The Role of Radiation Therapy

Transcription

1 The Role of Radiation Therapy and Surgery in the Treatment of Bronchogenic Carcinoma R Adams Cowley, M.D., Morris J. Wizenberg, M.D., and Eugene J. Linberg, M.D. A study of the combined use of preoperative irradiation and surgery in the treatment of bronchogenic carcinoma was initiated at the University of Maryland in 1956 [2]. All patients have been followed for at least five years. We hypothesized that by combining the curative potential of surgical extirpation with the effectiveness of high-voltage radiation therapy in controlling the primary lesion and local extension, it might be possible to increase the cure rate for carcinoma of the lung by making the therapy more applicable to larger numbers of patients with less selection of cases. The objectives of the hypothesis could be accomplished by rendering operable those tumors previously unresectable due to local extension into the carina, trachea, large vessels, chest wall, mediastinum, or supraclavicular areas. Radiation therapy would, in addition, be responsible for the control of mediastinal, scalene, and supraclavicular node metastases that could not be resected. Furthermore, irradiation producing cellular devitalization in the tumor might be expected to diminish or prevent local seeding and the production of distant metastases caused by surgical manipulation of the tumor. The aims of the study were to determine: The possibility of radical radiation therapy en bloc to the primary and contiguous lymph nodes, including the scalene and supraclavicular nodes. The feasibility of operation after irradiation. Whether radiation therapy can render operable cases previously considered inoperable. The possibility of improving the cure rate by such combined treatment. From the Division of Thoracic and Cardiovascular Surgery and the Division of Radiation Therapy, University of Maryland School of Medicine, Baltimore, Md. Presented at the Fifth Annual Meeting of The Society of Thoracic Surgeons, San Diego, Calif., Jan , VOL. 8, NO. 3, SEPTEMBER,

2 COWLEY, WIZENBERG, AND LINBERG TABLE 1. COMPOSITION OF STUDY GROUP INCLUDING HISTOLOGICAL FINDINGS OF PATIENTS STARTED ON PLANNED THERAPY Findings Squamous cell carcinoma Anaplastic (oat cell) Adenocarcinoma Undifferentiated No histology (Pancoast tumor) Originally operable Originally inoperable Total No. of Patients In selecting patients for inclusion in the study, the criterion was disease limited to one side of the chest, with or without mediastinal, scalene, or supraclavicular adenopathy, but without pleural effusion or distant metastasis. All patients, with the exception of 2 having Pancoast tumors, had histologically or cytologically proved carcinoma (Table 1). Those patients selected were irradiated using cobalt teletherapy. The technique has already been described [31. The primary tumor and its extensions were irradiated by a combination of fixed and rotational fields to a dose of 5,500 to 6,000 rads in five and a half to six weeks. Those patients with anaplastic cancers or with superior mediastinal involvement received radiation to both supraclavicular regions, as did those patients with positive scalene or supraclavicular nodes. Operation was planned after a waiting period of six to eight weeks unless some contraindication such as distant metastasis developed during the interval. EXPERIENCE AND RESULTS An analysis of our experience is best shown in the patient flow chart (Figure), which traces the course of the patients during the study period and relates the results of the study to our initial aims and hypothesis. It shows that during the study period 366 patients were seen, of whom 174 were excluded because of (1) the presence of distant metastasis, (2) a general condition already too poor to permit radical therapy, and (3) previous resections performed elsewhere with referral for postoperative irradiation. One hundred and ninety-two patients met the study criteria and were started on a course of radiation therapy preliminary to operation. Of these, 83 were originally considered operable and 109 inoperable, on the basis of either thoracotomy or other diagnostic studies. Of the entire group of 192, 50 patients developed metastasis between the initiation of radiation therapy and the dates scheduled for operation. Of these, none survived. Seventeen patients refused operation, and 2 of these have survived five years. Twenty-seven patients were considered to be in too poor a condition to undergo operation; none of these survived. Ninety-eight patients had exploratory thoracotomy following complete irra- 230 THE ANNALS OF THORACIC SURGERY

