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Endoscopy in Gastrointestinal Oncology - Slide 5 - R. Rosati - Esophageal cancer: the appropriate staging
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  • Mammalian cells initiate cell cycle arrest at different phases of the cell cycle in response to various forms of genotoxic stress to allow time for DNA repair, and thus preserving their genomic integrity. The protein kinases checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2), and mitogen-activated protein kinase–activated protein kinase 2 (MK2) have all been shown to be involved in cell cycle checkpoint control. Recently, cell cycle checkpoint abrogation has been proposed as one way to sensitize cancer cells to DNA-damaging agents due to the expected induction of mitotic catastrophe. Due to their overlapping substrate spectra and redundant functions, it is still not clear which kinase is mainly responsible for the cell cycle arrests conferred by clinically relevant chemotherapeutics

Endoscopy in Gastrointestinal Oncology - Slide 5 - R. Rosati - Esophageal cancer: the appropriate staging Presentation Transcript

  • 1. Esophageal cancer: the appropriate staging 3° Course on Endoscopy in Gastrointestinal Oncology Rome, March 2011 Riccardo Rosati, MD FACS Professor of Surgery University of Milan Head Dept. General & Minimally-Invasive Surgery Istituto Clinico Humanitas IRCCS
  • 2.
    • Highly aggressive disease
    • Often asymptomatic in early stages
    • Can develop metastases from an early stage
    • Two separate entities: ADC (rised incidence in last decades), SCC
    • Survival highly correlated with tumor invasion, lymphatic involvement, and metastatic spread
    • R0 resection : major surgical related prognostic factor
    • T and N : major disease related prognostic factors
    Esophageal cancer - Introduction
  • 3.
    • In collaboration with UICC
    • T classification changed for Tis and T4 cancers
    • Harmonizes cancer stagign across the esophagogastric junction
    • Previous staging produced different stage groupings for these cancers depending on use of either esophageal or gastric stage groupings
    • The new edition is for cancers of the esophagus and esophagogastric junction and includes cancer within the first 5 cm of the stomach that extend into the esophagogastric junction or distal thoracic esophagus
    • Previous stage groupings of esophageal cancer were based on a simple, orderly arrangement of increaasing anatomic T, then N, then M classification; these groupings were not consistent with data or cancer biology
    • The new system is based on a risk-adjusted analysis of worldwide data and it accounts for interactions of anatomic and nonanatomic cancer characteristics
    7° Edition of the AJCC Cancer Staging Manual - 2010 Rice TW, Ann Surg Oncol 2010
  • 4.
    • C Wittekind, B Oberschmid, Chirurg 2010
    • Removal and examination of regional lymph nodes important role in surgical therapy
    • Numbers of metastatic regional lymph nodes as well as the numer of removed examined lymph nodes important regarding estimation of the prognosis
    • It is essential to consider:
      • which lymph nodes are defined as regional in the UICC TNM classification
      • which definitions apply for the individual N categories
      • which recommendations are valid for the minimum numbers of lymph nodes to be removed and examined for particular tumor entities
    Gastrointestinal tumors – New classification of the UICC 2010 New classification Old classification N- Regional lymph nodes Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1-2 regional lymph nodes N2 Metastasis in 3-6 regional lymph nodes N3 Metastasis in 7 or more regional lymph nodes
  • 5.
      • Address patients for appropriate treatment plans
        • Immediate surgery (limited disease)
        • Neo adjuvant chemo or chemoradiotherapy (locally advanced disease) followed by surgery
        • Definitive chemo or chemoradiotherapy /palliation (distant metastatic disease)
      • Re-assessement after neo adjuvant treatment
    Staging: goals
  • 6.
      • Endoscopy: tumor diagnosis, specifies tumor site and type
      • EUS, EUS FNA: T and N staging, allows biopsies
      • CT: T and N staging, excluding M
      • MRI: similar to CT
      • PET and PET/CT: further informations on tumor activity, detects distant metastases
      • Bronchoscopy: in selected cases to rule out tracheal infiltration
      • Staging laparoscopy: diagnosis of smaller liver metastases and peritoneal seeding
    • Re-staging after neoadjuvant therapy
      • Same exams as for initial staging
    Staging
  • 7.
    • can assess the depth of penetration of the primary tumor
    • the five layers of the esophageal wall are depicted as five alternating layers of different echogenity
    • esophageal cancer appearing as a hypoechoic mass disrupting this pattern
    • can not be used in stenotic tumors (unless previous dilatation or use of smaller probes)
    • can visualize regional lymph nodes and assess their size
    • improved sensitivity and specificity for nodal metastasis with fine-needle aspiration (Saftoin, J Gastrointestin Liver Dis 2009, Polkowski, Best Pract Res Clin Gastroenterol 2009)
    • non-invasive procedure, low complications rate
    EUS - Advantages
  • 8.
