Oxaliplatin-based Chemotherapy Might Provide Longer Progression-Free Survival in KRAS Mutant Metastatic Colorectal Cancer

The identification of better regimens in currently available chemotherapeutic agents is crucial for treating patients with KRAS mutant metastatic colorectal cancer (mCRC). Records of mCRC patients who received first-line oxaliplatin- based or irinotecan-based regimens were reviewed retrospectively. Clinicopathologic features and treatment outcome of patients with first-line progression-free survival (PFS) and overall survival (OS) in association with KRAS mutation status were analyzed using the Cox proportional hazard model. Between 2007 and 2010, a total of 118 mCRC patients were enrolled. Among them, 67 were males and 51 were females. In patients who received first-line oxaliplatin-based regimens, the PFS was significantly longer in KRAS mutant patients (N = 32) than that in KRAS wild-type patients (N = 51). The median PFS was 8.5 months in KRAS mutant versus 5.8 months in KRAS wild-type patients (P = .008). In contrast, in patients who received first-line irinotecan-based regimens, the PFS was shorter in KRAS mutant patients (N = 15) than that in KRAS wild-type patients (N = 20). Median PFS was 3.9 months in KRAS mutant versus 6.0 months in KRAS wild-type patients (P = .23). Median OS between KRAS mutant and wild-type patients was not significantly different in both oxaliplatin-based and irinotecan-based regimens. In multivariate analyses, KRAS mutation remains an independent predictive factor for longer PFS in first-line oxaliplatin-based regimens. In conclusion, oxaliplatin-based chemotherapy in KRAS mutant mCRC might result in longer PFS than in KRAS wild-type mCRC.     

No Survival Benefit from Adding Cetuximab or Panitumumab to Oxaliplatin-Based Chemotherapy in the First-Line Treatment of Metastatic Colorectal Cancer in KRAS Wild Type Patients: A Meta-Analysis

Background

The efficacy of combined therapies of oxaliplatin-based chemotherapy and anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (MAbs) remains controversial in colorectal cancer (CRC). The aim of this study is to estimate the efficacy and safety of adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first line treatment in KRAS wild type patients with metastatic colorectal cancer (mCRC) through meta-analysis.

Methods

Medline, EMBASE, and Cochrane library, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) were searched. Eligible studies were randomized controlled trials (RCTs) which evaluated oxaliplatin-based chemotherapy with or without anti-EGFR drugs (cetuximab or panitumumab) in untreated KRAS wild type patients with mCRC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. Hazard ratios (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals.

Results

This meta-analysis included four RCTs with 1270 patients, and all of the patients were administered oxaliplatin-based chemotherapy regimens with or without anti-EGFR MAbs. The result of heterogeneity of OS was not significant. Compared with chemotherapy alone, the addition of cetuximab or panitumumab didn’t result in significant improvement in OS (HR = 1.00, 95%CI [0.88, 1.13], P = 0.95) or PFS (HR = 0.86, 95%CI [0.71, 1.04], P = 0.13). The subgroup analysis of cetuximab also revealed no significant benefit in OS (HR = 1.02, 95%CI [0.89, 1.18], P = 0.75) or in PFS (HR = 0.87, 95%CI [0.65, 1.17], P = 0.36). Patients who received combined therapy didn’t have a higher ORR (Risk Ratio = 1.08, 95%CI [0.86, 1.36]). Toxicities slightly increased in anti-EGFR drugs group.

Conclusions

The addition of cetuximab or panitumumab to oxaliplatin-based chemotherapy in first-line treatment of mCRC in wild type KRAS population did not improve efficacy in survival benefit and response rate. More RCTs are warranted to evaluate the combination of chemotherapy and targeted therapy.     

Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature

ImportanceThe EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC.ObjectiveTo document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. Data sources: MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts.ResultsEGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81–1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69–0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87–1.09) and PFS HR 0.92 (95% CI 0.83–1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I² = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72–0.94) compared to capecitabine (HR 1.09; 95% CI 0.91–1.30) and bolus 5FU (HR 1.07; 95% CI 0.79–1.45); subgroup interaction was present with I² = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I² = 89.7%, p = 0.002).

Conclusion and Relevance

The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.     

Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report

Background

Following failure of standard systemic chemotherapy, the role of hepatic transarterial therapy for colorectal hepatic metastasis continues to evolve as the experience with this technique matures. The aim of this study to gain a better understanding of the value of drug eluting bead therapy when administered to patients with unresectable colorectal hepatic metastasis.

