Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section F – Local Effects of Cancer and Its Metastasis

Chapter 58 – Lung Metastases

Valerie W. Rusch

SUMMARY OF KEY POINTS

Incidence

  

   

Lungs are the second most common site of metastases.

  

   

Lungs are the sole site of metastasis in 80% of patients with sarcoma and in 2% to 10% of patients with carcinoma.

Etiology

  

   

Hematogenous spread

  

   

Lymphangitic spread in carcinomas can occur early or late in the natural progression of all cancers.

  

   

It is not well understood why lung metastases take several years to develop.

Evaluation

  

   

Few lung metastases are symptomatic; only 15% to 20% of patients complain of cough or pain. All patients with isolated pulmonary metastasis from extrathoracic malignancy should be evaluated for the possibility of resection.

  

   

Initial imaging studies should consist of a plain chest radiograph followed by computed tomographic (CT) examination to predict resectability. Newer imaging modalities, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI), have not been shown to be as accurate or cost effective as CT.

  

   

CT is unable to distinguish reliably between malignant and benign lesions.

  

   

CT differs from the final pathology report in 42% of cases.

  

   

CT underestimates the number of malignant lesions in 25% of cases.

  

   

The accuracy of radiologic imaging is only 37%, underestimating the number of lesions by 39% and overestimating them by 25%, for patients undergoing bilateral exploration.

Prognostic Factors

  

   

Number of metastases

  

   

Disease-free interval (<36 months or >36 months).

  

   

Histology/organ site of primary tumor

Surgical Treatment

  

   

First described case of pulmonary metastasectomy was by Weinlechner in 1882.

  

   

Alexander and Haight described the first series of patients; 12 patients remained disease-free for 1 to 12 years.

  

   

General guidelines that should be met before undertaking a resection include the following:

  

   

Control of the primary tumor, or ability to resect the primary tumor

  

   

Ability to resect metastatic disease completely

  

   

Ability of the patient to withstand the extent of pulmonary resection required to remove all gross tumor

  

   

Absence of extrathoracic metastasis

  

   

Absence of better alternative treatment

  

   

The location of metastases determines the extent and type of resection:

  

   

Peripheral metastasis—parenchymal sparing

  

   

Central metastasis—lobectomy or pneumonectomy

  

   

Solitary endobronchial metastasis—lobectomy, sleeve lobectomy, or pneumonectomy

  

   

Ensure that all grossly palpable tumors are resected with clear margins.

  

   

More radical resection (lobectomy, pneumonectomy) does not increase survival.

  

   

Bilateral metastases and recurrence of pulmonary metastases are not contraindications to resection and should not deter resection in lesion(s) that can be removed completely.

INTRODUCTION

The first described case of pulmonary metastasectomy was reported in 1882 by a German surgeon named Weinlechner, who removed two incidental pulmonary nodules during a chest wall resection for sarcoma.[1] In 1939 Barry and Churchill[2] reported the first long-term survivor from pulmonary metastasectomy, a patient with metastatic renal cell cancer. Their patient survived 23 years after surgery. Subsequently, Alexander and Haight described the first series of patients undergoing pulmonary metastasectomy and its correlation to survival.[3] Twelve patients in their study remained free of disease for 1 to 12 years. Most important, from this early study came the first generally accepted criteria for pulmonary metastasectomy:

  

   

The primary tumor should be completely removed.

  

   

There should be no evidence of extrapulmonary disease.

  

   

The patient should be able to tolerate the planned operation from the standpoint of overall medical condition.

Subsequently these criteria were modified by other authors to reflect our improved understanding of the management of pulmonary metastases. Current additional criteria include the following:[4]

  

   

Control of the primary tumor, or ability to resect the primary tumor completely simultaneous with resection of metastasis

  

   

Ability to resect metastatic disease completely

  

   

Ability of the patient to tolerate the extent of pulmonary resection required to remove all gross tumor

  

   

Absence of extrathoracic metastasis

  

   

Absence of better alternative treatment

Although these criteria are widely used, there are continued attempts to refine the selection of patients for pulmonary metastasectomy.

Several prognostic factors that are not universal across all tumor histologies have been reported to affect outcome after pulmonary metastasectomy ( Table 58-1 ). The largest series of pulmonary metastectomies reported to date is from the International Registry of Lung Metastasis, which analyzed 5206 cases.[5] The overall 5-year survival after pulmonary metastasectomy without stratifying for tumor type was 36%. Factors associated with better prognosis included a long disease-free interval, complete resection, and a small number of lung nodules. A staging system based on these prognostic factors was proposed ( Fig. 58-1 ).

Table 58-1   -- Prognostic Factors after Pulmonary Metastasectomy

Disease-free interval

Mediastinal lymph node metastases

Number of pulmonary nodules

Tumor doubling time

Size of pulmonary nodules

Bilateral disease

Surgical margins

Histologic subtype

 

 

 
 

Figure 58-1  Survival of the four prognostic groups based on the analysis of 5206 patients entered into the International Registry of Lung Metastases. Group I includes patients who had completely resectable disease with a single metastasis and a disease-free interval after resection of the primary tumor (DFI) of 36 months or more; group II, patients who had completely resectable disease with multiple metastases or a DFI of less than 36 months; group III patients who had completely resectable disease with multiple metastases and a DFI of less than 36 months; and group IV patients with unresectable disease.  (From Pastorino U, Buyse M, Friedel G, et al: Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37.)

 

 

 

The role of surgery in the treatment of pulmonary metastases will continue to evolve as better systemic therapies become available. Currently, only a minority of patients with metastatic disease from any source are candidates for pulmonary metastasectomy; however, improved imaging studies and the widespread use of computed tomography (CT) might detect more patients who have small-volume pulmonary metastases and are therefore candidates for metastasectomy. A current perspective of the evaluation and treatment of patients with isolated lung metastases is presented in this chapter.

