Survival after hepatic resection of colorectal cancer metastases

BACKGROUND:

Most estimates of short‐ and long‐term survival after hepatic resection of colorectal cancer metastases are derived from surgical case series. For the current report, the authors used Medicare data to investigate operative mortality and long‐term survival in a national sample and examined the factors associated with survival.

METHODS:

Data were analyzed from Medicare enrollees (age ≥65 years) who were admitted to hospital between January 1, 2000 and December 31, 2004 with a primary diagnosis of colorectal cancer with resection. The sample was restricted to patients who subsequently underwent hepatic resection for liver metastases. The Medicare Denominator File was used to determine operative mortality and long‐term survival and the factors that were associated with those outcomes.

RESULTS:

Of the 306,061 Medicare beneficiaries who were diagnosed with colorectal cancer, 3957 patients were identified who underwent hepatic resection for liver metastases. The crude 30‐day and 90‐day mortality rates were 4% and 8.2%, respectively, and the 5‐year survival rate was 25.5%. Advancing age (hazards ratio [HR], 1.83; 95% confidence interval [95% CI], 1.32‐2.53 for age ≥80 years vs ages 65‐69 years), comorbid disease (HR, 1.40; 95% CI, 1.06‐1.85 for Charlson ≥5 vs Charlson 0), and synchronous colon/hepatic resection (HR, 2.46; 95% CI, 1.89‐3.20 for synchronous vs metachronous resection) were associated with worse 90‐day mortality. Similarly, long‐term mortality was associated with age (HR, 1.36; 95% CI, 1.18‐1.56), comorbid disease (HR, 1.51; 95% CI, 1.36‐1.69), and synchronous colon/hepatic resection (HR, 1.37; 95% CI, 1.24‐1.51 for synchronous vs metachronous resection).

CONCLUSIONS:

In this national study, short‐ and long‐term survival was worse than that reported in surgical case series. Subgroups at high risk for worse outcomes include the extreme elderly and those undergoing synchronous colon and hepatic resection. Cancer 2009. © 2009 American Cancer Society.     

Hepatic resection after down-staging of unresectable hepatic colorectal metastases

Half of the patients with colorectal cancer present with liver metastases at some point in their illness. Surgical resection, which offers the only chance of long-term survival, is an option in only 15% of patients at presentation. Novel chemotherapeutic treatments have enabled approximately 15% of those patients initially deemed inoperable to be down-staged to a point where surgery becomes an option. This aggressive approach, which requires close collaboration between surgeons and oncologists, results in a 40% 5-year survival rate, which is similar to that of patients operated without neoadjuvant chemotherapy. The hope for the future is the development of more effective chemotherapeutic regimens, which may allow more previously unresectable patients to benefit from curative surgery. This article reviews the literature and major areas of progress in treatments for unresectable colorectal cancer.     

Pulmonary resection of colorectal metastases in patients with or without a history of hepatic metastases

Introduction

In selected patients with isolated colorectal lung or liver metastases resection can provide an increase in overall survival and even cure. Here, we evaluate whether also patients with combined or sequential metastatic disease to liver and lung may still be candidates for surgical resection.

Methods

From 1997 till 2006 39 patients underwent pulmonary metastasectomy. Two subgroups were identified: resection of pulmonary metastases only (PM) and resection of hepatic and later pulmonary metastases (LPM).

Results

Patient characteristics were identical in both groups. Median follow-up in group PM was 35 months and 38 months in group LPM. Two-year survival in group PM was 61%, and in group LPM 81% (p = NS). Five-year survival was 30% and 20% in PM and LPM groups, respectively (p = NS). The median disease free survival was 12 months in the PM group and 13 months in the LPM group.The extent of pulmonary resection had no impact on survival. Complications occurred in seven patients in the PM group and two patients in the LPM group. Complication rate and severity were related to the extent of pulmonary resection. A small group of patients underwent repeated pulmonary resection without serious complications.

Conclusion

Resection of pulmonary colorectal metastases may improve survival, even in patients who underwent hepatic resection for colorectal liver metastases at an earlier stage.     

