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Survival Following Aggressive Resection of Pulmonary Metastases from Osteogenic Sarcoma: Analysis of Prognostic Factors
Survival Following Aggressive Resection of Pulmonary Metastases from Osteogenic Sarcoma: Analysis of Prognostic Factors Joe B. Putnam, Jr., M.D., Jack A. Roth, M.D., Margaret N. Wesley, Ph.D., Michael R. Johnston, M.D., and Steven A. Rosenberg, M.D., Ph.D.
lowing resection, and other patients cannot undergo complete resection at exploration. Pulmonary metastases will develop in 20 to 30% of all patients with malignant disease [lo, 17, 181 and the lungs initially will be the sole site of metastases in virtually all patients with osteogenic sarcoma. Therefore, patients with pulmonary metastases from osteogenic sarcoma provide an ideal group for the study of factors that influence survival following resection of pulmonary metastases [19-301. Recent studies suggest that several factors influence the postoperative survival of these patients. These factors include tumor doubling time [6, 10, 14-16, 221, disease-free interval (from primary operation to date of first lung recurrence) [3-6, 9-11, 141, multiplicity or bilaterality of lesions [ll, 14, 161, and resectability [14]. Although these studies documented benefit for patients following surgical resection of pulmonary metastases, the importance of these prognostic factors in postthoracotomy survival remains controversial. In our study, factors that influenced postoperative survival were evaluated in patients in whom metastatic pulmonary osteogenic sarcoma developed following resection of the primary tumor. Several Following the successful resection of a pulmo- prognostic criteria were identified and critically nary metastasis in a patient with metastatic re- analyzed for their ability to predict survival folnal cell carcinoma by Barney and Churchill [l], lowing resection of metastases. there have been frequent reports of long-term survivors following resection of pulmonary Material and Methods metastases [2-161. However, a notable percent- Between 1975 and 1982, 80 patients with osage of patients still die of tumor recurrence fol- teogenic sarcoma were entered into ongoing prospective trials in the Surgery Branch of the From the Surgery Branch, Division of Cancer Treatment, National Cancer Institute. Among the 48 paand the Biometric Research Branch, National Cancer Institute, Bethesda, MD. tients with recurrence, 43 had recurrence iniPresented at the Nineteenth Annual Meeting of The Society tially in the lungs only. Thirty-nine (91%) of of Thoracic Surgeons, San Francisco, CA, Jan 17-19, 1983. these 43 patients underwent thoracotomy (ApAddress reprint requests to Dr. Roth, Thoracic Oncology pendix). Thirteen patients (33%)underwent 2 or Section, Surgery Branch, National Cancer Institute, Building more thoracotomies. Ages ranged from 6 to 49 10, Room 10N116, Bethesda, MD 20205.
ABSTRACT Between 1975 and 1982, 80 patients with osteogenic sarcoma were entered into prospective trials in the Surgery Branch of the National Cancer Institute. In 43 of these patients, pulmonary metastases developed as the initial site of recurrence, and 39 underwent one or more thoracotomies for resection of the disease. The actuarial five-year survival for the group of 43 patients with pulmonary metastases was 40%. Various prognostic factors were analyzed for their influence on survival after thoracotomy. Age, sex, location of primary tumor, tumor doubling time, and involvement of one or both lungs (bilaterality)were not significant in predicting survival. Prognostic factors that influenced survival, calculated by regression analysis, included the number of nodules on preoperative lung tomograms (negative correlation, p = 0.0004), disease-free interval (positive correlation, p = 0.0136), resectability (positive correlation, p = 0.002), and the number of metastases resected at thoracotomy (negative correlation, p = 0.0032). The presence of 3 nodules or less on preoperative full-lung linear tomography was found to be the single most useful preoperative prognostic factor. The application of these prognostic factors preoperatively may identify patients who will benefit optimally from thoracotomy.
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517 Putnam et al: Resection of Pulmonary Metastases from Osteogenic Sarcoma
years (median, 16 years). There were 33 male (76.7%) and 10 female (23.3%)patients. Among the 5 patients with recurrence in nonpulmonary sites, 1 had recurrence in the primary site and 1 at another site and in the lungs simultaneously. Four patients with pulmonary metastases did not undergo thoracotomy because of the extent of pulmonary metastases, and were excluded from the analysis. One additional patient was excluded at initial thoracotomy because the tumor was unresectable. However, in contrast to all other patients in the study, she underwent reexploration following postoperative chemotherapy. At that time, all metastases were resected, and she is now alive and free from disease after the fourth thoracotomy. All patients were evaluated before entry into the protocol. Site and extension of primary disease were noted and metastases histologically documented. Patients underwent a complete physical evaluation including chest roentgenograms, conventional full-lung linear tomography at 1-cm intervals, and bone scan. When necessary, computed tomographic (CT) scan of the extremity was performed. Pulmonary nodules were identified on chest roentgenograms or full-lung linear tomography. These roentgenographic examinations were performed every 3 months during the follow-up period. The appearance of previously undetected nodules and the growth of existing nodules were the criteria used to designate the radiographic appearance of nodules as consistent with metastases. Conventional linear tomography has previously been shown to be a sensitive and specific technique for the early detection of metastases to the lung [27, 31, 321. Computed tomography of the lungs was not performed in these patients routinely. Patients considered for exploration for resection of metastases met the following criteria: (1) control of the primary tumor; (2) absence of other metastases; (3) radiological findings consistent with metastases on full-lung tomography; and (4) potential for operative resection of the tumor. Patients were explored by lateral thoracotomy or median sternotomy on one or more occasions. A median sternotomy was the
preferred initial procedure [33]. With that method, occult metastases in the contralateral lung could be identified and resected. Doublelumen endotracheal tubes and radial artery catheters were used routinely. The thorax was explored by both the surgeon and the assistant. The lungs were deflated sequentially and examined by palpation. All nodules were identified and resected using the TA automatic stapling device. Malignancy was confirmed on frozen section examination. Most nodules were subpleural, and therefore, lobectomy or pneumonectomy was rarely necessary. The lungs, chest wall, mediastinum, hilar nodes, and diaphragm were all examined, and local extension of tumor was resected. All tumor was removed whenever possible. Obvious anthracotic lymph nodes and granulomatous disease were not resected; however, if there was any doubt, the nodule was removed. Tumor doubling time was calculated by the method of Joseph and colleagues [34, 351 based on original observations by Collins and coworkers [36]. Briefly, all chest roentgenograms were examined for evidence of metastases. For those patients who had metastases present on preoperative chest roentgenograms, a tumor doubling time was calculated. Excluded were those patients whose chest roentgenograms were obtained less than 14 days apart. In patients with multiple nodules, the doubling time of the fastest growing nodule was used for statistical evaluation. Diameters of tumor nodules were plotted on semilogarithmic paper against time expressed in days between observations. A line was drawn between the points, and the horizontal distance was measured between the two doubling lines crossed by this line; this was called the tumor doubling time and was calculated only for nodules clearly delineated on serial chest roentgenograms.
