Carcinoembryonic Antigen Reduction Research Articles

Abstract CT194: N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study

Abstract Introduction. Zelenirstat (PCLX-001) is a small molecule inhibitor of N-myristoylation, a process that involves addition of the fatty acid myristate to over 200 proteins by two N-myristoyltransferases (NMT1 and 2). These include Src family kinases and c-Abl. Inhibition of N-myristoylation by zelenirstat leads to the degradation of non-myristoylated proteins and cancer cell death. We conducted a phase I trial to evaluate the safety, tolerability, and maximally tolerated dose (MTD) of zelenirstat in patients with refractory cancer. Methods. Differential mass spectrometry was performed in NMT1 and NMT2 CRISPR/Cas9 KOs or zelenirstat-treated HAP1 cells to identify N-myristoylation-regulated proteins. Fully consented patients with advanced solid malignancies or refractory B-cell lymphomas were administered escalating doses of zelenirstat in 28-day cycles until progression or dose-limiting toxicity (DLT). Results. Proteomic analysis of cells with genetic or pharmacological NMT inhibition was performed to gain insights into NMT substrates and function. In addition to the rapid degradation of SFKs, which disrupts the pro-survival signaling of RTKs, we identified multiple respiratory complex I proteins as the most degraded, including NDUFAF4. NMT1 KO and zelenirstat treatment disrupted complex I leading to oxidative phosphorylation (OXPHOS) inhibition, which is essential for both cancer stem cell survival and metastasis. Continuous once-daily zelenirstat at 20 mg to 210 mg was well tolerated, with no dose-limiting toxicities in 24 patients up to and including 210 mg. Gastrointestinal DLTs were observed in the 280 mg cohort, establishing 210 mg as the MTD. Oral absorption was rapid, and pharmacokinetics were suitable for once daily dosing. Seven patients had stable disease as best response, including pancreatic, ovarian and colon cancer patients; one colon cancer patient with 5 prior lines of therapy continues 210 mg beyond 11 cycles with reduction in carcinoembryonic antigen (CEA) and tumor dimensions. Kaplan-Meier analysis revealed longer progression-free survival (log-rank p=0.033) and overall survival (p=0.026) in the patients treated at 210 mg (n=7) when compared with patients treated in lower dose cohorts (n=17). Conclusion. Zelenirstat has a unique dual impact on growth signaling and OXPHOS. Having previously demonstrated pre-clinical efficacy in hematologic cancers in vitro and in vivo, we now demonstrate the therapeutic potential of zelenirstat in patients with refractory advanced solid malignancies, warranting further clinical evaluation in these indications. Citation Format: Luc Gerard Berthiaume, Erwan Beauchamp, Jay Gamma, Rony Pain, Morris A. Kostiuk, Christopher R. Cromwell, Eman W. Moussa, Olivier Julien, Basil P. Hubbard, John Kuruvilla, Laurie H. Sehn, Jennifer Spratlin, Rahima Jamal, Randeep Sangha, John R. Mackey. N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT194.

Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer.

O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer. Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1-7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers. MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells. Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations. TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.

Usefulness of Carcinoembryonic Antigen (CEA) in Evaluating Response to Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Abstract Background Lung cancer represents the top cause of death and the most common cancer worldwide. In the United States, lung cancer is the second most common cancer accounts for 12.9% of new cancer diagnoses and 27.4 of all cancer deaths. Non small cell lung cancer (NSCLC) represents up to 80% of all lung cancers which divided into two major types: squamous cell carcinoma (SCC) and nonsquamous cell carcinoma (NSCC, including adenocarcinoma, large-cell carcinoma, and other subtypes). Aim of the Work To assess the correlation between CEA (carcinoembryonic antigen) levels and response to platinum-based chemotherapy assessed by RECIST criteria of advanced non-small cell lung cancer patients. Patients and Methods This is a prospective study conducted between November 2018 and July 2019, 30 consecutive patients with advanced NSCLC previously treated with at least one line of chemotherapy were prospectively enrolled in thoracic malignancies department in Ain-Shams university hospital and Ismailia Teaching Oncology Hospital. The study was approved by the ethics committee at the faculty of medicine, Ain Shams University. Results In our study we evaluated response by CTs according to RECIST criteria and considered patients with clinical response (PR and SD) as responders and patients with PD as non-responders. Conclusion Our study found correlation between CEA and radiological response and patients with CEA reduction equal or more than 18.5% have objective response to treatment with Sensitivity and specificity 66.67% and 85.71% respectively.

