Liver-limited Metastasis Research Articles

ASO Visual Abstract: Prognostic Role of Preoperative Chemotherapy in Liver-Limited Metastasis from Gastric Cancer.

ASO Visual Abstract: Prognostic Role of Preoperative Chemotherapy in Liver-Limited Metastasis from Gastric Cancer.

ASO Author Reflections: Preoperative Chemotherapy Provides Survival Benefits Compared with Upfront Surgery for Patients with Liver-Limited Metastasis from Gastric Cancer.

ASO Author Reflections: Preoperative Chemotherapy Provides Survival Benefits Compared with Upfront Surgery for Patients with Liver-Limited Metastasis from Gastric Cancer.

Prognostic Role of Preoperative Chemotherapy in Liver-Limited Metastasis from Gastric Cancer.

We investigated the prognostic role of preoperative chemotherapy in patients who underwent hepatectomy for liver-limited metastasis (LLM) from gastric cancer (GC). A retrospective analysis was conducted for 52 consecutive patients who underwent macroscopically complete (R0 or R1) resection for synchronous or metachronous LLM from GC. Of the 52 patients, 18 (35%) received preoperative chemotherapy (PC group), while 34 (65%) underwent upfront surgery (US group). The PC group had a significantly longer overall survival than the US group (cumulative 5-year OS rate: 47.6% vs. 24.8%, p = 0.041). Multivariate analysis of OS revealed that preoperative chemotherapy was an independent favorable prognostic factor (hazard ratio: 0.445, p = 0.036). Patients showing a partial response to preoperative chemotherapy on RECIST had an improved OS compared with those exhibiting stable or progressive disease after preoperative chemotherapy and with US (p = 0.025), even among those with solitary LLM (p = 0.062) and multiple LLM (p = 0.026). At recurrence after hepatectomy for LLM, the PC group had a significantly higher incidence of solitary tumors than the US group (p = 0.043) and had a higher chance to undergo surgical resection for recurrent sites (p = 0.006). Preoperative chemotherapy can be recommended for patients with LLM from GC. The evaluation of the efficacy of preoperative chemotherapy offers additional information to determine the surgical indication for LLM.

INTRA-ARTERIAL CHEMOTHERAPY AS A CLINICAL OPTION FOR METASTATIC COLORECTAL CANCER: CONVERSION OF INOPERABLE LIVER METASTASES TO OPERABLE ILLUSTRATED WITH A CLINICAL CASE.

Colorectal cancer exerts a very high level of liver metastases, even on primary diagnosis, with 80%-90% unresectable nodules. At the same time, the possibility of resection has a significant impact on survival: 5-year survival is 6%-10% without liver surgery and up to 30% upon resection of liver metastases. Finding ways to improve resectability is a topical search for doctors all over the world. One of the promising methods to convert unresectable liver metastases of colorectal cancer into resectable ones is a hepatic artery infusion, or intra-arterial chemotherapy allowing for the delivery of cytotoxic drugs directly to the common hepatic artery via catheter or pump with decreased systemic toxicity and increased local drug concentration. In this article, we discuss the literature data on the impact of intra-arterial chemotherapy on the resectability of colorectal metastases in the liver and present the results of the successful clinical case. The literature shows a positive impact of the hepatic artery infusion on the resectability of hepatic metastases of colorectal cancer. The National Cancer Institute (Ukraine) has its own experience in hepatic artery infusion with further resection of primary-unresectable colorectal metastases in the liver. In our clinical case, a patient with liver-limited metastasis of colorectal cancer was initially inoperable due to the size of tumor lesions and an insufficient residual volume of the liver. Hepatic artery infusion tactics was chosen for this patient. The patient received six cycles of intra-arterial chemotherapy, namely five FOLFOX cycles and one 5-FU cycle, and then met the resectability criteria. Also, it is important to notice that the case demonstrates chemoresistance overcoming, since the patient had disease progression before, following systemically administered XELOX, and the period until readmission of the drugs was less than 6 months. So, hepatic artery infusion can be considered a promising method to convert unresectable liver metastases of colorectal cancer into resectable ones for highly selected patients.

The survival impact of radiotherapy on synchronous metastatic rectal cancer: metastatic site can serve for radiotherapy-decision.

