Adjuvant chemotherapy for early-stage non-small cell lung cancer: the past, the present and the future

Complete resection is mandatory in order to achieve a cure in patients with early-stage non-small cell lung cancer (NSCLC). However, despite complete resection, a substantial proportion of patients have disease recurrence, with distant metastases being the primary sites of failure. Recent trials have conclusively demonstrated the benefit of platinum-based adjuvant therapy in patients with resected stage IB and II NSCLC. The role of adjuvant chemotherapy in resected stage III NSCLC is less clear, with trials showing conflicting results. The role of targeted agents in this setting is being investigated. Gene expression profiling studies should help direct chemotherapy to those who would actually benefit from it, thereby saving others from unnecessary toxicity.     

Adjuvant chemotherapy in non-small cell lung cancer

Adjuvant chemotherapy is considered a standard of care for many malignancies, the most well known being breast and colon cancer. Unfortunately, less than a third of patients with non-small cell lung cancer (NSCLC) present with resectable disease and despite resection outcomes are often poor with a median 5-year survival of 40-50%. Modern chemotherapy for NSCLC provides both a survival advantage and an improvement in quality of life in the palliative setting. Several large studies using modern platinum-based regimens have been presented since the 1995 meta-analysis. This demonstrated a nonsignificant benefit for older platinum-based regiments. These studies have consistently shown a survival benefit across all stages of resection with acceptable toxicity. The absolute magnitude of benefit is consistent with that achieved in other malignancies where adjuvant chemotherapy is offered as a standard of care.     

Evidence-based guidelines for adjuvant therapy for resected adenocarcinoma of the pancreas

Pancreatic cancer, the fourth most common cause of cancer deaths, has a five-year survival rate of 5% or less. Surgical removal of the tumor may improve survival, but survival remains poor even in optimally resected patients. The best adjuvant therapy for patients with resected pancreatic cancer is not clear. Surgical resection followed by chemoradiation and maintenance chemotherapy has been considered the most beneficial treatment for improving survival, but more recent studies have suggested that chemotherapy alone is more effective. The purpose of this article is to review randomized controlled studies of adjuvant chemoradiation or chemotherapy alone in the treatment of resected pancreatic cancer and to determine the optimal adjuvant therapy after curative resection with negative or microscopically positive margins. The outcomes of interest were overall survival and disease-free survival. The results indicate that chemoradiation is an acceptable option for adjuvant treatment. Three of the four randomized controlled trials suggest that adjuvant chemoradiation for resected pancreatic cancer improves overall survival. Adding gemcitabine to the chemoradiation regimen also confers increased disease-free survival. Providers counseling patients regarding treatment options for resected pancreatic cancer should continue to recommend adjuvant therapy--a combination of chemotherapy including gemcitabine and radiotherapy--for appropriately selected patients.     

The role of adjuvant chemotherapy in early-stage and locally advanced non-small cell lung cancer

Adjuvant chemotherapy benefits only a small proportion of patients in the setting of resected early-stage non-small cell lung cancer, and in unselected patients, any benefit is modest. Analysis of clinical trials of adjuvant chemotherapy revealed that differential expression of DNA repair proteins and a 15-gene expression profile affected outcomes with treatment. Biomarkers and gene expression profiles are now being studied in prospective clinical trials to gauge their value in selection of adjuvant therapy and individualization of therapy.     

Lung cancer]

Since the late 1980s, lung cancer incidence in men has declined in Germany whereas in women there is still a rise. There is no approved screening program for lung cancer up to now and results from randomized trials like the National Lung Screening Trial are eagerly awaited. In stage II and IIIA non-small cell lung cancer (NSCLC), several positive trials have demonstrated the advantage of adjuvant chemotherapy which is now an established modality to improve cure rates. Epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC. Erlotinib, an EGFR tyrosine kinase inhibitor, has been approved for relapsed advanced-stage NSCLC. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor, a primary mediator of angiogenesis that is commonly overexpressed in solid tumors including lung cancer. Bevacizumab, in combination with chemotherapy, has demonstrated improved outcomes in advanced NSCLC and is now approved for selected patients with advanced-stage NSCLC. Patient selection for therapeutic use of bevacizumab is crucial to optimize safety. Ongoing trials explore multitargeted agents such as sorafenib, sunitinib, and vandetanib.     

Chemotherapy for lung cancer

Chemotherapy is currently a primary treatment modality for small-cell lung cancer (SCLC). Combination chemotherapy of anticancer agents improves survival and mortality rather than chemotherapy with single agent. On the other hand, the role of chemotherapy in advanced non-small cell lung cancer(NSCLC) is still controversial. Several meta-analysis demonstrated a small but significant survival benefit of cisplatin-based chemotherapy. In the limited stage SCLC and locally advanced NSCLC, a combination of chemotherapy and thoracic irradiation was found to be superior to chemotherapy alone by several randomized trials and meta-analysis. Concurrent administration of anticancer agents with thoracic irradiation may be optimal treatment. In the last few years, several new agents have demonstrated antitumor activity against lung cancer and randomized trials of these drugs are now under way.     

