Neoadjuvant chemotherapy in early-stage non-small cell lung cancer

Of the patients that undergo complete resection of early-stage non-small cell lung cancer (NSCLC), 30–60% will die. Postoperative adjuvant chemotherapy has yet to demonstrate an unequivocal benefit and there are significant difficulties in administering postoperative chemotherapy to patients with the significant comorbidities found in NSCLC. Currently, several trials are evaluating the role of preoperative chemotherapy in stage I and II NSCLC. This paper reviews the rationale for this approach and potential future developments.     

Adjuvant chemotherapy in early-stage non-small cell lung cancer

Approximately 80% of lung malignancies are non-small cell lung carcinoma (NSCLC). Patients diagnosed with early-stage disease (about 30% of patients) undergo surgery, but up to 50% develop local or distant recurrence. In an effort to improve survival for patients with resectable NSCLC, chemotherapy has been explored in the adjuvant setting. Several adjuvant trials were launched in the mid 1990s after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the International Adjuvant Lung Cancer Trial (IALT) study, with 1,867 patients included, confirmed the benefit of postoperative chemotherapy in resected NSCLC. More recently, modern platinum-containing doublets showed a 10% to 15% overall benefit compared to no adjuvant treatment. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.     

Neoadjuvant chemotherapy in early-stage non-small cell lung cancer

Of the patients that undergo complete resection of early-stage non-small cell lung cancer (NSCLC), 30-60% will die. Postoperative adjuvant chemotherapy has yet to demonstrate an unequivocal benefit and there are significant difficulties in administering postoperative chemotherapy to patients with the significant comorbidities found in NSCLC. Currently, several trials are evaluating the role of preoperative chemotherapy in stage I and II NSCLC. This paper reviews the rationale for this approach and potential future developments.     

Chemotherapy in stage I+II non-small cell lung cancer

Although surgical resection offers the best chance for long-term survival for patients with non-small cell lung cancer (NSCLC), the limited number of resectable patients and the presence of micrometastatic disease is limiting the effectiveness of this modality as sole treatment. Results of randomized trials demonstrated a survival benefit for preoperative (neoadjuvant) cisplatin-based chemotherapy in patients with stage IIIA NSCLC compared to surgery alone. In stage I+II NSCLC preoperative chemotherapy, although still experimental, clearly offers encouraging results. However, there is no evidence of its superiority over adjuvant chemotherapy. Moreover, for adjuvant therapy a benefit has not been established yet. Possibly current ongoing or recently finished trials may change the recommendations on adjuvant or neoadjuvant therapy for completely resected or resectable early disease in the future.     

The role of radiotherapy in treatment of stage I non-small cell lung cancer

Most information on results with radiotherapy (RT) for stage I non-small cell lung cancer (NSCLC) is based on retrospective studies on RT-treated inoperable NSCLC cases. Thus, the role of RT for stage I NSCLC, as a curative modality, has not yet been established. A literature search for studies on stage I non-small cell lung carcinoma (NSCLC) treated by RT alone resulted in 18 papers published between 1988 and 2000. The majority of stage I patients received RT treatment because they were medically inoperable. The main contraindications for surgery were grave impairment of pulmonary function and serious cardiovascular disease. Local recurrence was the most common reason for treatment failure (median value 40%) but varied highly between the studies, ranging from 6.4 to 70%. In contrast with local recurrence, regional failure was not a major problem (0-3.2%). Generally, smaller tumour size, low T-stage and increased dose had a favourable impact on local control and increased local control was followed by increased survival. No serious treatment complications were recorded in the majority of these studies. Overall treatment results were, however, disappointing. The median survival in these studies ranged from 18 to 33 months. The 3- and 5-year overall survival was 34+/-9 and 21+/-8% (mean value+/-1 S.E.), respectively. The cause-specific survival at 3 and 5 years was 39+/-10 and 25+/-9% (mean value+/-1 S.E.), respectively. Dose escalation, in a setting with conformal RT using involved field or stereotactic RT, should be the focus of developmental therapeutic strategies with inoperable stage I NSCLC to improve local control and survival.     

