Panitumumab in combination with cytotoxic chemotherapy for the treatment of metastatic colorectal carcinoma

The fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody panitumumab has been shown to improve progression-free survival when administered as a monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) and is approved in this setting. Two large randomized clinical trials have investigated panitumumab in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as a first-line therapy for mCRC and 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as a second-line therapy for mCRC. In these studies, the combination of panitumumab with FOLFOX or FOLFIRI resulted in improved progression-free survival compared with FOLFOX or FOLFIRI alone. Improved tumor response was also observed with the addition of panitumumab to FOLFIRI. As in monotherapy trials, the clinical benefits associated with panitumumab treatment were confined to patients with wild-type KRAS tumors, further showing the validity of KRAS mutational status as a predictive biomarker in mCRC. In addition to KRAS mutational status, a number of other potential predictive biomarkers are currently being investigated in mCRC and may eventually help identify patients who are likely to benefit from treatment with anti-EGFR monoclonal antibodies. Toxicities observed during treatment with panitumumab combined with FOLFOX or FOLFIRI were generally manageable and commonly included skin toxicities and gastrointestinal toxicities. Because it can lead to dose delays, dose reductions, and discontinuation, physicians and patients should carefully manage skin toxicity. Overall, the results of these two studies show that panitumumab improves outcomes when added to FOLFOX or FOLFIRI among patients with mCRC with wild-type KRAS.     

Epidermal Growth Factor Receptor Inhibition in the Management of Squamous Cell Carcinoma of the Lung

Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined.

Implications for Practice:

Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.     

Second-line treatment of non-small-cell lung cancer: chemotherapy or tyrosine kinase inhibitors?

After first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC), many patients remain candidates for a second-line treatment. Docetaxel, pemetrexed and erlotinib are currently approved in the USA and Europe as second-line therapy for NSCLC, while gefitinib is approved and licensed in Europe, but not in the USA, for EGF receptor-mutated patients in the same setting. Results of the registration trials for these four agents show similar efficacy in terms of objective response rate and survival, but significantly different toxicity and tolerability. Therefore, at the time of failure of first-line treatment, it is crucial to evaluate different clinical factors that could help choose the second-line treatment of metastatic NSCLC, as performance status and comorbidities; new predictive biomarkers will be validated in future trials. Considering the different predictive and prognostic factors, tyrosine kinase inhibitors could be a valid option for second-line treatment of NSCLC.     

Immunotherapy in Squamous Cell Cancer of the Esophagus

Treatment of esophageal carcinoma has changed dramatically following several landmark trials, which have proven the benefit of immunotherapy. The selective PD-1 (programmed cell death ligand-1)-inhibitor nivolumab has been shown to improve DFS in the adjuvant therapy setting (CheckMate-577). In the first-line treatment, PD-L1 positive (CPS ≥ 10) squamous cell carcinoma patients (pts) have been shown to have an increased OS following treatment with the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). Nivolumab also improved overall survival in the first line setting either combined with ipilimumab or with chemotherapy (CheckMate 648) compared to chemotherapy alone. In Asian first-line patients, phase III trials investigating camrelizumab (ESCORT 1), toripalimab (JUPITER 06), or sintilimab (ORIENT 15) in addition to chemotherapy also showed significant survival benefits. In the second-line setting, monotherapy with nivolumab (ATTRACTION-03), pembrolizumab (KEYNOTE-181), camrelizumab (ESCORT), and tislelizumab (RATIONALE 302) demonstrated a benefit in OS in comparison to chemotherapy. Here we will review these trials and integrate them into the current treatment algorithm.     

Second-line treatment of non-small-cell lung cancer: chemotherapy or tyrosine kinase inhibitors?

After first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC), many patients remain candidates for a second-line treatment. Docetaxel, pemetrexed and erlotinib are currently approved in the USA and Europe as second-line therapy for NSCLC, while gefitinib is approved and licensed in Europe, but not in the USA, for EGF receptor-mutated patients in the same setting. Results of the registration trials for these four agents show similar efficacy in terms of objective response rate and survival, but significantly different toxicity and tolerability. Therefore, at the time of failure of first-line treatment, it is crucial to evaluate different clinical factors that could help choose the second-line treatment of metastatic NSCLC, as performance status and comorbidities; new predictive biomarkers will be validated in future trials. Considering the different predictive and prognostic factors, tyrosine kinase inhibitors could be a valid option for second-line treatment of NSCLC.     

