273 Workshop Restaging after neoadjuvant chemoradiotherapy for rectal adenocarcinoma: role of F18-FDG PET

Poster workshops

Patients and methods: Included were 5 patients referred for primary radiotherapy for head and neck squamous cell carcinoma. ACT scan was made in treatment position using 5-ram slices. Levels IA to VI and the retro- and parapharyngeal nodal areas were delineated separately by 4 radiationoncologists, lnterobserver variability was expressed by the conformlty index (CI), defined as the ratio between the volume delineated by all observers and the total volume delineated by at least one of the 4 observers. The CI was averaged over all delineators and again over all patients. Results: In the first session, a protocol was used derived from 4 different protocols described in literature. Using this protocol, the CI varied from 0.37 to 0.56. After the first session, & meeting was organized with all the ~bservers together to evaluate the most important disagreements between the observers in each individual patient. Based on this evaluation, the protocol was adjusted in order to define the borders of the nodal levels more precisely. To evaluate the adjusted protocol a second session was organized using 5 new patient-sets. A significant improvement of the CI was observed for level II (CI 1st session: 0.43, CI 2nd session 0.53 (p=0.03)), level III (CI 1st session: 0.39, CI 2rid session: 0.51 (p=0.01)), level tV (CI 1st session: 0.41, CI 2nd session: 0.56 (p=0.007)) and for level ll-IV (CI 1st session: 0.51, CI 2nd session: 0.63 (p<0.001)). The CI of the second session varied from 0.44 to 0.63. Conclusion: In this study, considerable interobserver variability was noted between different experienced radiation-oncologists in the delineation of elective nodal areas, even in a single institution-setting A significant reduction of the interobserver variability can be obtained by a critical evaluation of the major disagreements between different observers and additionally by refining the definitions of the borders of the different nodal levels in the protocot. The results of this study stress the importance of testing the validity of such protocols for future multicenter studies. Furthermore, great caution should be taken in the translation of results with regard to ioco-regional control after parotid-sparing techniques reported by other institutions, 271

Workshop

The reasons for discrepancies in target volume delineation: I1: clinical p a r t

R.O. Mirimanoff 1, W. Jeanneret Sozzi 1, J.F. Valley 2, R. Moeckli2 1CHUV, Radie-oncology Department, Lausanne, Switzerland 2University Institute of Applied Radiophysics, Lausanne, Switzerland Objective : To understand the reasons from a clinical point of view regarding the different ways to delineate the target volumes between physicians, Materials and Methods : Swiss radiation oncology centres were sent clinical and radiological data of a prostate and of a head and neck case, and asked to delineate volumes and to fill a questionnaire. The goal was to understand the methods and the rationale to obtain the former. Eleven centres participated to the study. The clinical part of the study was based on a questionnaire to evaluate the differences in the volume definition (GTV, CTV and PTV) based on the ICRU 50 guidelines. To understand the physician?s decisions regarding the volumes and margins applied in the two cases, we analysed and compared the methods and tools which were used to achieve it in the two cases. We also looked at the intracentre coherence between the volumes drawn and the answers to the questionnaire. Results : As expected, we found large differences in the drawn target volumee between the centres, which were greater in the head and neck case than in the prostate case. The questionnaire revealed important variations in the planning methods, including planning CT techniques, as well as differences in the determination of GTV, CIV and PTV, and wide differences in the margins to be applied between these volumes. The correlation between contoured margins and stated margins (questionnaire) was fair in the prostate case and poor in the head and neck case. Many inconsietencies were noted within centres regarding consecutive answers. Detailed data will be presented at the meeting, Conclusions : In this study, where a rather easy case (prostate) and a more difficult case (head and neck) were used, we found wide differences in volumes, planning and concepts, and a number of intra and inter-centres inconsistencies which can partly explain the reasons for discrepancies in target volume delineation between physicians. A number of measures to improve these will be presented and discussed,

Friday, 20 September 2002 S9I

PET IN RADIOTHERAPY 272 Workshop Correlation of

F-18 FDG PET with morphometric tumor response after neoadjuvant chemoradiation in locally a d v a n c e d ( S t a g e III) N o n - S m a l l Cell Lung Cancer (NSCLC) M. Schmueckino 1, R.P. Baum 1, R. Bonnet 1, N. Presselt 1, K. Junket2, J. Leonhardi 1, C. Przetak 1, C.P. Schneider 3, K. Hoeffken 3, TG. Wendt4 1Zentralklinik Bad Berka, Depts. of Nuclear Medicine, Pneumology, Thoracic Surgery, Diagnostic Radiology, Bad Berka, Germany 2University Hospital Bergmannsheil, Dept. of Pathology, Bochum, Germany 3University of Jena, Dept. of Hematology and Oncology, Jena, Germany

