Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Carcinoma of the lung Rodney J. Landreneau MD To cite this article: Rodney J. Landreneau MD (1990) Carcinoma of the lung, Postgraduate Medicine, 87:1, 117-135, DOI: 10.1080/00325481.1990.11704526 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11704526
Published online: 17 May 2016.
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Citing articles: 1 View citing articles
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Date: 18 June 2016, At: 08:05
CME credit article
Carcinoma of the lung Who will benefit from surgery?
Rodney J. Landreneau, MD
Downloaded by [RMIT University Library] at 08:05 18 June 2016
Preview Although many people automatically think lung cancer patients are headed toward an early death, surgery can be curative for many with stage I and D disease and for some with certain types of stage InA disease. Besides the clinical stage of the disease, the extent of pulmonary resection required and the functional reserve of the patient determine whether surgical intervention should be attempted. Dr Landreneau describes staging by size, location, and changes on x-ray fUm and also discusses when adjuvant irradiation and chemotherapy should be considered to control recurrence. Carcinoma of the lung is the leading cause of cancer death in the United States, with a mortality rate of more than 80%. 1 One quarter of all cases are small-cell carcinoma, for which surgery has very limited application. 2 The remainder are non-small-cell carcinoma, for which surgery is the treatment of choice when the cancer is limited to the lung. Patients in the "gray zone" of regional lymphatic involvement may benefit from combinations of irradiation, surgery, and systemic chemotherapy. 3 •4 Surgical cure can be achieved in non-small-celllung cancer in up to 80% of cases of limited stage I involvement. 5 ·6 However, this category accounts for less than 20% of cases. Surgery may also have therapeutic benefit in patients with limited mediastinal lymph node involvement. 7· 10 Unfortunately, 50% of patients with lung cancer have extensive systemic involvement when the
disease is diagnosed (figure 1). 5 Careful preoperative and intraoperative staging is required to identify patients with limited local or regional disease who may benefit from surgery. The American Thoracic Society formulated an international staging system to improve communication and interpretation of results with various treatment regimens (table l ).U Assessment of the mediastinal lymph nodes and lungs by chest radiology and computed tomography (CT) and more invasive examination through bronchoscopy and mediastinoscopy provide important clinical staging parameters. Thorough thoracic exploration for extrapulmonary involvement and complete mediastinal node sampling are essential for accurate pathologic staging in patients undergoing surgery. Mapping of the mediastinal and hilar lymph nodes that are involved with metastatic carcinoma also helps
to establish prognosis. 12 This article focuses on the diagnostic methods and the surgical management of non-smallcell carcinoma of the lung. The algorithm in figure 2 summarizes the present management scheme used at the University of Missouri--Columbia School of Medicine.
Ev.Uuationofpotentially resectable cases Mass screening for lung cancer at an early curative stage with lung x-ray films and sputum cytologic examination has had limited value. 13 ln suspicious central pulmonary lesions, sputum cytologic examination has been beneficial in diagnosing malignancy in more than 70% of patients, 14 but it has been of little help in diagnosis of peripheral lung lesions. Metastatic spread must be excluded before resection of a presumed malignant pulmonary lesion is recommended. At the present time, the most effective initial evaluation for disseminated malignant disease consists of thorough history taking and physical examination, routine blood chemistry studies, chest radiography, and testing of urine and stool for occult blood. Occult metastases are detected by nuclear scanning in less than l% of patients who have normal baseline test results. 15 continued
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Standard posteroanterior and lateral chest x-ray films remain the most important initial evaluation for suspected malignant pulmonary lesions.
Figure 1. D1stnbutlon of cases of lung cancer by stage or extent of d1sease.
Adapted, w1th permiss1on. from Holmes.'
Standard posteroanterior and lateral chest x-ray films remain the most important initial evaluation for suspected malignant pulmonary lesions. 16 As seen on x-ray films, the size and location of the mass and the changes produced by the mass are important factors in the initial clinical staging of the malignant process. Radiologic characteristics of the pulmonary lesion can further alert the clinician to the cancer's possible cell type. Small-cell carcinoma is usually a bulky central lesion with mediastinal fullness, whereas adenocarciRodney J. Landreneau, MD Dr Landreneau IS ass1stant professor, diVISIOn of card1othorac1c surgery, department of surgery, and co-d1rector. card1ac transplant team. Un1vers1ty of M1ssoun-Columb1a School of Med1c1ne H1s academic 1nterests 1nclude management of gastroesophageal d1sease and esophageal cancer and general thorac1c oncology
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noma is usually peripheral (figure 3). Squamous cell carcinoma often appears as centrally located nodules, which can grow to considerable size and have central tumor cavitation. 17 Two thirds of lung cancers first appear as peripheral nodules of varying size, 15% to 50% of them solitary. 18 The probability of a lung nodule being malignant approximates the patient's age after the fourth decade of life. Thus, a patient aged 50 years has a 50% chance of having a malignant tumor if a new pulmonary nodule is found on chest films, whereas a person under age 30 years has less than a 1% chance of having cancer in a pulmonary nodule. The presence of calcium in a pulmonary nodule rules out malignant tumor in 90% of nodules seen on chest x-ray films.
The symptomatic status of the patient directly relates to longterm survival after surgical resection. Asymptomatic patients have a 50% chance of gaining long-term benefits from resection, but once symptoms appear this chance falls to about 20%. 19 The size of the malignant nodule at presentation also parallels prognosis. Patients with nodules less than 2 em in diameter have a 60% survival rate with resection, but the rate falls to less than 30% once the lesion has reached 7 em in diameter. 20 The location of the nodule also appears to affect the likelihood of mediastinallymph node involvement: Central tumors have a greater risk than the equivalent clinical stage of peripheral tumors. 21 cr has become a key component in evaluation of suspected malignant pulmonary tumors. A complete survey of the chest and upper abdomen should be done to identify thoracic involvement and metastasis to the liver and adrenal glands. Nodules that were not seen on chest films may be visible on cr scans and may indicate metastatic deposits from a remote primary tumor, although multiple small calcified lesions are more consistent with old granulomatous disease. 22 cr imaging has been most helpful in evaluation of mediastinallymphatic spread of malignant tumor. In healthy persons examined with cr. 90% have continued
CARCINOMA OF THE LUNG • VOL 87/I'K) 1/JANUAAY 1990/POSTGRADUATE MEDICINE
Asymptomatic patients have a 50o/o chance of gaining long-term benefits from resection of lung cancer, but once symptoms appear this chance falls to about 20o/o.
