Surgical Management of Second Primary and Metastatic Lung Cancer
Yvonne M. Carter
Dan J. Raz
David M. Jablons
More than half of the approximately 160,000 patients diagnosed with lung cancer annually in the United States have metastatic disease at the time of presentation.1 In the past, a selected few patients with metastases to other lung segments or the brain have been treated surgically; otherwise, there has not been a defined role for surgery in the treatment of advanced lung cancer. Recently, however, there have been increasing reports of surgical management of adrenal, liver, bone, and pleural metastases from primary lung cancer. Surgical resection is also indicated for a heterogeneous group of patients with multiple primary lung cancers (MPLCs). This chapter presents a guideline for addressing these special considerations in lung cancer.
MULTIPLE PRIMARY LUNG CANCERS
Patients with a history of current or previously treated lung cancer are at high risk for additional primary lung cancers because of a high prevalence of tobacco exposure. Although Bilroth and von Winiwarter2 first described MPLCs over 100 years ago, it is Beyreuther who is credited with directing attention to this subgroup of cancer patients with his 1924 report of two primary lung cancers in a tuberculosis patient. A review of the English literature from 1983 to 2002 identified MPLCs occurring in only 2.7% of more than 36,000 patients (Table 36.1). The true incidence of MPLCs has been difficult to estimate because diagnostic criteria have not been agreed upon and the staging system for lung cancer has changed multiple times in the last decade. Despite their rarity, the incidence and reports of such lesions seem to be increasing (Table 36.2). Martini and Melamed3 described diagnostic criteria for MPLC (Table 36.3).
EVALUATION AND MANAGEMENT OF SYNCHRONOUS PULMONARY TUMORS
Synchronous Primary Carcinomas of Lung Originally defined by Bilroth and von Winiwarter2 to (a) have different histologic characteristics, (b) originate from different locations, and (c) produce individual metastases, synchronous primary lung cancers are now frequently distinguished by different histologic patterns and locations—the same or different lobes. Controversy remains among investigators about the involvement of mediastinal lymph nodes as a factor in the classification of synchronous primary lung carcinomas. Many would, however, agree with Antakli et al., 4 who have suggested that tumors of the same histologic subtype only be categorized as synchronous in the absence of mediastinal nodal disease (Tables 36.4 and 36.5).
Primary Lung Carcinoma with Intrapulmonary Metastasis These tumors are similar in histology, but differ in anatomic location. Satellite nodules are metastatic lesions that occur within the same lobe as the index tumor. The American Joint Commission on Cancer (AJCC) has long defined satellite nodules as T4 (stage IIIb) disease, and ipsilateral intrapulmonary metastases as M1 disease (stage IV). However, in the absence of nodal involvement, several centers have reported that with lobar resection, patients with satellite nodules have 5-year survival of close to 60% comparable to patients with Ib or IIa disease.5,6 Meanwhile, Deslauriers et al.7 reported only a 22% 5-year survival among the 84 patients with satellite nodules. Zell et al.8 analyzed Surveillance, Epidemiology, and End Results (SEER) data and reported improved survival outcomes among patients with ipsilateral pulmonary metastases compared with other stage IV patients. The recent International Association for the Study of Lung Cancer (IASLC) proposed staging system downgrades satellite nodules to T3 disease and ipsilateral intrapulmonary metastases to T4 disease (see Chapter 30).9 This change is supported by validation studies carried out using population-based data.8,10 The role of chemotherapy either in a neoadjuvant or adjuvant setting for these patients has not been carefully studied. It is the bias of the authors of this chapter to treat patients with presumed or questionable T4 satellites with up-front chemotherapy, resection, and adjuvant therapy based on intraoperative findings.
