Response Of Colorectal Liver Metastases Research Articles

Pathological complete response of colorectal liver metastases following chemotherapy with S-1 and oxaliplatin (SOX) in combination with bevacizumab: A case report

Pathological complete response to systemic chemotherapy is associated with more favorable survival in patients with colorectal cancer liver metastases. We present a case of a 63-year-old man with multiple liver metastases from descending colon cancer. Following surgical resection of the primary tumor, the patient received systemic chemotherapy with S-1 and oxaliplatin in combination with bevacizumab. On achievement of a markedly favorable response to chemotherapy, surgical treatment of liver metastases was performed, and the liver tumors were successfully resected without any macroscopic residue. Histopathological analyses showed necrotic tissue in the complete absence of residual viable tumor cells. This is the first reported case of a patient with multiple liver metastases from descending colorectal cancer to achieve a pathological complete response following systemic chemotherapy with S-1 and oxaliplatin in combination with bevacizumab. This regimen is a systemic chemotherapy option to 'cure' liver metastasis from colorectal cancer.

Outcome of colorectal liver metastases vanishing under chemotherapy and finally missing after surgery.

3548 Background: Complete pathological response of colorectal liver metastases (CRLM) after chemotherapy is a rare phenomenon. Furthermore, complete clinical response does not mean complete pathological response, and does not mean cure. However, CRLM may disappear on preoperative imaging studies and become undetectable during hepatectomy, hence left in place and considered as missing CRLM. The aim of this study was to assess the long-term outcome of such missing CRLM. Methods: Between 1999 and 2007, among 523 patients operated for CRLM, missing CRLM were observed in 27 patients (5.1%). All of these patients received preoperative chemotherapy. Hepatic arterial infusion (HAI) of oxaliplatin associated to systemic 5-FU was administrated in 21 patients (10 before hepatectomy and 11 after). Hepatic resection was performed at least 3 months after CRLM vanishing on imaging. Results: These 27 patients initially presented with 286 LM (mean number of LM per patient: 10.6, range: 2-42). Among the 128 vanishing CRLM resected because still detectable during surgery, a complete pathologic response was observed in 29% of cases (n = 37). Overall, 158 missing CRLM were left in place in 27 patients (range per patient: 1 to 37). After a median follow-up of 56 months (15-129), hepatic recurrence was diagnosed in 13 patients (48%), and was significantly lower in patients who received adjuvant HAI compared to others (18% vs. 69%, p = 0.028). Recurrence occurred on the site of missing CRLM in 7 (26%) patients, including only one of the 11 patients who received adjuvant HAI. The overall 5-year survival rate of these highly chemosensitive patients was 85%. Conclusions: Vanishing but not missing metastases are still viable in 71% of cases. Vanishing and missing CRLM are definitively cured in 74% of cases. These excellent results are likely to be due to patient selection (on the duration of response to chemotherapy) and to the administration of adjuvant HAI oxaliplatin. No significant financial relationships to disclose.

Complete pathological response of colorectal liver metastases after chemotherapy and bevacizumab treatment: a case report

The vast majority of colorectal cancer patients who present with liver metastases are not initially candidates for hepatic resection. Although the combination of systemic chemotherapy and liver surgery can convert a significant proportion of patients from a palliative situation to a potentially curative situation, the majority of initially unresectable liver metastases do not respond sufficiently to initial chemotherapy to become resectable. More recently the addition of biologic agents (bevacizumab or cetuximab) to cytotoxic chemotherapy has increased the rate of tumor response, suggesting that the addition of these agents could improve resectability rate. Here we report the clinical case of a complete pathological response (pCR) in a 67-year-old male affected by metastatic colorectal cancer, with initially unresectable liver metastases, after treatment with chemotherapy and bevacizumab.

Complete Response of Colorectal Liver Metastases after Intra-Arterial Chemotherapy

We demonstrated that colorectal liver metastases considered in complete response after intra-arterial floxuridine-based chemotherapy had recurred in situ. One hundred and six colorectal liver metastases disappeared after intra-arterial chemotherapy. Persistent macroscopic disease was observed at surgery at the site of 52 of 106 liver metastases, even though computerized tomography scan and ultrasound showed a complete response. The sites of 35 initial liver metastases that were not visible at surgery were resected. Pathologic examination of these sites, considered in complete response, showed viable cancer cells in 22 of 35 cases. After 1 year of follow-up, 33 of 106 liver metastases considered in complete response had recurred in situ. After 2 years of follow-up, persistent macroscopic or microscopic residual disease or recurrence was observed in 86 (81%) of the 106 liver metastases. Nevertheless, 19% of the patients had a long-lasting response. This means that floxuridine given as intra-arterial hepatic chemotherapy can still be considered an interesting option of cure in the treatment of colorectal liver metastases. When feasible, the site of the lesion that disappeared after intra-arterial chemotherapy should be resected at surgery. The best palliative cure of liver metastases should be the combination of local-regional strategies like intra-arterial chemotherapy, surgery or radiofrequency ablation with the systemic approach.