Carcinoembryonic antigen reduction after medical treatment in patients with metastatic colorectal cancer: a systematic review and meta-analysis.

The introduction of new drugs and multimodal treatments for the management of patients with metastatic colorectal cancer (mCRC) has reduced the importance of time-to-event endpoints and reported the attention on the response-related endpoints. Furthermore, the prognostic role of the surgical scores before the resection of metastases has not been confirmed for multimodal treatments. The purpose of this research is to perform a meta-analysis of the studies that evaluated the relationship between carcinoembryonic antigen (CEA) response and outcome in patients with mCRC receiving systemic chemotherapy. A systematic review of the literature on two databases and a selection of studies that evaluated the relationship between CEA response and outcome were performed according to predefined criteria. After, three meta-analyses were carried out on the selected studies, each for each outcome variable. Nineteen studies have been selected. Fourteen studies (1475 patients) have documented a close association between radiological response and CEA response (odds ratio (OR), 9.03; confidence intervals (CIs), 5.14-15.87; I2 statistic (I2), 72%). Four studies have reported a longer progression-free survival for patients with a CEA response (hazard ratio (HR), 0.73; CIs, 0.64-0.83; I2, 23%). Finally, 10 studies (13 study cohorts) have shown a strong relationship between CEA response and overall survival (OS) (HR, 0.62; CIs, 0.55-0.70; I2, 35%). CEA response merits further investigation as a surrogate endpoint of clinical trials of first-line medical therapy of patients with mCRC, and should be studied as a prognostic factor for those patients who are candidates for multimodal treatment strategies.

Early Serum Carcinoembryonic Antigen Reduction Predicts Tumor Shrinkage and Overall Survival in Colorectal Cancer Patients with Distant Metastasis, after Primary Surgery Followed by Mfolfox6 Plus Bevacizumab Treatment

Advances in chemotherapy and molecular targeting therapy have significantly improved the overall survival of colorectal cancer patients with distant metastasis. Our therapeutic strategy for colorectal cancer patients with distant metastasis is to perform surgery for the primary lesion for preventing bowel obstruction and tumor hemorrhage, followed by intensive chemotherapy. From 2008 to June, 31 colorectal cancer cases were retrospectively analyzed. Initially, the primary lesion was surgically resected. Subsequently, the mFOLFOX6 plus bevacizumab regimen was initiated. The response rate was 48%, and the disease control rate was 79%. After a median follow-up of 15.4-month, the median overall survival (OS) was 23.9 months. Therapy was not stopped in any patients because of hemorrhage or bowel obstruction. The reduction rate of the serum carcinoembryonic antigen (CEA) level correlated with the objective response. Patients who had at least a reduction in the serum CEA level seemed to have a longer OS than those who had no reduction (median OS: 23.9 vs 15.3 months, p = 0.015). The results showed that our strategy of combining primary surgery with chemotherapy is safe and effective. Furthermore, serum CEA level reduction seems to be a good prognostic predictor for colorectal cancer patients for whom this strategy is used.

CEA serum level as early predictive marker of outcome during EGFR-TKI therapy in advanced NSCLC patients.

Considering the role of carcinoembryonic antigen (CEA) serum levels as potential useful predictive marker during chemotherapy treatment, we studied its applicability in advanced non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). Our retrospective cohort consists of 79 patients (33 EGFR mutated and 46 EGFR wild type or unknown) affected by advanced NSCLC, for whom CEA serum values at the beginning of TKI therapy and after the first month of treatment were available, regardless of treatment line. Baseline CEA value, percentage of CEA reduction after 1 month, and percentage of patients with ≥20 % CEA decrease after 1 month (CEA response) were correlated with disease control rate (DCR), progression-free (PFS), and overall (OS) survival, according to EGFR mutational status. Median baseline CEA levels were significantly higher in EGFR mutated (40.9 ng/ml; interquartile range (IQR) 8.9-197.6) than in wild-type cases (6.2 ng/ml; IQR 2.8-12.8; p = 0.003). Both percentage reduction in CEA levels (-10.7 vs. +13.4 %) and percentage of cases with CEA response (42 vs. 20 %) were significantly higher in mutated vs. wild-type/unknown patients (p = 0.007 and p = 0.027, respectively). In wild-type/unknown patients, CEA response was significantly correlated with DCR (p = 0.001) and resulted as a significant predictor of PFS both in univariate (p = 0.002) and in multivariate analyses (hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.11-0.66; p = 0.004); only a trend was found for OS prediction (p = 0.082). In EGFR-mutated group, CEA reduction did not show any correlation either with PFS or OS. CEA response after 1 month of EGFR-TKI therapy could be a useful marker, worthy to further studies, as early predictor of treatment outcome in EGFR wild-type/unknown unselected NSCLC cases for which no molecular predictor is yet available.

