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Special Treatment Issues^*

^* From the Multidisciplinary Thoracic Oncology Program, Division of Cardiothoracic Surgery (Dr. Detterbeck), University of North Carolina, Chapel Hill, NC; Division of Thoracic and Cardiovascular Surgery (Dr. Jones), University of Virginia, Charlottesville, VA; Division of Cardiothoracic Surgery (Dr. Kernstine), University of Iowa Hospitals and Clinics, Iowa City, IA; Division of Cardiothoracic Surgery (Dr. Naunheim), St. Louis University Health Sciences Center, St. Louis, MO.

Correspondence to: Frank C. Detterbeck, MD, FCCP, Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina at Chapel Hill, CB #7065, 108 Burnett-Womack Building, Chapel Hill, NC 27599-7065; e-mail: fdetter{at}med.unc.edu

	Abstract

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
This chapter of the Lung Cancer Guidelines addresses patients with particular forms of non-small cell lung cancer that require special considerations. This includes patients with Pancoast tumors, T4N0,1M0 tumors, satellite nodules in the same lobe, synchronous and metachronous multiple primary lung cancers (MPLC), and solitary metastases. For patients with a Pancoast tumor, a multimodality approach, involving chemoradiotherapy and surgical resection, appears optimal provided appropriate staging has been carried out. Patients with central T4 tumors that do not have mediastinal node involvement are uncommon. When carefully staged and selected, however, such patients appear to benefit from resection as part of the treatment as opposed to chemoradiotherapy alone. Patients with a satellite lesion in the same lobe as the primary tumor have a good prognosis and require no modification of the approach to evaluation and treatment from what would be dictated by the primary tumor alone. On the other hand, it is difficult to know how best to treat patients with a focus of the same type of cancer in a different lobe. Although MPLC do occur, the survival results after resection for either a synchronous presentation or a metachronous presentation with an interval of < 4 years between tumors are variable and generally poor, suggesting that many of these patients may have had a pulmonary metastasis rather than a second primary lung cancer. A thorough and careful evaluation of these patients is warranted to try to differentiate between patients with a metastasis and those with a second primary lung cancer, although criteria to distinguish them have not been defined. Finally, some patients with a solitary focus of metastatic disease in the brain or adrenal gland appear to benefit substantially from resection.

Key Words: adrenal metastasis • brain metastasis • carina • metachronous primary lung cancers • multiple primary lung cancer • Pancoast tumor • satellite nodules • superior sulcus tumor • superior vena cava • synchronous primary lung cancers • T4N0,1M0 tumor

	Introduction

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
In general, patients with an early stage non-small cell lung cancer (NSCLC) without mediastinal nodal involvement (stage I and II) are treated primarily with surgery, whereas those with a locally advanced lung cancer with mediastinal nodal involvement (stage IIIA and IIIB) are treated with chemotherapy and radiation. However, there are several relatively unusual presentations of NSCLC, in which the anatomic and biological issues appear to dictate a different approach. In addition, the presence of an isolated second focus of cancer in a patient with lung cancer presents a situation where the biology of this phenomenon is often not clear, and therefore the approach to treatment is difficult.

This section addresses patients with particular forms of NSCLC that require special considerations. These include patients with Pancoast tumors, T4N0,1M0 tumors, satellite nodules in the same lobe, synchronous and metachronous multiple primary lung cancer (MPLC), and solitary metastases. The scope of this project did not allow inclusion of special histologic types of lung cancer, such as typical and atypical carcinoid tumors, mucoepidermoid tumors, or bronchioloalveolar carcinomas.

	Methods

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
A formal meta-analysis was not available for any of the particular forms of NSCLC that are the subject of this chapter, and resources did not permit the American College of Chest Physicians (ACCP) to conduct such an analysis independently. Clinical guidelines from other organizations were available only with regard to Pancoast tumors. These involve primarily consensus opinion statements and are discussed in the section on Pancoast tumors.^{1 2 3 4 5} However, a systematic review of literature in each of these areas is available, published in the year 2001.⁶ The recommendations in this section rely heavily on the data from this review.

The data regarding the approach to these special situations was reviewed, summarized, and used to define management recommendations by the writing committee. This document was then reviewed by three independent reviewers, and further changes were made. The revised document and recommendations were further reviewed by the entire ACCP Guidelines committee to assure that it met the requirements of a balanced, accurate, and generally acceptable representation of the issues with regard to these particular forms of NSCLC.

	Pancoast Tumors

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
Definition
Lung cancers that occur in the apex of the chest and invade apical chest wall structures are called superior sulcus tumors or Pancoast tumors. The classic description of such patients involves a syndrome of pain radiating down the arm as a manifestation of brachial plexus involvement. With improvements in radiographic techniques, earlier diagnosis, and a more detailed understanding of the anatomy, a tumor can be classified as a Pancoast tumor if it invades any of the structures at the apex of the chest, including the most superior ribs or periostium, the lower nerve roots of the brachial plexus, the sympathetic chain near the apex of the chest, or the subclavian vessels. These tumors are now divided into anterior, middle, and posterior compartment tumors depending on the location of the chest wall involvement in relation to the insertions of the anterior and middle scalene muscles on the first rib.⁷ A syndrome of pain radiating down the arm is no longer a prerequisite for an apical tumor to be designated a Pancoast tumor.

