| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Thorac Cardiovasc Surg 1995;110:1130-1135
© 1995 Mosby, Inc.
GENERAL THORACIC SURGERY |
Copenhagen, Denmark
From the Department of Oncology, Finsen Center, National University Hospital, Copenhagen, Denmark.
Received for publication July 20, 1994. Accepted for publication Dec. 30, 1994. Address for reprints: Lars E. Stenbygaard, Department of Oncology, 5074 Finsen Center, National University Hospital, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark.
Abstract
A cohort of 137 patients with completely resected stage I or II adenocarcinoma of the lung was observed from the time of operation; the metastatic pattern determined at autopsy is described in relation to clinical, histologic, and laboratory variables. The pretreatment variables evaluated were performance status, age, gender, lactate dehydrogenase, stage, degree of differentiation, and histologic subtype of adenocarcinoma of the lung. Patients who survived longer than 30 days after operation were eligible for analysis, and 35 autopsies were performed in this patient group (autopsy rate: 39.8%). The most common intrathoracic metastatic sites were mediastinal lymph nodes (43%), lung (31%), pleura (20%), pericardium (9%), and heart (6%). The most common extrathoracic sites were liver (37%), brain (33%), bones (21%), adrenals (17%), and kidneys (17%). Patients undergoing resection for stage I disease had significantly fewer intrathoracic metastases than patients with stage II disease (p = 0.01). Patients who survived less than 1 year had significantly more extrathoracic metastases than patients who survived for a longer period (p = 0.01). Patients with highly differentiated tumors had fewer extrathoracic metastases than patients with less differentiated tumors. No other statistically significant differences were observed. Overall, patients with stage I adenocarcinoma of the lung had better local control of the disease at autopsy than those with stage II disease, but distant metastases are a large problem despite the favorable prognosis of this patient group. The extrathoracic metastatic potential was greatest for less differentiated tumors. An active adjuvant systemic therapy after resection is needed in selected patients with poorly differentiated adenocarcinomas of the lung, even in those with stage I disease. (J THORAC CARDIOVASC SURG 1995;110:1130-5)
Surgery is the treatment of choice in patients with stage I or stage II non-small-cell lung cancer (NSCLC) and it should be performed if the patient is physically fit for the operation. Even with complete resection, the risk of recurrence of the disease is high. Adenocarcinoma of the lung (ACL) attracts increasing attention because the incidence of ACL is increasing faster than that of other major histologic types of lung cancer. 
1 Some reports suggest that ACL is now the most frequent histologic type. 2 The prognosis and treatment results of ACL may differ from those of the other major types of NSCLC, 3,4 although this is not a uniform observation. 5 The five-year survival after apparently complete resection has been reported to be 40% to 69% for patients with stage I ACL and 25% for patients with stage II, 6 which emphasizes the need for adjuvant treatment. A detailed knowledge of the metastatic pattern in this disease is necessary to design appropriate programs for detection of relapse. It is also important to know whether any clinical variables predict specific metastatic patterns and may therefore be used in the selection of patient groups for adjuvant treatment.
Several studies, most of which were published three to four decades ago, have focused on autopsy findings in NSCLC. 7-12 Most of these studies included very heterogeneous patient populations, with all stages and different treatment modalities, making firm conclusions difficult. Autopsy of patients with cancer has previously been a routine procedure in many countries. More recently, the autopsy rate has declined substantially because of changes in the legal basis and also in the attitude of the population, 13-15 so that autopsy studies are increasingly difficult to obtain.
The purpose of the current study was to evaluate the metastatic pattern in relation to a variety of clinical, histologic, and laboratory parameters at the time of operation in a well-described cohort of patients with completely resected stage I or stage II ACL. Prognosis and determinants of survival in this patient group have been described previously. 16
PATIENTS AND METHODS
A cohort of patients in eastern Denmark who underwent complete resection of ACL stage I or stage II lesions during the period February 1981 through July 1985 were analyzed for prognostic variables. Preoperatively staging with mediastinoscopy or computed tomography of the mediastinum, or both, was done in all patients. Biopsy-proven disease spread to the mediastinum (stage III) was regarded as a sign of inoperability, and these patients were not included in the clinical trial. Lymphadenectomy or lymph node sampling was not routinely performed. 16 If a patient had symptoms related to metastatic disease, further examinations were performed before the patient was included in the operative trial and analyses. 16 All patients were subsequently followed up for survival and for metastatic pattern in case of autopsy.