Capecitabine monotherapy: safe and effective treatment for metastatic breast cancer

Optimal management for metastatic breast cancer frequently involves cytotoxic chemotherapy. Over the years, several complex multidrug regimens have been developed that were based upon a rationale of synergistic antitumor activity and nonoverlapping toxicities. However, recently the clinical value of these complex regimens has been called into question as several drugs used alone (monotherapy) or in sequence (serial single agent) have been shown to be both efficacious and better tolerated. Capecitabine (an orally administered fluoropyrimidine carbamate) is one such agent that has been proven to be effective when used alone for metastatic breast cancer, metastatic colorectal cancer, and adjuvant colon cancer. In this review, published (or reported in abstract form) data examining various aspects of clinical response and tolerability with single-agent capecitabine for (primarily) first- and second-line metastatic breast cancer are examined. For the most part, response rates are comparable with those of the more complex regimens. Dose reductions from the labeled dose of 1,250 mg/m(2) twice daily are relatively common. Toxicities (following dose reductions if needed) are generally manageable, even by more frail patients. Elderly patients are more likely to have impaired renal function or be receiving warfarin treatment, and special attention to these factors is warranted. Nonetheless, the drug administered alone is a reasonable choice when single-agent chemotherapy is entertained as a treatment option for metastatic breast cancer, including in the first-line setting.     

Optimal use of anti-EGFR monoclonal antibodies for patients with advanced colorectal cancer: a meta-analysis

This meta-analysis was performed to determine the optimal use of anti-EGFR mAb in the treatment of metastasized colorectal cancer (mCRC). Seventeen randomized clinical trials were included, all evaluating the added value of anti-EGFR mAb to standard treatment line in patients with KRAS wild-type mCRC. Hazard and odds ratios were pooled using a random effect model, weighted according to cohort size. Pooled data of six first- and two second-line studies demonstrated a significantly improved ORR (OR 1.62, CI 1.27–2.04; OR 4.78, CI 3.39–6.75, respectively) and PFS (HR 0.79, CI 0.67–0.94; HR 0.80, CI 0.71–0.91, respectively) with the addition of anti-EGFR mAb to chemotherapy, while OS remained similar. Two third-line anti-EGFR mAb monotherapy studies revealed an improved PFS and OS (HR 0.44, CI 0.35–0.52; HR 0.55, CI 0.41–0.74). Addition of anti-EGFR versus anti-VEGF mAb to first-line chemotherapy was evaluated in three studies; ORR and PFS were comparable, while OS was improved (HR 0.8, CI 0.65–0.97). The influence of the chemotherapy backbone on anti-EGFR mAb efficacy, evaluated with meta-regression, indicated a higher ORR with irinotecan-based versus oxaliplatin-based regimens, but comparable PFS and OS. Reported toxicity (≥3 grade) increased ~20% in all treatment lines with the addition of anti-EGFR mAb. Anti-EGFR treatment significantly improves response and survival outcome of patients with (K)RAS wild-type mCRC, regardless of treatment line or chemotherapeutic backbone. Saving anti-EGFR mAb as third-line monotherapy is a valid and effective option to prevent high treatment burden caused by combination therapy. Combination treatment with anti-EGFR mAb to achieve radical resection of metastases needs further investigation.     