Workup
There are no data that specifically address the reliability of the clinical examination in patients with Pancoast tumors with regard to the presence of distant metastases. In the absence of data to the contrary, the panel thought that Pancoast tumors should be treated like most other resectable lung cancers, meaning that imaging tests for distant metastases are not routinely necessary in the presence of a negative clinical evaluation. There is also no evidence regarding the reliability of CT or positron emission tomography (PET) scans for mediastinal node involvement specifically in patients with Pancoast tumors. The consensus of the panel was that, in the face of normal-sized lymph nodes by CT, mediastinoscopy should be performed, although a negative PET scan in the mediastinum may obviate this. In addition, mediastinoscopy should be performed in the presence of enlarged or PET-positive lymph nodes. The argument for this approach to intrathoracic staging is that it is consistent with the general recommendation for accurate staging before initiation of a major intervention, such as resection, and consistent with data demonstrating that N2,3 node involvement is a major negative prognostic factor. No firm recommendation can be made about whether mediastinoscopy should be done before or after preoperative therapy. An MRI demonstrates involvement of apical chest wall structures better than a CT scan,⁸ but CT provides more information about the presence of nodal enlargement, and pulmonary, hepatic, and adrenal metastases. Therefore, both a chest CT and an MRI are indicated to assess the resectability of a Pancoast tumor.

Treatment
The classic approach to curative treatment of Pancoast tumors has been preoperative radiotherapy followed by surgical resection. This dates back to an experience published in 1961 by Shaw et al,⁹ in which 12 of 18 patients treated with this approach were still alive at the time the paper was written. However, the follow-up was < 2 years in 90% of the patients.⁹ Alternatives are treatment with radiation alone, preoperative chemoradiotherapy and resection, or chemoradiotherapy without resection.

Treatment with radiation alone has achieved good palliation of pain in approximately 75% of patients.¹⁰ In general, very few patients treated with radiation alone are long-term survivors (approximately 5%).¹¹ However, many of these series have included patients with advanced stage tumors. Among studies that have involved primarily patients who had a reasonable chance of cure, the average median survival time was 16 months, and the average 5-year survival was 20% (range 15–23%).^{10 12 13 14}

Treatment with preoperative radiation and resection has resulted in an average median survival time of 22 months and a 5-year survival of 27%.¹¹ In these series, approximately one third of patients underwent an incomplete (R₁ or R₂) resection, and approximately one third of the resections involved only a limited resection of the affected lobe of the lung.¹¹ Retrospective analysis has found that a complete resection with negative margins (R₀) and a pulmonary resection involving at least a lobectomy are major factors associated with better survival.¹⁵ Furthermore, N2,3 lymph node involvement is a major negative prognostic factor and should generally be considered a contraindication to surgery.¹¹ Patients with vertebral body or subclavian vessel involvement have traditionally been considered to be unresectable, but it appears that, with improved surgical approaches to these structures, a few experienced centers have been able to achieve reasonable survival in such patients.^{16 17} The presence of Horner syndrome is also associated with poor survival.¹¹

A large phase II study of preoperative chemoradiotherapy in patients with Pancoast tumors has shown a complete resection rate of 92% and a good 2-year survival rate compared with historical controls of radiotherapy followed by surgery.¹⁸ Furthermore, local recurrences were seen in only 33% of those patients with a recurrence, whereas in series involving preoperative radiotherapy alone, the majority of recurrences involved the tumor bed. These data, in combination with the data for non-Pancoast stage III NSCLC, suggest that preoperative chemoradiotherapy is a significant improvement over preoperative radiotherapy, particularly in light of the fact that there are insufficient numbers of patients with Pancoast tumors to complete a randomized comparison.

Other published guidelines have recommended that patients with Pancoast tumors should be evaluated by a thoracic surgeon.³ If there is no evidence of mediastinal node involvement¹ or extensive local invasion,⁵ patients should undergo resection in combination with radiotherapy or chemoradiotherapy.^{1 4 5} Patients with inoperable Pancoast tumors should be treated with radiotherapy.² The latter two recommendations were rated grade B, whereas the strengths of the other statements were rated grade C. Thus other guidelines have reached the same conclusions as this ACCP document, although the recommendations in those other documents have been less detailed and more vaguely worded.

In summary, the available data suggests that the best survival is achieved by preoperative chemoradiotherapy followed by surgical resection in carefully selected patients. Preoperative radiotherapy followed by surgical resection is a reasonable alternative. Involvement of subclavian vessels or the vertebral column is associated with poor survival after resection. However, a few centers have gained experience with improved surgical approaches to these structures and have reported reasonable survival rates after resection. Involvement of mediastinal nodes is associated with poor survival after resection. At the time of resection, it is important to carry out a complete resection, which should involve at least a lobectomy. There is no data on how unresectable, yet potentially curable, patients with Pancoast tumors should be treated. However, extrapolation from the data for non-Pancoast stage III NSCLC suggests that chemoradiotherapy is the best approach. For patients in whom cure is not believed possible, radiotherapy offers good palliation of pain.

Recommendations: Pancoast tumor

1. For patients with a Pancoast tumor, a tissue diagnosis should be obtained prior to the initiation of therapy. Level of evidence, poor; benefit, substantial; grade of recommendation, C
   
2. Patients with a Pancoast tumor without evidence of mediastinal node involvement or distant metastases should be evaluated by an experienced thoracic surgeon for potential resection. Level of evidence, fair; benefit, substantial; grade of recommendation, B
   
3. Patients with a Pancoast tumor being considered for resection should undergo evaluation with an MRI of the thoracic inlet and brachial plexus, in addition to a CT of the chest. Level of evidence, fair; benefit, substantial; grade of recommendation, B
   
4. Resection of patients with a Pancoast tumor with involvement of the subclavian vessels or the vertebral column should not be routinely undertaken (outside of specialized centers). Level of evidence, poor; benefit, moderate; grade of recommendation, D
   
5. Patients with a Pancoast tumor being considered for curative resection should undergo a cervical mediastinoscopy. Involvement of mediastinal nodes represents a contraindication to resection. Level of evidence, good; benefit, substantial; grade of recommendation, A
   
