Adjuvant therapy in completely resected non-small-cell lung cancer

Less than 20% to 25% of patients with non-small-cell lung cancer (NSCLC) present with stage I or II disease and are best treated by surgical resection. Long-term survival in early NSCLC remains poor. The 5-year survival rate of patients who undergo complete surgical resection is only 40% to 50%. The majority of relapses after surgery are distant metastases; the risk of a local recurrence after complete resection is less than 10%. Postoperative treatments, including chemotherapy, radiotherapy, or both modalities together, have been evaluated widely, but unfortunately none of these treatments have demonstrated any significant impact on survival. Data regarding large-scale adjuvant chemotherapy trials that were closed for accrual almost 4 to 5 years ago will be fully available before the end of the year. It is hoped that a specific meta-analysis will be performed on the basis of these data.     

Adjuvant chemotherapy for resected non-small-cell lung cancer

Because of the high rate of distant disease recurrence, the 5-year survival of patients who have undergone complete surgical resection of localized non-small-cell lung cancer (NSCLC) is approximately 50%. Initial results from early studies of adjuvant postoperative chemotherapy reported an adverse effect of alkylating agent and older chemotherapy regimens on survival. Cisplatin-based combinations were the first to show a survival advantage. A 1995 meta-analysis of these studies suggested a 13% reduction in the hazard ratio for death (HR = 0.87), leading to a 5% survival benefit at 5 years. Still, these trials involved limited numbers of patients (N = 1,394), and the results failed to reach statistical significance (P = .08). Of the five largest subsequent randomized trials of platinum-based adjuvant therapy, three showed a significant survival advantage. Although it is impossible to determine the reasons for the differing outcomes of these studies, several key features distinguish them, and the data suggest that medically fit patients with resected stage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.     

Adjuvant therapy of resected non-small-cell lung cancer

Surgical resection of early-stage non-small-cell lung cancer (NSCLC) remains the standard of care in patients fit for surgery. Careful preoperative staging is imperative, as is pathologic documentation of the mediastinal nodal contents. Adjuvant postoperative thoracic radiation therapy (RT) clearly has an impact in reducing locoregional recurrence but has no clear impact on survival. The Postoperative RT (PORT) metaanalysis raised concerns about PORT, particularly in stage I/II NSCLC, suggesting it may negatively impact survival. This was not a concern in stage III NSCLC, in which the risk of locoregional recurrence is higher. However, distant recurrence remains the dominant pattern in resected NSCLC, suggesting that the majority of patients with early-stage resected NSCLC harbor occult micrometastatic disease. Historically, the role of adjuvant chemotherapy has been controversial, and its routine use was not supported by the published data, which consisted of a small number of underpowered trials using inadequately delivered, antiquated chemotherapy. More recently, larger trials have been reported with conflicting results. Like adjuvant PORT, chemotherapy combined with RT has not improved survival over PORT alone. The use of adjuvant cisplatin-based therapy did not show a survival advantage in the Adjuvant Lung Project Italy study but did in the International Adjuvant Lung Trial, creating controversy in the routine implementation of adjuvant therapy in all patients. Recently completed randomized trials by the Cancer and Leukemia Group B and the National Cancer Institute of Canada provide convincing evidence of a substantial benefit from adjuvant therapy in well-staged and completely resected stage I/II NSCLC. Currently, the totality of the data supports a discussion with patients with resected NSCLC regarding the potential benefits of adjuvant therapy.     

Adjuvant therapy of resected non-small-cell lung cancer

The administration of adjuvant therapy after complete resection of non-small-cell lung cancer is controversial. Radiation therapy and chemotherapy have been used individually and concomitantly in efforts to prevent local recurrence and improve survival. However, recent phase II and III trials and a meta-analysis have produced conflicting results. Postoperative adjuvant therapy remains a subject of active investigation.     

Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research

Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials'' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC.     

