Epidermal growth factor receptor inhibitors in colorectal cancer treatment: What's new?

Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds （fluoropyrimidines, irinotecan and oxaliplatin） and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes （fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab） achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefltinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.

Efficacy of Traditional Chinese Medicine in the Treatment of Rash Caused by Epidermal Growth Factor Receptor Inhibitors: A Frequency Statistics and Meta-Analysis

Objective:The aim of this study is to evaluate the efficacy of Traditional Chinese Medicine(TCM)in the treatment of rash caused by epidermal growth factor receptor inhibitors(EGFRIs).Materials and Methods:Foreign language database(such as Pub Med,Web of Science,Cochrane Library,EMBASE)and Chinese language database(such as China National Knowledge Infrastructure,VIP Database for Chinese Technical Periodicals[VIP],Wangfang,CBM disc)were searched for all trials of TCM in the treatment of rash caused by EGFRIs until January of 2019.We also looked through the references of relevant studies to supplement additional trials.The SPSS 25.0 was used for statistics of TCM with high frequency,and Review Manager 5.3 was used for meta-analysis.Results:A total of 22 studies were included in the study.We selected TCM whose frequency were>3.0%.They were Lonicera japonica(金银花),Licorice Roots Northwest Origin(生甘草),Cortex Dictamni(白鲜皮),Radix Sophorae Flavescentis(苦参),Schizonepeta(荆芥),Saposhnikovia Divaricate(防风).The meta-analysis revealed that the efficacy of TCM in treating EGFRIs-related rash was better than that of Western medicine or none.Conclusions:TCM could significantly relieve rash caused by EGFRIs,which is worth popularizing.Moreover,the mechanism deserves to be further explored.

Associations Between Epidermal Growth Factor Receptor Gene Mutation and Serum Tumor Markers in Advanced Lung Adenocarcinomas: A Retrospective Study

Objective To investigate the associations between epidermal growth factor receptor （EGFR） gene mutations and serum tumor markers in advanced lung adenocarcinomas. Methods We investigated the association between EGFR gene mutations and clinical features, including serum tumor marker levels, in 97 advanced lung adenocarcinomas patients who did not undergo the treatment of EGlaR tyrosine kinase inhibitors. EGFR gene mutation was detected by real-time PCR at exons 18, 19, 20, and 21. Serum tumor marker concentrations were analyzed by chemiluminescence assay kit at the same time. Results EGFR gene mutations were detected in 42 （43%） advanced lung adenocarcinoma patients. Gender （P=0.003）, smoking status （P=0.001）, and abnormal serum status of carcinoembryonic antigen （CEA, P=0.028） were significantly associated with EGFR gene mutation incidence. Multivariate analysis showed the abnormal CEA level in serum was independently associated with the incidence of EGFR gene mutation （P=0.046） with an odds ratio of 2.613 （95% Ch 1.018-6.710）. However, receiver operating characteristic （ROC） curve analysis revealed CEA was not an ideal predictive marker for EGFR gene mutation status in advanced lung adenocarcinoma （the area under the ROC curve was 0.608, P=0.069）. Conclusions EGFR gene mutation status is significantly associated with serum CEA status in advanced lung adenocarcinmoas. However, serum CEA is not an ideal predictor for EGFR mutation.

Advanced Lung Adenocarcinoma with EGFR 19-del Mutation Transformed into SCC after EGFR-tyrosine Kinase inhibitors Treatment:A Case report

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung cancer(NSCLC).CASE SUMMARY A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment.Secondary pathological tissue biopsy confirmed squamous cell carcinoma(SCC)transformation.Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time,while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC.Notably,EGFR-TKIs resistance includes primary and acquired.Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs,with SCC transformation being relatively rare.Our results provide more detailed results of the patient’s diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma.CONCLUSION Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.

Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer(NSCLC)

Purpose： A number of different clinical characteristics have been reported to singly correlate with therapeutic activity of epidermal growth factor receptor （EGFR） tyrosine kinase inhibitors （TKIs） in advanced non-small-cell lung cancer （NSCLC）. This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. Patients and methods： EGFR gene typing in 33 advanced NSCLC patients received gefitinib （250 mg/day） were analyzed with mutant-enriched PCR assay. Gefitinib response was evaluated with potential predictive factors retrospectively. Results： The overall objective response rate （ORR） and median progression-flee survival （PFS） in the 33 patients treated by gefitinib were 45.5% and 3.0 （2.0-4.0） months. The ORR and median PFS in EGFR gene mutation patients were significantly higher/longer than those in EGFR gene wild-type patients （P〈0.01）. Similarly, the ORR and median PFS in non-smoker patients were significantly higher/longer than those in smoker patients （P〈0.05, P〈0.01, respectively）. However, no difference for ORR and median PFS occurred between male and female patients. Logistic multivariate analysis showed that only EGFR mutated gene was significantly associated with the ORR （P〈0.01）. Both EGFR mutated gene and non-smoker were the major factors that contributed to PFS （P〈0.05）. Conclusions： EGFR mutated gene and non-smoker status are potential predictors for gefitinib response in NSCLC patients.

Efficacy of EGFR Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients Harboring Different Types of EGFR Mutations:A Retrospective Analysis

With the development of molecular pathology, many types of epidermal growth factor receptor（EGFR） mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors（EGFR-TKIs） in non-small cell lung cancer（NSCLC） patients with different types of EGFR mutations, especially in patients with single rare mutations or complex mutations（co-occurrence of two or more different mutations）, has not been fully understood. This study aimed to examine the efficacy of EGFR-TKIs in NSCLC patients with different types of EGFR mutations. Clinical data of 809 NSCLC patients who harbored different types of EGFR mutations and treated from January 2012 to October 2016 at Renmin Hospital and Zhongnan Hospital, Wuhan, were retrospectively reviewed. The clinical characteristics of these patients and the efficacy of EGFR-TKIs were analyzed. Among these patients, 377 patients had only the EGFR del-19 mutation, 362 patients the EGFR L858R mutation in exon 21, 33 patients single rare mutations and 37 patients complex mutations. Among these 809 patients, 239 patients were treated with EGFR-TKIs. In all the 239 patients, the disease control rate（DCR） was 93.7% with two patients（0.2%） achieving complete response（CR）, the median progression free survival（PFS） was 13.0 months（95% confidence interval [CI], 11.6–14.4 months）, and the median overall survival（OS） was 55.0 months（95% CI, 26.3–83.7 months）. Subgroup analysis revealed that the DCR in patients harboring single rare or complex mutations of EGFR was significantly lower than in those with del-19 or L858 R mutation（P〈0.001）. Patients with classic mutations（del-19 and/or L858 R mutations） demonstrated longer PFS（P〈0.001） and OS（P=0.017） than those with uncommon mutations（single rare and/or complex mutations）. Furthermore, the patients with single rare mutations had shorter median OS than in those with other mutations. Multivariate Cox regression analysis identified that the type of EGFR mutations was an independent risk factor for PFS（hazard ratio [HR]=0.308, 95% CI, 0.191–0.494, P〈0.001） and OS（HR=0.221, 95% CI, 0.101–0.480, P〈0.001）. The results suggest that the single rare or complex EGFR mutations confer inferior efficacy of EGFR-TKIs treatment to the classic mutations. The prognosis of the single rare EGFR mutations is depressing. EGFR-TKIs may be not a good choice for NSCLC patients with single rare mutations of EGFR. Further studies in these patients with uncommon mutations（especially for the patients with single rare mutations） are needed to determine a better precision treatment.

