- Email: [email protected]
Pulmonary Metastasectomy
Pulmonary Metastasectomy* Current Indications Valerie W. Rusch, MD, FCCP Surgical resection remains an important form of treatment for pulmonary metastases from a variety of solid tumors. The most significant factors in selecting patients for operation include control of the primary tumor, ability to resect all metastatic disease, absence of extrathoracic metastases, lack of better alternative systemic therapy, and sufficient cardiopulmonary reserve for the planned resection. A solitary pulmonary nodule and long tumor doubling times and disease-free intervals usually define patients who experience better long-
term survival after pulmonary resection but do not constitute absolute criteria by which to select such patients. Complete surgical resection is critical to achieving long-term survival and is best accomplished via a standard or "clamshell" thoracotomy or a median sternotomy. The decision to proceed with the surgical resection of pulmonary metastases should be a multidisciplinary one, made jointly by the thoracic surgeon and the medical oncologist. (CHEST 1995; 107:322S-832S)
pulmonary resection for metastatic disease was initially reported in the European literature by Divis in 1927. 1 The first such resection in North America was performed by Barney and Churchill in 1939. 2 A solitary mass removed by lobectomy proved to be a metastasis from renal cell carcinoma. The patient subsequently had a nephrectomy for the primary tumor and survived disease-free for over 20 years. From 1940 to the mid-1960s, pulmonary metastasectomy was performed infrequently and only in highly selected patients. At Memorial Sloan-Kettering Cancer Center (MSKCC), 25 patients with pulmonary metastases were treated surgically from 1940 to 1965.3 Operation was not considered unless the patient had a long disease-free interval following resection of the primary tumor, and had three or fewer lesions confined to one lung. During a similar time period, from 1941 to 1962, the Mayo Clinic performed 221 pulmonary resections on 205 patients for metastatic disease. 4 Although multiple nodules were not considered a contraindication to resection, patients with bilateral disease were thought to have a poor prognosis and thus were not considered for operation. The indications for pulmonary metastasectomy were very restricted, and although not explicitly stated, the large number of operations performed may reflect the high volume of cases seen at the Mayo Clinic rather than the common use of surgical resection. In the 1970s, experience from several institutions
suggested that more liberal indications for pulmonary metastasectomy were appropriate. A striking example was the treatment of metastatic osteogenic sarcoma at MSKCC. From 1940 to 1965, only five patients with this condition were treated surgically. During the same period, only 24 of 145 patients (17%) survived 5 years after resection of their primary tumor, and 118 of these patients (81%) died of pulmonary metastases. This experience prompted a more aggressive approach to the management of pulmonary metastases. Starting in 1965, a consecutive series of 22 patients with osteogenic sarcoma underwent pulmonary metastasectomy. Patients were considered for operation even if they had bilateral metastases or required multiple thoracotomies to remove all gross tumor. A total of 59 thoracotomies were performed in these 22 patients, with an overallS-year survival rate of 32%. This dramatic improvement in survival compared to historic experience strongly supported the aggressive use of pulmonary metastasectomy in these patients. 5 •6 During the last 25 years, surgical resection has become a widely accepted treatment for pulmonary metastases. 3 ·7- 14 Some of the criteria for patient selection, however, remain controversiaJ.l 5 In addition, advances in chemotherapy have changed the indications for surgical resection. For some cancers, pulmonary metastasectomy is performed to prolong life expectancy, whereas in others, it serves mainly to restage disease or to provide adjuvant treatment after initial chemotherapy. The role of pulmonary metastasectomy will undoubtedly continue to evolve as improvements in systemic treatment occur. This review provides a perspective on the current approach to the surgical management of pulmonary metastases.
*From the Thoracic Service, Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York. Reprint requests: Dr. Rusch, MSKCC, 1275 York Ave, New York, NY 10021
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Multimodality Therapy of Chest Malignancies: Update '94
l. Solitary right middle lobe metastasis from breast cancer. The nodule is discreet and well circumscribed. The abnormality in the periphery of th e lingula (arrow) is an area of chronic fibrosis that developed followin g previous treatment with highdose chemotherapy and autologous bone marrow transplantation . FIGUHE
CLINICAL PHESE;\ITATIO'I AND EvALUATION
Most pulmonary metastases do not cause symptoms and are detected incidentally on radiographic studies. Symptoms occur in 15 to 20% of patients and usually reflect the proximity of metastatic lesions to the central airways. Cough and hemoptysis are the most frequent symptoms. Fever, ill-defined chest discomfort, and paraneoplastic syndromes are occasionally seen. 7- 10.1 2- 14 ·16 Dyspnea may occur if a centrally located metastasis produces airway obstruction by way of either endobronchial tumor or extrinsic compression. Some series note involvement of the proximal airways in up to 28% of patients. True endobronchial metastases are infrequent and occur most often in colorectal, breast, and renal cancers. They are also seen occasionally in thyroid cancers and malignant melanomas. 17 -2 1 The radiographic presentation of pulmonary me-
FIGL'HE 2. Chest CT scans of patient with pulmonary metastases from a previous! y resected soft tissue sarcoma. The metastases are characteristically multiple, peripheral, and well-circumscribed. The two metastases are located in the right upper lobe (top) and the le ft lower lobe (bottom, arrow ).
I FiGUHE 3. Spontaneous pneumothorax (left, arrows) in a patient with metastatic soft tissue sarcoma. The metastases are best seen on CT scan (right , arrow) which also demonstrates the pneumothorax seen on chest x-ray film. The pneumothorax recurred despite pleurodesis with talc slurry via a chest tube. Thoracoscopy , mechani cal pleurodesis, and talc poudrage were required to control this complication of pulmonary metastases.
CHEST / 107 / 6 / JUNE, 1995 / Supplement
3235
FIGURE 4. Benign intraparenchymallymph node (arrow) mimicking the typical appearance of a pulmonary metastasis. This was wedge resected for diagnosis by VATS.
tastases has been comprehensively reviewed by Libshitz and North. 22 The typical appearance both on chest x-ray film and computed tomography (CT) scan is that of a smooth, well-circumscribed, peripheral pulmonary nodule (Fig 1). Lack of associated calcification and multiplicity of lesions (Fig 2) are the only features that potentially distinguish pulmonary metastases from benign pulmonary nodules such as hamartomas, fibromas, or granulomas. Occasionally, cavitation occurs; this feature is seen most often in metastatic squamous cell carcinomas. Spontaneous pneumothorax, notoriously resistant to standard methods of pleurodesis, is characteristic of metastatic sarcomas and is thought to be caused by necrosis of peripherally located metastases (Fig 3). Very small pulmonary metastases (<1 em in size) may be indistinguishable from intra parenchymal lymph nodes on CT scan (Fig 4). However, endobronchial or peribronchial metastases may have a much less discreet appearance because of associated hemorrhage or postobstructive atelectasis and pneumonitis (Fig 5). Several series have examined the accuracy of chest x-ray, standard whole-lung tomography, and CT scan in detecting pulmonary metastases. 22 In current practice, whole-lung tomography, once a standard preoperative evaluation, has been replaced by CT. Both the older and more recent series show that CT has a greater sensitivity but lower specificity than chest radiography in detecting pulmonary metastases.23-26 Standard contrast-enhanced CT scan has an approximate 25 to 30% rate of differing from the findings at operation by way of eitherfalse-positive or false-negative findings. Some tiny nodules seen on CT prove to be benign, and conversely, some metastases are so small that they are not detected by CT. 3245
Whether spiral CT scanning will improve the diagnostic accuracy of CT remains to be seen. 27 If a patient's clinical presentation and radiographic findings suggest the possibility of pulmonary metastases, a tissue diagnosis can usually be established by percutaneous needle aspiration or by bronchoscopy, depending on whether the nodule is located peripherally or centrally. Pulmonary nodules that are too small to be amenable to needle aspiration can be excisionally biopsied by video-assisted thoracic surgery (V ATS). 28 It is important to remember that a new pulmonary nodule in a patient who has previously had a primary cancer is not necessarily a metastasis; it can be benign or may be a second primary cancer. 29 ,30 The likelihood that a new pulmonary nodule is a metastasis as opposed to a second primary cancer is directly related to the original type of malignancy. In patients whose initial cancer was a sarcoma or melanoma, a new pulmonary nodule is approximately ten times more likely to be a metastasis than a second primary cancer. If the original pri-
FIGURE 5. Endobronchial (top) and peribronchial (bottom) metastasis from a uterine angiosarcoma. The patient presented with hemoptysis and partial collapse of left lung. The radiographic appearance of this lesion is more characteristic of a primary lung cancer than of a metastasis.