There are little data to support surgical resection of intrapulmonary metastases from lung cancer, although some patients
anecdotally are cured after complete resection. Patients with multifocal bronchioloalveolar carcinoma (BAC) are exceptions to the poor prognosis of multifocal lung cancer. Patients with multifocal BAC who undergo complete resection can achieve 5-year survivals of upward of 60%.11,12 These patients have a high rate of intrapulmonary recurrence. Epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) have been a useful adjuvant treatment in such patients, although the optimal time course of treatment has not been well studied. Lung transplantation has been used at selected centers in patients with unresectable multifocal BAC, who have no evidence of nodal or distant metastases with promising long-term results. The largest reported series (29 patients) reported a 5-year survival of 51%, although there was tumor recurrence in 13 patients (45%).13
anecdotally are cured after complete resection. Patients with multifocal bronchioloalveolar carcinoma (BAC) are exceptions to the poor prognosis of multifocal lung cancer. Patients with multifocal BAC who undergo complete resection can achieve 5-year survivals of upward of 60%.11,12 These patients have a high rate of intrapulmonary recurrence. Epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) have been a useful adjuvant treatment in such patients, although the optimal time course of treatment has not been well studied. Lung transplantation has been used at selected centers in patients with unresectable multifocal BAC, who have no evidence of nodal or distant metastases with promising long-term results. The largest reported series (29 patients) reported a 5-year survival of 51%, although there was tumor recurrence in 13 patients (45%).13
TABLE 36.1 Incidence of Multiple Primary Lung Cancers | ||||||||||||||||||||||||||||||||||||||||||
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TABLE 36.2 Incidence of Synchronous and Metachronous Lung Cancer in Patients with Multiple Primary Tumors | ||||||||||||||||||||||||||||||||||||||||||||
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TABLE 36.3 Criteria for the Diagnosis of Multiple Primary Lung Cancers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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One Primary Carcinoma and One Benign Lesion A significant proportion of the second pulmonary nodules discovered preoperatively by Kunitoh et al.14 were found to be benign. Pathologic diagnoses included infarction, granuloma, fibrosis, and hamartoma. A thorough metastatic evaluation is indicated in patients with a known lung carcinoma and a second indeterminate parenchymal mass. Positron emission tomography (PET) and fusion computed tomography (CT)/PET scanning are useful both for staging and to estimate the probability that a lesion is benign or malignant. Once there is no proof of metastatic disease, one could either observe the second lesion or opt to obtain a tissue sample for a histologic diagnosis. In the case of an ipsilateral nodule, the assessment can be performed at the time of thoracotomy. For contralateral
lesions, CT-guided fine-needle aspiration biopsy (FNAB), video-assisted thoracoscopic surgery (VATS) wedge resection, or Wang biopsy as well as mediastinoscopy at the time of surgery may be required.
lesions, CT-guided fine-needle aspiration biopsy (FNAB), video-assisted thoracoscopic surgery (VATS) wedge resection, or Wang biopsy as well as mediastinoscopy at the time of surgery may be required.
TABLE 36.4 Modified Criteria for Multiple Primary Lung Cancers | ||||||||||||||||
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TABLE 36.5 Incidence of Synchronous Primary Lung Cancer | |||||||||||||||||||||||||||||||||
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Evaluation Specific questions must be addressed in the evaluation of two distinct lung cancers.
Does the lesion(s) represent an extrathoracic primary carcinoma with pulmonary metastases?
Are mediastinal lymph nodes involved?
In the case of a primary lung cancer, is there evidence of distant metastatic disease?
What is the histologic diagnosis of the nodule(s)?
The accuracy of a cytologic diagnosis from an FNAB ranges from 60% to 80%.15,16,17 Treatment of two lung nodules should be based on a histologic diagnosis from either a core needle or a wedge biopsy. Disseminated neoplastic disease should be assessed with CT, PET, and brain magnetic resonance imaging (MRI).
Bronchoscopy allows for evaluation of the bronchial lumen, assessing for tumor involvement, communication with the esophagus, and obstruction. McElvaney et al.18 discovered synchronous endobronchial foci of adenocarcinoma in nearly 20% of surgical patients evaluated with bronchoscopy before surgical resection—only two of which were identified preoperatively. These data support the universal requirement for bronchoscopic examination prior to proceeding with any planned surgical resection.
