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Disappearance of local tumor of esophageal carcinoma after irradiation
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??Original Contribution
DISAPPEARANCE OF LOCAL TUMOR OF ESOPHAGEAL CARCINOMA AFTER IRRADIATION ZONG-YI
YANG,*
Dept. Radiation
HUA-Yu
Hu,?
JIE-HUA
YAN*
AND
XIAN-ZHI
Gut
Oncology, Cancer Institute. Chinese Academy of Medical Sciences. Beijing. China
The range of doses which may lead to disappearance of local tumor after radiation treatment of esophageal carcinoma is extensive. Its possibility may reach 33% if the dose exceeds 5000 rad. However, the sensitivity of this cancer varies greatly in different patients. In clinical practice, the total dose should be decided according to the response of the tumor. Disappearance of local tumor signified better prognosis than otherwise. Radiation ulcer can be easily mistaken as local recurrence. Based upon clinical symptoms and X ray film, the possibility of misdiagnosing ulceration as local recurrence after radiotherapy of more than 6000 rad was as high as 29% (12/ 42) in our experience. The pathogenesis and management of radiation ulcer in the esophagus are discussed. Esophageal cancer, Radiotherapy. INTRODUCI’ION
by irradiation. Of them, 279 patients had undergone planned preoperative irradiation (planned group). Fifty patients had had radical irradiation but received surgery because of local residual tumor or recurrence (radical group). Two patients received surgery for severe stricture in the esophagus after radical irradiation. All of the resected specimens were examined pathologically, and in 47 patients no local residual tumor was found in the esophagus.”
It is well known that a certain percentage of esophageal cancer can be eradicated by radiation, but the relationship between the dose and the disappearance of the tumor is unclear. In clinical practice, the dose to be given is actually decided on empirical basis as, at present, we could hardly know the optimum dose of each individual lesion. For example, a dose of 7000 rad/7 wk is often delivered to patients with moderate or advanced lesions of esophageal cancer in China. This should suffice for some patients, but it may not do so for others. The cancer will recur if the dose is less than what is required; on the other hand, if the dose exceeds what is tolerable, ulceration and perforation of the esophagus may occur. For this reason, we have analyzed 329 patients admitted from December 1959 to August 1974 with esophageal cancers who were irradiated with various doses before surgery in our hospital. Of them, 47 patients were found to have no residual tumor locally. These 47 patients were studied with special reference to the dose, the X ray findings leading to the misdiagnosis of recurrence, and their final outcome.
METHODS
Diagnosis
Thirty patients belonged to the “planned group” and 17 to the “radical group”. Apart from esophagography, they were diagnosed by the following methods: 7 by biopsy through esophagoscope, 4 by cytology before radiation, IO by pathology of metastatic lymph node in the resected specimens (Fig. I and 2), and 6 by clinical detection of lymph node metastasis or/and distant spread during follow-up. In the other 20 patients, although biopsy had never been done, the diagnosis was established by indirect microscopic evidence observed in the resected specimens. By indirect evidence, we mean in sifu observation of degenerated cancerous tissue, such as traces of Cancer nests, keratinized material in the muscular layer of the esophageal wall, or a limited number of dead but recognizable cancer cells, so called “ghost cells” (Fig. 3, 4 and 5). This
AND MATERIALS
Three hundred and twenty-nine patients with esophageal cancer received surgery after having been treated
Acknowledgement-The
Visiting Radiotherapist. t Associate Professor, Deputy Head of Dept. $ Professor, Head of Dept. Reprint requests to: Zong-yi Yang, Dept. of Radiation Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Pan jia Yao, Zuo An Men Wai, Chao Yang District. Beijing,
authors wish lo extend their thanks to Associate Professors Dr. Fu-sheng Liu and Dr. Jing-xian Li for reviewing the histopathologic slides and illustrations of the photomicrograms. Accepted for publication 6 June 1984. * Routine pathologic but not serial sections were done on the resected specimens.
