Phase II study of capecitabine plus oxaliplatin (XELOX) as first-line treatment and followed by maintenance of capecitabine in patients with metastatic colorectal cancer

Purpose  

The aim of this study is to evaluate the safety and efficacy of the combination of capecitabine and oxaliplatin (XELOX) as first-line treatment in Chinese patients with metastatic colorectal carcinoma (mCRC). Furthermore, we aimed to explore whether a maintenance therapy with oral capecitabine in patients who were non-progression to the XELOX regimen was able to improve the duration of disease control (DDC).     

Liver resection after chemotherapy and tumour downsizing in patients with initially unresectable colorectal cancer liver metastases

Objectives

Among patients with initially unresectable colorectal cancer liver metastases (CLM), a subset are rendered resectable following the administration of systemic chemotherapy. This study reports the results achieved in liver resections performed at a single hepatobiliary referral centre after downsizing chemotherapy in patients with initially unresectable CLM.

Methods

All liver resections for CLM performed over a 10-year period at the Toronto General Hospital were considered. Data on initially non-resectable patients who received systemic therapy and later underwent surgery were included for analysis.

Results

Between January 2002 and July 2012, 754 liver resections for CLM were performed. A total of 24 patients were found to meet the study inclusion criteria. Bilobar CLM were present in 23 of these 24 patients. The median number of tumours was seven (range: 2–15) and median tumour size was 7.0 cm (range: 1.0–12.8 cm) before systemic therapy. All patients received oxaliplatin-or irinotecan-based chemotherapy. Fourteen patients received combined treatment with bevacizumab. Negative margin (R0) resection was accomplished in 21 of 24 patients. There was no perioperative mortality. Ten patients suffered perioperative morbidity. Eighteen patients suffered recurrence of disease within 9 months. Rates of disease-free survival at 1, 2 and 3 years were 47.6% [95% confidence interval (CI) 30.4–74.6%], 23.8% (95% CI 11.1–51.2%) and 19.0% (95% CI 7.9–46.0%), respectively. Overall survival at 1, 2 and 3 years was 91.5% (95% CI 80.8–100%), 65.3% (95% CI 48.5–88.0%) and 55.2% (95% CI 37.7–80.7%), respectively.

Conclusions

Liver resection in initially unresectable CLM can be performed with low rates of morbidity and mortality in patients who respond to systemic chemotherapy, although these patients do experience a high frequency of disease recurrence.     

Evaluation of aggressively treated patients with unresectable multiple liver metastases from colorectal cancer

PURPOSE: The aim of this study was to assess the value of aggressively treating patients with unresectable liver metastases from colorectal cancer and a poor prognosis. METHODS: From 1988 to 1999, 64 patients with unresectable multiple liver metastases from colorectal cancer who had received hepatic arterial infusion chemotherapy were investigated. All patients did not have synchronous extrahepatic metastases at the time of initiating our treatment. When liver metastases were suitable for resection after hepatic arterial infusion chemotherapy, we excised them and repeated prophylactic hepatic arterial infusion chemotherapy as long as possible. We evaluated the efficacy of hepatic arterial infusion chemotherapy by computed tomography and divided these patients into responders and nonresponders. We performed univariate analysis using the log-rank test to calculate predictive factors. In addition, the Cox proportional hazards model was used to perform multivariate analysis of factors related to survival. RESULTS: The survival rate of all patients was 67.8 percent after 1 year and 10 percent after 5 years. However, the survival rate for 16 patients who received hepatectomy after hepatic arterial infusion chemotherapy was 35.1 percent after five years. Multivariate analysis demonstrated that the response after hepatic arterial infusion chemotherapy was the most indicative prognostic factor. CONCLUSIONS: The prognosis of selected patients who responded to hepatic arterial infusion chemotherapy and received hepatectomy was improved. Applying aggressive treatment as outlined in our strategy may improve the chances of long-term survival.     