Purpose: The metastatic site seems to represent a malignancy with a different biological characteristic. Radiotherapy, as a successful, well-tolerated, cost-effective and time-efficient intervention, is able to provide clear benefits for the treatment of locally advanced rectal cancer and has become an essential component of palliative oncology care. The real-world effect of radiotherapy on the survival outcomes of metastatic rectal cancer (mRC) patients might do exist and was worth exploring.Patients and methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database in this retrospective analysis. The statistical methods included Pearson's chi-square test, Log-rank test, Cox regression model and propensity score matching (PSM).Results: The multivariable Cox regression displayed that radiotherapy may not be used as a prognostic factor for mRC (p=0.057). However, radiotherapy may be associated with the prognosis if the metastatic site was excluded from the multivariate analysis (p<0.001). Radiotherapy seemed to fail to improve OS before PSM (p<0.001) and after PSM without the metastatic site as a matching factor (p<0.001). Nevertheless, there was no significant survival difference between radiotherapy and non-radiotherapy cohort after PSM with the metastatic site as a matching factor (p=0.057). All of M1a rectal cancer patients appear to obtain survival benefit from radiotherapy without the impact of PSM (p<0.001). Notwithstanding, radiotherapy was associated with improved OS of patients with rectal liver-limited metastasis (p=0.023) and did not appear to provide survival benefit for rectal lung-limited (p=0.386) and other-limited metastasis (p=0.385). Both of M1b mRC with and without liver metastasis did not seem to obtain survival benefit from radiotherapy.Conclusions: Carefully selected data from the SEER database suggested that radiotherapy appears to improve overall survival only in patients with rectal liver-limited metastasis.

SP6.1.9 Colorectal Cancer and Synchronous Liver-limited Metastatic Disease: The final results of the CoSMIC Inception Cohort Study

Abstract Aims Currently, evidence is inadequate to inform the selection of optimal treatment for patients with colorectal cancer and synchronous liver-limited hepatic metastases. Options include synchronous or staged surgery integrated with systemic chemotherapy. CoSMIC is the first inception cohort study to follow patients from point of presentation in order to identify factors influencing treatment and outcome. Methods Patients were identified at presentation to the regional liver metastases MDT at Manchester Royal Infirmary between April 2015-2018. Data were collected on demographics, intervention and outcome. The study was approved by Regional Ethics Committee (REC reference: 14/NW/1397). Results Of 125 patients recruited, 109 underwent surgery with 18 (17%) liver-first, 75 (69%) bowel-first and 16 (14%) undergoing synchronous resection. There were no differences in baseline demographics or co-morbidity. Eighty-eight completed the intended surgical pathway, with highest failure in liver-first patients where 39% did not proceed to subsequent bowel resection. Critical care occupancy between staged and synchronous resections (5.6 versus 5.2 days; P = 0.92), and inpatient stay (16.5 versus 16.8 days; P = 0.92) was not significant. There was no 30-day mortality. Cox regression analysis identified surgical sequence as a significant covariate (Х2= 31.3; P &amp;lt; 0.001). Survival was similar between surgical groups (Log-rank test; P = 0.87). Conclusions CoSMIC is the first prospective inception cohort study of colorectal cancer and synchronous liver-limited metastasis. The study population is small and from a single centre and thus could be influenced by recruitment and sample bias. However, the important novel finding is that there is no survival difference between treatment pathways.

Impact of multidisciplinary tumor board (MTB) discussion on the outcome of patients with liver-limited metastasis from colorectal cancer (LMCRC).

