Patients with stage IIIa non-small cell lung cancer

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1 GENERAL THORACIC When is it Best to Repeat a 2-Fluoro-2-Deoxy-D- Glucose Positron Emission Tomography/Computed Tomography Scan on Patients with Non-Small Cell Lung Cancer Who Have Received Neoadjuvant Chemoradiotherapy? Robert James Cerfolio, MD, and Ayesha S. Bryant, MSPH, MD Division of Cardiothoracic Surgery, Department of Surgery, and Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama Background. The ideal time to repeat a 2-fluoro-2- deoxy-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) scan to accurately restage a patient after neoadjuvant chemoradiotherapy for non-small cell lung cancer (NSCLC) is unknown. Methods. This retrospective cohort study used a prospective database of patients who underwent neoadjuvant chemoradiotherapy, an initial and repeat FDG- PET/CT scan, and pathologic staging. The accuracy of the clinical stage suggested by repeat FDG-PET/CT was compared with the actual pathologic stage. Receiver operating characteristic (ROC) curves were used to determine when it was most accurate to repeat the FDG- PET/CT after the completion of the last dose of chest radiation. Results. The study comprised 109 patients, 93 of whom patients received 60 Gy (or higher) of radiotherapy. The median time to restaging was 24 days (range, 2 to 88 days). ROC analysis showed the optimal time to restage patients was 26 days for overall staging (area under the curve [AUC], 0.88) and 29 days for N2 restaging (AUC, 0.82). The accuracy for overall stage was 3 (38%) of 8 for patients for less than 10 days, 28 (72%) of 39 for patients between 11 and 20 days, 42 (88%) of 49 between 21 and 30 days, and 8 (62%) of 13 for 31 days or more. The accuracy for these time intervals for the restaging of the N2 lymph node was 50% (1/2) 40% (2/5), 88% (7/8), and 100% (3/3), respectively. Conclusions. The optimal time to perform a repeat FDG-PET/CT scan after the completion of neoadjuvant chemotherapy and high-dose radiotherapy to maximize its accuracy for restaging patients with NSCLC is about 1 month after the last dose of radiation. (Ann Thorac Surg 2007;84:1092 7) 2007 by The Society of Thoracic Surgeons Patients with stage IIIa non-small cell lung cancer (NSCLC) from metastatic cancer to mediastinal lymph node (N2) disease represent approximately 25% of all patients diagnosed with NSCLC [1]. Many of these patients are treated with neoadjuvant (or induction) chemoradiotherapy after undergoing minimally invasive procedures to prove their N2 mediastinal lymph nodes metastases. Although the ideal therapy for these patients is controversial, many institutions offer resection for those patients who, after restaging, seem to be downstaged or have not progressed. The role of 2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) in clinically staging patients initially with NSCLC is well known [2 6]. The role of PET for restaging is also well described and it helps guide Accepted for publication May 14, Presented at the Poster Session of the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29 31, Address correspondence to Dr Cerfolio, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, th St S, ZRB 739, Birmingham, AL 35294; robert.cerfolio@ccc.uab.edu. further therapy as well as patient selection for surgery [7]. External beam radiation can cause false-positive results on the restaging PET scan [8, 9]. The best time to repeat the PET to maximize its accuracy for predicting the pathologic stage is unknown. The purpose of this study was to determine the ideal time to repeat a PET scan in patients with NSCLC who underwent induction chemoradiotherapy. Patients and Methods Patient Selection This was a retrospective cohort study using a prospective database. Patients who presented to one thoracic surgeon (RJC) during a 3-year period after neoadjuvant chemoradiotherapy (cisplatinum-based) for biopsy-proven NSCLC who underwent chest computed tomography (CT) scan and integrated FDG-PET/CT for staging and then for restaging at the University of Alabama at Birmingham center were eligible for this study. Patients were excluded if they were younger than 19 years old, or 2007 by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg CERFOLIO AND BRYANT 2007;84: OPTIMAL TIME FOR REPEAT PET POSTRADIATION 1093 Fig 1. Algorithm for the restaging of patients with stage IIIa (N2) non-small cell lung cancer after neoadjuvant chemoradiotherapy using