Role of adjuvant radiotherapy in completely resected non-small-cell lung cancer

Most long-term survivors of non-small-cell lung cancer (NSCLC) are patients who have had a completely resected tumour. However, this is only achievable in about 30% of the patients. Even in this highly selected group of patients, there is still a high risk of both local and distant failure. Adjuvant treatments such as chemotherapy (CT) and radiotherapy (RT) have therefore been evaluated in order to improve their outcome. In patients with stage II and III, administration of adjuvant platinum-based chemotherapy is now considered the standard of care, based on level 1 evidence. The role of postoperative radiation therapy (PORT) remains controversial. In the PORT meta-analysis published in 1998, the conclusions were that if PORT was detrimental to patients with stage I and II completely resected NSCLC, the role of PORT in the treatment of tumours with N2 involvement was unclear and further research was warranted. Thus at present, after complete resection, adjuvant radiotherapy should not be administered in patients with early lung cancer. Recent retrospective and non-randomised studies, as well as subgroup analyses of recent randomised trials evaluating adjuvant chemotherapy, provide evidence of the possible benefit of PORT in patients with mediastinal nodal involvement. The role of PORT needs to be evaluated also for patients with proven N2 disease who undergo neoadjuvant chemotherapy followed by surgery. The risk of local recurrence for N2 patients varies between 20% and 60%. Based on currently available data, PORT should be discussed for fit patients with completely resected NSCLC with N2 nodal involvement, preferably after completion of adjuvant chemotherapy or after surgery if patients have had preoperative chemotherapy. There is a need for new randomised evidence to reassess PORT using modern three-dimensional conformal radiation technique, with attention to normal organ sparing, particularly lung and heart, to reduce the possible over-added toxicity. Quality assurance of radiotherapy as well as quality of surgery – and most particularly nodal exploration modality – should both be monitored. A new large multi-institutional randomised trial Lung ART evaluating PORT in this patient population is needed and is now under way.     

Prognostic significance of apoptotic index in completely resected non-small-cell lung cancer.

PURPOSE: To evaluate the significance of apoptotic index (AI) as a prognostic factor after surgery for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 236 patients who underwent surgery for previously untreated pathologic stage I to IIIa NSCLC between 1985 and 1990 were reviewed. AI was defined as the number of apoptotic cells, detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling, per 1,000 tumor cells. Proliferative index (PI) and aberrant p53 expression were also evaluated immunohistochemically. RESULTS: The 5-year survival rate for the lowest-AI group (AI < 5.0) was 74.7%; those for the lower-AI group (5.0 < or = AI < 11.0) and the higher-AI group (11.0 < or = AI < 25.0) were 51.6% and 57.8%, respectively. These survival rates were significantly lower than that of the lowest-AI group (P =.021 and P =.043, respectively). The highest-AI group (25.0 < or = AI), however, showed the most favorable prognosis, with a 5-year survival rate of 83.2%. Multivariate analysis confirmed that a moderate AI (5.0 < or = AI < 11.0 or 11.0 < or = AI < 25.0) was a significant factor to predict poor prognosis. The PIs for the lowest-, the lower-, the higher-, and the highest-AI groups were 32.3%, 48.0%, 54.3%, and 50.7%, respectively. The lowest-AI group showed a favorable prognosis because of its low PI, whereas the lower- and the higher-AI groups had a poor prognosis caused by increased cancer-cell proliferation. The highest-AI group showed the most favorable prognosis because apoptotic cell death overcame cell proliferation. No significant correlation was observed between AI and aberrant p53 expression. CONCLUSION: AI proved to be an independent prognostic factor in NSCLC.     

Adjuvant chemotherapy in resected non-small cell lung cancer

There is still a high mortality ratio in completely resected non-small cell lung cancer patients either due to local or, more often, to metastatic recurrence. The NSCLC Collaborative Group Meta-analysis demonstrated a not statistically significant advantage in patients treated with cisplatin-based regimens. Many subsequent trials were unable to demonstrate the real effectiveness of cisplatin-based adjuvant chemotherapy with a significant rate of toxicity. The IALT trial demonstrated little advantage in overall and disease-free survival with acceptable toxicity. A recent meta-analysis of trials including 5716 patients demonstrated the role of cisplatin-based chemotherapy as adjuvant treatment of resected non-small cell lung cancer even if results shoud be carefully examined. At present, adjuvant chemotherapy in non-small cell cancer should not be reserved to experimental trials.     

Adjuvant chemotherapy in elderly patients with non-small-cell lung cancer.

BACKGROUND: More than two thirds of patients who die of lung cancer in the United States are over 65 years of age. More than 50% of lung cancer patients are diagnosed over the age of 65 and about 30% over the age of 70. METHODS: The authors review recent data from large randomized trials on adjuvant chemotherapy in patients with NSCLC. They discuss age-related changes in organ function, comorbidities and frailty in the elderly, and chemotherapy treatment in elderly patients with NSCLC. RESULTS: Randomized trials suggest that postoperative chemotherapy improves survival after surgery in patients with stage IB to IIIA NSCLC, and awareness of the efficacy of this approach is growing in the scientific community. Clinical data obtained in the young population cannot be automatically adopted in the elderly counterpart. Elderly patients tolerate chemotherapy poorly because of comorbidity and organ failure, and after lung surgery they are considered at higher risk of chemotherapy-induced toxicity. The survival benefit obtained with platin-based chemotherapy may vanish or decrease in the elderly due to a potential higher toxic death rate or lower compliance to treatment. CONCLUSIONS: Modified schedules or attenuated dose of platin-containing chemotherapy should be investigated in the adjuvant setting by specifically designed trials. Specifically designed prospective trials are needed to elucidate the role of this approach in the elderly.     

