Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided platinum-based 2-drug chemotherapy for unresectable nonsmall-cell lung cancer

BACKGROUND: The study investigated correlations between adenosine triphosphate / chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-guided platinum-based chemotherapy for unresectable nonsmall-cell lung cancer (NSCLC). METHODS: The authors performed an in vitro chemosensitivity test, ATP-CRA, to evaluate the chemosensitivities of anticancer drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine for chemonaive, unresectable NSCLC. The cell death rate was determined by measuring the intracellular ATP levels of drug-exposed cells compared with untreated controls. A sensitive drug was defined as a drug producing 30% or more reduction in ATP compared with untreated controls. Assay-guided platinum-based 2-drug chemotherapy was given to patients with pathologically confirmed NSCLC. RESULTS: Thirty-four patients were enrolled. Thirty tumor specimens were obtained by bronchoscopic biopsies and 4 obtained surgically. The median age was 61 years and 27 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The response rate was 43.8%. At a median follow-up period of 16.9 months, the median progression-free and overall survivals were 3.6 and 11.2 months, respectively. Patients were dichotomized into the platinum-sensitive (S; 20 patients) and resistant (R; 14 patients) groups. The positive/negative predictive values were 61.1% and 78.6% with a predictive accuracy of 68.8%. Although without significant differences in pretreatment parameters, the S-group showed better clinical response (P=.036), longer progression-free survival (P=.060), and longer overall survival (P=.025). CONCLUSIONS: Despite using bronchoscopic biopsied specimens, ATP-CRA and clinical outcomes correlated well after assay-guided platinum-based 2-drug chemotherapy for unresectable NSCLC. There was a favorable response and survival in the platinum-sensitive vs resistant groups.     

Safe liver resection following chemotherapy for colorectal metastases is a matter of timing

Neoadjuvant chemotherapy (NC) can improve the resectability of hepatic colorectal metastases (CRM). However, there is concern regarding its impact on operative risk. We reviewed 750 consecutive liver resections performed for CRM in a single unit (1996-2005) to evaluate whether NC affected morbidity and mortality. Redo hepatic resections or patients receiving adjuvant chemotherapy following primary resection were excluded. A total of 245 resections were performed in patients not requiring NC (control group) (mean age 63, 67% male) and 252 in patients who had NC (mean age 62, 67% male). The mean (s.d.) duration of surgery was less in the control group (241(64) vs 255(64)min, P=0.014) as was the mean blood loss (390(264) vs 449(424)ml, P=0.069). Postoperative mortality (2 vs 2%) and morbidity (27 vs 29%, P=0.34) was similar between groups. More NC patients developed septic (2.4%) or respiratory (10.3%) complications compared to controls (0 and 5.3%, P<0.03), with significantly more surgical complications if the interval between stopping NC and undergoing surgery was 相似文献   

Colorectal liver metastases contract centripetally with a response to chemotherapy: a histomorphologic study

BACKGROUND: Recently, there has been considerable interest in neoadjuvant chemotherapy for colorectal liver metastases. However, there is little information that defines how much liver should be removed after a favorable response. METHODS: Liver metastases from 2 groups of patients were analyzed: 25 metastases were evaluated from a group that did not receive chemotherapy and 26 lesions were studied from patients who had received systemic chemotherapy before resection. All patients except for 1 had 5-fluorouracil (5-FU), leucovorin (LV), and irinotecan (CPT-11); 1 had 5-FU and LV alone. The average duration of chemotherapy was 2.9+/-0.7 months. Separate assessments of the histopathologic features of the central and peripheral portions of each tumor were made. The pathologist was blinded to all clinical information. RESULTS: All of the untreated metastases had well-circumscribed borders. Irregular borders were seen in 6 of the postchemotherapy lesions (26%), which was particularly prominent in lesions that had significantly contracted. After chemotherapy, discrete islands of viable tumor cells outside of the main tumor mass were seen in 4 patients, but all were close to the peripheral margin of the tumor mass. Viable tumor cells were more frequent in the periphery of metastases, regardless of chemotherapy exposure. Central necrosis was prominent in untreated metastases, but disappeared after chemotherapy. In lesions treated with chemotherapy, central fibrosis was greater compared with untreated lesions. CONCLUSIONS: After a partial response to chemotherapy, liver metastases shrank in a generally concentric fashion. These findings support the practice of removing less liver after downsizing with chemotherapy.     