分子靶向药物给药模式对转移性结直肠癌患者生存的影响

目的 探讨两种不同类型靶向药物在不同给药模式下对转移性结直肠癌（mCRC）患者生存的影响。方法 回顾性分析135例接受过分子靶向治疗mCRC患者的临床病理特征、靶向治疗情况及随访资料,比较不同种类靶向药物及不同线数化疗联合靶向治疗对生存期（OS）的影响。结果 全组中接受抗EGFR单抗者、接受贝伐珠单抗者及接受抗EGFR单抗+贝伐珠单抗者的中位OS依次为20.7、24.4和41.6个月,接受两种靶向药物者比仅接受一种靶向药物者的中位OS有明显延长（P＜0.05）;一线化疗未联合靶向治疗者的中位OS为30.8个月,与一线化疗联合靶向治疗者的21.5个月相比,差异无统计学意义（P＞0.05）;三线及以上联合靶向治疗者的中位OS为37.0个月,高于三线前均联合靶向治疗者的137个月,差异有统计学意义（P＜0.05）;接受过三种化疗药物（伊立替康、奥沙利铂、氟尿嘧啶）及贝伐珠单抗和抗EGFR单抗两种靶向药物的患者中,三线及以上使用靶向者的中位OS为50.6个月,与三线前使用靶向者的41.6个月比较,差异无统计学意义（P＞0.05）。结论 接受过两类靶向药物治疗的mCRC患者比仅接受一类靶向药物者可能获得更好生存获益。患者使用靶向药物的时机并非越早越好,肿瘤生物学行为较好的患者更适合先化疗后靶向的治疗模式。     

抗VEGF与抗EGFR靶向药物联合化疗一线治疗转移结直肠癌Meta分析

目的 NCCN指南推荐抗VEGF或抗EGFR作为伴RAS野生型的转移结直肠癌(metastatic colorectal canc-er,mCRC)一线治疗的标准方案,但抗VEGF与抗EGFR在转移结直肠癌预后的差异性罕见系统评价参考.本研究拟通过系统评价分析抗VEGF与抗EGFR靶向药物联合化疗对转移结直肠癌疗效的影响.方法 计算机检索Cochrane、Pubmed、Web of science、Embase、ASCO、ESMO、Clinical Trials和中国生物医学文献数据库等,同时追溯参考文献.收集抗VEGF联合化疗对比抗EGFR联合化疗治疗mCRC头对头的随机对照试验(Randomized controlled trial,RCT),根据Cochrane系统评价手册5.3质量评价标准,采用Stata 12.0和Revman 5.3进行Meta分析.结果 共纳入3篇临床随机对照试验,共2014例研究对象.Meta分析结果显示,一线给予抗EGFR或抗VEGF联合化疗的mCRC患者,无论KRAS野生型(HR=1.03,95%CI为0.93~1.13)或RAS野生型(HR=0.92,95%CI为0.71~1.18)的无进展生存期(pogression free survival,PFS)均差异无统计学意义,P<0.05.一线给予抗EGFR联合化疗方案的总生存期(overall survival,OS)KRAS野生型(HR=0.82,95%CI为0.72~0.93)和RAS野生型患者(HR=0.79,95%CI为0.67~0.93)均优于抗VEGF联合化疗,P<0.05.mCRC伴KRAS野生型患者,接受抗EGFR联合化疗客观缓解率(objective re-sponse rate,ORR)显著提高,RR=0.84,95%CI为0.76~0.94;这种优势对于所有的RAS野生型患者更加明显,RR=0.80,95%CI为0.68~0.93.无论使用抗EGFR或抗VEGF联合化疗,左半结直肠癌患者相比右半结肠癌患者有生存获益PFS(HR=0.64,95%CI为0.45~0.91)及OS(HR=0.53,95%CI为0.36~0.76).结论 mCRC伴KRAS或RAS野生型患者的一线治疗,抗EGFR单克隆抗体可能是替代抗VEGF治疗作为晚期mCRC的初始治疗的最佳治疗方案.而对于肿瘤的位置而言,无论接受何种靶向药物治疗,左半结肠肿瘤相比右半结肠肿瘤的患者都具有更好的生存优势.     

Second-line therapy for small-cell lung cancer

Small-cell lung cancer (SCLC) recurs in the majority of patients, even though most patients respond to first-line therapy. Therefore second-line therapy is considered in almost all patients with SCLC in the course of disease. Efficacy of second-line chemotherapy is much lower than that of first-line treatment, but it can provide significant palliation and prolongation of survival for many patients. Patients receiving second-line therapy are divided into relapsed and refractory patients. Relapsed disease is defined as relapse or progression at least 3 months after the end of first-line therapy. All other situations, including a treatment-free interval <3 months or no response to first-line therapy, are termed refractory disease. The benefit from second-line chemotherapy is highest in patients with relapsed disease. Topotecan monotherapy improves survival and quality of life, as well as cancer-related symptoms in the second-line setting. Alternatively, doxorubicin-based combination therapy can be administered with a similar outcome but a slightly lower rate of symptom control. In refractory patients no standard therapy exists. Amrubicin, a novel anthracyline, showed promising activity in refractory and relapsed patients. Phase III trials are ongoing. Other agents with activity include irinotecan, paclitaxel, docetaxel, gemcitabine, bendamustine and vinorelbine.     