4University of Jena, Dept. of Radiation Oncology, Jena, Germany Aim: To determine the role of 2-[(18)F] fluoro-2- deoxy-D-glucose (FDG) positron emission tomography (PET) in morphometric tumor response after neoadjuvant chemoradiati0 n, findings in 32 patients were analyzed prospectively in an ongoing multicenter trial (LUCAS-MD). Materials and Methods: Inclusion criteria was histologically confirmed NSCLC stage IIIA/IIIB. For staging all patients received a PET scan in addition to a spiral CT and/or MRI before therapy. Neoadjuvant treatment consisted of 2-3 cycles of chemotherapy with paclitaxel (225 mg/m ') and carboplatin (AUC = 6), each dl q22 and a block of chemoradiation (45Gy, 1.5Gy b.i.d., concomitant with paclitaxel (50 mg/m2) and carboplatin (AUC = 2), each dl, d8, d15) followed by surgery. All patients received a second PET after completion of neoadjuvant therapy prior to surgery. Whole-body PET (ECAT Exact 47) studies (attenuation corrected, iteratively reconstructed) were obtained 60 min. after injection of 6 MBq/kg body weight F-18 FDG. For semi-quantitative analysis, the tumor standardized uptake values (SUV), the tumor to background SUV ratio (T/B ratio), the metabolic tumor diameter (MTD) and the metabolic tumor index (MT1 = SUV x MTD) were assessed in all primary tumors and in metastatic lymph nodes. Additionally, image fusion of PET with CT data was applied (using a HERMES Computer, Nuclear Diagnostics, Sweden). Results: So far; all patients (7/32) with complete metabolic response in lymph node metastases detected by PET, had no vital tumor cells (morphometric regression grade Ill). In primary tumors showing complete metabolic response, the regression grade was liB (less than 10% vital tumor cells) or Ill. Conclusion: Morphometric tumor response after neoadjuvant therapy correlates strongly with metabolic remission by FDG-PET. PET precedes the tumor response as measured by CT after neoadjuvant treatment and may predict the long term therapeutic outcome in stage Iit NSCLC. 273

Workshop

Restaging after neoadjuvant chemoradiotherapy for rectal adenocar¢inoma: role o f F18-FDGI PET C. Capirci 1, F. Chierichetti 2, G. Crepaldi 3, G. Mandofiti 1 1International Cancer Center, Radiotherapy, Rovigo, Italy 2State Hospital, Nuclear Medicine, Castelfranco, Italy 3International Cancer Center,. Oncology, Rovigo, Italy Background: Clinical staging accuracy to assess the complete response to neoadjuvant radio-chemotherapy for rectal cancer is controversial. The aim of the study was to compare the accuracy of FDG PET to predict the complete response after intensified radio-chem0therapy for rectal cancer. Methods: 50 patients with histologically proven adenocarcinoma in clinical stage II-IV disease (stage II 21 pts; stage Ill 24 pts; stage IV 5 pts), who were also eligible for surgery, were included in this study. All patients were submitted at diagnostic staging workup (DSW) with digital examination, proctoecopy with biopsy, EUS, CT or MRT pelvis/abdomen scan, chest X ray, coloscopy or barium enema. Following DSW, patients received neoadjuvant simultaneous radiochemotherapy (RTx/CTx) for 5 weeks. Diagnostic Restaging Workup(DRW)with digital examination, proctoecopy, EUS, MRTscan and F18-FDG PET was performed 4 weeks after completion of therapy. Afterwards patients were scheduled to undergo surgery, 8 weeks after the end of radio-chemotherapy. Results: At Ioco-regional DRW 6 patients had a complete clinical response, 25 patients were cT2N-, 3 patients cT2,N+, 12 patients cT3,N-, 2 patient cT3,N+, 2 patients cT4,N-. After preoperative therapies, only 5 patients were found cN+, while they were 28 at diagnosis time. Loco-regional PET assessment was negative, doubt-negative, doubt-positive, and positive in 30, 6, 2, and 12 cases, respectively. PET detected metastases in 8 patients. At pathologic feeding, irrespective of cM+ category, were found: pro,