Table 1. New international staging system for lung cancer
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TNM tumor classification
Stage grouping
Primary tumor (T) TX
Tumor proven by presence of malignant cells in bronchopulmonary secretions but not visualized radiologically or bronchoscopically, or any tumor that cannot be assessed (as in retreatment staging)
TO
No evidence of primary tumor
T1s
Carc1noma in situ
T1*
Tumor that is 3 em in greatest dimension, surrounded by lung or visceral pleura, and without evidence of invasion proximal to lobar bronchus on bronchoscopy
TX, NO, MO
Occult carcinoma with bronchopulmonary secretions containing malignant cells but without other evidence of primary tumor, metastasis to regional lymph nodes, or distant metastasis
StageO Tis, NO, MO
Stage I
T1. NO. MO T2
T3
T4t
Tumor> 3 em 1n greatest diameter or of any size that either invades visceral pleura or has associated atelectasis or obstructive pneumonitis extending to hilar region. On bronchoscopy, proximal extent of demonstrable tumor must be within lobar bronchus or at least 2 em distal to carina. Any associated atelectasis or obstructive pneumonitis must involve less than entire lung Tumor of any size with direct extension into chest wall (including superior sulcus tumors), diaphragm, or mediastinal pleura or pericardium without involving heart, great vessels, trachea, esophagus, or vertebral body; or tumor in major bronchus within 2 em of carina but not Involving carina Tumor of any size with invasion of mediastinum or involving heart, great vessels, trachea, esophagus, vertebral body, or carina; or presence of malignant pleural effusion
T2, NO, MO
No demonstrable metastasis to regional lymph nodes
N1
Metastasis to lymph nodes in peribronchial or ipsilateral hilar region, or both, including direct extension
N2
Metastasis to ipsilateral mediastinal lymph nodes and subcarinal lymph nodes
N3
Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, and ipsilateral or contralateral scalene or supraclavicular lymph nodes
Tumor that can be classified as T1 or T2 without any metastasis to nodes or distant metastasis
Stage II T1,N1,MO T2, N1. MO
Any tumor classified as T1 or T2 with metastasis to lymph nodes in peribronchial or ipsilateral hilar region only
Stage lilA T3, NO. MO T3, N1, MO T1, N2, MO T2, N2, MO T3, N2, MO
Nodal involvement (N) NO
Carcinoma in situ
Tumor that can be classified as T3 without nodal metastasis or with metastasis limited to peribronchial, ipsilateral hilar, and ipsilateral mediastinal lymph nodes. T1 and T2 tumors that have metastasized to level of ipsilateral mediastinal lymph nodes only are included
Stage 1118
Distant metastasis (M) MO M1
AnyT, N3, MO orT4, any N, MO
Tumor more extensive than T3; or any tumor with supraclavicular or contralateral medastinal lymph node involvement; or any tumor with malignant pleural effusion but without evidence of distant metastasis
Stage IV Any T, any N, M1
Any tumor with distant metastatic spread
No (known) distant metastasis Distant metastasis present. Specify site(s)
·uncommon superficial tumor of any size with invasive component limited to bronchial wall (may extend proximal to major bronchus) is classified as T1. tMost pleural effusions associated with lung cancer are due to tumor. In the few instances in which they are not, tumor should be staged as T1, T2, or T3, excluding effusion as a staging element. Adapted, with permission, from Mountain." VOL 87/NO 1/JANUARY 1990/POSTGRADUATE MEDICINE • CARCINOMA OF THE LUNG
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Malignant tumors of the upper lobe of the left lung have a predilection for spread to the aorticopulmonary window nodes.
Figure 2. Algorithm for management of non-small-cell carcinoma of lung.
mediastinal lymph nodes less than 10 mm in diameter. When lymph nodes are more than 20 mm in diameter, the likelihood of malignant mediastinal involvement is great. Physicians must confirm the presence of a malignant tumor histopathologically, because reactive nodes of this size are not uncommon when obstructive pneumonitis has been present. 23•24 Nuclear magnetic resonance imaging can also effectively depict mediastinal lymph node enlargement and should be used in patients who are allergic to the intravenous contrast agents used in cr. 25 At least 20% of patients with clinically limited lung cancer have mediastinal lymph node involvement, 26 and 18% have contralateral mediastinal spread. 21 The lobar pattern of lymphatic metastasis from eacp. lung is shown in figure 4. Insight into the pattern of spread is particularly important for malignant tumors of the upper lobe of the left lung, which have a predilection for spread to the aorticopulmonary window nodes, because access to this nodal station requires left anterior mediastinotomy for evaluation rather than a cervical approach. 27 We screen all patients who have lymph nodes larger than 15 mm in diameter (as determined by CT) with mediastinoscopy (figure 5). This approach has reduced the number of uncontinued on page 125
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Percutaneous aspiration biopsy should be considered for diagnosis of a pulmonary nodule in a patient who is physiologically unfit for surgery.
