Treatment of Esophageal Carcinoma by Combined Preoperative Chemotherapy

Transcription

1 Treatment of Esophageal Carcinoma by Combined Preoperative Chemotherapy Manjit S. Bains, M.D., David P. Kelsen, M.D., Edward J. Beattie, Jr., M.D., and Nael Martini, M.D. ABSTRACT Thirty-four patients with epidermoid carcinoma of the esophagus received a triple-drug regimen preoperatively consisting of cisplatin, vindesine, and bleomycin. Partial response to chemotherapy (greater than 50% reduction in measurable tumor size with concomitant improvement in swallowing function) was noted in 65% of the patients. Of the 34 patients, 28 (82%) had resectable disease. A one-stage high esophagogastrectomy utilizing the end-to-end anastomosis stapling device was performed on all 28 patients. Operation was followed by external radiation therapy to the esophageal bed, to a tumor dose of 5,500 rads delivered in 5 weeks. The postoperative median follow-up is now 14 months (range, 7 to 26 months). Thirteen patients are alive and well, and 10 patients have relapsed, 4 of whom are still alive with disease. Two patients died of postoperative complications, and 1 death was drug related. On the other hand, 5 of the 6 patients with unresected tumors died within 5 months. While the preliminary results are encouraging, longer follow-up will be required to determine whether the response rate to chemotherapy will result in a longer disease-free interval and longer survival. The great majority of patients with epidermoid carcinoma of the esophagus have done poorly despite our best efforts to improve local control of the tumor by surgery, radiation therapy, or a combination of these methods [l]. At the time of diagnosis, 60 to 80% of the patients are seen with advanced local disease or distant metastasis, where treatment can be palliative at best. From the Thoracic Service, Department of Surgery, and the Solid Tumor Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, NY. Presented at the Eighteenth Annual Meeting of The Society of Thoracic Surgeons, Jan 11-13, 1982, New Orleans, LA. Address reprint requests to Dr. Bains, 1275 York Ave, New York, NY Patients with earlier and potentially favorable disease who are treated with aggressive surgery or radical radiation therapy also have very poor long-term survival. The reported median survival for patients with localized disease varies from 6 to 11 months [2-51. Carcinomas in the lower two-thirds of the thoracic esophagus have generally been approached surgically, whereas those located in the upper third of the esophagus have mostly been treated with external irradiation. Tumors in the latter location have been considered inoperable by reason of early extension to the adjacent vital structures. Results of treatment in carcinoma of the thoracic esophagus have been so dismal that many physicians have justifiably directed their attention toward improving the quality of survival by improving the patients nutritional status and their ability to swallow whenever possible, while dismissing all efforts to treat the carcinoma itself. The most conservative members of this group are still proponents of an intraluminal prosthesis to restore swallowing. However, a bypass procedure, preferably a gastric pull-up, when feasible, is considered a better form of palliation and has been recommended by several institutions [6]. There is clearly a need for improved methods of treatment for esophageal carcinoma. Conventional chemotherapeutic agents have been tried and have been shown to be unsatisfactory owing to poor response [7, 81. Five years ago, we began to assess the value of intensive systemic chemotherapy with new agents. These were initially given to those patients with advanced esophageal carcinoma who could not benefit from operation or irradiation. Major objective responses were noted in 19% of the patients with the combination of cisplatin and bleomycin [91. A major response consisted of greater than 50% reduction in the size of all measurable tumor. Subsequently vindesine, a new Vinca alkaloid, used alone, demonstrated by The Society of Thoracic Surgeons

