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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3939-3945 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.8727 Complete Response of Colorectal Liver Metastases After Chemotherapy: Does It Mean Cure?
From the Assistance Publique–Hôpitaux de Paris, Hôpital Ambroise Paré; Department of Surgery; Department of Pathology; Department of Radiology; Department of Gastroenterology and Oncology, Boulogne; and the Université Versailles Saint Quentin en Yvelines, Versailles, France. Address reprint requests to Stéphane Benoist MD, PhD, Service de Chirurgie Générale et Digestive, Hôpital Ambroise Paré, 9, Avenue Charles de Gaulle, 92104 Boulogne Cedex, France; e-mail: stephane.benoist{at}apr.aphp.fr
PURPOSE: Most patients with colorectal liver metastases (LMs) receive systemic chemotherapy. This study aimed to determine the significance of a complete response on imaging of LMs after chemotherapy. PATIENTS AND METHODS: Between 1998 and 2004, 586 patients were treated for colorectal LMs in one institution. Of these, 38 with the following criteria were included in the study: fewer than 10 LMs before chemotherapy; disappearance of one or several LMs on computed tomography (CT) scan and ultrasound; surgery with intraoperative ultrasound within 4 weeks of imaging; no extrahepatic disease; follow-up at least 1 year after surgery. RESULTS: Overall, 66 LMs disappeared after chemotherapy as seen on CT scan. Persistent macroscopic disease was observed at surgery at the site of 20 of 66 LMs, despite CT scan showing a complete response. The sites of 15 initial LMs that were not visible at surgery were resected. Pathologic examination of these sites of LMs, considered in complete response, showed viable cancer cells present in 12 of 15 cases. The sites of 31 initial LMs that were not visible at surgery were left in place during surgery; after 1 year of follow-up, 23 of 31 LMs considered in complete response had recurred in situ. Overall, persistent macroscopic or microscopic residual disease or early recurrence in situ were observed in 55 (83%) of 66 LMs having a complete response on imaging. CONCLUSION: In most patients receiving chemotherapy for colorectal LMs, a complete response on CT scan does not mean cure.
Colorectal carcinoma is one of the most common cancers in the world. Approximately 50% of patients develop liver metastases at some point during the course of their disease.1-3 Patients who are candidates for surgical resection of their liver metastases can expect a prolonged survival or even a cure.4,5 Unfortunately, only 10% to 25% of patients are candidates for liver resection.6,7 In patients with unresectable metastases, chemotherapy is the treatment of choice, and although it is often used with palliative intent, it may also be used in an attempt to render the metastases resectable.8,9 Chemotherapy can also be administered as a neoadjuvant treatment for selected cases of resectable metastases.10 Thus, most patients receive chemotherapy. Imaging and, in particular computed tomography (CT) scan is used to monitor chemotherapy according to the new guidelines for response evaluation (RECIST criteria).11 Complete response is usually defined as the disappearance of target lesions on imaging and is considered as a good indicator to evaluate the efficacy of chemotherapy. The correlation between imaging and pathologic status is not well defined. Whether complete radiologic response is correlated with complete pathologic response is important for the management of patients. In particular, in patients in whom imaging has shown that liver metastases have disappeared in one liver lobe after chemotherapy, it is still not certain whether they need surgical resection of this lobe. Therefore, we conducted a prospective evaluation of the correlation between complete radiologic response and complete pathologic response in patients who had received systemic chemotherapy for colorectal liver metastases. In other words, this study was indicated to determine whether liver metastases that disappeared on imaging after chemotherapy were sterilized.
Patients Between 1998 and 2004, data on 586 consecutive patients treated in one institution for liver metastases from colorectal cancer were collected prospectively. Most of these patients had received systemic chemotherapy. Of these 586 patients, 38 met the following inclusion criteria: fewer than 10 liver metastases before start of chemotherapy (this avoided including patients with too many deposits that might have rendered the CT scan analysis less reliable); imaging showing the disappearance of one or several liver metastases after systemic chemotherapy; laparotomy with intraoperative ultrasound within 4 weeks of imaging; no extrahepatic disease; no previous liver resection or percutaneous radiofrequency; and follow-up at least 1 year after surgery. These 38 patients were included in this study.
Imaging Investigations
Indication and Regimen of Systemic Chemotherapy
Surgical Procedures
Pathologic Examination When the resected liver included the site of liver metastases having a complete response, the pathologist was informed about the location of the former liver metastases so that a lesion-by-lesion search could be carried out to detect any of viable tumor cells at the site of any liver metastasis that had disappeared.
Postoperative Management and Follow-Up Patients were followed up every 4 months during the first 2 years and every 6 months thereafter. At each follow-up visit, tumor recurrence was assessed by clinical examination and liver ultrasound. Abdominal and chest CT scans were carried out every 8 months. Liver metastases occurring during the follow-up period were recorded either as an in situ recurrence if they appeared at the site of a previous liver metastasis that have disappeared or as a new lesion. All surviving patients were followed for a minimum of 12 months after surgery.