Methods

This was an open-label, multi-center, single arm study, of unresectable colorectal hepatic metastasis patients who had failed standard therapy from 10/2006-10/2008. Patients received repeat embolizations with Irinotecan loaded beads(max 100 mg per embolization) per treating physician's discretion.

Results

Fifty-five patients underwent 99 treatments using Irinotecan drug eluting beads. The median number of total treatments per patient was 2(range of 1-5). Median length of hospital stay was 23 hours(range 23 hours - 10 days). There were 30(30%) sessions associated with adverse reactions during or after the treatment. The median disease free and overall survival from the time of first treatment was 247 days and 343 days. Six patients(10%) were downstaged from their original disease status. Of these, four were treated with surgery and two with RFA. Neither number of liver lesions, size of liver lesions or extent of liver replacement(<= 25% vs >25%) were predictors of overall survival. Only the presence of extrahepatic disease(p = 0,001), extent of prior chemotherapy (failed 1^st and 2^nd line vs > 2 line failure)(p = 0,007) were predictors of overall survival in multivariate analysis.

Conclusion

Chemoembolization using Irinotecan loaded beads was safe and effective in the treatment of patients as demonstrated by a minimal complication rate and acceptable tumor response.     

Can K-ras Gene Mutation Be Utilized as Prognostic Biomarker for Colorectal Cancer Patients Receiving Chemotherapy? A Meta-Analysis and Systematic Review

Introduction

K-ras gene mutations were common in colorectal patients, but their relationship with prognosis was unclear.

Objective

Verify prognostic differences between patient with and without mutant K-ras genes by reviewing the published evidence.

Method

Systematic reviews and data bases were searched for cohort/case-control studies of prognosis of colorectal cancer patients with detected K-ras mutations versus those without mutant K-ras genes, both of whom received chemotherapy. Number of patients, regimens of chemotherapy, and short-term or long-term survival rate (disease-free or overall) were extracted. Quality of studies was also evaluated.

Principal Findings

7 studies of comparisons with a control group were identified. No association between K-ras gene status with neither short-term disease free-survival (OR=1.01, 95% CI, 0.73-1.38, P=0.97) nor overall survival (OR=1.06, 95% CI, 0.82-1.36, P=0.66) in CRC patients who received chemotherapy was indicated. Comparison of long-term survival between two groups also indicated no significant difference after heterogeneity was eliminated (OR=1.09, 95% CI, 0.85-1.40, P=0.49).

Conclusions

K-ras gene mutations may not be a prognostic index for colorectal cancer patients who received chemotherapy.     

ERCC1 and TS Expression as Prognostic and Predictive Biomarkers in Metastatic Colon Cancer

In patients with metastatic colon cancer, response to first line chemotherapy is a strong predictor of overall survival (OS). Currently, oncologists lack diagnostic tests to determine which chemotherapy regimen offers the greatest chance for response in an individual patient. Here we present the results of gene expression analysis for two genes, ERCC1 and TS, measured with the commercially available ResponseDX: Colon assay (Response Genetics, Los Angeles, CA) in 41 patients with de novo metastatic colon cancer diagnosed between July 2008 and August 2013 at the University of California, San Diego. In addition ERCC1 and TS expression levels as determined by RNAseq and survival data for patients in TCGA were downloaded from the TCGA data portal. We found that patients with low expression of ERCC1 (n = 33) had significantly longer median OS (36.0 vs. 10.1 mo, HR 0.29, 95% CI .095 to .84, log-rank p = 9.0x10^-6) and median time to treatment to failure (TTF) following first line chemotherapy (14.1 vs. 2.4 mo, HR 0.17, 95% CI 0.048 to 0.58, log-rank p = 5.3x10^-4) relative to those with high expression (n = 4). After accounting for the covariates age, sex, tumor grade and ECOG performance status in a Cox proportional hazard model the association of low ERCC1 with longer OS (HR 0.18, 95% CI 0.14 to 0.26, p = 0.0448) and TTF (HR 0.16, 95% CI 0.14 to 0.21, p = 0.0053) remained significant. Patients with low TS expression (n = 29) had significantly longer median OS (36.0 vs. 14.8 mo, HR 0.25, 95% CI 0.074 to 0.82, log-rank p = 0.022) relative to those with high expression (n = 12). The combined low expression of ERCC1/TS was predictive of response in patients treated with FOLFOX (40% vs. 91%, RR 2.3, Fisher’s exact test p = 0.03, n = 27), but not with FOLFIRI (71% vs. 71%, RR 1.0, Fisher’s exact test p = 1, n = 14). Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer.     

