Chemotherapy for Adenocarcinoma and Alveolar Cell Carcinoma of the Lung Scott L. Faulkner, M.D., R. Benton Adkins, Jr., M.D., and Vernon H. Reynolds, M.D. ABSTRACT Ten patients with inoperable or recurrent adenocarcinoma or alveolar cell carcinoma of the lung have been treated with 5-fluorouracil (5-FU). Four of the patients treated with this drug had a marked objective and subjective response. Although 5-FU has not had a measurable effect on bronchogenic carcinoma in general, reappraisal with particular attention to adenocarcinoma and alveolar cell carcinoma seems warranted. M any factors influence the prognosis for patients with adenocarcinoma or alveolar cell carcinoma of the lung; these include the duration of symptoms, degree of cellular differentiation, extent of the primary lesion, and metastatic disease. Both neoplasms may appear as a solitary lesion, in which case there is a high resectability rate and 5-year cure rate [5, 7, 8, 121. However, many patients exhibit diffuse intrapulmonary disease, bilateral pulmonary lesions, pleural effusions, or extrathoracic metastases. Most of this latter group of patients are inoperable and die from their disease within 1 to 2 years [lo, 141. Neither radiotherapy nor chemotherapy has been beneficial in this group of patients to date [3, 71. Recently we have been impressed by the response of 4 patients with either adenocarcinoma or alveolar cell carcinoma to intravenously administered 5-fluorouracil (5-FU), although this antimetabolite has proved ineffective for treatment of bronchogenic carcinoma in general [6]. After considering the success of 5-FU in the treatment of metastatic adenocarcinoma of the breast and gastrointestinal tract [l], a more thorough evaluation of this drug in adenocarcinoma of the lung seems justified. Case Reports PATIENT 1 A 54-year-old woman was seen with bilateral lower lobe infiltrates and pleural effusions (Fig. 1). A lung biopsy demonstrated alveolar cell From the Depa.rtment of Surgery, Vanderbilt University Hospital. Nashville, Tenn. This investigation was supported in part by N.I.H. Training Grant no. GM01742-07 from the National Institute of General Medical Sciences. Accepted for publication June 6, 1974. Address reprint requests to Dr. Faulkner, Department of Surgery, Vanderbilt IJniveraity School of Medicine, Nashville, Tenn. 37232. 5 78 THE ANNALS OF THORACIC SURGERY
Chemotherapy for Carcinoma of the Lung FIG. 1. (Patient I.} (A} Admission chest roentgenogram demonstrates bilateral lower lobe infiltrates and pleural effusions. (B} Four months following initiation of 5-fluorouracil (5-FU} therah the infiltrates and pleural effusions have regressed. (C) The follow-up chest roentgenogram 2 years after initiation of 5-FU therapy is essentially normal. carcinoma, and a regimen of 5-FU was begun. The pleural effusions and infiltrates disappeared in 4 months (Fig. lb, C) and did not recur until 27 months following the initiation of chemotherapy. She subsequently developed cutaneous and bone metastases and recurrence of pleural effusions. PATIENT 2 A 42-year-old man was seen initially with a right upper lobe coin lesion, malignant pleural effusion, and metastases of poorly differentiated adenocarcinoma to axillary and cervical lymph nodes as well as metastatic cutaneous nodules. The patient was severely dyspneic on admission and was started on 5-FU. Over the next 6 months the patient s dyspnea disappeared, he gained weight, and the pleural effusions and pulmonary infiltrates disappeared. Eight months after the initiation of chemotherapy, however, the patient s general condition deteriorated, with enlargement of skin lesions and lymph nodes; he died within 2 months. PATIENT 3 A 45-year-old man was first seen with a right upper lobe coin lesion, bilateral hazy infiltrates, and bilateral axillary node metastases (Fig. 2A). Axillary node biopsy demonstrated adenocarcinoma. Over the next 8 months, while he was receiving 5-FU, the axillary nodes disappeared and the coin lesion decreased 50% in size (Fig. 2B). After 8 months the coin lesion began to increase slightly in size, although the patient has remained asymptomatic to date. PATIENT 4 A 59-year-old woman underwent a left upper lobectomy for adenocarcinoma of the lung with regional lymph node involvement. Six years later the patient presented with bilateral pulmonary nodules as well as an osteolytic VOL. 18, NO. 6, DECEMBER, 19 74 5 79