$92 Friday, 20 September 2002

pTmic, pT1, pT2, pT3, end pT4 stage in 14 (28%), 7 (14%) 2, (4%) 15 (30%), 9 (18%), and 3 (6%) patients, respectively. PET was negative or doubt-negative in 20/21 (95% sensibility) patients with pathologic stage 0 (pCR + cCR); was positive or doubt-positive in 13/29 (45% Specificity) cases with persistent cancer in surgical specimen. Predictive positive value (PPV), and predictive negative value (PNV) were 56%, and 93% respectively. Total accuracy was 66%. Conclusions: Correct detection of complete response stills remains an unresolved problem: PET showed high sensibility and high PNV, but low specificity and low PPV. In our experience PET tended to overestimate response when compared with pathologic assessment. We make a working hypothesis that false negative restaging PET could have good prognostic value 274

Workshop

Impact of PET scanning on randomised trials of radical radiotherapy in non-small cell lung cancer M. Mac Manus, R. Hicks, J. Matthews, D. Bali Peter Mac Callum Cancer Institute, Radiation Oncology, East Melbourne, Australia Background: FDG-PET enhances staging of non-small cell lung cancer (NSCLC) by detecting unsuspected nodal or metastatic disease. PETselected radical radiotherapy patients consequently have superior survival, We used prospective PET data from our center to model the impact of PET staging in design of a putative randomised trial comparing an established and a new radical radiotherapy/chemoradiotherapy regimen. Materials and Methods: The following data from a prospective NSCLC PET database were employed in sample size calculations. At our centre 30% of (153) radical radiotherapy candidates were actually treated palliatively because of PET-detected incurable metastatic (18%) or extensive Iocoregional disease (12%). These patients had 17% 2 year survival. In 22% of radically-irradiated patients, gross tumour would have been missed without PET imaging. For patients stilt eligible for radical radiotherapy after PET, 45% of (88) post treatment PET scans showed complete response (CR). Patients with CR after radical radiotherapy had 2 year survival of 82%; patients not achieving CR after radical radiotherapy had 2 year survival of 39%. These data were used to design a trial capable of detecting a survival benefit at 2 years resulting from a 20% increase in Iocoregional disease control in PET-selected patients. Results: We assume that the new treatment increases the CR rate in PET-staged patients by 20%, that is, from 45% to 65%, and that the 2 year survival rates for CR and non-CR patients in these patients remain 82% and 39% respectively on either treatment arm. Then the 2 year survival rate would be increased from 58.4% to 67.0% by the new treatment. The sample size needed to detect this difference with cc=0.05 and 80% power is 1036 patients. However, repeating this catculation for a cohort of patients who had not undergone PET, 30% of whom would have been found incurable (17% 2 year survival rate on either treatmerit) and for whom 22% of the remainder could not achieve CR because of geographic miss (estimated 20% 2 year survival rate on either treatment), the sample size would be 3546 patients to detect an increase in 2 year survival rates from 40.0% to 44.7%. Thus, roughly 3.5 times as many patients would be required without PET selection. Conclusions: PET staging allows randomised trials of radical radiotherapy/chemoradiotherapy in NSCLC to detect differences in outcomes between treatment groups with significantly fewer patients, 275

Workshop

Treatment planning of 3D-conformal radiation therapy based on the integrated computer-assisted Positron Emission Tomography (PET/C'F) imaging I.F. Ciemik 1, E. Dizendorf2, B. Reiner 1, C. Burger2, S. Khan 1, Ll.M. LOtolf 1, H. Steinetl2, G.K. Von Schuthess 2, B.G. Baumert3 1Radio-Onkologie, Universit~tsspital ZOrich, ZOrich, Switzerland 2Nukleare Medizin, Universitatsspital ZOrich, ZOrich, Switzerland 3Radiation Oncology, University Hospital, Maastricht, The Netherlands Background: Computer~assisted-treatment planning for 3-DRT is standard. The impact of further improving target delineation accuracy with integrating data with metabolically active areas determined by PET is unknown. Methods: 32 patients with head and neck tumours, bronchial, gynaecological or recto-anal carcinoma referred for curative RT were investigated. Computerassociated tomography (CAT) and positron emission tomography (PET) was obtained in treatment position prior to radiation. CAT and PET were fused for treatment planning. Delineation was performed with and without the PET. Interobserver variability was assessed. Results: Fusion accuracy of PET with CAT depended on the anatomical region, being 0.9 + 1.9 mm