Complete Response of Colorectal Liver Metastases After Chemotherapy: Does It Mean Cure?

Complete Response of Colorectal Liver Metastases After Chemotherapy: Does It Mean Cure?

Complete pathological response of colorectal liver metastases after neoadjuvant chemotherapy: myth or reality?

4063 Background: A complete clinical response (CCR) of colorectal liver metastases (CLM) following chemotherapy has been shown unrelated to the real disappearance of active tumor. By contrast, a complete pathological response (PCR) could be more clinically relevant, but has not been explored. The aim of this study was to evaluate the incidence and outcome as well as predictive factors of PCR, in patients resected from CLM after neoadjuvant chemotherapy. Methods: In our institution 791 consecutive patients with CLM underwent liver resection after neoadjuvant chemotherapy. CCR was defined as the disappearance of all lesions after chemotherapy, and PCR was defined as the total necrosis of all metastases on the resection specimen. Both were selected from a prospective database. Patients with and without PCR were compared, survivals were determined and predictive factors for PCR were analyzed using a multivariate risk model. Results: There were 0.4% CCR (3/791) and 4% PCR (31/791). Among the 31 patients with PCR, the median number of CLM was 2.0 (range 1–13) with a maximum diameter = 3 cm for most cases (73%) at diagnosis. Ten patients (32%) had extrahepatic metastases. Compared to patients without PCR, patients with PCR were younger (p< 0.05) and had a smaller maximum tumor size (p=0.007). Rate of objective response was higher (81% vs. 52%; p=0.002) and last chemotherapy regimen contained more frequently oxaliplatin than irinotecan (p=0.05). Number of chemotherapy cycles and treatment lines were not different. At multivariate analysis, 4 predictive factors of PCR were identified: age = 60 yrs, maximum size at diagnosis = 3 cm, CEA = 40 ng/ml at diagnosis and achievement of an objective response. The probability of PCR ranged from 0.2% when all were absent to 33.8% when all were present. PCR strongly impacted overall survival (OS) that was 69% and 62% at 5 and 10 years with a disease-free survival (DFS) of 42% for both. Conclusions: PCR concerns overall 4% of patients receiving neoadjuvant chemotherapy allowing for surgery, but as much as one third of those aged less than 60 years, developing response on liver metastases smaller than 3 cm, with low CEA values. Uncommon high survival rates are observed in this setting. PCR more than CCR is a reality and strongly impacts patient outcome. No significant financial relationships to disclose.

Predictors of a true complete response in colorectal liver metastases that disappear radiographically following chemotherapy

4058 Background: During chemotherapy for colorectal liver metastases (LM), some lesions disappear by CT scan. This may represent a true complete response (CR) with eradication of tumor or a reduced sensitivity of imaging due to chemotherapy induced hepatic steatosis. This study aimed to determine the significance of radiologic disappearance of LM treated with chemotherapy and factors predictive of a true CR. Methods: Between 2000 and 2003, 435 patients evaluated by a hepatobiliary surgeon were treated with neoadjuvant chemotherapy for LM. Inclusion criteria were fewer than 12 LM initially, disappearance of one or more LM by CT scan and a clinical follow-up of at least 1 year after disappearance. A pathologic CR (pCR) was defined as the absence of a LM in the resected specimen, a durable clinical CR (cCR) was defined as a LM that did not reappear during follow-up imaging. A LM was defined as found if it was detected by other imaging (MRI), at resection, or if it recurred during follow-up. LM that were found were compared to pCR and durable cCR to determine factors predictive of a true CR. Results: During chemotherapy, 39 (9%) patients had a total of 117 LM disappear by follow-up CT scan. The outcome is shown in the Table . Treatment with hepatic arterial infusion (HAI) chemotherapy (n=22) was associated with a significantly higher rate of pCR or durable cCR (42% vs. 14%, p<0.001). LM were also significantly more likely to represent a pCR or durable cCR when the surrounding liver did not demonstrate steatosis (p<0.001), when the patient’s BMI was <30 kg/m2 (p=0.002), and when a preoperative MRI was performed (p=0.01). Conclusions: Among disappearing LM, a pCR occurs in 37% and a durable cCR in 26%, yielding a true CR rate of 63%. The disappearing LM in patients treated with HAI chemotherapy were more likely to a represent true CR when compared to systemic chemotherapy alone. Hepatic steatosis and obesity impaired the ability to detect lesions by CT scan and MRI improved the preoperative detection rate of disappearing LM. [Table: see text] No significant financial relationships to disclose.