Statistical Methods Overall survival and postthoracotomy survival curves were estimated using the method of Kaplan and Meier [37]. Comparisons between groups were made using the generalized Wilcoxon test of Gehan [38]. The relative effect of various prognostic factors was assessed using
518 The Annals of Thoracic Surgery Vol 36 No 5 November 1983
Cox's proportional hazards model [39]. A univariate analysis identified the most important set of factors; of these, all pairs were analyzed. Other variables were added to the best pair to see if additional prognostic value was achieved. All p values were determined from two-tailed tests.
Results Sixty-two surgical procedures-46 lateral thoracotomies (74%) and 16 median sternotomies (26%)-were performed in 39 patients. Five of the explorations were staged lateral thoracotomies. The following resections were performed at initial or later thoracotomy: 1 or more wedge resections on 113 lobes, 4 segmentectomies, 12 lobectomies, and 1 pneumonectomy. No patient was noted to have metastases involving the hilar or mediastinal nodes. There were no operative deaths and only three minor postoperative complications, pneumonia in 2 patients and wound infection in 1. Only 1 of the 39 patients had an initial thoracotomy for benign disease. Granulomatous disease was confirmed by pathological findings. However, pulmonary metastases developed later. No patient undergoing a second thoracotomy had benign pulmonary disease. Few patients were seen with pulmonary symptoms relating to the metastases. Three of 43 patients had symptoms, including cough in 2 instances, chest pain in 2, and dyspnea from a pleural effusion in 1. Forty-three patients had recurrence initially in the lungs, and 39 of them underwent exploration for pulmonary metastases. The actuarial postthoracotomy five-year survival of 38 evaluated patients (1 was excluded as described earlier) was 40% (Fig l).All survivors are alive and disease free. Thirteen patients had two or more thoracotomies. Patients with synchronous metastases at the time of presentation of the primary lesion were excluded. Of the 38 patients undergoing thoracotomy, patients whose tumors were resectable had a significantly longer survival after thoracotomy (37 months, median) than those whose tumors were unresectable (median, 9 months; p = 0.002).
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Fig 1 . Postthoracotomy survival in 38 patients with pulmonary metastases from osteogenic sarcoma. Postthoracotomy survival was calculated from the date of initial thoracotomy.
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Fig 2. Postthoracotomy survival in patients with 3 nodules or less and patients with more than 3 nodules on preoperative lung tomograms ( p = 0.039, Gehan-Wilcoxon test).
Prognostic Factors Age, sex, and the location of the primary tumor were evaluated for their predictive value in patients with pulmonary metastases. None of these factors correlated significantly with postthoracotomy survival. NODULES ON PREOPERATIVE TOMOGRAPHY. The relationship between the number of nodules on preoperative tomography and postthoracotomy survival is shown in Figure 2. Patients with 3 or fewer nodules on preoperative lung tomograms had a significantly longer postthoracotomy survival (median, 37 months; N = 32) than those with more than 3 nodules (median, 10 months; N = 6; p = 0.039). If more than 16 nodules were found on preoperative tomograms, resection was not possible (N = 4).
519 Putnam et al: Resection of Pulmonary Metastases from Osteogenic Sarcoma
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Fig 4. Fostthoracotomy survival compared witk tumor doubling time ( p = 0.39 [not significant], Gekan-Wilcoxon test).
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TOMOGRAPHY. The influence of unilateral or bilateral nodules on survival was investigated. Eighteen patients had unilateral single nodules, 8 had unilateral multiple nodules, and 13 had bilateral nodules. One patient with bilateral metastases was excluded after initial thoracotomy, as described previously. No significant difference in postthoracotomy survival was noted between those patients with unilateral nodules on preoperative tomography and those with bilateral nodules. DISEASE-FREE INTERVAL. The effect Of the h i tial disease-free interval (time from resection of the primary tumor to date of the first pulmonary recurrence) was also examined for its value in predicting survival following thoracotomy . Patients with a disease-free interval of 6 months or PREOPERATIVE
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more had a longer postthoracotomy survival (38 months, median) than patients with a diseasefree interval of less than 6 months (median, 12 months; p = 0.09) (Fig 3). Although this was of borderline statistical significance for these arbitrary groupings, the disease-free interval did correlate significantly with survival when evaluated by regression analysis ( p = 0.0136). TUMOR DOUBLING TIME. No correlation could be found between tumor doubling time and survival in patients with pulmonary metastases from osteogenic sarcoma. Patients with tumor doubling times of 20 days or less and of more than 20 days were examined (Fig 4). There was no significant difference between the two survival curves ( p = 0.39). RESECTABLE VERSUS NONRESECTABLE LESIONS. Patients with resectable metastases survived longer (median, 37 months) than patients with unresectable metastases (median, 9 months; p = 0.002) (Fig 5). No patient with unresectable disease had a postthoracotomy survival greater than 20 months. PaNUMBER OF POSITIVE NODULES RESECTED. tients undergoing complete resection with 4 or fewer histologically confirmed metastases had a survival of 62% at 36 months (median not yet reached; N = 22) compared with patients with 5 nodules or more and a median survival of 16 months (N = 9; p = 0.105) (Fig 6). The maximum number of metastases resected was 25; that patient remains alive and free from tumor one year after resection of the primary tumor after two median sternotomies.