Poster workshops

for head and neck tumors, 1.6 ± 4.3 mm for tumors of the chest, and 0.4 + 2.5 mm for tumors of the the pelvis. PET-defined target volume accuracy overestimated CT-defined target volume by 1 mm. The gross target volume (GTV), as defined by macroscopic tumor tissue increased (>25%) after fusion with PET in two out of eight and decreased in two patients with head and neck tumors. In the five patients with lung cancer GTV increased in one and decreased in two cases. In patients with rectal or anal carcinoma significant target vo!ume increases were observed in 5 out of 11 patients and PET resulted in smaller volumes only in one patient. In gynaecological tumors, two out of eight patients resulted in significant GTV reduction, two resulted in an increased GTV delineation. Overall, in 53% of cases, volume delineation for the GTV was changed by PET. The modification of GTV translated into modified planning target volumes (PTV) and changed portal field sizes (>20%) in 47% of patients. In the presence of the PET, volume definition between radiation oncologists was more homogenous (p= 0.02). Conclusions: Integrated PET/CT improves on the accuracy in treatment planning and seems to resutt in more standardized volume definition. PET/CT-based treatment planning may lead to improved local tumor control. 276

Workshop

Using PET imaging and IMRT to generate a smart hypoxia b o o s t f o r head and neck tumours F. Paulsen 1, M. Albet2., S.M. Eschmann 3, L. Plasswilm 1, W. Budach 1, H.J. Machulla 4, F. Nuesslin 2, R. Bares 3, M. Bamberg 1 1University Hospital, Radiotherapy, Tuebingen, Germany 2university Hospital, Medical Physics, Tuebingen, Germany 3University Hospital, Nuclear Medicine, Tuebingen, Germany 4University Hospital, Radiopharmacy, Tuebingen, Germany Hypoxia is known to be the cause for reduced radiosensitivity of tumours. Hypothetically, increasing doses to the hypoxic subvolume may lead to higher local control rates. PET with the hypoxic cell tracer 18F-misonidazole (FMISO) has the potential to map the spatial hypoxia distribution. IMRT offers a method to deliver integrated boost doses to selected areas of reduced radiosensitivity without increasing toxicity to the surrounding tissues. In a retrospective study a planning process based on the 3-D distribution of the hypoxic marker FMISO was investigated. The IMRT planning was performed by the in-house tool Hyperion. Patients with advanced head and neck cancer underwent emission and transmission scans using a GE Millennium VG / Hawkeye scanner after injection Of 400 MBq FMtSO before radiotherapy and after 30 Gy. FMISO levels above a threshold of 1.4-times the cerebelladmuscular level were regarded as biologically significant (hypoxic). A 3-D distribution of FMISO level based cell sensitivity was defined. In contrast to a homogeneous dose delivery, a homogeneous level of cell survival probability was the objective for the optimization process. On this assumption an optimized dose distribution obtains which selectively boosts the hypoxic areas in the classical target volumes proportional to the local cell sensitivity to achieve a homogeneous level of cell kill. Normal tissue constraints were used to ensure isptoxicity. Based on the L-Q-model the effects of non-standard fraction sizes in normal tissues or the boost regions were studied. The optimization algorithm allows an assessment of the interaction between the required iso-cell kill and the normal tissue constraints. This method leads to a highly selective adaptation of the dose gradients to the prescribed levels of dose based on FMISO-uptake. The classical target volumes are respected with an integrated hypoxia-mediated dose boost. Depending on tumor size dose escalation was achieved with little influence of normal tissue isotoxicity constraints. Parotidal sparing was possible. The algorithm produces about 50 MLC field segments for static delivery. FMISOPET after 30 Gy showed changed activity distributions which was taken into account by an adapted treatment plan. IMRT and FMISO-PET allows functional imaging based treatment planning with hypoxia adapted dose distribution. The relevance of this approach has to be tested in future clinical investigations. 277

Workshop

The role of fdg-pet in the design of the radiation fields for patients with advanced esophageal cancer O. Vrieze 1, K. Haustermans I, W. De Wever 2, T. Lerut3, E. Van Cutsem 4, M. Hie/e 4, N. Ectors4, P. Flamen 5 1UH Gasthuisberg, Radiation Onco/ogy, Leuven, Be~glum 2UH Gasthuisberg, Radiology, Leuven, Be~glum 3UH Gasthuisberg, Thoracic Surgery, Leuven, Belgium