6. Patients with a potentially resectable, nonmetastatic Pancoast tumor (and good performance status) should undergo preoperative chemoradiotherapy prior to resection. A reasonable alternative for such patients is preoperative radiotherapy. Level of evidence, fair; benefit, moderate; grade of recommendation, B
   
7. At the time of resection of a Pancoast tumor, every effort should be made to achieve a complete resection. Level of evidence, good; benefit, substantial; grade of recommendation, A
   
8. Resection of a Pancoast tumor should consist of a lobectomy (instead of a wedge), as well as removal of the involved chest wall structures. Level of evidence, fair; benefit, moderate; grade of recommendation, B
   
9. For patients with a Pancoast tumor, postoperative radiotherapy is not recommended, in either completely or incompletely resected patients, because of lack of a demonstrated survival benefit. Level of evidence, poor; benefit, none; grade of recommendation, D
   
10. Patients with a good performance status and an unresectable but nonmetastatic Pancoast tumor should be considered for combination chemotherapy and radiotherapy with intent to cure. Level of evidence, poor; benefit, moderate; grade of recommendation, C
    
11. Palliative radiotherapy should be considered in patients who are not candidates for treatment with curative intent (ie, surgery, chemoradiotherapy etc.). Level of evidence, fair; benefit, moderate; grade of recommendation, B
    

	T4N0,1M0 Tumors

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
Patient Selection and Workup
Most patients with involvement of T4 structures have mediastinal node involvement as well. These patients should be treated with chemoradiotherapy, as is generally recommended for patients with stage IIIB NSCLC. However, selected patients with T4 involvement, but without mediastinal node involvement, can be viewed as candidates for surgery. Although many reports have demonstrated the technical feasibility of resection of T4 structures, fewer series have provided long-term survival data. The largest experience of resection for T4 involvement involved carinal resections, usually together with a right pneumonectomy (327 patients in whom long-term survival data were reported).¹⁹ A moderate experience is available with left atrial involvement (85 patients), and a smaller experience has been reported with involvement of the superior vena cava (40 patients).¹⁹ The fact that so few patients have been reported with long-term survival statistics underscores the fact that patients who are candidates for a surgical approach are extremely rare and highly selected.

A mediastinoscopy should be performed even if a CT suggests no N2,3 involvement in patients with T4 tumors being considered for a surgical approach. This argument is based on the fact that CT evaluation of the mediastinum in central tumors has a high false negative rate. Furthermore, the operative mortality and the poor survival of T4N2,3M0 patients argues that surgical resection be undertaken only in carefully selected patients. For patients who are being considered for carinal resection, it may be best to perform mediastinoscopy at the same time as resection, in order to prevent scarring and therefore lack of mobility of the airways at the time of reconstruction.

Outcomes After Surgery
In a fairly large series from Japan involving an aggressive approach to T4 tumors, approximately one third of patients were able to undergo complete (R₀) resection, one third a microscopically incomplete resection (R₁), and one third a grossly incomplete resection (R₂).²⁰ The 5-year survival rates for these groups were 22%, 18%, and 0%, respectively.²⁰ No data are available regarding how often a resection can actually be carried out among patients with involvement of specific T4 structures.

The data regarding the outcome after resection in patients with carinal involvement shows an average 5-year survival of 26%. However, the survival comes at a price of an average operative mortality of 18% (range 7–29%). It should be noted, however, that the survival statistics have included all operative deaths as well. The fact that the best reported 5-year survival (42%) comes from the largest series,²¹ which also reported an operative mortality of only 7%, can be interpreted to suggest that such resections should be undertaken only in experienced centers. Survival data for resections involving other T4 structures have involved fewer patients, making interpretation of the data difficult (Table 1 ). The survival of patients with left atrial involvement has been poor. In general, however, the survival of patients with involvement of other T4 structures has been similar to that reported for patients with carinal involvement.

Preoperative chemotherapy or chemoradiotherapy in patients with T4 tumors has been reported in several trials. A 5-year survival of 20% was reported among all patients in the largest trial (57 patients; 62% of whom underwent complete resection).²² These results are encouraging, given that 60% of the patients entered in the study had T4N2M0 tumors by careful surgical staging. By comparison, 5-year survival results for chemoradiotherapy without surgery in patients with stage IIIA,B tumors have been approximately 9% and 14% in large randomized trials involving sequential or concurrent chemoradiotherapy, respectively.²³ However, these latter series have included both stage IIIA and IIIB patients and have not reported data separately or reported any data specifically in patients with T4N0,1M0 tumors. A retrospective analysis of the Southwest Oncology Group experience suggested that patients with T4N0,1M0 tumors benefited from preoperative chemoradiotherapy and surgery compared with treatment with chemoradiotherapy alone (2-year survival of 64% vs 33%).²⁴

Recommendations: T4N0,1M0 tumors

• Patients with a clinical T4N0,1M0 NSCLC should be carefully evaluated (with imaging studies) for distant metastatic disease prior to considering surgical resection. Level of evidence, fair; benefit, substantial; grade of recommendation, B
  
• Resection of T4N0,1M0 tumors in selected patients may result in better survival than chemoradiotherapy without resection. Level of evidence, poor; benefit, moderate; grade of recommendation, C
  
• Mediastinoscopy should be done prior to surgical resection of patients with clinical T4N0,1M0 tumors. Level of evidence, fair; benefit, substantial; grade of recommendation, B
  

