The Role of Anti-EGFR Monoclonal Antibody in mCRC Maintenance Therapy.

Background: Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) combined with chemotherapy in patients with RAS (rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer (mCRC) can alleviate and stabilize the disease, effectively prolong the progression-free survival (PFS) and overall survival (OS), and improve the overall response rate (ORR), which is the first-line treatment standard scheme for RAS wild-type mCRC currently. However, whether anti-EGFR mAb can be used for the maintenance treatment after the first-line treatment of mCRC remains controversial. We reviewed the recent studies on anti-EGFR mAb. The contents include five parts, introduction, anti-EGFR mAb in mCRC and its status in first-line therapy, establishment of the maintenance treatment pattern after the standard first-line treatment for mCRC, research progress of anti-EGFR mAb in mCRC maintenance therapy, and conclusion. More studies support the maintenance treatment of anti-EGFR mAb, but some researchers raise the problems about high cost and drug resistance. Despite lack of the maintenance evidence of anti-EGFR mAb, especially lack of large-scale phase III prospective clinical trials, with the emergence of new evidence and more accurate screening of treatment-dominant groups, maintenance therapy with anti-EGFR mAb monotherapy or anti-EGFR mAb combined with fluorouracil-based schemes after first-line chemotherapy combined with anti-EGFR mAb therapy might strive for more treatment opportunities, optimize treatment strategies and prolong treatment continuity, and finally, lead to more survival benefit for suitable patients.

Associations of Clinical and Molecular Characteristics with the Response to Immune Checkpoint Blockade in Advanced Gastric Cancers.

Purpose: Immunotherapy provides a new treatment option for advanced gastric cancer (AGC). This study aims to explore the response markers of immunotherapy in AGCs. Methods: Next-generation sequencing was performed on 44 AGC patients who received immune checkpoint inhibitors and the associations between their outcomes after combination immunotherapy, and the clinicopathological/molecular characteristics were analyzed. Results: The current study cohort had a median progression-free survival (PFS) of 5.9 months, an overall survival (OS) of 12.1 months, and an objective response rate (ORR) of 36.4%. Through multivariable analysis of the clinical characteristics, primary tumor resection (HR = 2.66, 95% CI: 1.06-6.70, p=0.037) and increased proportion of lymphocytes after combination immunotherapy (HR = 0.40, 95% CI: 0.16-0.99, p=0.048) were revealed as independent predictors for patient outcomes. All the 18 patients who underwent genetic profiling were microsatellite-stable with a median TMB of four mutations per Mb. ATM alterations, PI3K pathway mutations, increased TMB, and positive PD-L1 expression were associated with the increased trend of PFS and ORR. According to the combination of baseline lymphocyte count, ATM mutation, TMB status, and PD-L1 expression, patients were stratified into higher- and lower-risk groups, with the lower-risk group showing improved PFS (HR = 4.7e-10, 95% CI: 0-inf, p=0.02) and ORR (75% vs. 0%, p=0.007). Conclusion: Several highly relevant potential biomarkers predictive of immunotherapy response in AGC patients have been identified in this research.

Cetuximab Can Be an Effective and Low-Toxicity Maintenance Treatment Drug in Patients With Metastatic Colorectal Cancer: A Real-World Study of Zhejiang Cancer Hospital.