Long-term complete response of unresectable liver metastases from colorectal cancer

Recent advances in chemotherapy for metastatic colorectal cancer, such as fluorouracil -leucovorin, irinotecan, oxliplatin, and bevacizumab, have been demonstrated to achieve a high response rate. For most patients with unresectable liver metastases, however, chemotherapy is still not considered to provide a sufficient long-term disease-free survival without a surgical resection. We herein report two cases of a complete response for more than 8 years after having received treatment consisting of hepatic arterial infusion of fluorouracil and oral chemotherapy for unresectable liver metastases. The clinicopathological characteristics of these two cases were as follows: the number of liver metastases, 20, 11; the maximum size, 1.2 cm, 2.8 cm; the serum carcinoembryonic antigen level, 1.2 ng/ ml, 2.4 ng/ml. The following computed tomography scan revealed the liver metastases to have completely disappeared 7 months and 22 months after the treatment, respectively. It is speculated that a small size and a low level carcinoembryonic antigen may predict a good response to chemotherapy for unresectable liver metastases from colorectal cancer.     

Pathological response grade of colorectal liver metastases treated with neoadjuvant chemotherapy

Background:

The complete resection of liver metastases from colorectal cancer is the major determinant of longterm survival. The effectiveness of current chemotherapy regimens has made treatment algorithms more flexible and resulted in many different options. Recently, the pathological response to chemotherapy has emerged as another important prognostic marker. Different systems have been used to grade the pathological response in these patients.

Methods:

This study prospectively evaluates the prognostic value of the pathological response grade (PRG) in liver metastases treated with neoadjuvant chemotherapy.

Results:

Between 2002 and 2006, 50 patients were treated with a sandwich chemotherapy regimen and underwent liver resection. Complete resection was achieved in 45 patients (90%). A strong pathological response to chemotherapy (<10% viable tumour cells in all lesions) was seen in 17 patients (34%). It was associated with a statistically significant longer overall survival (P= 0.019) and was also identified on multivariate analysis as an independent predictor of survival (odds ratio = 243).

Conclusions:

This pilot study demonstrates the prognostic potential of the PRG, which could be used clinically to select patients for an aggressive multimodal adjuvant algorithm. Larger multicentre studies are required to validate this particular grading system. The keys to longterm survival are resectability and chemo-responsiveness.     

Immune checkpoints and liver resection after neoadjuvant chemotherapy including bevacizumab in patients with microsatellite-stable colorectal liver metastases

BackgroundThe clinical value of immune checkpoint expression as prognostic biomarker in bevacizumab-pretreated patients with resected microsatellite-stable (MMS) colorectal liver metastases is unclear and was retrospectively investigated in this study.MethodsExpression analyses of IDO-1, PD-L1, and CTLA-4 were performed by immunohistochemistry in resected bevacizumab-pretreated colorectal liver metastases. Association of immune checkpoint expression in tumor cells and immune cells with response and clinical outcome was investigated. Expression profiles were compared with those of patients with anti-EGFR-targeted therapy and lung metastases, respectively.ResultsOne hundred thirty-six patients with MMS disease were investigated (79 (58.1%) male/57 (41.9%) female, median age 62.9 years (range 31.0–80.4)). High expression of IDO-1 in immune cells was associated with longer OS (not reached versus 44.8 months, HR 0.23 (95% CI 0.09, 0.55), P = 0.001). Low expression of CTLA-4 in tumor cells was associated with better histological response (26 major, 19 partial, 18 none versus 14 major, 23 partial, 30 none, P = 0.032). Expression profiles differed compared to patients with anti-EGFR-targeted therapy and patients with lung metastases.ConclusionImmune checkpoint expression was associated with response and survival. IDO-1 may serve as a novel prognostic and/or predictive biomarker in patients with MMS colorectal liver metastases.     