cisplatinum-based chemotherapy and concurrent high dose (60 Gy or greater) of radiotherapy. (CT computed tomography; maxsuv maximum standardized uptake value; PET positron emission tomography.) GENERAL THORACIC had a history of type I diabetes, or if they had typical carcinoid cancer. The University of Alabama at Birmingham s Institutional Review Board (IRB) approved the electronic prospective database used for this study and this trial. Patient consent was obtained for entry into the prospective database; the IRB granted a waiver for individual patient consent for this retrospective review. Radiologic Imaging Initial staging was performed as described at length by us previously [5]. Briefly, patients had chest CT with intravenous contrast and integrated FDG-PET/CT scans performed on an integrated PET/CT scanner (GE Discovery LS PET-CT Scanner, Milwaukee, WI). Patients were asked to fast for 4 hours and then received 555 MBq (15 mci) of FDG intravenously, followed by positron emission tomography (PET) after 1 hour. The scans were performed from the skull base to midthigh level. The CT examination was used for attenuation correction of PET images. The scanning time for emission PET was 5 min per bed position. Iterative reconstruction with CT attenuation correction was performed. The most recent CT scan of the chest was also available for visual correlation. Maximum standardized uptake value (maxsuv) of the primary and of each suspicious lymph node station (greater than 2.5) was determined by drawing regions of interest (ROI) on the attenuation corrected FDG-PET images around it. It was then calculated by the software contained within the PET or PET/CT scanner by the formula [10] C ( Ci ml) MaxSUV ID ( Ci) w (kg) where C is activity at a pixel within the tissue defined by an ROI, and ID is injected dose per kg of the patient s body weight (w). The maxsuv within the selected ROIs was used throughout this study exclusively. Staging and Restaging All patients were thoroughly initially clinically staged and pathologically staged before neoadjuvant therapy, as we have described [5], and their tumor (T), node (N), and metastasis (M) stage was recorded. Patients were then carefully restaged clinically and pathologically after the completion of the neoadjuvant chemoradiotherapy also as we have previously described [11] using the T, N, and M classification system [5, 12]. This is partially outlined in Figure 1. If the maxsuv of a biopsy-proven benign area decreased on the repeat PET, no further biopsies were performed after restaging. However, all biopsy-proven malignant areas were rebiopsied or resected. Patients with new suspected M1 disease in the liver, adrenal, or contralateral lung underwent definitive biopsy to prove or disprove M1 cancer. If the bone or brain was suspected to harbor metastases, magnetic resonance imaging (MRI) was considered the standard reference. If patients initially had biopsy-proven N3 or M1 disease, the stage was recorded but they were not resected. If proven N3 or M1 disease developed after neoadjuvant therapy, they were not resected. If patients initially had proven IIIA disease from N2 disease, selected patients underwent preoperative radiotherapy and cisplatinum-based chemotherapy and were restaged as previously described [13]. In general, we plan for doses of 60 to 66 Gy of radiotherapy. The initially positive node is then rebiopsied using repeat endoscopic ultrasound-guided fineneedle aspiration (EUS-FNA) for lymph node stations 4R and 4L (in some patients) and stations 7, 8, and 9 and using video-assisted thoracoscopy for stations 2R, 5, and 6, or open thoracotomy, or both, as previously described at length [5]. If down-staged or if appropriate, or both, patients then underwent thoracotomy, pulmonary resection, and complete thoracic lymphadenectomy. Complete thoracic lymphadenectomy is defined as complete removal (not biopsy) of all visible nodes in the chest; in the right chest, these are lymph node stations 2R, 4R, 7, 8, 9,