DIAGNOSIS

Few patients with pulmonary metastasis are symptomatic. It is estimated that only 15% to 20% of patients present with cough or nonspecific chest pain and even fewer still with hemoptysis. Traditionally, chest radiography has been the most commonly used and cost-effective modality for screening patients for metastasis from extrathoracic malignancy. The most frequent radiographic appearance of a pulmonary metastasis is a peripherally located, well-circumscribed nodule ( Fig. 58-2 ). [6] [7] Several less common radiographic characteristics have also been described. Cavitating lesions are associated with a differential diagnosis that includes benign, infectious, and malignant causes ( Fig. 58-3 ). When malignant, cavitary lesions are usually squamous cell carcinomas. The frequency of cavitation in metastatic nodules is approximately 4%; however, squamous cell malignancy is responsible for 69% of these lesions. Spontaneous pneumothorax also can occur with metastatic lung lesions and is thought to be caused by cavitation and erosion into a bronchiole wall. Spontaneous pneumothorax is most frequently seen in patients with sarcoma. It is said that a spontaneous pneumothorax in a patient with history of a sarcoma should prompt an evaluation for possible occult metastatic lung lesions. Calcification of pulmonary nodules is usually related to a benign process such as a hamartoma; however, metastatic lesions of many types (especially osteogenic sarcoma) are known to produce calcification ( Fig. 58-4 ). [6] [7] Calcification in metastatic lesions are thought to be produced by several processes in different tumor types, including bone formation in osteogenic sarcoma, mucinous calcification of adenocarcinomas, or dystrophic calcification of lesions such as synovial sarcoma or giant cell tumors of the bone.[6] Hemorrhage around lung nodules is also seen more frequently in benign lung lesions (e.g., fungal or mycobacterial infections) and is visualized as a halo around the lung nodule. This can also be seen in metastatic lesions and should raise the suspicion for metastasis in patients with a history of malignancy.

 
 

Figure 58-2  Two patients with metastatic sarcoma demonstrating typical findings of well-circumscribed peripheral lesions. A, Plain chest radiograph. B, Computed tomographic image.

 

 

 
 

Figure 58-3  Chest CT scan demonstrating cavitary lesion in a patient with metastatic colorectal cancer.

 

 

 
 

Figure 58-4  A and B, Chest CT scans of patient with metastatic osteosarcoma demonstrating the presence of calcifications in metastatic lesions.

 

 

Computed Tomography

The use of CT as an adjunct to plain film radiography for the diagnosis of pulmonary metastases has increased dramatically during the last decade. This has been facilitated by the development of high-speed helical scanners. It is clear that CT is able to visualize more lesions than chest radiography. [5] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] Chang and coworkers[11] reported that when compared with conventional radiography, CT was able to visualize nearly twice as many nodules.[18] CT is not able to distinguish reliably between malignant and benign lesions, however. McCormack and colleagues[8]retrospectively studied 144 patients who had both a chest x-ray and a CT to identify metastatic lesions. The CT results differed from the final pathology reports in 42% of cases, with CT scan underestimating the number of malignant nodules in 25% of patients. Pastorino and associates[5] reported results of imaging on 2988 patients undergoing pulmonary metastasectomy. The overall accuracy of radiologic assessment of the number of metastatic nodules was 61%, underestimating metastasis in 25% of patients. Interestingly, in those patients (1134) who had bilateral exploration, the accuracy of imaging was only 37%, underestimating the number of lesions in 39%, overestimating in 25%. The accuracy and sensitivity of CT also depends on the size of the lesions ( Table 58-2 ): the larger the lesion, the greater the sensitivity and accuracy. Munden and colleagues[14] reported on the clinical significance of pulmonary lesions less than 1 cm in diameter, finding malignant pulmonary lesions in 81% of patients with a history of malignancy. Multiple authors have described the ability of CT to detect a greater number of pulmonary nodules, while acknowledging a decreasing specificity of identifying malignant nodules with this diagnostic tool. [11] [15] Therefore, not all small pulmonary nodules in patients with a history of cancer can be assumed to represent metastatic disease. Currently, there are no established guidelines for the routine screening for pulmonary metastases. Many institutions still use periodic chest radiography as the only imaging modality to rule out pulmonary metastasis. Other authors suggest that the use of CT for routine screening is indicated in groups of patients whose primary tumors have an unusually high propensity to spread to the lungs. [13] [16] As the quality and speed of CT scanning progresses, it will probably become the sole screening tool for identifying pulmonary metastases. [11] [15]


Table 58-2   -- Detection of Pulmonary Metastasis by Computed Tomography

Year

Author

No. of Nodules

Sensitivity for Small Lesions

Sensitivity for Larger Lesions

1998

Waters et al[18,][*]

144

44% (≤5 mm)

91% (>5 mm)

1999

Diederich et al[9]

90

69% (≤6 mm)

95% (>6 mm)

2002

Margaritora et al[10,][†]

188

48% (≤6 mm)

87% (>6 mm)

*

Canine model

High-resolution CT group

 

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) provides the benefits of reduced radiation exposure (of particular interest for cases involving younger patients) and the ability to detect lesions at lung-mediastinal interfaces. MRI has not gained wide acceptance as a screening tool, however, mainly because of its increased time constraints and cost. Further technical considerations that are unfavorable include motion-related artifacts and an inability to detect calcified lesions. Kersjes and colleagues[19] performed a study comparing MRI and helical CT in the detection of pulmonary metastasis and showed MRI to have an overall accuracy of 84%. For lesions smaller than 5 mm, however, the sensitivity of MRI was only 36%. The routine use of MRI is currently not advocated as a screening tool for patients with pulmonary metastasis.