2 522 The Annals of Thoracic Surgery Vol 34 No 5 November 1982 DDP 3mg/ kg 1 Bleomycin 10mg/m2 DVA 1 IV push 3mg/rn2 r,t,-j SURGERY Bleomycin DVA REPEAT DVA 3rng/rn rods /5-6wks infusion ihemothe.c ~/-ka-/-klj-+4+~ DAYS Fig 1. Combined modality program involving preoperative chemotherapy, surgery, and radiation therapy. (DDP = cisplatin; DVA = vindesine; RT = radiation therapy.) an objective response rate of 18% in patients with advanced carcinoma of the esophagus [lo]. We have since combined cisplatin and bleomycin with vindesine in patients who have advanced inoperable disease [ll, 121. We have also used these three agents preoperatively in potentially operable patients with esophageal carcinoma. This article is a progress report on the results of this treatment regimen. Materials and Methods From July, 1979, to June, 1981, 65 consecutive patients with epidermoid carcinoma of the esophagus were considered for treatment by a combined modality regimen of chemotherapy, surgery, and radiation therapy. Of these 65 patients, 25 were inoperable because of documented metastatic disease at the time they were first seen. Four had major medical problems precluding surgery, and 2 refused operation. Thirty-four patients underwent operation after chemotherapy. Nineteen of these were men, and 15 were women. The ages of the patients ranged from 42 to 76 years, with a median of 60 years. The tumor was located in the cervical esophagus in 3 patients, in the upper thoracic esophagus in 19 patients, and in the lower thoracic esophagus in 12. All patients were staged according to the criteria of the American Joint Committee for Cancer Staging and End Result Reporting [13]. Only 4 had a T1 lesion (tumor that involved 5 cm or less of the esophageal length, that produced no obstruction, and that had no circumferential involvement and no extraesophageal spread), while the remainder had T2 lesions (tumor that involved more than 5 cm of the esophageal length without extraesophageal spread, or tumor of any size producing obstruction or involving the entire circumference). The length of the lesion on barium esophagogram ranged from 3 to 14 cm, with a median of 7 cm. Three-fourths of the lesions were circumferential. In addition to a detailed history and physical examination, all patients had a chest roentgenogram, barium swallow, complete blood count, an SMA-12, serum electrolyte determination, creatinine clearance, electrocardiogram, pulmonary function tests, and esophagoscopy. All those with lesions located in the cervical or upper thoracic esophagus also had bronchoscopy to rule out tracheal disease by direct extension. If the serum alkaline phosphatase level was elevated, scans of the liver and bone were obtained. The drug administration schedule consisted of intravenous cisplatin, 3 mglkg or 120 mg/m2 (whichever was less), on day 1 (Fig 1). The cisplatin was given after an overnight prehydration and mannitol-induced diuresis as previously described [14l. Bleomycin, 10 Ulm', was given intravenously as a loading dose on day 3, followed by a four-day infusion of 10 U/m2 per day. Vindesine, 3 mglm', was given intravenously on days 1, 8, 15, and 22. Metoclopramide hydrochloride was used for control of nausea and vomiting [151. Early in our series, 21 patients underwent a single course of cisplatin, bleomycin, and three

3 523 Bains et al: Esophageal Carcinoma and Combined Preoperative Chemotherapy doses of vindesine, followed by resection on day 21. A second identical course was given starting 10 to 14 days postoperatively. Thirteen patients received the entire chemotherapy regimen preoperatively in the hope of obtaining a greater degree of tumor response. Radiation therapy was given postoperatively to patients who had involvement of the periesophageal tissue, mediastinal or celiac node disease, positive resection margin, or unresectable tumor. A tumor dose of 5,500 rads was delivered to the involved area in 5 to 5% weeks [ll, 121. At the time of the scheduled operation, a laparotomy was first done to assess resectability. Resection was attempted in all patients. The presence of metastatic disease of celiac lymph nodes per se did not preclude resection. However, the presence of hepatic metastasis and fixation of the primary tumor or the celiac lymph nodes to the retroperitoneum, aorta, or pancreas were considered contraindications to resection. Resection included any extension of the tumor to the diaphragm or to periesophageal tissue. Esophagectomy was performed through a separate midline laparotomy and a right thoracotomy incision, with simultaneous access to both pleural and abdominal cavities. When the disease was