3 GENERAL THORACIC 1094 CERFOLIO AND BRYANT Ann Thorac Surg OPTIMAL TIME FOR REPEAT PET POSTRADIATION 2007;84: Table 1. Patient and Tumor Characteristics Characteristic N (%) or Median (range) (n 109) Age, median years (range) 61 (28 85) Gender Male 73 (67) Female 36 (33) Histology Squamous cell 48 (45) Adenocarcinoma 43 (39) Atypical carcinoid 4 (3) Other 14 (13) Initial stage a II 4 (3) IIIa (N2) 97 (90) IIIb (all other) 8 (7) Median radiation dose, cgy (range) 6000 ( ) (15) (85) Pathologic Stage CR (T0 N0 M0) 29 (28) I 35 (32) II 18 (17) III (N2) 18 (17) III (all other) 4 (4) IV 5 (4) a Before neoadjuvant chemoradiotherapy. CR complete responder. and the appropriate N1 nodes, and in the left chest, they are stations 4L, 5, 6, 7, 8, 9, and appropriate N1 nodes. Operations were performed within 40 days of the repeat staging studies. Pathologic review was performed with standard techniques, and immunohistochemical staining was used in selected cases at the pathologist s discretion. Definitions A patient was defined as having unsuspected N2 disease (false negative) if the integrated FDG-PET/CT scan did not suggested cancer in any of the N2 nodes but the patient had pathologic proof of metastatic NSCLC cancer in at least one N2 node. A patient was similarly defined as having a false-positive result if the integrated FDG- PET/CT scan suggested metastatic NSCLC in a specific N2 nodes but the pathologic examination showed the patient did not have disease in that node. The accuracy of the T status was similarly determined by the false positives and false negatives; however, for calculation of T status and overall accuracy, T1 and T2 were considered the same and T3 and T4 were considered the same. In addition, if the pathologic T was greater than the PET-predicted T, it was called a false negative; for instance, if the FDG-PET suggested a tumor was T2 but after resection it was T3 or T4, this was considered a false negative. If the pathologic T was less than the predicted T, this was called a false positive. Operative morbidity and mortality was defined as any morbidity or mortality occurring during the hospital stay or within 30 days after discharge from any cause. Statistical Methods Analysis was performed using SAS 9.0 (SAS Inst, Cary, NC). Accuracy, defined as true-negative plus the truepositive results divided by the sum of all true and false results, was determined for FDG-PET/CT using the pathology or biopsy results as the gold standard [14]. Receiver operating characteristic (ROC) curves were generated to identify the optimal cut point at maximal sensitivity and specificity from our data. Results There were 109 patients (73 men) with a median age of 61 years (range, 28 85). Patient and pathologic characteristics are shown in Table 1. The accuracy of integrated PET/CT for restaging based on the time interval between the last dose of radiochemotherapy and the repeat PET/CT scan is shown in Figure 2. The median time for this interval was 24 days (range, 2 to 88 days). Figure 3 depicts the ROC curves and identifies the optimal time to restage patients as 26 days for overall staging (area under the curve [AUC], 0.88). An additional ROC curve was constructed for the accuracy of predicting the pathology Fig 2. Accuracy of integrated 2-fluoro-2- deoxy-d-glucose positron emission tomography (PET)/computed tomography scan for restaging, overall (gray bars) and for N2 disease (black bars) based on the time interval between the last dose of radiotherapy and the repeat PET scan.

4 Ann Thorac Surg CERFOLIO AND BRYANT 2007;84: OPTIMAL TIME FOR REPEAT PET POSTRADIATION Fig 3. Receiver operating characteristic curve (black line) with 95% confidence intervals (gray lines) shows the optimal time to perform a repeat positron emission tomography scan after neoadjuvant chemoradiotherapy therapy for overall staging, which was 26 days after last dose of radiotherapy (area under the curve, diagonal line, 0.88). in the N2 lymph nodes. It showed the optimal time for restaging of N2 lymph nodes was 29 days (AUC, 0.82) and is shown in Figure More patients are undergoing neoadjuvant chemoradiotherapy for biopsy-proven metastatic NSCLC to the mediastinal (N2) lymph node. Some centers are now commonly using curative doses of 60 Gy of radiation or higher instead of the more traditional preoperative dose of 45 Gy [15, 16]. We have used doses of 60 Gy or higher routinely and have shown that surgery is safe in this highly irradiated field and complete response rates are also high [16, 17]. Pisters and colleagues [18] have shown that patients who have a complete response may have prolonged survival after resection. Thus, the surgeon is more frequently asked to consider patients for surgery after radiotherapy. The decision for surgery is made in part on the restaging PET scan; however, the best time to repeat this test after preoperative chemoradiotherapy is unknown. There are several theories concerning the effect of radiation