The role of serum carcinoembryonic antigen in predicting responses to chemotherapy and survival in patients with non-small cell lung cancer.

Previous studies indicated that carcinoembryonic antigen (CEA) could predict the therapeutic objective response (OR) and overall survival (OS) of patients with cancers, including non-small cell lung cancer (NSCLC). However, the role it could play in evaluating therapeutic responses and OS in patients with NSCLC requires further elucidation. Herein, we investigated the potential role of CEA in predicting OR and OS in patients with NSCLC. For this retrospective study, the medical records of 689 patients with NSCLC who were treated at Nanjing Jinling Hospital between January 2000 and August 2011 were reviewed. Serum levels of CEA of these patients were measured before and after chemotherapy. The relatedness between CEA levels and OR, and between CEA and OS were investigated for correlations via a series of statistical analyses. The baseline serum CEA level of 689 patients was 54.18 ± 143.45 ng/mL. Serum CEA significantly decreased after two cycles of chemotherapy (t = 2.196, P = 0.031). The receiver operator characteristic (ROC) curve analysis showed that a 5.28% reduction in CEA level was an appropriate cut-off value for predicting the OR to chemotherapy, with a sensitivity of 61.3% and a specificity of 62.4%. The Kaplan-Meier survival analysis indicated no significant correlation between baseline CEA and OS (P = 0.079). Our study shows that while the baseline level of CEA was not a prognostic factor, the post-treatment reduction of CEA can predict the OR in patients with NSCLC.

Usefulness of Serum Carcinoembryonic Antigen (CEA) in evaluating response to chemotherapy in patients with advanced non small-cell lung cancer: a prospective cohort study

BackgroundHigh serum carcinoembryonic antigen (CEA) levels are an independent prognostic factor for recurrence and survival in patients with non-small cell lung cancer (NSCLC). Its role as a predictive marker of treatment response has not been widely characterized.Methods180 patients with advanced NSCLC (stage IIIB or Stage IV), who had an elevated CEA serum level (>10 ng/ml) at baseline and who had no more than one previous chemotherapy regimen, were included. CEA levels were measured after two treatment cycles of platinum based chemotherapy (93%) or a tyrosine kinase inhibitor (7%). We assessed the change in serum CEA levels and the association with response measured by RECIST criteria.ResultsAfter two chemotherapy cycles, the patients who achieved an objective response (OR, 28.3%) had a reduction of CEA levels of 55.6% (95% CI 64.3-46.8) compared to its basal level, with an area under the ROC curve (AURC) of 0.945 (95% CI 0.91-0.99), and a sensitivity and specificity of 90.2 and 89.9%, respectively, for a CEA reduction of ≥14%. Patients that achieved a decrease in CEA levels ≥14% presented an overall response in 78% of cases, stable disease in 20.3% and progression in 1.7%, while patients that did not attain a reduction ≥14% had an overall response of 4.1%, stable disease of 63.6% and progression of 32.2% (p < 0.001). Patients with stable (49.4%) and progressive disease (22.2%) had an increase of CEA levels of 9.4% (95% CI 1.5-17.3) and 87.5% (95% CI 60.9-114) from baseline, respectively (p < 0.001). The AURC for progressive disease was 0.911 (95% CI 0.86-0.961), with sensitivity and specificity of 85 and 15%, respectively, for a CEA increase of ≥18%. PFS was longer in patients with a ≥14% reduction in CEA (8.7 vs. 5.1 months, p < 0.001). Reduction of CEA was not predictive of OS.ConclusionsA CEA level reduction is a sensitive and specific marker of OR, as well as a sensitive indicator for progression to chemotherapy in patients with advanced NSCLC who had an elevated CEA at baseline and had received no more than one chemotherapy regimen. A 14% decrease in CEA levels is associated with a longer PFS.