Intra-arterial chemotherapy for unresectable pancreatic cancer

Background:A phase II trial of a new intra-arterial chemotherapyregimen for unresectable pancreatic cancer (UPC). Patients and methods:Ninety-six patients with UPC were treatedwith intra-arterial chemotherapy at three-weekly intervals. The schedule usedwas FLEC: 5-fluorouracil 1000 mg/m², folinic acid 100mg/m², carboplatin 300 mg/m²; epirubicin 60mg/m². Results:The overall response rates by CT-scan evaluation were:15% partial response (PR), 44% stable disease (SD), 17%progressive disease (PD). The overall median survival was 9.9 months, and 10.6and 6.8 for UICC stage III and IV, respectively. Pain reduction occurred in42% of patients. A weight gain >7% from baseline occurred in8% of patients. A total of 341 courses of FLEC were administered. Grade3–4 hematological toxicity was seen in 25% of patients;ematemesis in 4%; grade 3 gastrointestinal toxicity in 3%; andgrade 3 alopecia in 16%. One sudden death, a pre-infarction angina, anda transitory ischemic attack were observed. The only complication related tothe angiographic procedure was an intimal dissection of the iliac artery. Conclusions:The intra-arterial FLEC regimen was well toleratedand active. It requires only one day of hospitalization. Efficacy could onlybe assessed in a randomized study against a gemcitabine containing regimen.     

Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients.

BACKGROUND: The aim of this study was to observe the effects of neoadjuvant therapy with irinotecan and 5-fluorouracil (5-FU)/folinic acid (FA) on the resection rate and survival of colorectal cancer patients with initially unresectable hepatic metastases. PATIENTS AND METHODS: Forty patients received neoadjuvant chemotherapy comprising irinotecan 180 mg/m(2) administered intravenously (i.v.) on day 1, FA 200 mg/m(2) i.v. on days 1 and 2, 5-FU 400 mg/m(2) i.v. bolus on days 1 and 2, and 5-FU 1200 mg/m(2) as a continuous 48-h i.v. infusion on day 1. The treatment was repeated every 2 weeks and response was assessed every 12 weeks (six cycles). RESULTS: The objective response rate to chemotherapy was 47.5% (n = 19), with two complete responses and disease stabilization in 11 (27.5.%) patients. Responses were unconfirmed for 11 patients undergoing surgery within 2 weeks. Treatment was well tolerated and adverse events were typical of the chemotherapy agents used. Twenty-seven (67.5%) patients reported hematological toxicity (35.0% grade 3/4) and 14 (35.0%) reported gastrointestinal toxicity (12.5% grade 3/4). Thirteen patients (32.5%) underwent potentially curative liver resection following chemotherapy. Chemotherapy was particularly effective in patients with large metastases on entry to the study. The median time to progression is 14.3 months and, at a median follow-up of 19 months, all patients are alive. CONCLUSIONS: Neoadjuvant therapy with irinotecan combined with 5-FU/FA enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. The effects of treatment on survival have yet to be determined.     

结直肠癌肝转移外科治疗策略

目前手术切除是结直肠癌肝转移（CRLM）唯一具有治愈可能的治疗方式。近年来随着全身化疗及靶向药物的发展、肝动脉灌注化疗的应用,对于CRLM 治疗的有效率明显升高,通过手术获益的患者逐渐增多;而如射频消融、二步切除等外科技术的进步,也为更多CRLM 患者提供了治愈的机会。多学科诊疗模式（MDT ）也为更多CRLM 患者的个体化诊治创造了机会,使未来CRLM 的治疗向更加精准的方向发展。     

Neoadjuvant chemotherapy (NCT) plus targeted agents versus NCT alone in colorectal liver metastases patients: A systematic review and meta-analysis

Purpose

To assess the efficacy of neoadjuvant chemotherapy (NCT) plus targeted agents versus NCT alone for the treatment of colorectal liver metastases (CRLM) patients.

Methods

Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All clinical studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), hepatic resection and R0 hepatic resection rate were extracted and analyzed using Comprehensive MetaAnalysis software (Version 2.0).

Results

A total of 40 cohorts with 2099 CRLM patients were included: 962 patients were treated with NCT alone, 602 with NCT plus anti-epidermal growth-factor receptor (EGFR)-monoclonal antibodies (MoAbs) and 535 with NCT plus bevacizumab. Pooled ORR was significantly higher for NCT plus bevacizumab or anti-EGFR-MoAbs than NCT alone [relative risk (RR) 1.53, 95% CI 1.30–1.80; p < 0.001; RR 1.53, 95% CI: 1.27–1.83, p < 0.001; respectively]. NCT plus bevacizumab significantly improved R0 hepatic resection rate (RR 1.61, 95% CI: 1.27–2.04, p < 0.001), but not for overall hepatic resection rate (RR 1.26, 95% CI: 0.81–1.94, p = 0.30). While hepatic resection and R0 hepatic resection rate was comparable between NCT plus anti-EGFR-MoAbs and NCT alone (p = 0.42 and p = 0.37, respectively).