on PET scans. The inflammatory effect of radiation may obscure tumor-specific metabolic changes [19]. Others have hypothesized that radiotherapy may trigger an initial increase in glucose metabolism by the tumor cells. Higashi and colleagues [20] found a 9.7-fold increase in FDG uptake in a human ovary adenocarcinoma cell line during days 0 to 12 after low-dose irradiation (30 Gy). Schneeweiss and colleagues [21] observed an increase in FDG uptake by human glioblastoma cells of 11.3% immediately after radiation. Most studies show that radiation leads to false-positive results and an increase in the maximum standardized uptake values. This concept is often discussed and is well recognized by nuclear radiologists, but data are lacking on this type of ill effect of radiation on PET in patients with NSCLC. We, and others, have shown that the change in the maxsuv is a predictor not only of the pathologic response of the primary pulmonary tumor but also of the mediastinal lymph nodes [22]. The repeat PET helps guide therapy and which area to biopsy based on the change in the maxsuv of previously biopsy-proven areas. The restaging PET should thus be performed on the same scanner as the initial study to help minimize the confounders that can affect the maxsuv. Among the factors that conspire to affect the maxsuv have been described and include the well that counts the amount of FDG given, the techniques of scanning, the amount of delivered FDG, and the patient s glucose level. The standardizing of techniques for PET scanning and rescanning are needed and are now well underway on national and international levels to allow for better comparison of the maxsuv from one center with results from another. Weber and colleagues [23] in 1999 showed the reproducibility of the maxsuv on the same machine. Thus for now, we still recommend that the repeat PET be done at the same center and in the same manner as the first PET scan. GENERAL THORACIC Comment Fig 4. Receiver operating characteristic curve (black line) with 95% confidence intervals (gray lines) shows the optimal time to perform a repeat positron emission tomography scan after neoadjuvant chemoradiotherapy for N2 restaging, which was 29 days after the last dose of radiotherapy (area under the curve, diagonal line, 0.82). All 97 patients with IIIa (N2) disease had biopsy-proven N2 nodes and then underwent rebiopsy or removal of the same node after neoadjuvant therapy.

5 GENERAL THORACIC 1096 CERFOLIO AND BRYANT Ann Thorac Surg OPTIMAL TIME FOR REPEAT PET POSTRADIATION 2007;84: The change in maxsuv may be altered by radiation. In this article, we have shown that the pathologic response rate after neoadjuvant chemoradiotherapy can be interpreted even after high-dose radiation, especially when the second PET scan is performed on the same scanner as the first. In 2004 [11], we showed that the higher the dose of radiation, the more difficult it is to interpret the change in the maxsuv, but one is still able to reliably interpret the repeat PET scan and the maxsuv values even after high dose (66 Gy) preoperative radiation. We found in this study that the most accurate time to repeat the integrated PET/CT scan was 26 days. We performed a separate analysis for the accuracy of repeat PET to predict the pathology of the mediastinal (N2) lymph nodes and it was maximized at 29 days. We found an accuracy of 88% for both. This is remarkably high, especially when one views this result in light of the fact that the initial integrated PET/CT may only be accurate in about 50% of patients [5]. In this study, the repeat PET was thus more accurate than the initial PET. This result should not be surprising because the repeat PET has the advantage of all of the biopsy results of all areas suggestive for disease identified after the first PET. Thus, areas that were falsely positive on the first scan can now be eliminated on the repeat scan if the maxsuvs of these sites have fallen. Because it is our practice to investigate or biopsy all suggestive sites after the first PET scan, it is not surprising that the repeat PET is more accurate than the first because it stands on the shoulders of the initial scan. Among the strengths of this study are that all patients underwent integrated PET/CT and not just a dedicated PET, and all were performed at one institution on one PET scanner. All patients underwent definitive biopsy or resection and thus all had pathologic confirmation. Finally, one surgeon entered all the