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Therapeutic alternatives in patients with esophageal cancer
Therapeutic Alternatives in Patients With Esophageal Cancer
William Ft. Campbell, Jr., MD, Kansas City, Kansas Sarah A. Taylor, MD, Kansas City, Kansas George E. Pierce, MD, Kansas City, Kansas Arlo S. Hermreck, MD, PhD, Kansas City, Kansas James H. Thomas, MD, Kansas City, Kansas
Optimal management of patients with squamous cell carcinoma of the esophagus remains controversial. Earlam and Cunha-Melo [I], in a collected series, found a 2 year survival rate of only 9 percent with surgical treatment. Although Nakayama et al [2] reported a 5 year survival rate of 37.5 percent after preoperative radiotherapy, Launois et al [3] reported no increase in survival for patients treated by this method. Recently, combined preoperative chemotherapy and radiotherapy have been reported to increase survival. Leichman et al [4] reported a median disease-free interval of 3.5 years in 92 percent of patients so treated who had no evidence of microscopic tumor in the resected esophagus. The present study compares morbidity, mortality, and survival rates in patients with squamous cell carcinoma of the esophagus treated with surgery alone, preoperative radiotherapy, or a combination of preoperative chemotherapy and radiotherapy. Material and Methods The records of 52 patients without distant metastasis treated for squamous cell carcinoma of the esophagus were reviewed. Nineteen patients (Group A) underwent operation without, preoperative radiotherapy. Twelve patients (Group B) underwent preoperative radiotherapy (mean exposure 4,228 rads) followed by surgery. Twentyone patients (Group C) received preoperative chemotherapy and radiotherapy. In this group, 3,000 rads were given in increments of 200 rads over a 19 day period. Cisplatin (75 mg/m2) was administered on days 1 and 29 and 5-fluorouracil (1,000 mg/m2 per day) was given as a continuous infusion on davs 1 to 4 and 29 to 32. From the Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas, and the Departments of Medicine and Surgery, Veterans Administration Medical Center, Kansas City, Missouri. Requests for reprints should be addressed to James H. Thomas, MD, Department of Surgery, University of Kansas Medical Center, 39th Street and Rainbow Boulevard, Kansas City, Kansas 66103. Presented at the 37th Annual Meeting of the Southwestern Surgical Congress, Las Vegas, Nevada, April 2%May 2. 1985.
Volume 150, December 1965
All patients were staged according to history, physical examination, upper gastrointestinal endoscopy, and in most instances, computerized axial tomography of the chest and abdomen. Group B and C patients were restaged after chemotherapy and radiotherapy. Operations were performed 3 to 6 weeks after completion of preoperative therapy. Clinical, laboratory, operative, and pathologic data were recorded for each patient. These included age, sex, race, risk factors for cancer, presenting symptoms, physical and radiographic findings, operative procedure, duration of operation, blood loss, postoperative complications, TNM staging, and duration of survival (Table I) 151.Resection was considered potentially curative if neither extraesophageal extension nor involved nodes were identified at operation. Complete follow-up was carried out for all patients. Clinical, laboratory, operative, and pathologic differences between groups were tested by standard statistical methods, including analysis of variance and Scheffe’s test. The life table method described by Cutler and Ederer [6] was used to calculate postoperative actuarial survival.
Patient ages ranged from 35 to 80 years (mean 61 years). Thirty-seven patients were male and 15 were female. Twenty-one patients (40 percent) were black. Alcohol and cigarette abuse were common (46 patients or 88 percent), as were symptoms of pain (36 patients or 69 percent) and weight loss of more than 20 pounds (27 patients or 52 percent). All patients complained of dysphagia. Mean serum albumin levels were within normal limits (3.9 mg/dl), but 25 patients (48 percent) were malnourished on physical examination. Seven tumors were found in the upper third of the esophagus, 31 in the middle third, and 14 in the lower third. Length of the tumor varied from 1 to 11 cm (mean 5.6 cm). One patient had stage I disease, 14 had stage II disease, and 37 had stage III disease without distant metastases.
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Campbell et al
TABLE I
TNM Staging System for Carcinoma of the Esophagus
Classification
TABLE II
Comparlson of Groups
%
n
Group 0 %
0 19
too
0 4 6
4 15
21 79
0 0 4
A
Definition Parameter
n
C
n
%
‘33 67
1 10 10
4 46 48
6 5
50 42
7 a
33 38
. .