The predictive role of consecutive measurements of serum CEA for treatment efficacy in advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations treated with gefitinib or erlotinib.

e19029 Background: Patients with non-small cell lung cancers (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations dramatically respond to EGFR tyrosine kinase inhibitors (TKIs) with approximately 70% response rate. Carcinoembryonic antigen (CEA) has been suggested to be associated with tumor recurrence, treatment efficacy and prognosis in some specific tumors. However, the role of CEA in NSCLC with EGFR mutations remains unclear. Therefore, we sought to elucidate whether the determination of serum CEA levels can predict the efficacy of EGFR TKIs in NSCLC harboring EGFR mutations. Methods: Medical records of 326 consecutive patients with advanced NSCLC between January 2007 and November 2012 were reviewed and a total of 104 patients with NSCLC harboring EGFR mutations treated with gefitinib or erlotinib ³2 weeks and with available data of serum CEA were identified for analysis. Results: Female, never smokers, adenocarcinoma histology and cases with pretreatment serum CEA ³ 5 ng/ml presented 63%, 76%, 96% and 68% of 104 eligible cases with mean age of 65.4 ± 13.7 years, respectively. The response rate of EGFR TKIs in patients with pretreatment CEA ³ 5 ng/ml was not significantly different (70% vs 91%, P = 0.339), and it was higher in those with reduction of CEA level after treatment than those without (94% vs 35%, RR=2.7, P &lt;0.001). The average change of pre- and post-treatment CEA in respondents and non-respondents was negative 112 ± 181 ng/ml and positive 368 ± 514 ng/ml, P &lt;0.001, respectively. In details, the pre- and post- treatment CEA levels in respondents were 246 and 71 ng/ml, P &lt; 0.001, respectively, and those in non-respondents were 157 and 268 ng/ml, P= 0.019, respectively. Furthermore, the post-treatment CEA level increased by 14% in non-respondents and decreased by 52% in respondents. Conclusions: Reduction or elevation of post-treatment serum CEA can predict the treatment efficacy in NSCLC patients with EGFR mutations treated with gefitinib or erlotinib. Further studies aiming to investigate the value of serum CEA levels in tumor progression and survival are warranted.

Dramatic Reduction of CEA Post Spray Cryotherapy in a Patient with Pleural Based Malignancy

Malignancy of the parietal pleural is a therapeutic challenge; current therapies largely target patient's regional symptoms related to effusions/tumor burden and restrictive physiology. Seldom are tumor ablation procedures considered. If alternatives to the current standard approaches could promote tumor ablation, address symptoms and be cost effective, studies to assess clinical impact of these alternatives may be warranted. We present a novel cryo- based technology for treating pleural malignant disease with a dramatic reduction in a tumor biomarker. We present a case of a 67-year-old man with mucinous adenocarcinoma of the pleura with elevated Carcinoembryonic Antigen (CEA) level who had an inadequate response to standard treatment. He underwent cryospray ablation of the parietal pleura with tumor destruction being documented both visually and with a significant decrease in his CEA level. This case demonstrates tumor necrosis, a rapid drop in serum CEA, as well as ease of treatment and continued evidence of safety and the feasibility of cryospray ablation in the pleural space. This case demonstrated that spray cryotherapy promoted tumor ablation and addressed symptoms within the pleura thereby indicating the need for further study. The degree of tumor necrosis in multiple clinical presentations (bulky, flat, studding, etc) awaits definition, as does the rate and timing of post-treatment pleurodesis and the possibility of an immunoregulatory or mortality effect.

Role of carcinoembryonic antigen as a marker for colorectal liver metastases

Carcinoembryonic antigen (CEA), a marker for colorectal adenocarcinoma, can monitor disease progression and treatment response. This study aims to determine the accuracy of CEA in the detection and resectability of colorectal liver metastases. Patients with primary colorectal cancer were divided into three groups: resectable hepatic metastases (group 1), unresectable metastases (group 2), and disease-free cases (group 3). The CEA concentration was recorded pre-and post-hepatectomy in group 1 and on radiological confirmation of disease state in the other groups. It was expressed as median (95% confidence interval [CI]), with predictors of concentration determined. Group 1 (n=141) had pre-operative CEA of 8.9 (4.6–13.1), with 38.1% of patients being normal. Maximum tumour diameter correlated with CEA level (r=0.41, P<0.0001). Post-hepatectomy CEA was 2.3 (1.9–2.7; P<0.0001), with 81.1% of patients being normal. Group 2 (n=158) had CEA of 20.6 (9.4–31.9). Group 3 (n=361) had CEA of 2.0 (1.8–2.2). Sensitivity of CEA pre-and post-hepatectomy was 61.2% and 69.3%, respectively, while specificity was 79.8% for both groups. Concentration was elevated in hepatic colorectal metastases but is not a marker of resectability. A CEA reduction post-resection indicates that it may be used as an indicator of treatment response, while CEA is increased by tumour burden and lesion size.