End Points
Statistical Analysis
Patients and Tumor Characteristics Imaging showed 183 liver metastases before treatment in the 38 patients included in this study (Table 1). Of these 183 liver metastases, 66 had disappeared on imaging after systemic chemotherapy. Imaging showed that preoperative chemotherapy resulted in a complete response of one liver metastasis in 22 patients, two metastases in eight patients, and three or more in eight patients. The mean maximum diameter at diagnosis of liver metastases with complete response on imaging was 2.2 ± 1.5 cm before treatment, and for liver metastasis greater than 4.5 cm, no complete response on imaging was observed.
Macroscopic Residual Disease at Surgery During laparotomy, liver examination and intraoperative ultrasound confirmed that 46 liver metastases had disappeared in 29 patients. However, macroscopic residual disease was observed at the site of 20 liver metastases in nine patients (24%) despite preoperative imaging showing a complete response. The mean size of these 20 residual liver metastases seen at surgery was 12.1 ± 6.8 mm (range, 3 to 25 mm). The size of residual lesions was less than 1 cm in six cases and less than 5 mm in one case. Of these nine patients, one had resectable liver metastases before chemotherapy. This patient underwent a right hepatectomy, and the pathologic examination confirmed the presence of viable tumor cells in the two liver metastases that supposedly disappeared that were detected at laparotomy. The remaining eight patients had initially unresectable metastases before chemotherapy. Of these eight patients, laparotomy detected residual disease in two patients precluding surgical resection. Six other patients underwent a liver resection combined with radiofrequency ablation of liver metastases. Univariate analysis (Table 2) showed no preoperative variable that was predictive for the persistence of macroscopic metastases at sites showing complete response on imaging.
Microscopic Residual Disease During surgery, liver examination and intraoperative ultrasound confirmed that in 15 patients who had received chemotherapy for initially resectable metastases, there was no remaining visible tumor at the site of 15 liver metastases that had disappeared on imaging. The characteristics of these patients are summarized in Table 3. All these patients underwent a liver resection including the site of the liver metastases that disappeared. Five patients underwent a right hepatectomy (segments 5, 6, 7, 8), seven underwent an extended right hepatectomy (segments 4, 5, 6, 7, 8), one underwent a trisegmentectomy (segments 4, 7, 8), and two underwent a bisegmentectomy (segments 6, 7). Pathologic examination of the sites of liver metastases having complete response on imaging and without visible disease at surgery showed the presence of viable tumor cells in 12 patients (80%). In the remaining three patients, pathologic examination showed only necrosis at the site of liver metastasis.
Twelve patients received postoperative systemic chemotherapy using the same regimen. Recurrence was observed 1 year after liver resection in 10 patients (66.6%): two hepatic recurrences, three extrahepatic recurrences, and five hepatic and extrahepatic recurrences. After 1 year, 14 of 15 patients were alive.
Tumor Recurrence In Situ During surgery, liver examination and intraoperative ultrasound confirmed that there was no remaining visible tumor at the site of 31 liver metastases that had disappeared on imaging. The characteristics of these patients are summarized in Table 4. All visible liver metastases were resected or treated by radiofrequency ablation. Twelve patients underwent the following liver resection: three right hepatectomies (segments 5, 6, 7, 8), two extended right hepatectomies (segments 4, 5, 6, 7, 8), three left hepatectomies (segments 2, 3, 4), one extended left hepatectomy (segment 2, 3, 4, 5), and three left lobectomies (segments 2, 3). Of these 12 patients, liver resections were associated with radiofrequency ablation in six cases. The two remaining patients underwent radiofrequency ablation of all visible liver metastases without liver resection. The sites of the 31 liver metastases having complete response were left in the remnant liver. All patients received postoperative systemic chemotherapy. The mean number of cycles of postoperative chemotherapy was 7.8 ± 2.9.
At follow-up after 1 year, CT scan or ultrasound showed that 23 (74%) of the 31 liver metastases having complete response had recurred in situ in 11 patients (79%). These 11 patients with recurrent disease received systemic chemotherapy, with one undergoing a repeat liver resection and two other patients being treated by percutaneous radiofrequency ablation. At 1 year, eight liver metastases having complete response had not recurred in situ in the three remaining patients, although two of these three patients had liver recurrences in another area of the liver. All 14 patients were alive 1 year after surgery. In summary (Fig 1), persistent macroscopic or microscopic residual disease or early recurrence in situ were observed in 55 (83%) of 66 liver metastases showing complete response on imaging.
