----tfat--a_c_c_p_se_ct_i_o_n_re_p_ort_1part_11________ The Lung Cancer Dilemma* John R. Benfield, M.D., F.C.C.P.
T
(Cheat 1991; 100:510-11)
his section of Chest is dedicated to providing insight into the state of the art pertaining to the management of lung cancer. There are seven articles by six authors who are clinicians. The scope of their discussions spans from molecular biology to epidemiology, but it does not reflect the state of practice as I regularly have opportunity to observe it. More often than not, at least at the beginning, there is delay and perhaps even confusion. Opinion about lung cancer management among practitioners, depending on their specialties, ages, and temperaments, ranges widely. At one end of the spectrum is denial that any treatment is effective; at the other end is undaunted use of radical operations and rigorous chemotherapy for the treatment of end-stage disease. This broad range reflects frustrations that might also be referred to as "the lung cancer dilemma." I will attempt to provide some perspective on what is actually new and proved, compared with what I believe still to be in the realm of hopeful projection. In diagnosis, it is clear that lung cancer can be detected early with the use of multifaceted screening methods.' Cytologic examinations of sputum and fine needle aspirates make accurate diagnosis of cancer possible over 90% of the time,1 and determination of cell type can be as much as 85% accurate.• It is not possible to exclude the possibility of cancer on the basis of samples from needle aspirates; therefore, the indication for excision of a lung lesion, after appropriate workup, is its presence. Too little appreciated are the limitations of biopsies. Small cell lung carcinomas (SCLCs) may be difficult to differentiate from atypical carcinoids•; in non-SCLCs (NSCLCs), heterogeneity is increasingly being recognized as nearly usual instead of the exception. 5 Cytogenetic and molecular biologic information does not yet suffice for the diagnosis oflung cancer. However, measurement of total DNA-ploidy can be an adjunct to diagnosis in difficult cases.8 Lung cancer is not a single disease; it is a group of diseases with widely variable biologic behavior. Therefore, accurate and complete diagnosis is imperative. Accordingly, there is rarely, if ever, justi6cation for observation to see if a lesion grows in order to determine whether it is cancer; enlargement would mean that valuable time had been lost, and lack of growth leaves the patient no closer to a solution than he was at the time of completion of the original investigations. There has been important progress in lung cancer staging nomenclature and methods. However, in my experience, these advances have yet to reach practice in a widespread manner. There is good reason to insist that the cell type of each bronchogenic cancer be identi6ed, and that each case *From the Division of Cardiothoracic Surgery, University of Califurnia, Davis, School of Medicine, Sacramento. Reprint requests: Dr. Benfield, 4301 X Street, Sacramento 95817
510
be staged according to currently accepted TNM nomenclature.' Less clear is the fine line between adequate and excessive use of tests for clinical staging. For a number of years, we routinely used computed tomography (Cf) in patients with proven lung cancer. Now we recommend CT under the following circumstances: (1) The plain chest radiograph suggests, but does not prove, the presence of enlarged mediastinal lymph nodes. (2) The patient has SCLC. (3) The patient has a superior sulcus tumor with Pancoast syndrome. I now believe that the routine use of CT or magnetic resonance imaging in patients with clinical stage I NSCLC is not justi6ed. Prior to CT scanning we used to do mediastinoscopy routinely.• We now use mediastinoscopy routinely for NSCLC in the following situations: (1) The CT study shows evidence of mediastinal metastases. (2) The patient has Pancoast syndrome, and proof of mediastinal metastases would dictate the use of definitive, rather than preoperative, radiotherapy (in such cases, we do the procedure before any irradiation is given). (3) The patient has poor cardiopulmonary reserve. (4) The patient has SCLC, and elective resection is being considered. Under the four circumstances just described, we feel that the 7% to 10% chance of finding mediastinal metastases in the absence of radiographically enlarged lymph nodes9 justi6es the use of mediastinoscopy in order to avert high-risk thoracotomy. There is the hope that radioisotope imaging with the use of tagged monoclonal antibodies might improve the accuracy of staging. I doubt that these hopes will translate into clinically useful reality within the near future. I am more hopeful that, at least for SCLC, there will be cytogenetic and biochemical tumor markers. 