| Lung cancer is the leading cause of cancer death in both men and women worldwide. Every year, an estimated1,350,000patients are diagnosed and1,200,000died from this disease, with over85%of these patients expected to have non-small cell lung cancer (NSCLC). Unfortunately, the majorities of patients present with advanced stage disease and are inoperable. The multi-therapy based on radiation, chemotherapy and target therapy is the mainstay of treatment in advanced disease. Better knowledge of the biological background of tumors and the availability of new drug and technologies offer oncologists the possibility to develop a more personalized treatment of cancer not only on an anatomical basis but on a molecular basis as well. However, everyday practice points out several clinical questions for many oncologists. For example, how to select patients who have a better prognosis could influence treatment decisions, how to potentially reduce therapeutic toxicity with the ultimate goal of improving survival, and so on. Considering all these clinical questions, molecular imaging may be a potential new tool for cancer patient's care.Positron emission tomography (PET) is the most sensitive and specific technique for imaging molecular pathways in vivo in man. PET uses positron-emitting radionuclides to label molecules, which can then be imaged in man. The inherent sensitivity and specificity of PET methodology is the major strength of technique. PET can image molecular interactions and pathways, providing quantitative kinetic information down to the subpicomolar level. PET/CT, which is combined by PET and CT, now is becoming the most useful molecular technology and play an important role in tumor diagnosis, treatment monitoring and treatment evaluation.Part One Molecular Imaging with11C-PD153035PET/CT Predicts Survival in Non-Small Cell Lung Cancer Treated with EGFR-TKIEpidermal growth factor receptor (EGFR), a member of the HER/Erb-B family of receptor tyrosine kinases, mediates cell proliferation, differentiation, survival, angiogenesis, and migration. This molecule consists of an extracellular domain that binds EGF, transforming growth factor alpha (TGF-a), and other growth factors; a short transmembrane region; and an intracellular tyrosine kinase domain. Ligand binding leads to homodimerization of EGFR or heterodimerization of EGFR with another receptor of the Erb-B family and phosphorylation of specific EGFR tyrosine residues. Tyrosine-phosphorylated receptors then recruit intracellular signaling proteins, converting extracellular signals to intracellular signal transduction events. Dysregulation of EGFR signaling pathways contributes to the development of malignancy via effects on cell-cycle progression, inhibition of apoptosis, induction of angiogenesis, and promotion of tumor-cell motility and metastasis. EGFR is known to be expressed more abundantly in malignant than in normal tissue, including40%-80%of NSCLC. The role of EGFR in carcinogenesis led to the development and extensive evaluation of EGFR blocking agents for cancer treatment. Two EGFR-targeted approaches have been explored:(a) mAbs targeting the EGFR extracellular domain and (b) small-molecule TKIs targeting the intracellular EGFR tyrosine kinase domain. The best studied of the anti-EGFR mAbs in NSCLC is cetuximab (ErbituxR; ImClone Systems, Inc., New York). Among the small-molecule TKIs, the best-studied are gefitinib (IressaR; AstraZeneca Pharmaceuticals, Wilmington, DE) and erlotinib (TarcevaR; Genentech, Inc., South San Francisco, CA). Both mAbs and TKIs generally have milder toxicity than conventional drugs, which are cytotoxic. Because they target cellular processes associated with tumor resistance to radiation (e.g., proliferation and angiogenesis), antibodies and TKIs have the potential to be combined effectively with radiotherapy in the treatment of NSCLC.However, overall response rate have been relatively disappointing (10-15%) in studies that examine all NSCLC patients collectively. It is a possibility that not all patients with lung cancer are suitable for anti-EGFR treatment, and that patients should be selected for this treatment. For example, in early studies, clinicians regarded such characteristics as the clinical markers to predict which patient would respond to the EGFR-TKI, including type of the tumor, smoking history, gender, and ethnicity. Despite this, response rate are not as promising as expected. Later several investigators reported that expression and mutation status of the EGFR were also associated with dramatic and durable regressions with these agents in patient with NSCLC. EGFR status has been measured by a variety of techniques, of which the most widely applied is immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), which tumor specimens were derived postoperatively or biopsy accessible. Unfortunately, there are still no suitable methods as a "molecular fingerprint" that can identify the subset of patients which are most likely to benefit from target treatment. Firstly, the biological study is related only to small specimens of tissue, but biological characteristic of solid tumor are not always homogenous and metastases can be quite different from the primary tumors. They can also change during the natural history of disease. Secondly, these markers can not be used to objectively monitor during the treatment. In addition, tumor biopsy often requires invasive and it is not possible to get in all situations.Considering all these questions, molecular imaging may be a potential new tool to involve these problems. PET has been used to follow the tumor response indirectly by measuring the metabolic activity using different tracers in the tumors. With the