Multimodality Therapy of Chest Malignancies: Update '94
mary tumor was a genitourinary or colorectal cancer, there is about a 50% chance that the new nodule is a metastasis. If the original tumor was a head and neck cancer, the new nodule is twice as likely to be a new primary lung cancer than a metastasis. 7·31 ·32 This finding is readily understood if it is remembered that most head and neck cancers and lung cancers share the etiology of being smoking-related tumors. In patients who have had a primary lung cancer, a new pulmonary nodule is more likely to be a second primary cancer if it is solitary and more than 2 years have elapsed since the resection of the first cancer. 33 Therefore, if nonsurgical treatment is being considered for a new pulmonary nodule in the setting of a previous primary cancer, it is important to establish a definitive tissue diagnosis before initiating therapy and not simply to assume that the patient has metastatic disease. In specific situations where surgical resection would offer appropriate treatment, regardless of whether the pulmonary nodule is primary or metastatic, exploratory thoracotomy without a preoperative diagnosis is an acceptable approach to management. CRITERIA FOR SURGICAL RESECTION
Chemotherapy-Sensitive Tumors Clinical experience has allowed the identification of criteria by which to select patients for surgical resection. Perhaps the most important factor influencing the use of surgical resection as the primary treatment for pulmonary metastases is how effective chemotherapy is for a particular type of cancer. A secondary factor is whether the natural history of that cancer is to metastasize predominantly to the lungs or to disseminate widely. Two types of cancer illustrate the evolution in the use of surgical resection because of improvements in chemotherapy: breast cancer and germ cell cancer. Metastatic breast cancer was a frequent indication for pulmonary resection in early surgical series?- 14 During the past 15 years, however, dramatic improvements in chemotherapy and the recognition that breast cancer usually produces widespread metastases have made pulmonary resection an uncommon form of treatment. A recent series34 reported an actuarial 5-year survival rate of 49.5% in a highly select group of 44 patients seen over a 10-year period who had resection of a solitary pulmonary metastasis from breast cancer. However, 40 of the 44 patients also received perioperative hormonal therapy or chemotherapy, making it difficult to assess the specific contribution of surgical resection in controlling disease. Outside of the unusual circumstance of a solitary pulmonary metastasis, most patients with breast cancer would now be treated nonsurgically.
Approximately 20 years ago, before the development of effective chemotherapy regimens for germ cell cancer, resection of pulmonary metastases was used to control this rapidly fatal disease. Today, metastatic germ cell cancer is treated primarily with cisplatin-based chemotherapy, with a high long-term cure rate. Pulmonary resection serves as adjuvant therapy to determine whether active microscopic tumor is still present after normalization of serum markers and to remove residual mature teratoma that potentially poses a problem of local control.35·36 A few highly select patients with a solitary metastasis and persistently elevated serum markers may benefit from resection in conjunction with continued chemotherapy,37 but for the majority of patients, pulmonary resection is no longer used as primary treatment.
Chemotherapy-Insensitive Tumors Unfortunately, most solid tumors that metastasize to the lung are relatively insensitive to currently available chemotherapy. Pulmonary resection is still an important primary form of treatment for these malignancies, which include colorectal cancer, some gynecologic cancers, various types of head and neck cancer, renal cell cancer, malignant melanoma, and osteogenic and soft tissue sarcomas (Table 1).7- 11 •38 The fundamental biology of these cancers and the genetic factors governing metastasis are still undefined, so the criteria used in selecting patients for pulmonary resection are clinical, and hence, relatively imprecise. These criteria are derived from retrospective analyses of surgical series that often include patients with many different types of primary tumors who are receiving a variety of additional treatments. Therefore, some of the criteria are controversial because they have not been proven consistently significant across reported series. Consistently important criteria include the following: (1) control of the primary tumor, or ability to resect primary tumor completely simultaneous with resection of metastases; (2) ability to resect metastatic disease completely; (3) ability of the patient to withstand the extent of pulmonary resection required to remove all gross tumor; (4) absence of extra thoracic metastases; and (5) absence of better alternative systemic treatment. 7-14·39 The criteria found to be important in only some reported series include the following: (1) the disease-free interval between resection of primary tumor and the development of pulmonary metastases (Table 2);10.12,40-43 (2) the tumor doubling time of pulmonary metastases (Table 3); 12·13·41 ·42 and (3) the number of pulmonary metastases.15.16·44 In a general sense, the latter criteria reflect tumor biology. Although these criteria may not be consistently reproducible across series, it is underCHEST /107 /6/ JUNE, 1995/ Supplement
3255
Table !-Primary Tumor Sites From Representative Series of Patients Undergoing Surgical Resection of Pulmonary Metastases*
Colorectal Soft tissue sarcoma Osteogenic sarcoma Melanoma Renal cell Breast Testis Gynecologic Head and neck Other Total
Wilkins et al,
Morrow et al,
Wright eta!,
Mountain et al,
19799
198010
Kodama et al,
19828
198411
McCormack,
199138
19907
35 14 4 9 28 9 14
19 0 0 12 30
19 0 0 6 14 18 8 12 9 14 100
51 49 76 58 27 30 20 9
21 15 4 0 13 8 6
43
9 20 100
lO
12 27 0 15 125
ll
0 18 142
0 363
4
80 N/A N/A
59 43 55 85 32 47 401
*N/ A=not available from this review.
standable that patients who have rapidly growing or numerous pulmonary metastases are less likely to benefit from surgical resection than are patients who have one or two slowly growing metastases. The criteria for surgical resection will continue to evolve as we gain a better understanding of tumor biology and as better systemic treatment becomes available. Although surgical resection is currently considered optimal treatment for patients who meet the above criteria, the decision to proceed with an operation is best made jointly by a thoracic surgeon and a medical oncologist. Some patients will remain disease free after the initial pulmonary resection, but unfortunately the majority will eventually relapse and require systemic treatment. It is wise to initiate multidisciplinary patient management early on, and not as an afterthought. TECHNIQUE OF PULMONARY RESECTION
The objective of resection of pulmonary metastases is to remove all gross tumor while preserving as much normal pulmonary parenchyma as possible. Most pulmonary metastases are discreet, small, subpleural nodules that can be completely removed by wedge resection using a CIA or T A stapler. 7 Nodules located in areas of the lung where a stapler cannot be easily applied can be excised with the needle-tip electrocautery. A conical-shaped wedge of pulmonary parenchyma is removed by cauterizing circumTable 2-Selected Series Showing A Significant Impact of Disease-Free Interval (DFI) on Overall Survival Author, yr
No. Patients
DFI
Creagan et al, 197940 Morrow et al, 198010 Takita et al, 1981 12 Putnam et al, 198341 van de Wal et al, 198642 Depadt et al, 198543
112 167 234 67 80 68
>l yr >5 yr >7 mo >l yr > l-5 yr >2 yr
3265
ferentially around the nodule, taking with it a 0.5- to 1.0-cm margin of normal lung tissue in all directions. When the nodule has been removed, meticulous hemostasis is obtained within the pulmonary parenchyma, and the pleural edges of the area of excision are reapproximated with sutures. 45 Stapling and electrocautery techniques can also be combined by applying a stapler across the deep portion of the pulmonary parenchymal margin once most of the excision has been performed with the cautery. An endoscopic CIA stapler is useful in this circumstance because it is narrower and easier to manipulate in a deep area of lung tissue than a standard CIA stapler. A laser can also be used to perform such wedge resections but is more sumbersome and has no particular advantages over needle-tip electrocautery. The argon beam electrocoagulator (Birtcher Corporation, Englewood, Colo) may be helpful in obtaining hemostasis in the pulmonary parenchyma and in sealing small air leaks. 46 Although more extensive surgical procedures like lobectomy and even pneumonectomy do not increase the chance of cure after metastasectom y, they are sometimes technically necessary to allow complete resection of centrally located metastases. These more extensive resections offer some patients the best treatment and may lead to long-term survival but should be considered carefully since many patients subsequently develop metastases in the remaining lung. 47 Table 3-Selected Series Reporting Tumor Doubling Time (TDT) Significantly Influences Overall Survival Author, yr
No. Patients
TDT,d