necessary thoracotomies and incomplete tumor resections to less than 20% while maintaining the potential for surgical extirpation of regional disease in the greatest number of patients. Patients with limited intranodal metastasis of squamous cell carcinoma found on mediastinoscopy may benefit from pulmonary resection and mediastinal lymphadenectomy, but in general, the presence of positive nodes on mediastinoscopy precludes surgical cure. 7·28 Bronchoscopic biopsy can successfully diagnose 90% of centrally located malignant lesions, but diagnostic accuracy falls significantly with small peripheral lesions. 29 Transbronchial aspiration biopsy has improved the diagnostic yield for peripheral pulmonary lesions. Transcartnal biopsy may detect malignant involvement of enlarged subcartnal nodes, thus avoiding the need for mediastinoscopy. 30 Thoracic surgeons should do bronchoscopy before thoracotomy to assess the extent of the malignant process and to ensure that an adequate bronchial margin can be obtained after resection. Percutaneous aspiration biopsy should be considered for diagnosis of a pulmonary nodule in a patient who is physiologically unfit for surgery. This technique is also useful for evaluation of metastasis to the liver, adrenal
Figure 3. Radiographic location of different lung cancer cell types. Adapted, with permission, from Jaubert and Ouimet-Brender"
glands, or kidneys seen on cr. Diagnosis can be made in up to 90% of cases, but complications from this technique are not uncommon. Patients who are candidates for curative resection obtain questionable benefit with
the addition of this procedure to the preoperative workup. 31 A thorough assessment of the patient's functional and cardiopulmonary reserve is essential before surgical exploration is done. 32 Recent myocardial infarccontinued
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Surgical resection of stage I and II carcinoma of the lung is generally considered to be potentially curative and is, in fact, the most effective treatment.
a Figure 4. Lobar pattern of lymphatic metastasis from right (a) and left (b) lungs.
tion or the presence of unstable angina pectoris may preclude immediate surgical treatment. An assessment of preoperative pulmonary function is also important in determining the risk of thoracotomy (table 2). When the calculated postresectional forced expiratory volume in 1 second is less than 800 ml, thoracotomy and resection should be approached cautiously. The patient should be encouraged to stop smoking and to institute a vigorous program of pulmonary hygiene before surgery to reduce the risk of pulmonary complications. Surgical therapy The goal of surgery in the management of lung cancer is to remove the primary tumor and all involved pulmonary and lym126
phatic tissue without sacrificing uninvolved lung. Determinants of surgical intervention are the clinical stage of the malignant tumor, the extent of pulmonary resection required, and the functional reserve of the patient. The "natrnal" 5-year survival rate for severe chronic obstructive pulmonary disease is about 30% and must be included in estimattng the benefits from surgery for such patients. 33 The probability of natrnal death in a particular age-group must also be considered in an elderly patient. 34 Less extensive resection should be considered when treating the elderly. even though the chance of local recurrence may be somewhat higher than after lobar resection or pneumonectomy. 35 Surgical resection of stage I
and II disease is generally considered to be potentially curative and is, in fact, the most effective treatment. Patients with limited mediastinal lymph node involvement can expect a 5-year survival rate of nearly 30% with complete surgical resection (figure 6). The survival benefit of surgical resection of stage IliA disease is minimal when subcarinal nodes and multiple nodal stations are positive or extracapsular nodes are involved. 7 However, surgery benefits patients with chest-wall involvement (stage mdisease) if mediastinal lymph node metastasis has not occurred, as well as patients with the "superior sulcus·· variety of stage mdisease. 36 If malignant mediastinal lymph node involvement is present, the benefit of surgical resection is minimal. 37 Careful and complete mediastinal lymph node dissection with pulmonary resection is essential to estimate the patient's prognosis (figure 7) and the need for adjuvant therapy. 11 Lobectomy is the standard resection for most primary malignant pulmonary tumors, because it affords satisfactory control of regional disease and longterm survival (equivalent to that achieved with pneumonectomy). Pneumonectomy is rarely appropriate without a diagnosis of malignant tumor before resection unless the lung has been totally destroyed by the pathologic process. Removal of the entire lung
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Palliative resection of lung carcinoma and debulking of the tumor are not beneficial therapeutic options at present. Laser bronchoscopy or radiation therapy offers more successful palliation.
a Figure 5. Transcervical mediastinoscopy. a. 3-cm transverse suprasternal incision made and dissection carried out through pretracheal fascia to peritracheal plane. b. Mediastinoscope introduced into peritracheal tissue through cervical incision. Biopsy of mediastinal nodes then carried out.
Adapted, with permission, from Wadhausen JA, Pierce WS. Transcervical mediastinoscopy. In: Waldhausen JA, Pierce WS, eds. Johnson's surgery of the chest. 5th ed. Chicago: Year Book Medical Publishers, 1985.37
should be lim1ted to patients with significant peribronchial lymph node involvement and those with a central twnor that cannot be otherwise resected. 38 Pnewnonectomy should be restricted to patients with sufficient pulmonary reserve to withstand such extensive resection. Cell type is also an Important factor in determln1ng the extent of resection required. Pnewnonectomy Is rarely indicated in treatment of adenocarcinoma, 28 because adenocarcinoma Is usually peripheral and systemic Involvement has usually occurred by the time It has reached a size that warrants pnewnonec-
tomy. Survival is not enhanced by pneumonectomy, and the risk of perioperative morbidity or mortality is significantly increased. In contrast. squamous cell carcinoma is more llkely to occur centrally and to undergo systemic spread later. 39 Pnewnonectomy can play a role in the management of central squamous cell lesions 1f the patient can tolerate the resection. Pall1ative resection of lung carcinoma and debulking of the twnor are not beneficial therapeutic options at present (table 3). Incomplete resection offers no survival benefit to the patient, reduces pulmonary reserve, and
VOL 87/NO 1/JANUARY 1990/POSTGRADUATE MEDICINE • CARCINOMA OF THE LUNG
subjects the patient to potential complications. 1•7 Laser bronchoscopy or radiation therapy offers more successful pall1ation. 40 Operative mortality rate is directly related to the patient's age and physiologic reserve and the extent of pulmonary resection required. Lobectomy and lesser resections carry less than a 3% operative risk: pnewnonectomy has at least twice this amount. Postoperative complications involving the cardiorespiratory system (most commonly cardiac arrhythmia and pnewnonta) occur in about 10% of patients. Bleeding, empyema, and bronchopleural fistula occur less often continued 127
Most investigators note perioperative complications of irradiation for lung cancer and are unconvinced of any survival benefit to the patient.