1
a
6
29
‘27
0 3
0 3
3;
Primary Tumor (T) TNM stage
TO TIS TI
T2
T3
No demonstrable tumor in the esophagus Carcinoma in situ A tumor less than 5 cm in length with no obstruction radiographically or circumferential involvement, and without extraesophageal spread A tumor more than 5 cm without extraesophageal spread, or of any length and associated with obstruction or circumferential involvement but without extraesophageal spread Any lesion which has evidence of extraesophageal spread Nodal Involvement
Nx No
NI
(N)
Not assessed (clinical evaluation) Negative nodes on surgical evaluation Positive nodes on surgical evaluation Distant Metastases (M)
Mx MO Ml
Not assessed No known distant metastases Distant metastases present Stage Grouping
I II Ill
T, No MOor T, Nx MO T2 No MOor T2 Nx MO Any T3, any N,, or any MI
Forty-five patients (87 percent) underwent operation. Curative resections were performed in 17 patients (33 percent). Twenty-eight patients (54 percent) were judged to have been palliated. Seven patients (13 percent) had apparent total regression of tumor after preoperative therapy and did not undergo operation. Curative operations included 17 total esophagectomies with reconstruction by gastroesophagostomy in 16 patients and colon interposition in 1 patient. Palliative procedures included esophageal bypass with gastroesophagostomy in 16 patients, colon interposition in 9 patients, and other operations in 3 patients. The mean blood loss was 1.1 liters. The average duration of operation was 4.3 hours. Postoperative complications occurred in 23 patients (51 percent) and included anastomotic leaks in 3 patients, pneumonia in 8 patients, respiratory failure in 3 patients, and sepsis in 5 patients. There were 10 perioperative deaths (22 percent), all of which occurred after palliative procedures. The cumulative survival rate at 2 years for all 52 patients was 21 percent. In patients with stage II and III disease, the 2 year cumulative survival rates were 68 percent and 3 percent, respectively. A comparison of results for Groups A, B, and C is presented in Table II. There were no differences between groups with regard to age, sex, race, inci-
666
0
II Ill Resections Curative Palliative Tumor resolved No operation (n) .Operative mortality Curative Palliative 2 Year cumulative survival Curative Palliative Stage II Staoe Ill
0
0 NA 0
‘66
67 0
. ...
.
52 0
100 15
57 0
NA = not available.
dence of alcoholism, tobacco abuse, benign esophageal disease, dysphagia, pain, weight loss of more than 20 pounds, physical findings of malnutrition, mean serum albumin levels, tumor size and location, amount of blood loss during operation, duration of operation, and number of postoperative complications. There was a significant difference in the distribution of patients based on TNM staging. All patients in Group A had stage III disease; by contrast, 8 patients (67 percent) in Group B and 10 patients (48 percent) in Group C had stage III disease. The single patient with stage I disease was in Group C. After preoperative therapy, only 1 patient in Group B with stage II disease had complete resolution of the primary tumor on endoscopy, whereas 11 patients (53 percent) in Group C had total regression. Twenty-one percent of patients in Group A (4 of 19 patients) and 50 percent of patients in Group B (6 of 12 patients) were resected for cure. Sixty-two percent of patients in Group C (13 of 21 patients) were considered potential candidates for curative resection, including 11 patients who had total regression of the primary tumor and 2 who did not. However, only 5 of these 11 patients underwent esophageal resection, and 2 of these 5 had residual microscopic tumor in the resected esophagus. The other six patients were followed without operation, and two subsequently had recurrence of tumor at the site of the primary tumor. Thus, 4 of 11 patients (35 percent) in Group C were incorrectly considered by endoscopy to have total resolution of the primary tumor. None of the patients who underwent palliative procedures survived 2 years (median survival 2 months). No patient in Group A (all with stage III
The American Journal of Surgery
Therapeutic Alternatives
disease) survived 2 years. In contrast, 2 year cumulative survival rates in Groups B and C were 67 percent and 52 percent, respectively, for patients with curative resections. In patients in Group C with apparent total regression of the esophageal tumor who underwent resection, the 2 year cumulative survival rate was 50 percent, compared with 20 percent for those without operation. Only 1 of 10 patients (10 percent) in Group C who had persistent tumor on restaging survived 2 years. The 2 year cumulative survival rates of patients with stage II disease in Groups B and C were 100 percent and 57 percent, respectively. No differences were found in the 2 year survival rates of patients with stage III disease regardless of the type of therapy employed (Group A 0, Group B 15 percent, and Group C 0). Comments It is estimated that 9,400 new cases of esophageal cancer will be diagnosed by the end of 1985 [7]. Earlam and Cunha-Melo [I] reviewed 83,783 patients with squamous cell carcinoma of the esophagus and found a 9 percent 2 year survival rate after surgery. Because of these poor results, alternative therapeutic approaches have been