development of molecular targeted therapy, several TK inhibitors have synthesized. In the seam time, the research of TK inhibitors as a precurosor of PET tracer is increasing. In recent ten years, several reversible and irreversible inhibitors, such as ML01, ML03were labeled with fluorine-18and carbon-11, repectively, and their potential as PET biomarkers was investigated both in vitro and in vivo.18F-ML01,11C-ML03has rapid in vivo metabolism, low bioavailability and, consequently, low accumulation of the labeled compound in the tumor, resulting in low tumor/blood uptake ratios. They can not used as a PET tracer for mornitoring EGFR. PD153035(4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline, AG1517), a quinazoline derivative, has been identified as a drug for the treatment of proliferative disease. PD153035has been shown to potently and selectively inhibit EGFR kinase activity by binding reversibly to the inner membrane ATP binding domain on the EGFR. PD153035was proposed to be used as a PET marker in1999by Fredriksson et al. Previous works confirmed that11C-PD153035tumor uptake was well correlated with EGFR expression. Therefore11C-PDl53035PET/CT has the potential to serve as an imaging marker for treatment monitoring and predicting patients who will respond to EGFR-TKI treatment.Purpose1. To determine whether11C-PD153035PET/CT is selective of the suitable patients with advanced NSCLC who are treated with EGFR-TKI.2. To determine whether early and follow-up11C-PD153035PET/CT can predictive patients'survival.Methods1. Synthesis of11C-PD153035 The general procedure of synthesis and carbon-11radiolabelled of PD153035(ABX advanced biochemical compounds, Germany) was performed in Tracer lab FXc system (GE Healthcare, USA).2. Treatment of NSCLC patients This was a prospective study of serial11C-PD153035PET/CT before and during treatment in patients receiving erlotinib for advanced NSCLC refractory to chemotherapy. Patients received erlotinib at an oral dose of150mg daily. Treatment continued until disease progression or the advent of intolerable adverse effects.3.11C-PD153035PET/CT imaging Baseline "C-PD153035PET/CT was performed within1week before the initiation of treatment, and follow-up11C-PD153035PET/CT was performed at1-2weeks and6weeks after start of treatment. Combined PET/CT scans were performed in the supine position with a PET/CT scanner (Discovery LS; GE Healthcare) capable of multislice helical CT for anatomic imaging and attenuation correction. The standardized uptake value (SUV) was calculated.4. EGFR-TKI treatment response evaluation Contrast CT for treatment monitoring was acquired in all patients within1week before ant at6-week intervals after the start of the treatment, or sooner if indicated by clinical progression. Responses were scored based on the Response Evaluation Criteria in Solid Tumors (RECIST). The best response was recorded for each patient.5. Follow-up of NSCLC patients Overall (OS) and progression-free survival (PFS) times were measured from the start of the treatment to the date of death or progression based on CT. Patients who were alive at the date of the last follow-up were censored for overall survival on that date.6. Statistical analysis Statistical analysis was performed using SAS version9.2.Results1. The median OS and PFS were7.5and2.8months, respectively. The6-month actuarial OS and PFS rates were62%and14%, respectively. 2. Baseline11C-PD153035SUVmax correlated strongly and highly significantly with overall and progression-free survival times. On Cox regression analysis, each unit increase in SUVmax reduced the hazard of death by60%(HR=0.40;95%CI=0.22-0.70;P=0.002) and reduced the hazard of progression by96%(HR=0.044;95%CI=0.01-0.22; p<0.001).3.11C-PD153035SUVmax early in treatment (at1-2weeks) also correlated with overall and progression-free survival with HR0.36(95%CI=0.17-0.75; p=0.007) and HR0.29(95%CI=0.14-0.60; p=0.001), respectively. Of note, SUVmax at1-2weeks correlated strongly with baseline SUVmax (r=0.87[95%CI=0.65-0.95], R2=0.75,p<0.0001).4. SUVmax at about6weeks did not correlate with baseline SUVmax (r=0.47[95%CI=-0.05-0.78], R2=0.22.p=0.066), and was not associated with overall (HR=0.66; p=0.25) or progression-free survival (HR=0.055;p=0.066) on Cox-regression analysis.5. For the Kaplan-Meier survival analysis, patients were stratified by greater or less than the median baseline11C-PD153035SUVmax value of2.92. Patients with baseline SUVmax≥2.92had significantly longer median OS (11.4vs.4.6months) and higher6-month OS (91%vs.30%) compared to patients with SUVmax<2.92(p=0.002). Similarly, median PFS (4.4vs.1.8months) and6-month PFS (27%vs.0%) were significantly better with high vs. low SUVmax (p<0.001).Conclusion1.11C-PD153035PET/CT may be a noninvasive and rapid method for identifying patients with refractory advanced NSCLC to respond to EGFR-TKI,2. The promising results of this study justify a larger trial of11C-PD153035PET/CT imaging in populations of patients receiving EGFR-TKIs for NSCLC, and correlation with EGFR tissue biomarkers.Part Two Noninvasive Evaluation of Microscopic Tumor Extensions Using Molecular Imaging in Non-Small Cell Lung CancerRadiation therapy is the main treatment modality for locally advanced NSCLC. Optimization of conformal radiotherapy of intrathoracic tumors is based on an improved definition of target volumes to (1) include all of the macroscopic tumor volume and microscopic extension, and (2) limit exposure of the surrounding healthy lung tissue. The achievement of this goal, practically impossible with classical external beam techniques, is nearly reached with the three-dimensional conformal radiation therapy (3DCRT) introduced in the last decade. But, because