Nuclear Imaging

Imaging with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is being used more frequently to assist in the staging of primary tumors. Most often, this is used at the time of diagnosis to rule out distant metastasis but is occasionally used to assess response to therapy. Currently FDG-PET is not used as a screening tool to identify pulmonary metastasis, but multiple authors support the eventual use of this modality as a screening tool. [20] [21] Dose and associates[21] studied 50 patients with breast cancer who had FDG-PET evaluation to determine presence of metastatic disease. FDG-PET had a sensitivity of 78.6% in identifying pulmonary metastasis as compared with conventional chest radiography, which had a sensitivity of 41.6%.[21] Other authors report that FDG-PET may not be superior to conventional imaging techniques in identifying pulmonary metastasis from bone and soft-tissue sarcomas. [22] [23] Lucas and coworkers[22] studied 62 patients with soft-tissue sarcoma who had FDG-PET during initial evaluation. The sensitivity of FDG-PET in detecting lung metastasis was 86.7% as compared with 100% for CT, leading the authors to conclude that CT is a superior imaging toolfor identifying these lesions. Further study is warranted to determine the true benefit, if any, of using FDG-PET as a routine screening tool for identifying patients with pulmonary metastasis. Because PET is currently unable to detect sub-centimeter lung lesions reliably, it is likely that CT will remain the most sensitive imaging modality.

SURGICAL APPROACHES TO LUNG METASTASIS

The goal of pulmonary metastasectomy is to achieve complete resection of all visible and palpable tumors in the lung. The surgical approach is dictated by the extent and location of disease and by the patient's performance status. There are several approaches available depending on the size, number, and location of the lesions. The advantages and disadvantages of these approaches are outlined in Table 58-3 .


Table 58-3   -- Surgical Approaches to Resection of Pulmonary Metastases

Surgical Approach

Advantages

Disadvantages

Unilateral Disease

 

 

 Posterolateral thoracotomy

Superior exposure and palpation of lung

Painful, large incision

 Videothoracoscopy (VATS)

Less painful

Inability to palpate, poor ability to detect deep lesions

Bilateral Disease

 

 

 Clamshell thoracotomy

Excellent bilateral exposure

Painful; sacrifice of both internal mammary arteries

 Simultaneous bilateral thoracotomies

One hospital stay/procedure

Painful

 Staged (sequential) bilateral thoracotomy

Allows technically complex procedures

Two hospitalizations and procedures

 Median sternotomy

Bilateral exposure, less painful

Poor exposure to posterior lung fields

 

 

The standard approach to the patient with disease localized to one hemithorax is a unilateral posterolateral thoracotomy. The thorax is usually entered through the fifth intercostal space. Several variations of this include muscle-sparing incisions, axillary incisions, or an anterior thoracotomy. All of these approaches allow full visual inspection and manual palpation of the entire lung.

During the past decade, the use of video-assisted thoracoscopy (VATS) has been described for pulmonary metastasectomy. This approach is controversial, however. [24] [25] [26] [27] [28] McCormack and colleagues[25] performed a prospective study evaluating the role of VATS to treat pulmonary metastasis. Eighteen patients had preoperative CT followed by VATS resection of all visible and CT-detected lesions. All patients then immediately underwent thoracotomy with resection of any additional lung nodules. Additional malignant lesions were found in 56% of patients after attempted VATS resection of the nodules found on preoperative imaging. The authors concluded that this high failure rate of CT and VATS warranted closure of the study before the intended 50 patients could be enrolled. Recently, other authors have advocated the use of VATS for patients with a solitary pulmonary metastasis. Mutsaerts and associates [24] [28] described their experience with 20 patients undergoing either VATS or thoracotomy for resection for single pulmonary metastasis. The 5-year survival and recurrence rates seemed to be similar to those seen with thoracotomy.[28] Other authors have described localization methods using radiotracer injection to help identify small or deeply located lesions during VATS resections.[26] Currently, the practice in our institution is to use VATS primarily for the diagnosis of metastatic disease, or as a therapeutic procedure in highly selected patients for whom thoracotomy may be a higher risk procedure. Thoracotomy or other open procedures remain our preferred approach to pulmonary metastasectomy because of the prognostic importance of complete resection and the potential for missing small metastases by VATS. However, a VATS approach may be appropriate for patients with one or two metastases clearly defined on high-quality imaging studies.

The approach to bilateral disease is more variable, but the principles remain the same. Median sternotomy, “clamshell” thoracotomy (bilateral anterior thoracotomy with transverse sternotomy), sequential bilateral thoracotomies, and simultaneous bilateral posterolateral thoracotomies are used as standard surgical approaches to the resection of bilateral metastases. [29] [30] [31] In general, resection of bilateral metastases is preferably done as a single operation. Sequential thoracotomies are performed only when the anatomic location of a lesion requires a complex or extensive operation, or when the patient's comorbidities dictate a more conservative approach to management.

In contrast to primary lung cancers, pulmonary metastases require only a local excision with a surrounding rim (1–2 cm) of benign lung tissue. This is accomplished most frequently by wedge resection performed by precision electrocautery or with a stapling instrument ( Fig. 58-5 ). Segmentectomy, lobectomy, or pneumonectomy are used less commonly. It is important to note that survival after metastasectomy is not increased by a more radical resection such as lobectomy or pneumonectomy. These procedures might be required technically to remove the lesion, however, and should be applied to do so if needed. The most important principle of these techniques is a clear margin of resection.

