Adjuvant chemotherapy for non-small cell lung cancer

The survival after complete resection for non-small cell lung cancer (NSCLC) is unsatisfactory. Until recently, the use of adjuvant therapy after resection for early stage disease has not been proven to improve survival. However, the efficacy of adjuvant therapy has been demonstrated in phase III prospective randomized trials. The appropriate use of adjuvant therapy, including biologic therapy, is currently under investigation.     

Adjuvant chemotherapy for resectable non-small cell lung cancer (NSCLC)

A randomized clinical trial of adjuvant chemotherapy has been evaluated for non-small cell lung cancer (NSCLC) patients, because the prognosis of early NSCLC does not enough after surgery (stage I: 70-80%, stage II: 50% in overall 5-years survival). Japanese guide line for lung cancer treatment (2005 edition) recommends adjuvant chemotherapy after complete resection for pathological stage IB, II and IIIA. Previous studies have suggested that uracil-tegafur has benefit for stage IB NSCLC patients, and platinum-based adjuvant chemotherapy has benefit for stage IB, II and IIIA NSCLC patients. In 2007 ASCO Annual Meeting, Harpole D talked about molecular prognostic profiles in early resected NSCLC. The goal of this study design is to validate a molecular-based tumor model that identifies those patients at low risk for cancer recurrence who will not benefit from adjuvant chemotherapy. The remaining patients will be randomly assigned to observation (the present standard of care) or adjuvant chemotherapy to determine the efficacy of adjuvant in this population. Biomarker for response of chemotherapy will be available to know who has benefit from adjuvant chemotherapy. When each patient has appropriate adjuvant chemotherapy, the prognosis is improved by that.     

Survival and prognostic factors of surgically resected T4 non-small cell lung cancer

BACKGROUND: Category T4 nonsmall cell lung cancer (NSCLC) encompasses heterogenous subgroups. We retrospectively analyzed the survival of patients with surgically resected T4 NSCLC to evaluate the evidence for prognostic implications according to the subgroups of T4 category, nodal status, and resection completeness. METHODS: Seventy-six patients with T4N0-2M0 NSCLC were divided into three subgroups within the T4 category: 24 patients with the tumor invading the mediastinal organs (mediastinal group), 16 with a malignant pleural effusion or dissemination (pleural group), and 36 with satellite tumor nodules within the ipsilateral primary tumor lobe (satellite group). Complete resection was possible in 47 patients (61.8%). The pathologic N statuses were N0 in 28, N1 in 13, and N2 in 35 patients. RESULTS: The overall survival of the 76 patients was 19.1% at 5 years. The overall 5-year survivals according to the three subgroups of the T4 category were as follows: mediastinal group, 18.2%; pleural group, 0%; and satellite group, 26.7% (mediastinal/satellite versus pleural, p = 0.037). Factors significantly influencing the overall 5-year survival were the pathologic N status (N2 versus N0-1, p = 0.022) and the completeness of resection (complete versus incomplete, p = 0.0001). A multivariate survival analysis demonstrated that the pathologic N status and the completeness of resection were significant independent predictors of a poorer prognosis even after adjusting for the subgroup of the T4 category. CONCLUSIONS: Resectable T4N0-1 NSCLC that is not due to pleural disease deserves consideration of aggressive surgical resection with expected 5-year survival of about 20%.     

Prognostic factors in patients with surgically resected stages I and II non-small cell lung cancer

BACKGROUND: About one-third to one-half of patients with early stages of non-small cell lung cancer (NSCLC) succumb to their disease. In this study, we attempted to identify prognostic factors that predict outcome in patients with stages I and II NSCLC. METHODS: A retrospective evaluation of 454 patients with surgically resected stages I and II NSCLC was performed to determine the impact of various clinical, laboratory, and pathological factors on patient outcome such as overall survival (OS) and event-free survival (EFS). RESULTS: Patients older than 65 years had shorter EFS and OS than younger patients (p = 0.002). Patients with preoperative hemoglobin less than or equal to 10 g% had shorter EFS and OS compared to patients with a hemoglobin greater than 10 g% (p = 0.001). Expectedly, OS and EFS were shorter in patients with stage II as compared to stage I patients (p < 0.001). In a multivariate analysis, age, hemoglobin level, and stage remain significant predictors for EFS and OS. CONCLUSIONS: Older age, anemia, and higher stage are important prognostic factors in patients with surgically resected stage I and II NSCLC.     