10 I am certain, however, that tests of this type will never fully replace histologic diagnosis. Treatment is the "bottom line." For us, the goal is to 6nd the best therapy for each patient, hoping to accomplish cure but settling for palliation if necessary. From the viewpoint of the patient, treatment is useless if it does not result in an acceptable quality of life. What benefit is curative pneumonectomy if the patient becomes disabled by respiratory insufficiency? What justi6cation is there for polypharmacy chemotherapy or neutron-beam radiotherapy if the side effects cause more symptoms than the disease? It is crucial that we decide for each patient whether treatment is expected to be primarily curative or palliative. When indicated, we must have the courage to delay treatment when there are no symptoms to relieve, and there is no hope of cure. The fundamental and controversial question underlying treatment recommendations is under what circumstances can lung cancer be cured? This question has no generally accepted answer, but it is possible to separate the responses into parts that are accepted with reasonable agreement and into components that are clearly arguable. Concerning cure, the only axiom is that primary NSCLC in stage I can be The Lung Cancer Dilemma (John R. Benfield)
permanently eradicated in up to 80% of cases by resection. It is factual that some patients with NSCLC in stages II and III achieve long-term survival, but the extent to which longterm survival is the result of treatment, as compared with the natural history of the cancer, is arguable. The evidence that long-term survival requires resection always is essentially solid. Occasional patients with SCLC appear to have long-term control of their neoplasms from chemotherapy or resection, but the curability of this type of cancer is still argued. 11 •11 It is reasonable to be optimistic and to accept the hypothesis that all types of lung cancer in all stages are potentially curable. However, whenever proposed therapy is likely to affect a patient's quality of life adversely, it is equally sensible to acknowledge the arguable efficacy of treatment for stage II and III cancers. For example, is it justified to do a right pneumonectomy for stage IIIA NSCLC in a patient with moderately impaired preoperative pulmonary function? I cannot definitively answer this and similar questions, but I can stress the need always to keep the riskbene&t balance uppermost in mind when treating lung cancer. For progress to be made, there must be a common language with which to describe lung cancers precisely, and there must be scientifically rigorous attention to systemic and locally adjuvant treatment methods. We must be willing to abandon tradition in favor of current evidence and approaches. Traditional language is illustrated by Meek (see next issue), who discusses "resectable but inoperable lung cancer." I know of no way to resect a lung cancer without operating. A cancer that is found to be nonresectable after an hour of dissecting the pulmonary hilum is hardly "inoperable.'' I suggest that the word "inoperable" be abandoned. "Inoperability" connotes inability to operate, either because the patient declines the recommendation or because the surgeon refuses to operate. If the surgeon declines to operate, he or she should define the reason for refusal in precise terms, using TNM nomenclature as an explanation for whether the lesion is considered curable or incurable and anatomic terms to explain why a lesion is considered resectable or nonresectable. Patterson (see pages 520 to 523) gives an in-depth discussion of neoadjuvant therapy. This is an attractive, thoroughly logical approach with historic roots in the 1950s. 13 The problem is the Jack of truly effective chemotherapy, failure of adjuvant irradiation to prolong life, 14 and refusal of many clinical investigators to do concurrently controlled studies. For the time being, neoadjuvant therapy belongs in carefully controlled cooperative clinical trials; it is not proven treatment, and therefore it is not ready for general therapeutic use. Nowhere in medicine is there greater frustration and greater opportunity than in the lung cancer dilemma. The frustration is the result of delayed diagnosis of a disease that is frequently aggressive and often systemic when it is discovered. Lung cancers have poorly predictable biologic behavior, and therapeutic decisions are therefore difficult. The opportunity lies in the fact that we have mastered the surgical and radiotherapeutic methods necessary for local control, and there is emerging evidence that we will soon have a better understanding of the family of diseases that constitute lung cancer. Molecular biologic, endocrinologic,
and cytogenetic methods promise eventually to provide insights as to who is a susceptible host, what tumor markers may signal early disease, and which neoadjuvant therapies are likely to work. REFERENCES