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Table 2. Interpretation of spirometry in relation to operative risk High risk
Moderate risk
Low risk
Vital capacity
< 185 L
1.85-3.0 L
>3.0 L
Forced vital capacity in first second
< 12 L
1.2-3.0 L
>3.0L
Maximum voluntary ventilation
< 28 L/min
> 30 < 80 L/min
> 80 Ljmin
Maximum midexpiratory flow
< 1 Lfsec
> 10 < 2.0 L/sec
> 2.0 Ljsec
Adapted, with permission, from Peters RM. Identification. assessment and management of surgical patients with chronic respiratory disease. In: Greenfield LJ, ed. Problems in general surgery. Vol 1, No. 1. Philadelphia: JB Lippincott. 1984:432-44.
but are significant problems that can occur after pulmonary resection.41 Neoadjuvant and adjuvant therapy Adjuvant irradiation and chemotherapy are aimed at controlling microscopic residual local disease and subclinical systemic metastasis .. About half of patients with surgically treated disease have systemic spread at the time of resection. Whether to prescribe adjuvant treatment would not be a problem if more effective and less toxic systemic agents were available to treat non-small-cell lung cancer. Present therapy targets patients with the greatest probability of significant postsurgical local and systemic recurrence. Despite its imprecision, the present staging system is the best means of identifying pa-
tients who may benefit from adjuvant therapy. RADIATION THERAPY-This adjunctive method may be of benefit in controlling microscopic local residual disease. Preoperative irradiation is controversial. Most investigators note perioperative complications and are unconvinced of any survival benefit to the patient. 42 An exception may be perioperative irradiation for superior sulcus tumors, which may provide some survival benefit. 36 Postoperative irradiation for stage II and msquamous cell carcinoma has been found to provide a modest improvement in local control but no survival advantage over surgical resection alone. 43 CHEMOTHERAPY-Early expe-
rience with single-agent adjuvant treatment was very discouraging. Present chemotherapeutic agents
have been relatively ineffective and significantly toxic when used singly for non-small-celllung cancer, but combination protocols have achieved a synergistic effect between moderately useful agents. Combination regimens using cisplatln (Platlnol) have been the most beneficial in the treatment of patients with unresectable regional disease. 44 The Lung Cancer Study Group 45 found some survival benefit among patients with stage II and madenocarcinoma treated with a postoperative regimen of cyclophosphamide (Cytoxan, Neosar), doxorubicin hydrochloride (Adriamycin), and cisplatin. Ferguson and associates 23 also found a survival benefit with postoperative chemotherapy for stage II carcinoma. The patient's functional status and degree of initial response to the chemotherapeutic agents are major determinants of success with these regimens. COMBINATION THERAPY-
Combining surgery, chemotherapy, and irradiation may enhance the control of advanced regional disease. Taylor and associates46 found that among patients with locally advanced lung cancer treated with preoperative irradiation, cisplatin, and fluorouracil (Adrucil), with or without mitomycin (Mutamycin), nearly half had minimal evidence of residual disease at surgical resection. Survival among the surgically treated group was twice that of continued
128
CARCINOMA OF THE LUNG • VOL 87/t¥::! 1/JANUARY 1990/POSTGRAOUATE MEDICINE
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Combining surgery, chemotherapy, and radiation therapy may enhance the control of advanced regional lung cancer.
Figure 6. Stages I, II, and IliA non·small-celllung cancer are potentially resectable; surgery is not indicated for stage IIIB. Stage I T1 (A) or T2 (B) tumor without lymph node metastasis. Stage II: T1 or T2 (A and B) tumor with lymph node involvement limited to peribronchial or hilar location. Stage IliA: any tumor (A and B) not involving mediastinum with ipsilateral mediastinal lymph node involvement (C). Stage IIIB any tumor with bilateral mediastinal lymph node involvement.
patients treated with only irradiation and chemotherapy. The results of other active and proposed neoadjuvant protocols should shed further light on the role of combination therapy. ~OTHERAPY--Effective
immunotherapy for cancer of the lung is in an investigative stage, but experimental data suggest that it w1ll be an important area of future therapeutic manipulation. 47 Early trials have not shown benefit with the use of nonspecific immunostimulants, but work with lymphokines and stimulated subsets of the lymphocyte population holds promise for future specific immunotherapy for lung cancer. 45·48 Cballenges for the future Several questions about surgical treatment of lung cancer remain.
Significant problems exist in deciding which lung cancer patients w1ll benefit from surgical treatment and which should have adjuvant therapy. The greatest challenge involves patients with stage II and IliA disease, in which nodal metastasis has occurred. Some w1ll benefit from complete surgical resection; the majority are more likely to eventually succumb to the disease. Subsets of patients with stage I involvement and with advanced disease are equally perplexing. Physicians sometimes assume, incorrectly, that the first group w1ll be cured and the second w1ll die early. As in cancer of the breast, at least 20% of stage I lung cancer patients die of systemic spread and 2% to 3% with advanced malignancy have prolonged survival. 49
The immunocompetence of the patient and the cellular interface with the malignant tissue have been shown to be as important for survival as is "total" surgical removal of gross disease. Nearly from the start of the neoplastic process, cancer cells are permeating the patient's circulation. 50 Further study is needed for clues to the patient's immune function and the neoplastic tissue that will predict surgical cure or the need to treat the cancer systemically. Whether a broader application of adjuvant therapy would benefit significant numbers of patients is uncertain. It ts certain that patients who could be cured by surgery alone would have unnecessary morbidity and that patients whose tumor is resistant to present adjuvant treatment methods would have a substancontinued
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The immunocompetence of the patient and the cellular interface with the malignant tissue have been shown to be as important for survival in patients with lung cancer as is "total" surgical removal of gross disease.
