Complete response of colorectal liver metastases after intra-arterial chemotherapy

AIMS AND BACKGROUND: We demonstrated that colorectal liver metastases considered in complete response after intra-arterial floxuridine-based chemotherapy had recurred in situ. METHODS AND STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.     

Retrospective analysis of pathological response in colorectal cancer liver metastases following treatment with bevacizumab

Aims

Pathological response has been shown to be a predictor for survival after preoperative chemotherapy and surgical resection of colorectal cancer liver metastases. This retrospective analysis evaluated the effect on pathological response of adding bevacizumab to standard neoadjuvant chemotherapy in patients with metastatic colorectal cancer (mCRC) and liver metastases.

Methods

Patient records from two Spanish centres were retrospectively examined for this analysis. Patients were included if they had stage IV mCRC with liver metastases, were unresectable or marginally resectable tumour before chemotherapy, and had oxaliplatin- or irinotecan-based chemotherapy, with or without bevacizumab, before resection. Tumour response was evaluated using response evaluation criteria in solid tumours (RECIST). Pathological response was assessed by pathologists blinded to treatment.

Results

Ninety-five patients were included. Good pathological responses (PR0/PR1) were observed in 37 patients (39 %). The RECIST response rate was 51 %. Only 42 % of patients with a good pathological response had a complete or partial response according to RECIST, while 57 % of those with a poor pathological response had a complete or partial response according to RECIST. RECIST response rates were similar with and without bevacizumab, although 49 % of bevacizumab-treated patients had a good pathological response versus 27 % of those receiving chemotherapy alone (χ ² P = 0.0302).

Conclusion

Pathological response may be a better indicator of treatment efficacy than RECIST for patients with mCRC receiving bevacizumab in the neoadjuvant setting. Adding bevacizumab to chemotherapy has the potential to increase pathological response rates. Well-designed prospective clinical studies are required to establish the efficacy and tolerability of this approach.     

Hepatic colorectal cancer metastases showing a distinctive pattern of pathological response after metronomic capecitabine and bevacizumab

A 48-year-old man was referred to our hospital with the diagnosis of colon cancer with multiple hepatic metastases. After right hemicolectomy, the rapid progression of liver disease was treated with metronomic capecitabine and bevacizumab according to a study protocol. A gradual regression of metastatic lesions was observed during a 9-month treatment period. After conversion of liver disease to resectability, the histological examination disclosed the complete necrosis of all lesions, with the exception of small neoplastic foci inside a single nodule. The comparison of this type of histological findings with the classic sclero-hyaline pathological response, as well as its importance as indicator of response to antiangiogenic treatment, is discussed.     

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.     

A case of liver metastases from rectal cancer showed a complete response by FOLFIRI and bevacizumab chemotherapy

A 62-year-old man had undergone anterior resection of rectum for rectosigmoid colon cancer with liver metastases. Postoperatively, the FOLOFOX6 regimen was performed in three courses. Metastatic liver tumors showed progressive disease(PD) on CT scan. The treatment was then changed to the FOLFIRI regimen for three courses. Metastatic liver tumors showed a partial response(PR)on CT scan. After six courses of the FOLFIRI regimen, the patient was given seven courses of the FOLFIRI +BV regimen. Hepatic resection of S2, S3, S4 and S6 segment was performed. The histological effect of chemotherapy was complete response(CR).     

Hepatectomy for colorectal liver metastases after neoadjuvant chemotherapy

The majority of patients with colorectal liver metastases receive systemic chemotherapy. In the context of unresectable liver metastases, the objective of chemotherapy based on new and more effective regimens is not only to prolong survival, but also to induce enough response and shrinkage of the tumor to render resectable patients initially not deemed to be surgical candidates. In patients with resectable liver metastases, the goal of chemotherapy is to improve the outcome after surgery and especially to decrease the risk of recurrence. Although the principles of combined modality treatment become widely accepted, this therapeutic strategy is also associated with potential risks related to the preoperative use of chemotherapy.     

A proposed new method for assessing the pathological response to chemotherapy in resected colorectal liver metastases

Background:

Pathological response (PR) to preoperative chemotherapy for colorectal liver metastases (CLM) is recognised as a prognostic factor of outcome. However, the optimal system to assess this parameter is still debated. This study focuses on current methods and proposes a possibly better method for assessing PR.

Methods:

Among 223 patients resected for CLM between 2004 and 2011, after more than three cycles of chemotherapy, the percentage of tumour cells, necrosis and fibrosis, and the tumour regression grade were assessed for each of 802 nodules. Pathological response was evaluated according to validated methods and their combinations. A new method combined the percentage of tumour cells and the size of all nodules as follows: , where n is each separate nodule, % is the percentage of remaining tumour cells within nodule n (%) and s is the size of nodule n (cm).The prognostic value of each method was calculated.