CEA多肽致敏的树突状细胞(DC)治疗晚期非小细胞肺癌临床初步研究

背景与目的树突状细胞(DC)为基础的免疫治疗是肿瘤治疗的新领域,对部分恶性肿瘤有较好的疗效。本研究的目的是应用癌胚抗原(CEA)致敏的DC治疗晚期非小细胞肺癌(NSCLC),观察其临床应用方法、毒副反应和剂量效应。方法选择CEA高表达的肺癌患者,体外培养外周血单个核细胞来源的DC及CIK,CEA多肽于培养的第5天加入培养液以致敏未成熟DC。将DC和CIK细胞静脉回输患者,观察回输后的疗效和毒副反应。结果共22例晚期NSCLC患者接受了DC治疗,回输DC数量为2.5×106~9.6×107,平均5.03×106;回输CIK细胞数量为3.4×108~46×108。治疗后CD3、CD8、NK、IFN-γ明显升高(P<0.05)。全组1年生存率为68.2%(15/22)。主要毒副反应为发热和皮疹。结论DC生物免疫治疗具有较好的耐受性和安全性。     

A critical review of the major indicators of prognosis after resection of hepatic metastases from colorectal carcinoma

Hepatic resections for metastatic colorectal cancer have dramatically increased, and there is clear evidence of the effectiveness of this type of surgery. Controversy, however, persists regarding appropriate patient selection, extent and timing of liver resection, and adjuvant or alternative therapeutic options. This article reviews the authors' experience with more than 600 hepatic resections and the relevant literature is discussed. The results underscore the importance of macroscopically and histologically complete tumor clearance, a so-called "R0 resection."     

A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma

Background:

To date, no adjuvant treatment has been shown to have a clear benefit in patients with hepatocellular carcinoma (HCC). In this prospective phase I/IIa study, we evaluated the safety and efficacy of adjuvant dendritic cell (DC) therapy in HCC patients who received primary treatment for HCC.

Methods:

Twelve HCC patients who had no viable tumour after primary treatments were included. Dendritic cell vaccines pulsed with cytoplasmic transduction peptide-attached alpha-fetoprotein, glypican-3 and melanoma-associated antigen 1 recombinant fusion proteins were injected subcutaneously near to inguinal lymph nodes. Adverse effects, time to progression (TTP), and associated immune responses were evaluated after DC vaccination.

Results:

Nine of 12 patients had no tumour recurrence up to 24 weeks after DC vaccination. Among a total of 144 adverse events, 129 events (89.6%) were regarded as adverse drug reactions, all of which were grade 1 or 2. The majority of patients showed enhanced anti-tumour immune responses after DC vaccination. Recurrence-free patients exhibited relatively stronger anti-tumour immune responses than patients who developed recurrence after DC vaccination, as evidenced by lymphocyte proliferation and IFN-γ ELISPOT assays. The median time of TTP was 36.6 months in the DC-vaccination group and 11.8 months in the control group (hazard ratio, 0.41; 95% confidence interval, 0.18–0.95; P=0.0031 by log-rank test).

Conclusions:

Adjuvant DC vaccine for HCC was safe and well tolerated in phase I/IIa study, and preliminary efficacy data are encouraging to warrant further clinical study in patients with HCC after primary treatments.     

Phase I trial of active specific immunotherapy with autologous dendritic cells pulsed with autologous irradiated tumor stem cells in hepatitis B‐positive patients with hepatocellular carcinoma

Background and Objectives

Hepatocellular carcinoma (HCC) is often associated with chronic hepatitis due to hepatitis‐B or ‐C viruses. Active specific immunotherapy (ASI) with autologous dendritic cells (DC) presenting antigens from autologous tumor stem cell (TC) lines is associated with promising long‐term survival in metastatic cancer, but hepatitis patients were excluded. ASI might benefit high‐risk primary HCC patients following surgical resection, but first it is important to show that ASI does not exacerbate hepatitis.

Methods

Previously untreated HCC patients with a solitary lesion > 5 cm, or three lesions with at least one > 3 cm, or more than three lesions, underwent surgical resection from which autologous TC lines were established. Irradiated TC were incubated with autologous DC to create DC‐TC. After one course of trans‐arterial chemoembolization therapy (TACE), three weekly subcutaneous injections of DC‐TC suspended in granulocyte‐macrophage colony stimulating factor were administered. Patients were monitored for eight weeks.

Results

HCC cell lines were established within five weeks for 15/15 patients. Eight patients, all with chronic hepatitis B, were treated. There was no increase in hepatic transaminases, hepatitis B antigens, or viral DNA.

Conclusion

Autologous DC‐TC did not exacerbate HBV in these HCC patients. A phase II efficacy trial is being planned. J. Surg. Oncol. 2015 111:862–867. © 2014 Wiley Periodicals, Inc.     