520 The Annals of Thoracic Surgery Vol 36 No 5 November 1983
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Fig 6 . Postthoracotomy survival compared with the number of metastases resected ( p = 0.105 [borderline significance], Gehan-Wilcoxon test).
Regression Analysis of Select Variables Regression analysis [39] of select factors, analyzed as continuous variables, was performed. This analysis determined that the number of nodules on preoperative tomograms (negative correlation, p = 0.0004), the number of histologically documented pulmonary metastases resected on exploration (negative correlation, p = 0.0032), the disease-free interval (positive correlation, p = 0.0136), and resectability (positive correlation, p = 0.002) all correlated with postthoracotomy survival. Using the variables just described, we determined whether combinations of these factors would increase the predictive value of the model significantly. Because the number of nodules on tomograms as a single factor had the most significant correlation with survival following thoracotomy, additional factors were combined with it to determine whether the predictive value was increased. Combining the number of tomographic nodules with the disease-free interval yielded the best paired combination yet did not increase the predictive value of the model in a significant fashion ( p = 0.15). No variable added a significant increase in predictive value to the number of nodules on preoperative lung tomograms. Comment Few studies describe objective criteria that can be reliably used to predict postthoracotomy survival of patients with osteogenic sarcoma [19301. A review by van Dongen and van Slooten
[40] suggested several prognostic factors that may influence postthoracotomy survival. Those include histology of the primary tumor; tumor doubling time; disease-free interval (from primary operation to date of first lung recurrence); size of metastases and the presence of mediastinal or hilar nodes; and the number of treated (resected) metastases. In the present study, we analyzed factors that potentially could predict the postthoracotomy survival for patients with pulmonary metastases from osteogenic sarcoma. The only significant prognostic indicators we found were the number of nodules identified on preoperative tomograms, the disease-free interval, resectability of the metastases, and the number of metastases resected. Other factors such as tumor doubling time, presence of bilateral or unilateral metastases, age and sex of the patient, and location of the primary tumor were considered but failed to demonstrate any prognostic value. The number of nodules on preoperative fulllung linear tomography was the most sensitive indicator of postthoracotomy survival. Patients with 3 or fewer nodules had appreciably greater survival (median, 37 months) than patients with more than 3 nodules (median, 10 months). In no patient with more than 16 nodules on preoperative tomography could complete resection be accomplished. However, the group with more than 3 nodules included only 6 patients, and thus a limitation of this study is that there were no patients with an intermediate number of nodules (more than 5 but fewer than 16) on preoperative tomograms. The disease-free interval has been thought by some [3-6, 9, 14, 40, 411 to influence postthoracotomy survival but was found to be of little or no value in other studies [8, 15, 421. Telander and associates [30] reported that patients who died of pulmonary metastases from osteogenic sarcoma had a disease-free interval of 3.5 months, while those still living had a median disease-free interval of 14 months. Burgers and co-workers [20] noted that the disease-free interval was significantly longer for patients who underwent thoracotomy. We found that a disease-free interval of 6 months or more was associated with an increase in postoperative
521 Putnam et al: Resection of Pulmonary Metastases from Osteogenic Sarcoma
survival (median survival, 38 months) compared with a disease-free interval of less than 6 months (median survival, 12 months; p = 0.09). When evaluated by regression analysis, the disease-free interval was found to be a significant prognostic factor influencing postthoracotomy survival. Numerous studies have commented on the apparent correlation between tumor doubling time and survival [6, 10, 15, 16, 34-36]. Tumor doubling time was calculated for 31 of our patients. Of those patients with a tumor doubling time less than or equal to 20 days, a median survival of 26 months was noted, while those patients with a tumor doubling time of greater than 20 days had a median survival of 37 months ( p = 0.39). No statistically significant predictive value for survival could be obtained based on the tumor doubling time alone. This finding agrees with the study by Huth and colleagues [6] demonstrating no difference in longterm survival for patients with rapid tumor doubling times compared with patients who had shorter doubling times. In their study, however, those patients with rapid doubling times had recurrence earlier. Various combinations of prognostic factors were analyzed. The combination of the number of nodules on preoperative tomography and the disease-free interval did not significantly increase the predictive value of the model ( p = 0.15) compared with the number of nodules on preoperative tomograms alone. When three or more factors were combined, such as number of nodules on preoperative tomography, diseasefree interval, and resectability, the predictive value again was not increased compared with the number of nodules alone. Based on our findings, the following conclusions can be drawn. 1. Patients with 3 or fewer nodules on preoperative tomograms have the most favorable prognosis of all individuals undergoing resection of pulmonary metastases from osteogenic sarcoma. 2. Patients with more than 16 nodules on preoperative full-lung tomograms were not candidates for resection at exploration.
3. A disease-free interval of less than 6 months indicates a poor prognosis for the patient yet should not exclude the patient from resection if otherwise appropriate. Use of these prognostic factors may result in a more rational selection of patients for exploration and may identify patients who will benefit from operative resection of pulmonary metastases from osteogenic sarcoma. Appendix Thoracic Explorations in Patients with Pulmonary Metastases from Osteogenic Sarcomaa
80 Patients with osteogenic sarcoma 32 Patients NED, never recurred 5 Recurred elsewhere 43 Initially recurred in lungs 4 No thoracotomy, DWD 39 Exploration No. 1 7 Unresectable, DWD 1 Other,’NED 31 Resectable 11 NED 7 DWD 13 Exploration No. 2 1 Unresectable, DWD 12 Resectable 6 NED 2 DWD 4 Exploration No. 3 1 Unresectable, DWD 3 Resectable 1 NED 1 DWD 1 Exploration No. 4 1 Resectable, DWD “A total of 62 operative procedures were performed in 39 Ptients, (including 5 staged thoracotomies). At initial exploration, the lesion in this patient’s disease was found to be unresectable. The patient subsequently was treated with postoperative chemotherapy. Later, exploration and complete resection were carried out. The patient remains active and disease free following her fourth thoracotomy. She was excluded from further analysis because her treatment differed from that of all other patients in this study. NED = no evidence of disease; DWD = dead with disease.