Second-line therapy for small-cell lung cancer

Small-cell lung cancer (SCLC) recurs in the majority of patients, even though most patients respond to first-line therapy. Therefore second-line therapy is considered in almost all patients with SCLC in the course of disease. Efficacy of second-line chemotherapy is much lower than that of first-line treatment, but it can provide significant palliation and prolongation of survival for many patients. Patients receiving second-line therapy are divided into relapsed and refractory patients. Relapsed disease is defined as relapse or progression at least 3 months after the end of first-line therapy. All other situations, including a treatment-free interval <3 months or no response to first-line therapy, are termed refractory disease. The benefit from second-line chemotherapy is highest in patients with relapsed disease. Topotecan monotherapy improves survival and quality of life, as well as cancer-related symptoms in the second-line setting. Alternatively, doxorubicin-based combination therapy can be administered with a similar outcome but a slightly lower rate of symptom control. In refractory patients no standard therapy exists. Amrubicin, a novel anthracyline, showed promising activity in refractory and relapsed patients. Phase III trials are ongoing. Other agents with activity include irinotecan, paclitaxel, docetaxel, gemcitabine, bendamustine and vinorelbine.     

Considerations for second-line therapy of non-small cell lung cancer

For patients with advanced non-small cell lung cancer and a good functional status, platinum-based first-line chemotherapy improves quality of life, reduces disease-related symptoms, and improves survival. The addition of bevacizumab to carboplatin and paclitaxel in the first-line setting has been shown to produce a higher response rate and longer progression-free survival and overall survival times than with carboplatin and paclitaxel. Despite these therapies, all patients inevitably experience disease progression. There are currently three agents approved for treating patients who progress after one prior regimen: docetaxel, pemetrexed, and erlotinib. Erlotinib is also indicated for patients who progress after two prior regimens. These agents appear to have similar efficacies in terms of response and overall survival, but have significantly different toxicity profiles. Currently, the choice of agent depends on a number of factors, including the patient's comorbidities, toxicity from previous treatments, the risk for neutropenia, smoking history, and patient preference. A better understanding of prognostic factors in the second-line setting may allow clinicians to better select patients for second-line therapy, and lead to better-designed second-line trials. Patients with a good performance status in second-line trials have a median survival duration of approximately 9 months, and may receive two second-line therapies during the course of their treatment. Several new agents have shown activity in phase II trials, and may be integrated into second-line therapy as single agents or in combination with current agents in the future.     

What Is the Best Systemic Therapy for Left-sided <Emphasis Type="Italic">RAS</Emphasis> Wild-type Metastatic Colorectal Cancer?

Purpose of Review

There is a significant difference in embryological origin, gene expression, gene mutation profile, and microbiome between the right-sided and left-sided colon. It has been shown that the sidedness of primary colorectal cancer is a significant prognostic factor and predictive to the clinical benefit of anti-epidermal growth factor receptor (EGFR) antibody-containing chemotherapy in patients with metastatic CRC. Herein, current clinical recommendations for the treatment of patients with left-sided RAS wild-type mCRC are reviewed.

Recent Findings

Retrospective analyses of prior randomized trials (CRYSTAL, PRIME, FIRE-3, CALGB 80405, and PEAK trials) showed that primary tumor sidedness is predictive to anti-EGFR antibody therapy in the first-line treatment of patients with RAS wild-type mCRC, and patients with left-sided RAS wild-type mCRC had a significantly better survival benefit with anti-EGFR antibody plus chemotherapy when compared with anti-VEGF treatment plus chemotherapy.