3 Treatment of Bronchogenic Carcinoma EXCLUDED E T. METS. POOR CONDlTION PREVIOUS RESECTION (FOR POSTOP. IRRAD.) IRRAD, 8 (1/8) REFUSED OPERATION 3 66 TOTAL PATIENTS SEEN STARTED ON PIANNED COMBINED EXPLORED THERAPY - 35 (0/35) DEVELOPED METS. BEFORE OPERATION 2 (1/91 REFUSED I OPERATION LTHERAPY 40 (6/40) RESECT. = 5 Yr. Survival L All figures within the ( ) refer to five-year survivals relative to number of patients in the subgroup. Of the 192 patients, 14 have survived five or more years. I- diation. Of these, 82 were resected. Eleven of the patients who underwent resection have survived for five years or longer, and 1 of the 16 patients found unresectable has also survived for more than five years. It should be noted at this point that almost half of the patients whose tumors were resected had originally been considered inoperable. Of the 98 patients who were explored after radiation therapy, 16 were found unresectable, 21 underwent lobectomy, and 61 underwent pneumonectomy (Table 2). In the unresectable group, only 1 has survived five years; 2 died postoperatively, and all the others have died of distant metastasis or active primary tumor. In the lobectomy group, 5 patients have survived in excess of five years, 4 died postoperatively, and all the others died of distant metastasis. Of the 61 patients who underwent pneumonectomy, there are only 6 five-year survivors. The major causes of death in this group fell into three categories: operative complications (23), distant metastasis (15), and intercurrent disease (15). COMMENT In reference to the original aims of the study, we have determined that it is possible to irradiate to radical doses the primary bronchogenic carcinoma and its contiguous lymph nodes with about a one-third probability of local tumor eradication; however, a large number of our VOL. 8, NO. 3, SEPTEMBER,

4 COWLEY, WIZENBERG, AND LINBERG TABLE 2. FATE OF 98 PATIENTS EXPLORED POSTIRRADIAlION No. of No. of Operation Patients Status Patients Unresected 16 Alive > 5 years 1 Dead, postop. period 2 Dead, active primary 3 Dead, metastasis 10 Lobectomy Pneumonectomy Alive > 5 years 5 Dead, postop. period 4 Dead, metastasis 12 Alive > 5 years 6 Dead, postop. period 19 Dead, late complications 4 Dead, metastasis 15 Dead, intercurrent disease 15 Dead, cancer other lung 1 Dead, hemorrhage 1 patients died [l]. Within the dosage range specified, local reaction is not a limiting factor in the ability to tolerate this treatment. One can also carry out the surgical procedure after radiation, as demonstrated by the fact that 98 of the 192 patients originally considered for this combined therapy were explored, and of those explored, 82% were actually resected. However, a high operative morbidity and mortality must generally be expected. Linberg [4], in an earlier examination of the complications resulting from the combined radiation and surgical treatment of lung cancer, found that the most feared and most common complication was empyema, ordinarily associated with a bronchopleural fistula. There were 21 such occurrences, ending fatally in 16 cases. The great majority of these were in patients with incurable lesions. Although irradiation of the bronchus was a factor, it cannot be forgotten that the cancer was extensive in most of these patients and was by far the most important etiological factor in the patient's complication and eventual death (Table 3). TABLE 3. COMPLICATIONS IN 82 RESECTIONS FOR BRONCHOGENIC CARCINOMA Complicationa Bronchopleural fistula and empyema Tumor in stump Previous thoracotomy Wound dehiscence Gangrenous abscess Number "Related to surgical-technical factors. Other complications included pulmonary insufficiency, cardiac failure, serum hepatitis, etc THE ANNALS OF THORACIC SURGERY

5 Treatment of Bronchogenic Carcinoma This study has also demonstrated that the application of highvoltage preoperative irradiation can render some inoperable cases subsequently operable; 40 of the 82 resections carried out were done in patients previously considered inoperable. Thus, while we have demonstrated the feasibility of such combined therapy, with resection in a large number of patients with less selection, the overall cure rate is not improved because of substantial losses due to operative mortality and development of metastatic disease. Of the 98 patients explored, 29 died as the result of operative complications and 37 more died of metastasis. An additional 50 patients had developed metastasis between their entry into the study and the date on which they were to have undergone operation. Both of these factors were of a magnitude entirely unexpected at the time that we formulated our hypothesis. We had hoped that the advantages of the two therapies would have an accumulative effect in the treatment of lung cancer. However, we had not anticipated that the disadvantages of each therapy would also have an additive effect, thus negating the hoped-for advantages of combining the two therapies. In summary, our findings would indicate that unless some method can be devised to lower drastically the operative mortality and morbidity associated with combined therapy, and to reduce the likelihood of the development of metastatic disease, preoperative irradiation and surgery such as we have described cannot be recommended for the routine management of bronchogenic carcinoma. The survival in the operable group of patients is no better than that in groups of patients treated by surgery alone; nor does the subsequent operation seem to improve the outlook for the inoperable patients who are irradiated previously. We would therefore recommend at this point that those patients who appear to have resectable lesions be considered for thoracotomy and resection and all others be treated by a radical course of radiation therapy. REFERENCES 1. Baker, N., Cowley, R., and Linberg, E. A follow-up in patients with bronchogenic carcinoma locally cured by preoperative irradiation. J. Thorac. Cardiovasc. Surg. 46:298, Bloedorn, F., and Cowley, R. Irradiation and surgery in the treatment of bronchogenic carcinoma. Surg. Gynec. Obstet. 11 1: 141, Bloedorn, F., Cowley, R., Cuccia, C., and Mercado, R. Combined therapy: Irradiation and surgery in the treatment of bronchogenic carcinoma. Amer. J. Roentgen. 85:875, Linberg, E., Cowley, R., Bloedorn, F., and Wizenberg, M. Bronchogenic carcinoma: Further experience with preoperative irradiation. Ann. Thorac. Surg. 1:371, VOL. 8, NO. 3, SEPTEMBER,