 
 

Figure 58-5  A–C, Method of wedge resection by using a stapling device. This technique is most suitable for peripherally located metastases adjacent to the fissures or edges of the lung.  (From Rusch VW: Surgical techniques for pulmonary metastasectomy. Sem Thorac Cardiovasc Surg 2002;14:4.)

 

 

 

The risk of resection of pulmonary metastasis using standard wedge resection is very low, with mortality generally 1% or less. Complications include bleeding, infection in the wound, or pneumonia and prolonged air leak. More extensive resections such as lobectomy or pneumonectomy carry only slightly higher morbidity rates, and these operations are very well tolerated by most patients.

The preoperative evaluation for these patients is similar to those undergoing lung resection for any other cause ( Fig. 58-6 ). Pulmonary function testing should be obtained for all patients to assure that the volume of lung resection will not compromise overall respiratory function. Thorough evaluation of underlying cardiovascular disease should also be undertaken, with preoperative stress testing as clinically indicated.

 
 

Figure 58-6  Management algorithm for patients with isolated pulmonary metastasis from extrathoracic malignancy. CXR, chest radiography; FNA, fine-needle aspiration; Hx, history; VATS, video-assisted thoracoscopy.

 

 

PULMONARY METASTASECTOMY FOR SPECIFIC TUMOR TYPES

Colorectal Cancer

It is estimated that 10% to 25% of patients with primary colorectal tumors will have detectable metastases at the time of diagnosis.[32] Despite advances in adjuvant therapy and surgery, 50% of all patients with colorectal cancer will develop some form of metastasis during their lifetimes.[33] Approximately 15% of patients having curative resection of their primary colorectal tumor will develop distant metastasis, including metastasis to the lung.[34] Pulmonary metastasis can occur even with favorable primary tumor characteristics. Okumura and coworkers[35] reported that 26% of pulmonary metastectomies were performed in patients with Duke's A or B primary colorectal cancer. Since Blalock[36] reported the first pulmonary metastasectomy for colorectal cancer in 1944, several authors have reported their experience regarding overall survival and prognostic factors. The 5- and 10-year survival rates range from 30% to 40% and 27% to 37%, respectively ( Table 58-4 ). [37] [38] [39] [40] It is clear from the literature that pulmonary metastasectomy for colorectal cancer is associated with long-term survival, especially when a complete resection is performed. McCormack and associates[41] reviewed 144 patients who underwent pulmonary metastasectomy for colorectal cancer and showed that survival for patients who underwent complete resection was approximately 40% at 5 years, whereas incomplete resection was associated with a poor prognosis.


Table 58-4   -- Survival of Patients Undergoing Pulmonary Metastasectomy for Colorectal Cancer,[*]

Year

Author

Number

5-Year Survival (%)

10-Year Survival (%)

1992

McAfee et al[37]

139

30.5

N/A

1996

Okumura et al[35]

159

40.5

27.7

1998

McCormack and Ginsberg[38]

287

40.0

32.0

2001

Zink et al[39]

110

32.6

N/A

2002

Saito et al[40]

165

39.6

37.2

*

Studies represent analysis of 100 patients or more.

 

As for other primary tumors, studies evaluating the disease-free interval, the number of lesions (multiple vs. single), and the presence of lymph node involvement have shown these to be significant prognostic factors after pulmonary metastasectomy for colorectal cancer. [35] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] Colorectal cancer is also unique in the fact that the serum tumor marker carcinoembryonic antigen (CEA), used as a marker for follow-up, has been shown to be a prognostic indicator for patients with pulmonary metastases. [37] [38] [39] [40] [41] [42] [43] [44] [45] [46]

There is some disagreement as to whether single, ipsilateral metastases are associated with a better prognosis than either multiple ipsilateral or bilateral metastases. The presence of bilateral metastases was previously thought to be a contraindication to metastasectomy. Recently, though, several authors have reported that the survival for patients with bilateral lesions is not significantly reduced as compared with patients who have multiple ipsilateral lesions. [38] [43] Although a solitary metastasis might be associated with a better prognosis than multiple metastases (either unilateral or bilateral), the main criteria used to select patients with multiple lesions is whether removal of these lesions is technically feasible and removal of the volume of lung parenchyma does not seem to compromise the patient's lung function to a significant extent.

CEA levels are elevated in 40% to 70% of patients before pulmonary metastasectomy. Most authors report elevated CEA levels to be an adverse prognostic factor. [39] [40] [44] [45] [47] The reason for this is unclear, although it has been postulated that the presence of CEA may promote adhesion or attachment of tumors cells or could be due to undetected extrathoracic metastasis.[48] Although an elevated CEA is not used currently to exclude patients from resection, it could be useful to consider this in the context of other known prognostic factors. For instance, a patient who rapidly develops pulmonary metastases after resection of the primary tumor, and who has multiple lung nodules and an elevated CEA level, might be treated initially with chemotherapy instead of going directly to pulmonary metastasectomy.

Hilar or mediastinal lymph node metastases occur in 1% to 28% of patients with colorectal pulmonary metastasis. [35] [40] [41] [42] [43] [45] Saito and colleagues[40] reported that 20 of 138 (14.5%) patients who underwent lymph node sampling had positive nodes. The 5-year survival was 48.5% for the patients without hilar or mediastinal lymph node metastasis, vs. 6.2% at 4 years for the patients with lymph node metastasis. More recently, Welter and associates[49] reported that 28 of 169 patients undergoing resection of colorectal pulmonary metastases had hilar or mediastinal nodal metastases. Nodal metastases had a highly significant adverse impact on survival. Okumura and coworkers[35] performed systematic lymph node dissection on 100 patients with colorectal pulmonary metastasis. Fifteen of these patients had positive lymph nodes with a 5-year survival of 6.7% as compared with a 50% survival for those with negative lymph nodes, indicating that complete lymph node dissection does not increase survival. The routine use of mediastinal lymph node dissection in patients with pulmonary metastases seems to be the exception rather than the norm. The presence of malignant lymph nodes could indicate a group of patients otherwise thought to be disease-free who might benefit from additional adjuvant therapy. We favor doing mediastinal lymph node sampling or dissection in these patients. Although these procedures might not have a therapeutic effect, they certainly provide important prognostic information.