After initial treatment, maintenance therapy is now commonly used in mCRC patients, which can help patients live longer, have lower side effects, and higher quality of life. The maintenance treatment may include chemotherapy, targeted therapy, or combined with chemotherapy and targeted therapy. But the evidence of cetuximab maintenance is still scant. Methods: We collected real-world data of wild-type RAS unresectable mCRC patients who were treated with cetuximab-based chemotherapy as the first-line therapy between January 2013 and December 2018 at the Zhejiang Cancer Hospital (Hangzhou, China). Results: A total of 177 patients were ultimately included in the study, and 107 patients had progression information in medical records; all patients had survival data. The median OS was 40.9 ms, ORR was 14.7%, and DCR was 73.5%. The subgroup analysis showed that the mOS was better in maintenance patients than in non-maintenance patients (47.1 vs. 28.6 ms, p = 0.001), patients with primary tumor resection had better mOS than who did not (47.1 vs. 35.4 ms, p = 0.038). In those 107 patients who had progression information, the median PFS was 9 ms, the median OS was 42.6 ms, ORR was 18.7%, and DCR was 84.1%. The subgroup analysis showed that the mPFS and mOS were 11.6 and 47.1 ms, respectively, in the maintenance group, which were significantly better than 6.1 ms and 28.7 ms in the non-maintenance group (p = 0.025 and 0.017, respectively). The mPFS and mOS in patients with efficacy evaluation of CR + PR + SD were 10.3 and 47.1 ms, respectively, which is significantly better than 2.8 and 13.5 ms in the PD patients (p = 0.012 and <0.001, respectively). The mOS was best in only lung metastases patients (60.9 ms), then only liver metastases patients (47.1 ms), and then in both liver and lung metastases (42.6 ms); the mOS in patients with other organs metastases was the worst (22.4 ms), p = 0.022. The mOS in male individuals is better than that in female individuals, 60.99 vs. 29.1 ms, respectively, p = 0.042. The primary tumor site and primary tumor resection also affect the OS, primary tumor resection better than did not (not reach the end vs. 35.7 ms, p = 0.048), left side better than right side (47.1 vs. 16.6 ms, p < 0.001), which is consistent with the literature report. There was no statistical difference in other subgroups. Conclusion: For patients with all RAS wild-type and initially unresectable mCRC who experienced standard first-line cetuximab-based treatment and maintenance treatment that contained cetuximab can significantly improve the mPFS and mOS, and the observed toxicity was mostly mild too. So, we consider that cetuximab can be an effective and safety maintenance drug in mCRC patients.

Surgical resection of the primary tumor leads to prolonged survival in metastatic pancreatic neuroendocrine carcinoma.

BACKGROUND: Palliative resection of the primary tumor for metastatic pancreatic neuroendocrine carcinoma (pNEC) patients is not recommended because of the poor prognosis compared to that of patients with well-differentiated, lower grade tumors. However, the published data supporting this recommendation regarding pNEC are limited. In the present study, we assessed whether palliative primary tumor resection in stage IV pNEC patients affects survival and identified other factors that affect survival in these patients. METHODS: We collected data from stage IV pNEC patients registered in the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2014. Univariate and multivariate Cox regression analysis were used to compare overall survival (OS) and cancer-specific survival (CSS) of patients who did or did not undergo primary tumor resection. RESULTS: We identified 350 patients with metastatic, poorly differentiated, and undifferentiated pNEC. A total of 14.3% (50/350) of patients underwent primary tumor resection. Multivariate Cox regression analysis showed that primary tumor resection provided a significant benefit for both OS and CSS in stage IV pNEC patients. Additionally, chemotherapy and the presence of the primary tumor in the pancreatic tail were independent positive prognostic factors for metastatic pNEC patients in the multivariate Cox regression analysis. CONCLUSIONS: The present study suggests that chemotherapy, location of the primary tumor in the pancreatic tail, and, most importantly, surgical removal of the primary tumor are associated with prolonged survival in stage IV pNEC patients.

Activation of the PERK-ATF4 pathway promotes chemo-resistance in colon cancer cells.

Colon cancer is a major health problem worldwide. While chemotherapy remains a main approach for treating late-stage colon cancer patients, most, if not all, of them will develop drug resistance and die of uncontrollable disease progression eventually. Therefore, identification of mechanism of drug resistance and development of overcoming strategy hold great significance in management of colon cancer. In this study, we discovered that activation of the PERK branch of the unfolded protein response (UPR) pathways is required for colon cancer cells to survive treatment of 5-Fluorouracil (5-FU), one of the first-line chemotherapeutics for late-stage colon cancer patients. Genetic and pharmacological inhibition of PERK or its downstream factors greatly sensitize colon cancer cells to 5-FU. Most importantly, in vivo use of PERK inhibitor synergizes with 5-FU in suppressing the growth of colon cancer cells in mouse models. In summary, our findings established a promising way to overcome resistance to chemotherapy in colon cancer.

The significance of multi-line chemotherapy for advanced gastric cancer: A retrospective analysis.