Adjuvant chemotherapy and the role of chemotherapy resistance testing for stage I non-small cell lung cancer

The frequency of in vitro chemotherapy resistance in NSCLC is extraordinary: however, its clinical relevance remains unproved. Future studies on the use of the EDR assay and its integration into clinical trials is justified. To achieve the goal "to do no harm", the EDR has a role in eliminating some ineffective agents to avoid unnecessary toxicity, and when possible, in directing therapy. Empiric adjuvant chemotherapy for resected NSCLC may soon become passe as reproducible and generally available molecular testing becomes more common. Profiles from DNA and RNA expression analysis not only help define patients at risk for early recurrence and unresponsiveness to commonly used cytotoxic drugs, but also assist in the development of new assays that are less expensive, reliable, and can be used more commonly than arrays.     

The present status of postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancers, with patients having a poor prognosis. Approximately one third of NSCLC patients present with early-stage disease in which potentially curative resection and multi-modality therapy. Although adjuvant chemotherapy is the standard practice for patients with stages I-III breast and colorectal cancer, the therapeutic efficacy of adjuvant chemotherapy, following complete surgical resection of early stage NSCLC, has not been fully established. Several prospective randomized trials for patients with early stage NSCLC (stages I-IIIA) have confirmed a survival benefit with cisplatin-based adjuvant chemotherapy, as demonstrated in the 1995 meta-analysis performed by the NSCLC Collaborative Group. Studies from Japan have reported that adjuvant therapy with uracil-tegaful (UFT) afforded an improvement of 4% in the 5-year survival rate and a relative risk reduction of 26% in mortality at 5 years among patients with T1-2N0 (stage I) disease. In particular, the Japan Lung Cancer Research Group has demonstrated an improvement in the 5-year survival rate of 11%, favoring chemotherapy with UFT in the subset of patients with T2N0 (stage IB) disease. Two published meta-analyses based on abstracts have estimated a relative risk reduction in mortality of 11-13% at 5 years. The Lung Adjuvant Cisplatin Evaluation (LACE), which was based on a pooled analysis of five randomized trials, has demonstrated that cisplatin-based adjuvant chemotherapy improved survival in patients with completely resected NSCLC. This benefit depended on stage, being greatest in patients with stage II or IIIA disease. This analysis has suggested that platinum-based adjuvant chemotherapy may have no benefit for patients with stage IA and only a marginal benefit for patients with stage IB. Thus, the information available at the current time supports the administration of adjuvant chemotherapy for patients who have undergone complete resection of stages IB-IIIA NSCLC. Further research is needed to define the role of adjuvant platinum-based chemotherapy and its use, in conjunction with chest radiotherapy as the treatment for patients with resected stages IB and IIIA NSCLC.     

Serum carcinoembryonic antigen level in surgically resected clinical stage I patients with non-small cell lung cancer

BACKGROUND: There is little general agreement concerning the effectiveness of serum carcinoembryonic antigen (CEA) as a prognostic indicator for non-small cell lung cancer (NSCLC) in clinical stage I patients. We conducted a retrospective study to investigate the relationship between serum CEA level and survival. METHODS: We assessed 297 consecutive patients with clinical stage I NSCLC who underwent surgical resection at Toneyama National Hospital from 1985 to 1998. Serum CEA levels were measured with an enzyme-linked immunosorbent assay kit with the upper limit of normal defined as 7.0 ng/mL based on the 95% specificity level for benign lung disease, in our hospital. RESULTS: There were 56 (19%) patients with serum CEA greater than 7.0 ng/mL. The high CEA group had a median survival time of 50 months and a 5-year survival rate of 49% compared with a 5-year survival rate of 72% (p < 0.0001) for the normal CEA group (n = 241). Patients with postoperatively high CEA levels (n = 15) had the worse prognosis (median survival time 35 months, and 5-year survival 18%) compared with patients whose levels returned to normal (n = 41, median survival time 8.8 months, and 5-year survival 68%; p = 0.01). These differences were also observed in patients with pathologic stage I or II tumors but not in those with pathologic stage III or IV tumors. CONCLUSIONS: Serum CEA level is a useful predictor of survival for patients with clinical stage I NSCLC, and a persistently high CEA level after surgery is an especially strong indicator of a very poor prognosis.     

Adjuvant chemotherapy for lung cancer

After analysing 1929 cases of resection for lung cancer under the classification of adjuvant therapy, histology, stage and chronology, we learned positive points of adjuvant chemotherapy and its problems. The five year survival rate of 45 cases of small cell carcinoma is 23.9% (oat cell 18.5%, intermediate 28.6%). Long-term survivors are always found among the stage I patients, however, better results (14.7%-60.6%) have been shown since 1980. This fact must be derived from recent achievements of chemotherapy. Seven cases of adjuvant surgery for small cell carcinoma shows needs of chemotherapy. The randomized controlled study by using vindesine for non-small cell carcinoma, stage III, and also other studies showed no signs of effectiveness of chemotherapy on non-small cell carcinoma. Clinical application of clonogenic cell assay has made an advance in selecting types of chemotherapy. The problems are, however, administration of drugs, i.e. selection of drugs, time and period to administrated, accurate diagnoses and precise judgement of clinical stage and drug tolerance of patients. We expect more effective drugs to come in the near future.     