6 COWLEY, WIZENBERG, AND LINBERG DISCUSSION DR. DONALD L. PAULSON (Dallas, Tex.): Our own experience with combined preoperative irradiation and resection for bronchogenic carcinoma in more than 100 patients since 1956 differs from that presented by Dr. Cowley, both in the selection of patients and in the radiation dosage. A moderate dosage in the range of 3,000 to 4,000 rads is given over a two- to four-week period, followed by a three- to four-week interval before operation. This interval was formerly of four to six weeks duration. In the superior pulmonary sulcus group, our results indicate 35% five-year survival, according to the actuarial or life-table method, in 41 patients treated by the combined approach from 1956 through There are now 9 five-year survivors, 12 three-year survivors, 8 seven-year survivors, 7 eight-year survivors, and so forth. Utilizing all our cases through 1967, 22 of 39 eligible patients survived one year, 14 of 21 two years, and 12 of 13 patients alive at two years survived three years. There were no deaths after three years. This suggests that the significant survival period is two years. Although these cases were not proved by biopsy before the institution of therapy, all of them were histologically proved at the time of resection. During the period , carcinoma in the hilar location was treated in 59 patients by combined therapy and in 63 patients by resection done primarily without preoperative irradiation. Extent of disease was comparable in the two groups. In the irradiated group, pneumonectomy was performed in 26 cases and lobectomy in 15. Thirty-six patients underwent pneumonectomy and 21 underwent lobectomy in the primary resection group. Combined bronchoplasty and lobectomy was done in 18 patients of the preoperative irradiation group and in only 6 of the primary resection group. Of the 59 patients receiving preoperative irradiation, 24 were initially considered to have inoperable lesions, and 17 had mediastinal node involvement. Twenty-two patients in the primary resection group had positive mediastinal nodes. If the number of combined bronchoplasties and lobectomies is added to the number of lobectomies alone, the preoperative irradiation group has 33 lobectomies, compared to 27 in the primary resection group. The cell types were comparable in both groups: 47 epidermoid carcinomas in the first group, 49 in the second, and a roughly equal distribution of other cell types. There were 6 operative deaths in each group and three bronchial fistulas and six empyemas in the irradiated group. As Dr. Cowley pointed out, it is difficult to determine whether this is related to preoperative irradiation per se or to the extent of the lesion being operated upon. Very often our indications are stretched with the use of preoperative irradiation, and as he experienced in his series, the more extensive the lesion, the more extensive the resection and the higher the morbidity and mortality. There were no fistulas or empyemas in the bronchoplasty cases of either group. Survival at five years for all resections is 40% for those receiving preoperative irradiation and 32% for the primary resection group. This apparent difference can be traced to the extent of the lesions resected. As I said, there were 18 bronchoplasties in the preoperative irradiation group, and survival at five years in this group is 66%, compared to 30% for the bronchoplasties without preoperative irradiation. Excluding the bronchoplasties, five-year survival is about 30% in both groups. Survival at five years in those patients with mediastinal node involvement is about the same in both groups, 8 and 10%. Apparently, preoperative irradiation adds little to survival in the extensive lesions, or Stage 3 cases. In this we are in agreement with Dr. Cowley. At present we believe our results justify continued selective use of pre- 234 THE ANNALS OF THORACIC SURGERY