Safety and Efficacy of Panitumumab Therapy After Progression With Cetuximab: Experience at Two Institutions

Cetuximab therapy has been effectively combined with cytotoxic chemotherapy in the first-, second-, and third-line treatment settings. In general, treatment with cetuximab is well tolerated, though it has been associated with the development of hypersensitivity reactions (HSRs). In the case of severe HSRs, further therapy with cetuximab is not possible. In contrast with cetuximab, HSRs have been rarely observed with panitumumab therapy. Currently, panitumumab is indicated for patients with metastatic colorectal cancer (mCRC) with progressive refractory disease, and there is recent evidence documenting its clinical efficacy with cytotoxic chemotherapy in the first-line and second-line settings. However, the safety and efficacy of panitumumab after progression with cetuximab has not been well documented. We present a retrospective review of our experience in treating 15 patients with mCRC who tolerated panitumumab with clinical benefit after failure on cetuximab therapy from November 2006 through September 2008 at the Yale Cancer Center in New Haven, CT and at the Saint Francis Cancer Treatment Center in Grand Island, NE. KRAS status was retrospectively assessed in patients with readily available tumor tissue. All 15 patients were treated with a standard dose of panitumumab 6 mg/kg intravenously every 2 weeks. No patient received premedication therapy. Of the 15 patients treated, 4 received only 2 doses of panitumumab but stopped further therapy because of deterioration in performance status. Of the 11 evaluable patients, we noted minor radiographic responses (Response Evaluation Criteria in Solid Tumors) in 3 patients and stable disease (SD) in 3 other patients after 8 weeks of therapy. Five patients had evidence for progressive disease, and further therapy was stopped. The median duration of SD was 4 months (range, 2-8 months). Among the 11 evaluable patients, 1 patient achieved > 50% reduction in carcinoembryonic antigen (CEA; 112 to 49 U/L), 3 patients had a 25% reduction (59 to 43 U/L, 84 to 61 U/L, and 67 to 42 U/L), and 1 patient had minor reduction in CEA (98 to 83 U/L). All patients tolerated panitumumab well with no occurrence of hypersensitivity reactions. Grade 3/4 toxicities were skin rash in 5 patients and asthenia in 1 patient. The other adverse events observed included grade 1-2 skin rash in 2 patients, grade 2 paronychia in 4 patients, grade 2 hypomagnesemia in 2 patients, and fatigue in 3 patients. One patient had wild-type KRAS, and this individual experienced a minor response to antibody therapy with > 50% reduction in CEA. A second patient was found to have mutant KRAS and, in terms of clinical response, this patient experienced SD for 6 months. The third patient evaluated had mutant KRAS, and this individual was unable to tolerate more than 2 doses and was therefore not evaluable for response. Panitumumab may represent an alternative treatment strategy for patients with refractory mCRC who have experienced failure with standard therapy including cetuximab-based regimens. Our relatively small clinical experience suggests that cetuximab and panitumumab may exert their antitumor activity through different mechanisms; however, further work is required to investigate this potentially interesting issue.

The metabolic response using 18F-fluorodeoxyglucose-positron emission tomography/computed tomography and the change in the carcinoembryonic antigen level for predicting response to pre-operative chemoradiotherapy in patients with rectal cancer

Background and purpose To predict tumor regression in pre-operative chemoradiotherapy (CRT) using 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) and serum carcinoembryonic antigen (CEA) in patients with rectal cancer. Materials and methods The metabolic response of the tumor was assessed by determining the maximal standardized uptake value (SUV max), absolute difference (ΔSUV max), and SUV reduction ratio (SRR) on pre- and post-CRT PET/CT scans. The serum CEA, absolute difference (ΔCEA), and the CEA reduction ratio (CRR) were also determined. A receiver-operating characteristic (ROC) curve was generated. Results Of all seventy two patients, mean pre- and post-CRT SUV max was 14.9 and 5.8, respectively. The mean pre- and post-CRT CEA level was 15.5 ng/ml and 5.4 ng/ml, respectively. Forty-three patients (59.8%) were classified as responders (Dworak’s tumor regression grade 3–4) and 36 patients (50%) achieved tumor down-staging. ROC analysis showed that both post-CRT SUV max and SRR were predictive factors for responders ( p = 0.03 and p = 0.02, respectively). A threshold of post-CRT SUV max was 5.4 and that of SRR was 53.1%. Pre-CRT SUV max, ΔSUV max, and all parameters in regard to CEA were not significant in ROC analysis. Conclusions The post-CRT SUV max and SRR are potential factors for predicting tumor response in pre-operative CRT. The patients with lower post-CRT SUV max and higher SRR could be expected to achieve maximum tumor regression after pre-operative CRT in this study.