resectable, a single-stage resection with reconstruction was performed. For lesions located in the cervical esophagus or at the thoracic inlet, a two-team approach was used to perform an extrathoracic esophagectomy through laparotomy and cervical incisions [16]. A mediastinal lymph node dissection was performed in every instance when a thoracotomy approach was used. The lymph node-bearing tissues around the celiac axis and left gastric area were also routinely excised. The proximal esophagus was transected as high as possible, or at least 5 cm above the palpable or pretreatment level of the tumor. A frozen-section analysis of the resected margin was always done in order to obtain a tumor-free margin. Esophagogastric anastomosis was accomplished using the end-toend anastomosis (EEA) stapler.* A gastric drainage procedure in the form of a pyloroplasty or a pyloromyomectomy was rou- 'United States Surgical Corporation, Norwalk, CT. tinely performed. If the primary tumor was not resectable and the patient had marked dysphagia, a palliative substernal bypass or insertion of a Celestin tube was done to restore swallowing. Owing to the use of bleomycin in this treatment regimen, meticulous care was taken during anesthesia to keep the FIOp (fractional concentration of oxygen in inspired gas) below 35% in order to prevent any pulmonary toxicity [17, 181. Nutritional support was given to all patients. Those tolerating oral intake were given dietary supplements. Otherwise, nutritional support was given preferably by the enteral route, through a small Silastic feeding tube (Dobhoff tube). Total parenteral nutrition was reserved for patients in whom a feeding tube could not be passed. Response to chemotherapy was evaluated by repeat barium esophagogram and confirmed by histological analysis of the resected specimen. Complete response was defined as total disappearance of the tumor, both radiologically and histologically. Response was considered significant, but partial, if at least 50% regression in the tumor mass was observed on the esophagogram concomitant with improvement in swallowing. Lesser responses were classified as minimal or no response. A curative resection was defined as one in which the primary tumor and its regional lymph nodes were removed, the margins of resection were not involved, and the tumor was not invading mediastinal structures other than the nodes. Resection was considered palliative when microscopic examination revealed that the surgical margins were not free of tumor, or when celiac or gastric nodes had metastatic tumor. Results Of the 34 patients studied, 22 (65%) had major radiographic regression of the tumor, with 6 of these (18%) showing no residual abnormality on the esophagogram. Four patients had minor regression, and 8 had no response. Histological analysis of the resected specimens in the chemotherapy responders showed no residual tumor at the primary site in 3 patients. Two of these patients had microscopic disease, 1 in a regional lymph node and the other in a celiac

4 524 The Annals of Thoracic Surgery Vol34 No 5 November 1982 lymph node. Although the third patient had no residual disease in the specimen, the site of the tumor was densely adherent to the aorta, and completeness of the resection could not be ascertained. Additionally, 4 patients had only microscopic disease presenting as carcinoma in situ or as foci of tumor within the muscularis layer. In all 4 patients, the lymph nodes were free of tumor. Of the 34 patients, 28 had resectable disease (82%); 16 had operations that were potentially curative, and 12 palliative. The remaining 6 patients had unresectable disease. Two patients (both with resectable tumor) died postoperatively (5.8%), 1 from a cerebrovascular accident and 1 from respiratory failure. Of the 6 patients with unresectable disease, 5 died within 5 months after initiation of therapy; 1 is alive with disease at 9 months. Of the 28 patients who had resections, 2 died postoperatively, 1 died of renal failure related to cisplatin therapy, and 2 died of other causes (myocardial infarction, and peripheral vascular disease with gangrene of the leg) at 8 and 10 months, respectively, without any clinical evidence of tumor. Ten patients have relapsed, 6 of whom have died. Thirteen patients are alive and free of disease. The median survival for the entire group is projected to be 18.5 months (Fig 