50 Background: MTB is a valuable tool in complex cases, since they involve different medical fields aiming for a more comprehensive decision-making process. Our aims are to describe MTB decisions in complex LMCRC, to analyze decisions compliance and evaluate outcomes. Methods: This is a retrospective analysis of medical records of patients diagnosed with liver metastasis of colorectal carcinoma (LMCRC) discussed at a single center, weekly-basis MTB from January 2019 to December 2020. Descriptive statistics was used for demographic and treatment characteristics and adhesion to MTB decisions. Survival was estimated by Kaplan-Meier method and log-rank tests. Results: Out of 1033 cases discussed at MTB, 63 met the inclusion criteria. Median age was 56.5 years (range 32 – 81), 61.9% were male, ECOG was 0-1 in 96.8%. Regarding primary tumor sidedness: 81% and 19% were left and right, respectively. Synchronous metastasis was present in 69.8% and wild-type RAS was found in 52.4% and MSI-H in 4.8%. At time of MTB, 68.3% and 4.8% had realized a first or second-line chemotherapy (CT) respectively. No previous therapy was described in 19% and 7.9% had received adjuvant CT. Previous hepatic resections occurred in 20.6%. After MTB, liver resection was recommended for 44.5%. Preoperative CT followed by one or two-stage surgery for 23.8%. Non-surgical treatments were offered for 17.5% and palliative CT for 14.3%. Decisions from the MTB were implemented in 93.6%. Reason for not performing (N = 4) were: one for disease progression, one for bureaucratic restriction and two for other reasons. Median follow-up time was 17.2m. At date of analysis, 31 patients (49.2%) had relapsed or progressed and 8 had died. Restricting for patients who underwent MTB decision (N = 59), mPFS was 14.71m. In resected cases (N = 40), who were discussed at the onset of liver metastasis diagnosis (without CT in the metastatic setting) had mPFS not reached, while who were discussed after first or second-line had mPFS of 9.39m (p 0.002). R0 resections were reached in 92.5%. Evaluating the 30-day postoperative mortality, there was one death. mPFS for palliative CT was 6.83m. Conclusions: In our analysis the adherence to MTB recommendation was high (above 90%) and patients selected for surgery presented a prolonged PFS. Our data suggest that selection of patients for liver metastasis resection in a MTB discussion should occur early in the course of treatment.

1865P Impact of multidisciplinary tumor board (MTB) in the treatment of liver-limited metastasis from colorectal cancer (LMCRC)

MTB is a valuable tool in complex cases, since they involve different medical fields aiming for comprehensive decision-making process. Our aims are to describe MTB decisions in complex LMCRC, to analyze decisions compliance and evaluate outcomes.

A Nomogram to Predict Individual Survival of Patients with Liver-Limited Metastases from Gastroenteropancreatic Neuroendocrine Neoplasms: A US Population-Based Cohort Analysis and Chinese Multicenter Cohort Validation Study

Introduction: Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with liver metastasis encompass a wide variety of clinical conditions with various prognosis, no statistical model for predicting the prognosis of these patients has been established. We sought to establish a more elaborative and individualized nomogram to predict survival of patients with liver-limited metastatic GEP-NENs. In addition, this nomogram was validated by both the Surveillance, Epidemiology, and End Results (SEER) database and a Chinese multicenter cohort. Methods: Patients diagnosed with GEP-NENs with liver-limited metastasis between 2010 and 2016 were identified from the SEER database. Kaplan-Meier survival analysis was performed to analyze survival outcomes. A nomogram was established based on the independent prognostic variables identified from univariate and multivariate Cox regression analyses. The nomogram was evaluated in both an internal validation SEER dataset and an external validation dataset composed of patients from the Chinese multicenter cohort. Results: A total of 1,474 patients from the SEER database and 192 patients from the multicenter cohort were included. Age, tumor size, differentiation, primary tumor resection, and liver metastasis resection were identified as independent prognostic factors by univariate and multivariate Cox analyses and were verified by Kaplan-Meier survival analysis (all p < 0.0001). A nomogram was developed and validated by calibration curves and areas under the curve of the external validation cohort, which showed good consistency and veracity in predicting overall survival. Conclusion: A nomogram was developed for the first time to predict the survival of patients with liver-limited metastases from GEP-NENs. Both internal and external validation demonstrated excellent discrimination and calibration of our nomogram. Based on this prognostic model, clinicians could develop more personalized treatment strategies and surveillance protocols.

Conversion surgery after cetuximab or bevacizumab plus FOLFIRI chemotherapy in colorectal cancer patients with liver- and/or lung-limited metastases.