Usefulness of monitoring serum carcinoembryonic antigen (CEA) to define response to chemotherapy and its correlation with survival in patients with non-small cell lung cancer with abnormal baseline CEA levels.

e18044 Background: Carcinoembryonic antigen (CEA, CEACAM5) is an oncofetal protein that functions as a cell-adhesion molecule. It is usually over-expressed in a variety of neoplasms; moreover, high serum CEA levels are an independent prognostic factor for recurrence and survival in patients with non small-cell lung cancer (NSCLC). To date, there are no markers that satisfactorily predict objective response to chemotherapy in NSCLC. Methods: The aim of the study was to evaluate the relationship of a change in serum CEA levels at baseline and after two cycles of treatment, to compare them with objective response (measured by RECIST) and to correlate it with progression free-survival (PFS) and overall survival (OS). Results: 182 (67.4%) of 270 patients had a baseline CEA serum level > 5 ng/mL (range 5-7,440). Treatment was platinum-based chemotherapy in 169 (92.9%) patients and a tyrosine kinase inhibitor was used in 13 (7.1%). The mean follow-up time was 12.6 mo. After two cycles of treatment, objective global response was 29.7% and ≤ 25% CEA reduction was found in 32.4%. One hundred percent of patients with complete response had a ≤ 25% CEA reduction value, 60% for partial response, 24.7% for stable disease and 9.3% for progressive disease (Pearson's X2 value 38.49, p < 0.0001). Sensitivity, specificity, positive predictive value and negative predictive value were 80%, 62%, 57% and 83% respectively. PFS was longer in patients with a 25% reduction in CEA (11.3 mo [CI 95% 9.5-13.1] vs 8.7 mo [CI 95% 7.5-9.8], p = 0.04) and OS showed a tendency for longer survival (19.9 mo [CI 95%12.3-27.5] vs 14.7 mo [CI 95% 13.2-16.1] p = 0.09). Conclusions: A 25% reduction from baseline CEA is associated with objective response and PFS. CEA is an accurate and specific predictor of objective response to treatment in locally advanced and advanced NSCLC. No significant financial relationships to disclose.

Declines in serum CYFRA21-1 and carcinoembryonic antigen as predictors of chemotherapy response and survival in patients with advanced non-small cell lung cancer

The aim of this study was to investigate the clinical value of serum cytokeratin 19 fragment (CYFRA21-1) and carcinoembryonic antigen (CEA) in the prediction of chemotherapy response and prognosis in patients with advanced non-small cell lung cancer (NSCLC). Serum CYFRA21-1 and CEA levels of 98 patients with advanced NSCLC were measured using immunoradiometric kits prior to and after 2 cycles of chemotherapy. After 2 cycles of chemotherapy, 45 patients achieved a radiological objective response (OR), 30 patients achieved stable disease (SD) and 23 patients had progressive disease (PD). Serum CYFRA21-1 and CEA were significantly decreased compared to baseline levels (P<0.001). By ROC curve analysis, a ≥60% reduction in CYFRA21-1 and a ≥25% reduction in CEA were the optimal cut-off levels with best sensitivity and specificity for the diagnosis of radiologic OR. The median survival of all patients was 10.2 months (range 2.6-26.3). Univariate survival analysis showed that the Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, radiologic OR, a ≥60% reduction in CYFRA21-1 and a ≥25% reduction in CEA were significant prognostic factors for better overall survival. The median overall survival time in patients with a ≥60% reduction in CYFRA21-1 was significantly longer than in those with a <60% reduction (P<0.001). Similarly, the median overall survival time in patients with a ≥25% reduction in CEA was also significantly longer than in those with a <25% reduction (P<0.001). Multivariate analysis showed that ECOG PS score, a ≥60% reduction in CYFRA21-1 and a ≥25% reduction in CEA were independent prognostic factors of survival, while radiologic OR was not. In conclusion, a ≥60% reduction in CYFRA21-1 and a ≥25% reduction in CEA may be reliable surrogate markers for the prediction of chemothrapy response and prognosis, especially for the diagnosis of radiologic OR.