2). Major but nonfatal postoperative complications occurred in 10 patients. Three had varying degrees of pulmonary problems, 1 of whom required a tracheostomy for prolonged respiratory support. Transient cardiac arrhythmias were noted in 6 patients. Only 1 patient developed an anastomotic leak. This was thought to be due to erosion into the stomach by the overlying chest tube, and it resolved once the tube was removed. Two patients have required dilation of an anastomotic stricture. In the early postoperative period, most patients had symptoms consistent with dumping; this resolved over a few weeks, however, and none had any delay in gastric emptying. Unresectable tumor was found in 6 patients due to invasion of the adjacent major vessels in 2, fixation of tumor to the posterior mediastinum in 3, and hepatic metastasis in 1. Of these 6 patients, 2 had shown significant radiographic response to chemotherapy, 13 DYE PATIENTS TICK HRAK (I I d 9, INOICATES LRST FOLLOW-UP li.00 2;. 00 3b.00 MONTHS SURVIVRL Fig 2. Survival from diagnosis in 34 patients. Boxes indicate patients receiving the chemotherapy regimen; tick marks indicate time of last follow-up. (DVB = combined regimen of cisplatin, vindesine, and bleomycin.) whereas 4 had little or no response (minimal response in 3, progression in 1). Two patients had a substernal gastric bypass, and 1 patient had insertion of a Celestin tube. In general, this chemotherapy regimen was well tolerated. Nephrotoxicity and myelosuppression were the major side effects. Even though high-dose cisplatin was used, nausea and vomiting were seen less frequently due to the use of a new antinausea drug, metoclopramide hydrochloride. Alopecia occurred in all patients, and half of the patients had some degree of peripheral neuropathy, which was marked in only 2. These complications were reversible in nearly all cases. One patient had severe renal damage and another suffered from irreversible hearing loss. Because of careful monitoring of FIO~ during the surgical treatment, no case of acute pulmonary failure attributable to bleomycin toxicity was noted. Comment Survival in patients with epidermoid carcinoma of the esophagus depends on control of both local tumor and distant metastases. Unfortunately, the majority of patients have incurable

5 525 Bains et al: Esophageal Carcinoma and Combined Preoperative Chemotherapy lesions when they are initially seen, due to locally advanced disease or to distant metastasis. It is because of this that local efforts to control the tumor by surgery and irradiation have failed in most instances. Although a sizable number of newly diagnosed patients with carcinoma of the esophagus are seen with localized, potentially curable disease, initial control of the tumor by surgery or radiation therapy is possible in only 20% of all patients. A five-year survival of 15 to 20% is reported in this favorable group alone. The remaining patients (80% of all patients with esophageal carcinoma) either have cancer beyond the limit of local therapy or have residual cancer after initial treatment. Pearson [5] in his extensive review of patients with esophageal cancer seen and treated in Scotland, indicated that in his favorable cases, a 19% survival was obtained by therapeutic external radiation alone. The favorable group consisted of 169 patients of 1,953 seen with esophageal carcinoma. Similarly, Nakayama and Kinoshita [19] reported a five-year survival of 37.5% in 191 patients with cancer of the thoracic esophagus treated by a short course of external radiation therapy followed by staged resection and reconstruction. This was a calculation of cumulative survival, whereas five-year follow-up was available in only 8 of the 191 patients, of whom 3 were alive and well. Since therl, a corrected report has adjusted the fiveyear survival to 22% after combined irradiation and surgery, compared with 13% for resection alone and 6% for external irradiation alone. Again, the favorable group in their series consisted of 191 patients out of 6,282 seen with esophageal carcinoma. Although external radiation therapy alone is successful in relieving obstruction in half of all patients, it has been, in our experience, unfortunately short-lived owing to prompt recurrence. We had therefore favored preoperative irradiation followed by surgical exploration and resection when feasible [201. Operable patients