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Abstract
RECIST AND PERCIST CRITERIA FOR RESPONSE TO THERAPY Background We need to accurately assess response to therapy for our patients with cancer, early in their treatment. Because modern treatments are costly (up to $10,000 per month), it is important to determine whether the current regimen is being effective and whether the patient will respond well with this treatment. If judged effective, stay the course. If current treatment is not being effective, then one could change management early, thus saving costs, avoiding unnecessary toxicities and improving quality of life. Anatomic Methods Tumor shrinkage has long been the standard for judging response to therapy since Moertel et al. published studies in 1976, comparing measurements of palpable tumors. WHO: In 1979 the World Health Organization (WHO) Handbook established imaging criteria for following solid tumors during therapy. Response was judged by tumor shrinkage. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were defined. Time to tumor progression (TTP), and progression free survival (PFS) defined when the disease recurred or progressed, including death in PFS. Measurable disease was defined with bidimensional tumor measurements, utilizing the product of longest diameter (LD) and short axis (SAX). RECIST 1.0: In 2000 the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute (NCI) task force published imaging criteria as the Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines. Measurable disease was defined unidimensionally, utilizing the LD. The LD of the target lesions was summed. CR: complete disappearance of all lesions. PR: ≥30% decrease of the sum. PD: ≥20% increase of the sum. For nontarget lesions, CR: complete resolution of all lesions; PD: unequivocal progression, or appearance of new lesions; SD: essentially stable, nontarget lesions such as pleural effusion. RECIST 1.1: Revised in 2009. Measurable disease defined unidimensionally, with the LD, except for lymph nodes in which the SAX is measured and must be ≥15mm at baseline. Normal lymph nodes defined as ≤10mm SAX. The SAX of the target lymph nodes is added to the sum of the LD of other target lesions. With conventional techniques (such as CXR or palpable lesions), target lesions need to be ≥20mm at baseline, or ≥10mm for spiral CT. CR: complete resolution. PR: ≥30% decrease of the sum. PD: ≥20% increase of the sum. For nontarget lesions, CR: complete disappearance, such as effusions or lymphangietic tumor. PD: “unequivocal” progression, or appearance of new lesions. PD can also be new “PET positive” lesions. Biomarkers We currently have several clinically accepted biomarkers for evaluating active tumors: serum thyroglobulin (TG) for thyroid cancer, prostate specific antigen (PSA) for prostate cancer, and CA-125 for ovarian cancer. With the advent of personalized medicine, other individual biomarkers, cell markers and genetic makers for a tumor are increasingly utilized and may require biopsy to evaluate evolving tumor mutations and chemo-resistance. New biomarkers include (HER2) for breast cancer, and KRAS gene mutations for epidermal growth factor receptor (EGFR) in colorectal cancer and lung cancer. PET-CT with FDG has also become an established imaging biomarker for hypermetabolic tumor activity. Functional Methods Functional methods for judging tumor response include dynamic contrast enhancement (DCE) with CT or MRI, MR spectroscopy (MRS), MR diffusion weighted imaging (DWI), ultrasound contrast enhancement, and optical coherence techniques. DCE is well accepted for GIST tumors and is being studied for lung cancer and breast cancer at UC Davis. Molecular Methods As early as 1990, gallium-67 was utilized with gamma cameras and then SPECT, for judging tumor response in lymphomas and Hodgkin’s disease, and to determine tumor activity if CT showed residual masses. In 2007, the Harmonization Criteria were established for judging tumor response with CT and PET-CT in malignant lymphomas and essentially replaced gallium. PET-CT with flourine-18 fluorodeoxyglucose (FDG) has become clinical standard-of-care in the staging and follow-up of many tumors, including lung cancer, esophageal cancer, head and neck cancers, brain tumors, lymphomas, GIST tumors (Choi criteria, 2007), colorectal cancer, melanoma, cervical and ovarian cancers. PET-CT is a quantitative technology but is often used with qualitative evaluation, comparing tumor uptake to background, liver or blood pool activity. Viewing the whole body MIP (Maximum Intensity Projection) images can often quickly determine whether the primary lesion and metastatic lesions have greatly increased or decreased in number or metabolic activity. However, quantitative techniques are more objective and likely more precise in judging response to therapy. Quantitative techniques include measuring various forms of Standard Uptake Value (SUV) and total glycolytic volume (TGV). The same acquisition principles of PET-CT with FDG are also being studied for other radiopharmaceuticals such as F-18-fluorothymidine (FLT) for DNA synthesis, F-18-fluoroethyltyrosine (FET) for amino acid metabolism, F-18-fluoromisonidazole for hypoxia imaging, and numerous other PET radiotracers. PERCIST: In 2009, Wahl et al. published a landmark article for PET-CT, “From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors”. PERCIST (Positron Emission tomography Response Criteria In Solid Tumors) is a set of recommendations to help make PET-CT even more quantitative and more precise. Current recommendations involve stringent quality control for equipment, software standardization, standard dosing, consistent timing from injection to acquisition, SUV peak rather than SUV max, SUL (SUV with lean body mass) and standardized ROI shape and size. Current recommendation is for a 1 cm[3], spherical ROI placed within the most hypermetabolic area of the tumor (SUV peak). Setting the required number of lesions and judging the summed response are still being evaluated. Conclusions RECIST 1.1 criteria and anatomic measurements will continue to play an important central role in clinical trials and for individual patients. PERCIST criteria are evolving and will slowly be introduced in carefully planned clinical trials. PET-CT with FDG has been proven to judge tumor response sooner than anatomic techniques alone, and it is thought that PERCIST criteria will help decrease the costs and duration of clinical trials, as well as improve the quality of life by decreasing prolonged exposures to ineffective treatments and associated toxicities.