of the present inability to define the boundaries between tumor and normal tissues in absolute terms, radiation target volumes have classically included a "safety" margin of surrounding normal tissue. In1993, the "International Commission on Radiation Units and Measurements"(ICRU) published Report50, which contained recommendations on how to report a treatment in external photon beam therapy. The recent ICRU Report62, supplement to ICRU50, revises some of the definitions and concepts especially to differentiate between internal movements and setup inaccuracy. However the initial concepts of gross tumor volume (GTV) and clinical target volume (CTV) are not reconsidered. The GTV corresponds to the tumor volume as delineated from palpation or imaging. The CTV is the volume of tissue including the GTV, associated with a significant probability of containing microscopic tumor extensions (subclinical disease). In addition to these clinicopathologic volumes, defined by the radiotherapist, other margins, such as the planning target volume (PTV) are defined. In the ICRU Report62, the PTV is specified with more accurate precision, its global concept being not changed.Although ICRU Report provided qualitative definitions of the margins to be used, the actual quantitative determination of these margins remains one of the difficult challenges in RT. It is generally accepted that the GTV, or radiographic size of gross disease, is equal to its pathologic size. This assumption can be fraught with inaccuracies, particularly for pulmonary malignancies, for a number of reasons:(1) respiratory motion during imaging,(2) subjective use and interpretation of "appropriate" window settings in the evaluation of the images and resultant target volume contours, and (3) the high level of interobserver variability in lung GTV contouring. In addition, modern imaging technology is incapable of accurately identifying all microscopic disease. That microscopic extension might not be uniform in three dimensions and can vary considerably by anatomic location, tumor size, histologic type, grade, and other characteristics further complicates the situation. The classic solution among radiation oncologists is the addition of a somewhat arbitrary1.5-2.0-cm margin to the GTV to account for a number of factors, including microscopic extension, daily setup error, and organ motion. Whether this amounts to an overestimation in the resultant target volume, thereby limiting dose escalation, or an underestimation, leading to inadequate treatment of subclinical disease, is unknown. Few retrospective data are available for NSCLC to objectively determine the appropriate CTV expansion beyond the gross tumor edge as defined on the pathologic information. However, these studies could not perform delineation in vivo and could not provide a patient-specific CTV margin.PET using the radiotracer F-FDG enables the imaging of glucose metabolism in vivo, which is elevated in most of NSCLC, and provides an individual and noninvasive method for detecting and staging NSCLC. In certain tumor cell types, glucose metabolism measured by FDG-PET may vary proportionately with the malignancy grade and proliferation status of the cancer cells. It was reported that microscopic extensions (ME) correlated with malignancy grade in lung cancer and reflected to cell proliferation. We hypothesis18F-FDG PET/CT may provide effective information of CTV margin for NSCLCPurpose1. To determine whether MEmax correlates with SUVmax in NSCLC patients.2. To determine whether MEmax correlates with MTV in NSCLC patients.Methods1. Synthesis of18F-FDGThe general procedure of synthesis and F-18radiolabelled of FDG (ABX advanced biochemical compounds, Germany) was performed in Tracer lab FXc system (GE Healthcare, USA).2. Selection of NSCLC patientsPatients initially diagnosed with NSCLC who were considered operable after routine staging procedures, including18F-FDG PET/CT, were enrolled.3.18F-FDG PET/CT imagingThe FDG-PET/CT scans were performed within1week before the surgery, using a PET/CT scanner (Discovery LS, GE Healthcare). The SUVmax and MTV of the tumors were measured in all patients. 4. Pathologic measurementThe experienced pathologist (D.M.) then outlined the tumor containing area on the HE-stained slides. The microscopic margin distance was measured from the slides. We determined the ME as the distance between microscopic disease (all islets found) and tumor boundary, for each patient. From this, the MEmax per patient was determined.5. Statistical analysisStatistical analysis was performed using SPSS13.0.Results1. Correlations between microscopic extension and SUVmaxAnalysis showed that there were positive correlations between MEmax and SUVmax. The overall correlation coefficient for SUVmax was0.777. In terms of the probability of covering ME with respect to a given margin, we suggested that a margin of1.93mm,3.90mm and9.60mm for SUVmax≤5,5-10and>10respectively, added to the GTV would be adequate to cover95%of ME.2. Correlations between microscopic extension and MTVAnalysis showed that there were positive correlations between MEmax and MTV. The overall correlation coefficient for MTV was0.724. In terms of the probability of covering ME with respect to a given margin, we suggested that a margin of1.92mm,3.80mm and10.90mm for MTV≤10cm3,10-70cm3, and>70cm3respectively, added to the GTV would be adequate to cover95%of ME.ConclusionThe SUVmax and MTV of FDG-PET/CT in primary tumor of NSCLC positively related to MEmax. The correlation in our prospective analysis suggests that the SUVmax provide helpful message for CTV definition more specifically and noninvasively in vivo.
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