Some metastatic colorectal cancer (mCRC) patients receive conversion surgery (CS), including metastasectomy after palliative chemotherapy. Although targeted agents significantly improved the outcomes, the clinical outcome of CS in the targeted agent era has not yet been thoroughly investigated. We analyzed the clinical data of 96 mCRC patients who initially had unresectable liver- and/or lung-limited metastases and underwent first-line cetuximab or bevacizumab plus FOLFIRI between January 2013 and June 2017. Liver-limited metastasis was seen in 44 patients (45.8%), lung-limited metastases in 21 patients (21.9%), and both liver and lung metastases in 31 patients (32.3%). Among them, 37 patients (38.5%) received cetuximab, and 59 patients (61.5%) received bevacizumab plus FOLFIRI. Overall response rate was 63.9% and 40.7%, respectively (p = 0.035). After median 8.7 (range 2.5-27.3) months, CS was performed in 11 patients (29.7%) in cetuximab group and 15 patients (25.4%) in bevacizumab group (p = 0.646). Median overall survival has not been reached in R0-resected patients (n = 23), during the median follow-up period of 22.5 (range 9.8-54.5) months. Median disease-free survival was 7.1 (95% CI 2.5-11.7) months: 11.0 (95% CI 3.1-19.0) months in cetuximab group and 3.2 (95% CI 0.0-7.8) months in bevacizumab group (p = 0.422). There was no progression after 18.5months and disease-free survival reached a plateau at 19.9%. A substantial proportion of patients could receive CS after cetuximab or bevacizumab plus FOLFIRI chemotherapy. R0-resected patients had excellent overall survival, although 80.1% of them eventually experienced recurrence. Some patients could achieve durable disease-free state.

Nomograms predicting Overall Survival and Cancer-specific Survival for Synchronous Colorectal Liver-limited Metastasis.

Background: Colorectal cancer (CRC) ranks as the third most frequent cancer type and the second leading cause of cancer-related death worldwide. The liver is the most common metastatic site of CRC with 20%-34% of patients suffering synchronous liver metastasis. Patients with colorectal liver-limited metastasis account for one-third of deaths from colorectal cancer. Moreover, some evidence indicated that CRC patients with synchronous liver disease encounter a worse prognosis and more disseminated disease state comparing with metastatic liver disease that develops metachronously.Methods: Data in this retrospective analysis were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms were constructed with basis from a multivariate Cox regression analysis. The prognostic nomograms were validated by C-index, time-dependent receiver operating characteristic (ROC) curve, decision curve analysis (DCA) and calibration curves.Results: A total of 9,958 CRC patients with synchronous liver-limited metastasis were extracted from the SEER database during 2010-2016. Both overall survival (OS) and cancer-specific survival (CSS) were significantly correlated with age, marital status, race, tumor location, pathological grade, histologic type, T stage, N stage, surgery for primary tumor, surgery for liver metastasis, chemotherapy and CEA. All of the significant variables were used to create the nomograms predicting OS and CSS. C-index values, time-dependent ROC curves, DCA curves and calibration curves, proved the superiority of the nomograms.Conclusions: Our research investigated a national cohort of almost 10,000 patients to create and verify nomograms based on pathological, therapeutic and demographic features to predict OS and CSS for synchronous colorectal liver-limited metastasis (SCLLM). The nomograms may act as an excellent tool to integrate clinical characteristics to guide the therapeutic choice for SCLLM patients.

A randomized phase II study of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab for previously untreated, liver-limited metastatic colorectal cancer that is unsuitable for resection (ATOM trial).

734 Background: It is still a topic of ongoing debate as to which of the two agents, anti-VEGF antibody or anti-EGFR antibody, is more effective in patients with KRAS Exon 2 or RAS wild-type metastatic colorectal cancer (mCRC) in the first-line setting. ATOM is a multicenter, randomized trial comparing mFOLFOX6 plus bevacizumab (Bmab arm) with mFOLFOX6 plus cetuximab (Cmab arm) in patients with liver-limited metastases unsuitable for upfront resection. Methods: Patients with previously untreated mCRC were eligible if they had ≥5 liver-limited metastatic lesions and/or had liver-limited metastases with the maximum lesion diameter of &gt; 5cm. Patients with KRAS Exon2-wild were registered but after Jan 2015 limited to those with all RAS-wild. Primary endpoint was progression-free survival (PFS), which was defined as the time from randomization to disease progression, recurrence after resection by surgery, or death from any cause (Central review). Key secondary endpoints included overall response rate (ORR), liver resection rate, and overall survival (OS). Results: A total of 122 pts were enrolled between May 2013 and April 2016. Of 116 eligible (59 in the Cmab arm and 57 in the Bmab arm), median age was 65/64 in the Cmab/Bmab arm; ECOG PS 0, 86/89%; all RAS wt, 98/95%; left-sided primary tumor, 76/84%. Efficacy results were summarized in the table. With a median follow-up of 24.3 months, the median PFS was 15.0 months in Cmab arm and 11.6 months in the Bmab arm with a hazard ratio of 0.803 (95%CI, 0.513–1.256), whereas ORR was 86% in the Cmab arm and 68% in the Bmab arm. Liver resection rate was 49% and 56% in the Cmab arm and the Bmab arm, respectively. Conclusions: In patients considered unsuitable for upfront resection of liver-limited metastasis, the two agents showed a similar efficacy. OS result will be presented elsewhere. Clinical trial information: NCT01836653. [Table: see text]

Liver and/or lung metastasectomy after cetuximab or bevacizumab+FOLFIRI chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).