Abstract
Thymic epithelial tumors represent a wide range of anatomical, clinical, histological, and molecular malignant entities, which may be aggressive and difficult to treat. The histopathological classification distinguishes thymomas from thymic carcinomas. Our current understanding of the carcinogenesis of these tumors remains limited; only few well-characterized preclinical models - mostly consisting of thymic carcinoma cell lines -, have been established. Several biomarkers studies have been reported; while tumor stage, completion of surgical resection, and - to a lesser extent – histology have been shown to significantly predict the outcome of patients, the expression of EGFR, KIT, or IGF1-R by immunohistochemistry failed to consistently demonstrate a prognostic value on the survival of patients. More recently, expression signatures have been reported, both for thymomas and thymic carcinomas, to correlate with metastasis-free survival; these results remain to be validated in separate cohorts, while prospective study to understand the clinical significance of these results will be required. The management of thymic epithelial tumors is a paradigm of cooperation between clinicians, surgeons, and pathologists from establishing the diagnosis to organizing the multimodal therapeutic strategy. Chemotherapy may be used in two clinical scenarios in thymic epithelial tumors: 1) chemotherapy may constitute primary part of the multimodal curative-intent treatment of locally-advanced tumors, and is subsequently combined with surgery or radiotherapy; the main objective is to achieve long-term survival with no evidence of tumor recurrence; 2) chemotherapy may be delivered as the sole treatment modality in unresectable, advanced, metastatic, or recurrent tumors; then a palliative-intent treatment, the aim is to improve tumor-related symptoms through achievement of tumor response, while no prolonged survival is expected. Novel treatment strategies are needed, especially for refractory, recurrent tumors, and thymic carcinomas, which carry a poor prognosis despite multimodal treatment. Potentially druggable targets are emerging, laying the foundations to implement personalized medicine for patients. Given the currently available targeted agents outside of a clinical trial, the signaling pathways that are relevant in the clinical care of patients are the KIT and the Vascular Endothelial Growth Factor (VEGF)-R (Receptor) pathways. Several tyrosine kinase inhibitors targeting KIT have been developed - including imatinib (Novartis, Basel, Switzerland), sunitinib (Pfizer, New-York, NY), and sorafenib (Bayer, West Haven, CT) - , most of which also potently inhibiting other kinases, including VEGFRs and Platelet-Derived Growth Factor Receptors. Collectively, KIT is overexpressed in 80% of thymic carcinomas, while KIT gene mutations are found only in 9% of cases. Clinically, KIT-mutant thymic carcinomas then represent a small molecular subset of thymic tumors. The clinical relevance of KIT mutations is more limited in thymic carcinoma than in other cancers like gastro-intestinal stromal tumor (GIST), as 1) KIT mutations are far less frequent; 2) KIT expression does not correlate with the presence of KIT mutation; and 3) non-pretreated KIT mutants are not uniformly sensitive to imatinib, based on the clinical and/or the preclinical evidence in thymic carcinoma and/or other KIT-mutant tumors. These findings may explain why the 2 reported phase II trials with imatinib, where patients were not selected, or selected based upon histologic type (B3 thymomas and thymic carcinomas) or KIT staining by immunohistochemistry, and not upon KIT genotyping, were negative. Multi-kinase inhibitors may also be of interest to target neoangiogenesis. The most potent pro-angiogenic molecules are those of the VEGF/VEGFR signaling pathway. VEGF-A and VEGFR-1 and -2 are overexpressed in thymomas and thymic carcinomas. Micro-vessel density and VEGF expression levels have been shown to correlate with tumor invasion, aggressive histology and clinical stage. In a phase II trial, bevacizumab was tested in combination with erlotinib in thymomas and thymic carcinomas. No tumor response was observed. Interestingly, despite the large tumor burden of thymic tumors and the frequent abutment to mediastinal vascular structures, no hemorrhagic side effect has been reported with the use of these drugs in these studies. Beyond the inhibition of KIT, sunitinib and sorafenib also inhibit VEGFR-1, VEGFR-2, VEGFR-3 at the nanomolar range. The effect of these drugs, especially in KIT-wild-type thymic carcinoma tumors may then be partially related to an anti-angiogenic effect. Promising new targets in thymoma and thymic carcinoma include IGF-1R and histone-deacetylase. Cixutumumab, an IGF1-R directed monoclonal antibody was recently reported to produce a promising 90%-disease control rate in refractory thymomas. Belinostat, a histone deacetylase inhibitor was evaluated in thymic malignancies in a recently completed phase II trial enrolling 41 patients (25 thymomas and 16 thymic carcinomas). Response and 2-year survival rates were 8% and 77% in thymomas. Given the rarity of the tumor, translation of pre-clinical findings to the clinic may be quick; several strategies have been implemented. A pragmatic approach is the recommendation for KIT genotyping in clinical practice, what represents a model of n-of-one trial approach in the field. Another approach to validate the concept of personalized medicine in thymic malignancies includes the development of open-label multicentric phase II trials, using high throughput genome analysis (CGH array, next generation sequencing) as a therapeutic decision tool, to compare a medical treatment administered according to the identified molecular anomaly of the tumor with a medical treatment administered without considering the genome analysis; thymic tumors have been integrated in some ongoing trials using such methodology. A third approach is to promote the enrollment of patients with refractory thymic tumor in phase I trials, what may lead to identify new molecular pathways of therapeutic interest; mTOR is emerging as a potential target, following tumor responses observed in phase I trials, with recent data from several groups. Along with the large variety of questions relative to the treatment strategy, thymic epithelial tumors represent a model of therapeutic implementation and achievement; in this setting, regional and international collaborative initiatives are mandatory to progress both in the understanding of the biological mechanisms underlying the development of thymic malignancies, and in the identification and validation of new targets with prognostic and predictive value.