Palliative chemotherapy is known to benefit patients with advanced gastric cancer by palliating symptoms and improving survival. The aim of the present study was to evaluate the efficacy and toxicity of chemotherapy regimens that are commonly used in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated by at least two chemotherapy regimens between May 2006 and July 2014 at Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. A total of 248 patients were reviewed, and 158 were evaluated in the final analysis, with a median age of 57 years and a Karnofsky performance status score of ≥80. The median progression-free survival (PFS) time was 168 days for first-line chemotherapy, 96 days for second-line chemotherapy, and the median overall survival (OS) time was 356 days. Further analysis revealed that patients with the disease controlled [complete response (CR) + partial response (PR) + stable disease (SD)], no matter whether they received first-or second-line chemotherapy, may have had an improved OS compared with patients with disease progression (PD). Patients who were treated with >2 lines of chemotherapy had an improved OS compared those who ceased treatment following failure of the second-line chemotherapy. The cycle number of chemotherapy that patients received was associated with OS. The site of the primary and metastatic tumors was also associated with OS. Other factors, including gender, age, histological type, whether a radical operation was received, and chemotherapy regimens, had no evident association with survival. The toxicities were generally tolerated. Taken together, the results from the present study have demonstrated that an increased cycle number of effective chemotherapy may prolong the survival of patients with advanced gastric cancer. Differences among the chemotherapy regimens had no clear correlation with survival.

A retrospective analysis of hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis.

Peritoneal metastasis (PM) is a poor prognostic factor in patients with gastric cancer. The aim of this study was to evaluate the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with advanced gastric cancer with PM by retrospective analysis. A total of 54 gastric cancer patients with positive ascitic fluid cytology were included in this study: 23 patients were treated with systemic chemotherapy combined with HIPEC (HIPEC+ group) and 31 received systemic chemotherapy alone (HIPEC- group). The patients were divided into 4 categories according to the changes of ascites, namely disappear, decrease, stable and increase. The disappear + decrease rate in the HIPEC+ group was 82.60%, which was statistically significantly superior to that of the HIPEC- group (54.80%). The disappear + decrease + stable rate was 95.70% in the HIPEC+ group and 74.20% in the HIPEC- group, but the difference was not statistically significant. In 33 patients with complete survival data, including 12 from the HIPEC+ and 21 from the HIPEC- group, the median progression-free survival was 164 and 129 days, respectively, and the median overall survival (OS) was 494 and 223 days, respectively. In patients with ascites disappear/decrease/stable, the OS appeared to be better compared with that in patients with ascites increase, but the difference was not statistically significant. Further analysis revealed that patients with controlled disease (complete response + partial response + stable disease) may have a better OS compared with patients with progressive disease, with a statistically significant difference. The toxicities were well tolerated in both groups. Therefore, HIPEC was found to improve survival in advanced gastric cancer patients with PM, but the difference was not statistically significant, which may be attributed to the small number of cases. Further studies with larger samples are required to confirm our data.

Paclitaxel combined with capecitabine as first-line chemotherapy for advanced or recurrent gastric cancer.

Chemotherapy is of crucial importance in advanced gastric cancer (AGC) patients, in order to obtain palliation of symptoms and improve survival. To date, no standard chemotherapy regimen has been established for AGC. The purpose of the present study was to evaluate the efficacy and toxicity of the combination regimen of paclitaxel and capecitabine (PX) as first-line chemotherapy in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated with PX as first-line chemotherapy between January 2001 and December 2012 at the Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. In total, 36 patients were enrolled, with a median age of 53.5 years and a Karnofsky performance status (KPS) score of ≥80. A median of 4 PX cycles were administered (range, 2-8 cycles). The median progression-free survival time was 3.7 months [95% confidence interval (CI), 2.9-4.5 months) and the median overall survival time was 12.0 months (95% CI, 9.8-14.1 months). From the 36 patients evaluated, one (2.8%) achieved a complete response, seven (19.4%) achieved a partial response, 24 (66.7%) exhibited stable disease and four (11.1%) exhibited progressive disease. The objective response rate was 22.2% (8/36), and the disease control rate was 88.9% (32/36). All 36 patients were assessed for treatment toxicity. Grade 3 or 4 adverse events included neutropenia (2.8% of patients), hand-foot syndrome (2.8%) and vomiting (2.8%). No neutropenic fever or treatment-related mortalities were observed. PX combination chemotherapy may be a valuable first-line therapy for advanced or recurrent gastric cancer.

[Enhanced cisplatin cytotoxicity by RNA interfering the excision repair cross-complementing gene 1 in lung cancer cell A549/DDP].