A phase II study of capecitabine plus oxaliplatin (XELOX): a new first-line option in metastatic colorectal cancer

Background: Capecitabine and oxaliplatin are both effective and well-tolerated monotherapies for the treatment of advanced colorectal cancer (CRC). Oxaliplatin has also been shown to be very effective when combined with 5-FU/LV in the first-line setting. Aim of the Study: Assess the efficacy and safety of capecitabine plus oxaliplatin (XELOX) in patients with previously untreated advanced CRC. Methods: Fifty-three patients with measurable disease received capecitabine 1,000 mg/m² twice daily on d 1–14 and oxaliplatin 130 mg/m² on d 1, every 3 wk. Of these, 52 were evaluable for safety and 49 for antitumor response. Results: There was a low rate of grade 1/2 adverse events; grade 3/4 events included leukopenia (10%), neutropenia (6%), thrombocytopenia (2%), nausea/vomiting (4%), and diarrhea (4%). The overall response rate was 39% (95% CI, 25–54%) and median time to disease progression was 7.8 mo. Conclusions: XELOX is an active and well-tolerated first-line treatment for advanced CRC. Randomized phase III studies are ongoing to compare XELOX with FOLFOX in view of the comparable efficacy and safety but superior convenience of XELOX therapy. Presented in part at the 39th American Society of Clinical Oncology Annual Meeting, Chicago, IL, May 31–June 3, 2003.     

Significance of pre-treatment immunological parameters in colorectal cancer patients with unresectable metastases to the liver

BACKGROUND/AIMS: In this study, we have compared the profiles of peripheral blood lymphocyte (PBL) subsets and serum cytokine levels of healthy individuals with those of patients with unresectable liver metastases from colorectal carcinoma before starting regional chemoimmunotherapy. Since the therapeutic responses are limited only to a subset of patients, we hypothesize that the initial status of immunity and individual immune response to a tumor might be significant to the therapeutic outcome. METHODOLOGY: Cellular and humoral immunological parameters were compared between 10 patients with colorectal cancer metastases to the liver responding and non-responding to regional intra-arterial chemo-immunotherapy, and 5 healty individuals. Analyses included a flow cytometric immunophenotyping of peripheral blood mononuclear cells (CD3, CD4, CD8, CD19, CD25, CD28, CD56, CD57, CD80 and HLA.DR), estimation of serum cytokine levels of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and other immunological parameters are soluble IL-2 receptor (sIL-2), carcinoembryonic antigen (CEA), gastrointestinal cancer-associated antigen (CA 19-9), and C-reactive acute phase protein (CRP). A significantly lower proportion of CD8 lymphocytes and a trend for decreased CD19, CD28 and CD80 was detected among colorectal cancer patients before liver-directed chemotherapy compared to healthy controls. RESULTS: The cancer patients showed a significantly increased population of peripheral NK cells as detected by both CD56+ and CD57+ phenotypes. Elevated serum levels of CRP, IL-4 and TNF-alpha, sIL-2R, but not IL-2, were also demonstrated in cancer patients as compared to controls. Activated CD25+ lymphocytes correlated negatively with CD28+ lymphocytes (r = -0.68, p < 0.01) and less significantly with CD4+ lymphocytes (r = -0.56, p < 0.05). The CD8+ cytotoxic cell subset might be negatively influenced by serum IL-4 (r = -0.57, p < 0.05). Positive correlation was found between sIL-2R and CRP (r = -0.78, p < 0.01), and between sIL-2R and TNF-alpha (r = 0.64, p < 0.05) serum levels in patients with progressive disease during the course of therapy, the initial proportions of CD4+, CD19+ and CD28+ lymphocytes were significantly lower than those among responders. Among humoral parameters, only sIL-2R showed a marginal correlation with therapeutic response, being more elevated among non-responding patients. Pre-treatment serum levels of CEA and CA 19-9 showed correlation with neither therapeutic response nor with any of the cellular or humoral immunological parameters analyzed. CONCLUSIONS: The results may serve as an initial guideline to open a discussion on the rationale of such a panel of tests, hopefully leading to standardized laboratory pre-selection and monitoring of patients treated with regional chemoimmunotherapy.     

