism of tumor and detects the biological characteristics of the disease, which is an efficient and non-invasive functional imaging technique. It shows superiority over conventional detection methods in early diagnosis and accurate staging of lymphoma, guiding treatment, judging efficacy, and estimation of recurrence and prognosis.
The combination of chemotherapy and radiotherapy in modern medicine has significantly improved the long-term survival rate of lymphoma patients. However, long-term follow-up has shown that treatment has also brought about many serious long-term adverse effects, including cardiopulmonary disease and second tumors. A 15-year follow-up study of patients with early-stage HL showed that treatment-related mortality was even higher than disease-related mortality. To reduce the number of long-term adverse effects of treatment, treatment regimens should be more individualized. The trend in lymphoma treatment is toward a prognostic risk factor-dependent treatment paradigm that strikes a balance between lowering treatment doses, improving patient quality of life, and reducing long-term relapse rates and mortality.
The prognostic risk factor-dependent treatment paradigm relies on an early and reliable prognostic stratification system. The most commonly used of the existing lymphoma prognostic stratification is the International Prognostic Index (IPI), which includes age, gender, stage, hemoglobin, lymphocytes, leukocytes, and albumin levels for HL patients, and age, stage, number of extra-nodal involvement sites, life status, and serum LDH levels. All existing prognostic risk factors do not address patient response to treatment, which is likely the most important independent risk factor. Currently, the evaluation of the efficacy of tumor patients is mainly based on the size of the tumor after treatment as a reference, but the performance of local tissue morphological changes induced by treatment lags behind tumor cell death when treatment is effective compared with tissue metabolic activity, and, conventional anatomical detection techniques such as X-ray radiography, CT, ultrasound or MRI do not distinguish well between the residual living tumor tissue after treatment and the fibrotic, scarred or necrotic tissue after treatment. However, SPECT/PET 18F-FDG imaging, which reflects the functional and metabolic changes, can reflect the treatment effect of lymphoma more accurately by observing the reuptake or not of 18F-FDG and the amount of uptake. FDG imaging after 3 cycles of chemotherapy, 5 cases were positive and 17 negative. At a median follow-up of 24 months, four of the five patients with positive results had disease progression, while only two of the 17 patients with negative results progressed. In another study including 121 patients with NHL (75 of whom had diffuse large B lymphoma), the role of 18F-FDG imaging after 2-3 cycles of chemotherapy was evaluated. The median follow-up time for all patients was 24.4 months. Progression-free survival at 5 years was 88% in patients with negative test results compared to 16.2% in those with positive results [6].In a retrospective analysis with a median follow-up of >3 years and including 85 patients with HL, Hutchings et al [7] noted that 18F-FDG metabolic imaging after 2-3 cycles of chemotherapy had a prognostic Kostakoglu et al [1] evaluated 18F-FDG uptake in 30 lymphoma patients before treatment and after cycle 1 chemotherapy. 15 patients were positive after 1 cycle of chemotherapy and 13 (87%) of them relapsed or persisted without remission. 18F -FDG imaging results were highly predictive of disease remission, with 87% of patients in complete remission at a median follow-up of 19 months. 23 patients underwent 18F-FDG imaging again at the end of all chemotherapy, but the false-negative rate (35%) was high, with reduced sensitivity and positive predictive value for prognosis, and therefore less relevant to progression-free survival. The correlation with progression-free survival was not as good as after the first cycle of chemotherapy.
One of the most critical issues in the early evaluation of treatment is the timely and accurate determination of whether the tumor is in remission, stable or progressive, so that those patients who are not sensitive to conventional chemotherapy regimens can be promptly identified and switched to more aggressive chemotherapy regimens or increased radiotherapy; those who are sensitive to treatment can avoid overtreatment and the resulting toxic effects and improve their prognosis. It has been demonstrated that those patients who are fast-acting to treatment achieve longer-term remission [8]. In this study, 40 patients underwent SPECT/PET early in chemotherapy (after 2-4 cycles), 24 patients had negative results, indicating that their tumor cells had good sensitivity to chemotherapeutic agents, and only 4 of them progressed and 1 died during follow-up. 10 of the 16 patients with positive findings progressed and 6 died. The median PFS was 15.5 months and 5.5 months, and the median OS was 17 months and 12.5 months for patients with negative and positive SPECT/PET findings early in chemotherapy, respectively, which were statistically significantly different. Positive SPECT/PET findings early in chemotherapy are an important risk factor for poor prognosis in patients with lymphoma.
The inflammatory response after chemotherapy leads to high FDG uptake, while the “suppressive” effect of chemotherapy leads to reduced FDG uptake by tumor cells, which affects the accuracy of 18F-FDG imaging results. The longer the interval, the higher the accuracy. On the other hand, 18F-FDG imaging needs to be performed as soon as possible in the early stage of treatment to evaluate the response to treatment and to guide the next step of treatment. Therefore, the time of 18F-FDG imaging in the early stage of treatment should be chosen after the end of the previous cycle of chemotherapy and when the next cycle of treatment is about to start.
Achieving complete remission is a necessary condition for curing lymphoma, and patients in complete remission can achieve longer progression-free survival than patients in partial remission. In this study, 43 patients underwent SPECT/PET examination at the end of all treatments. 33 patients had negative results, indicating that they had no SPECT/PET detectable residual tumor at the lesion, and only 5 of them progressed and 2 died during follow-up. 7 of the 10 patients with positive findings relapsed and 5 died. The median PFS of patients with negative and positive SPECT/PET findings at the end of treatment were 23 and 10 months, respectively, and the median OS was 27 and 17 months, respectively, which were statistically significant differences. Positive SPECT/PET findings at the end of treatment are an important risk factor for poor prognosis in patients with lymphoma.
The high correlation between early chemotherapy and post-treatment SPECT/PET findings and prognosis can be used to guide treatment dependent on prognostic risk factors. Patients with negative SPECT/PET findings early in chemotherapy need only be treated with the standard regimen and no additional treatment is necessary. Patients with positive early chemotherapy findings, especially when combined with other risk factors, are predicted to be at high risk of progression, recurrence and death. Patients with negative SPECT/PET results after all treatment do not need to receive further treatment. Patients with positive results at the end of treatment should be considered for further treatment after “false positives” have been excluded.