	Satellite Nodules and MPLC

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
Definitions
Occasionally, patients present with more than one focus of cancer within the lung. The American Joint Committee on Cancer staging system classifies a second focus of cancer within the same lobe as T4, whereas a second focus in another lobe is classified as M1. However, the classification does not help in grouping tumors according to similar biological situations. Although the secondary focus may represent a hematogenously spread metastasis, it may also be a second primary lung cancer or a second focus that is a manifestation of local spread. Distinguishing these situations is difficult. In this section, these tumors are classified according to clinical presentation, a method that at least has practical relevance in defining an approach to these patients. Thus, this section will distinguish a synchronous lesion within the same lobe as the primary tumor, two synchronous foci of cancer in different lobes, and two metachronous foci of cancer in the lung. Circumstances can be identified for each of these clinical presentations to reasonably allow them to be defined as satellite lesions, or synchronous and metachronous MPLC. In this document, as in the published literature, a satellite lesion is any additional focus of lung cancer of the same histologic type within the same lobe, regardless of the relative size or location in different segments, and regardless of whether it is discovered by the radiologist, the surgeon, or the pathologist.

Definitions for satellite lesions within the same lobe as the primary tumor, synchronous second primary lung cancers, and metachronous second primary lung cancers are given in Table 2 . In general, these criteria are relatively well accepted, but some authors have varied slightly in some details (eg, the minimum interval between metachronous MPLC). Many data are available regarding the incidence of a second primary lung cancer and the recurrence rates and patterns of resected lung cancer. Therefore, the incidence of a second primary cancer and the incidence of a solitary pulmonary metastasis can be estimated for different stages of the primary lung cancer and by location of the second focus of cancer, as shown in Figure 1 . Although such estimates are based on extrapolations from known data, the resulting incidences and distributions between synchronous and metachronous presentations or same histology and different histologic types are both internally consistent and very close to what is actually observed. Analysis of these rates suggests that the biological situation (ie, new primary vs locally or hematogenously spread metastasis) can be defined clearly in some clinical presentations (ie, satellite lesions, MPLC of different histologic types, and metachronous tumors with an interval of 4 years). In other clinical presentations, the biological situation is very unclear.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Estimated incidence of MPLC, solitary pulmonary metastases, and satellite lesions in different clinical presentations. These estimates are based on data concerning recurrence rates by stage and time interval, location of metastases, and the observed incidence of MPLC and satellite lesions for each clinical presentation. Pulm Mets=pulmonary metastasis. Adapted with permission from Detterbeck et al.27

In the following paragraphs, a prospective approach is formulated for patients with clinical stage I-III NSCLC in whom a second intraparenchymal focus of cancer is not only identified radiographically but is also proven to be malignant by cytologic studies. Patients with disseminated disease (extrathoracic metastases) are excluded. In addition, the 30% of patients with synchronous MPLC, in which the second cancer was found incidentally at thoracotomy, are excluded for obvious reasons. Patients with bronchioloalveolar carcinoma should also be considered separately. Finally, it must be emphasized that the majority (57–86%) of additional nodules seen radiographically in patients with clinical stage I-III NSCLC are benign lesions.^{25 26} Therefore, the considerations noted in the following discussion are relevant only when a histologic diagnosis of a MPLC has been made.

	Satellite Nodules of Cancer in the Same Lobe

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
Workup and Treatment Results
Studies that have reported on long-term survival specifically of patients with satellite nodules in the same lobe as the primary tumor have generally reported good survival. The overall 5-year survival rate of all patients, of whom approximately 60% have N1 or N2 involvement, is 34%.²⁷ The 5-year survival for patients with satellite nodules and no node involvement is 64% (range, 54 to 70%), which is similar to the survival for patients with stage I NSCLC without satellite nodules.²⁷ Direct comparisons have generally demonstrated a slightly inferior survival in patients with satellite nodules, stage for stage, compared with patients without satellite nodules.²⁸ Nevertheless, the survival of patients with satellite nodules in the same lobe is consistently higher than that reported for patients with a second cancer nodule in a separate lobe (5-year survival approximately 10%, range, 0 to 23% for all patients).²⁷

In general, no additional diagnostic workup is necessary in patients with a secondary lesion in the same lobe. First of all, the available data indicates that most secondary lesions in the same lobe as the primary tumor were found to be benign. Furthermore, the prognosis in those patients who are found to have a satellite nodule of cancer is only slightly inferior to those without a satellite focus, which argues that resection should be undertaken even in those patients who do, in fact, have a satellite focus of cancer. Therefore, there is little reason to attempt to definitively diagnose a second lesion preoperatively in patients with clinical stage I,II tumors with a second radiographic nodule in the same lobe. Furthermore, there is little reason to perform any additional preoperative staging investigations (eg, mediastinoscopy, CT of the head, bone scan) in patients with a second nodule in the same lobe as the primary tumor, other than what is dictated by the patient’s clinical status and the primary tumor.

Recommendations: Satellite Nodule in the Same Lobe

• No further diagnostic workup of a satellite nodule is needed in patients with suspected or proven lung cancer and a satellite nodule within the same lobe. Level of evidence, fair; benefit, moderate; grade of recommendation, B
  
• For patients with a satellite lesion within the same lobe as a suspected or proven primary lung cancer, distant organ scanning and confirmation of the mediastinal node status should be carried out as dictated by the primary lung cancer alone, and not modified due to the presence of the satellite lesion. Level of evidence, poor; benefit, small; grade of recommendation, C
  
• For patients with NSCLC and a satellite focus of cancer within the same lobe, resection via a lobectomy is the preferred treatment. Level of evidence, fair; benefit, substantial; grade of recommendation, B
  