Ⅲ A期非小细胞肺癌患者新辅助化疗的疗效分析

目的：观察新辅助化疗治疗Ⅲ A期非小细胞肺癌（NSCLC）总体缓解率、手术切除率和不良反应发生情况。方法：回顾分析20例术前临床诊断为Ⅲ A期NSCLC患者临床资料。结果：所有患者均完成术前诺维本＋顺铂（NP）或诺维本＋卡铂（NC）2周期化疗,休息2周后行手术治疗。手术完全切除肿瘤18例,手术切除率为90%;无手术死亡病例,围手术期肺部感染1例,心律失常1例,无其他并发症。结论：包含NP或NC的新辅助化疗可安全适用于Ⅲ A期NSCLC患者,并且对部分患者具有肿瘤降期和提高手术切除率的作用。     

Dendritic cells: a critical player in cancer therapy?

Cancer immunotherapy seeks to mobilize a patient's immune system for therapeutic benefit. It can be passive, that is, transfer of immune effector cells (T cells) or proteins (antibodies), or active, that is, vaccination. Early clinical trials testing vaccination with ex vivo generated dendritic cells (DCs) pulsed with tumor antigens provide a proof-of-principle that therapeutic immunity can be elicited. Yet, the clinical benefit measured by regression of established tumors in patients with stage IV cancer has been observed in a fraction of patients only. The next generation of DC vaccines is expected to generate large numbers of high avidity effector CD8 T cells and to overcome regulatory T cells and suppressive environment established by tumors, a major obstacle in metastatic disease. Therapeutic vaccination protocols will combine improved DC vaccines with chemotherapy to exploit immunogenic chemotherapy regimens. We foresee adjuvant vaccination in patients with resected tumors but at high risk of relapse to be based on in vivo targeting of DCs with fusion proteins containing anti-DCs antibodies, antigens from tumor stem/propagating cells, and DC activators.     

局部晚期结肠癌围手术期的治疗进展

局部晚期结肠癌由于不可手术切除、姑息性手术切除、易发生远处转移预后差。新辅助治疗通过缩小肿瘤、降低分期从而增加局部晚期结肠癌手术切除机会,提高R0切除率,但是新辅助治疗模式尚未形成统一。局部晚期结肠癌手术治疗遵循整块切除原则,以R0切除为目的,以全结肠系膜切除为标准术式。辅助化疗在降低术后复发及远处转移的作用已充分论证。本文从新辅助治疗、手术切除、辅助化疗3个方面作一综述,旨在为局部晚期结肠癌围手术期提供有价值的治疗选择和参考,使患者获得最佳的个体化治疗效果和生存获益。      

The 800-lb gorilla we all ignore: treatment of NSCLC in elderly and PS 2 patients

Patients with non-small cell lung cancer,NSCLC, typically have advanced disease on presentation. First-line palliative platinum-based doublet chemotherapy has emerged as the standard of care in fit, younger patients. However, patients with advanced age and/or impaired performance status have been relatively underrepresented in clinical trials. Retrospective analyses and the few existing prospective randomized trials in these populations have suggested a poorer overall prognosis, yet also provide evidence of benefit from systemic therapy. Toxicity is generally manageable, and in most cases, comparable to that of younger, healthier patients. There are clearly expanding roles for nonplatinum chemotherapy agents and newer targeted therapies, which have generally yielded decreased toxicity compared to platinum-based chemotherapy without sacrificing efficacy. Appropriate pretreatment assessment and proper patient selection is of paramount importance; it is imperative to treat patients who are most likely to garner benefit. In summary, data suggest that these relatively neglected populations of NSCLC patients can be safely treated, and can benefit from palliative systemic therapy. Single-agent chemotherapy is generally recommended over combination chemotherapy, although investigation of newer targeted therapies or alternative agents may allow for combination therapy in the near future. Further prospective investigation is absolutely warranted.     

Adjuvant chemotherapy for non-small-cell lung cancer

Survival rates following complete resection for patients with non-small-cell lung cancer are disappointing. Only 60-70% of patients with stage I disease (no lymph node involvement) are expected to survive 5 years. Attempts to improve survival have included the use of chemotherapy, radiation, or both before or after surgery. The majority of randomized trials examining the use of postoperative therapies have not found a survival benefit. Many of these trials have enrolled small numbers of patients and have been underpowered to detect small, but significant, survival differences. Recent data from large, randomized international trials have yielded conflicting results. The use of postoperative therapy should continue to be studied in clinical trials and a new meta-analysis incorporating results from recently completed randomized trials should be conducted.     