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effect of metastasectomy: fact or fiction? Ann Thorac Surg 30:378, 1980 3. Appelqvist P, Koikkalainen K, Tala P, et al: Surgical treatment of pulmonary metastases. Int Surg 64:13, 1979 4. Blondet R, Zlatoff P, Frieh JP, et al: Results of combined chemosurgical therapy for pulmonary metastases. J Surg Oncol 18:105, 1981 5. Creagan ET, Fleming TR, Edmonson JH, et al: Pulmonary resection for metastatic nonosteogenic sarcoma. Cancer 44:1908, 1979 6. Huth JF, Holmes EC, Vernon SE, et al: Pulmonary resection for metastatic sarcoma. Am J Surg 140:9, 1980 7. Le Brigand H, Merlier M, Wapler C, et al: Surgery in the treatment of pulmonary metastases. Recent Results Cancer Treat 62:213, 1977 8. Marks P, Ferrag MZ, Ashraf H: Rationale for the surgical treatment of pulmonary metastases. Thorax 36:679, 1981 9. Morrow CE, Vassilopoulos P, Grage TB: Surgical resection for metastatic neoplasms of the lung: experience at the University of Minnesota Hospitals. Cancer 45:2981, 1980 10. Morton DL, Joseph WL, Ketcham AS, et al: Surgical resection and adjunctive immunotherapy for selected patients with multiple pulmonary metastases. Ann Surg 178:360, 1973 11. Muhe E, Gall FP, Angerman B: Surgical treatment of metastases to the lung and liver. Surg Gynecol Obstet 152211, 1981 12. Ramming KP: Surgery for pulmonary metastases. Surg Clin North Am 60:815, 1980 13. Rodgers BM, Talbert JL, Alexander JA: Pulmonary metastases in childhood sarcoma. Ann Thorac Surg 29:410, 1980 14. Takita H, Edgerton F, Karakousis C, et al: Surgical management of metastases to the lung. Surg Gynecol Obstet 152:191, 1981 15. Takita H, Merrin C, Didolkar MS, et al: The surgical management of multiple lung metastases. Ann Thorac Surg 24:359, 1977 16. Temple WJ, Ketcham AS: Surgical management of isolated systemic metastases. Semin Oncol 7:468, 1980 17. Spencer H: Pathology of the Lung (Excluding Pulmonary Tuberculosis). Third edition. New York, Pergamon, 1977, vol 2 18. Willis RA: The Spread of Tumors in the Human Body. Third edition. London, Butterworth, 1973 19. Beattie EJ Jr, Martini N, Rosen G: The management of pulmonary metastases in children with osteogenic sarcoma with surgical resection combined with chemotherapy. Cancer 35:618, 1975 20. Burgers JM, Breur DK, van Dobbenburgh OA, et al: Role of metastasectomy without chemotherapy in the management of osteosarcoma in children. Cancer 45:1664, 1980 21. Dunn D, Dehner LP: Metastatic osteosarcoma to
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Discussion (Houston, TX): I congratulate the authors on a n excellent presentation. This is a fine study with precise analysis of prognostic factors. For many years my colleagues and I have pursued an aggressive surgical approach to the treatment of pulmonary metastasis. We believe that success with this approach is primarily dependent on the appropriate selection of patients, and Dr. Putnam and his colleagues have provided valuable insights that may substantially affect this selection process. We have undertaken resection for pulmonary metastases in 457 patients. The postthoracotomy survival in 166 patients undergoing apparent complete resection for sarcomatous pulmonary metastases in this series showed that the outcome for patients with osteogenic sarcoma was significantly better than that for the other cell types-54% survived five years or longer. The criteria for selection were similar to those of Dr. Putnam’s group. Patients with bilateral and multiple lesions were not considered inoperable per se but were evaluated according to the same criteria as patients with solitary nodules, and are included in these results. Dr. Putnam, was the incidence of pulmonary metastasis related to the primary treatment plan, and did any of the patients have chemotherapy before or after pulmonary resection? Twenty-nine of our patients with osteogenic sarcoma had planned surgical adjuvant therapy, and the outcome for this group was significantly better than that for 14 patients who did not receive such treatment. This was also true for our total series for patients with sarcoma and those with carcinoma. In our studies, w e have observed that the diseaseDR. CLIFTON F. MOUNTAIN
free interval is a variable prognostic element. Those patients with either sarcoma or carcinoma who manifested pulmonary metastases within the first year of treatment fared no worse than patients with a longer disease-free interval. In our 15 patients with osteogenic sarcoma whose first observed pulmonary metastasis was within 6 months of primary treatment, a significantly poorer outcome was observed than for those with longer disease-free status. However, that small group with the first observed pulmonary metastasis occurring within 7 to 12 months of primary treatment had the best survival compared with those who had a longer disease-free interval. Again, I congratulate the investigators, and I appreciate the opportunity and privilege of reviewing their manuscript. DR. HOWARD s. BROWN (Atlanta, GA): Dr. Putnam, was there any reason why tomograms rather than CT scans were used for the follow-up? I believe that thoracic CT scans are better and more accurate for evaluating metastatic pulmonary disease.