Hepatoma-derived growth factor as a prognostic marker in completely resected non-small-cell lung cancer

Hepatoma-derived growth factor (HDGF), unrelated to hepatocyte growth factor, is a heparin-binding protein originally purified from human hepatoma HuH-7 cells. HDGF exhibits mitogenic activities for certain hepatoma cells, fibroblasts and vascular smooth muscle cells, and angiogenic activities through nuclear targeting. Recently, HDGF was found to be a mitogen for lung epithelial cells in vitro and in vivo. This suggests that HDGF may play a critical role in the development and progression of lung cancer. We investigated, immunohistochemically, the relationship between HDGF expression and clinicopathological variables, and the prognostic significance of HDGF in 102 patients with completely resected non-small-cell lung cancer (NSCLC: 70 adenocarcinomas and 32 squamous cell carcinomas). To address the mechanism of action of HDGF, we evaluated the contribution of HDGF to tumor cell proliferation and intratumor angiogenesis using anti-Ki-67 and anti-CD31 antibodies, respectively. HDGF expression was strongly detected in the nucleus of cancer cells; the HDGF-labeling index (LI) was 20-95% (median 64.5%). There was no significant association between HDGF-expression level and clinicopathological variables. Patients with NSCLC showing a high HDGF-LI (> or =65%) had significantly worse overall and disease-free survivals than those with NSCLC showing a low HDGF-LI. Multivariate analysis revealed that HDGF is a significant independent prognostic factor, more powerful than pathological stage. Moreover, HDGF expression correlated with Ki-67-LI and intratumor microvessel density. We consider HDGF as a useful prognostic marker for patients with completely resected NSCLC and it may play a critical role in the pathobiology of lung cancer through its mitogenic and angiogenic activities.     

Long-term evaluation of intrapleural bacillus Calmette-Guerin with or without adjuvant chemotherapy in completely resected stages II and III non-small-cell lung cancer.

Between January 1979 and December 1980, 52 patients with completely resected stages II and III non-small-cell lung cancer (NSCLC) were randomly assigned to receive either adjuvant chemotherapy (cyclophosphamide, doxorubicin, and vincristine--CAV) plus intrapleural bacillus Calmette-Guerin (BCG) (n = 26) or adjuvant CAV alone (n = 26). Careful intraoperative staging was performed in all patients, and stratification for histology (squamous versus nonsquamous) and stage (II or III) ensured a balanced randomization for these factors. With a median follow-up time of 111 months, overall 10-year and median survival were 21% and 20 months (range 2-127 + months), respectively. Thirty-four (95%) patients relapsed in extrathoracic sites, and five (5%) developed loco-regional recurrence; their overall median disease-free interval (DFI) was 10 months (range 1-73 months). There was a 9% and 2.5 month difference in survival (p = .76) and disease-free interval (p = .67), respectively, favoring the BCG arm. There were no significant differences in the sites and patterns of first recurrence comparing the two treatment arms. In conclusion, there is no suggestion of a significant therapeutic advantage from intrapleural BCG in conjunction with adjuvant chemotherapy for completely resected stages II and III NSCLC.     

Adjuvant treatment in resected lung cancer

There have been many attempts to develop effective postoperative adjuvant therapy in patients with resected lung cancer. Metastatic disease is the commonest site of first recurrence. In squamous cell carcinoma local failure is another major problem and in adenocarcinoma brain metastases are frequent. There is evidence to suggest that radiotherapy can prevent local recurrence but does not appear to impact on survival. Response rates to chemotherapy alone and chemo-radiotherapy with prolongation of disease-free survival have been encouraging in locally advanced (resected stage II, III) disease when treated postoperatively. Results of clinical trials using immunotherapy or chemotherapy in early stage disease have been disappointing. Several prospective randomized studies by the Lung Cancer Study Group were undertaken to assess the merits of various adjuvant treatments and are presented.     