BACKGROUND AND OBJECTIVE: The excision repair cross-complementing gene 1 (ERCC1), which is important in the repair of cisplatin-DNA adducts, was reported to be related to cisplatin resistance in tumor cells. The aim of this study is to investigate the changes of cisplatin sensitivity by silencing ERCC1 gene in lung cancer cell. METHODS: The small interfering RNA (siRNA) targeting ERCC1 gene was designed and synthesized, and transfected to lung cancer cell A549/DDP. The mRNA and protein expression levels of ERCC1 were evaluated by RT-PCR and Western blot. The changes of cisplatin sensitivity after RNA interference were examined by methyl thiazolyl assay. RESULTS: In A549/DDP cell, the mRNA and protein levels of ERCC1 were decreased and the sensitivity to cisplatin was increased from 12.49 µg/mL to 9.27 µg/mL after transfection. CONCLUSIONS: The sensitivity to cisplatin of lung cancer cell A549/DDP could be enhanced by RNA interfering ERCC1 gene targeted code 346.

[Relationship between the protein expression of P53, c-erbB-2, vascular endothelial growth factor and CD44 and the survival rates of stage II( colorectal cancer patients without radiochemotherapy after radical resection].

OBJECTIVE: To investigate the relation between protein expression of 4 genes [P53,c-erbB-2,vascular endothelial factors(VEGF) and CD44]and survival rate in stage II( colorectal cancer(CRC) patients without radiochemotherapy after radical resection. METHODS: One hundred and fifty-nine cases of stage II(CRC without radiochemotherapy were enrolled in this study. The clinicopathological date and 5-year follow-up data were reviewed. Streptavidin-peroxidase immunohistochemical technique was used to detect the expression of P53, c-erbB-2, VEGF and CD44 in formalin-fixed, paraffin embedded sections of CRC tissues from above 159 patients. RESULTS: The 5-year survival rate was 82.4%. The rates of positive expression of P53, c-erbB-2, VEGF and CD44 were 58.5%(93/159), 26.4%(42/159), 57.9%(92/159) and 40.0%(54/159) respectively. The 5-year survival rates of positive expression patients were not significantly different with those of negative expression. chi(2) analysis showed that the positive expressions of 4 genes had no relationships with the prognosis. CONCLUSION: The expression of 4 gene proteins has no relationship with the prognosis of stage II( CRC patients without radiochemotherapy after radical resection.

Genetic polymorphisms and treatment response in advanced non-small cell lung cancer.

BACKGROUND: Genetic polymorphisms involved in DNA repair and apoptosis are suspected to influence patient response to cancer treatment. To evaluate the effect of genetic variations on chemotherapy and/or radiotherapy, we genotyped four single nucleotide polymorphisms (SNPs) in ATM (A60G), ERCC1 (Asn118Asn), APE1 (Asn148Glu), and iASPP (A67T), and examined their associations with treatment response among patients with advanced non-small cell lung cancer (NSCLC). METHODS: Included in the study were 230 patients diagnosed with inoperable advanced NSCLC. Of these patients, 76 received platinum-based chemotherapy, 125 received chemotherapy plus radiation, and 29 received radiotherapy only. The SNPs were genotyped using the TaqMan methods. RESULTS: Among the patients who received chemotherapy only, ERCC1 (Asn118Asn) genotype was significantly associated with treatment response. Patients with either one or two T alleles (T/T+C/T) at Asn118Asn were more likely not to respond to platinum-based chemotherapy compared to those without the T allele (OR=4.10, 95% CI: 1.31-12.85). For patients who were treated with both chemotherapy and radiotherapy, treatment response seemed to differ substantially between patients with different genotypes of iASPP (A67T). Patients carrying an A allele (A/T+A/A) at A67T were more likely to respond to combined chemotherapy and radiotherapy compared to those not carrying the A allele (OR=0.25, 95% CI: 0.08-0.74). An association with treatment response was also suggested for the selected polymorphism in APE1, but no association was found for the ATM polymorphism. CONCLUSION: We found that SNPs in ERCC1 and iASPP were associated with response to chemotherapy or combined chemotherapy and radiotherapy in NSCLC patients. These findings support the notion that genetic variations related to DNA repair or apoptosis may affect the effect of chemotherapy or radiation on NSCLC.