I thank Dr. Mountain for his kind remarks. About half the patients in our series received some type of chemotherapy for treatment of their primary tumor, and there was no significant difference in survival between patients who received chemotherapy and those who did not. At this point I cannot comment on the role of chemotherapy in the treatment of metastatic osteogenic sarcoma. Currently, an ongoing prospective randomized clinical trial is being conducted by the Pediatric Oncology Branch of the National Cancer Institute to study Dr. Rosen’s chemotherapy regimen for the treatment of this disease. As to whether the CT scan or lung tomography is the better method to determine if metastatic disease is present in the lung, we utilized lung tomograms primarily. The lung tomograms were performed every 3 months with roentgenograms obtained at 1-cm intervals. In general, CT scans were not performed. Studies have shown these scans to be a much more sensitive indicator of pulmonary pathological involvement. However, we have found that on the CT scan these abnormalities tend, in many instances, to be benign disease. The CT scan is more sensitive but less specific than are the lung tomograms, and we now are evaluating prospectively the value of the CT scan in the early detection of pulmonary metastases. D R . PUTNAM:
lowing resection, and other patients cannot undergo complete resection at exploration. Pulmonary metastases will develop in 20 to 30% of all patients with malignant disease [lo, 17, 181 and the lungs initially will be the sole site of metastases in virtually all patients with osteogenic sarcoma. Therefore, patients with pulmonary metastases from osteogenic sarcoma provide an ideal group for the study of factors that influence survival following resection of pulmonary metastases [19-301. Recent studies suggest that several factors influence the postoperative survival of these patients. These factors include tumor doubling time [6, 10, 14-16, 221, disease-free interval (from primary operation to date of first lung recurrence) [3-6, 9-11, 141, multiplicity or bilaterality of lesions [ll, 14, 161, and resectability [14]. Although these studies documented benefit for patients following surgical resection of pulmonary metastases, the importance of these prognostic factors in postthoracotomy survival remains controversial. In our study, factors that influenced postoperative survival were evaluated in patients in whom metastatic pulmonary osteogenic sarcoma developed following resection of the primary tumor. Several Following the successful resection of a pulmo- prognostic criteria were identified and critically nary metastasis in a patient with metastatic re- analyzed for their ability to predict survival folnal cell carcinoma by Barney and Churchill [l], lowing resection of metastases. there have been frequent reports of long-term survivors following resection of pulmonary Material and Methods metastases [2-161. However, a notable percent- Between 1975 and 1982, 80 patients with osage of patients still die of tumor recurrence fol- teogenic sarcoma were entered into ongoing prospective trials in the Surgery Branch of the From the Surgery Branch, Division of Cancer Treatment, National Cancer Institute. Among the 48 paand the Biometric Research Branch, National Cancer Institute, Bethesda, MD. tients with recurrence, 43 had recurrence iniPresented at the Nineteenth Annual Meeting of The Society tially in the lungs only. Thirty-nine (91%) of of Thoracic Surgeons, San Francisco, CA, Jan 17-19, 1983. these 43 patients underwent thoracotomy (ApAddress reprint requests to Dr. Roth, Thoracic Oncology pendix). Thirteen patients (33%)underwent 2 or Section, Surgery Branch, National Cancer Institute, Building more thoracotomies. Ages ranged from 6 to 49 10, Room 10N116, Bethesda, MD 20205.
ABSTRACT Between 1975 and 1982, 80 patients with osteogenic sarcoma were entered into prospective trials in the Surgery Branch of the National Cancer Institute. In 43 of these patients, pulmonary metastases developed as the initial site of recurrence, and 39 underwent one or more thoracotomies for resection of the disease. The actuarial five-year survival for the group of 43 patients with pulmonary metastases was 40%. Various prognostic factors were analyzed for their influence on survival after thoracotomy. Age, sex, location of primary tumor, tumor doubling time, and involvement of one or both lungs (bilaterality)were not significant in predicting survival. Prognostic factors that influenced survival, calculated by regression analysis, included the number of nodules on preoperative lung tomograms (negative correlation, p = 0.0004), disease-free interval (positive correlation, p = 0.0136), resectability (positive correlation, p = 0.002), and the number of metastases resected at thoracotomy (negative correlation, p = 0.0032). The presence of 3 nodules or less on preoperative full-lung linear tomography was found to be the single most useful preoperative prognostic factor. The application of these prognostic factors preoperatively may identify patients who will benefit optimally from thoracotomy.
516
517 Putnam et al: Resection of Pulmonary Metastases from Osteogenic Sarcoma
years (median, 16 years). There were 33 male (76.7%) and 10 female (23.3%)patients. Among the 5 patients with recurrence in nonpulmonary sites, 1 had recurrence in the primary site and 1 at another site and in the lungs simultaneously. Four patients with pulmonary metastases did not undergo thoracotomy because of the extent of pulmonary metastases, and were excluded from the analysis. One additional patient was excluded at initial thoracotomy because the tumor was unresectable. However, in contrast to all other patients in the study, she underwent reexploration following postoperative chemotherapy. At that time, all metastases were resected, and she is now alive and free from disease after the fourth thoracotomy. All patients were evaluated before entry into the protocol. Site and extension of primary disease were noted and metastases histologically documented. Patients underwent a complete physical evaluation including chest roentgenograms, conventional full-lung linear tomography at 1-cm intervals, and bone scan. When necessary, computed tomographic (CT) scan of the extremity was performed. Pulmonary nodules were identified on chest roentgenograms or full-lung linear tomography. These roentgenographic examinations were performed every 3 months during the follow-up period. The appearance of previously undetected nodules and the growth of existing nodules were the criteria used to designate the radiographic appearance of nodules as consistent with metastases. Conventional linear tomography has previously been shown to be a sensitive and specific technique for the early detection of metastases to the lung [27, 31, 321. Computed tomography of the lungs was not performed in these patients routinely. Patients considered for exploration for resection of metastases met the following criteria: (1) control of the primary tumor; (2) absence of other metastases; (3) radiological findings consistent with metastases on full-lung tomography; and (4) potential for operative resection of the tumor. Patients were explored by lateral thoracotomy or median sternotomy on one or more occasions. A median sternotomy was the
preferred initial procedure [33]. With that method, occult metastases in the contralateral lung could be identified and resected. Doublelumen endotracheal tubes and radial artery catheters were used routinely. The thorax was explored by both the surgeon and the assistant. The lungs were deflated sequentially and examined by palpation. All nodules were identified and resected using the TA automatic stapling device. Malignancy was confirmed on frozen section examination. Most nodules were subpleural, and therefore, lobectomy or pneumonectomy was rarely necessary. The lungs, chest wall, mediastinum, hilar nodes, and diaphragm were all examined, and local extension of tumor was resected. All tumor was removed whenever possible. Obvious anthracotic lymph nodes and granulomatous disease were not resected; however, if there was any doubt, the nodule was removed. Tumor doubling time was calculated by the method of Joseph and colleagues [34, 351 based on original observations by Collins and coworkers [36]. Briefly, all chest roentgenograms were examined for evidence of metastases. For those patients who had metastases present on preoperative chest roentgenograms, a tumor doubling time was calculated. Excluded were those patients whose chest roentgenograms were obtained less than 14 days apart. In patients with multiple nodules, the doubling time of the fastest growing nodule was used for statistical evaluation. Diameters of tumor nodules were plotted on semilogarithmic paper against time expressed in days between observations. A line was drawn between the points, and the horizontal distance was measured between the two doubling lines crossed by this line; this was called the tumor doubling time and was calculated only for nodules clearly delineated on serial chest roentgenograms.