7 Treatment of Bronchogenic Carcinoma operative irradiation for bronchogenic carcinoma at the chest wall level, particularly in the superior pulmonary sulcus, and for localized hilar lesions, such as the type for which we do a bronchoplasty. It should also be used whenever extended resection is contemplated, in the hope of attaining better localization. DR. ROBERT J. JENSIK (Chicago, Ill.): A summary of our data for May, 1962, through December, 1968, shows that under the two classifications Prior Irradiation and No Prior Irradiation operative procedures varied from pneumonectomy, tracheal sleeve, lobe or segments, to sleeve lobectomy. I would point out first of all that 80 to 85% of the patients in the Prior Irradiation group had advanced lesions with all the criteria of inoperability; yet we were able to accomplish almost a 90% resectability rate, compared to an 84% resectability rate in all those patients considered clinically operable. There were 13 operative deaths in the pneumonectomy group. This was in the first part of the study. I think we owe a debt to Osler Abbott for suggesting the use of steroids, for now, in patients undergoing total resection, mortality has been sharply reduced. In the three-year period from 1966 through 1968, there was only 1 death in 22 patients, 4 of whom had tracheal sleeve pneumonectomies. Resections were of two extremes. In one, a salvage of lung tissue was accomplished by the bronchoplasty or bronchial anastomotic procedure, as Dr. Paulson demonstrated, and 5 of that group of 28 patients survived more than five years. In the radical procedure of tracheal sleeve pneumonectomy, the lesion was located near the orifice of the right main bronchus or ascended up the lateral wall of the trachea. This location would constitute inoperability by most criteria. In our series there have been 8 patients so treated, 3 of whom are alive, 1 more than four and one-half years and 1 more than one and one-half years. I would suggest the use of standard survival curves for determining results, rather than a listing of two-, three-, four-, or five-year survivors. We demonstrated a 27% salvage in the first five years of our study with a sample size of 137 patients. I detect a waning of the flame of enthusiasm in the report of Dr. Cowley and his group. I certainly would like to support Dr. Paulson, and hope that the flame of enthusiasm can be fanned a little, rather than extinguished. DR. THOMAS W. SHIELDS (Chicago, Ill.): I think the pessimists ought to have equal time. I support Dr. Cowley and disagree to some extent with Drs. Paulson and Jensik. We first of all must realize that both these series are of selected patients and any attempt to evaluate the use of preoperative x-ray therapy should be conducted on a random basis. In an attempt to do this, the Chemotherapy Study Group of the Veterans Administration conducted a prospective study of the use of preoperative x-ray therapy in a group of randomly selected patients. The patients admitted to the study were those thought to have a clinically resectable tumor that had been proved by preoperative biopsy. After admission to the study the patients were randomized into two groups (British envelope system), one to receive preoperative x-ray therapy and the other to undergo operation only. Some three hundred patients made up the entire study. Approximately half of the patients underwent definitive resection of the tumor. Half the patients to be resected fell into each study group. Interestingly enough, in the group that was explored without preoperative x-ray therapy, 63 patients were not resectable. In contrast, of the patients who received preoperative roentgen therapy, though approximately 60 patients were lost because of metastasis or development of other problems during the period of roentgen therapy, only 20 patients were nonresectable at the time of exploration. Thus, it would seem that the use of preoperative roentgen therapy made it possible to remove more lesions in the patients who were explored. Unfortunately, our aim is not just to remove more tumors, but to prolong life. To date the survival curves based on 36-month survival figures, and including both groups of patients submitted to the study, are found to be superimposed, VOL. 8, NO. 3, SEPTEMBER,

8 COWLEY, WIZENBERG, AND LINBERG revealing that there has been no increment of benefit to those patients who received routine preoperative roentgen therapy. Even more distressing, when we analyze the patients who were subsequently resected for cure, in the preoperative irradiated group and the nonirradiated group, there was a significant loss of patients in the x-ray treated group compared to the operation only group. The postoperative mortality of both groups was about the same: the morbidity was not dissimilar, but there was a marked increase in deaths from the first month to the six months period in the patients who had been irradiated. We do not understand the reason for this. Whether it was due to increased loss of pulmonary function or injury to the cardiac system or due to the delay in definitive operative removal is unknown. But it seems that some of these patients who were resected for cure were actually harmed by the x-ray treatment rather than benefited. So I think we should not be too enthusiastic, certainly as to its use as a routine modality. In selected patients, under selected situations, yes. Otherwise, no. DR. COWLEY: I think Don Paulson has the answer when he says the name of the game is selection, and in our series we were not selecting. The National Institutes of Health cooperative lung cancer study continues a randomized study of about 800 patients. The five years are not up in all cases, but I think the results of this study will be more nearly like those I have described. If you select your patients on the same basis as we did and give them the same dosages of radiation, the survival rate will not increase. I have been aware of Dr. Paulson s work over the years, and his results can be attributed to two causes, better selection and resection after 3,000 to 4,000 roentgens, which is approximately 2,000 less than ours. We did not see very many patients on whom one could do a sleeve resection. I have no answer to Dr. Jensiks suggestion. I think he used the same radiation therapy we did, in the same amounts, and I am pleased to see his report. [NOTE: After the discussion, Dr. Jensik reported that his dose of irradiation was also in the 4,000 rad range, which could better explain his results.] 236 THE ANNALS OF THORACIC SURGERY