evaluated in the treatment of squamous cell carcinoma of the esophagus. Nakayama et al [2] proposed preoperative radiotherapy to facilitate tumor resectability and sterilize involved lymph nodes. In 191 patients treated with 2,000 to 2,500 rads, they reported a 5 year survival rate of 37.5 percent. Launois et al [3] described 62 patients who received a mean dose of 4,000 rads followed by operation and 47 patients who underwent operation without preoperative radiotherapy. No difference was found in resectability (75 percent versus 70 percent) or 5 year survival rate (9.5 percent versus 11.5 percent). Preoperative chemotherapy and radiotherapy has been shown to provide total resolution of primary squamous cell carcinoma of the esophagus. Leichman et al [4] found that 26 percent of patients (11 of 42) in a pilot study and 22 percent of patients (19 of 86) in a Southwest Oncology Group clinical trial had no cancer in the resected esophagus after preoperative chemotherapy and radiotherapy. Ninety-two percent of patients without cancer in the resected specimen were alive without disease a median of 3.5 years after surgery; however, if a complete response to the preoperative therapy was not obtained, patients relapsed and died from esophageal cancer. On the basis of these data, these investigators suggested that esophageal resection may not be warranted in the treatment of squamous cell carcinoma of the esophagus. We reviewed the results of therapy in 52 patients with squamous cell carcinoma of the esophagus treated during a 7 year period. During this time, treatment has changed from no preoperative thera-
Volume 150, December 1985
in Esophageal Cancer
py to preoperative radiotherapy and finally to combined preoperative chemotherapy and radiotherapy. In this longitudinal study, there was a progressive decrease in the incidence of patients with stage III disease. Since definitive staging is not determined until operation, this finding could have resulted either from effective preoperative therapy, or simply result from earlier diagnosis. Before therapy, all three groups were identical with regard to presenting symptoms and nutritional status. Thus, it seems unlikely that earlier diagnosis explains the progressive decrease in patients with stage III disease. The lower incidence of stage III disease in Group C patients can best be attributed to combined preoperative chemotherapy and radiotherapy. The rate of resectability improved during the course of this study as the percent of patients with stage II disease increased. Likewise, survival rates have improved with the increase in the rate of resectability. In contrast to the suggestion of Leichman et al [4] that surgery may not be necessary in patients treated with combined chemotherapy and radiotherapy, our data suggest a decreased survival rate when the esophagus is not resected in patients with apparent resolution of the primary tumor after preoperative therapy. Repeat endoscopy was not reliable in detecting the presence of persistent microscopic tumor. We suggest that patients with squamous cell carcinoma of the esophagus should be treated with preoperative chemotherapy and radiotherapy as outlined for Group C patients followed by esophagectomy in low risk patients. This recommendation is based on the observations that more than 50 percent of patients will have apparent preoperative total resolution of tumor, that local recurrence develops in patients who have undetected microscopic tumor, and that curative esophagectomy is associated with a low risk of death. Summary The records of 52 patients treated either with surgery alone (Group A), preoperative radiotherapy (Group B), or combined preoperative chemotherapy and radiotherapy (Group C) were reviewed to determine the optimal management of patients with squamous cell carcinoma of the esophagus. There was a significant difference in the number of patients with stage III disease between Groups A and C (100 percent and 48 percent, respectively). With the decrease in patients with stage III disease, both resectability rates in Groups A and C (21 percent and 62 percent) and 2 year cumulative survival (0 and 52 percent) increased. Eleven patients in Group C (53 percent) had apparent total resolution of the primary tumor after preoperative therapy. Microscopic tumor was present but was not detect-
667
Campbell et al
ed by repeat endoscopy in 35 percent of these patients. The survival rate was higher in patients with apparent total tumor regression who underwent esophageal resection. These results suggest that patients with squamous cell carcinoma of the esophagus are best treated with preoperative chemotherapy and radiotherapy followed by esophagectomy regardless of their response to preoperative therapy.
the esophagus to improve the survival rate. The present study, in addition to studies from Wayne State and from the Southwestern Oncology Group, offer encouragement for better survival rates. Dr. Thomas, I am curious about some technical details involving the operation. Do you ever use the EEA stapler in your anastomoses? Do you always place the anastomosis in the neck, or are there instances when the anastomosis is in the thorax? If follow-up does not include esophagoscopic examination, do you use computerized axial tomography or barium swallow instead?