FAULKNER, ADKINS, AND REYNOLDS FIG. 2. (Patient 3.) (A) Admission chest roentgenogram demonstrates a small right upper lobe coin lesion and bilateral infiltrates. (B) Eight months after 5-fluorouracil therah was begun, the infiltrates have cleared and the coin lesion has decreased 50% in size. metastasis to the fourth thoracic vertebra (Fig. 3A). After 5-FU was started, her chronic cough disappeared and the pulmonary nodules decreased in size by approximately 50% (Fig. 3B). One and a half years after the 5-FU therapy was started the pulmonary nodules increased in size, and the patient died 4 months later. PATIENT 5 A 60-year-old woman was first seen with dyspnea, substernal pain, and bilateral multinodular pulmonary infiltrates. Biopsy of a scalene node FZG. 3. (Patient 4.) (A) Admission chest roentgenogram demonstrates multiple bilateral metastatic pulmonary adenocarcinoma. (B) After intravenous administration of 5- fluorouracil weekly over the ensuing 6 months, the pulmonary lesions have decreased approximately 50% in size. 580 THE ANNALS OF THORACIC SURGERY
Chemotherapy for Carcinoma of the Lung demonstrated adenocarcinoma compatible with a primary adenocarcinoma of the lung. Over the first 2 months of 5-FU therapy the multinodular infiltrates became less distinct. During the third month of therapy the patient died secondary to central nervous system metastases. Five other patients have been treated with 5-FU. This group includes 2 patients with alveolar cell carcinoma and 3 with adenocarcinoma. One patient in each group had a primary diffuse neoplasm and extrathoracic metastases when first seen. The remaining 3 developed recurrence of their tumors less than 3 years following resection for solitary tumors. Each of the 5 patients received 5-FU for 3 to 6 months without measurable effect. One patient became less dyspneic subjectively, but the chest roentgenogram remained unchanged. Comment Ten patients with either adenocarcinoma or alveolar cell carcinoma of the lung who were treated with 5-FU have been presented. In order to place the experience with these patients in perspective, our total experience with these two neoplasms was reviewed. Between 1950 and 1972, 58 patients with adenocarcinoma and 54 with alveolar cell carcinoma of the lung were evaluated at the Vanderbilt University Affiliated Hospitals. Overall, patients with adenocarcinoma had a 15% 5-year survival rate, and patients with alveolar cell carcinoma had a 5-year survival rate of 12%; the majority of patients with either tumor failed to survive 2 years. In this latter group, the average survival for patients with adenocarcinoma was 7.0 months and for alveolar cell carcinoma 5.4 months. Of the 10 patients with adenocarcinoma who survived more than 2 years, only 3 died as a result of their tumor (at 2%, 7, and 8 years, respectively, following initial treatment). Of those 11 patients with alveolar cell carcinoma who survived more than 2 years, only 3 died of recurrent disease at 3%, 4, and 4% years, respectively. Four out of 10 patients (40y0) whose lesions were considered inoperable or who developed recurrent tumor had a significant objective and subjective remission while being maintained on 5-FU. The remission experienced by Patient 2 was only of short duration but was the most marked subjectively; his dyspnea, anorexia, weakness, and fatigue markedly improved for 6 months. At postmortem examination he had metastatic adenocarcinoma in both lungs, the pleura, chest wall, diaphragm, pericardium, mediastinal and mesenteric lymph nodes, liver, adrenal glands, brain, and kidney. Another patient (Patient 3) demonstrated an objective decrease in the size of both his primary tumor and axillary nodes for 8 months. The most dramatic objective remissions occurred in Patients 1 and 4: in Patient 1 bilateral infiltrates disappeared for 2 years, and in Patient 4 the pulmonary metastases markedly diminished for 1% years. Patient 5 had only a transient response. VOL. 18, NO. 6, DECEMBER, 1974 581