Conclusions

In comparison with NCT alone, NCT plus bevacizumab significantly improve ORR and R0 hepatic resection rate but not for hepatic resection rate. Our findings support the need to compare NCT plus bevacizumab with NCT alone in the neoadjuvant setting in large prospective trials due to its higher hepatic resection rate and R0 hepatic resection rate in CRLM patients.     

A contemporary systematic review on liver transplantation for unresectable liver metastases of colorectal cancer

The 5-year overall survival rate of a patient with unresectable metastatic colorectal cancer is poor at approximately 14%. Similarly, historical data on liver transplantation (LT) in those with colorectal liver metastases (CRLM) showed poor outcomes, with 5-year survival rates between 12% and 21%. More recently, limited data have shown improved outcomes in select patients with 5-year overall survival rates of approximately 60%. Despite these reported survival improvements, there is no significant improvement in disease-free survival. Given the uncertain benefit with this therapeutic approach and a renewed investigational interest, we aimed to conduct a contemporary systematic review on LT for CRLM. A systematic review of the literature was performed according to the preferred reporting items for systematic reviews and meta-analysis statement. English articles reporting on data regarding LT for CRLM were identified through the MEDLINE (via PubMed), Cochrane Library, and ClinicalTrials.gov databases (last search date: December 16th, 2021) by 2 researchers independently. A total of 58 studies (45 published and 13 ongoing) were included. Although early retrospective studies suggest the possibility that some carefully selected patients may benefit from LT, there is minimal prospective data on the topic and LT remains exploratory in the setting of CRLM. Additionally, several other challenges, such as the limited availability of deceased donor organs and defining appropriate selection criteria, remain when considering the implementation of LT for these patients. Further evidence from ongoing prospective trials is needed to determine if and to what extent there is a role for LT in patients with surgically unresectable CRLM.     

结直肠癌肝转移的治疗进展

肝脏是结直肠癌最常见的远处转移部位,近年来以化疗和手术为主的多学科综合治疗显著改善患者的生活质量和预后。本文就结直肠癌肝转移的治疗进展综述如下。     

Imaging in resectable colorectal liver metastasis patients with or without preoperative chemotherapy: results of the PROMETEO-01 study

Background:

The aim of the PROMETEO-01 Study was to define the diagnostic accuracy of imaging techniques in colorectal cancer liver metastasis (CRCLM) patients.

Methods:

Patients referred to Bologna S. Orsola-Malpighi Hospital performed a computed-tomography scan (CT), magnetic resonance (MR), 18F-FDG-PET/CTscan (PET/CT) and liver contrast-enhanced-ultrasound (CEUS); CEUS was also performed intraoperatively (i-CEUS). Every pathological lesion was compared with imaging data.

Results:

From December 2007 to August 2010, 84 patients were enrolled. A total of 51 (60.71%) resected patients were eligible for analysis. In the lesion-by-lesion analysis 175 resected lesions were evaluated: 67(38.3%) belonged to upfront resected patients (group-A) and 108 (61.7%) to chemotherapy-pretreated patients (group-B). In all patients the sensitivity of MR proved better than CT (91% vs 82% P=0.002), CEUS (91 vs 81% P=0.008) and PET/CT (91% vs 60% P=0.000), whereas PET/CT showed the lowest sensitivity. In group-A the sensitivity of i-CEUS, MR, CT, CEUS and PET/CT was 98%, 94%, 91%, 84% and 78%, respectively. In group-B the i-CEUS proved equivalent in sensitivity to MR (95% and 90%, respectively, P=0.227) and both were significantly more sensitive than other procedures. The CT sensitivity in group-B was lower than in group-A (77% vs 91%, P=0.024).

Conclusions:

A thoraco-abdominal CT provides an adequate baseline evaluation and guides judgment as to the resectability of CRCLM patients. In the subset of candidates for induction chemotherapy to increase the chance of liver resection, the most rational approach is to add MR for the staging and restaging of CRCLM.     

