J THoRAc CARDIOVASC SURG 1988;96:237-41
External beam and intraluminal radiotherapy in the treatment of carcinoma of the esophagus During a lo-year period, 46 patients with unresectable or inoperable carcinoma of the esophagus were treated with teletberapy-bracbytherapy combination at the University of Southern California School of Medicine. Stage distribution was as foDows: stage I, 5 (11%) patients;stage II, 23 (50%) patients;stage m, six (13%) patients; and stage IV, 12 (26%) patients. Thirteen patients were treated for recurrent disease, including 11 patients initiaUy treated with teletherapy and two who had had surgical resection. Radiotherapy was given by teletherapy in 33 and bracbytherapy in aU 46 patients. An average tumor dose was 50 Gy with teletherapy and 20 Gy per application with bracbytherapy. There were 25 patients who bad more than one bracbytherapy application. The 5-year actuarial survival rate for 28 patients with stageI or II diseasewas 12 %, with a median of 13 months, This compared with no 5-year survivals and a median survival of 10 monthsfor the 18 patients with stage m or IV disease. Failure at the primary site was seen in 16 (35%) patients. Complete response was seen in 20%, partial response in 76%, and no response in 4 %. Treatment was weD tolerated.Complications included esophageal stenosis in two patients and tracheoesophageal fistula in one. Teletherapy-bracbytherapy combination is an effective treatment in the management of unresectable or inoperable carcinoma of the esophagus.
Elizabeth Crist Hyden, MD, Bryan Langholz, PhD, Timothy Tilden, MD, Kenneth Lam, MD, Gary Luxton, PhD, Melvin Astrahan, PhD, Joanne Jepson, MD, and Zbigniew Petrovich, MD, Los Angeles, Calif.
RgnOSis of patients with carcinoma of the esophagus remains poor. The treatment of choice for early disease is surgery.t' Early diagnosis in carcinoma of the esophagus was shown to increase the resectability rate to over 90% and the 5-year survival rate to 25%.3 Radiotherapy has been used in the treatment of carcinoma of the esophagus since the beginning of this century. Initially, it was primarily intracavitary radiation (brachytherapy),4-6 but with technological advances the mainstay of treatment has become external radiation (teletherapy). The use of radiotherapy was usually limited to advanced unresectable or inoperable tumors. No studies have been published comparing radiotherapy with surgical therapy
From the Departments of Radiation Oncology and Preventive Medicine, University of Southern California School of Medicine, Los Angeles, Calif. Received for publication Sept. 16, 1987. Accepted for publication Jan. 4, 1988. Address for reprints: Zbigniew Petrovich, MD, USC Norris Cancer Hospital and Research Institute [441 Eastlake Ave., Los Angeles, CA 90033.
in the treatment of patients with a similar stage of the disease, because radiation was usually limited to unresectable or inoperable tumors,' with a 5-year survival rate ranging from 6% to 20%.8.9 Several studies have demonstrated the value of radiotherapy in controlling primary tumor in the esophagus, providing good palliation in 75% of patients and a 5-year survival rate of up to 10%.1(1.13 However, histologic examination of the esophagus at autopsy has shown 80% macroscopic or microscopic tumor irrespective of the cause of death" and systemic metastases in a similar percent of patients. I I Surgically treated patients tend to have a similar pattern of tumor spread." The use of adjuvant radiotherapy in patients with resectable disease has not been well defined. Some studies suggest that it benefits selected patients.v" whereas others report no benefit.' A combination of radiotherapy and bleomycin chemotherapy in a randomized trial has shown no benefit over radiotherapy alone." A recent report of a pilot study with radiation therapy and cisplatin plus 5fluorouracil chemotherapy demonstrated a good median survival," and randomized trials are needed to evaluate this treatment. 237
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2 3 8 Hyden et al.
Table I. Survival of patients by stage Stage
I + II III + IV
54 24 54
23 18 19
12 0 11
Table II. Survival by presence or absence of metastatic disease Survival (%) Stage
55 10 54
24 10 19
13 10 12
The purpose of this report is to evaluate our clinical experience with the use of a planned combination of teletherapy and brachytherapy in patients with unresectable or inoperable esophageal tumors. Patients and methods From 1976 through 1986, patients with unresectable or inoperable carcinoma of the esophagus were treated with teletherapy and brachytherapy at the Department of Radiation Oncology, University of Southern California School of Medicine in Los Angeles. There were 24 (52%) male and 22 (48%) female patients. Their ages ranged from 41 to 89 years with a median age of 64 years. Racial distribution of these patients was as follows: black 22 (48%), white 19 (41%), Oriental three (7%), and others two (4%). The most frequent symptom was dysphagia, seen in 42 (91%) patients. Weight loss was seen in 30 (65%) patients, half of whom lost more than 15 pounds. Two thirds of the patients treated had signs and symptoms of 4 months or less in duration. Initial performance status on the Karnofsky scale" was ambulatory in 37 (80%) and nonambulatory in the remaining nine (20%) patients. Histologic diagnosis was squamous cell carcinoma in 45 patients and adenocarcinoma in one. The tumor grades were as follows: poorly differentiated in 24 (52%), moderately well differentiated in 16 (35%), and well differentiated in four (9%); in two (4%) patients the tumor was not graded. The site of tumor origin was proximal esophagus in 15 (33%), middle in 23 (50%), and lower in the remaining eight (17%) patients. Varying degrees of esophageal obstruction were seen in 25 (54%) patients. Clinical staging was done according to the American Joint Commission on Cancer." Of the 46 patients treated, five (11%) had stage I, inoperable disease. Inoperability in these patients was due to severe cardiac disease in three patients and the presence of an incurable second primary cancer in two patients. Stage II was represented by 23 patients (50%), and six (13%) patients had stage III tumor. Twelve patients (26%) were in stage IV, with lymph nodes, lung, and liver being the most frequent sites of distant metastases. Most (72%) patients had no prior therapy, whereas 13 (28%) had
previously been treated. Of these 13 patients, 10 had prior radiotherapy and persistent or recurrent disease, and three patients had prior surgical therapy with postoperative radiotherapy. All three surgically treated patients had an esophagectomy, with two having macroscopic residual disease and one, who had T2 N3 MO disease, having a recurrent tumor in the esophagus 24 months after the operation. All 46 patients received intraluminal radiotherapy, with 33 patients also receiving external radiation. In the 13 patients with recurrent disease, brachytherapy alone was used for repeat treatment because of the previous high-dose teletherapy. External beam radiotherapy was administered with 4 or 15 MV roentgen rays five times a week at a dosage of 1.8 Gy a day. Tumor dose ranged from 38 to 63 Gy with an average dose of 50 Gy. In the patients who have received a tumor dose of more than 40 Gy, the spinal cord was excluded from the volume receiving a higher dose of radiation. Radiotherapy was given to gross tumor in the esophagus usually with a 5 em proximal and distal margin. Clinically uninvolved supraclavicular lymph nodes were included in the radiation portals for lesions of the proximal esophagus. Celiac axis lymph nodes were included in the treatment of tumors of the lower esophagus. Brachytherapy was typically given 2 weeks after the last external beam treatment. The procedure consisted of tumor visualization during esophagoscopy, to assess the tumor response and to obtain a biopsy specimen if necessary. With the aid of fluoroscopy, appropriate anatomic landmarks were identified to localize the proximal and distal extent of the tumor. After removal of the endoscope, an esophageal applicator was placed through the nose and positioned with the aid of a fluoroscope. The tube was designed at the University of Southern California in 1976 for intraluminal treatment of esophageal tumors, and it is available through Alpha Omega Services, Inc., of Los Angeles. It is 65 em in length and up to 11 nun in diameter. The tube has six channels spaced every 60 degrees to accept radioactive iridium 192. The central channel is used for feeding and, if it becomes necessary, for aspiration of gastric secretions. The position of the tube was always confirmed by orthogonal radiographs. After satisfactory localization, iridium 192 ribbons were manually afterloaded.
Volume 96 Number 2 August 1988
Radiotherapy in carcinoma of esophagus
, oo.--or-----------------------, ..J
> s a:
+-----,----r------r----'--r------r----r----1 o 3 5 6 TIME (years)
Fig. I, Actuarial survival of the 46 treated patients according to tumor stage at diagnosis.
Of the 46 patients treated, 22 (48%) had two brachytherapy procedures spaced 2 weeks apart. Twenty-one (46%) had a single procedure and three (6%) had three procedures. The applications was limited to one in those patients who had previously received a dose of more than 55 Gy with teletherapy. The patients who received a third application were those with local progression but no distant disease. Each intraluminal application was scheduled to deliver 20 Gy of radiation 5 mm from the outside surface of the esophageal tube. The dose rate at this point was from 45 to 60 cGy/hr. A rapid fall off of the radiation dose occurred. At 10 nun from the surface of the tube it was 12 Gy and at 15 mm it was reduced to 8 Gy. This permitted treatment of intraluminal tumors with relative sparing of the adjacent normal tissues. Tumor response was assessed jointly by a thoracic surgeon and a radiation oncologist. Complete response was defined as total tumor regression for 30 days or longer. Partial response was more than 50% tumor regression". No response was a lesser degree of tumor regression. Initially, tumor regression was assessed with esophagograms, computed tomographic scans, and endoscopy. In the last 6 years of the study tumor regression was biopsy confirmed. All patients were required to sign an informed consent form before administration of therapy. Survival was calculated from the day of diagnosis by the actuarial method."
Results The 5-year actuarial survival rate for the 46 patients treated was 11% with a median survival of 11 months. As expected, the patients with earlier stages of disease had a better survival rate: 12% at 5 years for the 28 patients with stage I or II disease compared with no survivalsover 3 years for patients with stage III and IV disease, p = 0.09 (Fig. 1 and Table I). None of the 12 patients with metastatic disease (M 1) survived more than 23 months, compared to the 34 patients with MO disease, p = 0.026 (Fig. 2 and Table II). There was no
m. Final status of all patients Status
Alive, no evidence of disease Death from primary tumor Death from regional tumor spread Death from distant metastases Death from intercurrent disease Lost to follow-up Total
difference in the survival rates of patients with tumors arising in the proximal, middle, or lower esophagus. Complete response was seen in nine (20%) patients, partial response in 35 (76%), no response in one, and progressivetumor in one patient. Nearly all patients had subjective improvement after completion of irradiation. Of the 30 patients who had lost weight, one third gained a substantial amount, one third maintained their weight, and one third continued to lose weight. Among nine patients whose status was nonambulatory before treatment, only one showed improvement in general condition. Among the 37 ambulatory patients, 28 maintained this status, five became nonambulatory, one died before 2 months' assessment, and in three patients the Karnofsley status was not assessed. The final status of all patients is shown in Table III. The most frequent cause of death was recurrent disease at the primary site, seen in 16 (35%) patients. Death caused by metastatic tumor was next in frequency (22%). An equal number of patients died of intercurrent disease. At death, from any cause, 38 (83%) patients had either microscopic or macroscopic tumor in the
The Journal of Thoracic and Cardiovascular Surgery
2 4 0 Hyden et al.
100 , - - - - , , - - - - - - - - - - - - - - - - - - - - - - - - - - ,
> ~ :i
Fig. 2. Actuarial survival according to presence or absence of metastatic disease at diagnosis.
esophagus. In 12 of these patients, the presence of tumor in the esophagus was not suspected. The remaining eight patients had no tumor at the time of death or last follow-up examination. Treatment for recurrent disease after brachytherapy consisted of chemotherapy in eight patients and surgical therapy in two. The two surgically treated patients had improved to a nutritional status that allowed a surgical attempt. One of these patients had died of surgical complications, and the other died 2 months postoperatively of progressive disease. No responses to chemotherapy were noted. Treatment complications developed in three patients. A tracheoesophageal fistula developed in patient 1, who died of presumed aspiration. Biopsy-proved tracheal invasion was present at diagnosis, and the treatment was given to relieve esophageal obstruction. In patient 2 significant stenosis developed at the tumor site, and again death was caused by aspiration pneumonia. Patient 3 also had post-treatment stenosis and died of metastatic disease with the primary site controlled. An additional 14 (30%) patients had symptoms and signs of esophagitis during administration of radiotherapy. The esophagitis responded well to the usual medical treatment with antacids. Discussion This study has shown the effectiveness of teletherapybrachytherapy combination in the treatment of unresectable or inoperable carcinoma of the esophagus. In addition to the survival benefits, an excellent palliative effect was noted. The treatment was uniformly well tolerated by the patients. With this technique, the
incidence of serious complications was very low. Similar treatment results have recently been reported.": 22 In a Japanese study of 119 patients, there was a clear and substantial survival advantage for patients receiving combined brachytherapy and teletherapy compared with those receiving teletherapy alone." Additionally, 35% of our patients died of recurrence of local-regional disease. The number of patients in whom asymptomatic microscopic or macroscopic local disease was detected at death has almost equaled the number of patients with symptomatic tumor recurrences. This persistence or recurrence of esophageal tumor appears similar to the surgical and radiotherapy data reported by others." 10. II. 13. 14 It seems that increase in the local-regional control rate may result in a longer survival and a better quality of life. In an attempt to increase the incidence of local-regional tumor control, we began to study the effect of intraluminal microwave hyperthermia in combination with brachytherapy for patients with unresectable esophageal carcinoma.v" To shorten the required hospitalization of patients undergoing brachytherapy, from 2 days to a few hours, we acquired a remote afterloading apparatus. It allows brachytherapy to be done on an outpatient basis and thus reduces the patient's discomfort. Successful teletherapy-brachytherapy requires a joint effort by the gastroenterologist, thoracic surgeon, and a radiation oncology team. REFERENCES I. Earlam R, Cunha-Melo JR. Oesophageal squamous cell carcinoma. 1. A critical review of surgery. Br J Surg 1980;67:381-90.
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2. Giuli R, Gignoux M. Treatment of carcinoma of the esophagus: retrospective study of 2,400 patients. Ann Surg 1980;192:44-52. 3. Wu Y, Huang K. Chinese experience in the surgical treatment of carcinoma of the esophagus. Ann Surg 1979;190:361-5. 4. Guisez J. Malignant tumors of the oesophagus. Laryngol Otol 1925;40:213-32. 5. Harriman FR. Malignancy of the larynx and esophagus treated by radium emanation. Laryngoscope 1927;37:66470. 6. Muir J. Radium implantation in esophageal cancer: description of operating esophagoscope-technique of application. Laryngoscope 1927;37:660-3. 7. Ear/am R, Cunha-Melo JR. Oesophageal squamous cell carcinoma. II. A critical review of radiotherapy. Br J Surg 1980;67:457-61. 8. Pearson JG. The value of radiotherapy in the management of esophageal cancer. Am J Roentgenol Radium Ther Nucl Med 1969;105:500-13. 9. Newaisky GA, Read GA, Duncan W, Kerr GR. Results of radical radiotherapy of squamous cell carcinoma of the oesophagus. Clin Radiol 1982;33:347-52. 10. Mantravadi RVP, Lad T, Briele H, Liebner EJ. Carcinoma of the esophagus: sites of failure. Int J Radiat Oncol BioI Phys 1982;8:1897-1901. 11. Anderson LL, Lad TE. Autopsy findings in squamous cell carcinoma of the esophagus. Cancer 1982;50:1587-90. 12. Elkon D, Lee MS, Hendrickson FR. Carcinoma of the esophagus: sites of recurrence and palliative benefits after definitive radiotherapy. Int J Radiat Oncol BioI Phys 1978;4:615-20. 13. Beatty JD, De Boer G, Rider WD. Carcinoma of the esophagus: pretreatment assessment, correlation of radiation treatment parameters with survival and identification and management of radiation treatment failure. Cancer 1979;43:2254-67.
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14. Parker EF, Gregorie HB. Carcinoma of the esophagus: long term results. JAMA 1976;235:1018-20. 15. Marks RD, Scruggs HJ, Wallace KM. Preoperative radiation therapy for carcinoma of the esophagus. Cancer 1976;38:84-9. 16. Earle JD, Gelber RD, Moertel CG, Hahn RG. A controlled evaluation of combined radiation and bleomycin therapy for squamous cell carcinoma of the esophagus. Int J Radiat Oncol Bioi Phys 1980;6:821-6. 17. Leichman L, Herskovic A, Leichman CG, et al. Nonoperative therapy for squamous cell cancer of the esophagus. J Clin Oncol 1987;5:365-70. 18. Kamofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM, ed. Evaluation of chemotherapeutic agents. New York: Columbia University Press, 1949:191-205. 19. American Joint Committee on Cancer. Manual for staging of cancer. 2nd ed. Philadelphia: JB Lippincott, 1986:61-6. 20. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:45781. 21. Syed NAM, Puthawala AA, Severance SR, Zamost BJ. Intraluminal irradiation in the treatment of esophageal cancer. Endocurieth Hyperthermia Oncol 1987;3:105-13. 22. Hishikawa Y, Kamikonya N, Tanaka S, Miura T. Radiotherapy of esophageal carcinoma: role of highdose-rate intracavitary irradiation. Radiother Oncol 1987;9:13-20. 23. Astrahan MA, Sapozink MD, Luxton G, Kampp TD, Petrovich Z. Intraluminal hyperthermia of the esophagus. Int J Hyperthermia [In press). 24. Petrovich Z, Astrahan MA, Lam K, Tilden T, Luxton G, Jepson J. Intraluminal thermoradiotherapy with teletherapy for carcinoma of the esophagus. Endocurieth Hyperthermia Oncol [In press).