Successful long-term management of a patient with late-stage metastatic colorectal cancer treated with panitumumab

Recent approval and introduction into clinical practice of epidermal growth factor receptor inhibitors such as the chimeric monoclonal antibody cetuximab and the fully human monoclonal antibody panitumumab have provided new treatment options for chemotherapy-refractory patients. Here, we report a case of a 47-year-old man with metastatic, chemotherapy-refractory colorectal cancer who achieved long-term partial remission during panitumumab therapy. A 41-year-old male patient presented with a 24-hour history of abdominal pain and fever. A computed tomography (CT) scan revealed a voluminous and perforated abscess with a suspected tumour lesion in the sigmoid colon. The patient underwent sigmoidectomy and was diagnosed with a poorly differentiated necrotic carcinoma of the sigmoid colon with invasion in 13 of 19 tested lymph nodes. A colonoscopy revealed multiple tubular adenomas and a positron emission tomography CT scan showed multiple and bilateral hyperfixating lumbar-aortic lymph nodes leading to a final tumour classification of T4N2M1. Carcinoembryonic antigen (CEA) was elevated. The patient achieved a partial response following six cycles of FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), then progressed and was enrolled in a trial where he received treatment with FOLFOX4 (oxaliplatin, leucovorin and 5-fluorouracil) with or without a vascular endothelial growth factor inhibitor (PTK787/ZK 222584 [valatinib]). Eight months later he progressed again and was included in a panitumumab (6mg/kg every 2 weeks) monotherapy trial. A partial response was noted after 8 weeks of therapy along with a rapid CEA reduction and decrease in lymph node size. The patient is continuing panitumumab treatment and is still in partial remission after 65 months' treatment. He has non-mutated KRAS and no human-anti-human antibodies have been detected. During treatment the patient has on occasion experienced grade 1-2 diarrhoea as well as folliculitis and acne-like rash up to grade 3 in severity. Cutaneous toxicity was managed with a combination dose interruption/reduction and the use of topical agents. No eye or nail toxicities occurred. This case shows that long-term responses are possible during panitumumab therapy and that this agent may be an effective long-term treatment option for selected patients with metastatic colorectal cancer. The associated skin toxicities can be successfully managed.

Correlation between Changes in Serum Level of CEA and CYFRA 21-1 and Objective Response of Chemotherapy.

Serum levels of tumor markers are associated with tumor metabolism or apoptosis, changes of which after chemotherapy may reflect tumor response to treatment. The aim of this study was to assess the predictive role of changes in serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) during chemotherapy in patients with advanced non-small cell lung cancer. Changes in serum levels of CEA and CYFRA 21-1 were investigated retrospectively after one cycle of chemotherapy in 42 patients with advanced NSCLC. Correlations between the changes and radiological objective response were analyzed. After two cycles of chemotherapy, radiological objective response rate was 28.6%. At baseline, gender, age, clinical stage, serum levels of CEA and CYFRA 21-1 were not different between patients with objective response (OR) and no response (NR). After one cycle of chemotherapy, compared to baseline level, declines in serum levels of CEA and CYFRA 21-1 were observed in patients with OR, but have no statistical significance. In contrast, reduction of CEA and CYFRA 21-1 over baseline after one cycle of chemotherapy showed statistically significant difference between OR and NR. When reduction percentages of CEA and CYFRA 21-1 were used to predict objective response of chemotherapy, the area under the ROC curve (AUC) was 0.875 for CEA and 0.919 for CYFRA 21-1. According to the ROC curve, a 22% reduction of CEA yielded a sensitivity of 58.3% and a specificity of 97%, 51% reduction of CYFRA 21-1 with a sensitivity of 83.3% and a specificity of 93.3%. When above reduction percentages were used as cutoffs for prediction of radiological objective response, combination of the CEA and CYFRA 21-1 yielded a sensitivity of 91.7% and a specificity of 86.7%. Reduction percentages of CEA and CYFRA 21-1 during chemotherapy could be used to evaluate chemotherapy efficacy in patients with advanced NSCLC. The cutoffs of reduction percentage need further research.

Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: Modern USA experience

Salvage therapy for patients with unresectable colorectal liver metastases that were refractory to oxaliplatin and irinotecan was performed via radioactive microspheres. High doses of radiation were delivered to tumors from permanently implanted 90Y microspheres, delivered through the hepatic arterial vessels. Patients from 7 institutions were selected for treatment after screening-defined vascular access to all the tumors, and imaging-confirmed microspheres would be implanted only in the liver tumors. All patients were followed with laboratory and imaging studies at regular intervals until death. Toxicities, both acute and late, were recorded, and actuarial survival determined. A total of 208 patients were treated from April 2002 to April 2005. Median follow-up of the 129 men and 79 women is 13 months (range, 1-42 months). Median survival is 10.5 months for responders but only 4.5 months in nonresponders. No treatment-related procedure deaths or radiation-related venoocclusive liver failures were found. Computed tomography partial response was 35%; positron emission tomography response of 91% and reduction in carcinoembryonic antigen of 70% were achieved. In this group of heavily pretreated patients, radioactive microspheres produced an encouraging median survival, with acceptable toxicity, and a significant objective response rate, which suggests that further investigation of this approach is warranted.