Evolution of missing colorectal liver metastases following inductive chemotherapy and hepatectomy

BACKGROUND: A dramatic response to chemotherapy in some patients with multiple bilateral and initially unresectable liver metastases (LM) from colorectal cancer sometimes leads to their disappearance from imaging studies. Our study was aimed at assessing the evolution of these metastases when they were also not found during liver surgery. PATIENTS: Among 104 hepatectomized patients for colorectal LM in 4 years, 15 patients were retrospectively eligible. Eligibility criteria were: initially unresectable LM; a dramatic response to chemotherapy; and the complete disappearance of at least one LM on imaging studies (ultrasonography (US), computed tomography, and magnetic resonance) during more than 3 months. In four patients (27%), the disappeared LM could be found and treated at laparotomy. The main selection criterion for the 11 studied patients of this series was the impossibility of finding and treating the disappeared LM sited in the remaining liver after hepatectomy, resulting in "missing LM." RESULTS: After a median follow-up of 31 months (range: 18-55) for the series, eight patients among the eleven (73%) did not present any recurrence of the missing LM. The median follow-up was 31.3 months for these eight patients. The three recurrences occurred respectively at 5, 5, and 8 months after surgery. CONCLUSIONS: The disappearance of LM after chemotherapy on high-quality imaging studies and after intra-operative liver exploration resulted in their definitive cure in approximately 70% of cases. The current dogma stipulating an obligatory resection of the initially affected part of the liver is no longer acceptable.     

Assessing the optimal duration of chemotherapy in patients with colorectal liver metastases

BACKGROUND AND OBJECTIVES: Few studies have addressed the optimal duration of chemotherapy, particularly prior to liver resection for colorectal liver metastases (CLM). The purpose of this retrospective analysis was to evaluate time to maximal response in patients receiving systemic +/- hepatic arterial infusion (HAI) chemotherapy alone for the treatment of CLM. METHODS: We reviewed 35 patients with CLM on clinical trials of HAI floxuridine/dexamethasone plus systemic oxaliplatin with 5-fluorouracil/leucovorin or irinotecan (PUMP + SYSTEMIC). We retrospectively identified 35 patients with CLM who received first-line systemic 5FU/leucovorin/oxaliplatin (FOLFOX) +/- bevacizumab (SYSTEMIC) during the same time period. Measurable disease was evaluated on CT scans performed at 2-month intervals. The sum of the products of bi-dimensional tumor measurements for representative lesions was compared both to baseline imaging and between consecutive time points. RESULTS: In responders to therapy, mean cumulative tumor reduction increased from 61% at 2 months to 73% at 4 months in the PUMP + SYSTEMIC group (P < 0.01) and from 39% to 56% in the SYSTEMIC group (P < 0.01). No significant incremental tumor reduction occurred between 4 and 6 months in either group. CONCLUSIONS: In responders to preoperative therapy, surgical resection should be considered after 2-4 months, when most patients have achieved maximal response.     

Treatment of colorectal cancer metastasis: The role of chemotherapy

5-Fluorouracil (5-FU) has been the main chemotherapeutic agent for the treatment of colorectal cancer for four decades with modest efficacy. Modulation of 5-FU by leucovorin or continuous infusion improves the response rate, but overall survival duration remains approximately 12 months. Many oral fluoropyrimidines have been studied, including capecitabine, UFT, S-1, and Eniluracil. Capecitabine has demonstrated equivalent efficacy with 5-FU and has been approved as first line treatment. The combinations of capecitabine with CPT-11 or oxaliplatin are being developed. CPT-11 demonstrated non-crossover resistance with 5-FU and was proven to be effective treatment for patients who received prior 5-FU. CPT-11 in combination with 5-FU has demonstrated improved response rate and overall survival duration over 5-FU or CPT-11. Oxaliplatin plus 5-FU has offered another effective treatment option for colorectal cancer. Both 5-FU plus leucovorin in combination with CPT-11 or oxaliplatin are widely used first-line chemotherapies for advanced colorectal cancer. Optimal combinations and sequences of treatment are being studied, since several effective regimens have become available.     

Development of a model to predict pathologic response to chemotherapy in patients with colorectal liver metastases

BackgroundPreoperative chemotherapy has widely been used in colorectal cancer liver metastasis (CRLM). Pathological response to chemotherapy is very important in evaluating tumor biology. However, there is still a lack of a non-invasive and accurate method to evaluate pathological response before surgery.MethodsWe retrospectively analyzed the clinicopathologic data of patients with CRLM who underwent liver resection after preoperative chemotherapy between January 2006 and December 2018. Pathological responses were defined as minor when there are ≥50% remnant viable cells and as major when 0–49% remnant viable cells exist.ResultsA total of 482 patients were included and randomly divided into training (n=241) and validation (n=241) cohorts. The proportion of major pathologic response was similar between the two groups (51.5% and 48.5%). Multivariate analysis determined the disease-free interval (DFI), tumor size, tumor number, and RAS status as independent predictors of major pathologic response to preoperative chemotherapy. The nomogram incorporating these variables showed good concordance statistics in the training cohort (0.746, 95% CI: 0.685–0.807) and validation cohort (0.764, 95% CI: 0.704–0.823). In addition, the nomogram showed good applicability in patients with different characteristics.ConclusionsThe established nomogram model performed well in predicting pathological response in patients with CRLM.