The efficacy of Kanglaite injection during treatment with tyrosine kinase inhibitor in elderly patients with non-small cell lung cancer

Objective Epidermal growth factor receptor–tyrosine kinase inhibitors(EGFR–TKIs) are widely used in the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC) patients. The Kanglaite injection(KLT) is a novel broad-spectrum anti-cancer injection produced from traditional Chinese medicinal herbs(coix seed). After its approval in 1995, KLT has become the most popular anti-cancer drug in China. As of this writing, no standard treatment guideline is available for elder patients with NSCLC, and the role of traditional Chinese medicinal herbs, including KLT, combined with TKI treatment remains unknown. This retrospective study evaluated the efficacy and safety of KLT in elderly NSCLC patients during TKI treatment.Methods Thirty elderly patients aged 71-79 years with histopathologically confirmed NSCLC attending the General Hospital of the Shenyang Military Region were enrolled in the study and received EGFR-TKI treatment. All participants received 200 m L KLT injections at the same time on days 1–21. Erlotinib(150 mg) or gefitinib(250 mg) was administered daily from days 1 to 21, and the cycle was repeated every 21 days. The endpoint of the primary study was the disease control rate.Results Thirty elderly patients were enrolled in this study. The objective response rate was 21.3% [95% confidence interval(CI): 8.6% to 35.2%], whereas the disease control rate was 80.4%(95% CI: 71.8% to 97.0%). The grade 3 or 4 adverse effects included leucopenia(13.7%), neutropenia(13.4%), anemia(2.9%), and nausea or vomiting(2.7%). Conclusion The administration of KLT combined with erlotinib or gefitinib showed high efficacy in elderly NSCLC patients. The adverse effects of the drug combination were well tolerated by the patients. KLT combined with TKI treatment might provide a satisfactory therapeutic strategy for elderly NSCLC patients.

Current status of pharmacological treatment of colorectal cancer

AIM: To review the clinical trials for the development in drugs for chemotherapeutic treatment of colorectal cancer(CRC).METHODS: A systematic review identified random-ized controlled trials(RCTs) assessing drugs for the treatment of CRC or adenomatous polyps from www.clinicaltrials.gov. Various online medical databases were searched for relevant publications.RESULTS: Combination treatment regimens of stan-dard drugs with newer agents have been shown to improve overall survival, disease-free survival, time to progression and quality of life compared to that with standard drugs alone in patients with advanced colorectal cancer. The FOLFOXIRI regimen has been associated with a significantly higher response rate, progression-free survival and overall survival compared to the FOLFIRI regimen. CONCLUSION: Oxaliplatin plus intravenous bolus fluo-rouracil and leucovorin has been shown to be superiorfor disease-free survival when compared to intravenous bolus fluorouracil and leucovorin. In addition, oxaliplatin regimens were more likely to result in successful surgi-cal resections. First line treatment with cetuximab plus fluorouracil, leucovorin and irinotecan has been found to reduce the risk of metastatic progression in patients with epidermal growth factor receptor-positive colorec-tal cancer with unresectable metastases. The addition of bevacizumab has been shown to significantly in-crease overall and progression-free survival when given in combination with standard therapy.

Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer

BACKGROUND Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown. AIM To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management. METHODS Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up. RESULTS Overall, 229 patients (males, 57.6%;mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity;the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%;emollients, 75.5%;both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low. CONCLUSION The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient’s quality of life appeared to be limited.

Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI

Objective： Non-small cell lung cancer （NSCLC） patients with epidermal growth factor receptor （EGFR）-activating mutations have higher response rate and more prolonged survival following treatment with single-agent EGFR tyrosine kinase inhibitor （EGFR-TKI） compared with patients with wild-type EGFR. However, all patients treated with reversible inhibitors develop acquired resistance over time. The mechanisms of resistance are complicated. The lack of established therapeutic options for patients after a failed EGFR-TKI treatment poses a great challenge to physicians in managing this group of lung cancer patients. This study evaluates the influence of EGFR-TKI retreatment following chemotherapy after failure of initial EGFR-TKI within at least 6 months on NSCLC patients. Methods： ＇i-he data of 27 patients who experienced treatment failure from their initial use of EGFR-TKI within at least 6 months were analyzed. After chemotherapy, the patients were retreated with EGFR-TKI （gefitinib 250 mg qd or erlotinib 150 mg qd）, and the tumor progression was observed. The patients were assessed for adverse events and response to therapy. Targeted tumor lesions were assessed with CT scan. Results： Of the 27 patients who received EGFR-TKI retreatment~ 1 （3.7%） patient was observed in complete response （CR）, 8 （29.6%） patients in partial response （PR）, 14 （51.9%） patients in stable disease （SD）, and 4 （14.8%） patients in progressive disease （PD）. The disease control rate （DCR） was 85.2% （95% CI： 62%-94%）. The median progression-free survival （mPFS） was 6 months （95% CI： 1-29）. Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCRwas 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EGFR-TKI, no patient in CR~ 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCRwas 85.7%, and the mPFS was 9.5 months. Significant difference was found between the two groups in PFS but not in response rate or D CR. Conclusion： Retreatment of EGFR-TKIs can be considered an option after failure of chemotherapy for patients who were previously controlled by EGFR-TKI treatment.