Impact of Pre-Treatment Lactate Dehydrogenase Levels on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer

Background

To investigate the impact of pre-treatment lactate dehydrogenase (LDH) levels on the outcome of patients with metastatic colorectal cancer treated with first-line chemotherapy with or without the anti-VEGF monoclonal antibody, bevacizumab, in a phase III prospective multicentre randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial.

Methods

Three hundred and seventy patients enrolled onto the ITACa first-line trial were considered for this study, 176 receiving chemotherapy (either FOLFIRI or FOLFOX) plus bevacizumab and 194 receiving chemotherapy only. Pre-treatment LDH levels were evaluated to identify a potential correlation with progression-free survival (PFS), overall survival (OS) and objective response rate.

Results

Information on pre-treatment LDH levels was available for 344 patients. High LDH levels were predictive of a lower median PFS (8.1 months vs. 9.2 months, p< 0.0001) and median OS (16.1 months vs. 25.2 months, p< 0.0001) in the overall population. In the chemotherapy plus bevacizumab group, median PFS was 9.1 and 9.8 months in patients with high LDH and low LDH, respectively (p= 0.073), whereas in the chemotherapy-only arm it was 6.9 and 9.1 months, respectively (p < 0.0001). In patients with high LDH, the addition of bevacizumab to chemotherapy led to a reduction in the rate of progressive disease (16.4 vs. 30.5%, p= 0.081) and to a prolonged PFS (p= 0.028).

Conclusion

A high LDH value was confirmed as a marker of poor prognosis. Bevacizumab reduced the progressive disease rate and improved PFS in the high-LDH subgroup, making serum LDH a potentially effective an easily available and marker to select patients who benefit from bevacizumab.

Trial Registration

NCT01878422 ClinicalTrials.gov     

Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer.

OBJECTIVES--To compare the length of survival and quality of life in patients given combination chemotherapy in addition to supportive care and in patients given only supportive care. DESIGN--Randomised study. SETTING--Gastrointestinal oncology departments. PATIENTS--40 previously untreated patients with histologically confirmed, measurable colorectal cancer that was locally recurrent or metastatic. INTERVENTIONS--Patients were allocated randomly to receive chemotherapy or only supportive care in a ratio of 2:1 according to performance status, metastatic disease of the liver, and weight loss in the six months before entering the study. Chemotherapy consisted of four week cycles of intravenous leucovorin (200 mg/m2/day) followed by 5-fluorouracil (550 mg/m2/day) and cisplatin (20 mg/m2/day), each drug being given on the first four days of the cycle. MAIN OUTCOME MEASURES--Length of survival and quality of life score with an optimised functional living index-cancer scale. RESULTS--Overall survival was significantly longer for patients given chemotherapy (11.0 months) than for those receiving supportive care alone (5.0 months; p = 0.006). Despite common association of chemotherapy with mild to moderate gastrointestinal symptoms, there was no significant difference between the two groups in global or subgroup quality of life scores. In patients with abnormal scores before treatment, quality of life seemed better in the chemotherapy arm. CONCLUSIONS--In this sample of patients with disseminated colorectal cancer the chemotherapy regimen was an effective form of palliative treatment.     

Gain of ALK Gene Copy Number May Predict Lack of Benefit from Anti-EGFR Treatment in Patients with Advanced Colorectal Cancer and RAS-RAF-PI3KCA Wild-Type Status

Introduction

Although cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations.

Patients and Methods

We evaluated the outcome of 68 patients with advanced colorectal cancer and RAS, BRAF and PI3KCA status according to ALK gene status (disomic vs. gain of ALK gene copy number – defined as mean of 3 to 5 fusion signals in ≥10% of cells). All consecutive patients received cetuximab and irinotecan or panitumumab alone for chemorefractory disease.