Prediction of chemotherapeutic response of colorectal liver metastases with dynamic gadolinium‐DTPA‐enhanced MRI and localized 19F MRS pharmacokinetic studies of 5‐fluorouracil

Systemic chemotherapy is effective in only a subset of patients with metastasized colorectal cancer. Therefore, early selection of patients who are most likely to benefit from chemotherapy is desirable. Response to treatment may be determined by the delivery of the drug to the tumor, retention of the drug in the tumor and by the amount of intracellular uptake, metabolic activation and catabolism, as well as other factors. The first aim of this study was to investigate the predictive value of DCE-MRI with the contrast agent Gd-DTPA for tumor response to first-line chemotherapy in patients with liver metastases of colorectal cancer. The second aim was to investigate the predictive value of 5-fluorouracil (FU) uptake, retention and catabolism as measured by localized (19)F MRS for tumor response to FU therapy. Since FU uptake, retention and metabolism may depend on tumor vascularization, the relationship between (19)F MRS and the DCE-MRI parameters k(ep), K(trans) and v(e) was also examined (1). In this study, 37 patients were included. The kinetic parameters of DCE-MRI, k(ep), K(trans) and v(e), before start of treatment did not predict tumor response after 2 months, suggesting that the delivery of chemotherapy by tumor vasculature is not a major factor determining response in first-line treatment. No evident correlations between (19)F MRS parameters and tumor response were found. This suggests that in liver metastases that are not selected on the basis of their tumor diameter, FU uptake and catabolism are not limiting factors for response. The transfer constant K(trans), as measured by DCE-MRI before start of treatment, was negatively correlated with FU half-life in the liver metastases, which suggests that, in metastases with a larger tumor blood flow or permeability surface area product, FU is rapidly washed out from the tumor.

Complete Response of Colorectal Liver Metastases After Chemotherapy: Does It Mean Cure?

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. 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. 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. In most patients receiving chemotherapy for colorectal LMs, a complete response on CT scan does not mean cure.

Complete radiological response of colorectal liver metastases (LM) after chemotherapy: Does it mean cure?

3501 Background: Most of patients with colorectal LM receive systemic chemotherapy. Complete response on imaging is considered a good indicator of the efficacy of chemotherapy. Whether complete radiological response is correlated to complete pathological response is not well known. The objective of this study was to determine the significance of complete radiological response of LM after chemotherapy. Methods: Between 1998 and 2004, 586 patients were treated in one institution for colorectal LM. 38 with the following criteria were included in the study: less than 10 LM before chemotherapy, disappearance of one or several LM on helical CT scan and ultrasound after chemotherapy, surgery with liver examination and intraoperative ultrasound within 4 weeks after imaging, no extra-hepatic disease, follow-up at least one year after surgery. Results: Overall, 66 LM disappeared on imaging after chemotherapy (38 patients). In 9 patients, persistent macroscopic disease was observed at surgery at the site of 20/66 (30%) LM although there were considered in complete response on imaging. In 15 patients, with no remnant disease at surgery, the sites of 15 initial LM were resected. Pathological examination of theses sites of LM considered in complete response showed the presence of viable tumor cells in 12/15 cases (80%). In 14 other patients, the sites of 31 initial LM, which were not visible at surgical exploration were left in place during surgery. After one year of follow-up, 23/31 (74%) LM considered in complete response had recurred in situ (11/14 patients). Overall, persistent macroscopic or microscopic residual disease or early recurrence in situ were observed in 55/66 LM (83%) with complete radiological response (32/38 patients). Conclusions: Complete radiological response in patients who have received chemotherapy is a useful tool to evaluate the effect of chemotherapy but it does not mean cure in most patients. This should be taken into account when considering multimodality treatment including chemotherapy and surgery. No significant financial relationships to disclose.