Results:

After a median follow-up of 47 months (3–106), the cumulative 5-year overall survival rate after liver resection was 59%. The proposed method categorised as follows: 0 residual tumour; 0.1–6-cm residual tumour; >6-cm residual tumour, and necrosis rate >50% stratified prognosis (P=0.0027; P=0.02), while the other methods did not. At multivariate analysis, our method remained an independent predictor of outcome (P=0.001).

Conclusions:

Combining the percentage of tumour cells multiplied by the size of each separate tumour seems to be a better method for assessing PR. External validation is required.     

Adjuvant chemotherapy after resection of liver metastases from colorectal cancer

Colorectal liver metastases are common and found in almost 50% of patients with colorectal cancer. Surgical excision, whenever possible, is the optimum form of treatment and should be carried out with the intention of removing all macroscopic disease (R0 resection). However, recurrence frequently occurs within the remaining liver as well as at extra-hepatic sites. The role of adjuvant systemic chemotheraphy in an attempt to reduce the incidence of recurrence has been investigated in several studies. This review discusses the possible incorporation of adjuvant systemic chemotheraphy following liver resection.     

Patterns of hepatotoxicity after chemotherapy for colorectal cancer liver metastases

Aim

The aim of this study was to assess chemotherapy associated hepatotoxicity after 3 months' treatment and to correlate patterns of hepatotoxicity with perioperative morbidity.

Methods

Liver specimens of 50 patients with liver metastases from colorectal cancer receiving XELOX or FOLFOX4 for six cycles and 13 specimens of non-chemotherapy patients subjected to liver resection were analyzed. Different patterns of hepatotoxicity were evaluated according to widely accepted pathohistological scores. Furthermore, the histomorphological findings were correlated with perioperative morbidity.

Results

Steatosis grades did not differ among the chemotherapy treated groups and non-chemotherapy patients. Chemotherapy showed an independent effect on fibrosis stage. Age and chemotherapy were independently associated with sinusoidal dilatation. Centrilobular vein fibrosis correlated with administration of chemotherapy. Higher fibrosis stages were associated with increased transfusion requirements.

Conclusion

XELOX and FOLFOX4 do not correlate with the development of steatosis or steatohepatitis. We do not detect a difference in liver injury between the XELOX and FOLFOX4 group. Although 5-fluorouracil based chemotherapy may cause profound changes in liver parenchyma, it can be safely applied. However, age and oxaliplatin predispose for the development of sinusoidal dilatation; therefore caution must be taken in old patients treated with oxaliplatin.     

Disappearing colorectal liver metastases: Strategies for the management of patients achieving a radiographic complete response after systemic chemotherapy

The mainstays of treatment for colorectal liver metastases (CRLMs) are surgery and chemotherapy. Chemotherapeutic benefits of tumor shrinkage and systemic control of micrometastases are in part counterbalanced by chemotoxicity that can modify the liver parenchyma, jeopardizing the detection of CRLM. This review addresses the clinical decision-making process in the context of radiographic and pathologic responses, the preoperative imaging workup, and the approaches to the liver for CRLM, which disappear after systemic chemotherapy.     

Complete response after chemoradiation in ampullary carcinoma: a case report

AIMS AND BACKGROUND: The case of a 70-year-old patient with resectable, poorly differentiated adenocarcinoma of the ampulla of Vater is presented. PATIENT AND METHODS: Due to intraoperative hemorrhagic complications, surgical resection was not feasible. The patient was treated with radiochemotherapy consisting of external beam radiotherapy (50.4 Gy; 1.8 Gy/fraction; 5 fractions/week) plus 5-FU (1000 mg/m2/day, continuous i.v. infusion, days 2-5, week 1 and 5 of radiotherapy) and mitomycin C (10 mg/m2 i.v., day 2, week 1 of radiotherapy). RESULTS: At five years' follow-up the patient was in good general condition, without any signs of disease according to CT scan, endoscopic retrograde cholangiopancreatography and tumor marker determination. Multiple random biopsies performed in the ampullary region were negative for tumor growth. CONCLUSIONS: In patients with ampullary carcinoma the use of concurrent chemoradiation should be considered, particularly when surgical resection is unfeasible due to medical contraindications or locally advanced disease.     

Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases

Background:

The purpose of this study was to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and ¹⁸F-fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) for evaluation of response to chemotherapy and bevacizumab and for prediction of progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) with potentially resectable liver lesions.

Methods:

A total of 19 mCRC patients were treated with FOLFOX/FOLFIRI and bevacizumab followed by surgery. Dynamic contrast-enhanced magnetic resonance imaging and FDG-PET/CT were performed before treatment and after cycle 5. PET results were quantified by calculating maximum standardised uptake value (SUV_max) whereas area under the enhancement curve (AUC), initial AUC (iAUC) and the endothelial transfer constant (K^trans) were used to quantify DCE-MRI. Pathological analysis of the resection specimen was performed, including measurement of microvessel density (MVD) and proliferation index.