Ramming, 198013 Takita et al, 1981 12 Putnam et al, 198341 van de Wal et al, 198642
91 234 67 80
>40 >45 >20 >136
Multimodality Therapy of Chest Malignancies: Update '94
Table 4-0utcome of Patients Undergoing Surgical Resection of Pulmonary Metastases From Colorectal Cancer Author, yr
No. Patients
5-yr Survival, %
Mansel et al, 198652 Goya et al, 198953 McAfee et al, 199254 McCormack et al, 199255
66 62 139 144
38 42 30.5 40
ally seen and may be associated with poorer longterm survival, but the implications for patient management are unclear. Systematic lymph node dissection, as performed for a primary lung cancer, is not generally indicated. In the interests of proper diagnosis and of resecting all gross tumor, any suspicious lymph nodes should be resected. RESULTS OF PULMONARY RESECTION IN SELECTED SOLID TUMORS
When a high-quality preoperative CT scan shows that metastatic disease is confined to one lung, most surgeons prefer to explore a patient via a standard thoracotomy. Bilateral metastases can be approached via a median sternotomy, but this incision limits the exposure to the posterior aspect of the lungs, particularly the left lower lobe. 48•49 A "clamshell" thoracotomy (bilateral anterior thoracotomy with transverse sternotomy), recently repopularized for lung transplantation, is now also being used for the resection of bilateral pulmonary metastases. Although this procedure appears to be more painful than a median sternotomy, it provides excellent exposure to the posterior aspect of both lungs. 50 The operative mortality of any of these approaches is less than 1% in multiple reported series. 7-1 4 Video-assisted thoracic surgery has been advocated for the resection of pulmonary metastases. 51 The identification of pulmonary nodules by VATS relies heavily on the preoperative CT scan and on the ability to visualize lesions in the periphery of the lung. As noted previously, CT scan often underestimates the number of pulmonary nodules present. 27 Since long-term survival appears to be directly related to the resection of all gross disease, it is imperative that the surgeon systematically inspect and palpate the lungs to ensure that all tumor is identified and removed. Therefore, most thoracic surgical oncologists are reluctant to perform VATS for therapeutic purposes and confine its use to the diagnosis and staging of pulmonary metastases. 28 Small pulmonary nodules are best identified with the lung sequentially inflated and deflated. Therefore, it is important that a double-lumen endotracheal tube be used in all operations. Bronchoscopy also is not performed routinely by most surgeons at the time of resection of pulmonary metastases; however, it is warranted prior to thoracotomy in patients who have centrally located lesions, symptoms suggestive of airway involvement, or tumor types that are prone to endobronchial involvement such as breast, colon, or renal cell cancer. The role of lymph node sampling or dissection in the management of pulmonary metastases has not been defined. Lymph node involvement is occasion-
Colorectal Cancer Small numbers of patients with colorectal cancer have been included within many series reporting the results of surgical resection for pulmonary metastases. The 5-year survival rate after resection ranges from 20 to 40%. 3 At least three larger series specifically address the issue of long-term outcome after pulmonary metastases from colorectal cancer (Table 4). 52-55 In a Japanese series of 62 patients,53 the 5- and 10-year survival rates were 42 and 22%, respectively. The highest survival rate was seen in patients who had a solitary metastasis that was less than 3.0 em in size. Gender, age, disease-free interval, and extent of pulmonary resection did not influence survival. At the Mayo Clinic, 139 consecutive patients underwent pulmonary resection for metastatic colorectal cancer between 1960 and 1988.52•54 With a median follow-up of 7 years, 30.5% of patients were alive at 5 years and 16.2% at 20 years. The 5-year survival rate for patients with a solitary metastasis was 36.9%, as compared with 19.3% for those with two metastases (p<0.05) and 7.7% for those with more than two metastases (p<0.01). An elevated carcinoembryonic antigen (CEA) level also had a significant adverse effect on survival. 54 The MSKCC experience has been similar to that at the Mayo Clinic. In 144 patients undergoing resection for pulmonary metastases from 1965 to 1988, the overallS-and 10-year survival rates were 40 and 30%, respectively. 55 The majority of patients (80 of 144) presented with a solitary metastasis and had a slightly but not statistically significant better survival than patients who had more than one nodule. Survival was not influenced by the disease-free interval. This series noted that the 11 patients who could not undergo a complete resection of all gross tumor because of borderline pulmonary reserve had a median survival of 9 months, and all died of progressive disease. Both the Mayo Clinic and MSKCC series found that patients could experience long-term survival after undergoing multiple sequential resections for pulmonary metastases. Osteogenic Sarcoma Surgical resection remains the only potentially CHEST /107/6/ JUNE, 1995/ Supplement
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Table 6-0utcome of Patients Undergoing Surgical Resection of Pulmonary Metastases From Malignant Melanoma
Table 5-0utcome of Patients Undergoing Surgical Resection of Pulmonary Metastases From Soft Tissue Sarcoma Author, yr
No. Patients
Ruth et al, 198062 Jablons et al, 198965 Casson et al, 1992 66 Gadd et al, 199369
43 57 58 65
5-yr Survival,
%
40 (4-yr) 35 25.8 23 (3-yr)
curative treatment for patients with pulmonary metastases from osteogenic sarcoma. After resection of the primary tumor, the routine use of adjuvant chemotherapy has improved the disease-free survival and altered the pattern of pulmonary recurrence. A multiinstitutional study performed by the Pediatric Oncology Group56 found that patients who did not receive adjuvant chemotherapy relapsed sooner and had significantly more pulmonary nodules than patients who received adjuvant chemotherapy. The patients who received adjuvant chemotherapy, however, were less likely to respond to additional systemic treatment after pulmonary resection. The only factor found to be predictive of survival in either group was whether the patients could be rendered surgically disease-free after initial relapse. Other contemporary series have confirmed the beneficial role of surgical resection in patients with pulmonary metastases from osteogenic sarcoma. 5·6 Reported 5-year survival rates vary from 20 to 40%, perhaps reflecting the small numbers of patients in these series and an individualized approach to management. The inability of chemotherapy alone to cure patients and the importance of complete surgical resection are findings common to all reported series.41,57-61
Soft Tissue Sarcoma Pulmonary resection also remains the only potentially curative treatment for soft tissue sarcomas, which almost always metastasize solely to the lung and are notoriously resistant to current chemotherapeutic agents. An early series of 112 patients with metastatic soft tissue sarcoma undergoing surgery at the Mayo Clinic from 1950 to 1976 reported a 5-year survival rate of 29%. 40 Survival was influenced adversely by a disease-free interval of less than 12 months and by the subsequent development of extrathoracic metastases. Gender, age, histology, number of lesions fully excised, and site of lung lesions did not affect survival. Huth and colleagues62 reported on 48 patients who underwent resection of pulmonary metastases from soft tissue sarcoma (Table 5). The 4-year survival rate of 40% was significantly influenced by the tumor doubling time (greater than or less than 40 days) and 328S
Author, yr
No. Patients
Cahan, 197373 Mathisen et al, 197971 Mountain et al, 198411 Thayer and Overholt, 1985 74 Pogrebniak et al, 198872 Gorenstein et al, 1991 70 Harpole et al, 199275
29 12 58 18 49 56 84
5-yr Survival,
%
34 (2-yr) MS* 13.3 11.1
MSl 25 20
*Median survival, 12 mo. lMedian survival, 13 mo. by the disease-free interval (greater than or less than 1 year). Several series have been published presenting experience with metastatic soft tissue sarcomas, first at the National Cancer Institute and subsequently at MD Anderson Cancer Center. 63 -66 Four or fewer nodules, a disease-free interval of greater than 1 year, and a tumor doubling time greater than 40 days were associated with significantly improved survival. It was also observed67 ·68 that reoperation for patients who relapse in the lungs is warranted, since the median survival of such patients was 25 months. At MSKCC, the long-term outcome in such patients has been less favorable. 69 The 8-year survival rate after complete resection of all pulmonary metastases in 65 patients was only 28%. Moreover, these patients represented only about half of all 185 patients who developed pulmonary metastases since many patients could not have a complete resection or required nonsurgical treatment. This experience suggests that patients with soft tissue sarcoma who can undergo complete resection of their pulmonary metastases are a highly select group and experience a 5-year survival rate of 20 to 85% (Table 5). 62·65,66,69 Unfortunately, no better alternative treatment is yet available.