Previously, the presence of both liver and lung metastases from colorectal cancer was thought to be a contraindication to metastasectomy. Synchronous or metachronous lung and liver metastasis occurs in approximately 5% of patients with colorectal cancer. Headrick and colleagues[50] reported 5- and 10-year survivals of 30% and 16%, respectively, for 58 patients who underwent resection of both liver and lung metastases from colorectal cancer. Decreasing morbidity and mortality rates for liver resection now make resection of both lung and liver metastases a viable option in carefully selected patients.

Bone and Soft-Tissue Sarcoma

Bone and soft-tissue sarcomas compose a histologically diverse group of tumors accounting for 1% of all adult malignancies, with approximately 6600 cases occurring in the United States annually. [51] [52]Metastasis will occur in 25% to 70% of patients with localized disease, and 10% will present with metastasis upon diagnosis.[52] Isolated pulmonary metastases occur in up to 20% of sarcoma patients during the course of their disease, with the lung being the site of failure after treatment in up to 90% of cases. [53] [54] Factors associated with an increased risk of pulmonary metastasis include high tumor grade, primary tumor size greater than 5 cm, lower extremity site, and histologic subtype.[53] The lack of effective systemic therapy for most soft-tissue sarcomas makes surgical resection the best treatment for pulmonary metastases. Several studies have shown that the complete resection of pulmonary metastases is associated with long-term survival. [5] [51] [53] [55] Billingsley and coworkers[51] reported that the 3-year actuarial survival was 46% in patients who had complete resection as compared with 17% (P < 0.001) for those with incomplete resection of pulmonary metastasis. The cumulative 5-year survival for patients with bone and soft-tissue sarcomas after pulmonary metastasectomy ranges from 31% to 40% ( Table 58-5 ). [5] [51] [55] [56] [57]


Table 58-5   -- Survival of Patients Undergoing Pulmonary Metastasectomy for Bone and Soft-Tissue Sarcomas,[*]

Year

Author

Number

5-Year Survival (%)

1995

Choong et al[55]

214

40

1996

van Geel et al[56]

255

38

1997

Pastorino et al[5]

1917

31

1999

Billingsley et al[51]

138

37

*

Studies represent analysis of 100 patients or more.

 

The histologic subtype of sarcoma influences both the development of pulmonary metastasis and overall survival. High-grade, undifferentiated, and alveolar soft-part sarcomas produce pulmonary metastasis in approximately 60% of patients.[51] Tumors that are high grade and histologic variants, such as liposarcoma, malignant fibrous histiocytoma, and malignant peripheral nerve tumor, have all been reported to be unfavorable prognostic factors. [51] [53] [58] Longer disease-free interval, fewer lesions, and unilaterality have also been reported to be favorable prognostic factors.

The incidence of hilar or mediastinal lymph node metastasis in patients with lung metastasis from sarcoma is 2%.[5] This low propensity for lymph node involvement is also a feature of primary sarcomas. Therefore, it seems that routine mediastinal lymph node sampling or dissection is unlikely to offer significant prognostic information or therapeutic benefit.

The rate of recurrence after pulmonary metastasectomy for sarcoma ranges from 45% to 83%; however, the role of repeat resection of pulmonary metastases has been studied by few authors. [53] [57] [58] [59] [60] Weiser and associates[61] reported experience from Memorial Sloan-Kettering Cancer Center in 86 patients who underwent repeat resection of pulmonary metastases for soft-tissue sarcoma. The 5-year survival after undergoing at least two operations for pulmonary metastasectomy was 36%. Patients who had a complete repeat resection had a median survival of 51 months, as compared with 6 months in those who could not be completely repeat resected. Poor prognostic indicators for repeat resection included three or more nodules, lesions greater than 2 cm in size, and high-grade primary tumors. This study strongly suggested a benefit for repeat or multiple procedures for clearance of pulmonary disease in carefully selected patients.

Pulmonary metastases from osteosarcoma occur most frequently in pediatric patients and respond better to chemotherapy than do soft-tissue sarcomas. Pulmonary metastasectomy within the context of a multimodality therapy program is a well-accepted approach to treatment and is associated with a 5-year survival of approximately 30%. Response to chemotherapy, the disease-free interval from resection of the primary tumor, and the number of metastases and complete resection are reported to influence overall survival. [62] [63] [64]