Patterns of heat shock protein (HSP70) expression and Kupffer cell activity following thermal ablation of liver and colorectal liver metastases

The time course and extent of thermal ablative injury differs in liver compared to tumour tissue. This may be influenced by differences in the expression of heat shock proteins (HSP) and the response of Kupffer cells to thermal injury. This study determines the expression and response of HSP70 and Kupffer cells to thermal ablative injury in a Murine model of colorectal liver metastases. Thermal ablation by laser (Nd-YAG wavelength 1064 nm) was induced in liver and colorectal cancer liver metastases in CBA strain mice. Laser energy was applied at 2 W for 50 s and produced incomplete tumour ablation. Established tissue injury was assessed in separate groups of animals at time points ranging from 12 h to 21 days following therapy. HSP70 and Kupffer cell expression at the margins of coagulated tissue was determined by immunohistochemical staining for HSP70 and F4/80 antigens, respectively. HSP70 was faintly expressed in the cytoplasm of all tumour cells, with distinct clusters exhibiting intense cytoplasmic and nuclear HSP70 staining (130 ± 19 cells mm−2). Comparatively, HSP70 expression was uncommon in untreated control liver specimens (2 ± 2 cells mm−2, p < 0.001). Thermal ablation increased expression of HSP70 at coagulated tissue margins. The peak response in tumours occurred at 2 days post-ablation and was significantly greater than the peak response in liver, occurring at 12 h (809 ± 80 cells mm−2 vs. 454 ± 52 cells mm−2, p < 0.001). HSP70 expression remained significantly elevated for 7 days following therapy in tumour tissue, compared to 3 days in liver. Kupffer cell numbers in untreated control tumours were significantly lower than in untreated control livers (285 ± 23 cells mm−2 vs. 451 ± 30 cells mm−2, p < 0.001). Following thermal ablation, there was an initial decrease in Kupffer cell numbers at the margin of coagulation with subsequent persistent increases thereafter. In liver tissue, the peak Kupffer cell response occurred at 5 days post-therapy and was significantly greater than the peak response in tumour tissue 3 days post-thermal ablation (1074 ± 34 cells mm−2 vs. 860 ± 53 cells mm−2, p = 0.007). Thermal ablation produces a greater and more prolonged HSP70 response in colorectal liver metastases than in liver tissue. It also induces persistent increases in Kupffer cell activity in liver and tumour tissue.

Correlation between tumour blood flow and fluorouracil distribution in a hypovascular liver metastasis model.

The poor response of colorectal liver metastases to fluorinated pyrimidine chemotherapy may be due to poor drug penetration into the tumour. Chemotherapy delivered by the blood to well perfused areas of tumour must reach less well perfused areas by diffusion. This study examined the relationship between intratumoural blood flow and drug uptake in a hypovascular liver metastasis animal model. We used a double isotope technique to examine the microdistribution of the blood flow tracer [125I]-iodoantipyrine (IAP) and fluorinated pyrimidine 5-[6-3H]-fluorouracil (5-FU) within intrahepatic, hypovascular HSN tumours. There was a significant fall (P < 10(-6)) in both IAP and 5-FU uptake between the liver/tumour edge and tumour centre which resulted in a significant covariation (P < 10(-5)) in tracer uptake with distance. The finding of a close covariation between blood flow and drug uptake in liver metastases suggested that 5-FU diffusion did not compensate for low 5-FU delivery in areas of poor tumour blood flow. The lower 5-FU levels in low compared with high areas of tumour blood flow could reduce the cytotoxic effect and increase the potential for development of drug resistance.

Regional therapy of isolated liver metastases from breast cancer

Because of the high rate of response in colorectal liver metastases, intra-arterial chemotherapy was studied in 14 patients with isolated breast cancer liver metastases. After extrahepatic metastasization had been ruled out, a catheter was placed surgically and connected to a cytostatic pump (in two cases) or to a subcutaneous infusion chamber (in 12 cases). Every four to six weeks, the patients with an infusion chamber received a modified FAM treatment (fluorouracil, doxorubicin, mitomycin C) for three days continuously. In 11 out of 14 patients (79%) a clear tumor reduction was observed (duration of remission 11 months). In an average of six cycles of chemotherapy administered, a total of 50% of the patients manifested local side effects (including two cases of toxic hepatitis, one case of biliary sclerosis). Systemic side effects were negligible. Termination of therapy was necessitated by three catheter tip migrations and two thromboses of the hepatic artery. Extrahepatic metastases occurred in six patients. Here, the average latency period between diagnosis of the primary tumor and that of liver metastasis was significantly shorter (x = 9 months) than in the other patients (x = 39 months). Intra-arterial chemotherapy thus represents a therapeutic method which, although complicated, is extremely effective in selected patients with isolated breast cancer liver metastases. A final evaluation must be subject to a randomized comparison with a systemic therapy.