Adjuvant, adoptive immunotherapy with tumor infiltrating lymphocytes plus interleukin-2 after radical hepatic resection for colorectal liver metastases: 5-year analysis

BACKGROUND AND OBJECTIVES: Conventional chemotherapy has not proven effective in improving long-term results of surgery for liver metastases from colorectal cancer. We assessed the usefulness of immunotherapy with tumor infiltrating lymphocytes (TIL) plus Interleukin-2 (IL-2) as adjuvant treatment. METHODS: Between 1995 and 1998, 47 patients were enrolled onto a prospective protocol; 25 entered the treatment group (A) and 22 entered the control group (B). All patients had undergone radical liver resection. TIL obtained from surgical specimens from group A patients were cultured and activated in vitro with IL-2, then reinfused into the patients with IL-2. We investigated pre- and post-IL-2 stimulation expression of T cell receptor (TCR) zeta- and epsilon-chains, p56(lck), Fas, and Fas-L by TIL immunostaining. RESULTS: Fourteen patients from group A (56%) received immunotherapy; 14 from group B (60%) underwent conventional chemotherapy, and the remaining 19 patients did not receive any treatment. No significant differences between the two groups were found in the actuarial and disease-free survival (DSF) rates after 1, 3, and 5 years. After IL-2 exposure, TCR zeta-chain expression significantly increased (P = 0.001); An increase in TCR epsilon-chain expression (P = 0.04), and p56(lck) (P = 0.03) was detected; TCR epsilon-chain expression was significantly increased in disease-free patients compared to those who relapsed (P = 0.04). Fas-L expression was correlated with the TCR epsilon-chain and p56(lck) levels (P = 0.05). CONCLUSIONS: Our data suggest that we are still a long way from being able to propose TIL + IL-2 treatment as an effective adjuvant therapy. However, the results confirm that the biological indicators examined could play an important role in modulating immunitary response against tumor cells.     

A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen.

Dendritic cells (DCs), antigen-presenting cells capable of priming naive T cells to specific antigens in an HLA-restricted fashion, have been demonstrated to induce protective T cell-mediated immunity in tumor-bearing animals. We performed this study to test the safety, feasibility, and clinical response of immunizations with in vitro-generated DCs, loaded with an HLA-A2-restricted peptide fragment of the tumor antigen carcinoembryonic antigen (CEA), for the treatment of patients with advanced CEA-expressing malignancies. Cell preparations enriched for autologous DCs were generated from the patients' plastic adherent peripheral blood mononuclear cells in serum-free media supplemented with granulocyte macrophage colony-stimulating factor and interleukin-4. Within the cell preparation, 66% of the cells expressed the phenotype typical for DCs (CD86high, HLA-DRhigh, and CD14low). The DCs were loaded with the CEA peptide CAP-1 and cryopreserved. Groups of three to six patients received four weekly or biweekly i.v. infusions of the CAP-1-loaded DC in escalating dose levels of 1 x 10(7), 3 x 10(7), and 1 x 10(8) cells/dose. A subset of the patients in the last group also received intradermal injections of 1 x 10(6) DCs. There were no toxicities directly referable to the treatments. One patient had a minor response, and one had stable disease. Skin punch biopsy at DC injection sites demonstrated pleomorphic infiltrates in the three patients evaluated. We conclude that it is feasible and safe to generate and administer large numbers of previously cryopreserved DCs loaded with CAP-1 peptide to patients with advanced malignancies.     

A pilot study of multimodality therapy for initially unresectable liver metastases from colorectal carcinoma: hepatic resection after hepatic arterial infusion chemotherapy and portal embolization

The prognosis of patients with unresectable liver metastases is poor, even if hepatic arterial infusion chemotherapy (HAI) or systemic chemotherapy is administered. A pilot study was performed to evaluate the feasibility and efficacy of multimodality therapy with hepatectomy after HAI and portal embolization for such patients. Eight patients with colorectal carcinoma and synchronous unresectable liver metastases underwent resection of the primary tumor and placement of a pump, followed by HAI with 5-fluorouracil and mitomycin C. Owing to shrinkage of the liver metastases, two patients could undergo extended right hepatic lobectomy after portal embolization, which was deemed to be essential to prevent post-operative hepatic failure. The median survival time of the eight patients was 30 months, with a response rate of 75%. Complications including sclerosing cholangitis and duodenal ulcer were observed in five patients (63%). Additional hepatectomy could be performed successfully after portal embolization without morbidity in two patients. These two patients are still alive more than 6 years after initiation of HAI and have been free of disease for more than 5 years after hepatectomy. Hepatectomy after HAI and portal embolization is feasible and may be an option to cure selected patients with initially unresectable liver metastases.      