References
Kent C. Westbrook (Little Rock, AR): Dr. Thomas, your report illustrates the trend toward combined modality therapy in the treatment of difficult tumors. We must be very cautious in interpreting the results of such a combined program. Are we actually improving survival rates with only 2 survivors in Group C of the 21 who completed the regimen? I am convinced that preoperative radiotherapy and chemotherapy shrink lesions and make them resectable, but I am not sure that long-term survival rates will improve. Dr. Thomas, if radiotherapy and chemotherapy are so effective in shrinking the tumor, why not simply treat these patients with radiotherapy and chemotherapy and omit surgery? Since 3,000 rads is not a curative dose of radiotherapy, why not increase it to 6,000 rads to eradicate the cancer?
1. Earlam R, Cunha-Melo JR. Oesophageal squamous cell carcinoma: I. A critical review of surgery. Br J Surg 1980;67:381-90. 2. Nakayama K, Orihata H, Yamaguchi K. Surgical treatment combined with preoperative concentrated irradiation for esophageal cancer. Cancer 1967;20:778-88. 3. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperative radiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet 1981;153:690-2. 4. Leichman L, Steiger Z, Seydel HG, Vaitkevicius VK. Combined preoperative chemotherapy and radiation therapy for cancer of the esophagus: the Wayne State University, Southwest Oncology Group, and Radiation Therapy Oncology Group experience. Semin Oncol 1984;11:178-85. 5. American Joint Committee For Cancer Staging and End-Results Reporting. Manual for staging of cancer. Chicago: Whiting Press, 1979. 6. Cutler SJ, Ederer F. Maximum utilization of life table method in analyzing survival. J Chronic Dis 1958;8:699-712. 7. Silverberg E. Cancer statistics, 1985. CA 1985;35:19-35.
William F. Sasser (St. Louis, MO): Attempts to increase survival rates in patients with this dreaded disease have taken three avenues: earlier diagnosis, more radical surgery, and combined modality treatment. In areas of the world where there is a high incidence of carcinoma of the esophagus, such as parts of China and Iran, improved diagnostic efforts have been undertaken to discover the disease while it is in stage I. Because of the success of early diagnosis, 5 year survival rates approaching 95 percent have been reported. Unless the incidence of the disease increases in the United States, it is doubtful that a screening test will be used to a greater degree to uncover the problem. More radical surgery has been tried with little improvement in results, whereas combined modality approaches have offered some improvement. I have one such patient who has been placed on the Southwestern Oncology Group protocol. He had an esophageal carcinoma which almost completely obstructed his esophagus. A computerized axial tomographic scan revealed a large lesion on the right side of the neck adjacent to the carotid artery. After going through a course of cisplatin and 5-fluorouracil therapy as well as radiotherapy, the mass disappeared and the patient could swallow food. He has been followed for 2 years. It is clear that something has to be done in the treatment of carcinoma of
668
Raymond C. Read (Little Rock, AR): Dr. Thomas, your report emphasizes the need for more information about the role of radiation and chemotherapy in this disease, but I want to reinforce what Dr. Westbrook said. Patients in Group A were operated on immediately. The other group presumably had a waiting period of 6 or 8 weeks during which they received radiotherapy and chemotherapy. This was a period when the most seriously ill patients were culled out, and so the results in that limited group, as Dr. Westbrook pointed out, would presumably be a lot better. Dr. Thomas, you seem to believe that there is no place for palliative surgery in these patients, even though most of the patients we see with esophageal cancer are incurable. What is your opinion of the role of surgery in regard to patients who have lymph node metastasis or advanced disease in the mediastinum? James H. Thomas (closing): Dr. Sasser, we do not use the EEA stapler for esophageal anastomoses. Dr. Read, we believe that it is important to resect the entire esophagus because of the tendency for submucosal spread by esophageal cancer. Esophagoscopy is important in evaluating these patients, but in our report, it was reliable in only 65 percent of patients so evaluated. Thus, patients may have persistent tumor when esophagoscopic findings are negative. We therefore suggest caution in accepting the results of esophagoscopy and are inclined to resect the esophagus in the majority of patients to ensure complete tumor removal. One member of our group is presently using additional radiotherapy rather than resection in patients who have apparent resolution of the primary tumor, as you suggested, Dr. Westbrook.
The American Journal of Surgery
William Ft. Campbell, Jr., MD, Kansas City, Kansas Sarah A. Taylor, MD, Kansas City, Kansas George E. Pierce, MD, Kansas City, Kansas Arlo S. Hermreck, MD, PhD, Kansas City, Kansas James H. Thomas, MD, Kansas City, Kansas
Optimal management of patients with squamous cell carcinoma of the esophagus remains controversial. Earlam and Cunha-Melo [I], in a collected series, found a 2 year survival rate of only 9 percent with surgical treatment. Although Nakayama et al [2] reported a 5 year survival rate of 37.5 percent after preoperative radiotherapy, Launois et al [3] reported no increase in survival for patients treated by this method. Recently, combined preoperative chemotherapy and radiotherapy have been reported to increase survival. Leichman et al [4] reported a median disease-free interval of 3.5 years in 92 percent of patients so treated who had no evidence of microscopic tumor in the resected esophagus. The present study compares morbidity, mortality, and survival rates in patients with squamous cell carcinoma of the esophagus treated with surgery alone, preoperative radiotherapy, or a combination of preoperative chemotherapy and radiotherapy. Material and Methods The records of 52 patients without distant metastasis treated for squamous cell carcinoma of the esophagus were reviewed. Nineteen patients (Group A) underwent operation without, preoperative radiotherapy. Twelve patients (Group B) underwent preoperative radiotherapy (mean exposure 4,228 rads) followed by surgery. Twentyone patients (Group C) received preoperative chemotherapy and radiotherapy. In this group, 3,000 rads were given in increments of 200 rads over a 19 day period. Cisplatin (75 mg/m2) was administered on days 1 and 29 and 5-fluorouracil (1,000 mg/m2 per day) was given as a continuous infusion on davs 1 to 4 and 29 to 32. From the Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas, and the Departments of Medicine and Surgery, Veterans Administration Medical Center, Kansas City, Missouri. Requests for reprints should be addressed to James H. Thomas, MD, Department of Surgery, University of Kansas Medical Center, 39th Street and Rainbow Boulevard, Kansas City, Kansas 66103. Presented at the 37th Annual Meeting of the Southwestern Surgical Congress, Las Vegas, Nevada, April 2%May 2. 1985.
Volume 150, December 1965
All patients were staged according to history, physical examination, upper gastrointestinal endoscopy, and in most instances, computerized axial tomography of the chest and abdomen. Group B and C patients were restaged after chemotherapy and radiotherapy. Operations were performed 3 to 6 weeks after completion of preoperative therapy. Clinical, laboratory, operative, and pathologic data were recorded for each patient. These included age, sex, race, risk factors for cancer, presenting symptoms, physical and radiographic findings, operative procedure, duration of operation, blood loss, postoperative complications, TNM staging, and duration of survival (Table I) 151.Resection was considered potentially curative if neither extraesophageal extension nor involved nodes were identified at operation. Complete follow-up was carried out for all patients. Clinical, laboratory, operative, and pathologic differences between groups were tested by standard statistical methods, including analysis of variance and Scheffe’s test. The life table method described by Cutler and Ederer [6] was used to calculate postoperative actuarial survival.
Patient ages ranged from 35 to 80 years (mean 61 years). Thirty-seven patients were male and 15 were female. Twenty-one patients (40 percent) were black. Alcohol and cigarette abuse were common (46 patients or 88 percent), as were symptoms of pain (36 patients or 69 percent) and weight loss of more than 20 pounds (27 patients or 52 percent). All patients complained of dysphagia. Mean serum albumin levels were within normal limits (3.9 mg/dl), but 25 patients (48 percent) were malnourished on physical examination. Seven tumors were found in the upper third of the esophagus, 31 in the middle third, and 14 in the lower third. Length of the tumor varied from 1 to 11 cm (mean 5.6 cm). One patient had stage I disease, 14 had stage II disease, and 37 had stage III disease without distant metastases.
665
Campbell et al
TABLE I
TNM Staging System for Carcinoma of the Esophagus
Classification
TABLE II
Comparlson of Groups
%
n
Group 0 %
0 19
too
0 4 6
4 15
21 79
0 0 4
A
Definition Parameter
n
C
n
%
‘33 67
1 10 10
4 46 48
6 5
50 42
7 a
33 38
. .
1
a
6
29
‘27
0 3
0 3
3;
Primary Tumor (T) TNM stage
TO TIS TI
T2
T3
No demonstrable tumor in the esophagus Carcinoma in situ A tumor less than 5 cm in length with no obstruction radiographically or circumferential involvement, and without extraesophageal spread A tumor more than 5 cm without extraesophageal spread, or of any length and associated with obstruction or circumferential involvement but without extraesophageal spread Any lesion which has evidence of extraesophageal spread Nodal Involvement
Nx No
NI
(N)
Not assessed (clinical evaluation) Negative nodes on surgical evaluation Positive nodes on surgical evaluation Distant Metastases (M)
Mx MO Ml
Not assessed No known distant metastases Distant metastases present Stage Grouping
I II Ill
T, No MOor T, Nx MO T2 No MOor T2 Nx MO Any T3, any N,, or any MI
Forty-five patients (87 percent) underwent operation. Curative resections were performed in 17 patients (33 percent). Twenty-eight patients (54 percent) were judged to have been palliated. Seven patients (13 percent) had apparent total regression of tumor after preoperative therapy and did not undergo operation. Curative operations included 17 total esophagectomies with reconstruction by gastroesophagostomy in 16 patients and colon interposition in 1 patient. Palliative procedures included esophageal bypass with gastroesophagostomy in 16 patients, colon interposition in 9 patients, and other operations in 3 patients. The mean blood loss was 1.1 liters. The average duration of operation was 4.3 hours. Postoperative complications occurred in 23 patients (51 percent) and included anastomotic leaks in 3 patients, pneumonia in 8 patients, respiratory failure in 3 patients, and sepsis in 5 patients. There were 10 perioperative deaths (22 percent), all of which occurred after palliative procedures. The cumulative survival rate at 2 years for all 52 patients was 21 percent. In patients with stage II and III disease, the 2 year cumulative survival rates were 68 percent and 3 percent, respectively. A comparison of results for Groups A, B, and C is presented in Table II. There were no differences between groups with regard to age, sex, race, inci-
666
0
II Ill Resections Curative Palliative Tumor resolved No operation (n) .Operative mortality Curative Palliative 2 Year cumulative survival Curative Palliative Stage II Staoe Ill
0
0 NA 0
‘66
67 0
. ...
.
52 0
100 15
57 0
NA = not available.
dence of alcoholism, tobacco abuse, benign esophageal disease, dysphagia, pain, weight loss of more than 20 pounds, physical findings of malnutrition, mean serum albumin levels, tumor size and location, amount of blood loss during operation, duration of operation, and number of postoperative complications. There was a significant difference in the distribution of patients based on TNM staging. All patients in Group A had stage III disease; by contrast, 8 patients (67 percent) in Group B and 10 patients (48 percent) in Group C had stage III disease. The single patient with stage I disease was in Group C. After preoperative therapy, only 1 patient in Group B with stage II disease had complete resolution of the primary tumor on endoscopy, whereas 11 patients (53 percent) in Group C had total regression. Twenty-one percent of patients in Group A (4 of 19 patients) and 50 percent of patients in Group B (6 of 12 patients) were resected for cure. Sixty-two percent of patients in Group C (13 of 21 patients) were considered potential candidates for curative resection, including 11 patients who had total regression of the primary tumor and 2 who did not. However, only 5 of these 11 patients underwent esophageal resection, and 2 of these 5 had residual microscopic tumor in the resected esophagus. The other six patients were followed without operation, and two subsequently had recurrence of tumor at the site of the primary tumor. Thus, 4 of 11 patients (35 percent) in Group C were incorrectly considered by endoscopy to have total resolution of the primary tumor. None of the patients who underwent palliative procedures survived 2 years (median survival 2 months). No patient in Group A (all with stage III
The American Journal of Surgery
Therapeutic Alternatives
disease) survived 2 years. In contrast, 2 year cumulative survival rates in Groups B and C were 67 percent and 52 percent, respectively, for patients with curative resections. In patients in Group C with apparent total regression of the esophageal tumor who underwent resection, the 2 year cumulative survival rate was 50 percent, compared with 20 percent for those without operation. Only 1 of 10 patients (10 percent) in Group C who had persistent tumor on restaging survived 2 years. The 2 year cumulative survival rates of patients with stage II disease in Groups B and C were 100 percent and 57 percent, respectively. No differences were found in the 2 year survival rates of patients with stage III disease regardless of the type of therapy employed (Group A 0, Group B 15 percent, and Group C 0). Comments It is estimated that 9,400 new cases of esophageal cancer will be diagnosed by the end of 1985 [7]. Earlam and Cunha-Melo [I] reviewed 83,783 patients with squamous cell carcinoma of the esophagus and found a 9 percent 2 year survival rate after surgery. Because of these poor results, alternative therapeutic approaches have been evaluated in the treatment of squamous cell carcinoma of the esophagus. Nakayama et al [2] proposed preoperative radiotherapy to facilitate tumor resectability and sterilize involved lymph nodes. In 191 patients treated with 2,000 to 2,500 rads, they reported a 5 year survival rate of 37.5 percent. Launois et al [3] described 62 patients who received a mean dose of 4,000 rads followed by operation and 47 patients who underwent operation without preoperative radiotherapy. No difference was found in resectability (75 percent versus 70 percent) or 5 year survival rate (9.5 percent versus 11.5 percent). Preoperative chemotherapy and radiotherapy has been shown to provide total resolution of primary squamous cell carcinoma of the esophagus. Leichman et al [4] found that 26 percent of patients (11 of 42) in a pilot study and 22 percent of patients (19 of 86) in a Southwest Oncology Group clinical trial had no cancer in the resected esophagus after preoperative chemotherapy and radiotherapy. Ninety-two percent of patients without cancer in the resected specimen were alive without disease a median of 3.5 years after surgery; however, if a complete response to the preoperative therapy was not obtained, patients relapsed and died from esophageal cancer. On the basis of these data, these investigators suggested that esophageal resection may not be warranted in the treatment of squamous cell carcinoma of the esophagus. We reviewed the results of therapy in 52 patients with squamous cell carcinoma of the esophagus treated during a 7 year period. During this time, treatment has changed from no preoperative thera-
Volume 150, December 1985
in Esophageal Cancer
py to preoperative radiotherapy and finally to combined preoperative chemotherapy and radiotherapy. In this longitudinal study, there was a progressive decrease in the incidence of patients with stage III disease. Since definitive staging is not determined until operation, this finding could have resulted either from effective preoperative therapy, or simply result from earlier diagnosis. Before therapy, all three groups were identical with regard to presenting symptoms and nutritional status. Thus, it seems unlikely that earlier diagnosis explains the progressive decrease in patients with stage III disease. The lower incidence of stage III disease in Group C patients can best be attributed to combined preoperative chemotherapy and radiotherapy. The rate of resectability improved during the course of this study as the percent of patients with stage II disease increased. Likewise, survival rates have improved with the increase in the rate of resectability. In contrast to the suggestion of Leichman et al [4] that surgery may not be necessary in patients treated with combined chemotherapy and radiotherapy, our data suggest a decreased survival rate when the esophagus is not resected in patients with apparent resolution of the primary tumor after preoperative therapy. Repeat endoscopy was not reliable in detecting the presence of persistent microscopic tumor. We suggest that patients with squamous cell carcinoma of the esophagus should be treated with preoperative chemotherapy and radiotherapy as outlined for Group C patients followed by esophagectomy in low risk patients. This recommendation is based on the observations that more than 50 percent of patients will have apparent preoperative total resolution of tumor, that local recurrence develops in patients who have undetected microscopic tumor, and that curative esophagectomy is associated with a low risk of death. Summary The records of 52 patients treated either with surgery alone (Group A), preoperative radiotherapy (Group B), or combined preoperative chemotherapy and radiotherapy (Group C) were reviewed to determine the optimal management of patients with squamous cell carcinoma of the esophagus. There was a significant difference in the number of patients with stage III disease between Groups A and C (100 percent and 48 percent, respectively). With the decrease in patients with stage III disease, both resectability rates in Groups A and C (21 percent and 62 percent) and 2 year cumulative survival (0 and 52 percent) increased. Eleven patients in Group C (53 percent) had apparent total resolution of the primary tumor after preoperative therapy. Microscopic tumor was present but was not detect-
667
Campbell et al
ed by repeat endoscopy in 35 percent of these patients. The survival rate was higher in patients with apparent total tumor regression who underwent esophageal resection. These results suggest that patients with squamous cell carcinoma of the esophagus are best treated with preoperative chemotherapy and radiotherapy followed by esophagectomy regardless of their response to preoperative therapy.
the esophagus to improve the survival rate. The present study, in addition to studies from Wayne State and from the Southwestern Oncology Group, offer encouragement for better survival rates. Dr. Thomas, I am curious about some technical details involving the operation. Do you ever use the EEA stapler in your anastomoses? Do you always place the anastomosis in the neck, or are there instances when the anastomosis is in the thorax? If follow-up does not include esophagoscopic examination, do you use computerized axial tomography or barium swallow instead?
References
Kent C. Westbrook (Little Rock, AR): Dr. Thomas, your report illustrates the trend toward combined modality therapy in the treatment of difficult tumors. We must be very cautious in interpreting the results of such a combined program. Are we actually improving survival rates with only 2 survivors in Group C of the 21 who completed the regimen? I am convinced that preoperative radiotherapy and chemotherapy shrink lesions and make them resectable, but I am not sure that long-term survival rates will improve. Dr. Thomas, if radiotherapy and chemotherapy are so effective in shrinking the tumor, why not simply treat these patients with radiotherapy and chemotherapy and omit surgery? Since 3,000 rads is not a curative dose of radiotherapy, why not increase it to 6,000 rads to eradicate the cancer?
1. Earlam R, Cunha-Melo JR. Oesophageal squamous cell carcinoma: I. A critical review of surgery. Br J Surg 1980;67:381-90. 2. Nakayama K, Orihata H, Yamaguchi K. Surgical treatment combined with preoperative concentrated irradiation for esophageal cancer. Cancer 1967;20:778-88. 3. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperative radiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet 1981;153:690-2. 4. Leichman L, Steiger Z, Seydel HG, Vaitkevicius VK. Combined preoperative chemotherapy and radiation therapy for cancer of the esophagus: the Wayne State University, Southwest Oncology Group, and Radiation Therapy Oncology Group experience. Semin Oncol 1984;11:178-85. 5. American Joint Committee For Cancer Staging and End-Results Reporting. Manual for staging of cancer. Chicago: Whiting Press, 1979. 6. Cutler SJ, Ederer F. Maximum utilization of life table method in analyzing survival. J Chronic Dis 1958;8:699-712. 7. Silverberg E. Cancer statistics, 1985. CA 1985;35:19-35.
William F. Sasser (St. Louis, MO): Attempts to increase survival rates in patients with this dreaded disease have taken three avenues: earlier diagnosis, more radical surgery, and combined modality treatment. In areas of the world where there is a high incidence of carcinoma of the esophagus, such as parts of China and Iran, improved diagnostic efforts have been undertaken to discover the disease while it is in stage I. Because of the success of early diagnosis, 5 year survival rates approaching 95 percent have been reported. Unless the incidence of the disease increases in the United States, it is doubtful that a screening test will be used to a greater degree to uncover the problem. More radical surgery has been tried with little improvement in results, whereas combined modality approaches have offered some improvement. I have one such patient who has been placed on the Southwestern Oncology Group protocol. He had an esophageal carcinoma which almost completely obstructed his esophagus. A computerized axial tomographic scan revealed a large lesion on the right side of the neck adjacent to the carotid artery. After going through a course of cisplatin and 5-fluorouracil therapy as well as radiotherapy, the mass disappeared and the patient could swallow food. He has been followed for 2 years. It is clear that something has to be done in the treatment of carcinoma of
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Raymond C. Read (Little Rock, AR): Dr. Thomas, your report emphasizes the need for more information about the role of radiation and chemotherapy in this disease, but I want to reinforce what Dr. Westbrook said. Patients in Group A were operated on immediately. The other group presumably had a waiting period of 6 or 8 weeks during which they received radiotherapy and chemotherapy. This was a period when the most seriously ill patients were culled out, and so the results in that limited group, as Dr. Westbrook pointed out, would presumably be a lot better. Dr. Thomas, you seem to believe that there is no place for palliative surgery in these patients, even though most of the patients we see with esophageal cancer are incurable. What is your opinion of the role of surgery in regard to patients who have lymph node metastasis or advanced disease in the mediastinum? James H. Thomas (closing): Dr. Sasser, we do not use the EEA stapler for esophageal anastomoses. Dr. Read, we believe that it is important to resect the entire esophagus because of the tendency for submucosal spread by esophageal cancer. Esophagoscopy is important in evaluating these patients, but in our report, it was reliable in only 65 percent of patients so evaluated. Thus, patients may have persistent tumor when esophagoscopic findings are negative. We therefore suggest caution in accepting the results of esophagoscopy and are inclined to resect the esophagus in the majority of patients to ensure complete tumor removal. One member of our group is presently using additional radiotherapy rather than resection in patients who have apparent resolution of the primary tumor, as you suggested, Dr. Westbrook.
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