This study shows that there is a discrepancy between a complete response being seen on imaging and the complete clearance of cancer in up to 83% of patients evaluated. In more than 25% of cases, macroscopic residual disease was found during surgical exploration at the site of liver metastases that were considered to have disappeared on imaging. In addition, in patients with no obvious disease at surgery, microscopic cancer was observed in the resected specimen from the site of initial liver metastases in 80% of patients. Finally, in patients with no more tumor observed and in whom the site of complete response was left in place, in situ recurrence was observed in 74% of cases after 1 year. These data show that, although complete response seen on imaging may be a useful criterion for evaluating the efficacy of chemotherapy, it does not mean the cure of cancer in most cases. The imaging methods used in all patients in this study were helical CT scan and ultrasound, as are similarly used in other expert institutions.8,14,15 Furthermore, ultrasound was carried out by two experienced radiologists, and all CT images were reviewed during multidisciplinary meetings. It has been reported that the sensitivity of helical CT scan in patients with colorectal metastasis is less than 85%, ranging from to 66% to 84%.16-20 The liver metastases studied here were detected using imaging methods and had subsequently disappeared after chemotherapy. In patients with persistent macroscopic disease at surgery, the morphologic changes to the structure of liver caused by chemotherapy, such as steatosis, may have been responsible for underestimating metastases in the remnant liver.21,22 This therefore raises the question of whether other imaging techniques such as magnetic resonance imaging (MRI) or positron emission tomography (PET) scan should be carried out in patients in whom liver metastases are not more visible by either helical CT scan or percutaneous ultrasound. There is still some debate over the superiority of unenhanced MRI over helical CT scan,16,23 and only MRI with liver specific contrast agents has been shown to be better than other techniques,17,19,20,23-25 although it is difficult to use routinely. PET scan is still being evaluated for detecting colorectal liver metastases, but it appears to have a high sensitivity for detecting these metastases.17,26 The evaluation of tumor response to treatment is critical for managing patients with advanced cancer. Tumor response, partial and complete response, is the most common criterion used to evaluate the effect of treatment. They are also commonly used as end points in clinical trials designed to estimate the potential benefits of new treatments.12,13,27-29 New guidelines for evaluating the response to treatment of solid tumors using imaging were recently established in an attempt to standardize response assessment (RECIST criteria).11 These new criteria for solid tumors have been validated in several studies.30-31 In these guidelines, the major objective response is defined as the disappearance of all target lesions. Thus, the response seen on imaging and, in particular, complete response is a very useful indicator for monitoring cancer treatment. However, as this study clearly shows, in most patients it cannot be considered as synonymous of cure. The number of patients with colorectal liver metastases receiving surgical resection is increasing.7,32 There is still much uncertainty concerning the timing, type and the extent of resections in patients who have received preoperative chemotherapy.33,34 In particular, it is unclear what to do when some liver metastases have shrunk or disappeared. Such questions can be discussed in patients with initially resectable liver metastases and in patients with initially unresectable metastases that become resectable after response to chemotherapy. In patients with resectable liver metastases, neoadjuvant chemotherapy is often administered in aggressive disease, and although its benefit is not yet formally proven, it can serve to test the chemoresponsiveness.3,10,14 The major question for the surgeon is whether the site of metastases that have disappeared should be included in the resection or can be left in place. This is particularly important when the disappearance of lesions allows the surgeon to perform a smaller resection with a lower risk. This study demonstrated that microscopic cancer persists in most of these sites. Thus, in most cases, resection of the sites of initial metastases is necessary. In such cases, technical problems for the surgeon are to identify the precise site of the liver needed to be resected and to achieve sufficient resection margin, since he cannot see or palpate any tumor or visualize it using intraoperative ultrasound. Therefore, medical oncologists should refer patients with resectable liver metastases to surgeons before any liver metastases have completely disappeared. In patients with unresectable metastases, accumulating data shows that neoadjuvant chemotherapy can render some patients resectable, hence giving the possibility of a prolonged survival.8,9,15,35 In some patients, surgery becomes feasible after chemotherapy because of metastases disappearing in one lobe of the liver, allowing resection of deposits in the opposite lobe. Thus, the sites of the metastases that disappeared are left in place. The natural histories of these lesions that are left in place remains unknown. In the present study, in situ recurrences were observed in 78% of patients, suggesting that active tumor was still present although not visible. This is consistent with the observation of viable tumor cells in most specimens after resection of sites of metastases showing complete response on imaging. In another series reporting 11 patients in whom liver metastases that disappeared were left in place, a local recurrence was observed in 27% of patients, although persistent viable tumor cells were observed after resection of the site of metastases showing complete response on imaging in 50% of patients.36 The difference between this study and the present study for the in situ recurrence rate may be due to the patients receiving intra-arterial hepatic chemotherapy after surgery in the previous study.36 In conclusion, a complete response seen on imaging in patients who have received chemotherapy for colorectal liver metastases does not mean cure in most patients. When feasible, the site of the lesion that disappeared should be resected at surgery. In other cases, further aggressive treatment, such as systemic or intra-arterial chemotherapy, biologic agents or ablative techniques should be considered to decrease local recurrence.
The authors indicated no potential conflicts of interest.
Supported by grants from the Association pour la Recherche en Oncologie Digestive (AROLD) association. S.B. and A.B. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