Summary

The primary tumor sidedness is a significant prognostic factor and predictive to anti-EGFR antibody-containing chemotherapy in patients with metastatic CRC. Based on the currently available data, chemotherapy plus anti-EGFR antibody is recommended for the first-line treatment of patients with left-sided RAS wild-type mCRC. Chemotherapy plus bevacizumab or anti-EGFR antibody is recommended for the second-line therapy of RAS wild-type mCRC regardless of sidedness. However, these recommendations are based on the limited data from the retrospective analyses of prior trials, warranting further prospective randomized trials.

     

A retrospective analysis of second-line chemotherapy or best supportive care in patients with advanced-stage non-small-cell lung cancer

BACKGROUND: We retrospectively evaluated the clinical characteristics and outcome of patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) enrolled in first-line chemotherapy trials conducted by our group with respect to receiving or not receiving subsequent treatment. PATIENTS AND METHODS: Data were collected from 634 patients with stage IIIB/IV NSCLC treated with platinum and nonplatinum agent-based first-line regimens. Patient survival was calculated from the day of registration to first-line chemotherapy trials (OS1) as well as from the day of first-line treatment failure or the initiation of second-line chemotherapy (OS2) until death. The decision for administering second-line chemotherapy was, in all cases, at the discretion of the physician. Two hundred twenty-four patients (35.3%) received second-line chemotherapy (second-line group) in the context of second-line clinical trials run by the same group, and 410 (64.7%) received best supportive care (BSC group). There were significant differences between second-line and BSC groups in terms of age, histology, early discontinuation of first-line chemotherapy, and performance status after first-line treatment. RESULTS: Three (1.3%) complete and 25 (11.2%) partial responses to second-line chemotherapy were observed for an overall response rate of 12.5% (95% confidence interval, 8.2%-16.8%). The median OS1 was 13 months and 7 months (P < 0.001) and the OS2, 7 months and 3 months (P < 0.001) for the second-line and BSC groups, respectively. Multivariate analysis revealed that good performance status, disease stage IIIB, response to first-line treatment, and late termination of first-line chemotherapy were significantly associated with increased survival. The administration of second-line chemotherapy was also independently correlated with better outcome. CONCLUSION: The second-line chemotherapy and BSC groups represent different populations of patients with NSCLC. Factors indicative of increased probability of survival could be used to identify the subgroup of patients most likely to benefit from second-line chemotherapy.     

Results from the prospective German TPK clinical cohort study: Treatment algorithms and survival of 1,174 patients with locally advanced,inoperable, or metastatic pancreatic ductal adenocarcinoma

Pancreatic cancer is a highly lethal malignancy. Developments in recent years have broadened our therapeutic armamentarium. Novel drugs such as nab-paclitaxel, liposomal irinotecan and chemotherapy regimens such as FOLFIRINOX have been successfully tested in clinical trials. Data on patients outside of clinical trials are scarce but necessary to assess and improve the standard of care. We present data on treatment and survival of 1,174 patients with locally advanced, inoperable, or metastatic pancreatic ductal adenocarcinoma. Between February 2014 and June 2017, patients were recruited by 104 sites at start of first-line therapy into the ongoing, prospective clinical cohort study TPK (Tumour Registry Pancreatic Cancer). As first-line therapy, 89% of patients received one of the three treatment regimens: gemcitabine monotherapy (23%), nab-paclitaxel plus gemcitabine (42%), or FOLFIRINOX (24%). The corresponding subgroups differed: Patients receiving gemcitabine monotherapy were older and more comorbid (median age 78 years, 73% ECOG ≥ 1) than patients receiving nab-paclitaxel plus gemcitabine (median age 71, 64% ECOG ≥ 1) or patients receiving FOLFIRINOX (median age 60, 52% ECOG ≥ 1). At least 40% of patients died before receiving second-line treatment. First-line progression-free survival was 4.6 months (95% CI: 3.7–5.2) for gemcitabine, 5.6 months (95% CI: 5.0–6.2) for nab-paclitaxel plus gemcitabine, and 6.3 months (95% CI: 5.5–6.9) for FOLFIRINOX. Our data represent the treatment reality in a German community setting. Although there are no stringent inclusion criteria for our cohort study, overall survival is comparable to that reported by randomised clinical trials.     

Second-line chemotherapy and its evaluation in small cell lung cancer.