1 National Cancer Institute Cooperative Early Lung Cancer Detection Program: summary and conclusions. Am ftev Hespir Dis 1984; 130:565-70 2 Stanley JH, Fish GD, Andriole JG, Gobien RP, Betsill WL, Laden SA, et al. Lung lesions: cytologic diagnosis by fine needle biopsy. Radiology 1987; 162:~91 3 DeCaro LF, Pale HY, Yokota S, Teplitz RI, Benfield JR. Intraoperative cytodiagnosis of lung tumors by needle aspiration. J Thone Cardiovasc Surg 1983; 85:404-8 4 Paladugu RR, Benfield JR, Pale HY, Ross RIC, Teplitz RL. Broncho-pulmonary Kulchitzky cell carcinomas I and II alias typical and atypical carcinoids. Cancer 1985; 55:1303-11 5 Yesner R. Tbe malignancy of large cell lung carcinomas. Ann Thone Surg 1989; 47:796-97 6 Pale HY, Teplitz RL, Ashdjian V, Yokota SB, Hammond WG, Benfield JR. Quantitative DNA determination by image analysis: II. Application to human and canine pulmonary cytology. Anal Quant Cytol 1983; 5:263-68 7 Mountain CF. A new international staging system for lung cancer. Chest 1986; 89(suppl):225S-33S 8 Benfield JR, DeCaro LF. When and how to invade for the diagnosis and staging of primary lung cancer. Am J Surg 1982; 143:670-74 9 Gross BH, Glazer GM, Orringer MB, Spizarny DL, Flint A. Bronchogenic carcinoma metastatic to normal sized lymph nodes: frequency and significance. Radiology 1988; 166:71-74 10 Benfield JR, Wain JC, Derrick M, Smith SS, Ohnuki Y, Bates SE, et al. Biochemical and cytogenetic studies of human lung cancers. J Thone Cardiovasc Surg 1988; 96:840-48 11 Bunn PA Jr. Operation for stage III A small cell lung cancer. Ann Thone Surg 1990; 49:691 12 Ginsberg RJ. Operation for small cell lung cancer: where are we? Ann Thone Surg 1990; 49:692-93 13 Katsuki H, Shimada K, Koyama A, Okita M, Yamaguchi Y, Okamoto T. Long term intermittent adjuvant chemotherapy for primary, resected lung cancer. J Thone Cardiovasc Surg 1975; 70:590-605 14 Holmes EC. Tbe lung cancer study group: effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med 1986; 315:1377-81
Lung Cancer* Making the Diagnosis Sergey Lyubsky, M.D., Ph.D.; and Myron) Jacobson, M.D., F.C.C.P.
I
(Cheat 1991; 100:511-20)
n current clinical practice, in the asymptomatic patient, lung cancer most commonly presents as a nodule or mass found on a chest x-ray film. Over the years, large seriesu have shown consistently that up to half of all such circumscribed nodules will be found to be carcinoma and the remainder benign. •From the Departments of Pathology (Dr Lyubsky) and Surgery (Dr Jacobson), State University of New York at Stony Brook and the Oepartment of Veterans Affairs, Northport, NY Reprint ~queats: Dr Lyubsky, Department of lbthology, s~ Stony Brook, NY 11794 CHEST I 100 I 2 I AUGUST, 1991
511
T
(Cheat 1991; 100:510-11)
his section of Chest is dedicated to providing insight into the state of the art pertaining to the management of lung cancer. There are seven articles by six authors who are clinicians. The scope of their discussions spans from molecular biology to epidemiology, but it does not reflect the state of practice as I regularly have opportunity to observe it. More often than not, at least at the beginning, there is delay and perhaps even confusion. Opinion about lung cancer management among practitioners, depending on their specialties, ages, and temperaments, ranges widely. At one end of the spectrum is denial that any treatment is effective; at the other end is undaunted use of radical operations and rigorous chemotherapy for the treatment of end-stage disease. This broad range reflects frustrations that might also be referred to as "the lung cancer dilemma." I will attempt to provide some perspective on what is actually new and proved, compared with what I believe still to be in the realm of hopeful projection. In diagnosis, it is clear that lung cancer can be detected early with the use of multifaceted screening methods.' Cytologic examinations of sputum and fine needle aspirates make accurate diagnosis of cancer possible over 90% of the time,1 and determination of cell type can be as much as 85% accurate.• It is not possible to exclude the possibility of cancer on the basis of samples from needle aspirates; therefore, the indication for excision of a lung lesion, after appropriate workup, is its presence. Too little appreciated are the limitations of biopsies. Small cell lung carcinomas (SCLCs) may be difficult to differentiate from atypical carcinoids•; in non-SCLCs (NSCLCs), heterogeneity is increasingly being recognized as nearly usual instead of the exception. 5 Cytogenetic and molecular biologic information does not yet suffice for the diagnosis oflung cancer. However, measurement of total DNA-ploidy can be an adjunct to diagnosis in difficult cases.8 Lung cancer is not a single disease; it is a group of diseases with widely variable biologic behavior. Therefore, accurate and complete diagnosis is imperative. Accordingly, there is rarely, if ever, justi6cation for observation to see if a lesion grows in order to determine whether it is cancer; enlargement would mean that valuable time had been lost, and lack of growth leaves the patient no closer to a solution than he was at the time of completion of the original investigations. There has been important progress in lung cancer staging nomenclature and methods. However, in my experience, these advances have yet to reach practice in a widespread manner. There is good reason to insist that the cell type of each bronchogenic cancer be identi6ed, and that each case *From the Division of Cardiothoracic Surgery, University of Califurnia, Davis, School of Medicine, Sacramento. Reprint requests: Dr. Benfield, 4301 X Street, Sacramento 95817