843 Background: Some mCRC pts who have liver and/or lung metastases (LLMs) could achieve cure after palliative chemotherapy and conversion surgery (CS) including metastasectomy. Though targeted agents including bevacizumab and cetuximab significantly improved outcomes in mCRC pts, the effect of targeted agents on cure rate after CS has not yet been thoroughly investigated. Methods: We analyzed clinical data of mCRC pts who initially had unresectable LLMs regardless of their size and number and underwent first-line cetuximab or bevacizumab+FOLFIRI. Pts who had metastasis other than liver and lung were excluded. Results: From January 2013 to May 2016, 87 pts (male, 56) were consecutively enrolled: liver-limited metastasis in 42 pts (48.3%), lung-limited metastasis in 17 pts (19.5%), and both liver and lung metastases in 28 pts (32.2%). Median age was 62 years (range, 37-85). K-RAS or N-RAS mutation was detected in 39 pts (46.4%) and B-RAF in 2 pts (3.1%) among mutation evaluated pts. Among them, 35 pts (40.2%) received cetuximab+FOLFIRI and the others (N = 52, 59.8%), bevacizumab+FOLFIRI. Median follow-up time was 20.0 months (range, 1.9-49.1). Response rate was 65.7% in the cetuximab group (CET) and 42.3% in the bevacizumab group (BEV) ( p= 0.032). Median progression-free survival was 19.1 months (95% confidence interval [CI], 11.2-27.1) in CET and 14.1 months (95% CI, 11.5-16.8) in BEV ( p= 0.249). CS was performed in 24 pts (27.6%) after median 8.7 months (range, 2.5-27.3) after initiation of chemotherapy. In CET, 11 pts (31.4%) including 8 pts with partial response (PR) and 3 pts with stable disease (SD) underwent CS and all (100%) attained R0. In BEV, 13 pts (25%) including 6 pts with PR and 7 pts with SD received CS and 11 of them (84.6%) achieved R0. Among pts with R0 resection, median disease-free survival (DFS) was 8.8 months (95% CI, 4.9-12.7) in CET and 3.2 months (95% CI, 0.0-7.4) in BEV ( p= 0.326). Conclusions: A substantial proportion of pts could receive CS after cetuximab or bevacizumab+FOLFIRI chemotherapy. CET tended to show higher rate of CS. However, the median DFS after R0 resection was not significantly different between the two groups.

Impact of Metastasectomy in the Multimodality Approach for BRAF V600E Metastatic Colorectal Cancer: The Mayo Clinic Experience.

BRAF V600E mutations are present in 8%-10% of patients with metastatic colorectal cancer (mCRC) and portend poor prognosis. This study investigated the impact of metastasectomy for patients with BRAF V600E mCRC. Using prospective clinical and molecular data, patients with BRAF V600E mCRC were analyzed for clinical characteristics and survival. Statistical analyses utilized the Kaplan-Meier method, log-rank test, and Cox proportional hazard models. Fifty-two patients were identified between July 1, 2008, and January 4, 2016. Patient characteristics included median age 65 years, 61% female, Eastern Cooperative Oncology Group performance status ≤1, 71% with right-sided tumors, and 28% with liver-limited metastasis. In the first-line setting, 7% (4/52) received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (BEV) and 81% were treated with doublet chemotherapy consisting of fluoropyrimidine, oxaliplatin, and BEV. Median overall survival (OS) for all 52 patients was 25 months with median progression-free survival (PFS) of 9.3 months. With median follow-up of 18.3 months, 21 patients underwent metastasectomy with longer OS (29.1 months vs. 22.7 months, hazard ratio [HR] = 0.33; confidence interval [CI], 0.12-0.78; p = .01) and PFS (13.6 months vs. 6.2 months, HR = 0.53, CI, 0.28-0.97; p = .03) compared with the non-metastasectomy cohort. In multivariate analysis, metastasectomy remained significant for improved survival outcomes (HR = 0.52; 95% CI, 0.07-1.02; p = .02). Median disease-free survival after metastasectomy was 9.7 months (95% CI, 5.5-19.5). Two patients remain disease-free at the time of last follow-up, with one patient without relapse for greater than 2 years (28.9 months). Multimodality therapy incorporating metastasectomy for BRAF V600E mCRC should be considered and might be associated with improved overall survival in select patients. BRAF V600E metastatic colorectal cancer (mCRC) represents an extremely difficult molecular subset of colorectal cancer to treat. To date, this subset remains refractory to standard chemotherapies, prompting extensive clinical investigation regarding novel treatment approaches and targeted modalities. While the use of metastasectomy for expanded RAS wild-type and RAS mutated mCRC has resulted in improved overall survival for select patients, utilization of metastasectomy in patients with BRAF V600E mCRC remains controversial. This article explores the authors' experience with BRAF V600E mCRC to ascertain whether a multidisciplinary approach incorporating metastasectomy for well-selected patients improves overall survival.