    • Pro
      • Meta-analysis: EUS most sensitive in the detection of regional lymph node metastases than CT and PET (van Vliet, Br J Cancer 2008)
      • 121 pts: EUS more accurate than CT for detecting abnormal lymph nodes , but metastatic lymph nodes detectable only by CT (Takizawa, Gastroent 2009)
      • 81 pts: EUS superior to PET CT for T staging and in identifying locoregional lymph nodes , while PET/CT superior in M staging (Walker, Mol Imaging Biol 2010)
      • 109 pts: EUS provided excellent T staging accuracy (Choi, Surg Endosc 2010)
      • 166 pts stratified for BMI (low, normal, high, and obese): EUS good to predict tumor infiltration irrespective of BMI when compared with CT (Twine, Eur Radiol 2009)
    • Cons
      • 179 pts (134 ADK, 45 SCC): insufficient diagnostic accuracy, particularly T2 cancers overstaged (Pech, Endoscopy 2010)
      • Review of the literature: EUS not sufficiently accurate in determining the T stage of HGD or superficial ADK (Young, Clin Gastroent Hepat 2010)
    EUS accuracy in preoperative staging EUS and EUS FNA: possible impact on patient management changes
  • 9.
    • Preoperative T staging
      • limited role in determining the exact depth of tumor infiltration of the esophageal wall
      • important role in exclusion of T4 disease, as indicateed by the preservation of fat planes between the esophageal cancer and adjacent structures
    • Preoperative N staging
      • intrathoracic and abdominal lymph nodes greater than 1 cm in diameter are considered to be enlarged and supraclavicular lymph nodes with a short axis greater than 5 mm are considered to be pathologic; sensitivity 30-60%; specificity 60-80% (Kim, Radiographics 2009)
    • Preoperative M staging
      • most important role of CT
    CT in preoperative staging
  • 10.
    • most commonly used radiopharmaceutical: 18F-FDG (glucose analogue transported intracellularly and phosphorylated)
    • in tumor: due to insufficient amount of intracellular glucose phosphatase, the FDG-6-phosphatase cannot undergo further metabolism and remains trapped inside the cell providing a signal of glycolytic activity throughout the body (Chin, Gut 2003)
    • PET images analyzed qualitatively and semiquantitatively
    • intensity of FDG uptake within a specific lesion expressed as SUV max (standardized uptake value): max activity in the region of interest / injected dose of FDG
    • integrated PET/CT
      • CT used to provide attenuation correction for the PET data and for anatomical co-registration
      • increased diagnostic confidence, improved anatomic localization and specificity
    PET and PET/CT - Technical issues
  • 11.
    • limited role in evaluating the extent of the primary tumor due to its limited spatial resolution (difficulty in revealing very small tumors) (Chuang, Q J Nucl Med Mol Imaging 2009; Marzola, Eur J Radiology 2010)
    • improvement of accuracy in detection of metastasis (Noble, Clin Radiol 2009)
    • limitations in N staging: inability to detect metastatic involvement in normal-sized lymph nodes and difficulty to differentiate between M+ and inflammatory enlarged lymph nodes (Marzola, Eur J Radiology 2010)
    • possible role in restaging after neoadjuvant therapy early prediction of response to treatment and detection of interval distant M+
    Role of PET and PET/CT A: FDG-non avid tumor, T2 by EUS B: FDG-avid tumor, T2 by EUS
  • 12.
    • Diagnosis of smaller metastasis, hepatic metastasis, and peritoneal seeding
    • Invasive diagnostic procedure
    • Multidisciplinary decision
    • Less invasive than exploratory laparotomy
    • Can decrease the start of neoadjuvant treatment rather than exploratory laparotomy, but data are limited
    • Combined thoracoscopic/laparoscopic staging to increase the number of positive lymph nodes identified (Chang, Surg Endosc 2009)
    • Low complication rate
    • Sensitivity: 71% peritoneal M+, 78% nodal M+, 86% liver M+ (Bonavina, J Surg Oncol 1997)
    • Only few pts have a change in their management based on these results (Bonavina, J Surg Oncol 1997; Romijn, Br J Surg 1998)
    Role of staging laparoscopy
  • 13.