Systemic Irinotecan or Regional Floxuridine Chemotherapy Prolongs Survival After Hepatic Cryosurgery in Patients with Metastatic Colon Cancer Refractory to 5-Fluorouracil

Most colorectal cancers metastatic to the liver are resistant to chemotherapy and are not amenable to surgical resection. This study evaluated our 6-year experience (July 1992—July 1998) in treating patients with unresectable hepatic colorectal metastases refractory to systemic 5-fluorouracil (5-FU). One hundred fifty-three patients underwent cryosurgical ablation (CSA) of 5-FU—resistant hepatic metastases. The patients then received either hepatic arterial floxuridine (FUDR), systemic CPT-11, or no postoperative adjuvant chemotherapy. Number, size, and location of hepatic metastases, carcinoembryonic antigen (CEA) levels, and type of postoperative treatment were analyzed. One to 15 lesions were frozen (median number, 3; median size, 6 cm), for a total of 73 synchronous and 80 metachronous lesions. Overall median survival was 28.4 months from the date of diagnosis of liver metastases and 16.1 months from the time of CSA. After cryosurgery alone, median survival was 13 months, which was significantly shorter than the post-CSA survival of 23.6 months with adjuvant CPT-11 and 21.2 months with hepatic FUDR ( P = 0.007). Predictors of survival included preoperative CEA, postoperative reduction in CEA, and adjuvant chemotherapy ( P < 0.05). Neither size, number of lesions, nor tumor location impacted survival. At a median follow-up of 13 months, 67% of patients have recurred (35% hepatic, 16% extrahepatic, and 49% both). Twenty percent of the recurrences were in the lobe of the CSA site. The 25 patients who underwent a second CSA had a median survival of 28.4 months from CSA and 40 months from the date of diagnosis of liver metastases. These data indicate that CSA offers an effective alternative for unresectable patients resistant to 5-FU. Systemic CPT-11 or regional FUDR may further prolong survival after CSA.

Release of Carcinoembryonic Antigen from Human Tumor Cells by Phosphatidylinositol-Specific Phospholipase C: Highly Effective Extraction and Upregulation from LS-174T Colonic Adenocarcinoma Cells

Carcinoembryonic antigen (CEA), produced by gastrointestinal tumor cells, is anchored to cell membrane by a glycosyl-phosphatidylinositol moiety which can be cleaved with phosphatidylinositol-specific phospholipase C (PI-PLC). We studied the extraction of CEA from living human colon carcinoma (LS-174T, HT-29, COLO-205, and HRT-18) and pancreatic carcinoma (CAPAN) cells by PI-PLC from Bacillus cereus. The total CEA content of LS-174T cells, quantitated by Triton X-1 14 extraction followed by radioimmunoassay or by immunohistochemistry, was 3.5-fold higher than that of other cells ( P < 0.001). The spontaneous release of CEA from LS-174T cells into culture medium was also higher than that from other cells ( P < 0.00 1), reaching 620 ng/107 cells (≈28% of cellular content) after 24 h. Overall, living LS-174T cells were highly susceptible to CEA extraction by PI-PLC, which was dependent on PI-PLC dose and on treatment time, leading in optimal conditions to the solubilization of 4100 ng/10 7 cells after 24 h (≈75% of total CEA). After 24 h treatment at the highest PI-PLC dose, cell lines remained viable and growing, and membrane CEA expression was not exhausted but only reduced as compared to untreated cells. At the same time, the amount of CEA solubilized by P1-PLC exceeded the CEA reduction in membranes, suggesting that enzyme treatment increased CEA turnover. This was particularly true for LS- 174T cells which maintained 54% of the expression of untreated cells, whereas the amount of CEA extracted by PI-PLC reached 190% of this expression. Growing LS-174T cells thus constitute an effective material for producing high quantities of CEA by PI-PLC cleavage, especially since these cells probably "regenerate" be cause of enhanced turnover during PI-PLC action, thus allowing continuous CEA production. These experimental conditions also provide an interesting model for studying the modulation of CEA expression and release.