Histopathologic subtyping of ACL and degree of differentiation was performed according to criteria of the World Health Organization 17 by one pathologist, who did not know the clinical results.
ACL was divided into acinar adenocarcinoma, papillary adenocarcinoma, bronchioloalveolar carcinoma, and solid carcinoma with mucus formation. Differentiation was divided into high, moderate, and low degrees of differentiation. Bronchioloalveolar carcinoma was defined as highly differentiated, and solid carcinoma with mucus formation was defined as poorly differentiated. 17
The pretreatment and treatment variables recorded included stage of disease, operation type, pulmonary symptoms, performance status, weight loss, age, gender, hemoglobin, leukocyte count, lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphotases. 16,18 Patient survival was recorded, and autopsy reports were requested in case of death. No patients were lost to follow-up.
The autopsy records were reviewed for organs with macroscopic or microscopic evidence of metastasis. Each organ, including sites in the central nervous system, was regarded as one site of metastasis; the specific number of metastases to each organ was not recorded.
The clinical part of the study was performed according to the Helsinki II declaration.
Nonparametric methods were used, with the 
2 test used for comparison of proportions and the Mann Whitney U test for comparison of discontinuous numeric variables between groups.
RESULTS
A total of 137 patients with stage I or stage II ACL underwent complete resection during a 4
-year period from February 1981 through July 1985; by October 1993, 108 of these patients had died. Forty-three autopsies were performed, corresponding to an autopsy rate of 39.8%. Eight patients died within 30 days after operation, and autopsies were performed on all. These patients were excluded from the general description of the metastatic pattern and analysis in relation to clinical parameters. No metastatic sites were found at autopsy in any of these eight patients. Results of pretreatment characteristics for these eight patients are given in Table I, together with those of the 129 patients who survived more than 30 days. The pretreatment characteristics did not differ significantly between the eight patients with early perioperative death and the patients with longer survival times.
|
Table II. The most common sites of metastasis were intrathoracic, with lung metastases, mediastinal lymph node involvement, and involvement of pleura, heart, and pericardium as frequent manifestations. Significant differences in frequency of organ involvement between stage I and stage II ACL were observed for primary lung (p = 0.04) and liver (p = 0.03). The most common among the extrathoracic metastatic sites were liver, brain, bones, adrenal glands, and kidneys. The median number of organs with tumor involvement was 2 (range 0 to 10); the median numbers of intrathoracic and extrathoracic sites with tumor involvement were 1 (range 0 to 5) and 1 (range 0 to 7), respectively.
|
Table III. The analyses were performed both for total number of metastatic sites and for intrathoracic (regional) sites and extrathoracic (distant) sites separately. Significant differences were observed between initial stage I and stage II disease, both with respect to the total number of metastases and the number of intrathoracic metastases, but not for the number of extrathoracic metastases. Patients with stage I disease had fewer metastases (median 1; range 0 to 10) than did those with stage II disease (median 5; range 0 to 8; p = 0.015). They also had fewer intrathoracic metastases (median 0; range 0 to 4) than those with stage II disease (median 3; range 3 to 5; p = 0.012). Patients surviving less than 1 year had significantly more extrathoracic (distant) sites than patients with longer survival times. Furthermore, patients with lesions having highly differentiated histologic features had fewer extrathoracic metastatic sites (median 0; range 0 to 3) than did patients with moderate or poorly differentiated tumors (median 1; range 0 to 7) but did not have more regional sites. No other significant differences were seen regarding other pretreatment variables such as gender, age, lactate dehydrogenase, performance status, histologic subtype, or degree of differentiation.
|
The observed difference in total number of metastases between initial stage I and stage II disease could result from different biologic characteristics of the tumors. The more aggressive, poorly differentiated tumors had a higher stage at the time of diagnosis and also had a higher number of involved organs at the time of death, despite an apparently complete resection. In addition, the presence of more extrathoracic sites in short-term survivors could be explained by a higher metastatic potential, corresponding to a more aggressive behavior of the tumor. New molecular biology techniques, such as detection of epithelial cytokeratin component 18 by monoclonal antibodies, could give further information about this characteristic. 19
The fewer extrathoracic sites in highly differentiated tumors compared with moderate and poorly differentiated tumors may explain the previously reported observation that these tumors have a better prognosis with a slower clinical progression and longer survival. 16
A high confidence for perioperative staging procedures is suggested by the observation that no sites of residual disease were found in the eight patients who died within 30 days after operation.
