Introduction 1 2 5 6 2 7 8 d 9 13 14 15 18 The aim of our study was to examine the effect of neoadjuvant chemotherapy for hepatic colorectal metastases on CT and FDG-PET/CT findings and to define the role of these imaging techniques in this setting. To do so, we compared CT and FDG-PET/CT findings with histopathological reports. Patients and Methods Patients Nonresectable tumors due to size, location, and number and assessment of the surgical team that complete (R0) resection was not technically possible. 19 Presence of extrahepatic disease. Oncologist’s preference—this applied to patients with MSKCC >2 that were referred from other hospitals for immediate surgery. The decision not to administer neoadjuvant therapy was not necessarily in agreement with our policy. Patient’s preference—patients who refused neoadjuvant therapy were assigned to immediate surgery when feasible. Neoadjuvant Chemotherapy Treatment consisted of a neoadjuvant chemotherapeutic combination of 5-fluorouracil, leucovorin, and either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). Seventeen patients (35%) were also given bevacizumab. Most of the group 2 patients were given neoadjuvant irinotecan unless they were enrolled on a multicenter study whose protocol consisted of the administration of neoadjuvant oxaliplatin. Staging Before undergoing neoadjuvant chemotherapy, all group 2 patients underwent a triphasic contrast-enhanced CT scan, and a FDG-PET/CT was performed in 30 (62.5%) of them. All 75 patients in group 1 and group 2 underwent FDG-PET/CT and abdominal CT before liver surgery. The time interval between the last course of chemotherapy and the FDG-PET/CT scan was at least 2 weeks, and surgical exploration took place within 1 month following the FDG-PET/CT scan in most of the cases. Because we used an integrated PET/CT technique, precise anatomical localization could be achieved and confirmed with the standard triphasic abdominal CT findings. PET/CT 18 Studies of all patients were retrieved and read in consensus by two experts (U.M. and E.E.-S.). All suspected sites of metastatic disease showing an increased FDG uptake were recorded. The location of hepatic lesions was recorded according to the Couinaud segmental classification. Hepatectomy All patients without extensive extrahepatic disease underwent surgical exploration and intraoperative ultrasound (IOUS). Resections of all metastatic sites were performed by either anatomic or R0 nonanatomic resection, with a tendency toward maximal parenchymal preservation with nonanatomic resections. Complete radiological response to neoadjuvant chemotherapy was defined as the complete resolution of all metastatic sites according to the CT and PET-CT. In these cases, careful palpation and IOUS were performed in search of remaining tumor or scarring. When there was no evidence of either, the tumor sites were resected according to the findings on the original imaging (i.e., before any response to neoadjuvant treatment). Detection of Hepatic Metastases To define the sensitivity of CT and FDG-PET/CT for liver metastases, imaging results were compared with the presence and size of liver lesions as demonstrated and measured by histopathological reports. Results Patients 1 2 Table 1 Study Patients’ Profiles   n n P Sex ratio (F/M) 0.50 0.92 0.22 Mean age, years (std deviation) 66 (9.8) 61.25 (10.9) 0.06 Site     Colon 9 (71%) 32 (66%) 0.74  Rectum 8 (29%) 16 (33%)  LN metastases (Duke’s >B in colonic specimen) 81.5% 82% 0.73 No. of liver tumors (mean) (std deviation) 1.19 (0.4) 2.52 (1.9) 0.0001 Max tumor diameter (largest) (std deviation) 3.53 cm (2.84) 3.9 cm (1.84) 0.49 Extrahepatic disease (no. of patients) 7 9 0.56 Prior liver resection 4 6 1 Mean MSKCC risk score (range) 1.82 (0–4) 2.48 (2–5) 0.003 Group 1, immediate hepatic resection; Group 2, hepatic resection following neoadjuvant chemotherapy LN Table 2 Operative Procedures Operative procedure (no. of patients; lesions) n n Right hepatic lobectomy 5 8 Left hepatic lobectomy 