Melanoma

Patients with metastatic melanoma have an especially poor prognosis. The most common sites of metastasis from melanoma are the lungs, distant subcutaneous tissue, and distant lymph nodes, with isolated lung metastasis occurring in 1.9% to 11% of patients. [65] [66] Tafra and coworkers[67] reported their experience with 106 patients with metastatic melanoma who underwent pulmonary metastasectomy. Sixty-five of these patients underwent a complete resection. Although the benefit of a complete (vs. an incomplete) resection on survival could not be demonstrated in a univariate analysis, a multivariate analysis found that surgical resection (vs. no operation) was associated with a significantly better survival (P = 0.0001). Other authors have reported that complete resection is associated with prolonged survival. [68] [69] Overall, the 5-year survival rates after resection of pulmonary metastasis from malignant melanoma vary from 4.5% to 27% ( Table 58-6 ). [20] [66] [67] [68] [70] [71] [72] This wide range of values probably reflects the relatively small numbers of patients included in some studies. Prognostic factors that have been reported include operation, number of nodules, prior immune therapy, histologic type, disease-free interval, and tumor-doubling time. [20] [65] [66] [67] [68] [69] [70] [71] [72] Harpole and colleagues[69] reported on a large series of patients who had pulmonary metastases from melanoma. Of the total of 945 patients, 112 (11.8%) underwent pulmonary metastasectomy. Histologic type (nodular and acral lentiginous lesions), high Clark level, and thicker primary tumors were significantly associated with pulmonary metastasis. The overall 5-year survival in this group was 4%. Patients who had a complete resection had a significantly higher median survival rate as compared with those who had only partial resection, although all patients who underwent operations survived longer than those who had no operation. An analysis of the subset of patients who had a solitary metastasis found that patients who underwent resection had a significantly better median survival than patients managed nonsurgically. Important prognostic factors after surgery included complete resection, a long disease-free interval from treatment of the primary tumor to the diagnosis of the pulmonary metastasis, treatment with chemotherapy, and the total number of nodules. These data suggest that appropriately selected patients with metastatic melanoma confined to the lungs can benefit from pulmonary metastasectomy.


Table 58-6   -- Survival of Patients Undergoing Pulmonary Metastasectomy for Malignant Melanoma

Year

Author

Number

5-Year Survival (%)

1985

Thayer et al[70]

18

11.1

1990

Karp et al[68]

22

4.5

1991

Gorenstein et al[66]

54

25.0

1995

Tafra et al[67]

106

27.0

1998

Ollila et al[72]

45

15.6

2002

Dalrymple-Hay et al[20]

121

22.1

 

 

Renal Cell Carcinoma

Barry and Churchill[2] performed the first pulmonary metastasectomy from renal adenocarcinoma in 1938. Approximately 30% of patients with renal cell carcinoma will present with metastasis, and approximately 30% to 50% of patients with initially localized tumors will develop distant metastases.[73] One-half of patients who have a radical nephroureterectomy will develop pulmonary metastases later and only 16% of these patients will have disease confined to the lung. [74] [75] The 5-year survival of patients with unresected metastasis is approximately 2.7%.[76] The 5-year survival after resection of isolated pulmonary metastasis is reported to range from 36% to 44% ( Table 58-7 ). [75] [76] [77] [78] [79] Several prognostic factors for survival have been identified, including complete resection, the disease-free interval between primary tumor treatment and metastasis, the number of metastases, and the presence or absence of lymph node metastases. [75] [76] [78]


Table 58-7   -- Survival of Patients Undergoing Pulmonary Metastasectomy for Renal Cancer,[*]

Year

Author

Number

5-Year Survival (%)

1994

Cerfolio et al[79]

96

36

1997

Fourquier et al[75]

50

44

1999

Friedel et al[77]

77

39

2002

Pfannschmidt et al[76]

149

42

2002

Piltz et al[78]

105

40

2006

Marulli et al[101]

59

53

*

Studies represent analysis of 50 patients or more.

 

Pfannschmidt and associates[76] reported one of the largest series of pulmonary metastasectomy for renal cell cancer; they found that complete resection was possible in 78% of patients and that these patients had a 5-year survival of 41.5% vs. 22.1% for those with incomplete resection. This survival rate of 22.1% in incompletely resected patients was better than that for patients who had no resection at all.

Hilar and mediastinal lymph node metastases are seen in 22% to 30% of patients with metastatic renal cell cancer. [75] [76] Fourquier and colleagues[75] and Pfannschnidt and associates[76] performed systematic mediastinal lymph node dissection on 50 and 191 patients, respectively. Both studies found that the presence of lymph node involvement was associated with a poorer survival. Although it is unknown whether lymph node dissection is therapeutic, it offers important prognostic information and should probably be performed in these patients.

Synchronous metastases are traditionally thought to be a relative contraindication to resection. The true incidence of synchronous versus metachronous metastases is in renal cell cancer is unclear, although in reported series of resected patients, synchronous lesions are less frequent and are thought to indicate a worse prognosis. [75] [76] On the other hand, Fourquier and colleagues[75] examined survival in completely resected patients with synchronous lung metastases. Although the overall survival rate was lower in patients with synchronous lesions (48% vs. 20%), this was not statistically significant and again appeared to offer a survival benefit relative to no resection at all.

The recent development of more effective systemic therapy for renal cell cancers through the use of antiangiogenesis agents may alter the need or indications for pulmonary metastasectomy. This is an evolving area of cancer management, and the impact of these drugs on pulmonary metastasectomy warrants study.

Head and Neck Cancer

Approximately 60,000 new cases of head and neck cancer occur each year in the United States.[80] The potential for metastatic spread is dependent on the stage of the primary tumor, with the rate of lung metastasis ranging from 4.3% to 25.1%.[81] Head and neck tumors and especially squamous cell cancers have a predilection for metastasizing to the lung, which is often the only site of metastasis.[82] The diagnosis of lung nodules in these patients becomes even more challenging when one realizes that 10% to 40% of lung nodules in these patients are actually second primary lung tumors.[83] There are few effective systemic therapy options for the treatment of lung metastasis from head and neck tumors, leaving surgical resection as the most viable option. The estimated 5-year survival after pulmonary metastasectomy in these patients ranges from 29% to 59% ( Table 58-8 ). [80] [81] [83] [84] The wide range of survival rates may be related to the heterogeneous histologic groups reported in most series. Squamous cell tumors of head and neck origin have a worse prognosis than their glandular counterparts such as thyroid, adenoid cystic, and mucoepidermoid tumors. [80] [81] [84] Liu and coworkers[80]reported on 83 patients undergoing pulmonary metastasectomy from head and neck tumors. In their series the 5-year overall survival for squamous cell tumors was 34% as compared with 64% for tumors of glandular origin (P = 0.14). Bilateral metastasis and recurrence of metastasis are not contraindications to resection and have not been shown to be adverse prognostic factors at this time.