The general pattern of metastatic sites observed in this study is in accordance with previously published large, nonconsecutive series. 10,20-22 The most frequent sites of metastatic involvement in the present study and in previous studies are shown in Table IV.
|
Local rate of metastasis in 140 patients who died within 30 days after resection has been reported to be 28.5%, and in those with adenocarcinoma up to 43%. 23 Later studies based on pattern of metastasis with clinical implications on treatment of relapse reported local recurrence rates from 11% to 18%. 6,24,25 Compared with autopsy data, these figures are smaller because they include the inaccuracy of the diagnostic tools and clinical decisions and represent an earlier step in the progression of the disease than the present autopsy data did. Only 5 of the 35 patients who survived more than 30 days after operation and had an autopsy died with local recurrence only, and our data did not allow firm conclusions on the relation of metastasis to the extent of the surgical procedure (Table V). Of the 15 patients who died without metastatic disease, 8 died in the postoperative period. The remaining 7 patients died of concurrent diseases: 3 of acute myocardial infarction, 1 of pulmonary embolism, 1 of acute pericarditis, 1 of pneumonia and acute pleuritis, and 1 of a new primary cancer (squamous cell carcinoma in the esophagus).
|
Common distant sites of relapse, both in the present study and in previous studies, 10,20-22 are liver, brain, bones, adrenals, and kidneys (see 
Table IV). These sites should be monitored in studies of adjuvant treatment of patients having complete resection to achieve accurate evaluation of relapse site and recurrence-free survival.
Metastatic spread to the spleen was more prevalent than previously reported and metastases to the pancreas and abdominal nodes were less prevalent. These differences may have been caused by real biologic differences between ACL and other histologic types of NSCLC, or they may be the result of stocastic variation caused by the limited number of patients in the studies compared in Table IV.
In conclusion, among patients with completely resected ACL, a highly differentiated histology and a survival time exceeding 1 year were associated with a significantly lower incidence of extrathoracic spread. Inversely, patients with poorly differentiated tumors and a short survival time (less than 1 year) had a significantly higher incidence of extrathoracic metastatic disease, even those initially having stage I disease. Locoregional control of disease is recognized as a well-defined problem, and adjuvant treatment is needed in ACL to improve the prognosis.
Highly effective adjuvant chemotherapy regimens in ACL have not yet been defined, even though promising results have been obtained from phase II trials. Future aspects could be to evaluate treatment results from adjuvant, postoperative chemotherapy in completely resected stage I and II ACL, especially in patients with such prognostic factors as poor differentiation with a high risk of distant metastasis and thereby a short predicted survival time.
References
This article has been cited by other articles:
|
|
 |
|
  S. Motohashi, A. Ishikawa, E. Ishikawa, M. Otsuji, T. Iizasa, H. Hanaoka, N. Shimizu, S. Horiguchi, Y. Okamoto, S.-i. Fujii, et al. A Phase I Study of In vitro Expanded Natural Killer T Cells in Patients with Advanced and Recurrent Non-Small Cell Lung Cancer Clin. Cancer Res., October 15, 2006; 12(20): 6079 - 6086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ishikawa, S. Motohashi, E. Ishikawa, H. Fuchida, K. Higashino, M. Otsuji, T. Iizasa, T. Nakayama, M. Taniguchi, and T. Fujisawa A Phase I Study of {alpha}-Galactosylceramide (KRN7000)-Pulsed Dendritic Cells in Patients with Advanced and Recurrent Non-Small Cell Lung Cancer Clin. Cancer Res., March 1, 2005; 11(5): 1910 - 1917. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Alifano, G. Benedetti, and R. Trisolini Can Low-Molecular-Weight Heparin Improve the Outcome of Patients With Operable Non-Small Cell Lung Cancer?: An Urgent Call for Research Chest, August 1, 2004; 126(2): 601 - 607. [Full Text] [PDF]
|
|
|
|
 |
|
 E. F. Patz Jr, J. J. Erasmus, H. P. McAdams, J. E. Connolly, E. M. Marom, P. C. Goodman, R. A. Leder, M. T. Keogan, and J. E. Herndon Lung Cancer Staging and Management: Comparison of Contrast-enhanced and Nonenhanced Helical CT of the Thorax Radiology, July 1, 1999; 212(1): 56 - 60. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