Mediastinoscopy has been established as an important component in the evaluation of patients with lung cancer. The use of endoscopic ultrasound (EUS) and endobronchial ultrasound (EBUS) to perform fine-needle aspiration (FNA) of mediastinal lymph nodes for staging have been increasing. EUS and EBUS offer less invasive staging of the mediastinum, but are operator dependent and result in far less tissue for analysis. Tournoy et al.19 recently reported similar diagnostic yields for EUS and mediastinoscopy, whereas Wallace et al.20 reported excellent yields when combining both EUS and EBUS. We currently employ EUS and EBUS in patients who have previously undergone mediastinoscopy, or who have other contraindications to mediastinoscopy or general anesthesia.
Treatment Surgical resection is indicated when there are two primary lung carcinomas without evidence of mediastinal lymph nodes or distant metastases—clinical stage I or II.21 Those patients with N1 disease (stage II) should be offered surgery and referred for adjuvant chemotherapy. The clinical stage of the tumors should be used to determine which lesion should be pursued initially.22,23,24,25,26 Other factors to consider before surgical resection of the second tumor are pathologic stage of the first tumor, extent of the second tumor, extent of resection required for the second tumor, and the patient’s pulmonary reserve. Also, possible benefit of systemic therapy prior to either initial resection or second resection should be considered.
In such cases where a second cancer is discovered intraoperatively in a different lobe, N2 disease should be ruled out and pulmonary function should be reviewed. In all cases, a mediastinal and hilar lymph node dissection should be performed initially with intraoperative frozen section analysis for accurate pathologic staging. Presence of N1 disease and certainly N2 would preclude pneumonectomy. Regardless of the surgical procedure chosen, the goal should always be complete resection of the tumors, as this has an evident impact on survival. If the patient has adequate respiratory reserve and no evidence of N2 disease, an anatomical resection should be pursued. If pulmonary function is insufficient, wedge resection should be considered. On the other hand, there are proponents of nonsurgical treatment in patients found to have positive hilar or mediastinal lymph nodes intraoperatively, based on a median survival of 11 months compared to 26 months in those with negative lymph nodes.24,27 Patients who do not undergo surgical resection are referred for definitive chemoradiation. In addition, ablative procedures such as radiofrequency ablation and CyberKnife should be considered.
Prognosis Stage for stage comparison, survival after resection of synchronous primary lung cancers is worse than for a solitary bronchogenic neoplasm.28 These data have led some to believe that synchronous lesions should be classified as stage IV disease.29 The lower survival rates may be explained by an overall greater probability of recurrent disease given two independent cancers, more aggressive biologic behavior, an inherent increased risk of developing a neoplastic process.25,27 The fact that the second lesion is usually treated with wedge or segmental resection—procedures associated with increased incidence of locoregional recurrence and lower survival—may also explain these poor survival results.30 Compared to other treatment methods (i.e., radiation therapy, ablative procedures, chemotherapy), surgery has still been shown to significantly prolong survival.
Metachronous Tumors The minimum duration of time, between treatment of a first primary tumor and the appearance second primary tumor, that defines metachronous tumor is considered to be 2 years.3,23,27,30,31,32,33,34,35 Multiple series
have cited a median of 48 months or longer between the treatment of the first lung tumor and the presentation of a second,23,31,32,36 whereas others report shorter time periods, between 24 and 48 months.27,33,34 Most recently, Aziz et al. reported an average tumor-free interval of 46 ± 14 months in patients with metachronous lesions; however, the 3-, 5-, and 10-year survival rates of 39%, 15%, and 2%, respectively, were no different than those in studies with a median interval of 24 months.37,38 Additionally, there is no consistent evidence relating the tumor-free interval to either the type of surgical resection or histologic cell type of the tumors.
have cited a median of 48 months or longer between the treatment of the first lung tumor and the presentation of a second,23,31,32,36 whereas others report shorter time periods, between 24 and 48 months.27,33,34 Most recently, Aziz et al. reported an average tumor-free interval of 46 ± 14 months in patients with metachronous lesions; however, the 3-, 5-, and 10-year survival rates of 39%, 15%, and 2%, respectively, were no different than those in studies with a median interval of 24 months.37,38 Additionally, there is no consistent evidence relating the tumor-free interval to either the type of surgical resection or histologic cell type of the tumors.
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