Improved survival after resection of colorectal liver metastases in patients with unresectable lung metastases

BackgroundModern systemic therapies considerably improve tumour control and thus open the possibility of new surgical approaches in metastatic colorectal cancer. In this retrospective clinical cohort with a comparison group, we investigated whether liver resection in a combined liver–lung-metastasised stage is justified if pulmonary disease is not resected.MethodsFrom 283 patients treated in our institution between 2000 and 2014 for combined colorectal liver- and lung metastases, 35 patients had their pulmonary metastases left in situ while they were eligible for both treatment options: resection versus non-resection of liver metastases. Effectively, 15 of these patients received whereas 20 did not receive a liver resection. In these patients, we compared overall survival and determined risk factors that are associated with poor survival, applying a Cox-Proportional Hazards model.ResultsPatients whose liver metastases were resected showed significantly longer median survival compared to patients who did not undergo hepatic surgery (median 2.6 vs 1.5 years, P = 0.0182). The Cox-Proportional Hazards model revealed hepatic metastasectomy to be the strongest determinant of patient survival (HR 5.27; CI: (1.89, 14.65)).ConclusionOur results suggest that surgical removal of liver metastases may be beneficial in selected patients even if concomitant lung metastases cannot be resected.     

XELOX联合贝伐珠单克隆抗体方案转化治疗同时性结肠癌并发肝转移患者初步研究

目的 探讨应用奥沙利铂和卡培他滨(XELOX)联合贝伐珠单克隆抗体方案转化治疗同时性结肠癌并发肝转移患者疗效及安全性。方法 2015年6月～2017年7月我院诊治的41例初始不可切除的结肠癌并发肝转移患者,实施了XELOX联合贝伐珠单克隆抗体方案的转化治疗,观察了转化治疗应答率、转化结果、不良反应和总生存期(OS)。结果 41例初始不可切除的结肠癌并发肝转移患者均接受了不少于4个疗程的转化治疗。在转化治疗后,31例(75.6%)患者呈部分缓解(PR),其中14例(34.1%)患者接受了根治性手术;在转化治疗后随访13～26个月(中位随访时间为18个月),转化手术组与未手术组1 a总生存率分别为92.3%(失访1例)和66.7%,经Log-rank 检验发现转化手术组患者总生存期显著长于未手术组(P=0.019)。结论 应用贝伐珠单克隆抗体联合XELOX方案治疗同时性结肠癌并发肝转移患者安全有效,部分初始不可切除患者可以通过转化治疗再次获得手术机会,而一旦实施转化手术,有望延长患者的生存时间。     

Conversion surgery after S-1 plus oxaliplatin combination chemotherapy for advanced gastric cancer with multiple liver metastases

Conversion therapy for gastric cancer is a new therapeutic concept. We report a case of a patient with advanced gastric cancer who underwent conversion surgery due to a remarkable regression of multiple liver metastases following chemotherapy. A 71-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy (EGD) revealed an irregular, nodular, ulcerated lesion in the lower third of the stomach. Analysis of biopsy specimens revealed a poorly differentiated adenocarcinoma. Abdominal contrast-enhanced computed tomography (CT) showed multiple liver mass lesions. The patient was clinically diagnosed with advanced gastric cancer with liver metastases and received S-1 plus oxaliplatin chemotherapy. After 6 cycles of chemotherapy, CT and magnetic resonance imaging showed complete resolution of the liver metastases, and EGD detected mucosal irregularities only. Since there was no evidence of further metastatic lesions in other organs, the patient underwent distal gastrectomy with D2 lymphadenectomy. The gross appearance of the surgically resected specimen showed a slightly elevated tumor measuring 4.5?×?3.5 cm. Pathological examination confirmed the diagnosis of a moderately differentiated gastric adenocarcinoma invading the muscularis propria with no lymph node metastases. The postoperative course was uneventful. The patient has continued to receive S-1 and oxaliplatin chemotherapy, and there has been no evidence of recurrence for 3 months following the operation. We propose that conversion therapy might be an effective treatment for patients with advanced gastric cancer; however, further studies and assessments are needed to confirm and establish this treatment strategy.     