Malignant Melanoma The survival of patients with metastases from malignant melanoma has in general been poor because of the capricious behavior of this tumor and its propensity to metastasize to sites other than the lung. Several series have reported the results of surgical resection of pulmonary metastases (Table 6)_1 1,70- 75 The largest such series, from the Duke University Cancer Center, is based on 7,564 patients treated from 1970 to 1990. 74 Pulmonary metastases, which developed in 945 patients (12%), were associated with an overall 5-year survival rate of only 4%. However, a favorable group of 226 patients who underwent resection of a solitary nodule experienced a 5-year survival of 20%. Patients with two pulmonary nodules had a significantly better postthoracotomy Multimodality Therapy of Chest Malignancies: Update '94
survival than did patients with three or more nodules. The disease-free interval also significantly influenced survival. These data support the selective use of pulmonary resection in patients who have metastases from malignant melanoma.
Other Solid Tumors Similar results can be cited for other solid tumors with pulmonary metastases. A 5-year survival rate of approximately 30% is seen after resection of pulmonary metastases in selected patients with renal cell cancers, various head and neck cancers,76•77 and some nonovarian gynecologic cancers,78 to name a few. The behavior of renal cell cancers is particularly unpredictable, and anecdotal spontaneous regression of tumor is a recognized event in this disease. 79-81 In head and neck cancers, the 5-year survival rates after resection of pulmonary metastases are approximately 30% but vary according to cell type and site of origin of the primary tumor. CoNCLUSIONs
Surgical resection remains an important form of treatment for pulmonary metastases from a variety of solid tumors. The most significant factors in selecting patients for operation include control of the primary tumor, ability to resect all metastatic disease, absence of extrathoracic metastases, and lack of better alternative systemic therapy. One or two pulmonary nodules, long tumor doubling times, and disease-free intervals usually define patients who experience a better outcome after pulmonary resection but do not constitute absolute criteria by which to select such patients. Complete surgical resection is critical to achieving long-term survival and is best accomplished via a standard or clamshell thoracotomy or a median sternotomy. In most cases, the decision to proceed with surgical resection of pulmonary metastases should be made jointly by the thoracic surgeon and the medical oncologist as part of a multidisciplinary approach to the management of this problem. REFERENCES
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6 Shah A, Exelby PR, Rao B, et a!. Thoracotomy as adjuvant to chemotherapy in metastatic osteogenic sarcoma. J Pediatr Surg 1977; 12:983-90 7 McCormack P. Surgical resection of pulmonary metastases. Semin Surg Oncol1990; 6:297-302 8 Wright JO III, Brandt B III, Ehrenhaft JL. Results of pulmonary resection for metastatic lesions. ] Thorac Cardiovasc Surg 1982; 83:94-9 9 Wilkins EW Jr, Head JM, Burke JF. Pulmonary resection for metastatic neoplasms in the lung: experience at the Massachusetts General Hospital. Am J Surg 1979; 135:480-83 10 Morrow CE, Vassilopoulos PP, Grage TB. Surgical resection for metastatic neoplasms of the lung: experience of the University of Minnesota hospitals. Cancer 1980; 45:2981-85 11 Mountain CF, McMurtrey MJ, Hermes KE. Surgery for pulmonary metastasis: a 20-year experience. Ann Thorac Surg 1984; 38:323-30 12 Takita H, Edgerton F, Karakousis C, eta!. Surgical management of metastases to the lung. Surg Gynecol Obstet 1981; 152:191-94 13 Ramming KP. Surgery for pulmonary metastases. Surg Clin North Am 1980; 60:815-24 14 Takita H, Merrin C, Didolkar MS, eta!. The surgical management of multiple lung metastases. Ann Thorac Surg 1977; 24:359-64 15 Putnam JB Jr, Roth JA. Prognostic indicators in patients with pulmonary metastases. Semin Surg Oncol1990; 6:291-96 16 Joseph WL. Criteria for resection of sarcoma metastatic to the lung. Cancer Chemother Rep 1974; 58:285-90 17 Kemeny N, Conti J, Klimstra D, eta!. Colon carcinoma metastatic to the trachea: report of a case and a review of the literature. Am J Clin Oncol1994; 17:227-29 18 Baumgartner W A, Mark JBD. Metastatic malignancies from distant sites to the tracheobronchial tree. J Thorac Cardiovasc Surg 1980; 79:499-503 19 MacMahon H, O'Connell DJ, Cimochowski GE. Pedunculated endotracheal metastasis. Am J Roentgenol1978; 131:713-14 20 Kenny JN, Smith WL, Brawer MK. Endobronchial metastases from prostatic carcinoma. Ann Thorac Surg 1988; 45:223-24 21 Kamby C, Vejborg I, Kristensen B, eta!. Metastatic pattern in recurrent breast cancer: special reference to intrathoracic recurrences. Cancer 1988; 62:2226-33 22 Libshitz HI, North LB. Pulmonary metastases. Radio! Clin North Am 1982; 20:437-51 23 Chang AE, Schaner EG, Conkle DM, eta!. Evaluation of computed tomography in the detection of pulmonary metastases. Cancer 1979; 43:913-16 24 Creagan ET, Frytak S, Pairolero P, et a!. Surgically proven pulmonary metastases not demonstrated by computed chest tomography. Cancer Treat Rep 1978; 62:1404-05 25 Mintzer RA, Malave SR, Neiman HL, eta!. Computed vs conventional tomography in evaluation of primary and secondary pulmonary neoplasms. Radiology 1979; 132:653-59 26 Piekarski J-D, Schlumberger M, Leclere J, et a!. Chest computed tomography (CT) in patients with micronodular lung metastases of differentiated thyroid carcinoma. Int J Radiat Oncol Bioi Phys 1985; 11:1023-27 27 McCormack PM, Ginsberg KB, Bains MS, et a!. Accuracy of lung imaging in metastases with implications for the role of thoracoscopy. Ann Thorac Surg 1993; 56:863-66 28 Rusch VW, Bains MS, Burt ME, eta!. Contribution of videothoracoscopy to the management of the cancer patient. Ann Surg Oncol1994; 1:94-8 29 Cahan WG, Castro EB. Significance of a solitary lung shadow in patients with breast cancer. Ann Surg 1975; 181:137-43 30 Cahan WG, Shah JP, Castro EB. Benign solitary lung lesions in patients with cancer. Ann Surg 1978; 187:241-44 CHEST /107/6/ JUNE, 1995/ Supplement
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31 Johnson H, Fantone J, Flye MW. Histological evaluation of the nodules resected in the treatment of pulmonary metastatic disease. J Surg Oncoll982; 21:1-4 32 Cahan WG, Castro EB, Hajdu SI. The significance of a solitary lung shadow in patients with colon carcinoma. Cancer 1974; 33:414-21 33 The Lung Cancer Study Group, Thomas PA Jr, Rubinstein L. Malignant disease appearing late after operation for TlNO non-small-cell lung cancer. J Thorac Cardiovasc Surg 1993; 106:1053-58 34 Lanza LA, Natarajan G, Roth JA, eta!. Long-term survival after resection of pulmonary metastases from carcinoma of the breast. Ann Thorac Surg 1992; 54:244-48 35 Toner GC, Panicek DM, Heelan RT, eta!. Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 1990; 8:1683-94 36 Logothetis CJ, Samuels ML, Trindade A, eta!. The growing teratoma syndrome. Cancer 1982; 50:1629-35 37 Wood DP Jr, Herr HW, Motzer RJ, eta!. Surgical resection of solitary metastases after chemotherapy in patients with nonseminomatous germ cell tumors and elevated serum tumor markers. Cancer 1992; 70:2354-57 38 Kodama K, Doi 0, Higashiyama M, eta!. Surgical management of lung metastases: usefulness of resection with the neodymium:yttrium-aluminum-garnet laser with median sternotomy. J Thorac Cardiovasc Surg 1991; 101:901-08 39 McCormack PM, Bains MS, Beattie EJ Jr, eta!. Pulmonary resection in metastatic carcinoma. Chest 1978; 73:163-66 40 Creagan ET, Fleming TR, Edmonson JH, eta!. Pulmonary resection for metastatic nonosteogenic sarcoma. Cancer 1979; 44:1908-12 41 Putnam JB Jr, Roth JA, Wesley MN, eta!. Survival following aggressive resection of pulmonary metastases from osteogenic sarcoma: analysis of prognostic factors. Ann Thorac Surg 1983; 36:516-23 42 van de Wal HJ, Verhagen A, Lecluyse A, eta!. Surgery of pulmonary metastases. Thorac Cardiovasc Surg 1986; 34:153-56 43 Depadt G, Delacrois R, Mauretta J, eta!. Surgical treatment of pulmonary metastasis: problems and prospects. In: Hellman K, Eccles SA, eds. Proceedings. Philadelphia: Taylor and Francis, 1985; 5-8 44 Joseph WL, Morton DL, Adkins PC. Prognostic significance of tumor doubling time in evaluating operability in pulmonary metastatic disease. J Thorac Cardiovasc Surg 1971; 61:23-32 45 Cooper JD, Perelman M, Toad TRJ, et al. Precision cautery excision of pulmonary lesions. Ann Thorac Surg 1986; 41:51-3 46 Rusch VW, Schmidt R, Shoji Y, eta!. Use of the argon beam electrocoagulator for performing pulmonary wedge resections. Ann Thorac Surg 1990; 49:287-91 47 Putnam JB Jr, Suell DM, Natarajan G, et al. Extended resection of pulmonary metastases: is the risk justified? Ann Thorac Surg 1993; 55:1440-46 48 Johnston MR. Median sternotomy for resection of pulmonary metastases. J Thorac Cardiovasc Surg 1983; 85:516-22 49 Roth JA, Pass HI, Wesley MN, eta!. Comparison of median sternotomy and thoracotomy for resection of pulmonary metastases in patients with adult soft-tissue sarcomas. Ann Thorac Surg 1986; 42:134-38 50 Bains MS, Ginsberg RJ, Jones WG, eta!. The clamshell incision: an improved approach to bilateral pulmonary and mediastinal tumor. Ann Thorac Surg 1994; 58:30-3 51 Dowling RD, Ferson PF, Landreneau RJ. Thoracoscopic resection of pulmonary metastases. Chest 1992; 102:1450-54 52 Mansel JK, Zinsmeister AR, Pairolero PC, et a!. Pulmonary resection of metastatic colorectal adenocarcinoma: a ten year experience. Chest 1986; 89:109-12