Statistical Methods Overall survival and postthoracotomy survival curves were estimated using the method of Kaplan and Meier [37]. Comparisons between groups were made using the generalized Wilcoxon test of Gehan [38]. The relative effect of various prognostic factors was assessed using
518 The Annals of Thoracic Surgery Vol 36 No 5 November 1983
Cox's proportional hazards model [39]. A univariate analysis identified the most important set of factors; of these, all pairs were analyzed. Other variables were added to the best pair to see if additional prognostic value was achieved. All p values were determined from two-tailed tests.
Results Sixty-two surgical procedures-46 lateral thoracotomies (74%) and 16 median sternotomies (26%)-were performed in 39 patients. Five of the explorations were staged lateral thoracotomies. The following resections were performed at initial or later thoracotomy: 1 or more wedge resections on 113 lobes, 4 segmentectomies, 12 lobectomies, and 1 pneumonectomy. No patient was noted to have metastases involving the hilar or mediastinal nodes. There were no operative deaths and only three minor postoperative complications, pneumonia in 2 patients and wound infection in 1. Only 1 of the 39 patients had an initial thoracotomy for benign disease. Granulomatous disease was confirmed by pathological findings. However, pulmonary metastases developed later. No patient undergoing a second thoracotomy had benign pulmonary disease. Few patients were seen with pulmonary symptoms relating to the metastases. Three of 43 patients had symptoms, including cough in 2 instances, chest pain in 2, and dyspnea from a pleural effusion in 1. Forty-three patients had recurrence initially in the lungs, and 39 of them underwent exploration for pulmonary metastases. The actuarial postthoracotomy five-year survival of 38 evaluated patients (1 was excluded as described earlier) was 40% (Fig l).All survivors are alive and disease free. Thirteen patients had two or more thoracotomies. Patients with synchronous metastases at the time of presentation of the primary lesion were excluded. Of the 38 patients undergoing thoracotomy, patients whose tumors were resectable had a significantly longer survival after thoracotomy (37 months, median) than those whose tumors were unresectable (median, 9 months; p = 0.002).
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Fig 2. Postthoracotomy survival in patients with 3 nodules or less and patients with more than 3 nodules on preoperative lung tomograms ( p = 0.039, Gehan-Wilcoxon test).
Prognostic Factors Age, sex, and the location of the primary tumor were evaluated for their predictive value in patients with pulmonary metastases. None of these factors correlated significantly with postthoracotomy survival. NODULES ON PREOPERATIVE TOMOGRAPHY. The relationship between the number of nodules on preoperative tomography and postthoracotomy survival is shown in Figure 2. Patients with 3 or fewer nodules on preoperative lung tomograms had a significantly longer postthoracotomy survival (median, 37 months; N = 32) than those with more than 3 nodules (median, 10 months; N = 6; p = 0.039). If more than 16 nodules were found on preoperative tomograms, resection was not possible (N = 4).
519 Putnam et al: Resection of Pulmonary Metastases from Osteogenic Sarcoma
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UNILATERAL
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TOMOGRAPHY. The influence of unilateral or bilateral nodules on survival was investigated. Eighteen patients had unilateral single nodules, 8 had unilateral multiple nodules, and 13 had bilateral nodules. One patient with bilateral metastases was excluded after initial thoracotomy, as described previously. No significant difference in postthoracotomy survival was noted between those patients with unilateral nodules on preoperative tomography and those with bilateral nodules. DISEASE-FREE INTERVAL. The effect Of the h i tial disease-free interval (time from resection of the primary tumor to date of the first pulmonary recurrence) was also examined for its value in predicting survival following thoracotomy . Patients with a disease-free interval of 6 months or PREOPERATIVE
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more had a longer postthoracotomy survival (38 months, median) than patients with a diseasefree interval of less than 6 months (median, 12 months; p = 0.09) (Fig 3). Although this was of borderline statistical significance for these arbitrary groupings, the disease-free interval did correlate significantly with survival when evaluated by regression analysis ( p = 0.0136). TUMOR DOUBLING TIME. No correlation could be found between tumor doubling time and survival in patients with pulmonary metastases from osteogenic sarcoma. Patients with tumor doubling times of 20 days or less and of more than 20 days were examined (Fig 4). There was no significant difference between the two survival curves ( p = 0.39). RESECTABLE VERSUS NONRESECTABLE LESIONS. Patients with resectable metastases survived longer (median, 37 months) than patients with unresectable metastases (median, 9 months; p = 0.002) (Fig 5). No patient with unresectable disease had a postthoracotomy survival greater than 20 months. PaNUMBER OF POSITIVE NODULES RESECTED. tients undergoing complete resection with 4 or fewer histologically confirmed metastases had a survival of 62% at 36 months (median not yet reached; N = 22) compared with patients with 5 nodules or more and a median survival of 16 months (N = 9; p = 0.105) (Fig 6). The maximum number of metastases resected was 25; that patient remains alive and free from tumor one year after resection of the primary tumor after two median sternotomies.
520 The Annals of Thoracic Surgery Vol 36 No 5 November 1983
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Fig 6 . Postthoracotomy survival compared with the number of metastases resected ( p = 0.105 [borderline significance], Gehan-Wilcoxon test).