have received 4,000 to 4,500 rads to the entire mediastinum in 4 to 5 weeks. Following a 4- week rest period, resection was performed. Our experience with preoperative radiation therapy followed by resection in localized tumors of the thoracic esophagus was comparable to the re- sults obtained by Pearson and by Nakayama and Kinoshita. The five-year survival in our favorable group of patients so treated was 19%. This favorable group consisted of 85 patients (4.3%) of 1,953 with esophageal carcinoma seen at Memorial Sloan-Kettering Cancer Center. In a more recent update of 76 patients receiving preoperative radiation therapy at Memorial Sloan-Kettering Cancer Center during the period 1965 to 1976, 54% had resectable disease. Seven survived for more than three years [21]. Conventional chemotherapeutic agents have been of little benefit in the treatment of this disease; the use of investigational drug combinations has been more rewarding. Initial studies using cisplatin, a new heavy metal antineoplastic agent, began at Memorial Hospital in 1976 [9]. The drug was used in combination with bleomycin, given as an infusion, on the basis of data showing the effectiveness of these agents in patients with advanced squamous cell carcinomas of the head and neck. As already discussed, major responses were seen in about one-fifth of the patients. In the follow-up study with vindesine, an 18% complete and partial response rate was noted, including responses in patients who had received several courses of cisplatin and bleomycin [lo]. The three drugs appear to lack cross-resistance. Each of the three agents has a different spectrum of toxicity (bleomycin s major toxicity is pulmonary fibrosis; cisplatin s major toxicity is renal damage and nausea and vomiting; and vindesine s major toxicity is a peripheral neuropathy). They also have differing mechanisms of actionbleomycin causes DNA strain breaking, cisplatin functions as an alkylating agent, and vindesine is an inhibitor of mitosis. Because of these characteristics, the three agents were combined in the current trial. The current study, which is still in progress, demonstrates that cisplatin, vindesine, and bleomycin together form an effective combination of agents in the treatment of esophageal carcinoma. It is now incumbent on us to compare the current modes of preoperative chemotherapy with preoperative radiotherapy frequently used by many institutions. We have therefore designed and recently embarked on a randomized protocol comparing these two

6 526 The Annals of Thoracic Surgery Vol34 No 5 November 1982 forms of treatment when given preoperatively. Both of these treatments are then reversed and given postoperatively to patients with residual disease or with involved regional lymph nodes after resection. Ideally, a third arm of treatment is necessary-that of comparing treatment by surgery alone as opposed to preoperative chemotherapy or postoperative radiation therapy. The number of patients we see, however, is too small to permit further randomization. We sincerely hope that our preliminary observations of effective response will translate into prolonged survival as further follow-up information becomes available. Supported in part by the National Cancer Institute, Grant CA References 1. Moertel C: The esophagus. In Holland JF, Frei E I11 (eds): Cancer Medicine. Philadelphia, Lea & Febiger, 1973, pp Rambo VB, O Brien PH, Miller MC, et al: Carcinoma of the esophagus. J Surg Oncol 7:355, 1975, pp Parker E, Gregorie H, Ariants J, Ravevel J: Carcinoma of the esophagus. Ann Surg 171:746, Marks R, Scruggs H, Wallace K: Preoperative radiation therapy for carcinoma of the esophagus. Cancer 38:84, Pearson JG: The value of radiotherapy in the management of squamous esophageal cancer. Br J Surg 58:794, Orringer MB, Sloan H: Substemal gastric bypass of the excluded thoracic esophagus for palliation of esophageal carcinoma. J Thorac Cardiovasc Surg 70:836, Ravry M, Moertel CG, Schutt AJ, et al: Treatment of advanced squamous cell carcinoma of the gastro-intestinal tract. Cancer Chemother Rep 57:493, Ezdinli EZ, Gelber R, Desai DV, et al: Chemotherapy of advanced esophageal carcinoma, Cancer 46:2149, Kelsen DP, Cvitkovic E, Bains M, et al: Cisdichlorodiammineplatinum (II) and bleomycin in the treatment of esophageal carcinoma. Cancer Treat Rep 62:1041, Kelsen DP, Bains M, Cvitkovic E, et al: Vindesine