	Synchronous Second Primary Lung Cancer

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
Definition
A synchronous second focus of lung cancer in a different lobe is easily defined as a second primary lung cancer when the two sites are of different histologic types. Cancers may also be distinguished on the basis of different molecular genetic characteristics. In the absence of molecular analysis, it is difficult to distinguish two synchronous cancers that are of the same histologic type as separate primary lung cancers. One proposed requirement for classification as synchronous second primary lung cancers is that there be no mediastinal node involvement and no sites of distant metastases when the two cancers are of the same histologic type.²⁷ It can be estimated that the incidence of a second primary cancer using this definition is slightly higher than the incidence of a isolated pulmonary metastasis, given what is known about the incidence of MPLC and the rate and sites of spread of lung cancer.²⁷ On the other hand, when mediastinal node involvement is present, the incidence of an isolated pulmonary metastasis is higher than that of a second primary cancer.²⁷ Although the exact incidence of multiple primary cancers and isolated pulmonary metastasis may not be fully defined by these estimates, at the very least it is clear that the identification of two synchronous foci of cancer of the same histologic type is difficult.

Patient Selection and Treatment Results
The survival of patients with synchronous (different lobe) MPLC (either same or different histologic types) is highly variable, consistent with the difficulty of reliably classifying these tumors.²⁷ The 5-year survival for all patients ranges from 0 to 70%, and the survival of patients in whom both tumors are classified as stage I ranges from 0 to 79%.^{29 30 31 32} This data suggests that a great deal of caution is necessary in classifying two synchronous foci of cancer as two separate primary lung cancers. Approximately one third of the second foci of cancer are found incidentally at the time of resection.²⁷ Approximately 60% of synchronous second primary lung cancers are squamous cell cancers, and in approximately 60% of the cases, the tumors are of the same histologic type.²⁷

The first issue to consider in approaching patients with a synchronous second focus of lung cancer in a different lobe is the accuracy of the diagnosis. If two histologic types of primary NSCLC are diagnosed preoperatively, it must be remembered that the accuracy of determining lung cancer cell type by cytologic studies is only 60 to 80%.^{33 34 35 36} A histologic or core needle diagnosis should be obtained, especially if there is evidence of mediastinal lymph node involvement, because this increases the probability that the second focus is an isolated pulmonary metastasis. Even when a diagnosis of synchronous second primary lung cancers is secure, careful staging with distant organ scanning and mediastinoscopy should be carried out because the survival of patients with synchronous MPLC is poor, even in patients who have cancers of different histologic types.³⁷

Patients with a synchronous second cancer of similar histologic type present a conundrum. These patients should undergo an extensive search for mediastinal involvement, distant metastases, or an extrapulmonary primary cancer. Genetic marker analysis may be useful in distinguishing between MPLC and a metastasis. In the absence of distant metastases, lymph node involvement, or evidence that the second focus of cancer is a metastasis, resection is reasonable, although the reported long-term survival is generally poor.

Occasionally, patients not suspected of having a second primary cancer are found intraoperatively to have a second cancer. It is usually difficult to determine whether the histologic type of the two cancers is the same or different on frozen section examination. There are no published data that address this specific situation. The panel believes it is reasonable to proceed with a resection of each lesion if each appears to be a resectable primary lung cancer, given that the patient has already been exposed to the morbidity of a thoracotomy. However, this can only be recommended if the patient has adequate pulmonary reserve to tolerate the resection, if there is no mediastinal nodal involvement, and if there is no clinical evidence of distant metastases. Concerns about the adequacy of pulmonary reserve may make it necessary to perform a limited resection (segmentectomy or wedge) of one or both of the lesions. Nevertheless, the resection must be a complete resection (R₀); if this cannot be achieved, then nothing more than a biopsy of the lesions for diagnosis is indicated. The prognosis after resection in such situations has not been defined, but is likely to be poor, similar to the survival of patients with synchronous primary lung cancers that are recognized or at least suspected preoperatively.

Recommendations: Synchronous Second Primary Lung Cancer

• Patients suspected of having two synchronous primary lung cancers should have a thoughtful search for an extrathoracic primary cancer to rule out the possibility that both of the lung lesions represent metastases from an extrathoracic primary. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients suspected of having two synchronous primary lung cancers, a careful and thorough search for distant metastases should be performed. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients suspected of having two synchronous primary lung cancers, the absence of mediastinal node involvement should be confirmed (usually via mediastinoscopy) prior to resection. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients with two synchronous primary lung cancers, resection of both lung cancers is reasonable provided a careful search for distant metastases or mediastinal lymph node involvement has been carried out and is negative. Level of evidence, poor; benefit, moderate; grade of recommendation, C
  
• If a patient (not suspected of having a second focus of cancer) is discovered intraoperatively to have a second cancer in a different lobe, it is recommended that a resection of each lesion be undertaken, provided the patient has adequate pulmonary reserve and provided there is no N2 nodal involvement. Level of evidence, poor; benefit, moderate; C
  

	Metachronous Second Primary Lung Cancer

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
Definition
A metachronous second focus of lung cancer is easily defined as a second primary lung cancer when the two tumors are different histologic types. When they are of the same type, the second focus can be reliably defined as a second primary if there is no evidence of systemic metastases and at least a 4-year interval between the two.²⁷ Some authors have included patients with > 2-year interval,³⁸ but the estimated incidence of a solitary pulmonary metastasis from the previous lung cancer is practically the same as the estimated incidence of a new primary lung cancer.²⁷ Therefore, an interval of 2 to 4 years represents a gray area, where it is difficult to determine whether a new lesion is a second primary. If the interval is < 2 years, it is much more likely that the lesion is a metastasis from the original cancer than a second primary lung cancer.