多模式综合治疗胃癌

胃癌在全球恶性肿瘤致死原因中排名第二位。尽管完整外科手术切除是治愈早期胃癌的唯一方法,但是,对于进展期胃癌,单纯手术长期生存者仅占30%。为了提高现状,必须进行包括化疗、放疗及外科治疗的多模式综合治疗。最近的临床试验已经证明,联合不同的新辅助或辅助治疗方案生存获益优于单纯手术。此外,实施化疗联合新的靶向药物治疗在进展期胃癌多模式综合治疗中起至关重要的作用。本文重点讨论胃癌多模式综合治疗的方法及提高疗效的未来策略。     

Adjuvant systemic chemotherapy with gemcitabine for stage IV pancreatic cancer: a preliminary report of initial experience

BACKGROUND: The effects of gemcitabine on postoperative adjuvant chemotherapy were evaluated in patients with stage IV pancreatic cancer. The results were compared with those of our historical control patients treated with surgery alone. PATIENTS AND METHODS: Nineteen patients with stage IV pancreatic cancer who had pancreatic resection with curative intent during the 5 years up to February 2003 were enrolled in this study. Nine cases received postoperative adjuvant chemotherapy with biweekly administration of 1,000 mg/m(2) gemcitabine, while the remaining 10 cases underwent surgery without any adjuvant chemotherapy. Results: The chemotherapy was well tolerated with only mild symptomatic and hematologic toxicities. The disease-specific cumulative survival rates of the chemotherapy and surgery-alone groups were 86 and 70% at 1 year, and 50 and 12% at 2 years, with a median survival of 20 and 14 months, respectively (p = 0.0255). The disease-free interval was improved, and the occurrence of hepatic metastasis was reduced in the chemotherapy group compared with the surgery-alone group. CONCLUSIONS: Adjuvant systemic chemotherapy utilizing gemcitabine was feasible with acceptable adverse effects, and showed some survival benefit in stage IV pancreatic cancer patients. Further investigation into gemcitabine-based combination therapies is warranted.     

Pembrolizumab for the first-line treatment of non-small cell lung cancer

Introduction: Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field.

Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and ?189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created.

Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.     

Adjuvant chemotherapy in oesophageal cancer: a meta-analysis and experience from the Shanghai Cancer Hospital

Whether adjuvant chemotherapy increases survival of oesophageal cancer patients has been widely debated. The present study used meta-analysis software to combine data from six studies up to July 2007 that were found and selected as suitable, comprising a total of 1001 oesophageal cancer patients. The results indicated that adjuvant chemotherapy did not significantly improve outcome in oesophageal cancer patients. A trend towards improved outcome from adjuvant chemotherapy was found in lymph node-positive patients, but did not reach significance. In our own study including 270 oesophageal cancer patients, adjuvant chemotherapy did not improve overall patient survival, but did improve survival for patients with metastases in cervical and/or celiac lymph nodes (stage IVa). Although our study had the largest patient sample, more prospective clinical trials with large numbers of patients are necessary to confirm the value of adjuvant chemotherapy in stage IVa patients.     

Radiation therapy for extrahepatic bile duct cancer: Current evidences and future perspectives

Extrahepatic bile duct cancer (EBDC) is a rare malignancy that involves neoplastic changes extending from both hepatic ducts to the common bile duct. The treatment of choice is surgical resection, but the predominant pattern of initial treatment failure is locoregional recurrence. Accordingly, adjuvant radiotherapy has been administered after surgical resection based on these rationales. At this time, there is minimal evidence supporting adjuvant radiotherapy, because there have been no phase III trials evaluating its benefit. Relatively small retrospective studies have tried to compare outcomes associated with EBDC treated with or without radiotherapy. We aimed to review studies investigating adjuvant radiotherapy for resected EBDC. Because less than one-third of EBDC cases are amenable to curative resection at diagnosis, other locoregional treatment modalities need to be considered, including radiotherapy. The next aim of this review was to summarize reports of definitive radiotherapy for unresectable EBDC. Patients with advanced EBDC often experience biliary obstruction, which can lead to jaundice and progress to death. Biliary stent insertion is an important palliative procedure, but stents are prone to occlusion after subsequent ingrowth of the EBDC. Radiotherapy can be effective for maintaining the patency of inserted stents. We also reviewed the benefit of palliative radiotherapy combined with the biliary stent insertion. Lastly, we discuss the existing gaps in the evidence supporting radiotherapy in the management of EBDC.     