in the treatment of esophageal carcinoma: 11. a phase I1 study. Cancer Treat Rep 63:2019, 1979 Kelsen DP, Bains M, Chapman R, et al: Cisplatin, vindesine and bleomycin (DVB) combination chemotherapy for esophageal carcinoma. Cancer Treat Rep 65:781, Kelsen D, Bains M, Hilaris B, et al: Cisplatinbased preoperative chemotherapy of esophageal carcinoma. In Salmon SE, Jones SE (eds): Adjuvant Therapy of Cancer: Vol3. New York, Grune & Stratton, American Joint Committee for Cancer Staging and End-Result Reporting: Manual for Staging of Cancer, 1978, pp Hayes DM, Cvitkovic E, Golbey RB, et al: High dose cis-platinum diammine dichloride. Cancer 39:1372, Gralla RJ, Itri LM, Sharon EP, et al: Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med 305:905, Bains MS, Spiro RH: Total extrathoracic esophagectomy and laryngectomy for carcinoma involving the cervical esophagus with immediate reconstruction by gastric transposition. Surg Gynecol Obstet 149:693, Goldiner PL, Carlon GC, Cvitkovic E, et al: Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J 1:1664, Goldiner PL, Schweizer 0: The hazards of anesthesia and surgery in bleomycin-treated patients. Semin Oncol 6:121, Nakayama K, Kinoshita Y: Surgical treatment combined with preoperative concentrated irradiation. JAMA 227:178, Goodner JT: Surgical and radiation treatment for cancer of the thoracic esophagus. Am J Roentgen01 Radium Ther Nucl Med 105:523, Kelsen DP, Ahuja R, Hopfan S, et al: Combined modality therapy of esophageal carcinoma. Cancer 48:31, 1981 Discussion DR. JOHN c. ALEXANDER, JR (New York, NY): Squamous carcinoma of the esophagus represents one of the most difficult and frustrating diseases that we as thoracic surgeons face. The authors are to be congratulated for their aggressive and innovative approach to this discouraging problem. Esophageal surgery has become safer in the last decade, but still carries a significant mortality and morbidity. We are familiar with the usual pattern of morbidity in patients subjected to esophagogastrectomy. Recently, major improvements have been made in this area. The stapling device appears to reduce the incidence of anastomotic leaks and their associated morbidity and mortality. Liberal perioperative use of hyperalimentation has improved the general condition of our patients and has lessened, to a degree, the problems associated with malnutrition so often seen in this group. The benefits of preoperative

7 527 Bains et al: Esophageal Carcinoma and Combined Preoperative Chemotherapy chemotherapy presented by Dr. Bains are encouraging but, as the authors point out, preliminary. We would all hope that these promising results, in time, will become solid facts. I would offer a word of caution, however. Even in the hands of experts at Memorial Hospital, aggressive chemotherapy is potentially harmful. The current report describes 1 death attributed to chemotherapy-induced renal failure and 1 perioperative septic death that may have been related to chemotherapy. Chemotherapy used as the authors describe has a new and different series of problems with which we are obliged to become familiar. Renal failure, depressed white cell count, sepsis, nausea, vomiting, alopecia, hearing loss, and impaired wound healing all must be kept in mind. The most striking chemotherapy-related problem that jeopardizes these surgical patients is pulmonary insufficiency. Patients who receive bleomycin develop a severe interstitial pneumonitis when exposed to even modest increases in inspired oxygen for any length of time. Attention to this detail is critical to the success of this treatment regimen. In conclusion, these promising results have a price. New and possibly still unknown problems await us as aggressive chemotherapy becomes an integral part of the treatment for this and other diseases that we are called upon to treat. A team approach to patient management is critical. The surgeon, anesthesiologist, chemotherapist, radiation therapist, and nutritionist must all work together closely and understand each others strengths and weaknesses if the patient is to benefit fully. DR. ZWI STEIGER (Allen Park, MI): I was glad to learn that Dr. Bains uses chemotherapy alone, because we at Wayne State University use chemotherapy and radiotherapy, and we weren t sure what effects each of them has. Since 1977 we have used 5-fluorouracil and mitomycin C, for which we later substituted cis-platinum. Simultaneously, we give 3,000 rads to the tumor. The chemotherapy is repeated on completion of radiotherapy. The operation is done approximately 60 days after initiating treatment. We have treated 112 patients to date, 59 of whom have had an esophagectomy. In 20 patients (34%) no residual tumor was seen grossly or histologically. In 1 patient, in whom no residual tumor of the esophagus was found, liver metastases were seen. This confirms what we and others believe: that the chemotherapeutic agents have radiosensitizing properties and, therefore, an advantageous effect over chemotherapy or radiotherapy alone. Some respiratory complications were attributed to the combined treatment, but overall the benefits outweigh the disadvantages. The combined treatment makes resectable most lesions previously considered locally nonresectable. It makes the operation technically easier. We hope that it will improve the dismal outlook for carcinoma of the esophagus. DR. HOWARD s. BROWN (Atlanta, GA): I think we need all the help we can get with this horrible disease. I would like to ask Dr. Bains whether he used this regimen on any patient with early involvement of the trachea and, if so, if an inoperable patient was converted to a resectable patient as a result. Also, I would like to ask if he noticed any problems with oxygen toxicity when using the double-lumen endotracheal tube in patients who had had the preoperative chemotherapy regimen. I find that the doublelumen tube is extremely helpful, but very high FIO~ concentrations are often needed to oxygenate the patient adequately when collapsing one lung. I wonder whether he has found any trouble with oxygen toxicity when having to use high oxygen concentrations. DR. EDWARD J. BEATTIE (New York, NY): I would like first to thank Dr. Alexander for his very pertinent comments; second, I congratulate Dr. Steiger. He has a very interesting series, and we too will await his end results to see what effect his protocol has on the survival curves. We certainly need something more than surgery alone. Our thought in this experiment, as he pointed out, was to try to determine what preoperative chemotherapy alone might do. We would need the cooperation of many institutions if we were to compare preoperative chemotherapy with preoperative radiotherapy. Dr. Brown asked about involvement of the trachea. We have not used chemotherapy preoperatively in cancer of the esophagus when the trachea was involved. One would have a good chance of causing a tracheoesophageal fistula. We have been careful about using preoperative radiation therapy when cancer of the esophagus appears to involve the trachea. I would like to stress again the oxygen toxicity of bleomycin. However, I do not believe that bleomycin alone is involved in oxygen toxicity. Some years ago, our anesthesia department found that the interstitial fibrosis and respiratory insufficiency that followed chemotherapy resulted from oxygen toxicity. We are now careful not to raise the inspired oxygen concentration in a thoracotomy patient above 35%. Since doing that, we have not produced respiratory insufficiencies. Dr. Bains has showed that 75% of these cancers had better than a 25% objective remission from chemotherapy. To me, this is very remarkable. With that kind of response, it certainly appears reasonable to continue this study. My second point is that chemotherapy does not seem to make the surgery more difficult. It does appear to be well tolerated. Dr. Alexander s comments

8 528 The Annals of Thoracic Surgery Vol34 No 5 November 1982 about the toxicity of the regimen are well founded. The protocol pays very careful attention to detail, and this is not an easily given minor treatment course. It takes a sophisticated chemotherapist to do this safely. Obviously, what is needed is simplification of these chemotherapy protocols. We would hope to get better drugs with fewer side effects. If this technique works, it will be a big stimulus to find new drugs. Preoperative chemotherapy is the best way of carrying out in vivo chemotherapy sensitivity testing. This is an important principle. If one finds a sensitive tumor, one can then use the chemotherapy as a prophylactic adjuvant, as with breast cancer. Chemotherapy does open up a new area in esophageal cancer, and we may make some progress in this area, which is long overdue.