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Fig. 1. 2900 rad given before operation, section shows no residual cancer cell. Only traces of cancer nests and foreign giant cell reaction in the esophageal wall (Fig. 3, H.E. 300). In the same resected specimen, metastatic cancer was observed in a para-esophageal lymph node, which was outside irradiation (Fig I. H.E. 300).
shows that there has been genuine cancer which has disappeared upon irradiation. Radiation techniques Radiation source. 6oCo was used in 261 patients; high energy electron beam in 60 and orthovoltage X ray in 8 patients. Porfal: the length of the portal was decided by the length of the lesion while the width was set at 6 cm. Portals of 6 X 12 cm* or 6 X 15 cm* were commonly used. Number of Portals. In planned group, double anterior and posterior portals were used. For the radical group, three portals were usually used, one perpendicular portal in front and two oblique ones in the back, all converging at the esophagus. Dose and jiiaclionation. in the planned group, a total dose of less than 5000 rad was delivered to all except 4 patients. Fractionation of 1000 rad/l wk was often adopted. However, when the total dose was less than 1500 rad, the fraction was 1000 to 1500 rad/3 to 5 fractions/3 to 7 days. In radical group, all patients were given
a total dose of more than 5000 rad, on the rate of 1000 rad/5 fractions/ 1 wk. Intervalbetween the end ofradiation and the operalion. In the planned group, the interval was 2 to 12 days in the lOOO-rad group, 4 to I8 days in the 2000%rad group, 7 to 22 days in the 3000-rad group and 14 days to 1 month or more in the 4000~rad and 5000-rad groups. In radical group, the interval was less than 6 months in 38 patients, 6 to 12 months in 1 1 patients, and 8 years in 1 patient.
RESULTS Relation between irradiation dose and disappearance of local tumor: Forty-seven of 329 patients ( 14%) had no local residual cancer. If the irradiation dose exceeded 5000 rad, this rate could be as high as 33% ( 18/54) or 25% (l/4) in the planned group and 35% (17/50) in the radical group (Table 1). It is observed from Table 1 that the dose leading to the disappearance of local tumor varies greatly, i.e., from 1500 to 8200 rad. However, 2 other
‘069
Disappearance of local tumor 0 Z.-Y. YANG PI al.
Fig. 2. After irradiation
of 7000 rad. an ulcer, niche and narrow lumen were observed at the original
site of the
lesion in the esophageal wall
on the X ray film (Fig. 7). Microscopic section shows a large area of extensive necrosis and granulation tissue formation at the original site of the lesion in the esophageal wall. Metastatic cancer was found in the left gastric lymph node, which was outside the irradiation field (Fig. 2. H.E. 1200).
patients who had received more than 9000 rad all had obviously viable cancerous tissues in the specimens.
metastasis and cancer invasion through the wall is listed in Table 3.
Prognosis o$the 47 patients withoutresidual cancer Twenty-three patients are alive and free of disease-a Syear survival rate of 49% and IO-year survival of 47%. In contrast, the prognosis in 282 patients with residual cancer after irradiation is rather poor, the 5- and IO-year survival rates being 28 and 19%, respectively (Table 2). This is statistically significant between differences (p < 0.05, p < 0.01). In 24 patients who died, 9 died of cancer (7 of lymph node metastasis and 2 of blood spread), IO others died of non-cancerous diseases, and 5 patients died of unknown causes.
Factors leading to the disappearance of local cancer The length of lesion was irrelevant to the disappearance of local cancer. In the planned group, the rate of disappearance was 12% (9/78) when the lesion measured less than 5 cm, 10% (21/201) if it was more than 5 cm. In the radical group, the rate of disappearance was 33% (2/6) if the lesion is less than 5 cm and 34% (15/44) if more than 5 cm. In order to study the effect ofthe interval between the radiation and the operation on the rate of disappearance of local cancer, it was necessary to choose a certain group of patients. They had to conform to the criteria of having been treated by similar doses and the group should comprise an adequate number of patients. Consequently, the 4000-rad group was selected as there were more patients in this group than any others. The rate of disappearance of local lesions was I 5% (3/20) with interval of 7 to I3 days, 16% (7/44) with 14 to 20 days, 38% (lO/26) with 2 1 to 27 days, and 12% (3/32) with
Prognosticfactors Tumor size, lymph node metastasis, degree of invasion into the esophageal wall, and dosage in the planned group were analyzed. The results are shown in Table 2. In 249 patients who had received planned preoperative radiation but still had residual cancer, the influence of lymph node
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Fig. 3. 2900 rad given before operation. section shows no residual cancer cell. Only traces of cancer nests and foreign giant cell reaction in the esophageal wall (Fig. 3, H.E. 300). In the same resected specimen, metastatic cancer was observed in a para-esophageal lymph node, which was outside irradiation (Fig. I. H.E. 300).