Survival of patients with colorectal cancer liver metastases treated by regional chemotherapy

BACKGROUND/AIMS: Liver is the most common site of metastatic disease in colorectal cancer. Superior response rate was demonstrated in trials comparing hepatic arterial administration of cytotoxic agents with systemic chemotherapy. METHODOLOGY: Records of 109 consecutive patients with colorectal carcinoma metastatic to the liver treated by regional chemotherapy, who underwent implantation of a port system into hepatic artery or portal vein tributaries between 1991 and 1999, were reviewed and survival was evaluated using the log-rank test and multivariate analysis (Cox's proportional hazard regression). RESULTS: The median survival from diagnosis was 24 months. Survival was significantly longer for patients treated by radical resection, and patients treated in 1997-1999. On multivariate analysis, treatment by 6 or more chemotherapy cycles, stage 1 liver metastases, treatment with irinotecan and radical resection were associated with better survival, while the presence of extrahepatic disease had an adverse effect on the risk of death. Extrahepatic spread was subsequently detected in almost half of the patients who had originally isolated liver metastases. CONCLUSIONS: Patients treated by liver resection had the best outcome, while patients with extrahepatic diseases had poor prognosis. The prognosis of patients treated by regional chemotherapy improved significantly with the advent of irinotecan and better selection.     

Radioembolization and systemic chemotherapy improves response and survival for unresectable colorectal liver metastases

Purpose  

To evaluate the role of radioembolization and systemic chemotherapy as a combined modality therapy for unresectable colorectal liver metastases.     

Chemotherapy for the conversion of unresectable colorectal cancer liver metastases to resection

Resection of colorectal liver metastases (CLM) is the ultimate aim of treatment strategies in most patients with liver-confined metastatic colorectal cancer. Long-term survival is possible in selected patients with initially resectable or unresectable CLM. As a majority of patients have unresectable liver disease at the outset, there is a clear role for chemotherapy to downstage liver disease making resection possible. Studies of systemic chemotherapy with or without biologic therapy in patients with unresectable CLM have resulted in increased response rates, liver resection rates and survival. A sound physiologic rationale exists for the use of hepatic arterial infusion (HAI) therapy. Studies have shown that HAI with floxuridine combined with systemic chemotherapy increases response rates and liver resection rates in those patients with initially unresectable CLM. Toxicity from preoperative chemotherapy, biologic therapy and HAI therapy may adversely affect hepatic resection but can be kept minimal with appropriate monitoring. All conversion strategies should be decided by a multidisciplinary team.     

Long-term survival of patients downstaged by oxaliplatin and 5-fluorouracil combination followed by rescue surgery for unresectable colorectal liver metastases

OBJECTIVES: To evaluate long-term survival of patients resected for primarily unresectable colorectal liver metastases downstaged by systemic chemotherapy. METHODS: Among a group of 82 patients with advanced colorectal cancer, 39 had unresectable liver metastases. After treatment with systemic 3-weekly 5FU/folinic acid/oxaliplatin chemotherapy, the outcome of 11 patients made resectable thanks to chemotherapy was compared to that of 28 patients who were not. Criteria for non-resectability consisted of diffuse bilobar invasion with inability to achieve complete resection, unilobar or bilobar invasion plus vascular extension (invasion of inferior vena cava or 2 supra-hepatic veins plus continuity with the 3rd) or involvment of hepatic pedicle. Before and after surgery, CT scan evaluation was performed every 2 months. Progression free survival was defined as the time between starting chemotherapy and recurrence of the disease. We used Kaplan-Meier survival curves and log-rank test for comparisons, P values were two-sided and considered significant if<0.05. RESULTS: Progression free survival times were 14 and 6 months, median overall survival were 60 and 18.5 months, respectively, in favour of secondary resected subjects. CONCLUSION: Considering the magnitude of the survival benefit, one may question the need and feasibility for trials to assess more formally the impact of surgery in that setting.     