Regression Analysis of Select Variables Regression analysis [39] of select factors, analyzed as continuous variables, was performed. This analysis determined that the number of nodules on preoperative tomograms (negative correlation, p = 0.0004), the number of histologically documented pulmonary metastases resected on exploration (negative correlation, p = 0.0032), the disease-free interval (positive correlation, p = 0.0136), and resectability (positive correlation, p = 0.002) all correlated with postthoracotomy survival. Using the variables just described, we determined whether combinations of these factors would increase the predictive value of the model significantly. Because the number of nodules on tomograms as a single factor had the most significant correlation with survival following thoracotomy, additional factors were combined with it to determine whether the predictive value was increased. Combining the number of tomographic nodules with the disease-free interval yielded the best paired combination yet did not increase the predictive value of the model in a significant fashion ( p = 0.15). No variable added a significant increase in predictive value to the number of nodules on preoperative lung tomograms. Comment Few studies describe objective criteria that can be reliably used to predict postthoracotomy survival of patients with osteogenic sarcoma [19301. A review by van Dongen and van Slooten
[40] suggested several prognostic factors that may influence postthoracotomy survival. Those include histology of the primary tumor; tumor doubling time; disease-free interval (from primary operation to date of first lung recurrence); size of metastases and the presence of mediastinal or hilar nodes; and the number of treated (resected) metastases. In the present study, we analyzed factors that potentially could predict the postthoracotomy survival for patients with pulmonary metastases from osteogenic sarcoma. The only significant prognostic indicators we found were the number of nodules identified on preoperative tomograms, the disease-free interval, resectability of the metastases, and the number of metastases resected. Other factors such as tumor doubling time, presence of bilateral or unilateral metastases, age and sex of the patient, and location of the primary tumor were considered but failed to demonstrate any prognostic value. The number of nodules on preoperative fulllung linear tomography was the most sensitive indicator of postthoracotomy survival. Patients with 3 or fewer nodules had appreciably greater survival (median, 37 months) than patients with more than 3 nodules (median, 10 months). In no patient with more than 16 nodules on preoperative tomography could complete resection be accomplished. However, the group with more than 3 nodules included only 6 patients, and thus a limitation of this study is that there were no patients with an intermediate number of nodules (more than 5 but fewer than 16) on preoperative tomograms. The disease-free interval has been thought by some [3-6, 9, 14, 40, 411 to influence postthoracotomy survival but was found to be of little or no value in other studies [8, 15, 421. Telander and associates [30] reported that patients who died of pulmonary metastases from osteogenic sarcoma had a disease-free interval of 3.5 months, while those still living had a median disease-free interval of 14 months. Burgers and co-workers [20] noted that the disease-free interval was significantly longer for patients who underwent thoracotomy. We found that a disease-free interval of 6 months or more was associated with an increase in postoperative
521 Putnam et al: Resection of Pulmonary Metastases from Osteogenic Sarcoma
survival (median survival, 38 months) compared with a disease-free interval of less than 6 months (median survival, 12 months; p = 0.09). When evaluated by regression analysis, the disease-free interval was found to be a significant prognostic factor influencing postthoracotomy survival. Numerous studies have commented on the apparent correlation between tumor doubling time and survival [6, 10, 15, 16, 34-36]. Tumor doubling time was calculated for 31 of our patients. Of those patients with a tumor doubling time less than or equal to 20 days, a median survival of 26 months was noted, while those patients with a tumor doubling time of greater than 20 days had a median survival of 37 months ( p = 0.39). No statistically significant predictive value for survival could be obtained based on the tumor doubling time alone. This finding agrees with the study by Huth and colleagues [6] demonstrating no difference in longterm survival for patients with rapid tumor doubling times compared with patients who had shorter doubling times. In their study, however, those patients with rapid doubling times had recurrence earlier. Various combinations of prognostic factors were analyzed. The combination of the number of nodules on preoperative tomography and the disease-free interval did not significantly increase the predictive value of the model ( p = 0.15) compared with the number of nodules on preoperative tomograms alone. When three or more factors were combined, such as number of nodules on preoperative tomography, diseasefree interval, and resectability, the predictive value again was not increased compared with the number of nodules alone. Based on our findings, the following conclusions can be drawn. 1. Patients with 3 or fewer nodules on preoperative tomograms have the most favorable prognosis of all individuals undergoing resection of pulmonary metastases from osteogenic sarcoma. 2. Patients with more than 16 nodules on preoperative full-lung tomograms were not candidates for resection at exploration.
3. A disease-free interval of less than 6 months indicates a poor prognosis for the patient yet should not exclude the patient from resection if otherwise appropriate. Use of these prognostic factors may result in a more rational selection of patients for exploration and may identify patients who will benefit from operative resection of pulmonary metastases from osteogenic sarcoma. Appendix Thoracic Explorations in Patients with Pulmonary Metastases from Osteogenic Sarcomaa
80 Patients with osteogenic sarcoma 32 Patients NED, never recurred 5 Recurred elsewhere 43 Initially recurred in lungs 4 No thoracotomy, DWD 39 Exploration No. 1 7 Unresectable, DWD 1 Other,’NED 31 Resectable 11 NED 7 DWD 13 Exploration No. 2 1 Unresectable, DWD 12 Resectable 6 NED 2 DWD 4 Exploration No. 3 1 Unresectable, DWD 3 Resectable 1 NED 1 DWD 1 Exploration No. 4 1 Resectable, DWD “A total of 62 operative procedures were performed in 39 Ptients, (including 5 staged thoracotomies). At initial exploration, the lesion in this patient’s disease was found to be unresectable. The patient subsequently was treated with postoperative chemotherapy. Later, exploration and complete resection were carried out. The patient remains active and disease free following her fourth thoracotomy. She was excluded from further analysis because her treatment differed from that of all other patients in this study. NED = no evidence of disease; DWD = dead with disease.