more than 28 days. There was no evidence to show that the longer the interval, the higher the incidence of disappearance of local cancer. Misdiagnosis
In the radical group, 44 patients were given a dose of more than 6000 rad (Table 1). Apart from 2 patients who underwent surgery for severe stricture, the other 42 patients were clinically considered as local recurrence or cancer uncontrolled before exploration. After resection, there were 12 patients whose lesions showed absence of residual cancer. The rate of misdiagnosed was 29% ( 12142). X rayjindings of lesions misdiagnosed as recurrence The barium esophagogram showed ulcer or niche in 6 patients, marked filling defect in 2 patients, and stiff esophageal wall with irregularly narrowed lumen in 4 patients. In our experience, the presence of ulcer and niche but not filling defect is more likely to be mistaken as recurrence. DISCUSSION In the present series, the 5, IO-, 15- and 20-year survival rates are 3 l%, 23%, 17% and 1 1% respectively. There is
no difference in the survival rates of the planned group and the radical group. However, the prognosis of patients without local residual cancer was better than that of those with residual tumor and statistical significance is noted between their respective survivals (p < 0.05). In the planned group, dose was not relevant to prognosis except in the 2000%rad group. As shown in Table 2, the survival rates of the various dose groups are similar. As most of the patients in the 4000-rad group actually received 4000 rad/4 wks, and it has become traditional in the combined clinic in our chest section (consisting of surgeon and radiotherapist) to set the preoperative dose between 3000 and 4000 rad, we consider 4000 rad or under is acceptable for preoperative radiation. It was believed that the longer lesion, lymph node metastasis, and invasion through the wall were unfavorable prognostic factors. But, as we discovered in the present series, the length of lesion does not influence the survival, although both lymph node metastasis and extension through the wall do exert unfavorable factors which influence the prognosis, especially in the planned group (p < 0.01, Table 2). In the 249 patients who had residual cancer after planned preoperative radiation, the presence of positive nodes seemed more fatal than the invasion through the wall (although y > 0.05, Table 3). The prognosis was worst when both
Disappearance of local tumor 0 Z.-Y. YANG ef d.
,
Fig. 4. After a dose 4000 rad, stiffness and irregular narrow lumen delivered by a smooth wall was observed on the X ray film (Fig. 6). Only traces of cancer nests, foam ceil and foreign giant cell reaction present in the esophageal wall (Fig. 4. H.E..1000).
factors were present; the prognosis was best if both factors were absent (Table 3). It is generally known that esophageal carcinoma can be eradicated by radical irradiation in a certain percentage of the patients. Yet, up to now, there has been no authentic report ori the relationship between the dose and disappearance of local cancer. In the present series, the dose leading to disappearance of local cancer ranges from 1500 to 8200 rad. This shows that the radiosensitivity of esophageal carcinoma could hardly be considered as constant. However, there is a tendency that the possibility of annihilating the local lesion increases with the dose given. To our surprise, a few lesions completely disappeared when the dose was under 4000 rad. In our series, the lowest doses were 1500 rad/12 days, 2000 rad/15 days, and 2900 rad/26 days. Unfortunately, in the former two treatments, biopsy had never been done. For the latter, histologic proof was obtained from metastasis in the paraesophageal lymph nodes in the resected specimen (Fig. 1). When the dose exceeded 5000 t-ad, 33% of the lesions were eliminated. It should be stressed that it is impossible to rely solely on giving higher doses in the hope of eradicating all the cancer tissue. In Table I, there were two patients who had received more than 9000 rad, still the
cancer tissue presented. It seems that some of the highly sensitive cancer of the esophagus would require only low or moderate dose for elimination while the moderately sensitive cancer would need a higher dose, but those of low sensitivity are not amenable no matter how high dose is administered. Radiation of lower dose (under 5000 tad in 5 weeks) is often considered as palliative in nature. In clinical practice, even if tumor regresses rapidly, the total dose is rarely reduced for fear of tumor regrowth. In fact, some patients treated by such a palliative dose did survive for more than 5 years. We had 7 other patients with esophageal cancer (not included in the present series; in 2 of them the lesion was longer than 8.5 cm) who, for various reasons, received only palliative doses of 4000 rad in 4 weeks to 5000 rad in 5 weeks. They all survived without tumor regrowth for 6 to 17 years. One of them had a very sensitive cancer of 5 cm in length. The tumor regressed rapidly when the dose reached 4900 rad, but the radiation had to be stopped because perforation of the esophageal wall occurred. Surprisingly, this patient is now still living, 17 years after irradiation. This implies that long-term control of tumor is possible for patients with radiosensitive cancers, even though the total dose is re-
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Fig. 5. 6000 rad delivered before operation. Section of the resected specimen shows traces of cancer nests, keratinized material, foreign giant cell reaction and “ghost cell” in the esophageal wall without any viable cancer cell (H.E. 300).