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Figure 7. Survival by stage for non-small-cell carcinoma of lung.
P
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Carcinoma of the lung Rodney J. Landreneau MD To cite this article: Rodney J. Landreneau MD (1990) Carcinoma of the lung, Postgraduate Medicine, 87:1, 117-135, DOI: 10.1080/00325481.1990.11704526 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11704526
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [RMIT University Library]
Date: 18 June 2016, At: 08:05
CME credit article
Carcinoma of the lung Who will benefit from surgery?
Rodney J. Landreneau, MD
Downloaded by [RMIT University Library] at 08:05 18 June 2016
Preview Although many people automatically think lung cancer patients are headed toward an early death, surgery can be curative for many with stage I and D disease and for some with certain types of stage InA disease. Besides the clinical stage of the disease, the extent of pulmonary resection required and the functional reserve of the patient determine whether surgical intervention should be attempted. Dr Landreneau describes staging by size, location, and changes on x-ray fUm and also discusses when adjuvant irradiation and chemotherapy should be considered to control recurrence. Carcinoma of the lung is the leading cause of cancer death in the United States, with a mortality rate of more than 80%. 1 One quarter of all cases are small-cell carcinoma, for which surgery has very limited application. 2 The remainder are non-small-cell carcinoma, for which surgery is the treatment of choice when the cancer is limited to the lung. Patients in the "gray zone" of regional lymphatic involvement may benefit from combinations of irradiation, surgery, and systemic chemotherapy. 3 •4 Surgical cure can be achieved in non-small-celllung cancer in up to 80% of cases of limited stage I involvement. 5 ·6 However, this category accounts for less than 20% of cases. Surgery may also have therapeutic benefit in patients with limited mediastinal lymph node involvement. 7· 10 Unfortunately, 50% of patients with lung cancer have extensive systemic involvement when the
disease is diagnosed (figure 1). 5 Careful preoperative and intraoperative staging is required to identify patients with limited local or regional disease who may benefit from surgery. The American Thoracic Society formulated an international staging system to improve communication and interpretation of results with various treatment regimens (table l ).U Assessment of the mediastinal lymph nodes and lungs by chest radiology and computed tomography (CT) and more invasive examination through bronchoscopy and mediastinoscopy provide important clinical staging parameters. Thorough thoracic exploration for extrapulmonary involvement and complete mediastinal node sampling are essential for accurate pathologic staging in patients undergoing surgery. Mapping of the mediastinal and hilar lymph nodes that are involved with metastatic carcinoma also helps
to establish prognosis. 12 This article focuses on the diagnostic methods and the surgical management of non-smallcell carcinoma of the lung. The algorithm in figure 2 summarizes the present management scheme used at the University of Missouri--Columbia School of Medicine.
Ev.Uuationofpotentially resectable cases Mass screening for lung cancer at an early curative stage with lung x-ray films and sputum cytologic examination has had limited value. 13 ln suspicious central pulmonary lesions, sputum cytologic examination has been beneficial in diagnosing malignancy in more than 70% of patients, 14 but it has been of little help in diagnosis of peripheral lung lesions. Metastatic spread must be excluded before resection of a presumed malignant pulmonary lesion is recommended. At the present time, the most effective initial evaluation for disseminated malignant disease consists of thorough history taking and physical examination, routine blood chemistry studies, chest radiography, and testing of urine and stool for occult blood. Occult metastases are detected by nuclear scanning in less than l% of patients who have normal baseline test results. 15 continued
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Standard posteroanterior and lateral chest x-ray films remain the most important initial evaluation for suspected malignant pulmonary lesions.
Figure 1. D1stnbutlon of cases of lung cancer by stage or extent of d1sease.
Adapted, w1th permiss1on. from Holmes.'
Standard posteroanterior and lateral chest x-ray films remain the most important initial evaluation for suspected malignant pulmonary lesions. 16 As seen on x-ray films, the size and location of the mass and the changes produced by the mass are important factors in the initial clinical staging of the malignant process. Radiologic characteristics of the pulmonary lesion can further alert the clinician to the cancer's possible cell type. Small-cell carcinoma is usually a bulky central lesion with mediastinal fullness, whereas adenocarciRodney J. Landreneau, MD Dr Landreneau IS ass1stant professor, diVISIOn of card1othorac1c surgery, department of surgery, and co-d1rector. card1ac transplant team. Un1vers1ty of M1ssoun-Columb1a School of Med1c1ne H1s academic 1nterests 1nclude management of gastroesophageal d1sease and esophageal cancer and general thorac1c oncology
118
noma is usually peripheral (figure 3). Squamous cell carcinoma often appears as centrally located nodules, which can grow to considerable size and have central tumor cavitation. 17 Two thirds of lung cancers first appear as peripheral nodules of varying size, 15% to 50% of them solitary. 18 The probability of a lung nodule being malignant approximates the patient's age after the fourth decade of life. Thus, a patient aged 50 years has a 50% chance of having a malignant tumor if a new pulmonary nodule is found on chest films, whereas a person under age 30 years has less than a 1% chance of having cancer in a pulmonary nodule. The presence of calcium in a pulmonary nodule rules out malignant tumor in 90% of nodules seen on chest x-ray films.
The symptomatic status of the patient directly relates to longterm survival after surgical resection. Asymptomatic patients have a 50% chance of gaining long-term benefits from resection, but once symptoms appear this chance falls to about 20%. 19 The size of the malignant nodule at presentation also parallels prognosis. Patients with nodules less than 2 em in diameter have a 60% survival rate with resection, but the rate falls to less than 30% once the lesion has reached 7 em in diameter. 20 The location of the nodule also appears to affect the likelihood of mediastinallymph node involvement: Central tumors have a greater risk than the equivalent clinical stage of peripheral tumors. 21 cr has become a key component in evaluation of suspected malignant pulmonary tumors. A complete survey of the chest and upper abdomen should be done to identify thoracic involvement and metastasis to the liver and adrenal glands. Nodules that were not seen on chest films may be visible on cr scans and may indicate metastatic deposits from a remote primary tumor, although multiple small calcified lesions are more consistent with old granulomatous disease. 22 cr imaging has been most helpful in evaluation of mediastinallymphatic spread of malignant tumor. In healthy persons examined with cr. 90% have continued
CARCINOMA OF THE LUNG • VOL 87/I'K) 1/JANUAAY 1990/POSTGRADUATE MEDICINE
Asymptomatic patients have a 50o/o chance of gaining long-term benefits from resection of lung cancer, but once symptoms appear this chance falls to about 20o/o.