4 4 Central hepatectomy 0 3 Right trisegmentectomy 1 0 Nonanatomic resections 15 29 Left lat segmentectomy 2 2 Explorative laparotomy (no resection) 0 2 Group 1, immediate hepatic resection; Group 2, hepatic resection following neoadjuvant chemotherapy Detection of Hepatic Metastases 3 3 P P Table 3 FDG-PET and CT—Comparison With Pathological Results   n n P PET  TP 29 48   True negative (complete response) – 20   FP 2 4   FN 2 50   Sensitivity 93.3% 49% <0.0001  Specificity – 83.3%  CT  TP 28 64   True negative (complete response) – 18   FP 1 6   FN 4 34   Sensitivity 87.5% 65.3% 0.038  Specificity – 75%  Group 1, immediate hepatic resection; group 2, hepatic resection following neoadjuvant chemotherapy Four of the six false-positive (FP) results on FDG-PET involved patients who had previously undergone hepatic resection. These lesions were discovered on follow-up FDG-PET/CT. Uptake was observed along the resection site, and these patients underwent nonanatomic liver resections for suspected locally recurrent lesions. Pathologic evaluation failed to reveal any tumor cells. The positive predictive value of FDG-PET/CT for metastasis recurrence in the resection site was only 33%, and specificity was 60%. 4 P Table 4 Sensitivity of FDG-PET: Correlation With Tumor Size Tumor size <1 cm 1–3 cm >3 cm Group 1 sensitivity (total no. of lesions) n n n Group 2 sensitivity (total no. of lesions) n n n Group 1, immediate hepatic resection; group 2, hepatic resection following neoadjuvant chemotherapy n n 5 Table 5 FDG-PET and CT in Patients who Received Chemotherapy With or Without Bevacizumab: Comparison With Pathological Results   Bevacizumab − Bevacizumab + P PET  TP 29 19   True negative (complete response) 17 3   FP 2 2   FN 20 30   Sensitivity 59% 39% 0.068 CT  TP 33 31   True negative (complete response) 13 5   FP 6 0   FN 16 18   Sensitivity 67% 63% 0.9 Detection of Extrahepatic Metastases In group 1, there were one FP result for extrahepatic disease (suspected recurrence in colonic anastomosis, abdominal wall), one true-positive (TP) result (recurrence in mesocolic lymph nodes), and one false negative (FN) result (in a patient with peritoneal metastases). In group 2, there was one FP result (for suspected peritoneal metastasis), three TP results (recurrence in paraaortic lymph nodes and solitary lung metastasis), and two FN results (for peritoneal metastases). Discussion 15 16 17 19 20 14 P P 20 20 4 P 21 Time interval between the FDG-PET and surgery. In our series, two patients with FN results (two hepatic lesions) underwent surgery more than 2 months after FDG-PET was performed. Viable tumors were discovered at the site of the original metastases which had disappeared on FDG-PET following neoadjuvant treatment. Although it is conceivable that the relatively long interval between FDG-PET and surgery may have contributed to the FN results, we believe that these tumors may have been FN due the small size of the lesions following partial pathological response to chemotherapy. 22 23 Conclusions The sensitivity of FDG-PET in detecting colorectal hepatic metastases decreases significantly following neoadjuvant chemotherapy. This may result in a higher-than-expected rate of nonresectable disease discovered at the time of laparotomy and in more extrahepatic recurrences following resection. We recommend staging patients with a “baseline” contrast-enhanced FDG-PET/CT both before and after the administration of neoadjuvant therapy. The extent of hepatic resection should be guided by systematic integration of data from all additional imaging modalities (abdominal CT, IOUS), as well as by the original imaging findings (before the neoadjuvant treatment). We recommend resection of all metastases that achieved complete radiological response, whenever technically possible. Longer follow-up and further studies are required to justify neoadjuvant treatment and screening with FDG-PET/CT in patients with colorectal metastases to the liver who are at high risk of recurrence.