330S
53 Goya T, Miyazawa N, ·Kondo H, et al. Surgical resection of pulmonary metastases from colorectal cancer: 10-year followup. Cancer 1989; 64:1418-21 54 McAfee MK, Allen MS, Trastek VF, eta!. Colorectallung metastases: results of surgical excision. Ann Thorac Surg 1992; 53:780-86 55 McCormack PM, Burt ME, Bains MS, eta!. Lung resection for colorectal metastases: 10-year results. Arch Surg 1992; 127: 1403-06 56 Goorin AM, Shuster JJ, Baker A, et a!. Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multi-institutional osteosarcoma study. J Clin Oncol1991; 9:600-05 57 Meyer WH, Schell MJ, Kumar M, et a!. Thoracotomy for pulmonary metastatic osteosarcoma: an analysis of prognostic indicators of survival. Cancer 1987; 59:374-79 58 Gundry SR, Coran AG, Lemmer J, et a!. The influence of tumor microfoci on recurrence and survival following pulmonary resection of metastatic osteogenic sarcoma. Ann Thorac Surg 1984; 38:473-78 59 Belli L, Scholl S, Livartowski A, et a!. Resection of pulmonary metastases in osteosarcoma: a retrospective analysis of 44 patients. Cancer 1989; 63:2546-50 60 Carter SR, Grimer RJ, Sneath RS, eta!. Results of thoracotomy in osteogenic sarcoma with pulmonary metastases. Thorax 1991; 46:727-31 61 Goorin AM, Delorey MJ, Lack EE, eta!. Prognostic significance of complete surgical resection of pulmonary metastases in patients with osteogenic sarcoma: analysis of 32 patients. J Clin Oncol1984; 2:425-31 62 Huth JF, Holmes EC, Vernon SE, eta!. Pulmonary resection for metastatic sarcoma. Am J Surg 1980; 140:9-16 63 Putnam JB Jr, Roth JA, Wesley MN, eta!. Analysis of prognostic factors in patients undergoing resection of pulmonary metastases from soft tissue sarcomas. J Thorac Cardiovasc Surg 1984; 87:260-68 64 Roth JA, Putnam JB Jr, Wesley MN, eta!. Differing determinants of prognosis following resection of pulmonary metastases from osteogenic and soft tissue sarcoma patients. Cancer 1985; 55:1361-66 65 Jablons D, Steinberg SM, Roth J, eta!. Metastasectomy for soft tissue sarcoma: further evidence for efficacy and prognostic indicators. J Thorac Cardiovasc Surg 1989; 97:695-705 66 Casson AG, Putnam JB, Natarajan G, eta!. Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 1992; 69:662-68 67 Pogrebniak HW, Roth JA, Steinberg SM, et a!. Reoperative pulmonary resection in patients with metastatic soft tissue sarcoma. Ann Thorac Surg 1991; 52:197-203 68 Casson AG, Putnam JB, Natarajan G, et a!. Efficacy of pulmonary metastasectomy for recurrent soft tissue sarcoma. J Surg Oncoll991; 47:1-4 69 Gadd MA, Casper ES, Woodruff JM, eta!. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993; 218:705-12 70 Gorenstein LA, Putnam JB Jr, Natarajan G, eta!. Improved survival after resection of pulmonary metastases from malignant melanoma. Ann Thorac Surg 1991; 52:204-10 71 Mathisen DJ, Flye MW, Peabody J. The role of thoracotomy in the management of pulmonary metastases from malignant melanoma. Ann Thorac Surg 1979; 27:295-99 72 Pogrebniak HW, Stovroff M, Roth JA, eta!. Resection of pulmonary metastases from malignant melanoma: results of a 16year experience. Ann Thorac Surg 1988; 46:20-3 73 Cahan WG. Excision of melanoma metastases to lung: problems in diagnosis and management. Ann Surg 1973; 178:703-09 7 4 Thayer JO Jr, Overholt RH. Metastatic melanoma to the lung: Multimodality Therapy of Chest Malignancies: Update '94
75 76 77 78
long-term results of surgical excision. Am J Surg 1985; 149:558-62 Harpole DH Jr, Johnson CM, Wolfe WG, eta!. Analysis of 945 cases of pulmonary metastatic melanoma. J Thorac Cardiovasc Surg 1992; 103:743-50 Finley RK III, Verazin GT, Driscoll DL, eta!. Results of surgical resection of pulmonary metastases of squamous cell carcinoma of the head and neck. Am J Surg 1992; 164:594-98 Rendina EA, de Vincentiis M, Primerano G, eta!. Pulmonary resection for metastatic laryngeal carcinoma. J Thorac Cardiovasc Surg 1986; 92:114-17 Seki M, Nakagawa K, Tsuchiya S, eta!. Surgical treatment of
pulmonary metastases from uterine cervical cancer: operation method by lung tumor size. J Thorac Cardiovasc Surg 1992; 104:876-81 79 Kirk D. Spontaneous regression of metastatic renal carcinoma. Br J Surg 1987; 74:1-2 80 Mann LT. Spontaneous disappearance of pulmonary metastases after nephrectomy for hypernephroma: four-year followup. J Urol1948; 59:564-66 81 Chapple CR, Gannon MX, Shah VM, et a!. Spontaneous regression of pulmonary metastases from renal adenocarcinoma before nephrectomy. Br J Surg 1987; 74:69-70
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term survival after pulmonary resection but do not constitute absolute criteria by which to select such patients. Complete surgical resection is critical to achieving long-term survival and is best accomplished via a standard or "clamshell" thoracotomy or a median sternotomy. The decision to proceed with the surgical resection of pulmonary metastases should be a multidisciplinary one, made jointly by the thoracic surgeon and the medical oncologist. (CHEST 1995; 107:322S-832S)
pulmonary resection for metastatic disease was initially reported in the European literature by Divis in 1927. 1 The first such resection in North America was performed by Barney and Churchill in 1939. 2 A solitary mass removed by lobectomy proved to be a metastasis from renal cell carcinoma. The patient subsequently had a nephrectomy for the primary tumor and survived disease-free for over 20 years. From 1940 to the mid-1960s, pulmonary metastasectomy was performed infrequently and only in highly selected patients. At Memorial Sloan-Kettering Cancer Center (MSKCC), 25 patients with pulmonary metastases were treated surgically from 1940 to 1965.3 Operation was not considered unless the patient had a long disease-free interval following resection of the primary tumor, and had three or fewer lesions confined to one lung. During a similar time period, from 1941 to 1962, the Mayo Clinic performed 221 pulmonary resections on 205 patients for metastatic disease. 4 Although multiple nodules were not considered a contraindication to resection, patients with bilateral disease were thought to have a poor prognosis and thus were not considered for operation. The indications for pulmonary metastasectomy were very restricted, and although not explicitly stated, the large number of operations performed may reflect the high volume of cases seen at the Mayo Clinic rather than the common use of surgical resection. In the 1970s, experience from several institutions
suggested that more liberal indications for pulmonary metastasectomy were appropriate. A striking example was the treatment of metastatic osteogenic sarcoma at MSKCC. From 1940 to 1965, only five patients with this condition were treated surgically. During the same period, only 24 of 145 patients (17%) survived 5 years after resection of their primary tumor, and 118 of these patients (81%) died of pulmonary metastases. This experience prompted a more aggressive approach to the management of pulmonary metastases. Starting in 1965, a consecutive series of 22 patients with osteogenic sarcoma underwent pulmonary metastasectomy. Patients were considered for operation even if they had bilateral metastases or required multiple thoracotomies to remove all gross tumor. A total of 59 thoracotomies were performed in these 22 patients, with an overallS-year survival rate of 32%. This dramatic improvement in survival compared to historic experience strongly supported the aggressive use of pulmonary metastasectomy in these patients. 5 •6 During the last 25 years, surgical resection has become a widely accepted treatment for pulmonary metastases. 3 ·7- 14 Some of the criteria for patient selection, however, remain controversiaJ.l 5 In addition, advances in chemotherapy have changed the indications for surgical resection. For some cancers, pulmonary metastasectomy is performed to prolong life expectancy, whereas in others, it serves mainly to restage disease or to provide adjuvant treatment after initial chemotherapy. The role of pulmonary metastasectomy will undoubtedly continue to evolve as improvements in systemic treatment occur. This review provides a perspective on the current approach to the surgical management of pulmonary metastases.