Table 1. New international staging system for lung cancer
Downloaded by [RMIT University Library] at 08:05 18 June 2016
TNM tumor classification
Stage grouping
Primary tumor (T) TX
Tumor proven by presence of malignant cells in bronchopulmonary secretions but not visualized radiologically or bronchoscopically, or any tumor that cannot be assessed (as in retreatment staging)
TO
No evidence of primary tumor
T1s
Carc1noma in situ
T1*
Tumor that is 3 em in greatest dimension, surrounded by lung or visceral pleura, and without evidence of invasion proximal to lobar bronchus on bronchoscopy
TX, NO, MO
Occult carcinoma with bronchopulmonary secretions containing malignant cells but without other evidence of primary tumor, metastasis to regional lymph nodes, or distant metastasis
StageO Tis, NO, MO
Stage I
T1. NO. MO T2
T3
T4t
Tumor> 3 em 1n greatest diameter or of any size that either invades visceral pleura or has associated atelectasis or obstructive pneumonitis extending to hilar region. On bronchoscopy, proximal extent of demonstrable tumor must be within lobar bronchus or at least 2 em distal to carina. Any associated atelectasis or obstructive pneumonitis must involve less than entire lung Tumor of any size with direct extension into chest wall (including superior sulcus tumors), diaphragm, or mediastinal pleura or pericardium without involving heart, great vessels, trachea, esophagus, or vertebral body; or tumor in major bronchus within 2 em of carina but not Involving carina Tumor of any size with invasion of mediastinum or involving heart, great vessels, trachea, esophagus, vertebral body, or carina; or presence of malignant pleural effusion
T2, NO, MO
No demonstrable metastasis to regional lymph nodes
N1
Metastasis to lymph nodes in peribronchial or ipsilateral hilar region, or both, including direct extension
N2
Metastasis to ipsilateral mediastinal lymph nodes and subcarinal lymph nodes
N3
Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, and ipsilateral or contralateral scalene or supraclavicular lymph nodes
Tumor that can be classified as T1 or T2 without any metastasis to nodes or distant metastasis
Stage II T1,N1,MO T2, N1. MO
Any tumor classified as T1 or T2 with metastasis to lymph nodes in peribronchial or ipsilateral hilar region only
Stage lilA T3, NO. MO T3, N1, MO T1, N2, MO T2, N2, MO T3, N2, MO
Nodal involvement (N) NO
Carcinoma in situ
Tumor that can be classified as T3 without nodal metastasis or with metastasis limited to peribronchial, ipsilateral hilar, and ipsilateral mediastinal lymph nodes. T1 and T2 tumors that have metastasized to level of ipsilateral mediastinal lymph nodes only are included
Stage 1118
Distant metastasis (M) MO M1
AnyT, N3, MO orT4, any N, MO
Tumor more extensive than T3; or any tumor with supraclavicular or contralateral medastinal lymph node involvement; or any tumor with malignant pleural effusion but without evidence of distant metastasis
Stage IV Any T, any N, M1
Any tumor with distant metastatic spread
No (known) distant metastasis Distant metastasis present. Specify site(s)
·uncommon superficial tumor of any size with invasive component limited to bronchial wall (may extend proximal to major bronchus) is classified as T1. tMost pleural effusions associated with lung cancer are due to tumor. In the few instances in which they are not, tumor should be staged as T1, T2, or T3, excluding effusion as a staging element. Adapted, with permission, from Mountain." VOL 87/NO 1/JANUARY 1990/POSTGRADUATE MEDICINE • CARCINOMA OF THE LUNG
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Malignant tumors of the upper lobe of the left lung have a predilection for spread to the aorticopulmonary window nodes.
Figure 2. Algorithm for management of non-small-cell carcinoma of lung.
mediastinal lymph nodes less than 10 mm in diameter. When lymph nodes are more than 20 mm in diameter, the likelihood of malignant mediastinal involvement is great. Physicians must confirm the presence of a malignant tumor histopathologically, because reactive nodes of this size are not uncommon when obstructive pneumonitis has been present. 23•24 Nuclear magnetic resonance imaging can also effectively depict mediastinal lymph node enlargement and should be used in patients who are allergic to the intravenous contrast agents used in cr. 25 At least 20% of patients with clinically limited lung cancer have mediastinal lymph node involvement, 26 and 18% have contralateral mediastinal spread. 21 The lobar pattern of lymphatic metastasis from eacp. lung is shown in figure 4. Insight into the pattern of spread is particularly important for malignant tumors of the upper lobe of the left lung, which have a predilection for spread to the aorticopulmonary window nodes, because access to this nodal station requires left anterior mediastinotomy for evaluation rather than a cervical approach. 27 We screen all patients who have lymph nodes larger than 15 mm in diameter (as determined by CT) with mediastinoscopy (figure 5). This approach has reduced the number of uncontinued on page 125
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Percutaneous aspiration biopsy should be considered for diagnosis of a pulmonary nodule in a patient who is physiologically unfit for surgery.