Table 58-8   -- Survival of Patients Undergoing Pulmonary Metastasectomy for Head and Neck Cancer

Year

Author

Number

5-Year Survival (%)

1992

Finley et al[83,][*]

18

29

1996

Wedman et al[84]

21

59

1997

Nibu et al[81]

32

32

1999

Liu et al[80]

83

50

*

Included only patients with squamous cell carcinoma metastasis.

 

Germ Cell Tumors

Germ cell tumors compose only 1% of cancers but are the most common neoplasm in men aged 15 to 35 years. The vast majority of these tumors arise in the testis, with an annual incidence of 5 cases per 100,000.[85] The survival of patients with germ cell tumors has increased dramatically during the past 30 years because of cisplatin-based chemotherapy.[85] Monitoring of treatment and recurrence has been made possible by the use of sensitive tumor markers, including α-fetoprotein and human chorionic gonadotropin.

Pulmonary metastasis at the time of presentation in these patients is common, approaching 50% in patients with retroperitoneal disease.[86] Residual masses after chemotherapy are present in approximately 50% of patients and could contain viable malignancy, mature teratoma, or only fibrosis and/or necrosis.[86] Surgical resection of these lesions is crucial to identifying which of the preceding components is present, to predicting outcome, and to determining if any further therapy is warranted. The estimated 5-year survival rate after pulmonary metastasectomy ranges from 59% to 77% ( Table 58-9 ). [85] [86] [87]The most significant prognostic factor is the presence of viable tumor cells in the resected specimen. Liu and coworkers[85] reviewed the experience at Memorial Sloan-Kettering Cancer Center over a 28-year period of 157 patients undergoing pulmonary metastasectomy for germ cell tumors. After resection, viable tumor was found in 70 patients (44.5%), necrosis in 47 patients (29.9%), and mature teratoma in 40 patients (25.4%). Survival was significantly poorer in those patients with viable tumor cells (43% over 10 years) as compared with those patients with necrosis/fibrosis (86% 10-year survival) or mature teratoma (84% 10-year survival).[85] The presence of mature teratoma in a specimen did not significantly worsen prognosis. The inability to make an accurate determination of the presence or absence of viable tumor cells in all residual lesions after treatment for germ cell tumors mandates that all of these lesions be resected to determine overall prognosis and potential for further therapy.


Table 58-9   -- Survival of Patients Undergoing Pulmonary Metastasectomy for Germ Cell Tumors

Year

Author

Number

5-Year Survival (%)

1998

Cagini et al[86]

141

77

1994

Anyanwu et al[87]

104

59

1998

Liu et al[85]

157

68

2005

Kesler et al[88]

134

42.3

 

 

More recently, Kesler and colleagues[88] reported the results of resection in 134 patients with either lung or mediastinal metastases. The overall survival at 5 years was 42.3%. Older patient age, lung rather than mediastinal metastases, and the number of metastases (four or more) adversely influence survival.

Breast Cancer

Breast cancer is the most prevalent cancer among women in the United States, with approximately 100,000 cases occurring annually.[89] Approximately 15% to 25% of patients with metastatic disease will have their disease confined to the thorax. The data regarding pulmonary metastasectomy are controversial, with most studies analyzing the outcome of encompassing small groups of patients treated over several decades. The largest series reported to date is by Friedel and colleagues[90] from the International Registry of Lung Metastases. They reported on 467 patients undergoing pulmonary metastasectomy for breast cancer. Complete resection of all metastasis was possible in 84% of patients. The 5-year overall survival was 38% in patients with complete resection, as compared with 18% of patients with incomplete resection (P = 0.0009). A long disease-free interval and fewer lesions were associated with a longer survival in this group.[90] McDonald and associates[91] reported on 60 patients undergoing pulmonary metastasectomy for breast cancer and failed to show a survival benefit for surgical management. Because breast cancer also frequently progresses to extrathoracic disease and is sensitive to current systemic therapies, pulmonary metastasectomy is rarely an appropriate treatment option. Indeed breast cancer is an example of the evolution of the role of pulmonary metastasectomy. Before the advent of effective hormonal and chemotherapy, pulmonary metastasectomy was commonly performed for breast cancer with metastases confined to the lungs. Surgery is now infrequently considered for treatment.

Nonsurgical Approaches to Lung Metastasis

Two therapeutic options are emerging as potentially effective alternatives to resection in selected patients with lung metastases: stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA). SBRT is a method for delivering focused radiation to a tumor while excluding tissues not grossly involved with the tumor. It is usually delivered as high-dose hypofractionated treatment over just a few days and is therefore an attractive option for patients who have advanced disease or who may also require chemotherapy within a short interval of local therapy. Several small series now report excellent local tumor control rates with low toxicity ( Table 58-10 ). Small, solitary peripheral tumors have been considered the ideal target for SBRT, although some series include patients with larger tumors, multiple lesions, or tumors that include the midline and the hilum.[92] The length of follow-up after SBRT is relatively short in most series, and there are no randomized trials comparing SBRT to surgical pulmonary metastasectomy. The optimal total radiation dose and dose per fraction, and the need for respiratory gating during treatment, are not yet fully defined.[93]


