The Clinical Applications Of¹¹C-choline(CHO) Uptake In Brain Metastasis Derived From Non-small Cell Lung Cancer And Analysis Of Factors Relation To Survival

BACKGROUND AND OBJECTIVE:Lung cancer is the most common cancer worldwide and a leading cause of mortality. Non-small cell lung cancer(NSCLC) accounts for about75%～80%of the total lung cancer. The incidence of brain metastases with NSCLC appears to be rising year by year as a result of superior imaging modalities, earlier detection, and more effective treatment of systemic disease.Over the years, the diagnosis of brain metastases depends mainly on computed tomography (CT) and magnetic resonance imaging (MRI), especially MRI. However, conventional and enhanced MRI scan cannot provide the extent and heterogeneity of tumor proliferation and other biological information because it reflects the water content of the lesion, blood flow void phenomenon and contrast agent through the blood-brain barrier into the lesion. Positron-emission tomography (PET) can provide valuable metabolic information by the use of positron labeled glucose, amino acids and other metabolites in the human body as an imaging agent. PET/CT combines the functional imaging of PET and precise positioning of CT and is used for quick accessing of multi-level images, three-dimensional quantitative results, and three-dimensional body scan, which is important in early diagnosis and prognosis of brain metastases. Recently,11C-choline has been introduced as a new tracer for PET imaging in a variety of malignant tumors. In tumor cells, the only metabolic way of choline is to participate in the synthesis of phospholipid. Choline is incorporated into cells through phosphorylcholine synthesis and is integrated into the cell membranes. Once phosphorylated, choline will stay in the cell, which is called "chemical retention." This provides the biological rationale for the use of [methyl-11C]choline (11C-choline) in oncological PET studies. In vitro phosphorus-31magnetic resonance spectroscopy studies have revealed the high content of phosphorylcholine in most cancers; while in corresponding normal tissues this choline metabolite is present at low or undetectable levels. Moreover, phosphorylcholine will reduce when a treatment is effective. Therefore, the choline uptake rate of tumor tissue reflects not only the rate of synthesis of the cell membrane, but also an indicator of tumor cell proliferation.The tracer of11C-choline has the advantage of clear tumor imaging with the surrounding normal tissue a very limited uptake of choline, a very low radioactivity, a relatively high tumor11C-choline uptake, and a high radioactivity of tumor/non tumor ratio. If applied properly,11C-choline has potential advantages in brain tumor imaging, although that may make a certain false positive and false-negative rate for the reason of an increased uptake in some benign tumors and tumor-like lesions.Over the past several decades, WBRT has been the mainstay of treatment for brain metastases and increased the median survival time to3to6months. More recently, the combination of WBRT with temozolomide (TMZ), especially with a low-dose has shown promising response rates in NSCLC patients with brain metastases. Clinical variables predictive of survival in patients with brain metastases have been well studied. Important variables include:age, performance status (most commonly designated by the Karnofsky performance status [KPS] score, number of brain metastases (single or multiple), primary tumor type, and systemic tumor activity (controlled versus uncontrolled). Of these, the KPS score has consistently been shown to be the major determinant of survival, secondary only to treatment regimen in most studies. Time from primary tumor diagnosis to development of brain metastases holds prognostic value as well, with long intervals being favorable.11C-CHO PET is supposed to have some prognosis value for it good imaging in brain metastases which reflects the proliferation of tumor cells.STUDY CONTENTS:1. Clinical usefulness of11C-choline PET/CT for identifying NSCLC with brain metastasis.2. Low-dose temozolomide concomitant with whole-brain radiotherapy compared with whole-brain radiotherapy alone for non-small cell lung cancer patients with brain metastases.3. Analysis of prognostic factors of survival in NSCLC patients with brain metastases.METHODS:1. MR imaging and11C-choline PET/CT examinations were performed in30NSCLC patients with brain metastasis or suspected brain metastases.11C-choline uptakes were evaluated by a visual analysis and semi-quantitative analysis using the standardized uptake value (SUV). Analysis the correlation between SUV values and gender, age, pathological type and ECOG score. Calculate the sensitivity and specificity of the various indicators of11C-choline PET/CT imaging in diagnosis of brain metastasis.2.90patients diagnosed with brain