Updates in the management of brain(leptomeningeal) metastasis of lung cancer

Brain(leptomeningeal) metastasis is one of the most common and severe complications of lung cancer. This article interprets expert consensus on the treatment advice for brain(leptomeningeal) metastasis of lung cancer, expounding on its epidemiology, diagnostic standards, efficacy assessment, treatment advice, and other aspects.

Histological transformation of non-small cell lung cancer:Clinical analysis of nine cases

BACKGROUND Histological transformation is one of the numerous mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors(EGFRTKIs).Given its rarity,the underlying transformational mechanisms,clinical features,and therapeutic prognoses are only studied through limited case reports.AIM To analyze the clinical characteristics and underlying mechanisms in non-small cell lung cancer(SCLC)patients with histological transformation after treatment with EGFR-TKIs.METHODS We retrospectively investigated nine patients diagnosed with non-SCLC transforming to SCLC,large-cell neuroendocrine carcinoma(LCNEC),or squamous cell carcinoma on re-biopsy after first-or third-generation EGFR-TKIs.RESULTS The median age of nine patients was 60 years.Among them,six patients had the EGFR 19del mutation,one had the L858R mutation,and one had wild-type EGFR.The level of plasma NSE was measured in six patients with SCLC or LCNEC transformation when transformation occurred,and five patients had elevated plasma NSE levels.All patients received standard chemotherapy after transformation with the exception of one patient who received chemotherapy and anlotinib.CONCLUSION Tumor re-biopsy should be performed routinely when EGFR-TKI therapy fails in lung cancer patients to avoid ignoring histological transformation and to select a subsequent therapeutic strategy.The transformed tumor retained the original EGFR mutation,indicating that histological transformation represents an evolution from the initial tumor.

Small cell lung cancer transformations from non-small cell lung cancer: Biological mechanism and clinical relevance

Lung cancer is a leading cause of cancer deaths worldwide,consisting of two major histological subtypes:small-cell lung cancer(SCLC)and non-small-cell lung cancer(NSCLC).In some cases,NSCLC patients may undergo a histological transformation to SCLC during clinical treatments,which is associated with resistance to targeted therapy,immunotherapy,or chemotherapy.The review provides a comprehensive analysis of SCLC transfor-mation from NSCLC,including biological mechanism,clinical relevance,and potential treatment options after transformation,which may give a better understanding of SCLC transformation and provide support for further research to define better therapy options.

Leptomeningeal metastases from non-small cell lung cancer:state of the art and recent advances

Patients with leptomeningeal metastases(LM)from non-small cell lung cancer(NSCLC)have a poor outcome with survival of less than 1 year regardless of advancements in treatment strategy.In the past,some randomized clinical trials have been conducted with heterogeneous inclusion criteria,diagnostic parameters,response evaluation and primary endpoints.Efforts to develop a standardized magnetic resonance imaging(MRI)assessment and liquid biopsy techniques to monitor disease evolution in plasma or cerebrospinal fluid(CSF)are underway.This review aims to cover the main clinical and diagnostic challenges of LM from NSCLC,in particular the role of MRI,CSF cytology and liquid biopsy for the diagnosis and monitoring of the disease,as well as the most recent clinical trials on targeted therapies.Targeted therapy,such as epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase rearranged inhibitors,represent a feasible treatment with encouraging results in terms of disease control and survival.For ineligible patients,immune checkpoint inhibitors could represent a therapeutic option with acceptable tolerance,although clinical trials focused on LM from NSCLC are lacking and represent a research focus for the future.