Irinotecan hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: a phase II clinical study

AIMS AND BACKGROUND: The advantage of delivering chemotherapy by hepatic arterial infusion is the acquisition of a high concentration of the drug in the target. Irinotecan (CPT-11) is active for the treatment of advanced colorectal cancer. In phase I studies, doses of 20 mg/m2/d for 5 days given every 4 weeks as continuous infusion or 200 mg/m2 as a short 30-min infusion given every 3 weeks is recommended for phase II studies. METHODS AND STUDY DESIGN: Twelve patients with a median liver substitution of 30% (20-50%) were enrolled, 6 progressed after a FOLFOX-induced partial response and 6 progressed after 5-fluorouracil and folinic acid. All patients had a surgically (n = 6) or angiographically placed port (n = 6). They received hepatic arterial infusion chemotherapy with CPT-11 (200 mg/m2) on an out-patient basis, every 3 weeks as a short 30-min infusion for six cycles. RESULTS: Four partial responses were observed (33%) lasting 24, 15, 12 and 8+ weeks, 3 stable disease (25%) lasting more than 12 weeks, and 5 progressions (41%). Six patients (50%) presented a >30% reduction in CEA. Toxicity was G2 diarrhea in 5 patients (41%) and G2 myelosuppression in 6 (50%); one patient had abdominal right upper quadrant pain requiring analgesics. CONCLUSIONS: CPT-11 is active as hepatic arterial infusion chemotherapy in liver metastases from colorectal cancer and can rescue systemically pretreated patients. Our schedule seems safe, feasible and well accepted on an out-patient basis.     

The impact of caudate lobe involvement after hepatic resection for colorectal metastases

Background

Hepatic resections involving the caudate lobe are technically challenging with results from some centers indicating inferior outcomes. We assessed outcomes following hepatic resection for colorectal metastases involving the caudate lobe in a tertiary care center.

Methods

Operative and oncological data from a prospectively maintained database were analyzed on 687 patients undergoing hepatic resection for colorectal metastases between 1993 and 2006. Patients were analyzed as those with caudate lobe metastases (CLM) and compared with those without caudate lobe involvement (NCLM).

Results

Fifty-two of 687 patients had metastases involving the caudate lobe (8%). Patients with caudate lobe involvement were more likely to require an extended hepatic resection (75% vs 27%, P = 0.001), perioperative blood transfusion (29% vs 14%, P = 0.002), have a positive resection margin (57% vs 32%, P = 0.001) and stay longer in hospital (12 vs 8 days, P = 0.001). There was no difference in the complication rates (37% vs 29%) or 30-day mortality between the two groups (2% vs 1%). The median disease free (20 months vs 21 months), and cancer specific survival (42 months vs 59 months) were also similar in the CLM and NCLM groups.

Conclusions

Although caudate lobe involvement adds to the technical complexity of hepatic resection, these patients can be offered long term survival, similar to other patients with hepatic metastases from colorectal cancer.     

Intraoperative electrochemotherapy of colorectal liver metastases: A prospective phase II study

Background and objectivesA previous pilot study proved the feasibility, safety and efficacy of electrochemotherapy in the treatment of colorectal liver metastases. The aim of this study was to evaluate long-term effectiveness and safety of electrochemotherapy in the treatment of unresectable colorectal liver metastases.Patients and methodsIn this prospective phase II study, patients with metachronous colorectal liver metastases were included. In all patients, at least one metastasis was unresectable due to its central location or a too-small future remnant liver volume. Patients were treated by electrochemotherapy using intravenously administered bleomycin during open surgery. Treated were 84 metastases in 39 patients. Local tumor control, progression-free survival and overall survival were evaluated.ResultsThe objective response was 75% (63% CR, 12% PR). The median duration of the response was 20.8 months for metastases in CR and 9.8 months for metastases in PR. The therapy was significantly more effective for metastases smaller than 3 cm in diameter than for larger ones. There was no difference in response according to the metastatic location, i.e., metastases in central vs. peripheral locations. Progression-free survival was better in patients who responded well to electrochemotherapy compared to those metastases that had a partial response or progressive disease. However, there was no difference in overall survival, with a median of 29.0 months.ConclusionsElectrochemotherapy has proven to be safe and effective in the treatment of colorectal liver metastases, with a durable response. It provides local tumor control that enables patients with unresectable metastases to receive further treatments.     

Survival after complete surgical resection of multiple metastases from renal cell carcinoma

BACKGROUND:

Although a role for resection of solitary metastases from renal cell carcinoma (RCC) has been described, the utility of surgery in patients with multiple sites of disease has been less well defined. The authors report the survival of patients who underwent complete metastasectomy for multiple RCC metastases.