metastases underwent treatment and for a long-term follow-up. Analysis the correlations between long-term survival and various clinical factors and biological factors by Cox proportional hazards model, such as gender, age, pathological type, ECOG score, treatment patterns and11C-CHO intake.3. Ninety NSCLC patients with untreated brain metastases were randomly assigned to receive either low-dose temozolomide concomitant with WBRT or WBRT alone. Clincial efficacy and toxicity were compared after a long-time follow up. 4. Pathological examination:Routine HE staining and immunohistochemical examination for biopsy specimens, and observation of biopsy specimens under an optical microscope.5. Statistical analysis:Statistical analysis was performed with the SPSS13.0software. Quantitative results were expressed as mean±SD (X±s), median, and range. The sensitivity, specificity, accuracy, and positive and negative predictive values were calculated. Differences in continuous variables between groups were evaluated using the Student's t test or the Mann-Whitney rank sum test. Patient groups were compared using the χ2test. The Fisher exact test was used for comparison of frequencies, and Spearman correlation coefficients were calculated to quantify bivariate correlations between data. A receiver operating characteristic (ROC) analysis was performed to compare the diagnostic ability. Cox proportional hazards model was used for multivariate regression analysis. A P-value of<0.05was considered significant.RESULTS:1. Of30NSCLC patients26were confirmed with brain metastases after surgery, magnetic resonance imaging and/or follow-up, with a total of45metastatic lesions. The diagnostic sensitivity of brain metastases with11C-choline is86.7%(39/45), the specificity is85.7%(6/7), th accuracy is86.5%(45/52).2. The means of the four semi-quantitative indicators of SUVmax, L/WM, L/CTX and L/MCU are1.1276,4.1160,9.0769,4.7203, respectively,which have high diagnostic value for brain metastases, with all AUCs>0.9(P<0.01).3. Metastasis diameter has statistical correlation with SUVmax, with a correlation coefficient of0.454(P<0.01). There are no statastical differences of tumor sizes and SUVmax values between different sexes and different age intervals.4. The means of the four semi-quantitative indicators of SUVmax, L/WM, L/CTX and L/MCU in brain metastases with squamous cell carcinom are1.3178,5.1638, 10.3739,5.4774, respectively, and in brain metastases with adenocarcinoma are1.0007,3.4175,8.2119,4.2156, respectively. The identification values of different pathological types with the four semi-quantitative indicators are poor, with AUCs being0.642,0.711,0.626,0.619, respectively. Only the indicator of L/MCU has a certain degree of identification,(P=0.018).5. The response rate was73.3%and77.8%for the WBRT with concurrent low-dose temozolomide arm and WBRT alone arm, respectively(P>0.05). The median survival time was10.0months in the WBRT with concurrent low-dose temozolomide arm and7.7months for WBRT alone arm. There was a survival advantage in the combination arm (P=0.002).6. Headache, rash and alopecia were common in both arms, even more than grade III hair loss was frequent. Hematological and gastrointestinal toxic effects were mild in WBRT alone arm. The most common adverse events in WBRT with concurrent low-dose temozolomide arm were hematologic toxicity and gastrointestinal reactions. More than grade Ⅱ hematological toxicity, gastrointestinal reactions and abnormal liver function were significantly more frequent in the combination arm than those in the WBRT alone arm.7. Cox proportional hazards model analysis in survival data of90patients showed that primary tumor histological type, ECOG score, combined visceral metastasis and simultaneous temozolomide chemotherapy is an independent factor affecting survival (P<0.05), while gender, age and the number of brain metastases has no correlations with survival (P>0.05). The other Cox proportional hazards model analysis in survival data of26patients with brain metastases showed that SUVmax, L/WM and L/MCU affect survival (P<0.05), while L/CTX affect none on that of survival (P>0.05).CONCLUSION:1.11C-CHO PET/CT is very effective in detecting brain metastasis originating from NSCLC, but is limited in identifying pathological types. Pathological type and diameter has statistical correlation with11C-CHO up-take, while sex and age has no statistical correlation with that of11C-CHO.2. WBRT combined with low dose TMZ significantly prolonged survival than WBRT alone for NSCLC patients with brain metastases and was well tolerated. Clinical factors relevant to survival are primary tumor histological type, ECOG score, combined visceral metastasis and simultaneous temozolomide chemotherapy, and biological factors relevant to survival are SUVmax, L/WM and L/MCU. These clinical and biological factors can to some extent nredict prognosis.