ⅠB期非小细胞肺癌术后辅助化疗的争议和共识

临床上有20％～25％的非小细胞肺癌（NSCLC）患者可手术治疗,但5年生存率也只有40％左右。辅助化疗是部分早期可切除肺癌的标准治疗方式,可使4％～15％的患者生存获益。但是,ⅠB期NSCLC是否能从辅助化疗中获益仍存在争议。近年来,多个临床研究评价了ⅠB期NSCLC辅助化疗的疗效,我们通过分析这些临床研究,寻找ⅠB期NSCLC的高危人群和辅助化疗的适应证。     

Surgical approach to non-small cell lung cancer stage I and II

No patient with a potentially curable lung cancer should be denied the opportunity for a curative resection. Solitary pulmonary nodules should be approached as though they were malignant until proven otherwise, either by definitive histologic or extremely convincing circumstantial clinical evidence. Consequently, thoracotomy should be performed, assuming that the patient is physiologically able, if cancer cannot be definitely excluded. The evaluation of patients with synchronous lung nodules is complex owing to the possible causes of the two nodules but should be pursued because of its important effect on therapeutic outcome. The major factor influencing survival is the extent of the tumor at the time of resection. When metastatic lymph nodes are found at the time of surgery, regardless of the location, the survival rate is significantly lower. Lobectomy for patients with stage I disease is usually sufficient treatment, but when the tumor is large (exceeding 4 cm) or centrally located or when hilar lymph nodes are involved, a pneumonectomy must be considered in order to eradicate local disease. Those patients with N1 disease can obtain improved survival when resection is combined with adjuvant radiation and chemotherapy.     

Prognostic factors in stage I/II non-small cell lung cancer

Even in localized stages of non-small cell lung cancer, which are amenable to curative surgery, prognosis has remained disappointing over the last decades. Thus, in these tumor stages, adjuvant therapy strategies are discussed. In the last decade, numerous prognostic factors have been investigated, which might select patients for additional treatment. In this review, the prognostic impact of individual tumor cell dissemination, tumor cell proliferation, apoptosis, several parameters of angiogenesis (microvessel density, VEGF, bFGF, VEGF receptors), p53, bcl-2, ras, p27(Kip1), erbB-2, telomerase as well as the retinoblastoma tumor suppressor gene is analysed. Up to now, none of these factors has gained a sufficient selectivity to serve as an exclusive discriminator for adjuvant therapy. Nevertheless, a combination of several parameters might contribute to characterize patient subgroups with localized non-small cell lung cancer at high risk for distant relapse.     

Role of chemotherapy and targeted therapy in early-stage non-small cell lung cancer

Introduction: Adjuvant platinum based chemotherapy is accepted as standard of care in stage II and III non-small cell lung cancer (NSCLC) patients and is often considered in patients with stage IB disease who have tumors ≥ 4 cm. The survival advantage is modest with approximately 5% at 5 years.

Areas covered: This review article presents relevant data regarding chemotherapy use in the perioperative setting for early stage NSCLC. A literature search was performed utilizing PubMed as well as clinical trial.gov. Randomized phase III studies in this setting including adjuvant and neoadjuvant use of chemotherapy as well as ongoing trials on targeted therapy and immunotherapy are also discussed.

Expert commentary: With increasing utilization of screening computed tomography scans, it is possible that the percentage of early stage NSCLC patients will increase in the coming years. Benefits of adjuvant chemotherapy in early stage NSCLC patients remain modest. There is a need to better define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy. Trials for adjuvant targeted therapy, including adjuvant EGFR-TKI trials and trials of immunotherapy drugs are ongoing and will define the role of these agents as adjuvant therapy.     

168例Ⅰ和Ⅱ期非小细胞肺癌放射治疗疗效观察

目的　探讨Ⅰ和Ⅱ期非小细胞肺癌单纯放射治疗的疗效及预后因素。方法　 16 8例中鳞癌 94例 ,腺癌 19例 ,鳞腺混合癌 3例 ,癌未分型 5 2例。放射治疗采用60 Co或 10MVX射线常规外照射 ,剂量为 4 0～ 76Gy。用Kaplan Meier法和Logrank法分析比较生存率 ,用Cox进行多因素回归分析。结果　放射治疗剂量≥ 6 5Gy组放射治疗结束时X射线片显示治疗有效 (CR +PR)率明显高于 <6 5Gy组 (χ2 =4 .4 2 ,P =0 .0 4 )。中位生存时间 2 2个月 ,总 1、3、5年生存率分别为 6 7.6 %、2 8.0 %、15 .7%。Cox回归模型分析显示放射治疗前患者是否伴有其他内科疾病及卡氏评分是影响患者预后的独立因素。结论　对于放弃手术治疗的早期非小细胞肺癌 ,放射治疗仍是一种有效的治疗手段。经选择的部分病例放射治疗剂量有必要达到 6 5Gy ,从而提高肿瘤局部控制率和患者生存率。     

