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该研究探讨了可手术切除的NSCLC中隐匿性转移患病率及其与生存率的关系。1999年07月至2004年03月，1,047例符合条件的患者（538例男性，509例女性；中位年龄，67.2岁）入组研究，其中50%患有腺癌，66%患有I期NSCLC。仅29例患者的胸膜腔灌洗液为细胞学检查阳性。66/821份(8.0%)骨髓标本及130/580份(22.4%)淋巴结标本中发现隐匿性转移。在单变量和多变量分析中，淋巴结隐匿性转移与无疾病生存期（危险比[HR], 1.50; P = .031）及总体生存期（HR, 1.58; P = .009）显著较差有关，而骨髓隐匿性转移与其无关。在早期NSCLC中，通过IHC检测出的淋巴结隐匿性转移可预示着患者预后较差
试验从1999年-2004年,总共纳入了1047例可手术切除的NSCLC患者,手术前后均进行胸腔灌洗并行细胞学检查,肋骨骨髓和所有的组织学检查阴性的淋巴结均用免疫组化的方法检测隐匿性转移,结果显示,早期NSCLC免疫组化检测淋巴结隐匿转移与患者的预后不良有关,胸水和肋骨骨髓隐匿性转移检查与预后无统计学差异.
Occult Metastases in Lymph Nodes Predict Survival in Resectable Non-Small-Cell Lung Cancer: Report of the ACOSOG Z0040 Trial Rusch VW, Hawes D, Decker PA, et al
J Clin Oncol. 2011 Oct 17. [Epub ahead of print] Study Summary One of the more promising areas of research that has yet to translate to routine practice is the detection of micrometastatic disease, whether in the form of circulating tumor cells or occult metastases (OMs). The American College of Surgeons Oncology Group (ACOSOG) recently reported their results on the Z0040 trial that looked for OMs in 3 sources: (1) washings of the pleural space at the time of surgery; (2) specimens from bone marrow collected from resected rib; and (3) specimens from lymph nodes that appeared to be negative for cancer involvement on routine pathology review. The key questions asked by the study were as follows:
How common is it to see OMs in the pleural space, marrow, and "negative" lymph nodes? Do patients who test positive for OMs fare worse than patients who do not have them?
In order to test these questions, the ACOSOG enrolled 1047 patients from 1999 to 2004 with resectable stage I-III non-small cell lung cancer (NSCLC). The study participants were equally distributed by sex and had a median age of 67 years; 50% had adenocarcinoma and 66% had stage I disease. For the purposes of the trial, surgery included pleural lavage and a detailed search for positive cytology of the fluid using immunohistochemistry (IHC) with anticytokeratin antibodies. Participating patients also had bone marrow extracted from a 3-4 cm section of rib, and both the marrow and all resected nodes that were considered negative for cancer involvement by routine examination were evaluated in detail for IHC-positive cells consistent with OMs. All IHC-based pathologic evaluation was conducted at a single lab at the University of Southern California, Los Angeles, California. Patients were then followed for a minimum of 5 years of surveillance for disease-free and overall survival. The ACOSOG investigators reported that OMs in the pleural space or bone marrow were very uncommon (3% and 8%, respectively), and the low frequency of OMs in the pleural space made it difficult to draw any meaningful conclusions about these patients. For those with OMs in the bone marrow, the investigators reported the same frequency of involvement from stage Ia to IIIB (very few patients with stage IIIB NSCLC underwent surgery, as one would expect), and these patients showed no evidence of faring worse than those whose marrow revealed no OMs. In contrast, detection of OMs in lymph nodes that were considered negative for cancer was both more common and more predictive of an important difference in clinical outcomes. Nodal OMs were detected in 22.4% of patients who underwent surgery and, as might be expected, were more commonly detected in patients with higher-stage disease, although OMs were still seen in about 17% of patients with a smaller, otherwise node-negative cancer. The prognostic value of this variable was statistically and -- I would argue -- clinically significant: Nodal OMs were associated with an approximately 60% higher risk for disease recurrence or death (hazard ratios, 1.63, P = .009 and 1.59, P = .007 for disease-free and overall survival, respectively) compared with those who did not have nodal OMs. Viewpoint What are the implications of this work? The study authors commented that these results are "directly relevant to clinical practice," and I agree. We struggle in the postoperative setting over which patients truly need adjuvant chemotherapy to eradicate micrometastatic disease. Although it is standard practice to recommend adjuvant chemotherapy to patients with clearly node-positive disease, the question of which patients with node-negative disease are more likely to be helped or harmed by adjuvant chemotherapy remains an open question. We have seen in some studies that patients with a low risk for recurrence, whether determined on the basis of higher tumor ERCC-1 expression[1] or smaller tumor size,[2] who receive adjuvant chemotherapy after potentially curative surgery have worse outcomes than those patients who are followed by observation alone. However, it is very easy to imagine that the patients with microscopic OMs in their lymph nodes and no other evidence of nodal involvement and who are at considerable risk for recurrence and death from lung cancer are the patients mostlikely to benefit from adjuvant chemotherapy. We do not know that with certainty, but these results are compelling enough to have led me to work with my own multidisciplinary team, and especially pathologists, to pursue a similar strategy for patients with what otherwise appears to be node-negative resected NSCLC. These data suggest that, even though the TNM staging system does not recognize nodes in patients with NSCLC to be positive on the basis of IHC alone, the presence or absence of OMs may be critical in helping to distinguish which patients are clearly more or less likely to be the beneficiaries of adjuvant chemotherapy.
ReferencesOlaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006;355:983-991. Strauss GM, Herndon JE II, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008;26:5043-5051.
隐匿性淋巴结转移可预测可切除性非小细胞肺癌的存活率：ACOSOG Z0040试验报告
在早期非小细胞肺癌患者中，IHC检测到淋巴结中有微转移者预后更差。
J Clin Oncol. 2011 Nov 10;29(32):4313-9. Epub 2011 Oct 11.
Occult Metastases in Lymph Nodes Predict Survival in Resectable Non-Small-Cell Lung Cancer: Report of the ACOSOG Z0040 Trial.
Rusch VW, Hawes D, Decker PA, Martin SE, Abati A, Landreneau RJ, Patterson GA, Inculet RI, Jones DR, Malthaner RA, Cohen RG, Ballman K, Putnam JB Jr, Cote RJ.
Source
Thoracic Surgery Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; ruschv@mskcc.org.
Abstract
PURPOSE
The survival of patients with non-small-cell lung cancer (NSCLC), even when resectable, remains poor. Several small studies suggest that occult metastases (OMs) in pleura, bone marrow (BM), or lymph nodes (LNs) are present in early-stage NSCLC and are associated with a poor outcome. We investigated the prevalence of OMs in resectable NSCLC and their relationship with survival.
PATIENTS AND METHODS
Eligible patients had previously untreated, potentially resectable NSCLC. Saline lavage of the pleural space, performed before and after pulmonary resection, was examined cytologically. Rib BM and all histologically negative LNs (N0) were examined for OM, diagnosed by cytokeratin immunohistochemistry (IHC). Survival probabilities were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazards regression model were used to compare survival of groups of patients. P < .05 was considered significant.
Results
From July 1999 to March 2004, 1,047 eligible patients (538 men and 509 women; median age, 67.2 years) were entered onto the study, of whom 50% had adenocarcinoma and 66% had stage I NSCLC. Pleural lavage was cytologically positive in only 29 patients. OMs were identified in 66 (8.0%) of 821 BM specimens and 130 (22.4%) of 580 LN specimens. In univariate and multivariable analyses OMs in LN but not BM were associated with significantly worse disease-free survival (hazard ratio [HR], 1.50; P = .031) and overall survival (HR, 1.58; P = .009).
CONCLUSION
In early-stage NSCLC, LN OMs detected by IHC identify patients with a worse prognosis. Future clinical trials should test the role of IHC in identifying patients for adjuvant therapy.
Prognostic Study of Metastases in Patients With Stage I, Stage II, or Stage III Non-small Cell Lung Cancer That Can Be Removed by Surgery
This study has been completed.
First Received on November 1, 1999. Last Updated on November 5, 2011 History of Changes
| Sponsor: | American College of Surgeons | | Collaborator: | National Cancer Institute (NCI) | | Information provided by: | National Cancer Institute (NCI) | | ClinicalTrials.gov Identifier: | NCT00003901 |
 Purpose RATIONALE: Prognostic testing for early signs of metastases may help doctors detect metastases early and plan more effective treatment. PURPOSE: Phase III trial to study the relationship between early signs of metastases and survival in patients who have stage I, stage II, or stage III non-small cell lung cancer that can be removed by surgery.
| Study Type: | Interventional | | Study Design: | Primary Purpose: Diagnostic | | Official Title: | A Prospective Study of the Prognostic Significance of Occult Metastases in the Patient With Resectable Non-Small Cell Lung Carcinoma |
| Estimated Enrollment: | 1200 | | Study Start Date: | July 1999 | | Primary Completion Date: | October 2011 (Final data collection date for primary outcome measure) |
Detailed Description: OBJECTIVES:
Determine the relationship between three indicators of occult metastases (cytological examination of pleural lavage, immunohistochemistry (IHC) assay of lymph nodes, and IHC assay of rib bone marrow) and survival of patients with resectable non-small cell lung cancer. Determine the relationship between these indicators and conventional histology. Model survival considering the indicators and other patient attributes that are of prime prognostic significance. Determine the relationships between the indicators and the site of first recurrence in these patients. Determine the prevalence of the indicators in these patients. Determine the relationships between the indicators and disease free survival in these patients.
OUTLINE: All patients undergo complete lymph node sampling or dissection. A small portion of rib is removed at this time. Some patients may have primary tumor completely removed. Lymph nodes and bone marrow from the rib section are examined for occult metastases using immunohistochemical staining methods and standard staining methods. Patients are followed at 1, 4, 8, and 12 months, every 6 months for 2 years, and then annually for 2 years. PROJECTED ACCRUAL: A total of 1200 patients will be accrued for this study over 4 years.
Eligibility
| Ages Eligible for Study: | 18 Years and older | | Genders Eligible for Study: | Both | | Accepts Healthy Volunteers: | No |
Criteria
DISEASE CHARACTERISTICS:
Histologically proven stage I, IIA, IIB, or IIIA non-small cell lung cancer (NSCLC)
Histological confirmation may be preoperative or intraoperative
Clinically resectable disease
Squamous cell, adenocarcinoma, or large cell
Thoracotomy with intention of complete resection planned
Pneumonectomy, bilobectomy, lobectomy, or anatomic segmentectomy, with or without sleeve resection
No pleural effusion
PATIENT CHARACTERISTICS: Age: Performance status: Life expectancy: Hematopoietic: Hepatic: Renal: Pulmonary: Other: PRIOR CONCURRENT THERAPY: Biologic therapy: Chemotherapy: Endocrine therapy: Radiotherapy: Surgery:
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