Multivariate analysis of the prognostic factors of patients with unresectable synchronous liver metastases from colorectal cancer

PURPOSE: It frequently is observed that widely varying prognoses are given for patients with the same extent of liver metastases from colorectal cancer, even though the same treatment is performed on these patients. One of the reasons for this variance is that prognostic factors for these patients have not been defined. This study was designed to elucidate which clinicopathologic factors were the most important in the prognosis of 73 patients with unresectable synchronous liver metastasis from colorectal cancer. METHODS: Univariate and multivariate analysis of 11 clinicopathologic factors were performed using the Cox proportional hazard model. Survival curves were generated using the Kaplan-Meier method. RESULTS: Extent of liver metastases was the most significant variable in this survival analysis, although the extent of lymph node metastases of the primary lesion also was significant. However, the method of treatment was not a significant determinant in the survival for patients with unresectable liver metastases. Median survival of patients with H₁, H₂, and H₃ was 13, 12, and 6 months, respectively, and there was a significant difference between survival curves for patients with H₁ and patients with H₃. Median survival of patients with n₀, n₁ and n₂ was 13, 7, and 7 months respectively, and there was a significant difference between survival curves for patients with n₀ and patients with n₂. Median survival of 6 patients with H₁ and n₀ and of 17 patients with H₃ and n₂ was 28 and 4 months, respectively. There was a significant difference in survival curves between these two groups. CONCLUSION: Longevity of patients with unresectable synchronous liver metastases from colorectal cancer is affected adversely by the presence of nodal metastases and extent of liver metastases. This should be considered in the planning treatment.     

Bevacizumab-based neoadjuvant chemotherapy for colorectal cancer liver metastases: Pitfalls and helpful tricks in a review for clinicians

Bevacizumab added to chemotherapy has shown encouraging efficacy in the neoadjuvant therapy of colorectal cancer liver metastases. In absence of biological predictor factors of efficacy to bevacizumab-based treatment, the assessment of response may be a crucial point to select patients who may benefit the most from surgery. At the same time the pathological response after liver resection could represent a guide for the next therapeutic plan. In the pre-surgical phase, conventional computed tomography and response evaluation with RECIST criteria may underestimate the response to anti-angiogenic drugs. Modified computed tomography criteria of response, morphologic changes as well as novel imaging techniques and metabolic assessment by fluorodeoxyglucose positron emission tomography seem to be promising methods for the assessment of response and for leading the clinical choices. Pathological response at the time of surgery is an important prognostic factor and a surrogate of survival for resected patients. Different classification criteria to assess pathological response have been developed, residual viable tumor, tumor regression grade (TRG), modified TRG and tumor thickness at the tumor-normal interface, but to date a superiority of one approach over the others has not been clearly established. In this review, we evaluate the available data with the aim to help the clinicians in the pre- and post-surgical care of patient with colorectal cancer liver metastases treated with bevacizumab-based neoadjuvant strategy.     

CapeOX方案治疗老年病人不可切除的结直肠癌肝转移的意义

目的 探讨CapeOX方案对不可切除的结直肠癌肝转移老年病人的治疗效果.方法 对不可切除的转移性结直肠癌老年病人,应用CapeOX方案化疗,每2周期评估一次化疗效果.如化疗后可行手术切除则考虑手术,术后继续CapeOX方案化疗.结果 2004年1月至2006年1月共收治符合标准的病人16例,化疗后8例缓解(缓解率50%),其中3例行根治性切除,5例化疗后肿瘤稳定或缓解但未能行肝切除的病人中位生存期为23.2月;4例化疗后稳定;4例化疗无效的病人中位生存期为6.25月.结论 CapeOX方案结合肝切除术可使部分病人获得治愈,同时CapeOX化疗方案可以使部分病人肿瘤症状缓解,延长病人生命.