Patient Selection and Treatment Results
Among studies reporting on metachronous second primary lung cancers, approximately two thirds of these have been tumors of the same histologic type (most often squamous cell).²⁷ The average time interval between tumors in these studies is 48 months. Approximately 80% of second primary lung cancers are found on a routine chest radiograph, and approximately 75% are stage I.²⁷ Approximately 65% of second primary lung cancers are able to be resected, with approximately one third of the resections involving a limited resection. The operative mortality for the resection has been reported to average 7%.²⁷ The 5-year survival of all patients who present with a second primary is approximately 20%.^{30 32 39 40} The survival of patients able to undergo resection of the second primary is 36%.^{30 31 32 37 41 42 43 44} The survival of patients who are found to have a second primary lung cancer that is pathology stage I is also only 36% (range 20–50%).^{30 31 37 40 41 43}

A careful search for sites of recurrence should be conducted in patients who present with a nodule that is suspected of being a metachronous second primary lung cancer. This is particularly important if the histologic type is the same as the primary cancer and if the interval between cancers has been < 4 years. A new cancer appearing in < 2 years should be assumed to be a metastasis unless it is clearly of a different histologic type. Although some cancers appearing between 2 and 4 years after the first primary lung cancer are probably MPLC, a fair amount of doubt about this exists until the interval has been > 4 years. Resection of a second primary lung cancer that is early stage should be undertaken, although the prognosis is not as good as that of an early stage single primary lung cancer.

Recommendations: Metachronous Second Primary Lung Cancer

• A careful and thorough search for distant metastases should be performed in patients suspected of having metachronous second primary lung cancers. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• Resection of a metachronous second primary lung cancer is reasonable provided a careful search for other distant metastases or mediastinal lymph node involvement has been carried out and is negative. Level of evidence, poor; benefit, moderate; grade of recommendation, C
  

	Isolated Brain Metastasis

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
Patient Selection and Workup
Approximately 25% of patients with stage IV NSCLC have a brain metastasis as well as other sites of metastatic disease.⁴⁵ The median survival of patients with a brain metastasis is approximately 2 months when treated with steroids alone, and 3 to 6 months when treated with whole brain radiotherapy (WBRT).⁴⁵ Because the survival of patients with a brain metastasis is so short, there is reason to consider aggressive treatment of the brain metastasis with either surgical resection or radiosurgery as a palliative treatment to prolong survival. However, a subset of patients with stage IV disease has a brain metastasis as the only site of metastatic disease. In this group, it is reasonable to consider aggressive therapy of both the primary lesion as well as the isolated metastatic site as a potentially curative therapy. This latter group is the focus of this section. Patients with a brain metastasis who are treated with surgery or radiosurgery of the brain metastasis as a palliative treatment are discussed in the chapter on palliative care.

Aggressive treatment of a brain metastasis may involve either surgical resection of the metastasis or ablation of the metastasis by radiosurgery. This latter technique involves a precisely focused beam of radiation with a steep fall-off of the dose outside of the target area, hence the name radiosurgery. Although no randomized trial of surgery vs radiosurgery has ever been completed, comparison of the results of these techniques in patients treated palliatively suggests that they are similar with regard to survival, local control, morbidity, and mortality.^{46 47} A number of technical issues often favor one of these treatments over the other; therefore, they are best viewed as complimentary modalities. In the discussion in this section, they will be considered together as similar methods of aggressive treatment of a brain metastasis.

Patients with a brain metastasis should be selected for curative treatment only after a thorough search for other sites of disease has been negative. Furthermore, it is obvious that only patients in whom both the brain metastasis and the primary tumor can be completely resected can be considered candidates for curative treatment (synchronous presentation). It appears reasonable to assume that patients with N2,3 involvement and a brain metastasis are not good candidates for curative therapy, although data demonstrating this is lacking.⁴⁷ Therefore, it appears reasonable to perform mediastinoscopy in selecting patients for resection of the brain metastasis and the primary lesion. The histologic subtype does not play a role.⁴⁷ The number of brain metastases may not play a role as long as the number is small ( 3), and they can all be completely resected (as has been demonstrated by several retrospective studies in patients treated for palliation).^{48 49 50 51}

The outlook is likely to be more optimistic for patients who are younger, female, or have a metachronous presentation.⁴⁷ The outlook may also be better in patients with supratentorial lesions and those with a brain metastasis < 3 cm in diameter. However, these considerations are relative and should not necessarily exclude patients who are otherwise fit and in whom a complete resection is likely to be achieved.

Treatment Outcomes
Survival statistics of patients with a brain metastasis who were treated with curative intent have been reported by a number of studies.⁴⁷ The overall survival for all patients is fairly consistent, and averages 14% (range, 8 to 21%). The 5-year survival for completely resected patients averages 21% (range, 16 to 30%).⁴⁷ The operative mortality in these studies has been low, averaging 2%.⁴⁷ Approximately two thirds of the cases involved a metachronous presentation.⁴⁷

There are conflicting data regarding the role of adjuvant WBRT following resection of an isolated brain metastasis. Retrospective analyses of patients who were primarily treated with curative intent have suggested either no survival benefit⁵² or a significant benefit.⁵³ The rate of intracranial recurrence among patients treated primarily with palliative intent was lower after WBRT in a randomized study,⁵⁴ while retrospective analyses in such patients have shown conflicting results.⁴⁷ It is likely that a benefit, might only be seen in patients without other sites of metastases, given the experience with prophylactic cranial irradiation in patients with small cell lung cancer. There is no data regarding the role of adjuvant chemotherapy for patients who have undergone curative resection of a brain metastasis.