data in a prospective database and also performed the staging and operations on all patients. This reduces the confounding variables of the study. The primary limitation of this study is that we did not examine a continuous interval of days between the last dose of radiation and the repeat PET scan. To state what day is truly the best time to repeat the PET, patients should have received a repeat PET scan each day after the completion of their radiation and had their pathology checked each day as well. This was not done because it is not clinical practical. Finally, the treating oncologist ordered the repeat scans for some patients and thus some scans were ordered sooner or later than we may have preferred. This fact, however, allowed us to perform this study. The clinical impact of accurate restaging cannot be understated. For example, if a patient has a right upper lobe NSCLC and a biopsy-proven metastatic N2 4R paratracheal mediastinal lymph node and the maxsuv of that node decreases by greater than 50% after repeat PET, we now go directly to thoracotomy if the result of endobronchial ultrasound-guided biopsy (EBUS) specimen of that node is negative. We no longer start off with a video-assisted approach to biopsy the 4R station before thoracotomy. Another example is the test we select to biopsy the lymph node. If the reduction in a paraesophageal (station 8) lymph node is less than that in a paratracheal lymph node, then we will choose endoscopic EUS-FNA instead of EBUS. A final potential important concept of the change in the maxsuv concerns several new multiinstitutional studies that may randomize patients who are complete responders to surgery versus observation. One was never able to truly predict who was a complete responder before the change in the maxsuv data was presented. The accuracy of restaging is needed for that study to be correctly done to truly know who is a complete responder. In conclusion, we have shown that the optimal time to perform a repeat integrated FDG-PET/CT scan after the completion of neoadjuvant chemoradiotherapy using high doses of 60 Gy or more in patients with NSCLC is about 1 month. References 1. Bulzebruck H, Bopp R, Drings P, et al. New aspects in the staging of lung cancer. Prospective validation of the International Union Against Cancer TNM classification. Cancer. 1992;70: Cerfolio RJ, Ojha B, Bryant AS, Bass CS, Bartalucci AA, Mountz JM. The role of FDG-PET scan in staging patients with nonsmall cell carcinoma. Ann Thorac Surg 2003;76; Lardinois D, Weder W, Hany TF, et al. Stating of non-small cell lung cancer with integrated positron emission tomography and computed tomography. N Engl J Med 2003;348: Aquino SL, Asmuth JC, Alpert NM, Halpern EF, Fischman AJ. Improved radiologic staging of lung cancer with 2-[18]- flouro-2-deoxy-d-glucose-positron emission tomography and computed tomography registration. J Comput Assist Tomogr 2003;27: Cerfolio RJ, Bryant AS, Ojha B, Eloubeidi M. Improving the inaccuracies of clinical staging of patients with NSCLC: a prospective trial. Ann Thorac Surg 2005;80: Reed CE, Harpole DH, Posther KE, et al. Results of the American College of Surgeons Oncology Group Z0050 trial: the utility of positron emission tomography in staging potentially operable non-small cell lung cancer. J Thorac Cardiovasc Surg. 2003;126: Cerfolio RJ. Positron emission tomography scanning with 2-fluoro-2-deoxyglucose as a predictor of response for nonsmall cell cancer. J Thorac Cardiovasc Surg 2003;125: Mawlawi O, Pan T, Macapinla HA. PET/CT Imaging techniques, considerations and artifacts. J Thorac Imaging 2006; 21: Hautzel H, Muller-Gartner H. Early changes in fluorine- 18-FDG uptake during radiotherapy. J Nucl Med 1997;38: Nabi HA, Zubeldia JM. Clinical applications of F18-FDG in oncology. J Nucl Med Technol 2002;30: Cerfolio RJ, Bryant AS, Winokur TS, Ohja B, Bartolucci AA. Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Ann Thorac Surg 2004;78: Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:

6 Ann Thorac Surg CERFOLIO AND BRYANT 2007;84: OPTIMAL TIME FOR REPEAT PET POSTRADIATION 13. Cerfolio RJ, Bryant AS, Ojha B. Restaging patients with N2 (stage IIIa) non-small cell lung cancer after neoadjuvant chemoradiotherapy: a prospective study. J Thorac Cardiovasc Surg 2006;131: Beck J. Likelihood ratios: another enhancement of sensitivity and specificity. Arch Pathol Lab Med 1986;110: Sonett JR, Krasna MJ, Suntharalingam M, et al. Safe pulmonary resection after chemotherapy and high-dose thoracic radiation Ann Thorac Surg 1999;68: Cerfolio RJ, Bryant AS, Spencer SA, Bartolucci AA. Pulmonary resection after high-dose and low-dose chest irradiation. Ann Thorac Surg 2005;80: Cerfolio RJ, Bryant AS, Yamamura M. Intercostal muscle flap to buttress the bronchus at risk and the thoracic esophagealgastric anastomosis. Ann Thorac Surg 2005;80: Pisters KM, Kris MG, Gralla RJ, Zaman MB, Heelan RT, Martini N. Pathologic complete response in advanced nonsmall cell lung cancer following preoperative chemotherapy: implications for the design of future non-small cell lung cancer combined modality trials. J Clin Oncol 1993;11: Gillham CM, Lucey JA, Keogan M, et al. (18) FDG uptake during induction chemoradiation for oesophageal cancer fails to predict histomorphological tumour response. Br J Cancer 2006; 95: Higashi K, Clavo AC, Wahl RL. In vitro assessment of 2-flouro-2-deoxy-D-glucose, L-methionine and thymidine as agents to monitor the early response of a human adenocarcinoma cell like to radiotherapy. J Nucl Med 1993;34: Schneeweiss FA, Sharan FN, Hautzel H, Rub TH, Muller- Gartner HW. Effect of ionizing radiation on conversion factor between deoxyglucose and glucose (lumped constant) in human glioblastoma cells in vitro. J Nucl Med 1995;36: Bryant AS, Cerfolio RJ, Klemm KM, Ojha B. Maximum standard uptake value of mediastinal lymph nodes on integrated FDG-PET-CT predicts pathology in patients with non-small cell lung cancer. Ann Thorac Surg 2006; 82: Weber WA, Ziegler SI, Thodtmann R, Hanauske A, Schwaiger M. Reproducibility of metabolic measurements in malignant tumors using FDG-PET. J Nucl Med 1999;40: GENERAL THORACIC Requirements for Maintenance of Certification in 2008 Diplomates of the American Board of Thoracic Surgery (ABTS) who plan to participate in the Maintenance of Certification (MOC) process which will begin in 2008 must hold an unrestricted medical license in the locale of their practice and privileges in a hospital accredited by the JCAHO (or other organization recognized by the ABTS). In addition, a valid ABTS certificate is an absolute requirement for entrance into the Maintenance of Certification process. If your certificate has expired, the only pathway for renewal of a certificate is to take and pass the Part I (written) and the Part II (oral) certifying examinations. The names of individuals who have not maintained their certificate will no longer be published in the American Board of Medical Specialties directories. Diplomates names will be published upon successful completion of the Maintenance of Certification process. The CME requirements are 30 Category I credits earned during each year prior to application. At least half of these CME hours need to be in the broad area of thoracic surgery. Category II credits are not allowed. Interested individuals should refer to the Booklet of Information for Maintenance of Certification for a complete description of acceptable CME credits. Diplomates in the Maintenance of Certification process will be required to complete all sections of the SESATS self-assessment examination. It is not necessary for Diplomates to purchase SESATS individually because it will be sent to them after their application has been approved. Diplomates may apply for Maintenance of Certification in the year their certificate expires, or if they wish to do so, they may apply up to two years before it expires. However, the new certificate will be dated 10 years from the date of expiration of their original certificate or most recent recertification certificate. In other words, going through the Maintenance of Certification process early does not alter the 10-year validation. Diplomates certified prior to 1976 (the year that time-limited certificates were initiated) are also required to participate in MOC if they wish to maintain valid certificates. The deadline for submission of application for the Maintenance of Certification is May 10 of each year. All ABTS diplomates will receive a letter from the Board outlining their individual timeline and MOC requirements. A brochure outlining the rules and requirements for Maintenance of Certification in thoracic surgery is available upon request from the American Board of Thoracic Surgery, 633 North St. Clair St, Suite 2320, Chicago, IL 60611; telephone (312) ; fax (312) ; info@abts.org. This booklet is also published on the website: by The Society of Thoracic Surgeons Ann Thorac Surg 2007;84: /07/$32.00 Published by Elsevier Inc