Table 58-10   -- Published Treatment Concepts and Results of Stereotactic Radiotherapy of Targets in Thorax

Author

No. of Patients

No. of Targets

Average No. of Targets (per patient)

Median Lesion Volume (range)

Central Tumor Dose (Gy)/No. of Fractions

Isodose Treated (%)

Crude Local Control (%)

Median Follow-up Time in Months (range)

Acute Toxicity (Grade 1–2) (%)

Acute Toxicity (Grade 3–5) (%)

Blomgren et al, 1998[102]

13

17

1.3

48 mL (3–198)

21–66/1–3

66

94

8.2 (3.5–25)

NA

NA

Uematsu et al, 1993[103]

45

66

1.5

2.5 cm (0.8–4.8)

38–94/5–15

80

97

11 (3–31)

11

0

Wulf et al, 2001[104]

26

27

1

57 mL (5–277)

45/3

65

85

8 (2–33)

22

8 (Grade 5)

Nakagawa et al, 2000[105]

15

22

1.5

Chest wall 40 mL (5–126), Central lung 4.5 mL (0.8–13)

15–45/1[*]
18–25/1[*]

NA

95

10 (1–82)

100 (Grade 1)

0

Uematsu et al, 2001[106]

50

50

1

3.2 cm (0.8–5)

38–75/5–10

80[†]

94

36 (22–66)

[‡]

0

Nagata et al, 2002[107]

40

43

1.1

12.6 mL (0.5–39)

40–48/4

100

94

18 (3–29)

95 (Grade 1)

0

Hara et al, 2002[108]

19

23

1.2

4 mL (1–16)

23–36/1

100

79

13 (3–24)

5 (Grade 2)

5 (Grade 3)

Onimaru et al, 2003[109]

45

57

1.3

2.6 cm (0.6–6)

48–60/8

100

88

18 (2–44)

2.2 (Grade 2)

2.2 (Grade 5)

Hof et al, 2003[110]

10

10

1

12 mL (5–19)

19–26/1

100

80

15 (8–30)

70 (Grade 1)

0

Lee et al, 2003[111]

28

34

1.2

41.4 mL (4.4–230)

30–40/3–4

100

91

18 (7–35)

100 (Grade 1)

0

Timmerman et al, 2003[112]

37

37

1

22.5 mL (1.5–157)

24–60/3

100

84

15.2 (2–30)

95 (Grade 1–2)

5 (Grade 3)

Wulf et al, 2004[113]

61

71

1.2

17 mL (1–277)

33–56/1–3

66–80

92

9–11 (2–61)

7

0

Okunieff et al, 2006[92]

49

125

2.6

4.7 mL (0.1–125)

50/10

100

94

18.7 (4–61)

41 (Grade 1–2)

2 (Grade 3)

From Okunieff P, Petersen AL, Philip A, et al: Stereotactic body radiation therapy (SBRT) for lung metastases. Acta Oncol 2006;45:808–817.

NA, not available.

 

*

Only tumor peripheral dose reported. All but one patient also received 20–40 Gy fractionated radiation.

Prescribed doses were 30–60 Gy. The isodose line used varied and for this table it was assumed to be 80% based on the examples published.

“Most” patients had Grade 1. No patients experienced toxicity greater than Grade 1.

 

 

RFA is a thermal energy system delivered via percutaneous needle placed under imaging guidance into a tumor. RFA causes tumor destruction by coagulation necrosis. There is even less experience with RFA than with SBRT for the treatment of pulmonary metastases. Currently most institutions limit the use of RFA to peripheral tumors less than 5 cm in size. However, local recurrence rates of up to 50% are reported, and serious complications including hemorrhage, pneumothorax, severe pleuritic pain, and effusions occur with RFA. Long-term follow-up data in large numbers of patients are lacking. [94] [95] [96] [97]

Both SBRT and RFA are potentially promising alternatives to surgical pulmonary metastasectomy in selected patients. However, well-designed prospective clinical trials are needed to define the indications for these nonsurgical approaches along with the associated risks and long-term outcome. Certainly, either of these modalities may be appropriate options for patients who are not surgical candidates.

Other Investigational Approaches to Lung Metastases

Two additional approaches have been investigated for the treatment of unresectable pulmonary metastases: isolated lung perfusion (ILP), and transpulmonary chemoembolization. [98] [99] ILP is an extension of the technique of isolated organ perfusion originally developed for limb perfusion of patients with malignant melanoma or sarcoma. First developed by Johnston and coworkers[100] in 1983, ILP requires surgical exploration via thoracotomy or median sternotomy, isolation and cannulation of the pulmonary artery and veins, and chemotherapy perfusion of the isolated lung. However, clinical trials in humans have shown that ILP can be associated with significant pulmonary toxicity. The technical complexity and potential morbidity of this approach to treatment have prevented widespread acceptance of ILP. It remains an investigational treatment modality that should only be used within the context of clinical trials.[98]

Transpulmonary chemoembolization is a method of delivering chemotherapy to the lung without surgery. Selective percutaneous image-guided catheterization of segmental pulmonary arteries is performed with a balloon catheter that occludes blood inflow. Chemotherapy is injected into the segmental pulmonary artery, which is then occluded by a second injection of microspheres. In a small trial involving 23 patients, Vogl and colleagues[99] performed transpulmonary embolization of 26 lung metastases. Tumor regression was observed in 8 patients and tumor stabilization in 6 patients. Treatment was well tolerated with only minor complications. Though clearly an investigational approach to treatment, transpulmonary chemoembolization seems to warrant further study for patients with unresectable pulmonary metastases.

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