510
be staged according to currently accepted TNM nomenclature.' Less clear is the fine line between adequate and excessive use of tests for clinical staging. For a number of years, we routinely used computed tomography (Cf) in patients with proven lung cancer. Now we recommend CT under the following circumstances: (1) The plain chest radiograph suggests, but does not prove, the presence of enlarged mediastinal lymph nodes. (2) The patient has SCLC. (3) The patient has a superior sulcus tumor with Pancoast syndrome. I now believe that the routine use of CT or magnetic resonance imaging in patients with clinical stage I NSCLC is not justi6ed. Prior to CT scanning we used to do mediastinoscopy routinely.• We now use mediastinoscopy routinely for NSCLC in the following situations: (1) The CT study shows evidence of mediastinal metastases. (2) The patient has Pancoast syndrome, and proof of mediastinal metastases would dictate the use of definitive, rather than preoperative, radiotherapy (in such cases, we do the procedure before any irradiation is given). (3) The patient has poor cardiopulmonary reserve. (4) The patient has SCLC, and elective resection is being considered. Under the four circumstances just described, we feel that the 7% to 10% chance of finding mediastinal metastases in the absence of radiographically enlarged lymph nodes9 justi6es the use of mediastinoscopy in order to avert high-risk thoracotomy. There is the hope that radioisotope imaging with the use of tagged monoclonal antibodies might improve the accuracy of staging. I doubt that these hopes will translate into clinically useful reality within the near future. I am more hopeful that, at least for SCLC, there will be cytogenetic and biochemical tumor markers. 10 I am certain, however, that tests of this type will never fully replace histologic diagnosis. Treatment is the "bottom line." For us, the goal is to 6nd the best therapy for each patient, hoping to accomplish cure but settling for palliation if necessary. From the viewpoint of the patient, treatment is useless if it does not result in an acceptable quality of life. What benefit is curative pneumonectomy if the patient becomes disabled by respiratory insufficiency? What justi6cation is there for polypharmacy chemotherapy or neutron-beam radiotherapy if the side effects cause more symptoms than the disease? It is crucial that we decide for each patient whether treatment is expected to be primarily curative or palliative. When indicated, we must have the courage to delay treatment when there are no symptoms to relieve, and there is no hope of cure. The fundamental and controversial question underlying treatment recommendations is under what circumstances can lung cancer be cured? This question has no generally accepted answer, but it is possible to separate the responses into parts that are accepted with reasonable agreement and into components that are clearly arguable. Concerning cure, the only axiom is that primary NSCLC in stage I can be The Lung Cancer Dilemma (John R. Benfield)
permanently eradicated in up to 80% of cases by resection. It is factual that some patients with NSCLC in stages II and III achieve long-term survival, but the extent to which longterm survival is the result of treatment, as compared with the natural history of the cancer, is arguable. The evidence that long-term survival requires resection always is essentially solid. Occasional patients with SCLC appear to have long-term control of their neoplasms from chemotherapy or resection, but the curability of this type of cancer is still argued. 11 •11 It is reasonable to be optimistic and to accept the hypothesis that all types of lung cancer in all stages are potentially curable. However, whenever proposed therapy is likely to affect a patient's quality of life adversely, it is equally sensible to acknowledge the arguable efficacy of treatment for stage II and III cancers. For example, is it justified to do a right pneumonectomy for stage IIIA NSCLC in a patient with moderately impaired preoperative pulmonary function? I cannot definitively answer this and similar questions, but I can stress the need always to keep the riskbene&t balance uppermost in mind when treating lung cancer. For progress to be made, there must be a common language with which to describe lung cancers precisely, and there must be scientifically rigorous attention to systemic and locally adjuvant treatment