*From the Thoracic Service, Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York. Reprint requests: Dr. Rusch, MSKCC, 1275 York Ave, New York, NY 10021
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Multimodality Therapy of Chest Malignancies: Update '94
l. Solitary right middle lobe metastasis from breast cancer. The nodule is discreet and well circumscribed. The abnormality in the periphery of th e lingula (arrow) is an area of chronic fibrosis that developed followin g previous treatment with highdose chemotherapy and autologous bone marrow transplantation . FIGUHE
CLINICAL PHESE;\ITATIO'I AND EvALUATION
Most pulmonary metastases do not cause symptoms and are detected incidentally on radiographic studies. Symptoms occur in 15 to 20% of patients and usually reflect the proximity of metastatic lesions to the central airways. Cough and hemoptysis are the most frequent symptoms. Fever, ill-defined chest discomfort, and paraneoplastic syndromes are occasionally seen. 7- 10.1 2- 14 ·16 Dyspnea may occur if a centrally located metastasis produces airway obstruction by way of either endobronchial tumor or extrinsic compression. Some series note involvement of the proximal airways in up to 28% of patients. True endobronchial metastases are infrequent and occur most often in colorectal, breast, and renal cancers. They are also seen occasionally in thyroid cancers and malignant melanomas. 17 -2 1 The radiographic presentation of pulmonary me-
FIGL'HE 2. Chest CT scans of patient with pulmonary metastases from a previous! y resected soft tissue sarcoma. The metastases are characteristically multiple, peripheral, and well-circumscribed. The two metastases are located in the right upper lobe (top) and the le ft lower lobe (bottom, arrow ).
I FiGUHE 3. Spontaneous pneumothorax (left, arrows) in a patient with metastatic soft tissue sarcoma. The metastases are best seen on CT scan (right , arrow) which also demonstrates the pneumothorax seen on chest x-ray film. The pneumothorax recurred despite pleurodesis with talc slurry via a chest tube. Thoracoscopy , mechani cal pleurodesis, and talc poudrage were required to control this complication of pulmonary metastases.
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FIGURE 4. Benign intraparenchymallymph node (arrow) mimicking the typical appearance of a pulmonary metastasis. This was wedge resected for diagnosis by VATS.
tastases has been comprehensively reviewed by Libshitz and North. 22 The typical appearance both on chest x-ray film and computed tomography (CT) scan is that of a smooth, well-circumscribed, peripheral pulmonary nodule (Fig 1). Lack of associated calcification and multiplicity of lesions (Fig 2) are the only features that potentially distinguish pulmonary metastases from benign pulmonary nodules such as hamartomas, fibromas, or granulomas. Occasionally, cavitation occurs; this feature is seen most often in metastatic squamous cell carcinomas. Spontaneous pneumothorax, notoriously resistant to standard methods of pleurodesis, is characteristic of metastatic sarcomas and is thought to be caused by necrosis of peripherally located metastases (Fig 3). Very small pulmonary metastases (<1 em in size) may be indistinguishable from intra parenchymal lymph nodes on CT scan (Fig 4). However, endobronchial or peribronchial metastases may have a much less discreet appearance because of associated hemorrhage or postobstructive atelectasis and pneumonitis (Fig 5). Several series have examined the accuracy of chest x-ray, standard whole-lung tomography, and CT scan in detecting pulmonary metastases. 22 In current practice, whole-lung tomography, once a standard preoperative evaluation, has been replaced by CT. Both the older and more recent series show that CT has a greater sensitivity but lower specificity than chest radiography in detecting pulmonary metastases.23-26 Standard contrast-enhanced CT scan has an approximate 25 to 30% rate of differing from the findings at operation by way of eitherfalse-positive or false-negative findings. Some tiny nodules seen on CT prove to be benign, and conversely, some metastases are so small that they are not detected by CT. 3245
Whether spiral CT scanning will improve the diagnostic accuracy of CT remains to be seen. 27 If a patient's clinical presentation and radiographic findings suggest the possibility of pulmonary metastases, a tissue diagnosis can usually be established by percutaneous needle aspiration or by bronchoscopy, depending on whether the nodule is located peripherally or centrally. Pulmonary nodules that are too small to be amenable to needle aspiration can be excisionally biopsied by video-assisted thoracic surgery (V ATS). 28 It is important to remember that a new pulmonary nodule in a patient who has previously had a primary cancer is not necessarily a metastasis; it can be benign or may be a second primary cancer. 29 ,30 The likelihood that a new pulmonary nodule is a metastasis as opposed to a second primary cancer is directly related to the original type of malignancy. In patients whose initial cancer was a sarcoma or melanoma, a new pulmonary nodule is approximately ten times more likely to be a metastasis than a second primary cancer. If the original pri-
FIGURE 5. Endobronchial (top) and peribronchial (bottom) metastasis from a uterine angiosarcoma. The patient presented with hemoptysis and partial collapse of left lung. The radiographic appearance of this lesion is more characteristic of a primary lung cancer than of a metastasis.
Multimodality Therapy of Chest Malignancies: Update '94
mary tumor was a genitourinary or colorectal cancer, there is about a 50% chance that the new nodule is a metastasis. If the original tumor was a head and neck cancer, the new nodule is twice as likely to be a new primary lung cancer than a metastasis. 7·31 ·32 This finding is readily understood if it is remembered that most head and neck cancers and lung cancers share the etiology of being smoking-related tumors. In patients who have had a primary lung cancer, a new pulmonary nodule is more likely to be a second primary cancer if it is solitary and more than 2 years have elapsed since the resection of the first cancer. 33 Therefore, if nonsurgical treatment is being considered for a new pulmonary nodule in the setting of a previous primary cancer, it is important to establish a definitive tissue diagnosis before initiating therapy and not simply to assume that the patient has metastatic disease. In specific situations where surgical resection would offer appropriate treatment, regardless of whether the pulmonary nodule is primary or metastatic, exploratory thoracotomy without a preoperative diagnosis is an acceptable approach to management. CRITERIA FOR SURGICAL RESECTION
Chemotherapy-Sensitive Tumors Clinical experience has allowed the identification of criteria by which to select patients for surgical resection. Perhaps the most important factor influencing the use of surgical resection as the primary treatment for pulmonary metastases is how effective chemotherapy is for a particular type of cancer. A secondary factor is whether the natural history of that cancer is to metastasize predominantly to the lungs or to disseminate widely. Two types of cancer illustrate the evolution in the use of surgical resection because of improvements in chemotherapy: breast cancer and germ cell cancer. Metastatic breast cancer was a frequent indication for pulmonary resection in early surgical series?- 14 During the past 15 years, however, dramatic improvements in chemotherapy and the recognition that breast cancer usually produces widespread metastases have made pulmonary resection an uncommon form of treatment. A recent series34 reported an actuarial 5-year survival rate of 49.5% in a highly select group of 44 patients seen over a 10-year period who had resection of a solitary pulmonary metastasis from breast cancer. However, 40 of the 44 patients also received perioperative hormonal therapy or chemotherapy, making it difficult to assess the specific contribution of surgical resection in controlling disease. Outside of the unusual circumstance of a solitary pulmonary metastasis, most patients with breast cancer would now be treated nonsurgically.