METHODS:

The authors identified 887 patients who underwent nephrectomy for RCC between 1976 and 2006 who developed multiple metastatic lesions. The impact of complete metastasectomy on survival was evaluated controlling for the timing, location, and number of metastases and for patient performance status.

RESULTS:

Of 887 patients, 125 (14%) underwent complete surgical resection of all metastases. Complete metastasectomy was associated with a significant prolongation of median cancer‐specific survival (CSS) (4.8 years vs 1.3 years; P < .001). Patients who had lung‐only metastases had a 5‐year CSS rate of 73.6% with complete resection versus 19% without complete resection (P < .001). A survival advantage from complete metastasectomy also was observed among patients with multiple, nonlung‐only metastases, who had a 5‐year CSS rate of 32.5% with complete resection versus 12.4% without complete resection (P < .001). Complete resection remained predictive of improved CSS for patients who had ≥3 metastatic lesions (P < .001) and for patients who had synchronous (P < .001) and asynchronous (P = .002) multiple metastases. Moreover, on multivariate analysis, the absence of complete metastasectomy was associated significantly with an increased risk of death from RCC (hazard ratio, 2.91; 95% confidence interval, 2.17‐3.90; P < .001).

CONCLUSIONS:

The current results indicated that complete resection of multiple RCC metastases may be associated with long‐term survival and should be considered when technically feasible in appropriate surgical candidates. Cancer 2011. © 2011 American Cancer Society.     

Immunohistochemically detected hepatic micrometastases predict a high risk of intrahepatic recurrence after resection of colorectal carcinoma liver metastases

BACKGROUND: Hepatic metastases from colorectal carcinoma frequently recur after resection and hepatic micrometastases most likely are important in the development of such recurrences. The objectives of the current study were to assess the feasibility of the immunohistochemical detection of hepatic micrometastases from colorectal carcinoma and to determine their clinical significance. METHODS: Fifty-three patients underwent curative hepatic resection for colorectal carcinoma metastases. Multiple tissue sections were cut from the advancing margin of the largest hepatic metastasis in each patient and were stained with an antibody against cytokeratin-20 to detect hepatic micrometastases, which were defined as discrete microscopic cancerous lesions surrounding the dominant metastasis. RESULTS: Normal hepatocytes and intrahepatic bile duct epithelia stained negative for cytokeratin-20 in all patients, whereas the largest hepatic tumors stained positive in 46 patients (86.8%). Among the 46 patients with hepatic tumors that were positive for cytokeratin-20, hepatic micrometastases were found immunohistochemically in 32 patients (69.6%). The presence of hepatic micrometastases was associated with a larger number of macroscopic hepatic metastases (P = 0.047) and patients with hepatic micrometastases were found to demonstrate a higher probability of intrahepatic recurrence (P = 0.003) compared with those patients without hepatic micrometastases. In addition, patients with hepatic micrometastases demonstrated a worse survival (10-year survival rate of 21.9%) compared with those patients without hepatic micrometastases (10-year survival rate of 64.3%) (P = 0.017). CONCLUSIONS: Immunohistochemical detection of hepatic micrometastases is feasible in patients with colorectal carcinoma liver metastases. Hepatic micrometastasis indicates widespread hepatic involvement and thus predicts an increased risk of intrahepatic recurrence after hepatic resection and a poorer patient prognosis.     

Preclinical evaluation of autologous dendritic cells transfected with mRNA or loaded with apoptotic cells for immunotherapy of high-risk neuroblastoma

Children with high-risk neuroblastoma (NB) have a poor clinical outcome. The purpose of the present study was to evaluate different strategies for immunotherapy of high-risk NB based on vaccination with antigen-loaded dendritic cells (DCs). DCs are professional antigen-presenting cells with the ability to induce antitumor T-cell responses. We have compared DCs either loaded with apoptotic tumor cells or transfected with mRNA from the NB cell line HTB11 SK-N-SH, for their capacity to induce T-cell responses in vitro. Monocyte-derived DCs from healthy donors were loaded with tumor-derived antigens in the form of apoptotic cells or mRNA, matured and used to prime autologous T cells in vitro. After 1 week, T-cell responses against antigen-loaded DCs were measured by ELISPOT assay. DCs loaded with apoptotic NB cells or transfected with NB-cell mRNA were both able to efficiently activate autologous T cells. Both T cells of the CD8+ and CD4+ subset were activated. T cells activated by NB mRNA transfected DCs extensively crossreacted with DCs loaded with apoptotic NB cells and vice versa. The results indicate that loading of DCs with apoptotic NB cells or transfection with tumor mRNA represent promising strategies for development of individualized cancer vaccines/cancer gene therapy in treatment of NB.