    • Neoadjuvant therapy widespread among pts with stage IIB or III
    • Therapeutic response can be assessed
      • early assessment allows evaluation of the responsiveness of a tumor and identification of nonresponding pts
      • late response assesment allows appraisal of the prognosis
    • Possible source of heterogeneity: CT alone or CT-RT
    Assessment of response to neoadjuvant therapy
    • 80 pts with localized ca
    • histomorphologic regression: objective response parameter
    • diagnostic accuracy of endoscopy, rebiopsy, and EUS: inadequate
      • (Schneider, Ann Surg 2008)
  • 14.
    • CT
      • not accurate
      • low sensitivity and specificity
      • difficulty in differentiating between viable tumor and reactive change such as inflammation or scar tissue
    • EUS
      • less accurate for restaging than for initial staging
      • most common error: overstaging, since fibrosis and inflammation indistinguishable from residual tumor
      • possible understaging: related to microscopic foci of viable tumor within the esophageal wall
      • more accurate than CT
      • measurement of residual tumor size might correlate with response to neoadjuvant therapy
    Assessment of response to neoadjuvant therapy
  • 15.
    • FDG-PET – PET/CT
      • best imaging modality (Westerterp, Radiology 2005)
      • correlation between quantitative decrease in FDG uptake after neoadjuvant therapy and pt survival and pathologic response to therapy (Swisher, Cancer 2004)
      • possible false-positive interpretations: during or soon after RT due to inflammation or ulceration within the esophagus and after completion of neoadj th due to mucosal biopsy
      • possible false-negative interpretations: in patiens with partial response and small volume viable tumors
      • evaluation of early response: SUV decrease to differentiate between responding and nonresponding significantly associated with histopathologic tumor response, but low accuracy in detecting nonresponding (van Heijl, Ann Surg 2011)
    Assessment of response to neoadjuvant therapy
  • 16. R.T. 67 yo adenocarcinoma lower esophagus cT2-3, N1 ycT0, N0 CT: Al Sarraf 3 cycles RT 45 Gy 3/2011: transthoracic esophagectomy with laparoscopic gastrolysis ypT1b, N1 (1/36) EGDS: linear scar EGDS: large ulcerated mass ¾ esoph lunen 9/2010 2/2011
  • 17.
    • Metzger, Pharmacogenomics 2010
      • 66 pts
      • pretreatment biopsy
      • Two novel markers, CUL2 and STK11, predictive for response in SCC and STK11 in ADC
    • Theisen, Dis Esoph 2008
      • 18 pretreated pts analyzed for a gene expression profile available prior to therapy
      • potential predictive value
    • Kobayashi, Surgery 2008
      • Glasgow prognostic score (GPS): inflammation-based prognostic score associated with poor outcome in a variety of tumors
      • 48 pts with stage II/III SCC tumors
      • GPS measured prior to neoadjuvant therapy was an independent predictor of po outcome
    Develompments in response prediction to neoadjuvant therapy
  • 18.
    • Duong, Ann Surg Onc 2007
      • 46 pretreated pts (21 SCC and 25 ADK)
      • tumor biopsy sample before neoadjuvant therapy
      • a 32-gene classifier was produced
      • 10 of 21 SCC pts were accurately identified as unlikey to benefit from neoadjuvant therapy
    • Sarbia, Br J Cancer 2007
      • 94 pretreated SCC pts
      • tumor biopsy sample before neoadjuvant therapy
      • positive tumors for CHK2 (checkpoint kinase 2) expression showed clinically determined regression after neoadjuvant therapy than negative tumors
    Predictive response to neoadjuvant therapy
  • 19. Tumor grade p= 0.00001 Nodal status p= 0.0005 Tumor grade and nodal status p= 0.00003 Radical vs residual disease p= 0.00005 Survival and prognostic factors
    • EUS T and N stage, location of the tumor, and SUV of the primary tumor associated with disease-specific survival in 125 pts (Omloo, Endoscopy 2008)
    • SUV measure, reflecting the metabolic activity of tumor and malignancy, as a prognostic factor (Pan, Eur J Gastroenterol Hepatol 2009) ; independent predictor of survival (Sepesi, J Gastrointest Surg 2009)
    • SUV of the regional lymph nodes correlated with the severity of nodal involvement (Hsu, Ann Thorac Surg 2009)
  • 20.
    • R0 resection is the therapeutic goal for patients affected by cancer of the esophagus
    • accurate preoperative staging is crucial in determining the most suitable therapy
    • each imaging modality has its pros and cons
    • CT, EUS, and PET – PET/CT are complementary modalities for preoperative staging and therapeutic monitoring of pts
    • early assesment of response of neoadjuvant therapy is the current most interesting field of investigation
    • assessement of response after neo-adjuvant therapy no currently available guidelines for the optimal timing of PET - PET/CT; possible role of histologic markers, such as p53 , ki-67 , and EGFR for the early prediction of tumor response
    Conclusions