necessary thoracotomies and incomplete tumor resections to less than 20% while maintaining the potential for surgical extirpation of regional disease in the greatest number of patients. Patients with limited intranodal metastasis of squamous cell carcinoma found on mediastinoscopy may benefit from pulmonary resection and mediastinal lymphadenectomy, but in general, the presence of positive nodes on mediastinoscopy precludes surgical cure. 7·28 Bronchoscopic biopsy can successfully diagnose 90% of centrally located malignant lesions, but diagnostic accuracy falls significantly with small peripheral lesions. 29 Transbronchial aspiration biopsy has improved the diagnostic yield for peripheral pulmonary lesions. Transcartnal biopsy may detect malignant involvement of enlarged subcartnal nodes, thus avoiding the need for mediastinoscopy. 30 Thoracic surgeons should do bronchoscopy before thoracotomy to assess the extent of the malignant process and to ensure that an adequate bronchial margin can be obtained after resection. Percutaneous aspiration biopsy should be considered for diagnosis of a pulmonary nodule in a patient who is physiologically unfit for surgery. This technique is also useful for evaluation of metastasis to the liver, adrenal
Figure 3. Radiographic location of different lung cancer cell types. Adapted, with permission, from Jaubert and Ouimet-Brender"
glands, or kidneys seen on cr. Diagnosis can be made in up to 90% of cases, but complications from this technique are not uncommon. Patients who are candidates for curative resection obtain questionable benefit with
the addition of this procedure to the preoperative workup. 31 A thorough assessment of the patient's functional and cardiopulmonary reserve is essential before surgical exploration is done. 32 Recent myocardial infarccontinued
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Surgical resection of stage I and II carcinoma of the lung is generally considered to be potentially curative and is, in fact, the most effective treatment.
a Figure 4. Lobar pattern of lymphatic metastasis from right (a) and left (b) lungs.
tion or the presence of unstable angina pectoris may preclude immediate surgical treatment. An assessment of preoperative pulmonary function is also important in determining the risk of thoracotomy (table 2). When the calculated postresectional forced expiratory volume in 1 second is less than 800 ml, thoracotomy and resection should be approached cautiously. The patient should be encouraged to stop smoking and to institute a vigorous program of pulmonary hygiene before surgery to reduce the risk of pulmonary complications. Surgical therapy The goal of surgery in the management of lung cancer is to remove the primary tumor and all involved pulmonary and lym126
phatic tissue without sacrificing uninvolved lung. Determinants of surgical intervention are the clinical stage of the malignant tumor, the extent of pulmonary resection required, and the functional reserve of the patient. The "natrnal" 5-year survival rate for severe chronic obstructive pulmonary disease is about 30% and must be included in estimattng the benefits from surgery for such patients. 33 The probability of natrnal death in a particular age-group must also be considered in an elderly patient. 34 Less extensive resection should be considered when treating the elderly. even though the chance of local recurrence may be somewhat higher than after lobar resection or pneumonectomy. 35 Surgical resection of stage I
and II disease is generally considered to be potentially curative and is, in fact, the most effective treatment. Patients with limited mediastinal lymph node involvement can expect a 5-year survival rate of nearly 30% with complete surgical resection (figure 6). The survival benefit of surgical resection of stage IliA disease is minimal when subcarinal nodes and multiple nodal stations are positive or extracapsular nodes are involved. 7 However, surgery benefits patients with chest-wall involvement (stage mdisease) if mediastinal lymph node metastasis has not occurred, as well as patients with the "superior sulcus·· variety of stage mdisease. 36 If malignant mediastinal lymph node involvement is present, the benefit of surgical resection is minimal. 37 Careful and complete mediastinal lymph node dissection with pulmonary resection is essential to estimate the patient's prognosis (figure 7) and the need for adjuvant therapy. 11 Lobectomy is the standard resection for most primary malignant pulmonary tumors, because it affords satisfactory control of regional disease and longterm survival (equivalent to that achieved with pneumonectomy). Pneumonectomy is rarely appropriate without a diagnosis of malignant tumor before resection unless the lung has been totally destroyed by the pathologic process. Removal of the entire lung
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Palliative resection of lung carcinoma and debulking of the tumor are not beneficial therapeutic options at present. Laser bronchoscopy or radiation therapy offers more successful palliation.
a Figure 5. Transcervical mediastinoscopy. a. 3-cm transverse suprasternal incision made and dissection carried out through pretracheal fascia to peritracheal plane. b. Mediastinoscope introduced into peritracheal tissue through cervical incision. Biopsy of mediastinal nodes then carried out.
Adapted, with permission, from Wadhausen JA, Pierce WS. Transcervical mediastinoscopy. In: Waldhausen JA, Pierce WS, eds. Johnson's surgery of the chest. 5th ed. Chicago: Year Book Medical Publishers, 1985.37
should be lim1ted to patients with significant peribronchial lymph node involvement and those with a central twnor that cannot be otherwise resected. 38 Pnewnonectomy should be restricted to patients with sufficient pulmonary reserve to withstand such extensive resection. Cell type is also an Important factor in determln1ng the extent of resection required. Pnewnonectomy Is rarely indicated in treatment of adenocarcinoma, 28 because adenocarcinoma Is usually peripheral and systemic Involvement has usually occurred by the time It has reached a size that warrants pnewnonec-
tomy. Survival is not enhanced by pneumonectomy, and the risk of perioperative morbidity or mortality is significantly increased. In contrast. squamous cell carcinoma is more llkely to occur centrally and to undergo systemic spread later. 39 Pnewnonectomy can play a role in the management of central squamous cell lesions 1f the patient can tolerate the resection. Pall1ative resection of lung carcinoma and debulking of the twnor are not beneficial therapeutic options at present (table 3). Incomplete resection offers no survival benefit to the patient, reduces pulmonary reserve, and
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subjects the patient to potential complications. 1•7 Laser bronchoscopy or radiation therapy offers more successful pall1ation. 40 Operative mortality rate is directly related to the patient's age and physiologic reserve and the extent of pulmonary resection required. Lobectomy and lesser resections carry less than a 3% operative risk: pnewnonectomy has at least twice this amount. Postoperative complications involving the cardiorespiratory system (most commonly cardiac arrhythmia and pnewnonta) occur in about 10% of patients. Bleeding, empyema, and bronchopleural fistula occur less often continued 127
Most investigators note perioperative complications of irradiation for lung cancer and are unconvinced of any survival benefit to the patient.