Recommendations: Isolated Brain Metastasis

• Patients with an isolated brain metastasis from NSCLC should be considered for a curative approach. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients with an isolated brain metastasis from NSCLC who are being considered for a curative approach, a careful search for other distant metastases should be carried out with imaging tests. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients with a synchronous presentation of isolated brain metastases and a resectable primary lung cancer, mediastinoscopy should be done to rule out N2,3 involvement prior to curative resection. Level of evidence, poor; benefit, moderate; grade of recommendation, C
  
• For patients with no other sites of metastases and a synchronous resectable N0,1 primary NSCLC, resection or radiosurgical ablation of an isolated brain metastasis should be undertaken (as well as resection of the primary tumor). Level of evidence, fair; benefit, substantial; grade of recommendation, B
  
• For patients with no other sites of metastases and a previously completely resected primary NSCLC (metachronous presentation), resection or radiosurgical ablation of an isolated brain metastasis should be undertaken. Level of evidence, fair; benefit, substantial; grade of recommendation, B
  
• For patients who have undergone a curative resection of an isolated brain metastasis, adjuvant whole brain radiotherapy is reasonable, although there is conflicting and insufficient data regarding a benefit with respect to survival or the rate of recurrent brain metastases. Level of evidence, poor; benefit, unclear; grade of recommendation, I
  
• For patients who have undergone a curative resection of an isolated brain metastasis (and resection of the primary tumor), adjuvant chemotherapy can be neither recommended nor recommended against because of insufficient data regarding this issue. Level of evidence, poor; benefit, unclear; grade of recommendation, I
  

	Isolated Adrenal Metastasis

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Patient Selection and Treatment Results
Highly selected patients have been reported who have undergone resection of an adrenal metastasis from NSCLC with intent to cure. The overall 5-year survival for these patients has been 10 to 23%.^{47 55 56} Survival after resection of the primary and the adrenal metastasis appears to be good primarily in patients without nodal involvement.^{47 56} Other factors such as the histologic type, synchronous vs metachronous presentation, and ipsilateral vs contralateral location do not have prognostic value in the limited number of reported patients who underwent this treatment.^{47 55 56}

Recommendations: Isolated Adrenal Metastasis

• Patients with an isolated adrenal metastasis from NSCLC should be considered for a curative approach. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients with an isolated adrenal metastasis being considered for curative therapy, a careful search for other distant metastases should be carried out with imaging tests. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients with a synchronous presentation of an isolated adrenal metastasis and a resectable primary lung cancer, mediastinoscopy should be done to rule out N2,3 involvement prior to resection. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For carefully selected patients with no other sites of metastases and a synchronous resectable N0,1 primary NSCLC, resection of an isolated adrenal metastasis from NSCLC should be undertaken (as well as resection of the primary tumor). Level of evidence, poor; benefit, moderate; grade of recommendation, C
  
• For patients with no other sites of metastases and a previously completely resected primary NSCLC (metachronous presentation), resection of an isolated adrenal metastasis should be undertaken. Level of evidence, poor; benefit, moderate; grade of recommendation, C
  

	Summary

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
The available data for patients with Pancoast tumors suggests that the best survival is achieved by preoperative chemoradiotherapy followed by surgical resection in carefully selected patients. Preoperative radiotherapy followed by surgical resection is a reasonable alternative. Involvement of subclavian vessels, vertebral column, or mediastinal lymph nodes is associated with poor survival after resection. At the time of resection, it is important to carry out a complete resection that should involve at least a lobectomy. There is no data on how unresectable, yet still potentially curable, patients with Pancoast tumors should be treated. However, extrapolation from the data for non-Pancoast stage III NSCLC suggests that chemoradiotherapy is the best approach. For patients in whom cure is not believed to be possible, radiotherapy offers good palliation of pain.

Although most patients with T4 NSCLC have N2,3 or M1 involvement, surgical resection should be pursued in highly selected patients with T4N0,1M0 tumors. The survival of such patients in whom a complete resection was achieved appears to be better than after treatment with chemoradiotherapy alone. However, the operative mortality is relatively high, and patients must be carefully staged and selected. Preoperative chemoradiotherapy may also be beneficial.

An additional small pulmonary nodule is not an infrequent finding on a CT scan in patients with a NSCLC. Most of these lesions are benign. If the lesion is within the same lobe as the lung cancer, no special workup is necessary other than what would usually be done, because lobectomy is associated with good survival, even when a second focus of cancer is present (satellite lesion). If a second lesion in another lobe is suspected of being malignant, it is difficult to define whether this represents a synchronous second primary lung cancer or a manifestation of systemic disease. The patient should undergo a thorough investigation for evidence of metastatic disease before making a decision regarding treatment. The prognosis and whether resection should be undertaken is difficult to define when two lesions of the same histologic type are present in different lobes. Resection of both lesions may be appropriate, but the prognosis is likely to be much worse than for similar staged isolated primary lung cancers.

A careful search for sites of recurrence should be conducted in patients who present with a nodule that is suspected to be a metachronous second primary lung cancer. This is particularly important if the histologic type is the same as the primary cancer and if the interval between cancers has been < 4 years. A new cancer appearing in < 2 years should be assumed to be a metastasis unless it is clearly of a different histologic type. Although some cancers appearing between 2 and 4 years after the first primary lung cancer may be MPLC, a fair amount of doubt about this exists until the interval has been > 4 years. Resection of an early stage second primary lung cancer should be undertaken, although the prognosis is not as good as that for an early-stage single primary lung cancer.

Patients who have previously undergone complete resection of the primary tumor but are subsequently found to have a solitary cranial or adrenal metastasis should be evaluated for resection of the metastasis with curative intent. In addition, patients who present with a resectable primary lung cancer and a solitary metastasis to the brain and possibly also to the adrenal gland should be evaluated for possible resection of both lesions with curative intent. It is necessary to perform a careful search for other sites of metastases, and patients with mediastinal node involvement should be excluded from such an approach. Five-year survival rates of 15 to 20% have consistently been reported in patients who have undergone resection of a solitary metastasis (as well as resection of the primary tumor).