Impact of metastasectomy in the multimodality approach for BRAFV600E metastatic colorectal cancer (mCRC): The Mayo Clinic experience.

e15045 Background: BRAF V600E mutations are present in 7% of mCRC patients (pts) and portend a poor prognosis. Data guiding initial treatment decisions are limited. This study investigates the management approach and clinical impact of utilizing metastasectomy for pts with BRAF V600E mCRC. Methods: By using prospective clinical and molecular data from Mayo Clinic, pts with BRAF V600E mCRC were analyzed for clinical characteristics, treatment and survival outcomes. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: 164 pts with BRAF V600E mCRC were identified between 6/1999-8/2015. Complete follow up data were available for 52 pts. Median age of 65 years, 61% female, ECOG PS ≤ 1, 71% of pts had right sided tumors and 28% presented with liver limited metastasis. Only 7% (4/52) received FOLFOXIRI/BEV (average of 8 cycles). Peripheral neuropathy, pending BRAF status , and prior progression on FOLFOX, were the most common reasons documented for avoiding FOLFOXIRI/BEV. FOLFOX/BEV was the most common 1st line regimen used (32% of pts). Median overall survival (mOS) for all 52 pts was 25 months (mo) with median progression free survival (PFS) of 9.3 mo, reflecting worse survival when compared to BRAF wild-type control patients treated at Mayo Clinic (249 pts, mOS: 43 mo). With median follow up of 18.3 mo, 21 pts who underwent metastasectomy had improved OS (29.1mo vs. 22.7mo, HR = 0.33; CI: 0.12-0.78; p = 0.01) and PFS (13.6mo vs. 6.2mo, HR = 0.53, CI: 0.28-0.97; p = 0.03) when compared to the non-metastasectomy cohort, respectively. In multivariate analysis, metastasectomy remained statistically significant for improved survival outcomes (HR 0.52; 95% CI 0.07-1.02; p = 0.02). Median relapse-free survival after metastasectomy was 9.7 mo (95% CI, 5.5 mo-19.5 mo). Only 2 pts remain disease free at the time of last follow up, with 1 pt without recurrent disease for greater than 2 years (28.9 mo). Conclusions: The use of multimodality therapy incorporating metastasectomy for BRAF V600E mCRC is a critical component for enhanced survival outcomes.

REOX: Evaluation of the Efficacy of Retreatment With an Oxaliplatin-containing Regimen in Metastatic Colorectal Cancer: A Retrospective Single-center Study