Results

No ALK translocations or amplifications were detected. ALK gene copy number gain was found in 25 (37%) tumors. Response rate was significantly higher in patients with disomic ALK as compared to those with gain of gene copy number (70% vs. 32%; p = 0.0048). Similarly, progression-free survival was significantly different when comparing the two groups (6.7 vs. 5.3 months; p = 0.045). A trend was observed also for overall survival (18.5 vs. 15.6 months; p = 0.885).

Conclusion

Gain of ALK gene copy number might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy.     

Sequential Cytokine-Induced Killer Cell Immunotherapy Enhances the Efficacy of the Gemcitabine Plus Cisplatin Chemotherapy Regimen for Metastatic Nasopharyngeal Carcinoma

In this study, we investigated the efficacy of sequential cytokine-induced killer cell (CIK) immunotherapy with gemcitabine plus cisplatin (GC) regimen chemotherapy in metastatic nasopharyngeal carcinoma (NPC) patients. Between September 2006 and April 2010, 222 NPC patients with distant metastasis after radiotherapy completion were retrospectively analyzed: 112 patients received 4–6 cycles of GC chemotherapy at 4-week intervals, followed by at least 4 cycles of CIK immunotherapy at 2-week intervals (GC+CIK group); the remaining 110 patients received 4–6 cycles of GC chemotherapy alone (GC group). The evaluation of long-term efficacy showed that the progression-free survival (PFS) rate was significantly higher in the GC+CIK group (log-rank test; p = 0.009), as was the overall survival (OS) rate (p = 0.006). In conclusion, sequential CIK treatment may be effective in enhancing the therapeutic efficacy of GC chemotherapy for metastatic NPC patients. This study provides a basis for alternative therapeutic strategies for metastatic NPC.     

Prospective analysis of KRAS wild-type patients with metastatic colorectal cancer using cetuximab plus FOLFIRI or FOLFOX4 treatment regimens

Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor, has proven to be efficient in the treatment of metastatic colorectal cancer. We made a prospective study of the efficacy and toxicities of cetuximab-combination first-line (FOLFOX4) versus second/third-line (FOLFIRI) chemotherapy in 98 KRAS wild-type patients who had metastatic colorectal cancer. Wild-type KRAS had been identified by direct sequencing. Associations between clinical response/progression-free survival/overall survival/toxicities and cetuximab-combination chemotherapy timing were evaluated. The overall response rate was significantly higher for first-line treatment than for second/third-line treatment (relative risk = 1.707, 95% confidence interval = 1.121-2.598). Both progression-free survival and overall survival indicated significantly longer survival of first-line treatment than second/third-line treatment patients. This study is a validation of a molecular analysis of KRAS wild-type status for the prediction of response to cetuximab-combination chemotherapy for metastatic colorectal cancer patients; its predictive role was less prominent in the second/third-line than in the first-line treatment patients.     

Clinical Implication of UGT1A1 Promoter Polymorphism for Irinotecan Dose Escalation in Metastatic Colorectal Cancer Patients Treated with Bevacizumab Combined with FOLFIRI in the First-line Setting

PURPOSE: This study aimed to identify the efficacy and toxicity of the FOLFIRI regimen (fluorouracil, leucovorin, and irinotecan) with irinotecan dose escalation plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC) via UGT1A1 genotyping. METHODS: We administered bevacizumab plus FOLFIRI with irinotecan dose escalation to treat 70 mCRC patients. The UGT1A1 *1/*1 and *1/*28 genotypes started with a 180-mg/m² dose of irinotecan, and UGT1A1 *28/*28 genotype started with a dose of 120 mg/m². The dose of irinotecan was escalated at increasing intervals of 20 to 30 mg/m² until grade 3/4 adverse events (AEs) occurred. The clinical response rate, toxicity, and survival were analyzed. RESULTS: The clinical response and disease control rates of mCRC patients treated with FOLFIRI plus bevacizumab were significantly better in patients with UGT1A1 *1/*1 and *1/*28 genotypes than in patients with UGT1A1 *28/*28 (P = .006 and P < .001, respectively). Grade 3/4 AEs were significantly more common in mCRC patients with the UGT1A1 *28/*28 genotype (P < .001). Progression-free survival was significantly higher in UGT1A1 *1/*1 and *1/*28 patients (P = .002). mCRC patients who underwent metastasectomy achieved better overall survival than those who did not undergo metastasectomy (P = .015). CONCLUSIONS: Our study showed that mCRC patients with UGT1A1 *1/*1 and *1/*28 genotypes could receive escalated doses of irinotecan to obtain a more favorable clinical outcome without significant AEs.     

Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors

The evidence of lymphocytopenia has been demonstrated to predict a poor prognosis in terms of survival in advanced cancer patients. This finding is not surprising because of the fundamental role of lymphocytes in mediating tumor cell destruction. Despite the importance of lymphocytes in the pathogenesis of cancer, there are only few data about the profile and the function of lymphocytes during the various antitumor therapies, and in particular the relation between lymphocyte pretreatment number and response to chemotherapy remains to be established. The present study was performed to evaluate whether the evidence of lymphocytopenia before the onset of treatment may influence the efficacy of chemotherapy in metastatic cancer patients affected by the most frequent tumor types. The study included 183 patients (lung cancer: 89; colorectal cancer: 63; breast cancer: 31), 95 of whom had been previously treated with chemotherapy. The chemotherapeutic regimens consisted of oxaliplatin plus 5-fluorouracil and folates in untreated colorectal cancer, weekly irinotecan in pretreated colorectal cancer, cisplatin plus gemcitabine or etoposide in untreated lung cancer, weekly vinorelbine in pretreated lung cancer, and taxotere in breast cancer patients who had been previously treated with anthracyclines. Lymphocyte count was considered to be abnormally low for values below 1500/mm3. Lymphocytopenia was found in 79/183 (43%) patients, without any significant differences in relation to tumor histology. A complete response (CR) was achieved in 6/104 patients with a normal lymphocyte count and in none of the 79 lymphocytopenic patients. A partial response (PR) was obtained in 39 patients with a normal lymphocyte count and in only eight patients with a low lymphocyte count prior to therapy. Therefore, irrespective of the type of chemotherapy, the objective tumor response rate (CR + PR) in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (8/79 vs 45/104; p < 0.001). This study shows that the evidence of lymphocytopenia prior to chemotherapy is associated with a lower efficacy of treatment in terms of objective tumor regression rates in patients with metastatic solid tumors, and suggests that the action of chemotherapy may depend at least in part on an interaction with the antitumor immunity. Pretreatment lymphocyte count may represent a new, simple biological marker to be taken into consideration by oncologists in the chemotherapeutic treatment of metastatic cancer.     

Anti-PD1 checkpoint inhibitor with or without chemotherapy for patients with recurrent and metastatic nasopharyngeal carcinoma

PurposeTo compare the efficacy and safety of anti-PD1 checkpoint inhibitor plus chemotherapy with anti-PD1 checkpoint inhibitor alone in recurrent and metastatic nasopharyngeal carcinoma (R/M NPC) progressing after first or subsequent-line therapy.Methods and materialsA total of 67 patients with recurrent and metastatic nasopharyngeal carcinoma from our hospital were included. All patients were sorted into two arms: anti-PD1 checkpoint inhibitor+ chemotherapy arm and anti-PD1 checkpoint inhibitor arm. We retrospectively estimated objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in patients of both arms. Chi-square test and Kaplan–Meier methodology were used to analyze.ResultsFrom September 2018 to March 2020, this research included 67 patients. For anti-PD1 checkpoint inhibitor+ chemotherapy arm, partial response and stable disease were observed in fourteen and 11 patients, respectively, for an ORR of 53.8%. For anti-PD1 checkpoint inhibitor arm, complete response and partial response were observed in one and 5 patients, respectively, for an ORR of 14.6%. The incidence of hyperprogressive disease was higher in the anti-PD1 checkpoint inhibitor group compared with anti-PD1 checkpoint inhibitor+ chemotherapy group (39.0% vs 3.8%, p<0.05). Univariable analyses discovered that 6-month PFS and OS benefits were observed for anti-PD1 checkpoint inhibitor+ chemotherapy arm compared to anti-PD1 checkpoint inhibitor arm (65.4% vs. 28.6%, P = 0.001; 100.0% vs. 73.5%, P = 0.014).ConclusionIn present study, we revealed that adding chemotherapy to anti-PD1 checkpoint inhibitor significantly improved 6-month PFS and OS for patients with R/M NPC progressing after first-line therapy. It warrants further study.     

Overall Survival of Stage III Colon Cancer with Only One Lymph Node Metastasis Is Independently Predicted by Preoperative Carcinoembryonic Antigen Level and Lymph Node Sampling Status

Background

This study identified predictors of favorable overall survival (OS) for stage III colon cancer patients who had only one lymph node (LN) metastasis (N1a).