duced. The reason that they been satisfactorily explained. dinary tumor sensitivity may for unexpectedly good local
have lived so long has not Up to the present, extraorbe a reasonable explanation control of long survival of
Table I. Relation between dose and the rate of disappearance of local tumor Planned group
Radical group
NO.
Dose @ad)
looo--group 2000-group 3000-group 4000-group 5000~group 6000-group 7000-group 8000-group 9oc@-group Total
No. treated
without tumor
63 26 70 I16 4
1 2 3 23
279
30
I
% 2 7 4 20 25
II
No. treated
No. without tumor
%
6 14 25 3 2
3 3 9 2 0
50 21 36 60 0
50
17
34
these patients. It is noteworthy that some of the patients with highly sensitive tumors would show an almost normal esophagogram at 4000 rad, but when further irradiated to the planned 7000 rad, serious pain in the back and within the esophagus may ensue. Shortly afterwards, an ulcer may appear in the esophagus which may go to the degree of perforation and bring the patient to death. This is probably a result of early complete regression of the sensitive tumor and the “overdose” causing damage to the tumor bed and the surrounding normal tissues which refuse to heal. If the dose were properly lowered for the sensitive cancers, favorable outcome and longterm survival may be possible. It is sufficient to say that high dose, sometimes although not always, may lead to worse results, so-called supra-lethal dose. For esophageal cancer, the irradiation dose should not be inflexibly set at a constant magnitude, e.g., 7000 rad in 7 weeks. It may be advisable to adjust the total dose according to the response of tumor to radiation. Periodic observation of the cancer during the irradiation can never be overstressed. A range of dose of 5000 rad in 5 weeks to 7000 rad in 7 weeks is clinically practical. For poor or
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Disappearance of local tumor 0 Z.-Y. YANG er a/. Table 2. Survival rate related to the factors S-yearsurvival
Planned group Radical group
No.
Alive
%
279 50
84 I8
329
No.
Alive
C
30
169 33
30 5
70
23
202
28 17
I3 8
46 47
22 IO
49
45
21
47\1
32
II
34
3
28 27
232 30
43 6
IS 20
147 23
22 2
I5 9
4
33
70 9
0
8 0
282
79
28 j
262
49
19
170
24
I4
4
7
60 I9 58 2 0
I5 0 I2 0 0
25 0 21 0 0
I4 I2 IO 0 0
2 0 3 0 0
I4 0 30 0 0
II3 59
27 3
24 5
42 I4
S
I
I2 7
24 8
4 I
17 I3
8 0
I 0
I3 0
91 79 21 II
I9 II 5 0
21 I4 24 0
34 22 6 2
5 I I 0
5 5 I7 0
57 II2 4 29
I2 IS I 4
21 I6 25 I4
24 32 2 6
2 4 0 I
8 I3 0 I7
“planned” No residual ca. ,.mdical”
“planned” With residual ca. “radical..
Planned group
1000 Zoo0 3000 4000 5000
No.