	Summary of Recommendations

TOP Abstract Introduction Methods Pancoast Tumors T4N0,1M0 Tumors Satellite Nodules and MPLC Satellite Nodules of Cancer... Synchronous Second Primary Lung... Metachronous Second Primary Lung... Isolated Brain Metastasis Isolated Adrenal Metastasis Summary Summary of Recommendations References

 
Pancoast Tumors

1. For patients with a Pancoast tumor, a tissue diagnosis should be obtained prior to the initiation of therapy. Level of evidence, poor; benefit, substantial; grade of recommendation, C
   
2. Patients with a Pancoast tumor without evidence of mediastinal node involvement or distant metastases should be evaluated by an experienced thoracic surgeon for potential resection. Level of evidence, fair; benefit, substantial; grade of recommendation, B
   
3. Patients with a Pancoast tumor being considered for resection should undergo evaluation with an MRI of the thoracic inlet and brachial plexus, in addition to a CT of the chest. Level of evidence, fair; benefit, substantial; grade of recommendation, B
   
4. Resection of patients with a Pancoast tumor with involvement of the subclavian vessels or the vertebral column should not be routinely undertaken (outside of specialized centers). Level of evidence, poor; benefit, moderate; grade of recommendation, D
   
5. Patients with a Pancoast tumor being considered for curative resection should undergo a cervical mediastinoscopy. Involvement of mediastinal nodes represents a contraindication to resection. Level of evidence, good; benefit, substantial; grade of recommendation, A
   
6. Patients with a potentially resectable, nonmetastatic Pancoast tumor (and good performance status) should undergo preoperative chemoradiotherapy prior to resection. A reasonable alternative for such patients is preoperative radiotherapy. Level of evidence, fair; benefit, moderate; grade of recommendation, B
   
7. At the time of resection of a Pancoast tumor, every effort should be made to achieve a complete resection. Level of evidence, good; benefit, substantial; grade of recommendation, A
   
8. Resection of a Pancoast tumor should consist of a lobectomy (instead of a wedge), as well as removal of the involved chest wall structures. Level of evidence, fair; benefit, moderate; grade of recommendation, B
   
9. For patients with a Pancoast tumor, postoperative radiotherapy is not recommended, either in completely or incompletely resected patients, because of lack of a demonstrated survival benefit. Level of evidence, poor; benefit, none; grade of recommendation, D
   
10. Patients with a good performance status and an unresectable, but nonmetastatic Pancoast tumor should be considered for combination chemotherapy and radiotherapy with intent to cure. Level of evidence, poor; benefit, moderate; grade of recommendation, C
    
11. Palliative radiotherapy should be considered in patients who are not candidates for treatment with curative intent (ie, surgery, chemoradiotherapy etc.). Level of evidence, fair; benefit, moderate; grade of recommendation, B
    

T4N0,1M0 Tumors

• Patients with a clinical T4N0,1M0 NSCLC should be carefully evaluated (with imaging studies) for distant metastatic disease prior to considering surgical resection. Level of evidence, fair; benefit, substantial; grade of recommendation, B
  
• Resection of T4N0,1M0 tumors in selected patients may result in better survival than chemoradiotherapy without resection. Level of evidence, poor; benefit, moderate; grade of recommendation, C
  
• Mediastinoscopy should be done prior to surgical resection of patients with clinical T4N0,1M0 tumors. Level of evidence, fair; benefit, substantial; grade of recommendation, B
  

Satellite Nodules of Cancer in the Same Lobe

• No further diagnostic workup of a satellite nodule is needed in patients with suspected or proven lung cancer and a satellite nodule within the same lobe. Level of evidence, fair; benefit, moderate; grade of recommendation, B
  
• For patients with a satellite lesion within the same lobe as a suspected or proven primary lung cancer, distant organ scanning and confirmation of the mediastinal node status should be carried out as dictated by the primary lung cancer alone, and not modified due to the presence of the satellite lesion. Level of evidence, poor; benefit, small; grade of recommendation, C
  
• For patients with NSCLC and a satellite focus of cancer within the same lobe, resection via a lobectomy is the preferred treatment. Level of evidence, fair; benefit, substantial; grade of recommendation, B
  

Synchronous Second Primary Lung Cancer

• Patients suspected of having two synchronous primary lung cancers should have a thoughtful search for an extrathoracic primary cancer to rule out the possibility that both of the lung lesions represent metastases from an extrathoracic primary. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients suspected of having two synchronous primary lung cancers, a careful and thorough search for distant metastases should be performed. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients suspected of having two synchronous primary lung cancers, the absence of mediastinal node involvement should be confirmed (usually via mediastinoscopy) prior to resection. Level of evidence, poor; benefit, substantial; grade of recommendation, C
  
• For patients with two synchronous primary lung cancers, resection of both lung cancers is reasonable provided a careful search for distant metastases or mediastinal lymph node involvement has been carried out and is negative. Level of evidence, poor; benefit, moderate; grade of recommendation, C
  
• If a patient (not suspected of having a second focus of cancer) is discovered intraoperatively to have a second cancer in a different lobe, it is recommended that a resection of each lesion is undertaken, provided the patient has adequate pulmonary reserve and there is no N2 nodal involvement. Level of evidence, poor; benefit, moderate; grade of recommendation, C
  

Metachronous Second Primary Lung Cancer

• A careful and thorough search for distant metastases should be performed in patients suspected of having metachronous second primary lung cancers. Level of eviden