Nonsurgical therapy for stages I and II non-small cell lung cancer

For patients who have stages I and II non-small cell lung cancer (NSCLC) and who are unable or unwilling to undergo surgical resection, nonsurgical treatment modalities have been used with curative intent. Conventionally fractionated radiotherapy has been the mainstay of nonsurgical therapy; however, advances in technology and the clinical application of radiobiologic principles have allowed more accurately targeted treatment that delivers higher effective doses to the tumor, while respecting the tolerance of surrounding normal tissues. This article discusses nonsurgical approaches to the treatment of early-stage NSCLC, including several promising techniques, such as radiation dose escalation, altered radiation fractionation, stereotactic radiotherapy, and radiofrequency ablation.     

Second primary tumors following adjuvant therapy of resected stages II and IIIa non-small cell lung cancer

The occurrence of second primary tumors (SPTs) following adjuvant therapy for resected stages II and IIIa non-small cell lung cancer (NSCLC) was investigated. Data regarding SPTs were prospectively collected in all patients accrued to Eastern Cooperative Group Oncology E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC). Four hundred eighty-eight patients were accrued to the study, 242 to the RT arm and 246 to the CRT arm. Median follow-up was 73 months. Thirty patients (6.1%) developed 33 SPTs, 20 in the RT arm and ten in the CRT arm. Ten SPTs occurred within the upper aerodigestive tract, six in the RT arm and four in the CRT arm. Twenty-three SPTs occurred in other organs, 17 in the RT arm and six in the CRT arm. Median time to detection of a SPT for those patients randomized to RT and CRT was 43 and 36 months, respectively. The incidence of SPTs was 1.8% per patient-year of follow-up. Excluding skin tumors, the relative risk of death following diagnosis of a SPT for patients randomized to the CRT arm as compared with those randomized to RT alone was 2.26 (95% confidence interval, 0.78-5.58, P=0.12). Patients are at risk for developing a SPT following resection of stages II and IIIa NSCLC. The majority of SPTs occur outside the aerodigestive tract. Following development of a non-skin SPT, the survival difference between patients who had received adjuvant CRT and those treated with adjuvant RT alone was not significant.     

Neoadjuvant and adjuvant therapy of non-small cell lung cancer

Though surgery offers the best chance of cure for patients with non-small cell lung cancer (NSCLC), many patients who undergo complete tumor resection will die of recurrent disease. Chemotherapy and radiotherapy have been employed both individually and in combination in an effort to prevent local recurrence and extrathoracic metastatic disease. However, the administration of neoadjuvant or adjuvant therapy remains controversial. Phase II and III trials with traditional radiotherapy schedules and cytotoxic drugs have produced conflicting results. Novel approaches utilizing long-term administration of less toxic drugs and targeted biologic therapies are promising.     

Role of adjuvant therapy in resected stage II/IIIA non-small-cell lung cancer

The role of adjuvant therapy following complete resection of node-positive (stage II/IIIA) non-small-cell lung cancer remains controversial. Five-year survival rates in pathologic stage II disease range from 30% to 50% and in resected stage IIIA disease from 10% to 30%. The majority of recurrences following surgery are distant metastases. This two-part review, which began in the December 2001 issue, analyzes the role of adjuvant therapy in this setting, using an evidence-based approach and focusing primarily on randomized trials and meta-analyses. The key variables in evaluating these studies are elucidated, ranging from the extent of mediastinal, systemic, and "molecular" staging to the quality of the adjuvant treatments administered. Some of the potential flaws inherent in meta-analyses are reviewed. To date, there is no convincing evidence that any therapy consistently improves survival in the adjuvant setting. Postoperative radiotherapy has been associated with a significant improvement in local control, particularly in patients with pathologic N2 disease. Chemotherapy should be offered to patients on appropriate clinical trials, and active phase III trials are reviewed. Future strategies include novel chemotherapy, methods to reduce toxicity, the emerging role of neoadjuvant therapy, and the promise of new biologic agents.     

非小细胞肺癌辅助靶向治疗进展

目前术后Ⅱ~ⅢA期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者推荐进行术后辅助化疗,但在带来生存获益的同时,化疗毒性难以忽视,寻找新的高效、低毒、个体化治疗方案迫在眉睫。表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI）依靠其高效低毒的特点,目前在晚期非小细胞肺癌得到广泛应用,为了探索更加有效的治疗模式,国内外学者进行了大量的尝试,试图将靶向治疗延伸到术后辅助治疗的范畴。以期真正指导临床实践,使非小细胞肺癌患者术后能够从靶向治疗获益,提高术后生存率。      

Neoadjuvant and adjuvant therapy of non-small cell lung cancer.