Toripalimab in an advanced non-small cell lung cancer patient with poor general condition after multiline treatment: a case report

Several clinical trials have proven that immunotherapy can improve survival and benefit non-small cell lung cancer (NSCLC) patients. In patients who progress after chemotherapy, immune checkpoint inhibitor (ICI) monotherapy can prolong overall survival compared with patients receiving single-agent chemotherapy. A 61-year-old man diagnosed with advanced NSCLC and without driver variants received first-line chemotherapy but experienced recurrence. During subsequent treatment, the disease progressed rapidly, and his general condition deteriorated; therefore, toripalimab monotherapy was initiated. Surprisingly, he responded well, and symptoms were relieved after several treatment cycles despite pseudoprogression, shown in chest images. For driver gene-negative NSCLC patients who progress after chemotherapy and who develop poor performance status (PS), ICIs are an option to alleviate symptoms and improve survival. Furthermore, immunotherapy in patients with pseudoprogression may also provide a survival benefit.     

Metastatic malignant melanoma of the gastrointestinal tract

Malignant melanoma is one of the most common malignancies to metastasize to the gastrointestinal (GI) tract. Metastases to the GI tract can present at the time of primary diagnosis or decades later as the first sign of recurrence. Symptoms may include abdominal pain, dysphagia, small bowel obstruction, hematemesis, and melena. We report 2 cases of malignant melanoma metastatic to the GI tract, followed by a review of the literature. The first case is a 72-year-old man who underwent resection of superficial spreading melanoma on his back 13 years previously who presented with dysphagia. A biopsy specimen of a mucosal fold in a gastric fundus noted during endoscopy was taken and revealed metastatic malignant melanoma, which was resected 1 month later. Three weeks later, the patient was found to have an ulcerated jejunal metastatic melanoma mass, which was also resected. The second case is a 63-year-old man with an ocular melanoma involving the chorold of the left eye that had been diagnosed 4 years previously, which had been excised several times, who presented with anorexia, dizziness, and fatigue. He was found to have cerebellar and stomach metastases. He underwent adjuvant radiation therapy, chemotherapy, and surgical resection of the gastric melanoma metastasis. In patients with a history of melanoma, a high index of suspicion for metastasis must be maintained if they present with seemingly unrelated symptoms. Diagnosis requires careful inspection of the mucosa for metastatic lesions and biopsy with special immunohistochemical stains. Management may include surgical resection, chemotherapy, immunotherapy, observation, or enrollment in clinical trials. Prognosis is poor, with a median survival of 4 to 6 months.     

Trastuzumab for the treatment of non-small-cell lung cancer

OBJECTIVE: To evaluate trastuzumab for the treatment of advanced non-small-cell lung cancer (NSCLC).DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-January 2003), EMBASE (1974-January 2003), International Pharmaceutical Abstracts (1970-January 2003), Proceedings of the American Society of Clinical Oncology (1995-January 2003), and Genentech. Key search terms included trastuzumab, lung cancer, Herceptin, and NSCLC.DATA SYNTHESIS: Research has revealed that NSCLC specimens may express the protein HER-2/neu. The monoclonal antibody against HER-2/neu, trastuzumab, could prove valuable for patients. An evaluation of the studies exploring trastuzumab for management of NSCLC was conducted. Phase II clinical trials reveal variable response rates from no improvement to a partial response rate of 42%. Due to a lack of clinical trials and deficiencies in the literature, the ultimate benefit of this agent remains to be proven.CONCLUSIONS: Clinical data from ongoing trials indicate potential synergy when trastuzumab is added to standard chemotherapy. The ultimate benefit in NSCLC remains to be proven.     

Necitumumab for non-small cell lung cancer

Introduction: Targeting the EGFR pathway is a rational approach to treat patients with advanced NSCLC. Necitumumab, a second-generation recombinant fully human immunoglobulin G1 monoclonal antibody directed against EGFR, has recently been assessed in combination with first-line cisplatin-based chemotherapy.

Areas covered: This article reviews literature on necitumumab development, from preclinical data to results of Phase III clinical trials, either published or presented in international scientific conferences. Ongoing clinical trials were searched with the clinical-trials.gov website.

Expert opinion: During the last decade, advances in treatment of metastatic NSCLC have been exclusively achieved in patients with non-squamous histology. In this context, any treatment improvement, even modest, was eagerly awaited for patients with squamous NSCLC. In this patient’s population, the SQUIRE Phase III study demonstrated a relatively small, but statistically significant survival benefit in patients treated with necitumumab in combination with standard chemotherapy (cisplatin and gemcitabin) compared with those treated with chemotherapy alone. However, the identification of predictive biomarker for treatment outcome is still needed to select the patients who will experience a large benefit from the targeted treatment.