The role of surgery in stage IIIA non-small cell lung cancer

For most patients who have stage III non-small cell lung cancer (NSCLC), a combination of chemotherapy and radiation represents the current treatment of choice. Recent developments include the use of adjuvant chemotherapy after up-front surgery in subgroups of patients who have stage III disease, as well as innovative ways to deliver concurrent chemoradiotherapy or combinations of chemotherapy with higher-dose conformal radiotherapy techniques. This article focuses on patients who have stage IIIA NSCLC and reviews the different possibilities for their treatment. Special emphasis is given to the inclusion of surgery into the different approaches to this disease stage. The current literature on this topic is reviewed, and the different aspects of surgical treatment in the management of stage IIIA NSCLC are discussed.     

Indications for chemotherapy in stage IV non-small cell lung cancer

Treatment of stage IV NSCLC has been a controversial issue during the last decade. However, there is now clear evidence that cisplatin-containing chemotherapy regimens lead to prolonged survival with an increase of the 1-year survival rates at about 10%. New drugs like gemcitabine, the taxanes (paclitaxel, docetaxel), and vinorelbine have shown very promising single-agent activity and have been included into modern combination chemotherapy regimens achieving response rates of 40 to 50% and 1-year survival rates of between 30 and 40%. In comparison to single-agent cisplatin or cisplatin/etoposide as 'standard treatment approaches', most of these modern combinations could demonstrate advantages in terms of response, survival and improved QOL. Patients with favourable prognostic factors are at the moment frequently treated with platinum-based combination chemotherapy often including one of these newer active drugs. Patients with adverse prognostic factors such as elderly or stage IV patients with a reduced performance status are preferably treated with single agents such as gemcitabine, paclitaxel or vinorelbine.     

Ⅰ期非小细胞肺癌的预后因素

Ⅰ期非小细胞肺癌(NSCLC)临床预后因素包括肿瘤大小和患者年龄、手术方式和胸膜浸润情况等.分子生物学预后因素包括肿瘤细胞信号通路中的表皮生长因子及其受体、细胞周期素和凋亡基因Bcl-2、p53的异常表达等,以及肿瘤血管生成中基质金属蛋白酶(MMP)、血管内皮生长因子(VEGF)的异常表达等.因此,需要将Ⅰ期NSCLC临床和分子生物学预后因素两方面综合考虑,才能准确判断预后.     

Radiation therapy for medically inoperable stage I and II non-small cell lung cancer

The published results of primary radiation therapy for early stage NSCLC, indicate that it is a reasonable alternative in patients with medical contraindications or who refuse surgery, resulting in acceptable morbidity, local control, and survival rates. There is no conclusive evidence that EMI is of benefit. Consequently treatment with involved field alone, may be considered when there is no evidence of hilar involvement, or when it is necessary to limit the volume of lung tissue irradiated. Although the data are not conclusive, there is evidence to suggest that the total dose of radiation delivered to the primary should be sufficient to eradicate gross disease (60 Gy or higher). Such does result in high response rates particularly for T1 tumors. There is also an indication that complete responders have better survival than other patients, suggesting that radiotherapeutic strategies to enhance tumor eradication may improve survival.     

Adjuvant therapy in resectable non-small cell lung cancer

In order to improve the management of lung cancer at various stages, we analyzed results of treatment in 928 of 1024 patients who were registered at our Hospital Tumor Registry of 1952-1983 with a pathological diagnosis of TNM for carcinoma of the lung after pulmonary resection. The 5-year-survival rate was 43% in 928 patients excluded the cases who were lost follow-up or succumbed within post-operative 1 month. The 5-year-survival rate was 77% for the stage I, 54.7% for the stage II, 17% for the stage III and 4% for the stage IV. The 5-year-survival rate by therapeutic modality was as follows: 52% for the group with chemotherapy, 35% for the one without adjuvant therapies, 29% for the one with irradiation and 15% for the one with radiochemotherapy. Patients with adenocarcinoma who underwent curative surgery showed improvement of survival by postoperative chemotherapy. No increase in survival time was noticed in the irradiated group with N2.     

Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer

Background:

Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.

Methods:

FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I–II. The FISH results were correlated with clinico-pathological features and overall survival (OS).

Results:

The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.

Conclusions:

FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.