Present treatment options for non-small cell lung cancer in the adjuvant and neoadjuvant settings are far from ideal. The bottom line of improvement in overall survival by any treatment modality used has yet to be achieved. For this to happen, better drug therapy will be required. Future trials should be carefully designed with intraoperative staging and stratification of patients by histology, stage, and potentially immunologic markers, ploidy, and molecular biologic markers such as growth factors and their receptors. Combination of individual therapies to maximal toxicity in an attempt to overcome inherent tumor resistance will be key. The use of colony-stimulating factors, with high-dose chemotherapy integrated with hyperfractionated radiotherapy, may be seen in future studies. Combining standard chemotherapy and radiotherapy with cytokines or immunotherapy using interleukin-1 and -2, or tumor necrosis factor or monoclonal antibodies to growth factors may be seen in innovative trials. By such meticulously and intelligently designed trials, progress in adjuvant and neoadjuvant treatment of the important group of patients with locally advanced non-small cell lung cancer will occur.     

Predictive markers in the adjuvant therapy of non-small cell lung cancer

Adjuvant chemotherapy increases the 5-year survival rate of patients with completely resected non-small cell lung cancer (NSCLC) by absolute 5%. Molecular-targeted therapies and predictive biomarkers to select those patients who benefit hold promise to further improve the outcome. Several biomarkers including ERCC1, BRCA1, EGFR, or gene signatures have been characterized in retrospective analyses of adjuvant therapy trials. However, differences in trial design and laboratory tests might have affected the outcome and might explain discordant results. With regard to many biomarkers, laboratory tests for their assessment remain to be standardized. After standardization of these tests and further validation studies, biomarkers might allow individualizing adjuvant treatment in patients with completely resected NSCLC in the future.     

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.     

Twelve-year follow-up of trimodality therapy for stage IIIA non-small cell lung cancer.

Non-small cell carcinoma of the lung (NSCLC) remains a formidable problem with a poor 5 year survival for stage III patients. Between 1985-1991, 53 patients with biopsy proven Stage IIIA NSCLC were treated with a trimodality treatment program. Chemotherapy, consisting of two cycles of continuous infusion cisplatinum and bolus etoposide, was started on days 1 and 28 of radiation therapy (54 Gy + 5.4 Gy boost in 6 1/2 weeks) directed to the lung primary and mediastinum. Four to six weeks after radiation therapy, patients underwent thoracotomy for radical pulmonary resection. Three weeks post surgery, the same chemotherapy was repeated for two cycles every 28 days. Forty-seven out of 53 patients (89%) achieved a clinical response after induction chemoradiation. Of these 47 patients, 33 underwent thoracotomy and 27 of them completed surgical resection. Treatment was well-tolerated. All surviving patients have no or minimal respiratory toxicities. With a median follow up of 9 1/2 years, surgically treated patients have a disease specific survival of 42% at 12 years. One patient survived beyond 9 years without surgery. Concurrent chemoradiation plus surgery is well tolerated and offers patients with Stage IIIA NSCLC significant long term survival benefit and warrants further assessment in a randomized trial.     

Surgical approach to non-small cell lung cancer stage IIIA

Patients with stage IIIa non-small cell carcinoma of the lung who could benefit from surgical treatment include those with tumors that invade chest wall, diaphragm, or mediastinum, as well as patients who present with mediastinal lymph node involvement. As long as surgery remains the most effective mode of treatment in non-small cell lung carcinoma, it is important that it be made available, when indicated, to the greatest number of patients possible. The continuing high incidence of deaths due to distant metastases underscores the need to combine effective chemotherapy and radiotherapy with the surgical treatment.     

Chemo-radiotherapy versus chemo-surgery in stage IIIA non-small cell lung cancer

Forty patients with non-small cell lung cancer stage IIIA, aged 33-72 years were allocated to two groups in order to get therapy of two different combined modalities. All the patients were staged and considered inoperable. Staging was done by bronchoscopy, CT scan, bone scan and in patients with mediastinal lymph nodes less than 2 cm in size by thoracotomy. Group A patients were programmed to have induction chemotherapy and then radiotherapy while patients of group B to have induction chemotherapy, of the same kind as Group A and then surgery. Chemotherapy included cis-platinum 90 mg/m(2) given once every 3 weeks for 4-6 courses. Radiotherapy of Group A patients was 5000 cGy in the primary tumor site and mediastinum. Toxicity was tolerable. The following results were obtained: a) high response rate (over 70%) after chemotherapy, b) 66% of Group B patients were redered operable and c) the survival rate was significantly higher in patients with chemo-surgery versus those with chemo-radiotherapy.     

Surgery and chemoradiation in stage IIIA non-small cell lung cancer]

Combination of surgery and radiotherapy has become a standard regimen in multiple cancers. Because of its toxicity and the higher metastatic potential of lung cancer, leading to underestimate the impact of loco-regional treatments, this strategy is currently used only in a clinical trial setting. Recent results from phase III studies comparing surgery and radiotherapy in stage IIIA-N2 locally advanced non-small cell lung cancer after induction treatment showed that surgery should only be performed in patients presenting with a major mediastinal downstaging and possible curative resection within a lobectomy. In all other cases, exclusive chemoradiation remains the therapeutic standard at the time. In this way, all patients with stage III non-small cell lung cancer may receive induction treatment, consisting either in chemotherapy or in sequential or concurrent chemoradiation, which has shown its feasibility and its efficacy regarding tumor response, resectability and local control rates. These two induction regimens are currently compared in randomized trials including stage III resectable and unresectable tumors at time of diagnosis. These developments make treatment of locally advanced non-small cell lung cancer a model for multimodal strategies in oncology, combining chemotherapy, radiotherapy and surgery.     

Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer

Consensus on adjuvant therapy for completely resected non-small cell lung cancer until 2002 was as follows. (1) There was no significant impact of postoperative adjuvant chemotherapy based on meta-analysis and previous clinical trials. (2) Confirmatory studies are necessary in large-scale prospective clinical trials. However, recent mega trials have introduced epoch-making changes for postoperative adjuvant chemotherapy in clinical practice since ASCO 2003. The effectiveness of UFT in N0 patients was confirmed. Patients with completely resected stage I non-small cell lung cancer, especially T2N0 adenocarcinoma, will benefit from adjuvant chemotherapy with UFT. The results of the International Adjuvant Lung Trial (IALT) have confirmed the meta-analysis in 1995. Also, both the JBR10 and Cancer and Leukemia Group B (CALGB) 9633 studies have also confirmed positive IALT results of the benefit for postoperative platinum-based chemotherapy in completely resected non-small cell lung cancer. Adjuvant chemotherapy for pathological stage IB to II, completely resected non-small cell lung cancer is standard care based on clinical trials. UFT showed the strongest evidence for IB in Japan. Platinum doublet chemotherapy with third-generation anticancer agents is also recommended. Adjuvant chemotherapy should be offered as standard care to patients after completely resected early stage non-small cell lung cancer. However, there is no evidence of the feasibility and efficacy for adjuvant chemotherapy with the platinum-based regimen in Japan. Careful management should be necessary in such treatment.The ASCO-JSCO Joint Symposium was held in Kyoto, Japan, on October 29, 2004.     

早期非小细胞肺癌完全切除术后的辅助治疗

外科手术切除是早期非小细胞肺癌的标准治疗方式,文献报道外科可以提供给早期肺癌病人最佳的治愈率。然而,标准的肺叶切除或全肺切除及纵隔淋巴结清扫后IA期病人的5年生存率为68.5%,IB期为66.6%,许多病人死于癌转移[1]。而肺段切除则较多发生局部复发     

The influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer

This study evaluates the influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer (NSCLC). The Eastern Cooperative Oncology Group conducted a randomized prospective trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC. A laboratory correlative study assessed the prevalence and prognostic significance of p53 and K-ras mutations. Patients were randomized to receive either radiotherapy (RT) alone or four cycles of cisplatin and VP-16 administered concurrently with radiotherapy (CRT). Median survival was 35 months for the 285 men and 41 months for the 203 women enrolled in the study (P = 0.12). The relative risk (RR) of death for men vs women was 1.19 (95% confidence interval [CI], 0.95-1.49). Median survival of the 147 men and 95 women randomized to the RT arm was 39 months each (P = 0.35). Median survival of the 138 men and 108 women randomized to the CRT arm was 30 and 42 months, respectively (P = 0.18). Disease recurrence patterns were similar between the genders. Univariate and multivariate analyses demonstrated improved survival for women with tumors of non-squamous histology (P < 0.01). The distribution of p53 and K-ras mutations was similar between the genders and had no influence on survival. Gender does not influence survival following adjuvant RT or CRT administered to patients with completely resected stages II and IIIa NSCLC. However, women with non-squamous histology have increased survival when compared to men.     

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.     

Surgical adjuvant chemotherapy in non-small cell lung cancer

In two different controlled prospective randomized trials the Lung Cancer Study Group has shown that adjuvant CAP chemotherapy is effective in prolonging the disease-free survival. These studies indicate that the adjuvant chemotherapy has its effect by way of diminishing systemic recurrences and that the adjuvant therapy is more effective in non-squamous than in squamous disease. In addition, the benefit of the treatment is more apparent in patients with more advanced, though resectable, disease. It is also becoming clear that chemotherapy either alone or in combination with radiation therapy can result in relatively high response rates in patients with disease localized to the thorax. Indeed, many of these individuals can then undergo surgical resection. It remains to be determined, however, whether or not this preoperative therapy will be effective in prolonging survival. In the future it is quite likely that optimum therapy will involve the use of preoperative treatment either with chemotherapy alone or a combination of chemotherapy and radiation therapy, followed postoperatively with adjuvant chemotherapy with a non-cross resistant regimen. In addition, a major problem is brain recurrences. Indeed the brain was the most frequent site of first recurrence systemically in many of these studies. Thus, more effective therapy directed at CNS disease will have to be developed before major breakthroughs can be anticipated in the surgical adjuvant therapy of lung cancer.     

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.