Approximately 20 years ago, before the development of effective chemotherapy regimens for germ cell cancer, resection of pulmonary metastases was used to control this rapidly fatal disease. Today, metastatic germ cell cancer is treated primarily with cisplatin-based chemotherapy, with a high long-term cure rate. Pulmonary resection serves as adjuvant therapy to determine whether active microscopic tumor is still present after normalization of serum markers and to remove residual mature teratoma that potentially poses a problem of local control.35·36 A few highly select patients with a solitary metastasis and persistently elevated serum markers may benefit from resection in conjunction with continued chemotherapy,37 but for the majority of patients, pulmonary resection is no longer used as primary treatment.
Chemotherapy-Insensitive Tumors Unfortunately, most solid tumors that metastasize to the lung are relatively insensitive to currently available chemotherapy. Pulmonary resection is still an important primary form of treatment for these malignancies, which include colorectal cancer, some gynecologic cancers, various types of head and neck cancer, renal cell cancer, malignant melanoma, and osteogenic and soft tissue sarcomas (Table 1).7- 11 •38 The fundamental biology of these cancers and the genetic factors governing metastasis are still undefined, so the criteria used in selecting patients for pulmonary resection are clinical, and hence, relatively imprecise. These criteria are derived from retrospective analyses of surgical series that often include patients with many different types of primary tumors who are receiving a variety of additional treatments. Therefore, some of the criteria are controversial because they have not been proven consistently significant across reported series. Consistently important criteria include the following: (1) control of the primary tumor, or ability to resect primary tumor completely simultaneous with resection of metastases; (2) ability to resect metastatic disease completely; (3) ability of the patient to withstand the extent of pulmonary resection required to remove all gross tumor; (4) absence of extra thoracic metastases; and (5) absence of better alternative systemic treatment. 7-14·39 The criteria found to be important in only some reported series include the following: (1) the disease-free interval between resection of primary tumor and the development of pulmonary metastases (Table 2);10.12,40-43 (2) the tumor doubling time of pulmonary metastases (Table 3); 12·13·41 ·42 and (3) the number of pulmonary metastases.15.16·44 In a general sense, the latter criteria reflect tumor biology. Although these criteria may not be consistently reproducible across series, it is underCHEST /107 /6/ JUNE, 1995/ Supplement
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Table !-Primary Tumor Sites From Representative Series of Patients Undergoing Surgical Resection of Pulmonary Metastases*
Colorectal Soft tissue sarcoma Osteogenic sarcoma Melanoma Renal cell Breast Testis Gynecologic Head and neck Other Total
Wilkins et al,
Morrow et al,
Wright eta!,
Mountain et al,
19799
198010
Kodama et al,
19828
198411
McCormack,
199138
19907
35 14 4 9 28 9 14
19 0 0 12 30
19 0 0 6 14 18 8 12 9 14 100
51 49 76 58 27 30 20 9
21 15 4 0 13 8 6
43
9 20 100
lO
12 27 0 15 125
ll
0 18 142
0 363
4
80 N/A N/A
59 43 55 85 32 47 401
*N/ A=not available from this review.
standable that patients who have rapidly growing or numerous pulmonary metastases are less likely to benefit from surgical resection than are patients who have one or two slowly growing metastases. The criteria for surgical resection will continue to evolve as we gain a better understanding of tumor biology and as better systemic treatment becomes available. Although surgical resection is currently considered optimal treatment for patients who meet the above criteria, the decision to proceed with an operation is best made jointly by a thoracic surgeon and a medical oncologist. Some patients will remain disease free after the initial pulmonary resection, but unfortunately the majority will eventually relapse and require systemic treatment. It is wise to initiate multidisciplinary patient management early on, and not as an afterthought. TECHNIQUE OF PULMONARY RESECTION
The objective of resection of pulmonary metastases is to remove all gross tumor while preserving as much normal pulmonary parenchyma as possible. Most pulmonary metastases are discreet, small, subpleural nodules that can be completely removed by wedge resection using a CIA or T A stapler. 7 Nodules located in areas of the lung where a stapler cannot be easily applied can be excised with the needle-tip electrocautery. A conical-shaped wedge of pulmonary parenchyma is removed by cauterizing circumTable 2-Selected Series Showing A Significant Impact of Disease-Free Interval (DFI) on Overall Survival Author, yr
No. Patients
DFI
Creagan et al, 197940 Morrow et al, 198010 Takita et al, 1981 12 Putnam et al, 198341 van de Wal et al, 198642 Depadt et al, 198543
112 167 234 67 80 68
>l yr >5 yr >7 mo >l yr > l-5 yr >2 yr
3265
ferentially around the nodule, taking with it a 0.5- to 1.0-cm margin of normal lung tissue in all directions. When the nodule has been removed, meticulous hemostasis is obtained within the pulmonary parenchyma, and the pleural edges of the area of excision are reapproximated with sutures. 45 Stapling and electrocautery techniques can also be combined by applying a stapler across the deep portion of the pulmonary parenchymal margin once most of the excision has been performed with the cautery. An endoscopic CIA stapler is useful in this circumstance because it is narrower and easier to manipulate in a deep area of lung tissue than a standard CIA stapler. A laser can also be used to perform such wedge resections but is more sumbersome and has no particular advantages over needle-tip electrocautery. The argon beam electrocoagulator (Birtcher Corporation, Englewood, Colo) may be helpful in obtaining hemostasis in the pulmonary parenchyma and in sealing small air leaks. 46 Although more extensive surgical procedures like lobectomy and even pneumonectomy do not increase the chance of cure after metastasectom y, they are sometimes technically necessary to allow complete resection of centrally located metastases. These more extensive resections offer some patients the best treatment and may lead to long-term survival but should be considered carefully since many patients subsequently develop metastases in the remaining lung. 47 Table 3-Selected Series Reporting Tumor Doubling Time (TDT) Significantly Influences Overall Survival Author, yr
No. Patients
TDT,d
Ramming, 198013 Takita et al, 1981 12 Putnam et al, 198341 van de Wal et al, 198642
91 234 67 80
>40 >45 >20 >136
Multimodality Therapy of Chest Malignancies: Update '94
Table 4-0utcome of Patients Undergoing Surgical Resection of Pulmonary Metastases From Colorectal Cancer Author, yr
No. Patients
5-yr Survival, %
Mansel et al, 198652 Goya et al, 198953 McAfee et al, 199254 McCormack et al, 199255
66 62 139 144
38 42 30.5 40
ally seen and may be associated with poorer longterm survival, but the implications for patient management are unclear. Systematic lymph node dissection, as performed for a primary lung cancer, is not generally indicated. In the interests of proper diagnosis and of resecting all gross tumor, any suspicious lymph nodes should be resected. RESULTS OF PULMONARY RESECTION IN SELECTED SOLID TUMORS
When a high-quality preoperative CT scan shows that metastatic disease is confined to one lung, most surgeons prefer to explore a patient via a standard thoracotomy. Bilateral metastases can be approached via a median sternotomy, but this incision limits the exposure to the posterior aspect of the lungs, particularly the left lower lobe. 48•49 A "clamshell" thoracotomy (bilateral anterior thoracotomy with transverse sternotomy), recently repopularized for lung transplantation, is now also being used for the resection of bilateral pulmonary metastases. Although this procedure appears to be more painful than a median sternotomy, it provides excellent exposure to the posterior aspect of both lungs. 50 The operative mortality of any of these approaches is less than 1% in multiple reported series. 7-1 4 Video-assisted thoracic surgery has been advocated for the resection of pulmonary metastases. 51 The identification of pulmonary nodules by VATS relies heavily on the preoperative CT scan and on the ability to visualize lesions in the periphery of the lung. As noted previously, CT scan often underestimates the number of pulmonary nodules present. 27 Since long-term survival appears to be directly related to the resection of all gross disease, it is imperative that the surgeon systematically inspect and palpate the lungs to ensure that all tumor is identified and removed. Therefore, most thoracic surgical oncologists are reluctant to perform VATS for therapeutic purposes and confine its use to the diagnosis and staging of pulmonary metastases. 28 Small pulmonary nodules are best identified with the lung sequentially inflated and deflated. Therefore, it is important that a double-lumen endotracheal tube be used in all operations. Bronchoscopy also is not performed routinely by most surgeons at the time of resection of pulmonary metastases; however, it is warranted prior to thoracotomy in patients who have centrally located lesions, symptoms suggestive of airway involvement, or tumor types that are prone to endobronchial involvement such as breast, colon, or renal cell cancer. The role of lymph node sampling or dissection in the management of pulmonary metastases has not been defined. Lymph node involvement is occasion-