BackgroundTreatment of metastatic colorectal adenocarcinoma (mCRC) has evolved, and survival is over 30 months in contemporary trials. Nevertheless, there is a paucity of effective regimes after the first or second-line treatment. Thus, reexposure to previously used drugs has become a treatment strategy for some patients. We aimed to evaluate the efficacy of retreatment with an oxaliplatin-containing regimen in mCRC and correlate this with clinicopathologic features. Patients and MethodsWe retrospectively analyzed 83 patients with mCRC who underwent reexposure to oxaliplatin (REOX). REOX was defined as a second trial of an oxaliplatin-containing regimen after a previous failure. Primary endpoint was time to treatment failure (TTF). ResultsThe median age was 53.5 years, and the female/male ratio was 51.8%/48.2%. The site of the primary tumor was colon (67.5%) and rectal (32.5%). KRAS was mutated in 39.8%. Liver-limited metastasis was found in 19.3% of patients. The main regimen was 5-fluorouracil, levoleucovorin, and oxaliplatin (mFOLFOX6) (84.3%). Bevacizumab and cetuximab were used in 42.2% and 6% of patients, respectively. REOX was used in the third and fourth lines in 48.2% and 25.3% of patients, respectively. The median TTF after REOX was 6.04 months. Overall survival (OS) was 10.04 months. Disease control (complete response + partial response + stable disease) was observed in 56.6%, whereas 42.2% had progressive disease. Partial response + complete response to previous oxaliplatin was predictive of prolonged OS. Patients who attained disease control had better median OS compared with those with progressive disease (14.5 vs. 6.24 months; P < .0001). ConclusionIn the setting of heavily pretreated patients with mCRC, REOX was an effective treatment, with mTTF of 6.04 months in our cohort. Selection of patients with the longest time since previous oxaliplatin can translate in better outcome. Further studies should be conducted to confirm our data.

Surgical treatment of liver metastasis of gastric cancer: a retrospective multicenter cohort study (KSCC1302).

The necessity of surgical treatment of liver metastases of gastric cancer is still controversial. We conducted a multicenter retrospective cohort study of liver-limited metastasis of gastric cancer treated surgically between 2000 and 2010. In this study, 103 patients were registered, with nine patients excluded from the analysis as they did not meet the eligibility criteria. Of the 94 patients, 69 underwent surgical resection, 11 underwent surgical resection combined with radiofrequency ablation or microwave coagulation therapy for small or deep tumors, and 14 underwent radiofrequency ablation or microwave coagulation therapy only. Synchronous and metachronous metastases were found in 37 and 57 patients, respectively. The 3- and 5-year overall survival rates of all the patients were 51.4 and 42.3%, respectively. The 3- and 5-year relapse-free survival rates were 29.2 and 27.7%, respectively. No significant difference in prognosis was observed between the patients who underwent surgical resection and those who underwent ablation therapy. The patients with hepatic solitary lesions and low-grade lymph node metastases of primary gastric cancer had significantly better overall survival and relapse-free survival. To our knowledge, this study is the largest series and first multicenter cohort study of liver-limited metastasis of gastric cancer. The study indicated that patients with a single liver metastasis with a grade lower than N2 lymph node metastasis of the primary lesion are the best candidates for liver resection.

Impact of somatic mutations on patterns of metastasis in colorectal cancer.

Somatic mutation status in metastatic colorectal cancer (mCRC) is becoming increasingly clinically relevant as it may be correlated not only with response to biologic therapies, but also with site-specific pattern of metastatic spread and outcome. In this review, we describe our current understanding of associations between mutational activation of the KRAS, BRAF, PIK3CA, and NRAS oncogenes and clinical outcomes and metastatic patterns of mCRC. The presence of a KRAS mutation is associated with a distinct pattern of metastatic spread with decreased liver metastases and increased lung, brain, and bone metastases. In patients who undergo resection of colorectal liver metastases (CLM) with curative intent, KRAS mutation is associated increased risk of recurrence, worse survival, and increased recurrence outside of the liver, particularly in the lung, but also in the brain and bone. BRAF mutation, a poor prognostic factor in mCRC, is associated with decreased liver-limited metastasis and increased peritoneal and distant lymph node metastases. PIK3CA mutation does not clearly affect outcomes in the metastatic setting, but is associated with concurrent KRAS mutations, and has been associated with an increased incidence of lung and brain metastases, metastatic sites preferentially involved in KRAS mutant mCRC. NRAS mutation may confer worse survival and early studies suggest NRAS mutation may promote tumorigenesis in the setting of colorectal inflammation. As metastasectomy with curative intent is increasingly considered in patients with mCRC, understanding patterns of metastasis associated with tumor mutations may help focus medical treatment, surgical management, and surveillance in patients with mCRC.

Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizamab for patients with unresectable colorectal liver-limited metastasis.