Substantial risk affects the stage-dependent outcomes of cisplatin-based adjuvant chemotherapy for completely resected non-small cell lung cancer

Purpose

Effective adjuvant chemotherapy (Adj.C) for completely resected non-small cell lung cancer (NSCLC) was recently established. However, there may be some unresolved adverse effects, as have been observed in early stage populations or long-term survivors after other types of Adj.C. The substantial risk in such patients was examined by a mathematical method.

Methods

Variables X and Y were defined by two outcomes of Adj.C: X = the ability to eliminate micro-metastasis and Y = the development of effects that threaten life. Then, the following formula was generated: Survival benefit = (death rate) X ? (death rate) X Y ? (survival rate) Y. We then solved for X and Y and verified our findings using reported data from clinical trials.

Results

By solving two simultaneous equations for the formula applied to the data for stage (1) IA and (2) IIIA in the LACE study (J Clin Oncol 26:5043–5051, 2008), X and Y were 2.6 and 1.9, respectively. When these values were applied in the formula for stage IB patients in the same study, the theoretical (?2.3 %) and reported values (2.5 %) were close. When these were applied for stage IB–IIIA patients in the IALT study (N Engl J Med 350:351–360, 2004), the theoretical (5.0 %) and reported values (4.1 %) were also similar.

Conclusion

Assuming a substantial risk provides an explanation for the stage-dependent outcomes of Adj.C for completely resected NSCLC.     

Postoperative chemotherapy for resected non-small-cell lung cancer

Surgical resection is the treatment of choice for patients with stage I and stage II non-small-cell lung cancer (NSCLC—squamous cell, adenocarcinoma, and large-cell carcinoma). Distant recurrence is an important cause of death after complete surgical resection, occurring in 30–60% of patients. Postoperative adjuvant chemotherapy has been studied for over three decades in randomized controlled trials but is not considered standard therapy for this group of patients. The use of multidrug regimens including cisplatin has produced a prolongation of disease-free survival, but until recently no overall survival benefit has been shown. A new generation of studies is now warranted, employing the more active combinations identified in the 1980s or incorporating one of the many promising new agents being tested in NSCLC. The use of improved supportive care measures, such as the new serotonin receptor antagonist antiemetics, is required to increase compliance with chemotherapy in this group of patients. With this approach, the real goal of adjuvant system chemotherapy—to increase the number of patients actually cured of their cancer—may be attained in early stage NSCLC.

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Resumen La resección quirúrgica es el tratamiento de la elección para pacientes con cáncer pulmonar de células no pequenas (escamacelular, adenocarcinoma y carcinoma de células grandes) en estados I (T1,2;N0) y II (T1,2:N1). La recurencia a distancia es una causa importante de muerte luego de resección quirúrgica completa, lo cual ocurre en 30–60% de los casos. La quimioterapia postoperatoria coadyuvante ha sido valorada por más de tres decenios en ensayos clínicos randomizados, y no se ha considerado una modalidad terapéutica estándar para este grupo de pacientes. El uso de regímenes con múltiples drogas, incluyendo el cisplatino, ha resultado en prolongación de la supervivencia libre de enfermedad, pero hasta hace poco tiempo no se había demostrado un beneficio sobre la supervivencia global. Se requiere una nueva generación de estudios clínicos empleando las combinaciones de drogas más activas identificadas en los años 1980s, o incorporando uno de los numerosos promisorios nuevos agentes que están siendo ensayados en el cáncer pulmonar de células no pequeñas (NSCLC). El uso de los mejores métodos de soporte, tales como los nuevos agentes antieméticos antagonistas de los receptores de serotinina, está indicado a fin de mejorar la tolerancia a la quimioterapia en este grupo de pacientes. Con tal aproche es posible que se logre el propósito real de la quimioterapia sistémica coadyuvante: incrementar el número de pacientes con cáncer de células no pequeñas en estado inicial verdaderamente curados.