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Table 2. Interpretation of spirometry in relation to operative risk High risk
Moderate risk
Low risk
Vital capacity
< 185 L
1.85-3.0 L
>3.0 L
Forced vital capacity in first second
< 12 L
1.2-3.0 L
>3.0L
Maximum voluntary ventilation
< 28 L/min
> 30 < 80 L/min
> 80 Ljmin
Maximum midexpiratory flow
< 1 Lfsec
> 10 < 2.0 L/sec
> 2.0 Ljsec
Adapted, with permission, from Peters RM. Identification. assessment and management of surgical patients with chronic respiratory disease. In: Greenfield LJ, ed. Problems in general surgery. Vol 1, No. 1. Philadelphia: JB Lippincott. 1984:432-44.
but are significant problems that can occur after pulmonary resection.41 Neoadjuvant and adjuvant therapy Adjuvant irradiation and chemotherapy are aimed at controlling microscopic residual local disease and subclinical systemic metastasis .. About half of patients with surgically treated disease have systemic spread at the time of resection. Whether to prescribe adjuvant treatment would not be a problem if more effective and less toxic systemic agents were available to treat non-small-cell lung cancer. Present therapy targets patients with the greatest probability of significant postsurgical local and systemic recurrence. Despite its imprecision, the present staging system is the best means of identifying pa-
tients who may benefit from adjuvant therapy. RADIATION THERAPY-This adjunctive method may be of benefit in controlling microscopic local residual disease. Preoperative irradiation is controversial. Most investigators note perioperative complications and are unconvinced of any survival benefit to the patient. 42 An exception may be perioperative irradiation for superior sulcus tumors, which may provide some survival benefit. 36 Postoperative irradiation for stage II and msquamous cell carcinoma has been found to provide a modest improvement in local control but no survival advantage over surgical resection alone. 43 CHEMOTHERAPY-Early expe-
rience with single-agent adjuvant treatment was very discouraging. Present chemotherapeutic agents
have been relatively ineffective and significantly toxic when used singly for non-small-celllung cancer, but combination protocols have achieved a synergistic effect between moderately useful agents. Combination regimens using cisplatln (Platlnol) have been the most beneficial in the treatment of patients with unresectable regional disease. 44 The Lung Cancer Study Group 45 found some survival benefit among patients with stage II and madenocarcinoma treated with a postoperative regimen of cyclophosphamide (Cytoxan, Neosar), doxorubicin hydrochloride (Adriamycin), and cisplatin. Ferguson and associates 23 also found a survival benefit with postoperative chemotherapy for stage II carcinoma. The patient's functional status and degree of initial response to the chemotherapeutic agents are major determinants of success with these regimens. COMBINATION THERAPY-
Combining surgery, chemotherapy, and irradiation may enhance the control of advanced regional disease. Taylor and associates46 found that among patients with locally advanced lung cancer treated with preoperative irradiation, cisplatin, and fluorouracil (Adrucil), with or without mitomycin (Mutamycin), nearly half had minimal evidence of residual disease at surgical resection. Survival among the surgically treated group was twice that of continued
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Combining surgery, chemotherapy, and radiation therapy may enhance the control of advanced regional lung cancer.
Figure 6. Stages I, II, and IliA non·small-celllung cancer are potentially resectable; surgery is not indicated for stage IIIB. Stage I T1 (A) or T2 (B) tumor without lymph node metastasis. Stage II: T1 or T2 (A and B) tumor with lymph node involvement limited to peribronchial or hilar location. Stage IliA: any tumor (A and B) not involving mediastinum with ipsilateral mediastinal lymph node involvement (C). Stage IIIB any tumor with bilateral mediastinal lymph node involvement.
patients treated with only irradiation and chemotherapy. The results of other active and proposed neoadjuvant protocols should shed further light on the role of combination therapy. ~OTHERAPY--Effective
immunotherapy for cancer of the lung is in an investigative stage, but experimental data suggest that it w1ll be an important area of future therapeutic manipulation. 47 Early trials have not shown benefit with the use of nonspecific immunostimulants, but work with lymphokines and stimulated subsets of the lymphocyte population holds promise for future specific immunotherapy for lung cancer. 45·48 Cballenges for the future Several questions about surgical treatment of lung cancer remain.
Significant problems exist in deciding which lung cancer patients w1ll benefit from surgical treatment and which should have adjuvant therapy. The greatest challenge involves patients with stage II and IliA disease, in which nodal metastasis has occurred. Some w1ll benefit from complete surgical resection; the majority are more likely to eventually succumb to the disease. Subsets of patients with stage I involvement and with advanced disease are equally perplexing. Physicians sometimes assume, incorrectly, that the first group w1ll be cured and the second w1ll die early. As in cancer of the breast, at least 20% of stage I lung cancer patients die of systemic spread and 2% to 3% with advanced malignancy have prolonged survival. 49
The immunocompetence of the patient and the cellular interface with the malignant tissue have been shown to be as important for survival as is "total" surgical removal of gross disease. Nearly from the start of the neoplastic process, cancer cells are permeating the patient's circulation. 50 Further study is needed for clues to the patient's immune function and the neoplastic tissue that will predict surgical cure or the need to treat the cancer systemically. Whether a broader application of adjuvant therapy would benefit significant numbers of patients is uncertain. It ts certain that patients who could be cured by surgery alone would have unnecessary morbidity and that patients whose tumor is resistant to present adjuvant treatment methods would have a substancontinued
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The immunocompetence of the patient and the cellular interface with the malignant tissue have been shown to be as important for survival in patients with lung cancer as is "total" surgical removal of gross disease.
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Figure 7. Survival by stage for non-small-cell carcinoma of lung.
P