Methods

Variables, including preoperative carcinoembryonic antigen (CEA) level, LN sampling status, and the choices of postoperative adjuvant chemotherapy, were recorded. Prognostic significance was determined using the log-rank test and multivariate Cox regression analysis.

Results

The median 42-month follow-up period included 363 eligible patients. Among them, 230 (63.3%) received only 5-flurouracil (5-FU) adjuvant chemotherapy; 76 (20.9%) underwent oxaliplatin-based regimens; and 57 (15.7%) chose surgery alone. The 5-year survival rate of these evaluated patients was 75%, 63%, and 77%, respectively (P = 0.823). Multivariate analysis revealed that normal preoperative CEA level (≦5 ng/mL) and adequate LN sampling (LN ≧ 12) were significant predictors for higher 5-year OS (P < 0.001; P = 0.007, respectively). However, the use of postoperative adjuvant chemotherapy in these N1a colon cancer patients did not significantly affect their 5-year OS.

Conclusions

A preoperative CEA level of less than or equal to 5 ng/mL, and curative surgery with an adequate lymphadenectomy determined a favorable OS outcome in stage III colon cancer with only one LN metastasis.     

Androgen depletion and repletion as a means of potentiating the effect of cytotoxic chemotherapy in advanced prostate cancer

Seventy-five patients with stage D-2 prostate cancer refractory to orchiectomy have been entered in a controlled trial to test whether androgen priming enhances the efficacy of chemotherapy. All patients are treated with aminoglutethimide and hydrocortisone as a means of achieving medical adrenalectomy and are given cyclic i.v. chemotherapy with cytoxan, adriamycin and 5-fluorouracil. Patients in the stimulation arm (N = 39) receive, in addition, fluoxymesterone (5 mg p.o. b.i.d.) for 3 days before and on the day of chemotherapy. A similar response rate was observed in the stimulation and control arm (83% vs 74% respectively) when the analysis was restricted to evaluable patients. When all patients were included, a significantly higher response rate was observed in the control arm (64% vs 49%, P less than 0.05) as a result of the larger fraction of unevaluable patients in the stimulation arm (41% vs 14%). Median duration of response is 9 months in the stimulation and 10 months in the control arm. Median overall survival in the stimulation and control group is 12 months and 16 months respectively. Significant toxicity consisting of exacerbation of bone pain and, in two patients, development of reversible spinal cord compression was observed following androgen priming. Our results suggest that combined medical adrenalectomy and chemotherapy are highly effective in the treatment of advanced prostate cancer. Thus far, no additional benefit has been observed with androgen priming.     

Platinum-Based Versus Non-Platinum-Based Chemotherapy as First Line Treatment of Inoperable,Advanced Gastric Adenocarcinoma: A Meta-Analysis

Background

Although the platinum regimen is adopted widely nowadays in spite of the excessive side effects, there is still no international standard for palliative chemotherapy of advanced gastric cancer. This meta-analysis assessed the efficacy and tolerability of platinum versus non–platinum chemotherapy as first-line palliative treatment in patients with inoperable, advanced gastric cancer.

Methods

Randomized phase II and III clinical trials on first-line palliative chemotherapy in inoperable, advanced gastric cancer were identified by electronic searches of PubMed, Embase, and the Cochrane Controlled Trial Register, and hand searches of relevant abstract books and reference lists. Response rates, overall survival, and toxicity were analyzed. Depending on whether new-generation agents (S-1, taxanes and irinotecan) were utilized, the non–platinum regimens were divided into two subgroup.

Results

Compared to non-platinum regimens containing new-generation agents, the use of platinum-based regimens was associated with better response (risk ratio (RR) = 1.94, 95%CI[1.48, 2.55], p<0.001), an increase of overall survival (hazard ratio (HR) = 0.85, 95%CI[0.78, 0.92], p<0.001), a higher risk of hematological and non-hematological toxicity. No statistically significant increase in response (RR = 1.03, 95%CI [0.85, 1.24], p = 0.76) or overall survival (HR = 1.07, 95%CI [0.88, 1.30], p = 0.49) was found when platinum therapies were compared to new-generation agent based combination regimens. The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nausea and vomiting, and neurotoxicity, but not for diarrhea and toxic death rate.