The literature on second-line chemotherapy for small cell lung cancer between 1989-1999 is reviewed. The reports consisted mainly of phase II studies and included a total of 1749 patients. The information was frequently incomplete with respect to duration of response on first-line chemotherapy and the length of treatment free interval. The overall second-line response rate was 20%. Obviously, new chemotherapy regimens are needed for relapsed small cell lung cancer. We propose a methodology for future trials based on the distinction between sensitive and refractory patients. The latter group of patients who progress on or within a short time of induction of treatment are candidates for single arm phase II trials with agents with unknown or new mechanisms of action or new combination regimens. The sole endpoint of this type of phase II studies is response rate. For sensitive patients we propose re-induction chemotherapy as the standard against which investigational agents or combination regimens should be tested. Major end-points include response rate, toxicity and quality of life. Regimens with demonstrated therapeutic activity in this setting could be tested as first-line chemotherapy in phase II trials.     

Vinflunine in the treatment of advanced bladder cancer

Accounting for 14,000 deaths in the USA last year, research informs us that advanced bladder cancer is a lethal disease with a median survival that has remained a little over 1 year for the past two decades. For the majority of patients with metastatic disease, chemotherapy with cisplatin-based combinations is the standard first-line treatment. Although initial response rates are high, disease progression is common, creating a growing number of patients in need of effective second-line chemotherapy. For this population, no standard of care currently exists. Salvage chemotherapy is associated with low response rates and studies exploring potential clinical benefit over supportive care alone are limited to nonrandomized Phase II trials. Vinflunine, a novel anti-mitotic drug from the Vinca alkaloid class, is the first and only agent that has been compared with supportive care in the second-line setting. In Europe, vinflunine is approved as a treatment option for patients with advanced urothelial cancer who have failed a prior platinum-containing regimen. To date, in the USA, there is no FDA-approved second-line chemotherapy for patients with metastatic bladder cancer and treatment continues to emphasize patient enrollment into a clinical trial.     

Role of targeted therapy in metastatic colorectal cancer

Colorectal cancer (CRC) is a significant cause of cancer-related morbidity and mortality all over the world. Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC (mCRC), with a median overall survival of approximately 2 years and more in the past two decades. The biologic agents that have proven clinical benefits in mCRC mainly target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In particular, bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated significant survival benefits in combination with cytotoxic chemotherapy in the first-line, second-line, or salvage setting. Aflibercept, ramucirumab, and regorafenib are also used in second-line or salvage therapy. Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy. Based on the evidence from large randomized clinical trials, personalized therapy is necessary for patients with mCRC according to their tumor biology and characteristics. The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mCRC.     

Ceftaroline fosamil as first-line versus second-line treatment for acute bacterial skin and skin structure infections (ABSSSI) or community-acquired bacterial pneumonia (CABP)

The Clinical Assessment Program and Teflaro^® Utilization Registry (CAPTURE) is a multicenter registry study of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP) patients treated with ceftaroline fosamil in the US. Data for this analysis were collected between August 2011 and February 2013 at US study centres by randomly ordered chart review. Clinical success rates among ABSSSI patients were >81% when ceftaroline fosamil was used as first- or second-line therapy, including monotherapy and concurrent therapy. Among CABP patients, clinical success rates were >77% among first-line and second-line patients and patients who received first-line concurrent therapy or second line monotherapy or concurrent therapy. For CABP patients treated with ceftaroline fosamil as first-line monotherapy, the clinical success rate was 70%. Ceftaroline fosamil is an effective treatment option for patients with ABSSSI or CABP with similar clinical success rates when used as first-line or second-line treatment.     

Recent advances for the treatment of pancreatic and biliary tract cancer after first-line treatment failure

Here, we evaluate clinical trials on chemotherapy for patients with pancreatic or biliary tract cancer after first-line treatment failure. Clinical trials on conventional and innovative medical treatments for progressive pancreatic and biliary cancer were analyzed. Metronomic chemotherapy, which consists of the administration of continuative low-dose of anticancer drugs, was also considered. A significant extension of overall survival was achieved with second-line, regimens in patients with gemcitabine-refractory pancreatic cancer. Moreover, many Phase II studies, including chemotherapy and target molecules and immunotherapy, have reported promising results, in both pancreatic and biliary cancer. However, data in these patients’ setting are very heterogeneous, and only few randomized studies are available.