Adjuvant chemoradiation versus chemotherapy in completely resected advanced gastric cancer with D2 nodal dissection

Aim: Adjuvant chemoradiation has become a standard of care in the USA. We evaluated the efficacy and toxicity of adjuvant chemoradiation versus chemotherapy in completely resected locally advanced gastric cancer. Methods: Patients with stage IIIA, IIIB and IV (without metastasis) gastric cancer were treated with chemoradiation and 5‐fluorouracil/cisplatin (FP) (arm A) or FP (arm B). Arm A consisted of one cycle of FP followed by 4500 cGY to radiation field with capecitabine. One month after completion of radiotherapy, patients received three additional cycles of FP every 3 weeks. Arm B consisted of six cycles of FP. Results: A total of 61 patients were enrolled, of whom 31 were placed in arm A and 30 in arm B. The median follow‐up duration was 77.2 months (range 24–92.8 months). We did not find any difference in 3‐year disease‐free survival between arm A and B (80.0 vs 75.2%, respectively; P = 0.887). There was no significant difference between the arms in 5‐year disease‐free survival (76.7 vs 59.1%, respectively; P = 0.222) or overall survival (70.1 vs 70.0%, respectively; P = 0.814). Seven patients (22.6%) relapsed in arm A and 12 patients (40%) relapsed in arm B. Grade 3/4 neutropenia occurred in 48.5% of patients in arm A and 22.9% in arm B. Grade 3 nausea or vomiting occurred in 6% in arm A and 14.6% in arm B. Conclusion: We could not make any conclusion about the benefit of adding radiation to adjuvant chemotherapy.     

Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer.

BACKGROUND: We designed a prospective study to test epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) in resected stage I-IIIA non-small-cell lung cancer (NSCLC) and to correlate overexpression with survival. PATIENTS AND METHODS: EGFR expression was evaluated in 130 consecutive NSCLC patients after radical surgery (60 squamous cell carcinomas, 48 adenocarcinomas, 22 large cell carcinomas: stage I, 41 (31%); stage II, 37 (29%) and stage IIIA, 52 (40%). RESULTS: Overall, 101 of 130 (78%) specimens expressed EGFR, and with a cut-off value of 10% positive cells 48 cases (37%) were classified as positive. At univariate analysis, EGFR was significantly more expressed in stage III (50%) than stage I (20%) and stage II (25%) (P <0.03). No correlation with histotype was found. After a median follow-up of 84 months, both median survival time (18 versus 50 months), 2-year (43% versus 70%) and 5-year (31% versus 46%) survival rates of positive cases were significantly lower than negative ones [P <0.001; hazard ratio 1.96; 95% confidence interval (CI) 1.16-3.30]. At the multivariate analysis, EGFR overexpression and stage emerged as independent factors for cancer-related mortality. CONCLUSION: In patients with radically resected stage I-IIIA NSCLC, EGFR overexpression predicts shorter survival, thus representing a valuable prognostic factor.     

Adjuvant chemotherapy for early-stage non-small-cell lung cancer. Single-centre experience and literature review

Background In recent years platinum-based chemotherapy has become the standard of care for patients with good performance status after complete resection in stages IB-IIIA non-small-cell lung cancer (NSCLC), although the benefit is mainly in stages II and IIIA. Patients and methods In a retrospective trial we evaluate the clinical efficacy and toxicity profile of a platinum- and taxanes-based adjuvant chemotherapy in completely resected IB-IIIA NSCLC. The primary end point was relapse- free survival (RFS); principal secondary end points were overall survival (OS) and safety of the regimen. Potential predictive factors of efficacy and clinical patterns of relapse were also analysed. Results From January 2003 to December 2006, 41 patients met the inclusion criteria and were evaluable. Median age at diagnosis was 68.1 years (CI 95% 54-72; range 45-78). Most patients were males (87.7%) and had an Eastern Cooperative Oncology Group performance status score (PS) of 0-1 (87.8%), and 53.6% had adenocarcinomas. Pathological stages were as follow: 48.7% stage IB, 24.3% stage II and 26.8% stage IIIA. 75.6% of patients underwent a lobectomy and mediastinal lymphadenectomy and were treated with a combination of carboplatin AUC6 and paclitaxel 200 mg/m(2) (85.36%) for 3 or 4 cycles. With a median follow-up of 18.2 months (range 5.1-46.5), 26 patients (63%) were free of disease and 32 of them were alive (78%). Median RFS was 12.1 months (CI 95% 9.8-14.9) and median OS had not been reached at the time of analysis. Patients with PS相似文献