FAULKNER, ADKINS, AND REYNOLDS The lesions in all these patients eventually became refractory to 5-FU. The remaining 5 patients demonstrated no response to therapy. Our treatment protocol for 5-FU has been described by VanWay and associates [13]. The patient is given a loading dose of intravenous 5-FU, 12 mg. per kilogram of body weight daily for four days, and then 12 mg./kg. once a week. All patients responded to the 5-FU with a mild leukopenia; in only 1 patient did the leukocyte count drop below 3,000 cells per cubic millimeter, but this was corrected simply by withholding 5-FU for 2 weeks. Chemotherapy for advanced or inoperable bronchogenic carcinoma has failed to demonstrate a significant increase in survival statistics [2]. When disease appears to be limited to one hemithorax, radiotherapy alone is as effective as several chemotherapeutic agents used alone or in combination with radiotherapy [2]. However, if all cases of lung cancer are evaluated with relationship to cell type, slightly different conclusions are possible. For squamous cell carcinoma, mechlorethamine causes a small increase in median survival over controls [2]. Cyclophosphamide appears to increase median survival time in patients with oat cell carcinoma [4]. Selawry [12] reports objective remission rates of 20 to 32y0 in patients with adenocarcinoma who were treated with methotrexate, mechlorethamine, mitomycin C, chloroethyl cyclohexyl nitrosourea, and hexamethylmelamine. In patients with bronchogenic carcinoma 5-FU has an objective remission rate of 6y0 [6]. This is the same as in the placebo-treated group in a controlled study of benefits of postoperative radiotherapy [9]. However, few reports on the efficacy of 5-FU specify cell type. In approximately 25y0 of patients with metastatic cancer of the breast and gastrointestinal tract, 5-FU has proved an effective palliating agent [ 11. Although this communication describes the responses of only 10 patients, the good results (objective remission in 40y0) as well as the demonstrated success of 5-FU in other adenocarcinomas suggest that continued trials in adenocarcinoma and alveolar cell carcinoma of the lung must be carried out. References 1. Ansfeld, F. J. Chemotherapy of Disseminated Solid Tumors. Springfield, Ill.: Thomas. 1966. 2. Carbone, P. P., Frost, J. K., Feinstein, A. R., Higgins, G. A., Jr., and Selawry, 0. S. Lung cancer: Perspectives and prospects. Ann. Intern. Med. 73:1003, 1970. 3. Golbey, R. B., and Karnovsky, D. A. Types and Techniques of Chemotherapy. In W. L. Watson (Ed.), Lung Cancer: A Study of Five Thousand Memorial Hospital Cases. St. Louis: Mosby, 1968. P. 347. 4. Greene, R., Humphrey, E., and Close, H. Alkylating agents in bronchogenic carcinoma. Am. J. Med. 46:576, 1969. 5. Jackman, R. J., Good, C. A., Clagett, 0. T., and Woolner, L. B. Survival rates in peripheral bronchogenic carcinoma up to 4 cm. in diameter presenting as solitary pulmonary nodules. J. Thorac. Cardiovnsc. Szrrg. 57:1, 1969. 6. Livingston, R. B., and Carter, S. K. Single Agents in Concer Chemotherapy. New York: Plenum, 1970. Pp. 207-208. 582 THE ANNALS OF THORACIC SURGERY
Chemotherapy for Curcinomu of the Lung 7. McNamara, J. J., Kingsley, W. B., Paulson, D. L., Arndt, J. H., Salinas- Izaquiree, S. F., and Urschel, H. C., Jr. Alveolar cell (bronchiolar) carcinoma of the lung. J. Thorac. Cardiovasc. Surg. 57:648, 1969. 8. Munnell, E. R., Lawson, R. C., and Keller, D. F. Solitary bronchiolar carcinoma of the lung. J. Thorac. Cardiovasc. Surg. 52261, 1966. 9. Roswit, B., Patno, M. E., Rapp, R., Veinberg, A., Feder, B., Stahlberg, J., and Reid, C. B. The survival of patients with inoperable lung cancer: A large scale randomized study of radiation therapy versus placebo. Radiology 90:688, 1968. 10. Sasser, W. F., Bennett, D. E., Ferguson, T. B., and Burford, T. H. Primary adenocarcinoma of the lung in men. Ann. Thorac. Surg. 5:508, 1968. 11. Selawry, 0. S. Monochemotherapy of bronchogenic carcinoma with special reference to cell type: 111. Cancer Chemother. Rep. 4: 177, 1973. 12. Steele, J. D., and Buell, P. Survival in bronchogenic carcinomas resected as solitary pulmonary nodules. Proc. Natl. Cancer Conf. (sixth), 1968. P. 835. 13. VanWay, C. W., 111, and Reynolds, V. H. A new method for treatment of carcinoma of the breast and colon with 5-fluorouracil. Am. Surg. 36:210, 1970. 14. Viragh, Z., and Woods, J. R. Alveolar carcinoma of the lung. Med. Thorac. (Basel) 19: 129, 1962. VOL. 18, NO. 6, DECEMBER, 1974 583