Results:

Both AUC and iAUC were significantly decreased following bevacizumab therapy (median change of 22% (P=0.002) and 40% (P=0.001) for AUC and iAUC, respectively). Progression-free survival benefit was shown for patients with >40% reduction in K^trans (P=0.019). In the group of radiological responders, the median baseline SUV_max was 3.77 (IQR: 2.88–5.60) compared with 7.20 (IQR: 4.67–8.73) in nonresponders (P=0.021). A higher follow-up SUV_max was correlated with worse PFS (P=0.012). Median MVD was 10.9. Progression-free survival was significantly shorter in patients with an MVD greater than 10, compared with patients with lower MVD (10 months compared with 16 months, P=0.016).

Conclusion:

High relative decrease in K^trans, low follow-up SUV_max and low MVD are favourable prognostic factors for mCRC patients treated with bevacizumab before surgery.     

A case of resection of synchronous multiple liver metastases from colorectal cancer after hepatic infusion chemotherapy and systemic chemotherapy

A 70-year-old man was admitted for tranverse colon cancer with multiple liver metastases. Hepatic arterial infusion chemotherapy and systemic chemotherapy (FOLFOX 4) were conducted postoperatively. Thirteen months after the first surgery, liver metastases became resectable and hepatectomy was performed. Though multiple liver metastases were unresectable at the time of the first examination, hepatectomy was possible followed by hepatic arterial infusion chemotherapy and systemic chemotherapy.     

Complete pathological response after chemotherapy or immune checkpoint inhibitors in deficient MMR metastatic colorectal cancer: Results of a retrospective multicenter study

About 5% of the patients with metastatic colorectal cancers (mCRC) present microsatellite instability (MSI)/deficient mismatch repair system (dMMR). While metastasectomy is known to improve overall and progression-free survival in mCRC, specific results in selected patients with dMMR/MSI mCRC are lacking. Our study aimed to describe metastasectomy results, characterize histological response and evaluate pathological complete response (pCR) rate in patients with dMMR/MSI mCRC. We retrospectively reviewed data from all consecutive patients with dMMR/MSI mCRC who underwent surgical metastasectomy between January 2010 and June 2021 in 17 French centers. Primary outcome was to assess the pCR rate defined by tumor regression grade (TRG) 0. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), and explored TRG as predictive factor for RFS and OS. Among the 88 patients operated, 109 metastasectomies were performed in 81 patients after neoadjuvant treatment [chemotherapy ± targeted therapy (CTT): 69, 85.2%; immunotherapy (ICI): 12, 14.8%], and pCR was achieved in 13 (16.1%) patients. Among the latter, pCR rate were 10.2% in the patients having received CTT (N = 7) and 50.0% in the patients treated with ICI (N = 6). Radiological response did not predict TRG. With a median follow-up of 57.9 (IQR 34.2-81.6) months, median RFS was 20.2 (15.4-not reached) months, median OS was not reached. Major pathological responses (TRG0 + TRG1) were significantly associated with longer RFS (HR 0.12, 95% CI 0.03-0.55; P = .006). The pCR rate of 16.1% achieved with neoadjuvant treatment in patients with dMMR/MSI mCRC is consistent with previously reported rates in pMMR/MSS mCRC. Immunotherapy showed better pCR rate than chemotherapy ± targeted therapy. Further prospective trials are needed to validate immunotherapy as neoadjuvant treatment in resectable/potentially resectable dMMR/MSI mCRC and identify predictive factors for pCR.     

A case report of conversion therapy for initially unresectable colorectal cancer liver metastases after cetuximab as third-line treatment

The introduction of monoclonal antibodies into the treatment protocols for metastatic colorectal cancer(mCRC)has significantly improved outcomes. There are some patients with mCRC, initially judged unresectable, who become resectable after chemotherapy. For patients with isolated liver metastases, surgical resection is recommended when feasible. We experienced a case in which an initially unresectable mCRC liver metastases converted into a resectable one after cetuximab monotherapy as third-line treatment. The sample from hepatectomy was a pathologically complete response; no remnants were detected. The management of liver metastases contributes to improvements in the clinical setting. For conducting a multimodal treatment of mCRC, the participation of various specialists such as medical oncologists, colorectal/hepaticsurgeons and diagnostic/therapeutic radiologists is indispensable. Furthermore, it is necessary to construct an evidence-based consensus on potentially resectable CRC liver metastases in each hospital.     

Induction chemotherapy and surgery of colorectal liver metastases

Surgery is the only curative treatment for patients with colorectal liver metastases with recent reports documenting 5-year survival results of 40-50%. In unresectable patients, the use of more effective regimens of chemotherapy has contributed to improve the results of survival at short term and new onco-surgical strategies have emerged. By allowing resection of previously unresectable liver metastases, these onco-surgical strategies now offer 15-20% of patients a real potential of long-term remission (5-year survival 30-40%). Chemotherapy is also used in the adjuvant setting, to prevent post-operative recurrence. In resectable metastases, it may also be used as neo-adjuvant treatment to control tumor progression before surgery and to select the patients likely to really benefit from liver resection. The objective of this article is to describe this multidisciplinary approach of liver metastases and to report the results of these new strategies.