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kidney with metastasis to the lung cured by nephrectomy and lobectomy. J Urol 42269, 1939 2. Aberg T, Malmberg K-A, Nilsson B, NGu E: The
522 The Annals of Thoracic Surgery Vol 36 No 5 November 1983
effect of metastasectomy: fact or fiction? Ann Thorac Surg 30:378, 1980 3. Appelqvist P, Koikkalainen K, Tala P, et al: Surgical treatment of pulmonary metastases. Int Surg 64:13, 1979 4. Blondet R, Zlatoff P, Frieh JP, et al: Results of combined chemosurgical therapy for pulmonary metastases. J Surg Oncol 18:105, 1981 5. Creagan ET, Fleming TR, Edmonson JH, et al: Pulmonary resection for metastatic nonosteogenic sarcoma. Cancer 44:1908, 1979 6. Huth JF, Holmes EC, Vernon SE, et al: Pulmonary resection for metastatic sarcoma. Am J Surg 140:9, 1980 7. Le Brigand H, Merlier M, Wapler C, et al: Surgery in the treatment of pulmonary metastases. Recent Results Cancer Treat 62:213, 1977 8. Marks P, Ferrag MZ, Ashraf H: Rationale for the surgical treatment of pulmonary metastases. Thorax 36:679, 1981 9. Morrow CE, Vassilopoulos P, Grage TB: Surgical resection for metastatic neoplasms of the lung: experience at the University of Minnesota Hospitals. Cancer 45:2981, 1980 10. Morton DL, Joseph WL, Ketcham AS, et al: Surgical resection and adjunctive immunotherapy for selected patients with multiple pulmonary metastases. Ann Surg 178:360, 1973 11. Muhe E, Gall FP, Angerman B: Surgical treatment of metastases to the lung and liver. Surg Gynecol Obstet 152211, 1981 12. Ramming KP: Surgery for pulmonary metastases. Surg Clin North Am 60:815, 1980 13. Rodgers BM, Talbert JL, Alexander JA: Pulmonary metastases in childhood sarcoma. Ann Thorac Surg 29:410, 1980 14. Takita H, Edgerton F, Karakousis C, et al: Surgical management of metastases to the lung. Surg Gynecol Obstet 152:191, 1981 15. Takita H, Merrin C, Didolkar MS, et al: The surgical management of multiple lung metastases. Ann Thorac Surg 24:359, 1977 16. Temple WJ, Ketcham AS: Surgical management of isolated systemic metastases. Semin Oncol 7:468, 1980 17. Spencer H: Pathology of the Lung (Excluding Pulmonary Tuberculosis). Third edition. New York, Pergamon, 1977, vol 2 18. Willis RA: The Spread of Tumors in the Human Body. Third edition. London, Butterworth, 1973 19. Beattie EJ Jr, Martini N, Rosen G: The management of pulmonary metastases in children with osteogenic sarcoma with surgical resection combined with chemotherapy. Cancer 35:618, 1975 20. Burgers JM, Breur DK, van Dobbenburgh OA, et al: Role of metastasectomy without chemotherapy in the management of osteosarcoma in children. Cancer 45:1664, 1980 21. Dunn D, Dehner LP: Metastatic osteosarcoma to
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Discussion (Houston, TX): I congratulate the authors on a n excellent presentation. This is a fine study with precise analysis of prognostic factors. For many years my colleagues and I have pursued an aggressive surgical approach to the treatment of pulmonary metastasis. We believe that success with this approach is primarily dependent on the appropriate selection of patients, and Dr. Putnam and his colleagues have provided valuable insights that may substantially affect this selection process. We have undertaken resection for pulmonary metastases in 457 patients. The postthoracotomy survival in 166 patients undergoing apparent complete resection for sarcomatous pulmonary metastases in this series showed that the outcome for patients with osteogenic sarcoma was significantly better than that for the other cell types-54% survived five years or longer. The criteria for selection were similar to those of Dr. Putnam’s group. Patients with bilateral and multiple lesions were not considered inoperable per se but were evaluated according to the same criteria as patients with solitary nodules, and are included in these results. Dr. Putnam, was the incidence of pulmonary metastasis related to the primary treatment plan, and did any of the patients have chemotherapy before or after pulmonary resection? Twenty-nine of our patients with osteogenic sarcoma had planned surgical adjuvant therapy, and the outcome for this group was significantly better than that for 14 patients who did not receive such treatment. This was also true for our total series for patients with sarcoma and those with carcinoma. In our studies, w e have observed that the diseaseDR. CLIFTON F. MOUNTAIN
free interval is a variable prognostic element. Those patients with either sarcoma or carcinoma who manifested pulmonary metastases within the first year of treatment fared no worse than patients with a longer disease-free interval. In our 15 patients with osteogenic sarcoma whose first observed pulmonary metastasis was within 6 months of primary treatment, a significantly poorer outcome was observed than for those with longer disease-free status. However, that small group with the first observed pulmonary metastasis occurring within 7 to 12 months of primary treatment had the best survival compared with those who had a longer disease-free interval. Again, I congratulate the investigators, and I appreciate the opportunity and privilege of reviewing their manuscript. DR. HOWARD s. BROWN (Atlanta, GA): Dr. Putnam, was there any reason why tomograms rather than CT scans were used for the follow-up? I believe that thoracic CT scans are better and more accurate for evaluating metastatic pulmonary disease.
I thank Dr. Mountain for his kind remarks. About half the patients in our series received some type of chemotherapy for treatment of their primary tumor, and there was no significant difference in survival between patients who received chemotherapy and those who did not. At this point I cannot comment on the role of chemotherapy in the treatment of metastatic osteogenic sarcoma. Currently, an ongoing prospective randomized clinical trial is being conducted by the Pediatric Oncology Branch of the National Cancer Institute to study Dr. Rosen’s chemotherapy regimen for the treatment of this disease. As to whether the CT scan or lung tomography is the better method to determine if metastatic disease is present in the lung, we utilized lung tomograms primarily. The lung tomograms were performed every 3 months with roentgenograms obtained at 1-cm intervals. In general, CT scans were not performed. Studies have shown these scans to be a much more sensitive indicator of pulmonary pathological involvement. However, we have found that on the CT scan these abnormalities tend, in many instances, to be benign disease. The CT scan is more sensitive but less specific than are the lung tomograms, and we now are evaluating prospectively the value of the CT scan in the early detection of pulmonary metastases. D R . PUTNAM: