Inr J Rndmfwn Oncrh~y Em/ Phw Vol. Pnnted 8” the USA All rights reserved.
24. pp.
235-240 Copyright
0360.3016192 95.Oil + .W 0 1992 Pergamon Press Ltd.
??Clinical Original Contribution
INTRACAVITARY BRACHYTHERAPY COMBINED WITH EXTERNAL-BEAM IRRADIATION FOR SQUAMOUS CELL CARCINOMA OF THE THORACIC ESOPHAGUS MASATO HAREYAMA, M.D.,’ MASAMICHI NISHIO, M.D.,’ YOSHIKAZU KAGAMI, M.D.,* NAOTO NARIMATSU, M.D.,* AKIO SAITO, M.D.3 AND TOMOYASU SAKURAI, M.D.* ‘Department of Radiology, Sapporo Medical College, S- 1, W- 16, Chuo-ku, Sapporo, 060 Japan; ‘Department of Radiology, National Sapporo Hospital, 4-2 Kikusui, Shiroishi-ku, Sapporo, 003 Japan; 3Department of Radiology, 18-16 Kawaharacho, Hakodate, 041 Japan
During the 15 year period from 1974 to 1988, 277 patients with previously untreated, histologically confirmed, squamous cell carcinoma of the thoracic esophagus were treated with the Time Dose and Fractionation (TDF) factor of more than 99. Of these, 161 patients were treated with external beam irradiation combined with intracavitary brachytherapy. Intracavitary brachytherapy was done for all patients for whom insertion of an outer applicator 1 cm in diameter was possible and for whom a relatively good performance status was seen at completion of external beam irradiation. Except for mild radiation-induced esophagitis, no acute radiation injuries were noted. The early clinical effect of radiation upon the esophageal lesion was determined by esophagography and esophagoscopy, approximately 1 month after the combined radiotherapy; a complete response was observed in 86 (53.4%) of the 161 patients. Furthermore, after a 5 year follow-up, local control of esophageal cancer was found to have been successful in 51 (31.7%) of the 161 patients. The highest rate of local control was associated with the following criteria: Stage I, Tl, tumor length less than 5 cm, and superficial or tumorous type of tumor. The 5-year actuarial survival rates were 43.3% for Stage I, 21.1% for Stage II, and 0% for both Stages III and IV. Benign radiationinduced esophageal ulcerations or strictures did develop in five of the long-term survivors, suggesting that the dosage is close to the maximal tolerance of the esophagus. We recommend that 1500-2000 cGy in two or three fractions is the optimal dosage for intracavitary radiation of the esophageal mucosa after external irradiation of 5500 cGy in 22 fractions for 5.5 weeks or 6000 cGy in 30 fractions for 6 weeks. We believe that intracavitary treatment of esophageal carcinoma is a highly effective and a safe therapeutic modality, not only as a palliative therapy, but also as a radical treatment for patients in Stages I and II. Thoracic esophageal carcinoma, Radiotherapy, Intracavitary brachytherapy.
INTRODUCTION
in spite of advances in technology, survival with radiotherapy has been unsatisfactory (19, 21) except for the
Although some authors report a 5-year survival rate of approximately 20% for carcinoma of the esophagus, in selected patients with combined pre- or post-operative irradiation and radical surgery ( 1, 16), most authors report 5-year survival rates of approximately 10% or lower (24, 26). Surgical resection is usually chosen in Japan, except that radiotherapy is usually applied in most cases of thoracic esophageal cancer, with or without intercurrent disease, because of long-term malnutrition, advanced stage, and the advanced age of these patients. On the other hand,
results reported by Pearson (25). This is due partly to a high incidence of lymph node and distant metastasis and, more importantly, to difficulties in achieving local control by radiotherapy ( 18). At present, even when radiotherapy is combined with chemotherapy (3,29) the prognosis for patients with esophageal carcinoma is not greatly improved. In an attempt to improve local control of radiation for radioresistant carcinoma of the esophagus, we have combined intracavitary brachytherapy, as a boost therapy, to the external irradiation. In this report, we analyze the
Reprint requests to: Masato Hareyama, M.D., Department of Radiology, Sapporo Medical College, S-l, W-16, Chuo-ku, Sapporo 060, Japan. Acknowledgements-The authors thank Mr. J. L. Nolin (Sap poro Medical College) for English editing and Prof. K. Morita (Sapporo Medical College) for editorial assistance.
This work was supported in part by grants from the Japanese Ministry of Health and Welfare and the Japanese Ministry of Education, Science and Culture. Accepted for publication 6 April 1992.
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results of this combined external and intracavitary irradiation and discuss its role in the treatment of carcinoma of the esophagus. METHODS
Volume 24, Number 2, 1992
Table 1. Patient characteristics and radiation response of the primary lesion of esophageal cancer treated by combined external irradiation and intracavitary treatment Complete response at 1 month after Local control combined after a 5 year radiotherapy follow-up
AND MATERIALS
During the 15 year period from 1974 to 1988,368 patients with previously untreated, histologically confirmed squamous cell carcinoma of the thoracic esophagus were treated primarily by radiotherapy at the Department of Radiology, National Sapporo Hospital. Of these, 9 1 patients were subjected to symptomatic irradiation with TDF below 98, because of massive distant metastasis, significant extra-esophageal spread, complications, or poor performance status. The remaining 277 patients were treated with TDF above 99, with 161 (58.1%) of these receiving combined intracavitary brachytherapy. Intracavitary brachytherapy was done for all patients for whom insertion of an outer applicator 1 cm in diameter was possible and for whom a relative good performance status was seen at completion of external beam irradiation. Pretreatment evaluation included the following examinations: complete blood count, liver function test, serum protein, double-contrast esophagography, chest x-ray, esophagoscopy, and biopsy. Since 1983, CT scanning has also been used to detect liver metastasis and/or juxta-regional lymph node involvement. The age of patients receiving brachytherapy ranged from 47 to 88 years with a median of 64 years. There were 139 males and 22 females, for a ratio of 6.3:1. The characteristics of the 16 1 patients receiving intracavitary brachytherapy are shown in Table 1. Tumor length ranged from 1.1 cm to 15.0 cm, with a median of 6.0 cm. Tumors of spiral type, according to the esophagographic classification by the Japanese Society for Esophageal Disease (14), numbered 59 and dominated the patient population. For staging, the 1978 UICC TNM classification (30) was used. Stage II was found to be most common (7 1 patients). External beam radiation was administered using 6MV or 1OMV photons. The field of radiation included a minimum of 3 cm normal margin both above and below the primary lesion and the width was between 6 and 8 cm. All fields were treated at each treatment session. Prophylactic irradiation of the regional lymph nodes was not performed except in cases in which lymph node metastases were observed. Irradiation was initiated with a parallelopposing anterior and posterior pair of fields; a tumor dose of 200 cGy was given five times a week from 1974 until 1977, while a tumor dose of 250 cGy was given four times a week after 1977. After administration of 40005000 cGy, the field was changed to two oblique portals to avoid excessive irradiation to the spinal cord after analyzing the isodose distribution. Total dosage ranged from
* Nelaton rubber catheter No. 10, Izumo Gomu Co., Tokyo, Japan.
No. of cases (%) Total Stage* I II III IV T factor 1 2 3 Site of tumor UT MT LT Length of tumor < 5 cm 5-10 cm > 10cm Type of tumor Superficial Tumorous Serrated Spiral Funnelled
161
No. (W)
No. (W)
86 (53.4)
51 (31.7)
(18.6) (44.2) ( 18.6) (18.3)
27 (90.0) 40 (56.3) 8 (26.7) 11 (36.7)
17 24 3 7
33 (20.5) 105 (65.2) 23 (14.3)
29 (87.9) 53 (50.5) 4 (17.4)
18 (54.5) 31 (29.5) 2 (8.7)
12 (7.4) 104 (64.6) 45 (28.0)
4 (33.3) 56 (53.8) 26 (57.8)
34 (32.7) 17 (37.8)
64 (39.7) 89 (55.3) 8 (5.0)
44 (68.8)
40 (44.9) 2 (25.0)
25 (39.1) 25 (28.1) 1 (12.5)
15 (9.3) 31 (19.3) 42 (26.1) 59 (36.6) 14 (8.7)
15 (100.0) 20 (64.5) 26 (6 1.9) 19 (32.2) 6 (42.9)
8 (53.3) 13 (41.9) 15 (35.7) 12 (20.3) 3 (21.4)
30 71 30 30
(56.7) (33.8) (10.0) (23.3)
0 (0)
* 1978 UICC classification. UT = Upper thoracic esophagus; MT = Middle thoracic esophagus; LT = Lower thoracic esophagus.
4750 to 7000 cGy; commonly, 5500 cGy was given in 22 fractions four times per week over an interval of 5.5 weeks or 6000 cGy was given in 30 fractions five times per week over an interval of 6 weeks. Intracavitary brachytherapy following external irradiation was performed in all patients in whom the combination was thought to be possible and to have some merit. Within approximately 2 weeks after external radiotherapy, the patients were examined by esophagography, with or without esophagoscopy, to establish the location of the primary lesion and to determine the field of radiation for intracavitary brachytherapy. Intracavitary treatment was started 2 weeks after the last external irradiation. Thirty minutes before this treatment, 15 to 30 mg of pentazocine and 0.5 mg of atropine sulfate were given intramuscularly. No general anesthetic was needed. After local anesthesia was applied to the oral cavity, a flexible gastric lavage catheter* 1 cm in diameter as an outer applicator tube, was inserted via the mouth into the stomach under fluo-
Brachytherapy for carcinoma of the esophagus 0 M. HAREYAMA rt al.
231
roscopy and stabilized in place (Fig. 1). To allow subsequently rapid and precise placement of the radium tubes, an inner tube containing dummy markers was first placed in the outer applicator tube and secured in the desired position under fluoroscopic observation (Fig. 2). After the patient had been moved to the treatment room, the inner tube with the dummy markers was replaced with an inner tube containing four or five radium tubes of 370 MBq (10 mg) each tube arranged longitudinally. Since 1990, cesium tubes have been used in view of the difficulty of radiation protection from radium. Treatment volume was thought the residual carcinoma within a level 0.5 cm below the esophageal mucosa. The dosage was calculated to be approximately 200 cGy/hour at the surface of the esophageal mucosa (i.e., at the surface of the outer tube which was 0.5 cm from the radium). The applicator was removed after each treatment. A dose of 400- 1000 cGy was delivered during each treatment. If necessary, the intracavitary treatments were repeated at intervals of at least 1 week three times at most. The actuarial survival rate was calculated by the Kaplan and Meier method and statistical analyses were carried out using the Log-rank test. RESULTS During intra-esophageal irradiation, some patients who were uncomfortable were intramuscularly given additional pentazocine, so that there was no interrupting of the treatment. Two hours after the completion of intracavitary therapy, oral intake was possible. Except for mild radiation-induced esophagitis, no acute radiation injuries were noted. One month after combined radiotherapy bariumcontrasted esophagography, or in most cases esophagography and esophagoscopy, was done to evaluate the early clinical effect of radiation upon the esophageal lesion. Complete response was judged by the following criteria: (a) disappearance of the mass shadow; (b) no narrowing observed in the esophageal lumen; (c) and no or slight rigidity of the esophageal wall without residual ulceration.
Fig. 1. The patient: the outer applicator the mouth and stabilized in place.
tube was inserted
via
Fig. 2. Irradiation dummy markers.
field for intra-esophageal
brachytherapy
and
A complete response 1 month after combined radiotherapy was observed in 86 (53.4%) of the 16 1 patients. On the basis of a 5-year clinical follow-up, a histopathological examination or postmortem examination, local control of esophageal cancer was found to have been successful in 5 1 (3 1.7%) of the 16 1 patients. Table 1 shows the results of analysis according to stage, T factor, site, length and type of tumor as determinationed by radiological examination. The highest rate of local control was associated with Stage I, T 1, tumor length less than 5 cm, and superficial or tumorous type of tumor. Twenty-three (20.9%) of the 110 patients with residual tumor or local recurrence received salvage operations. These 23 patients included 7 in Stage I, 12 in Stage II, 3 in Stage Ill and 1 in Stage IV. The actuarial survival rate included the effect of this salvage operation. The 5-year actuarial survival rates were 43.3% for Stage I, 2 1.1% for Stage II, and 0% for both Stages Ill and IV (Fig. 3). Significant differences at p < 0.05 were observed between Stage I and the other stages, as well as between Stage II and Stages III and IV. The 5-year actuarial survival rate was 32.2% for patients with tumor lengths less than 5 cm and 10.4% in those with lengths ranging from 5 to 10 cm (Fig. 4). No one in the group with tumor lengths exceeding 10 cm survived the 5-year period. A significant difference (p -=z0.05) was noted between the group with lengths less than 5 cm and that with lengths 5 to 10 cm or more.
1. J.
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Volume
24, Number
I
0
12
24
36
Time
48
60
5y (%I
-1
30
43.3
-____- II
71
21 .l
.-.-.-.
111
29
0
N
31
0
Tumor
brachytherapy
The 5-year actuarial survival rates according to tumor type were: superficial, 4 1.6%; tumorous, 32.3%; serrated, 16.1%; spiral, 9.3%; and funnelled, 7.1% (Fig. 5). Signif-
80
3 60
cz
j
20
1.
“1_.
Ji_:,_,
i._._._._._._._._.l~~~~_~~______,
i
I 12
‘--I
1
1
0
24
Time
1
12
36
24
I
36
I
I
I
48
60
Time in Months
n
Fig. 3. The actuarial survival of intra-esophageal by stage.
.? L
1
0
in Months
Stage
.. . . .
2, 1992
48
60
type
n
5y (%)
-
superficial
15
41.6
------
tumorous
31
32.3
.-.-.-.
serrated
42
16.1
._.._.._.
spiral
59
9.3
............
funnelled
14
7.1
Fig. 5. The actuarial survival of intra-esophageal brachytherapy by tumor type.
icant differences were observed between the superficial type and the others and between the tumorous and spiral types. The 5-year actuarial survival rates according to tumor sites were: 16.7% in upper thoracic esophageal cancer, 16.8% in middle thoracic esophageal cancer, and 22.3% in lower thoracic esophageal cancer (Fig. 6). There were no significant differences between these groups. Of the 23 patients that underwent salvage operation, five (21.7%) survived the 5-year period. Three of these survivors belonged to a group of seven patients in Stage I and 2 to a group of 12 in Stage II. Benign radiation-induced esophageal ulcerations or strictures developed in five patients. One underwent a bypass procedure, while another was treated repeatedly by bougienage. The other three recovered under conservative treatment.
in Months DISCUSSION
Length
n
5y (%)
-
10 cm
1Ocm
8
0
Fig. 4. The actuarial survival of intra-esophageal brachytherapy by tumor length.
Esophageal carcinomas are extremely refractory: in patients treated with radiotherapy alone, there has been a 5-year survival rate of less than 10% ( 19,2 1). The greatest problem in radiotherapy is control of the primary lesion, which is believed to be the cause of the poor therapeutic results (18). Until 1973, we treated patients by external irradiation alone, and varied total dosages, dose distributions, and fields of irradiation in order to improve the
239
Brachytherapy for carcinoma of the esophagus 0 M. HAREYAMA et al.
1_
1
1
12
I
24
Time
36
-
UT
______
M-f-
.-._.-
LT
60
in Months
n
Site
48
5y (%I
12
16.7
104
16.8
45
22.3
Fig. 6. The actuarial survival of intra-esophageal brachytherapy by tumor site.
therapeutic results. However, the therapeutic outcome was unsatisfactory, reminding us of the difficulty of controlling the primary lesion by radiotherapy. The anatomic structures surrounding the thoracic esophagus present difficulties in eradicating the primary lesion by external beam irradiation. Because of the absence of serosa in the esophagus, extraesophageal infiltration often leads to esophageal fistulas, sometimes with fatal complications such as radiation pneumonitis, pericarditis, myocarditis, and spinal cord damage. These difficulties outweigh the benefits, even when some improvement in the local cure rate might be expected with increased dosages. In a study of patients that had undergone preoperative irradiation followed by esophagectomy, Iizuka (13) suggested that, following radiotherapy, cancer cells disappear from the muscularis propria with residual malignant cells remaining in the esophageal mucosa. Our findings concurred with their opinion. Thus, the focal point in radiotherapy for carcinoma of the esophagus is eradication of the residual tumor cells around the esophageal mucosa without incurring esophageal perforation or other serious complications. Compared to a high dose rate, a low dose rate by continuous irradiation is believed to produce a greater therapeutic effect on the basis of radiation biology (8, 11, 15). Thus, in spite of progress in therapeutic devices, brachytherapy is still used for carcinoma of the tongue ( 12) and the uterine cervix (22) with results showing good local control and prognosis. Intracavitary irradiation using radium has been recommended by Lederman (17); however, it has been dis-
continued due to a steep dose gradient with subsequent risk of esophageal perforation and the complexity of the associated technique. Rider and Mendoza (27), however, reported superior therapeutic results in 12 selected patients with surgical indications who were first treated with external beam irradiation at a dosage of 3500 to 4000 cGy in 3.5 to 4 weeks, followed by intracavitary radium irradiation at a dosage of 3000 cGy on 3 consecutive days. For the reasons given above, we have combined intracavitary brachytherapy with external radiotherapy as a standard treatment since 1974 and the early results of this modality have been reported (6, 7, 20). Recently, there have been several reports on intracavitary irradiation of esophageal carcinoma, but most have dealt only with radiation responses of the primary lesion (2,4, 23, 28) and early survival rates, and the number of patients observed has been small (5, 10). Fleischman et al. (4) reported that intraluminal irradiation using cesium was effective as a palliative treatment. Flores et al. (5) applied iridium to patients with carcinoma of the esophagus and cardia and reported a 3-year survival rate of 19% (5 of 26 patients with esophageal carcinoma). Hishikawa et al. ( 10) combined external radiotherapy with intracavitary irradiation using cobalt at a high dose rate in 43 patients and reported a 2-year survival rate of 27.9%. The intracavitary brachytherapy adopted by the present authors has the following advantages: (a) the outer applicator inserted into the esophagus is composed of rubber which is flexible and totally safe with no danger of esophageal perforation; (b) oral intake is possible immediately after the procedure; and (c) this therapeutic modality is no more stressful for the patients than external irradiation. The optimum dosage distributions of the external and intracavitary brachytherapy are still being considered. The rate of control in the primary esophageal lesion was 3 1.7% (5 1 of 16 1 patients) at the 5-year follow-up. If the results are limited to Stages I and II, where good survival can be expected, the rate of local control was found to be 40.6%
100
80
0
r
, 12
24
36
48
60
Time in Months Fig. 7. The actuarial survival of intra-esophageal brachytherapy for 101 Patients with Stages I and II.
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I. J. Radiation Oncology 0 Biology0 Physics
(4 1 of 10 1 patients). The 5-year actuarial survival rate of
this group was 27.5% (Fig. 7). Thus intracavitary brachytherapy is believed to be an extremely effective modality of radical radiotherapy, although the patients are limited to those that can permit insertion of an outer applicator 1 cm in diameter. Radiation-induced esophageal ulcerations or strictures did develop in five of the long-term survivors, suggesting that the dosage is close to the maximal tolerance of the esophagus. Hishikawa et al. (9) reported that over 90% of his patients treated by intracav-
Volume 24, Number 2, 1992
itary irradiation had radiation-induced ulcers after treatment. Therefore, we recommend that 1500-2000 cGy in two or three fractions is the optimum dosage for intracavitary brachytherapy of the esophageal mucosa after external irradiation of 5500 cGy in 22 fractions for 5.5 weeks or 6000 cGy in 30 fractions for 6 weeks. In a conclusion, we believe that intracavitary treatment of esophageal carcinoma is a highly effective and a safe therapeutic modality, not only as a palliative therapy, but also as a radical treatment for patients in Stages I and II.
REFERENCES I. Akakura, I.; Nakamura, Y.; Kakegawa, T.; Nakayama, R.; Watanabe, H.; Yamashita, H. Surgery of carcinoma of the esophagus with preoperative radiation. Chest 57:4757; 1970. 2. Burt, P. A.; Notley, H. M.; Stout, R. A simple technique for intraluminal irradiation in oesophageal tumors using the high-dose-rate microselectron. Br. J. Radiol. 62:748750;1989. 3. Cordice, Jr., J. W. V. Carcinoma of the esophagus seen in a 12-year period at Queens Hospital Center. J. Natl. Med. Assoc. 82:273-279;1990. 4. Fleischman, E. H.; Kagan, A. R.; Bellotti, J. E.; Streeter, Jr., 0. E.; Harvey, J. C. Effective palliation for inoperable esophageal cancer using intensive intracavitary radiation. J. Surg. Oncol. 44:234-237;1990. 5. Flores, A. D.; Nelems, B. N.; Evans, K. E.; Hay, J. H.; Stoller, J. S.; Jackson, S. M. Impact of new radiotherapy modalities on the surgical management of cancer of the esophagus and cardia. Int. J. Radiat. Oncol. Biol. Phys. 17:937-944;1984. 6. Hareyama, M.; Nishio, M.; Ibayashi, J.; Hamada, M. A radiotherapeutic trial for esophageal cancer combined with external beam and radium bougie (Abstr.). In: The Japan Society for Cancer Therapy, 13th Congress English Abstract, Tokyo, Japan, October 7-9, 1975; 327-328. 7. Hareyama, M.; Sakurai, T.; Nishio, M.; Koizumi, Y.; Moriya, H.; Koshiba, R.; Hamada, M.; Ibayashi, J.; Fujita, M. Radiotherapy of esophageal cancer combined external beam and intracavitary radium therapy. Jpn. J. Cancer Clin. 23: 1199-1205;1977. 8. Hill, R. P.; Bush, R. S. The effect of continuous or fractionated irradiation on a murine sarcoma. Br. J. Radiol. 46: 167-174;1973. 9. Hishikawa, Y.; Tanaka, S.; Miura, T. Esophageal ulceration induced by intracavitary irradiation for esophageal carcinoma. Am. J. Roentgenol. 143:269-273;1984. IO. Hishikawa, Y.; Kamikonya, N.; Tanaka, S.; Miura, T. Radiotherapy of esophageal carcinoma: Role of high-dose-rate intracavitary irradiation. Radiother. Oncol. 9: 13-20; 1987. Il. Hall, E. J. Radiation dose-rate: A factor of importance in radiobiology and radiotherapy. Br. J. Radiol. 45:8 l-97;1972. 12. Horiuchi, J.; Okuyama, T.; Shibuya, H.; Takeda, M. Results of brachytherapy for cancer of the tongue with special emphasis on local prognosis. Int. J. Radiat. Oncol. Biol. Phys. 8:829-835;1982. 13. lizuka, T. Treatment of esophageal cancer. Jpn. J. Cancer Clin. 15:297-301;1969. 14. Japanese Society for Esophageal Diseases: Guide lines for the clinical and pathological studies on carcinoma of the esophagus. Tokyo Japan: Kanehara Co., Ltd.; 1989. 15. Kal, H. B.; Barendsen, G. W. Effects of continuous irradiation at low dose-rates on a rat rhabdomyosarcoma. Br. J. Radiol. 45:279-283; 1972. 16. Katlic, M. R.; Wilkins, Jr, E. W.; Grillo, H. C. Three decades of esophageal squamous carcinoma at the Massachusetts
17.
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General Hospital. J. Thorac. Cardiovasc. Surg. 99:929938;1990. Lederman, M. Carcinoma of the oesophagus, with special reference to the upper third. Part II. Physical considerations. Br. J. Radiol. 39: 197-204; 1966. Mantravadi, R. V. P.; Lad, T.; Briele, H.; Liebner, E. J. Carcinoma of the esophagus: Site of failure. Int. J. Radiat. Oncol. Biol. Phys. 8: 1897- 190 1; 1982. Newaishy, G. A.; Read, G. A.; Duncan, W.; Kerr, G. R. Results of radical radiotherapy of squamous cell carcinoma of the esophagus. Clin. Radiol. 33:347-352; 1982. Nishio, M.; Sakurai, T.; Sakawa, K.; Saito, A.; Ibayashi, J.; Hamada, M.; Koshiba, R.; Suzaki, K.; Hareyama, M. Intracavitary radium therapy combined with external irradiation for the treatment of esophageal cancer. Jpn. J. Cancer Clin. 24: 1099-I 105;1978. Okawa, T.; Kita, M.; Tanaka, M.; Ikeda, M. Results of radiotherapy for inoperable locally advanced esophageal cancer. Int. J. Radiat. Oncol. Biol. Phys. 17:49-54;1989. Okawa, T.; Kita, M.; Goto, M.; Tazaki, E. Radiation therapy alone in the treatment of carcinoma of the uterine cervix: Review of experience at Tokyo Women’s Medical College (1969- 1983). Int. J. Radiat. Oncol. Biol. Phys. 13: 18451849;1987. Pakisch, B.; Jiittner-Smolle, F. G.; Poier, E.; Stucklschweiger, G.; Zurl, B.; Poschauko, H.; &tl, M.; Leitner, H.; Hammer, J.; Friehs, G.; Hackl, A. Iridium-192 high-dose-rate intracavitary brachytherapy with and without external-beam irradiation in unresectable oesophageal cancer. Reg. Cancer Treat. 3:202-205;1990. Parker, E. F.; Gregorie, H. B.; Prioleau, Jr, W. H.; Marks, R. D.; Bartles, D. M. Carcinoma of the esophagus-observations of 40 years. Ann. Surg. 195:6 18-622; 1982. Pearson, J. G. The value of radiotherapy in the management of squamous oesophageal cancer. Brit. J. Surg. 58:794798;1971. Petrovich, Z.; Lam, L.; Langholz, B.; Formenti, S.; Luxton, G.; Tildon, T. Surgical therapy and radiotherapy for carcinoma of the esophagus. J. Thorac. Cardiovasc. Surg. 98: 614-617;1989. Rider, W. D.; Diaz Mendoza, R. Some opinions on treatment of cancer of the esophagus. Am. J. Roentgenol. 105: 514-517;1969. Rowland, C. G.; Pagliero, K. M. Intracavitary irradiation in palliation of carcinoma of oesophagus and cardia. Lancet 2:981-983;1985. Seydel, H. G.; Leichman, L.; Byhardt, R.; Cooper, J.; Herskovic, A.; Libnock, J.; Pazdur, R.; Speyer, J.; Tschan, J. Preoperative radiation and chemotherapy for localized squamous cell carcinoma of the esophagus: A RTOG study. Int. J. Radiat. Oncol. Biol. Phys. 14:33-35;1987. UICC, International Union Against Cancer. TNM classification of malignant tumors, 3rd edition; 1978.
24. pp.
235-240 Copyright
0360.3016192 95.Oil + .W 0 1992 Pergamon Press Ltd.
??Clinical Original Contribution
INTRACAVITARY BRACHYTHERAPY COMBINED WITH EXTERNAL-BEAM IRRADIATION FOR SQUAMOUS CELL CARCINOMA OF THE THORACIC ESOPHAGUS MASATO HAREYAMA, M.D.,’ MASAMICHI NISHIO, M.D.,’ YOSHIKAZU KAGAMI, M.D.,* NAOTO NARIMATSU, M.D.,* AKIO SAITO, M.D.3 AND TOMOYASU SAKURAI, M.D.* ‘Department of Radiology, Sapporo Medical College, S- 1, W- 16, Chuo-ku, Sapporo, 060 Japan; ‘Department of Radiology, National Sapporo Hospital, 4-2 Kikusui, Shiroishi-ku, Sapporo, 003 Japan; 3Department of Radiology, 18-16 Kawaharacho, Hakodate, 041 Japan
During the 15 year period from 1974 to 1988, 277 patients with previously untreated, histologically confirmed, squamous cell carcinoma of the thoracic esophagus were treated with the Time Dose and Fractionation (TDF) factor of more than 99. Of these, 161 patients were treated with external beam irradiation combined with intracavitary brachytherapy. Intracavitary brachytherapy was done for all patients for whom insertion of an outer applicator 1 cm in diameter was possible and for whom a relatively good performance status was seen at completion of external beam irradiation. Except for mild radiation-induced esophagitis, no acute radiation injuries were noted. The early clinical effect of radiation upon the esophageal lesion was determined by esophagography and esophagoscopy, approximately 1 month after the combined radiotherapy; a complete response was observed in 86 (53.4%) of the 161 patients. Furthermore, after a 5 year follow-up, local control of esophageal cancer was found to have been successful in 51 (31.7%) of the 161 patients. The highest rate of local control was associated with the following criteria: Stage I, Tl, tumor length less than 5 cm, and superficial or tumorous type of tumor. The 5-year actuarial survival rates were 43.3% for Stage I, 21.1% for Stage II, and 0% for both Stages III and IV. Benign radiationinduced esophageal ulcerations or strictures did develop in five of the long-term survivors, suggesting that the dosage is close to the maximal tolerance of the esophagus. We recommend that 1500-2000 cGy in two or three fractions is the optimal dosage for intracavitary radiation of the esophageal mucosa after external irradiation of 5500 cGy in 22 fractions for 5.5 weeks or 6000 cGy in 30 fractions for 6 weeks. We believe that intracavitary treatment of esophageal carcinoma is a highly effective and a safe therapeutic modality, not only as a palliative therapy, but also as a radical treatment for patients in Stages I and II. Thoracic esophageal carcinoma, Radiotherapy, Intracavitary brachytherapy.
INTRODUCTION
in spite of advances in technology, survival with radiotherapy has been unsatisfactory (19, 21) except for the
Although some authors report a 5-year survival rate of approximately 20% for carcinoma of the esophagus, in selected patients with combined pre- or post-operative irradiation and radical surgery ( 1, 16), most authors report 5-year survival rates of approximately 10% or lower (24, 26). Surgical resection is usually chosen in Japan, except that radiotherapy is usually applied in most cases of thoracic esophageal cancer, with or without intercurrent disease, because of long-term malnutrition, advanced stage, and the advanced age of these patients. On the other hand,
results reported by Pearson (25). This is due partly to a high incidence of lymph node and distant metastasis and, more importantly, to difficulties in achieving local control by radiotherapy ( 18). At present, even when radiotherapy is combined with chemotherapy (3,29) the prognosis for patients with esophageal carcinoma is not greatly improved. In an attempt to improve local control of radiation for radioresistant carcinoma of the esophagus, we have combined intracavitary brachytherapy, as a boost therapy, to the external irradiation. In this report, we analyze the
Reprint requests to: Masato Hareyama, M.D., Department of Radiology, Sapporo Medical College, S-l, W-16, Chuo-ku, Sapporo 060, Japan. Acknowledgements-The authors thank Mr. J. L. Nolin (Sap poro Medical College) for English editing and Prof. K. Morita (Sapporo Medical College) for editorial assistance.
This work was supported in part by grants from the Japanese Ministry of Health and Welfare and the Japanese Ministry of Education, Science and Culture. Accepted for publication 6 April 1992.
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results of this combined external and intracavitary irradiation and discuss its role in the treatment of carcinoma of the esophagus. METHODS
Volume 24, Number 2, 1992
Table 1. Patient characteristics and radiation response of the primary lesion of esophageal cancer treated by combined external irradiation and intracavitary treatment Complete response at 1 month after Local control combined after a 5 year radiotherapy follow-up
AND MATERIALS
During the 15 year period from 1974 to 1988,368 patients with previously untreated, histologically confirmed squamous cell carcinoma of the thoracic esophagus were treated primarily by radiotherapy at the Department of Radiology, National Sapporo Hospital. Of these, 9 1 patients were subjected to symptomatic irradiation with TDF below 98, because of massive distant metastasis, significant extra-esophageal spread, complications, or poor performance status. The remaining 277 patients were treated with TDF above 99, with 161 (58.1%) of these receiving combined intracavitary brachytherapy. Intracavitary brachytherapy was done for all patients for whom insertion of an outer applicator 1 cm in diameter was possible and for whom a relative good performance status was seen at completion of external beam irradiation. Pretreatment evaluation included the following examinations: complete blood count, liver function test, serum protein, double-contrast esophagography, chest x-ray, esophagoscopy, and biopsy. Since 1983, CT scanning has also been used to detect liver metastasis and/or juxta-regional lymph node involvement. The age of patients receiving brachytherapy ranged from 47 to 88 years with a median of 64 years. There were 139 males and 22 females, for a ratio of 6.3:1. The characteristics of the 16 1 patients receiving intracavitary brachytherapy are shown in Table 1. Tumor length ranged from 1.1 cm to 15.0 cm, with a median of 6.0 cm. Tumors of spiral type, according to the esophagographic classification by the Japanese Society for Esophageal Disease (14), numbered 59 and dominated the patient population. For staging, the 1978 UICC TNM classification (30) was used. Stage II was found to be most common (7 1 patients). External beam radiation was administered using 6MV or 1OMV photons. The field of radiation included a minimum of 3 cm normal margin both above and below the primary lesion and the width was between 6 and 8 cm. All fields were treated at each treatment session. Prophylactic irradiation of the regional lymph nodes was not performed except in cases in which lymph node metastases were observed. Irradiation was initiated with a parallelopposing anterior and posterior pair of fields; a tumor dose of 200 cGy was given five times a week from 1974 until 1977, while a tumor dose of 250 cGy was given four times a week after 1977. After administration of 40005000 cGy, the field was changed to two oblique portals to avoid excessive irradiation to the spinal cord after analyzing the isodose distribution. Total dosage ranged from
* Nelaton rubber catheter No. 10, Izumo Gomu Co., Tokyo, Japan.
No. of cases (%) Total Stage* I II III IV T factor 1 2 3 Site of tumor UT MT LT Length of tumor < 5 cm 5-10 cm > 10cm Type of tumor Superficial Tumorous Serrated Spiral Funnelled
161
No. (W)
No. (W)
86 (53.4)
51 (31.7)
(18.6) (44.2) ( 18.6) (18.3)
27 (90.0) 40 (56.3) 8 (26.7) 11 (36.7)
17 24 3 7
33 (20.5) 105 (65.2) 23 (14.3)
29 (87.9) 53 (50.5) 4 (17.4)
18 (54.5) 31 (29.5) 2 (8.7)
12 (7.4) 104 (64.6) 45 (28.0)
4 (33.3) 56 (53.8) 26 (57.8)
34 (32.7) 17 (37.8)
64 (39.7) 89 (55.3) 8 (5.0)
44 (68.8)
40 (44.9) 2 (25.0)
25 (39.1) 25 (28.1) 1 (12.5)
15 (9.3) 31 (19.3) 42 (26.1) 59 (36.6) 14 (8.7)
15 (100.0) 20 (64.5) 26 (6 1.9) 19 (32.2) 6 (42.9)
8 (53.3) 13 (41.9) 15 (35.7) 12 (20.3) 3 (21.4)
30 71 30 30
(56.7) (33.8) (10.0) (23.3)
0 (0)
* 1978 UICC classification. UT = Upper thoracic esophagus; MT = Middle thoracic esophagus; LT = Lower thoracic esophagus.
4750 to 7000 cGy; commonly, 5500 cGy was given in 22 fractions four times per week over an interval of 5.5 weeks or 6000 cGy was given in 30 fractions five times per week over an interval of 6 weeks. Intracavitary brachytherapy following external irradiation was performed in all patients in whom the combination was thought to be possible and to have some merit. Within approximately 2 weeks after external radiotherapy, the patients were examined by esophagography, with or without esophagoscopy, to establish the location of the primary lesion and to determine the field of radiation for intracavitary brachytherapy. Intracavitary treatment was started 2 weeks after the last external irradiation. Thirty minutes before this treatment, 15 to 30 mg of pentazocine and 0.5 mg of atropine sulfate were given intramuscularly. No general anesthetic was needed. After local anesthesia was applied to the oral cavity, a flexible gastric lavage catheter* 1 cm in diameter as an outer applicator tube, was inserted via the mouth into the stomach under fluo-
Brachytherapy for carcinoma of the esophagus 0 M. HAREYAMA rt al.
231
roscopy and stabilized in place (Fig. 1). To allow subsequently rapid and precise placement of the radium tubes, an inner tube containing dummy markers was first placed in the outer applicator tube and secured in the desired position under fluoroscopic observation (Fig. 2). After the patient had been moved to the treatment room, the inner tube with the dummy markers was replaced with an inner tube containing four or five radium tubes of 370 MBq (10 mg) each tube arranged longitudinally. Since 1990, cesium tubes have been used in view of the difficulty of radiation protection from radium. Treatment volume was thought the residual carcinoma within a level 0.5 cm below the esophageal mucosa. The dosage was calculated to be approximately 200 cGy/hour at the surface of the esophageal mucosa (i.e., at the surface of the outer tube which was 0.5 cm from the radium). The applicator was removed after each treatment. A dose of 400- 1000 cGy was delivered during each treatment. If necessary, the intracavitary treatments were repeated at intervals of at least 1 week three times at most. The actuarial survival rate was calculated by the Kaplan and Meier method and statistical analyses were carried out using the Log-rank test. RESULTS During intra-esophageal irradiation, some patients who were uncomfortable were intramuscularly given additional pentazocine, so that there was no interrupting of the treatment. Two hours after the completion of intracavitary therapy, oral intake was possible. Except for mild radiation-induced esophagitis, no acute radiation injuries were noted. One month after combined radiotherapy bariumcontrasted esophagography, or in most cases esophagography and esophagoscopy, was done to evaluate the early clinical effect of radiation upon the esophageal lesion. Complete response was judged by the following criteria: (a) disappearance of the mass shadow; (b) no narrowing observed in the esophageal lumen; (c) and no or slight rigidity of the esophageal wall without residual ulceration.
Fig. 1. The patient: the outer applicator the mouth and stabilized in place.
tube was inserted
via
Fig. 2. Irradiation dummy markers.
field for intra-esophageal
brachytherapy
and
A complete response 1 month after combined radiotherapy was observed in 86 (53.4%) of the 16 1 patients. On the basis of a 5-year clinical follow-up, a histopathological examination or postmortem examination, local control of esophageal cancer was found to have been successful in 5 1 (3 1.7%) of the 16 1 patients. Table 1 shows the results of analysis according to stage, T factor, site, length and type of tumor as determinationed by radiological examination. The highest rate of local control was associated with Stage I, T 1, tumor length less than 5 cm, and superficial or tumorous type of tumor. Twenty-three (20.9%) of the 110 patients with residual tumor or local recurrence received salvage operations. These 23 patients included 7 in Stage I, 12 in Stage II, 3 in Stage Ill and 1 in Stage IV. The actuarial survival rate included the effect of this salvage operation. The 5-year actuarial survival rates were 43.3% for Stage I, 2 1.1% for Stage II, and 0% for both Stages Ill and IV (Fig. 3). Significant differences at p < 0.05 were observed between Stage I and the other stages, as well as between Stage II and Stages III and IV. The 5-year actuarial survival rate was 32.2% for patients with tumor lengths less than 5 cm and 10.4% in those with lengths ranging from 5 to 10 cm (Fig. 4). No one in the group with tumor lengths exceeding 10 cm survived the 5-year period. A significant difference (p -=z0.05) was noted between the group with lengths less than 5 cm and that with lengths 5 to 10 cm or more.
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Volume
24, Number
I
0
12
24
36
Time
48
60
5y (%I
-1
30
43.3
-____- II
71
21 .l
.-.-.-.
111
29
0
N
31
0
Tumor
brachytherapy
The 5-year actuarial survival rates according to tumor type were: superficial, 4 1.6%; tumorous, 32.3%; serrated, 16.1%; spiral, 9.3%; and funnelled, 7.1% (Fig. 5). Signif-
80
3 60
cz
j
20
1.
“1_.
Ji_:,_,
i._._._._._._._._.l~~~~_~~______,
i
I 12
‘--I
1
1
0
24
Time
1
12
36
24
I
36
I
I
I
48
60
Time in Months
n
Fig. 3. The actuarial survival of intra-esophageal by stage.
.? L
1
0
in Months
Stage
.. . . .
2, 1992
48
60
type
n
5y (%)
-
superficial
15
41.6
------
tumorous
31
32.3
.-.-.-.
serrated
42
16.1
._.._.._.
spiral
59
9.3
............
funnelled
14
7.1
Fig. 5. The actuarial survival of intra-esophageal brachytherapy by tumor type.
icant differences were observed between the superficial type and the others and between the tumorous and spiral types. The 5-year actuarial survival rates according to tumor sites were: 16.7% in upper thoracic esophageal cancer, 16.8% in middle thoracic esophageal cancer, and 22.3% in lower thoracic esophageal cancer (Fig. 6). There were no significant differences between these groups. Of the 23 patients that underwent salvage operation, five (21.7%) survived the 5-year period. Three of these survivors belonged to a group of seven patients in Stage I and 2 to a group of 12 in Stage II. Benign radiation-induced esophageal ulcerations or strictures developed in five patients. One underwent a bypass procedure, while another was treated repeatedly by bougienage. The other three recovered under conservative treatment.
in Months DISCUSSION
Length
n
5y (%)
-
10 cm
1Ocm
8
0
Fig. 4. The actuarial survival of intra-esophageal brachytherapy by tumor length.
Esophageal carcinomas are extremely refractory: in patients treated with radiotherapy alone, there has been a 5-year survival rate of less than 10% ( 19,2 1). The greatest problem in radiotherapy is control of the primary lesion, which is believed to be the cause of the poor therapeutic results (18). Until 1973, we treated patients by external irradiation alone, and varied total dosages, dose distributions, and fields of irradiation in order to improve the
239
Brachytherapy for carcinoma of the esophagus 0 M. HAREYAMA et al.
1_
1
1
12
I
24
Time
36
-
UT
______
M-f-
.-._.-
LT
60
in Months
n
Site
48
5y (%I
12
16.7
104
16.8
45
22.3
Fig. 6. The actuarial survival of intra-esophageal brachytherapy by tumor site.
therapeutic results. However, the therapeutic outcome was unsatisfactory, reminding us of the difficulty of controlling the primary lesion by radiotherapy. The anatomic structures surrounding the thoracic esophagus present difficulties in eradicating the primary lesion by external beam irradiation. Because of the absence of serosa in the esophagus, extraesophageal infiltration often leads to esophageal fistulas, sometimes with fatal complications such as radiation pneumonitis, pericarditis, myocarditis, and spinal cord damage. These difficulties outweigh the benefits, even when some improvement in the local cure rate might be expected with increased dosages. In a study of patients that had undergone preoperative irradiation followed by esophagectomy, Iizuka (13) suggested that, following radiotherapy, cancer cells disappear from the muscularis propria with residual malignant cells remaining in the esophageal mucosa. Our findings concurred with their opinion. Thus, the focal point in radiotherapy for carcinoma of the esophagus is eradication of the residual tumor cells around the esophageal mucosa without incurring esophageal perforation or other serious complications. Compared to a high dose rate, a low dose rate by continuous irradiation is believed to produce a greater therapeutic effect on the basis of radiation biology (8, 11, 15). Thus, in spite of progress in therapeutic devices, brachytherapy is still used for carcinoma of the tongue ( 12) and the uterine cervix (22) with results showing good local control and prognosis. Intracavitary irradiation using radium has been recommended by Lederman (17); however, it has been dis-
continued due to a steep dose gradient with subsequent risk of esophageal perforation and the complexity of the associated technique. Rider and Mendoza (27), however, reported superior therapeutic results in 12 selected patients with surgical indications who were first treated with external beam irradiation at a dosage of 3500 to 4000 cGy in 3.5 to 4 weeks, followed by intracavitary radium irradiation at a dosage of 3000 cGy on 3 consecutive days. For the reasons given above, we have combined intracavitary brachytherapy with external radiotherapy as a standard treatment since 1974 and the early results of this modality have been reported (6, 7, 20). Recently, there have been several reports on intracavitary irradiation of esophageal carcinoma, but most have dealt only with radiation responses of the primary lesion (2,4, 23, 28) and early survival rates, and the number of patients observed has been small (5, 10). Fleischman et al. (4) reported that intraluminal irradiation using cesium was effective as a palliative treatment. Flores et al. (5) applied iridium to patients with carcinoma of the esophagus and cardia and reported a 3-year survival rate of 19% (5 of 26 patients with esophageal carcinoma). Hishikawa et al. ( 10) combined external radiotherapy with intracavitary irradiation using cobalt at a high dose rate in 43 patients and reported a 2-year survival rate of 27.9%. The intracavitary brachytherapy adopted by the present authors has the following advantages: (a) the outer applicator inserted into the esophagus is composed of rubber which is flexible and totally safe with no danger of esophageal perforation; (b) oral intake is possible immediately after the procedure; and (c) this therapeutic modality is no more stressful for the patients than external irradiation. The optimum dosage distributions of the external and intracavitary brachytherapy are still being considered. The rate of control in the primary esophageal lesion was 3 1.7% (5 1 of 16 1 patients) at the 5-year follow-up. If the results are limited to Stages I and II, where good survival can be expected, the rate of local control was found to be 40.6%
100
80
0
r
, 12
24
36
48
60
Time in Months Fig. 7. The actuarial survival of intra-esophageal brachytherapy for 101 Patients with Stages I and II.
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(4 1 of 10 1 patients). The 5-year actuarial survival rate of
this group was 27.5% (Fig. 7). Thus intracavitary brachytherapy is believed to be an extremely effective modality of radical radiotherapy, although the patients are limited to those that can permit insertion of an outer applicator 1 cm in diameter. Radiation-induced esophageal ulcerations or strictures did develop in five of the long-term survivors, suggesting that the dosage is close to the maximal tolerance of the esophagus. Hishikawa et al. (9) reported that over 90% of his patients treated by intracav-
Volume 24, Number 2, 1992
itary irradiation had radiation-induced ulcers after treatment. Therefore, we recommend that 1500-2000 cGy in two or three fractions is the optimum dosage for intracavitary brachytherapy of the esophageal mucosa after external irradiation of 5500 cGy in 22 fractions for 5.5 weeks or 6000 cGy in 30 fractions for 6 weeks. In a conclusion, we believe that intracavitary treatment of esophageal carcinoma is a highly effective and a safe therapeutic modality, not only as a palliative therapy, but also as a radical treatment for patients in Stages I and II.
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