Colorectal Cancer Small numbers of patients with colorectal cancer have been included within many series reporting the results of surgical resection for pulmonary metastases. The 5-year survival rate after resection ranges from 20 to 40%. 3 At least three larger series specifically address the issue of long-term outcome after pulmonary metastases from colorectal cancer (Table 4). 52-55 In a Japanese series of 62 patients,53 the 5- and 10-year survival rates were 42 and 22%, respectively. The highest survival rate was seen in patients who had a solitary metastasis that was less than 3.0 em in size. Gender, age, disease-free interval, and extent of pulmonary resection did not influence survival. At the Mayo Clinic, 139 consecutive patients underwent pulmonary resection for metastatic colorectal cancer between 1960 and 1988.52•54 With a median follow-up of 7 years, 30.5% of patients were alive at 5 years and 16.2% at 20 years. The 5-year survival rate for patients with a solitary metastasis was 36.9%, as compared with 19.3% for those with two metastases (p<0.05) and 7.7% for those with more than two metastases (p<0.01). An elevated carcinoembryonic antigen (CEA) level also had a significant adverse effect on survival. 54 The MSKCC experience has been similar to that at the Mayo Clinic. In 144 patients undergoing resection for pulmonary metastases from 1965 to 1988, the overallS-and 10-year survival rates were 40 and 30%, respectively. 55 The majority of patients (80 of 144) presented with a solitary metastasis and had a slightly but not statistically significant better survival than patients who had more than one nodule. Survival was not influenced by the disease-free interval. This series noted that the 11 patients who could not undergo a complete resection of all gross tumor because of borderline pulmonary reserve had a median survival of 9 months, and all died of progressive disease. Both the Mayo Clinic and MSKCC series found that patients could experience long-term survival after undergoing multiple sequential resections for pulmonary metastases. Osteogenic Sarcoma Surgical resection remains the only potentially CHEST /107/6/ JUNE, 1995/ Supplement
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Table 6-0utcome of Patients Undergoing Surgical Resection of Pulmonary Metastases From Malignant Melanoma
Table 5-0utcome of Patients Undergoing Surgical Resection of Pulmonary Metastases From Soft Tissue Sarcoma Author, yr
No. Patients
Ruth et al, 198062 Jablons et al, 198965 Casson et al, 1992 66 Gadd et al, 199369
43 57 58 65
5-yr Survival,
%
40 (4-yr) 35 25.8 23 (3-yr)
curative treatment for patients with pulmonary metastases from osteogenic sarcoma. After resection of the primary tumor, the routine use of adjuvant chemotherapy has improved the disease-free survival and altered the pattern of pulmonary recurrence. A multiinstitutional study performed by the Pediatric Oncology Group56 found that patients who did not receive adjuvant chemotherapy relapsed sooner and had significantly more pulmonary nodules than patients who received adjuvant chemotherapy. The patients who received adjuvant chemotherapy, however, were less likely to respond to additional systemic treatment after pulmonary resection. The only factor found to be predictive of survival in either group was whether the patients could be rendered surgically disease-free after initial relapse. Other contemporary series have confirmed the beneficial role of surgical resection in patients with pulmonary metastases from osteogenic sarcoma. 5·6 Reported 5-year survival rates vary from 20 to 40%, perhaps reflecting the small numbers of patients in these series and an individualized approach to management. The inability of chemotherapy alone to cure patients and the importance of complete surgical resection are findings common to all reported series.41,57-61
Soft Tissue Sarcoma Pulmonary resection also remains the only potentially curative treatment for soft tissue sarcomas, which almost always metastasize solely to the lung and are notoriously resistant to current chemotherapeutic agents. An early series of 112 patients with metastatic soft tissue sarcoma undergoing surgery at the Mayo Clinic from 1950 to 1976 reported a 5-year survival rate of 29%. 40 Survival was influenced adversely by a disease-free interval of less than 12 months and by the subsequent development of extrathoracic metastases. Gender, age, histology, number of lesions fully excised, and site of lung lesions did not affect survival. Huth and colleagues62 reported on 48 patients who underwent resection of pulmonary metastases from soft tissue sarcoma (Table 5). The 4-year survival rate of 40% was significantly influenced by the tumor doubling time (greater than or less than 40 days) and 328S
Author, yr
No. Patients
Cahan, 197373 Mathisen et al, 197971 Mountain et al, 198411 Thayer and Overholt, 1985 74 Pogrebniak et al, 198872 Gorenstein et al, 1991 70 Harpole et al, 199275
29 12 58 18 49 56 84
5-yr Survival,
%
34 (2-yr) MS* 13.3 11.1
MSl 25 20
*Median survival, 12 mo. lMedian survival, 13 mo. by the disease-free interval (greater than or less than 1 year). Several series have been published presenting experience with metastatic soft tissue sarcomas, first at the National Cancer Institute and subsequently at MD Anderson Cancer Center. 63 -66 Four or fewer nodules, a disease-free interval of greater than 1 year, and a tumor doubling time greater than 40 days were associated with significantly improved survival. It was also observed67 ·68 that reoperation for patients who relapse in the lungs is warranted, since the median survival of such patients was 25 months. At MSKCC, the long-term outcome in such patients has been less favorable. 69 The 8-year survival rate after complete resection of all pulmonary metastases in 65 patients was only 28%. Moreover, these patients represented only about half of all 185 patients who developed pulmonary metastases since many patients could not have a complete resection or required nonsurgical treatment. This experience suggests that patients with soft tissue sarcoma who can undergo complete resection of their pulmonary metastases are a highly select group and experience a 5-year survival rate of 20 to 85% (Table 5). 62·65,66,69 Unfortunately, no better alternative treatment is yet available.
Malignant Melanoma The survival of patients with metastases from malignant melanoma has in general been poor because of the capricious behavior of this tumor and its propensity to metastasize to sites other than the lung. Several series have reported the results of surgical resection of pulmonary metastases (Table 6)_1 1,70- 75 The largest such series, from the Duke University Cancer Center, is based on 7,564 patients treated from 1970 to 1990. 74 Pulmonary metastases, which developed in 945 patients (12%), were associated with an overall 5-year survival rate of only 4%. However, a favorable group of 226 patients who underwent resection of a solitary nodule experienced a 5-year survival of 20%. Patients with two pulmonary nodules had a significantly better postthoracotomy Multimodality Therapy of Chest Malignancies: Update '94
survival than did patients with three or more nodules. The disease-free interval also significantly influenced survival. These data support the selective use of pulmonary resection in patients who have metastases from malignant melanoma.
Other Solid Tumors Similar results can be cited for other solid tumors with pulmonary metastases. A 5-year survival rate of approximately 30% is seen after resection of pulmonary metastases in selected patients with renal cell cancers, various head and neck cancers,76•77 and some nonovarian gynecologic cancers,78 to name a few. The behavior of renal cell cancers is particularly unpredictable, and anecdotal spontaneous regression of tumor is a recognized event in this disease. 79-81 In head and neck cancers, the 5-year survival rates after resection of pulmonary metastases are approximately 30% but vary according to cell type and site of origin of the primary tumor. CoNCLUSIONs
Surgical resection remains an important form of treatment for pulmonary metastases from a variety of solid tumors. The most significant factors in selecting patients for operation include control of the primary tumor, ability to resect all metastatic disease, absence of extrathoracic metastases, and lack of better alternative systemic therapy. One or two pulmonary nodules, long tumor doubling times, and disease-free intervals usually define patients who experience a better outcome after pulmonary resection but do not constitute absolute criteria by which to select such patients. Complete surgical resection is critical to achieving long-term survival and is best accomplished via a standard or clamshell thoracotomy or a median sternotomy. In most cases, the decision to proceed with surgical resection of pulmonary metastases should be made jointly by the thoracic surgeon and the medical oncologist as part of a multidisciplinary approach to the management of this problem. REFERENCES
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