Conclusion

New-generation agent based combination regimens achieved similar response rate and overall survival as platinum-based therapy that had generally higher side effects. S-1, taxanes and irinotecan seemed to be valid options for patients with inoperable, advanced gastric cancer as first-line chemotherapy.     

贝伐单抗二线治疗转移性结直肠癌的临床观察

目的:观察贝伐单抗二线治疗转移性结直肠癌患者的临床疗效和毒副反应。方法:回顾性分析2008年8月至2011年10月我院经组织病理学证实的转移性结直肠癌患者21例,一线治疗进展后,二线治疗方案中加用贝伐单抗,用法为5mg/kg,每2-3周1次,与化疗方案同步。化疗方案以奥沙利铂及伊立替康为基础,完成2-3周期治疗后评定疗效,观察毒副反应。结果:21例患者中PR1例,SD11例,PD9例,客观缓解率为4.8%,疾病控制率为57.1%,中位TTP为3.7个月。患者出现的不良反应有骨髓抑制、皮疹、恶心呕吐、腹泻、肝功能损害、神经毒性等,贝伐单抗所致高血压的发生率为14.3%(3/21),鼻衄发生率为4%(2/21)。结论:二线治疗中使用贝伐单抗,对一线治疗进展后的转移性结直肠癌疗效有限,毒副反应可耐受。     

Assessment of the Relation between the Expression of Oxaliplatin Transporters in Colorectal Cancer and Response to FOLFOX-4 Adjuvant Chemotherapy: A Case Control Study

Background

Adjuvant chemotherapy for colorectal cancer is mainly based on the combination of 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX-4). The pharmacological target of oxaliplatin remains intracellular and therefore dependent on its entry into cells. The intracellular distribution of oxaliplatin is mediated by organic cation transporters 1, 2 and 3 (OCT1, 2 and 3), copper transporter 1 (CTR1) and ATPase Cu²⁺ transporting beta polypeptide (ATP7B) and may modulate the efficacy of oxaliplatin-based chemotherapy. The aim of this study was to perform a retrospective study to assess the relation between the expression of oxaliplatin transporters in colorectal cancer before chemotherapy and the response to FOLFOX-4 adjuvant chemotherapy in responder and non-responder patients.

Methods

This retrospective study was conducted at a single center (University Hospital of Clermont-Ferrand, France). The target population was patients with resectable colorectal cancer operated between 2006 and 2013. Inclusion criteria were defined for the responder patients as no cancer recurrence 3 years after the end of chemotherapy, and for the non-responder patients as cancer recurrence within 1 year. Other inclusion criteria were stages IIb–IV cancers, first-line adjuvant FOLFOX-4 chemotherapy, and the availability of resected primary tumor samples. Exclusion criteria were preoperative chemotherapy and/or radiotherapy, a targeted therapy, other anticancer drugs, cancer recurrence between the first and the third year after the end of chemotherapy and follow-up < 3 years. Immunostaining of oxaliplatin transporters (OCT1, 2, 3, CTR1 and ATP7B) and Ki-67 was assessed in tumor samples.

Results

Retrospectively, 31 patients have been selected according to inclusion and exclusion criteria (15 responders and 16 non-responders). Before FOLFOX-4 regimen, OCT3 expression was significantly lower in responder patients compared to non-responders (p<0.001). According to multivariate analysis, OCT3 remains an independent criterion for adjuvant FOLFOX chemotherapy response (p = 0.039). No significant relation is reported between chemotherapy response and the expression of OCT1 (p = 0.49), OCT2 (p = 0.09), CTR1 (p = 0.45), ATP7B (p = 0.94) and Ki-67 (p = 0.34) in tumors.

Conclusions

High expression of OCT3 could be an independent factor related to resistance to FOLFOX-4 chemotherapy.     

Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes

BackgroundBreast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo- naïve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers.MethodsPatient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing.ResultsForty-eight breast cancers (24 post-chemotherapy, 24 chemo-naïve) were implanted and 13 BCXs were established (27%). BCX engraftment was higher in TNBC compared to hormone-receptor positive cancer (53.8% vs. 15.6%, p = 0.02), in tumors from patients who received NeoCT (41.7% vs. 8.3%, p = 0.02), and in patients who had progressive disease on NeoCT (85.7% vs. 29.4%, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile.ConclusionsBCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.