174 Background: Reports have demonstrated the activity of combining both Irinotecan and Oxaliplatin into a FOLFOXIRI therapy. An option to gain similar benefits and less toxicity to FOLFOXIRI would be to administer the irinotecan through an hepatic arterial apporach. The aim of this study was to assess the maximal response and adverse event rates of Irinotecan Drug Eluting Beads (DEBIRI) with FOLFOX and Bevacizumab (Bev) as a first line treatment for unresectable colorectal liver metastasis (CLMs). Methods: Metachronous and Synchronous CLMs were randomly assigned to mFOLFOX6/Bev or mFOLFOX6, Bev and DEBIRI (FOLFOXDEBIRI). Primary end point was optimal response rates and adverse events. Secondary endpoints were patients (pts) converted to resection and survival. Results: The intention-to-treat population comprised 70 pts, 40 pts randomly assigned to the FOLFOXDEBIRI arm and 30 pts to FOLFOX/Bev arm. Both were similar with synchronous disease (50% vs. 36%), extent liver involvement (35% vs. 31%), but greater percentage in the FOLFOXDEBIRI arm of ECOG 1/2 (57% vs. 31%), p=0.04) and extra-hepatic disease (51% vs. 36%, p=0.02). Median number of chemotherapy cycles was similar in both arms of 8, with a similar Grade 3/4 adverse event rate of 54% FOLFOXDEBIRI and 46% FOLFOX/Bev arm. The overall response rate was significantly greater in the FOLFOXDEBIRI arm vs. FOLFOX/BEV at 2 mons (78% vs. 54%), 4 mons (95% vs. 70%) and 6 mons (76% vs. 60%, p=0.03). Significantly greater downsizing to resection in the FOLFOXDEBIRI arm vs. FOLFOX/Bev (35% vs. 16%, p=0.05), with an improved median progression free survival (15.3 mons vs. 7.6 mons). Overall improvement in hepatic specific progression free survival was seen in the treatment arm (12.8 mons vs. 10.5 mons). Conclusions: Simultaneous mFOLFOX6 with bevacizumab and hepatic arterial irinotecan drug eluting beads is safe, without causing chemotherapy delivery delays and without increasing chemotherapy toxicity. Simultaneous FOLFOXDEBIRI leads to improved overall response rates, improved hepatic progression free survival, and more durable overall progression free survival in patients downsized to resection. Clinical trial information: NCT00932438.

Oxaliplatin given by hepatic arterial infusion (HAI) or systemic (SYS) with capecitabine in patients (pts) with unresectable liverlimited metastasis (Ur-LLM) from colorectal cancer (CRC).

e14593 Background: Whether therapy of Ur-LLM from CRC by HAI is superior to SYS is unknown. Methods: First line phase II study of pts. with Ur-LLM from CRC. Included were 88 pts. HAI oxaliplatin (100 mg/m2) was given to 66 pts. every 2nd week (wk) for a median of 11 series (1-12) and capecitabine 3500 mg/m2 day 1-7 every 2nd wk for a median of 12 (2-14) series. Vessel variation made HAI unsuitable for 22 pts. They had systemic oxaliplatin (130 mg/m2) for a median of 8 (1-10) series with capecitabine 2000 mg/m2 day 1-14 every 3rd wk for a median of 8 series (1-45) with bevacizumab 7½ mg/kg day 1 in 14 pts. Primary endpoints were response, secondary median overall and therapy free survival (mOS) and toxicity. KRAS mutation status was determined in all pts. with the DxS kit. Survival was evaluated by the Kaplan Meier method and differences with the log rank test. 95% confidence interval are given in brackets. Results: Pts. treated with HAI and SYS were comparable. HAI yielded higher response rates than SYS (table 1). Pts. with KRAS-WT tumors treated with HAI had a mOS of 61 (43-80) mths, with KRAS-MT tumors 28 (21-35) mths (p&lt; 0.0001). SYS in KRAS-WT and MT types yielded equal mOS 36 (27-45) mths and 27 (12-44) mths. Pts. with KRAS-WT tumors treated with HAI lived longer than when treated with SYS (p=0.05). Pts. with HAI with KRAS-WT tumors lived without any kind of therapy for a median of 27 (16-37) mths with 42% living more than 40 mths. with KRAS-MT tumors 8 (3-13) mths (p&lt;0.0001) with 12% living more than 40 mths. Therapy free mOS with SYS in patients with KRAS-WT and KRAS-MT tumors was19 (0-39) mths.for pts. and 12 (4-20) mths respectively with 17% and 22% living more than 2 years.The findings were independent of cetuximab-based therapy in later lines. The toxicity was comparable. Conclusions: Effect of HAI oxaliplatin combined with capecitabine on response and survival is restricted to pts. with KRAS-WT tumors. [Table: see text]