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Résumé La résection chirurgicale est le traitement de choix chez le patient atteint de cancer bronchopulmonaire (qu'il s'agisse de cancer épithélial, glandulaire ou à grandes cellules à l'exclusion des cancers à petites cellules) aux stades I et II. Les récidives à distance, dont la fréquence se situe entre 30 et 60%, sont la cause principale de décès lorsque la résection a été complète. La chimiothérapie adjuvante postopératoire, évaluée maintenent depuis plus de trois décennies par des études randomisées, n'est pourtant pas encore appliquée de façon systématique chez ces patients. L'utilisation de chimiothérapies combinées comprenant le cisplatine peut laisser espérer une prolongation de survie sans maladie, mais jusqu'à une époque encore récente, aucune bénéfice de survie globale n'a été démontré. D'autres études sont nécessaires à présent, en utilisant des combinaisons plus puissantes, identifiées dans les années 1990, ou en incluant une des nouvelles drogues actuellement étudiées dans les cancers pulmonaires (en dehors des cancers à petites cellules). L'utilisation de médicaments de soutien, tels les antiémétiques, antogonistes des récepteurs de la sérotonine, est nécessaire pour augmenter la compliance de la chimiothérapie chez ce groupe de patients. Avec cette approche thérapeutique, le vrai but de la chimiothérapie adjuvantec'est-à-dire augmenter le nombre de patients guéris de leur cancer-peut être obtenu à un stade précoce.

     

肺内淋巴结精准取材对肺癌患者术后N分期的影响

目的探讨非小细胞肺癌(NSCLC)患者肺内淋巴结转移情况及其对病理分期的影响。 方法选取2015年1月1日至2016年3月31日期间在天津市胸科医院胸外科接受肺叶或全肺切除及系统性淋巴结清扫术的177例肺癌患者进行分析。首先按照外科医师清扫的淋巴结常规取材进行病理诊断,得出N分期;由病理科医师再对第12、13组淋巴结进行分检精准取材,得出一个新的N分期,比较并分析前后两个N分期的差异。同时,进一步分析这两组淋巴结转移的危险因素。 结果全组患者共检出N1站淋巴结1 268枚,常规取材(第10、11组淋巴结)共检出736枚,精准取材(第12、13组淋巴结)共检出532枚。联合NSCLC的常规取材和肺内淋巴结的精准取材,患者的N1淋巴结检出的中位数为7枚(2～24枚),与NSCLC的常规取材相差4枚(0～18枚),N1淋巴结的检出数明显增加(P<0.001)。联合NSCLC的常规取材和肺内淋巴结的精准取材,共检出转移N1淋巴结240枚,中位转移数量为0枚(区间：0～7枚;第75百分位数：1枚;第90百分位数：3枚),与NSCLC的常规取材相比(区间：0～5枚;第75百分位数：0枚;第90百分位数：2枚),N1淋巴结的转移个数明显增加(P<0.001)。分层分析结果显示：第12、13组淋巴结的转移与手术方式、手术部位、病理类型、肿瘤大小以及纵隔淋巴结转移存在一定相关性(P<0.05),但与患者的年龄、性别以及术后病理是否存在脉管癌栓无明显相关性(P>0.05)。有15例患者的N分期由于肺内淋巴结的精准取材由N0升为N1,占全组患者的8.4%。 结论常规NSCLC取材方式容易漏检N1区域的淋巴结,并且相当一部分还是转移淋巴结。因此,提倡NSCLC肺内淋巴结精准取材以提高病理分期的准确性。     

The prognosis of surgically resected N2 non-small cell lung cancer: the importance of clinical N status.

BACKGROUND: Clinical trials dealing with multimodal strategy for N2 non-small cell lung cancer are now being watched with keen interest, and the feasibility of this strategy is to be confirmed. N2 lung cancer, however, is composed of several subgroups with different prognoses. The prognostic factors still remain controversial. METHODS: Between January 1986 and July 1997, 222 patients with lung cancer underwent surgical intervention at our institute; these patients were eventually given a diagnosis of metastasis to ipsilateral mediastinal lymph nodes. All patients underwent mediastinal lymph node dissection or sampling. Sixteen clinicopathologic factors were investigated by univariable and multivariable analyses to identify significant prognostic factors among resected N2 disease. Clinical N status was evaluated by computed tomographic scan. RESULTS: The overall 5-year survival was 27%. Multivariable analyses among overall patients revealed 4 significant prognostic factors (P <.05): clinical N2 status, incomplete resection, larger tumor size, and multiple diseased N2 nodes. Based on the result, 32 patients with both clinical N2 status and pathologic multiple N2 nodes showed a 5-year survival of 5%, whereas 76 patients with neither of the factors showed a 5-year survival of 57% (P <.001). CONCLUSION: The prognosis of surgically resected N2 disease varies tremendously according to the 4 significant prognostic factors. These factors should be clearly described in reporting clinical trials on N2 lung cancer. Clinical N status evaluated by computed tomographic scan should be 1 criterion to perform a clinical trial for N2 disease among a homogeneous population with respect to prognosis.