methods. We must be willing to abandon tradition in favor of current evidence and approaches. Traditional language is illustrated by Meek (see next issue), who discusses "resectable but inoperable lung cancer." I know of no way to resect a lung cancer without operating. A cancer that is found to be nonresectable after an hour of dissecting the pulmonary hilum is hardly "inoperable.'' I suggest that the word "inoperable" be abandoned. "Inoperability" connotes inability to operate, either because the patient declines the recommendation or because the surgeon refuses to operate. If the surgeon declines to operate, he or she should define the reason for refusal in precise terms, using TNM nomenclature as an explanation for whether the lesion is considered curable or incurable and anatomic terms to explain why a lesion is considered resectable or nonresectable. Patterson (see pages 520 to 523) gives an in-depth discussion of neoadjuvant therapy. This is an attractive, thoroughly logical approach with historic roots in the 1950s. 13 The problem is the Jack of truly effective chemotherapy, failure of adjuvant irradiation to prolong life, 14 and refusal of many clinical investigators to do concurrently controlled studies. For the time being, neoadjuvant therapy belongs in carefully controlled cooperative clinical trials; it is not proven treatment, and therefore it is not ready for general therapeutic use. Nowhere in medicine is there greater frustration and greater opportunity than in the lung cancer dilemma. The frustration is the result of delayed diagnosis of a disease that is frequently aggressive and often systemic when it is discovered. Lung cancers have poorly predictable biologic behavior, and therapeutic decisions are therefore difficult. The opportunity lies in the fact that we have mastered the surgical and radiotherapeutic methods necessary for local control, and there is emerging evidence that we will soon have a better understanding of the family of diseases that constitute lung cancer. Molecular biologic, endocrinologic,
and cytogenetic methods promise eventually to provide insights as to who is a susceptible host, what tumor markers may signal early disease, and which neoadjuvant therapies are likely to work. REFERENCES
1 National Cancer Institute Cooperative Early Lung Cancer Detection Program: summary and conclusions. Am ftev Hespir Dis 1984; 130:565-70 2 Stanley JH, Fish GD, Andriole JG, Gobien RP, Betsill WL, Laden SA, et al. Lung lesions: cytologic diagnosis by fine needle biopsy. Radiology 1987; 162:~91 3 DeCaro LF, Pale HY, Yokota S, Teplitz RI, Benfield JR. Intraoperative cytodiagnosis of lung tumors by needle aspiration. J Thone Cardiovasc Surg 1983; 85:404-8 4 Paladugu RR, Benfield JR, Pale HY, Ross RIC, Teplitz RL. Broncho-pulmonary Kulchitzky cell carcinomas I and II alias typical and atypical carcinoids. Cancer 1985; 55:1303-11 5 Yesner R. Tbe malignancy of large cell lung carcinomas. Ann Thone Surg 1989; 47:796-97 6 Pale HY, Teplitz RL, Ashdjian V, Yokota SB, Hammond WG, Benfield JR. Quantitative DNA determination by image analysis: II. Application to human and canine pulmonary cytology. Anal Quant Cytol 1983; 5:263-68 7 Mountain CF. A new international staging system for lung cancer. Chest 1986; 89(suppl):225S-33S 8 Benfield JR, DeCaro LF. When and how to invade for the diagnosis and staging of primary lung cancer. Am J Surg 1982; 143:670-74 9 Gross BH, Glazer GM, Orringer MB, Spizarny DL, Flint A. Bronchogenic carcinoma metastatic to normal sized lymph nodes: frequency and significance. Radiology 1988; 166:71-74 10 Benfield JR, Wain JC, Derrick M, Smith SS, Ohnuki Y, Bates SE, et al. Biochemical and cytogenetic studies of human lung cancers. J Thone Cardiovasc Surg 1988; 96:840-48 11 Bunn PA Jr. Operation for stage III A small cell lung cancer. Ann Thone Surg 1990; 49:691 12 Ginsberg RJ. Operation for small cell lung cancer: where are we? Ann Thone Surg 1990; 49:692-93 13 Katsuki H, Shimada K, Koyama A, Okita M, Yamaguchi Y, Okamoto T. Long term intermittent adjuvant chemotherapy for primary, resected lung cancer. J Thone Cardiovasc Surg 1975; 70:590-605 14 Holmes EC. Tbe lung cancer study group: effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med 1986; 315:1377-81
Lung Cancer* Making the Diagnosis Sergey Lyubsky, M.D., Ph.D.; and Myron) Jacobson, M.D., F.C.C.P.
I
(Cheat 1991; 100:511-20)
n current clinical practice, in the asymptomatic patient, lung cancer most commonly presents as a nodule or mass found on a chest x-ray film. Over the years, large seriesu have shown consistently that up to half of all such circumscribed nodules will be found to be carcinoma and the remainder benign. •From the Departments of Pathology (Dr Lyubsky) and Surgery (Dr Jacobson), State University of New York at Stony Brook and the Oepartment of Veterans Affairs, Northport, NY Reprint ~queats: Dr Lyubsky, Department of lbthology, s~ Stony Brook, NY 11794 CHEST I 100 I 2 I AUGUST, 1991
511