Alive
%
30 36
260 47
56 I4
22
102
31
307
30 I7
I4 9
47 53
47
23
249
rad rad rad rad rad
63 26 70 II6 4
20 3 23 38 0
32 I2 33 33 0
“Planned”
node negative node positive
176 103
71 14
40 I2 *
“Radical”
node negative node posirivc
39 II
IS 2
38 I8
confined in extending through confined in extending through
I48 131 32 I8
57 28 I4 3
39 21 + 43 I7
,.Planned..
less than 5 cm more than S cm
..Radical..
less than 5 cm more than 5 cm
78 201 6 44
26 58 3 IS
33 29 50 34
“Planned” “Radical”
20-year survival
I S-year survival
IO-year survival P
CO.05
CO.0 I
<0.05
P
63 26 69 98 4
IS 3 I2 26 0
24 I2 I7 27 0
I65 95
47 9
28 9
31 IO
13 I
35 IO
139 121 31 16
42 I4 I2 2
30 I2 $ 39 I3
75 I85 6 41
I8 38 3 II
24 21 50 27
moderately sensitive lesions, 7000 rad in 7 weeks is needed. If the lesion is highly sensitive, the dose should be lowered accordingly. The idea of bringing down the dose for sensitive cancers is based on the basic premise that the esophageal cancer can be cured and, at the
CO.0 I
CO.0 I
P
No.
Alive
%
I8 I6
56 8
6
II
I
I3
35
I7
64
7
II
8
36
4
3
30
2
2 I
P
same time, the supra-lethal damage in the normal tissues can be avoided. How should we judge on the radiosensitivity of the esophageal cancer and decide on the optimum dose? This problem is not yet solved and needs further studies. Ac-
Table 3. The prognosis related to the combined factors of degree of invasion of tumor (confined or extending through the wall) and-lymph node metastasis (positive or negative) in 249 patients who had received planned preoperative radiation but still had residual cancer
Syear survival No.
Alive
0
80
38
48
I O-year survival P
No.
Alive
%
76
26
34
l5-year survival P
20-year survival
No.
Alive
46
No.
Alive
90
49
1I
22
24
3
13
Node positive plus extending through Node positive plus confined in Node negative plus extending through Node negative plus confined in
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cording to our experience, the following three points are worth mentioning: 1) The sensitivity of esophageal cancer may be estimated by the rate of cancer resolution in relation to the dose increment. The rate shrinkage is observed by weekly barium meal screening or bi-weekly esophagography. A speedy shrinkage by a lower dose implies that the cancer is sensitive to irradiation and only a low or moderate total dose is needed. Otherwise, a higher total dose should be delivered. Although it is generally believed that the poorly differentiated cancer also readily responds to radiation, they are uncommon in esophageal cancer. Our material shows only 8.7% (36/417) belonged to this type.’ In the present group of irradiated patients who showed no local residual cancer, 7 of them had been biopsied before radiotherapy and none of them had
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poorly differentiated cancer. Instead, all of them show squamous cell carcinoma grade 2. Three of these 7 patients received doses of only 3000, 4000, and 4000 rad respectively. It is obvious that the response could be explained not only by intrinsic radiosensitivity but also by poor pathologic differentiation. 2) According to our serial esophagograms taken at weekly intervals, i.e. every 1000 rad, those taken at 4000 rad have the critical significance. The sensitive lesions often completely or nearly disappear at 4000 rad. 3) In typing of the lesions as shown on esophagogram before irradiation, the small fungating and intralumenal types are usually highly sensitive to irradiation. The clinical reduction of tumor seen on the X ray film usually conforms well with the degeneration observed under the microscope and both are closely related to the prognosis.
Fig. 6. After a dose 4000 rad, stiffness and irregular narrow lumen delivered by a smooth wall was observed on the X ray film (Fig. 6). Only traces of cancer nests, foam cell and foreign giant cell reaction present in the esophageal wall (Fig. 4, H.E. 1000).
Disappearance of local tumor ??Z.-Y. YANG t’/ (I/.
2075
i *.
The 5-year survival rate is 19.7% 4 3.6% if the lesion on the X ray film “disappears” after irradiation. “Marked reduction” would give a 5-year survival of 10% + 2% while the “fair reduction”, 7.3% +- 290 and “no change”, 0.6% rt 0.5%.2 The findings on the X ray film of local recurrence after irradiation were mainly filling defect, narrowing of the lumen and ulcer or niche on the esophageal wall. Whenever these signs appeared on the X ray film, they were almost invariably diagnosed as local recurrence. However,
this diagnosis carried a 29% error on patients who had received more than 6000 rad. Consequently, it is necessary to keep this in mind when diagnosing a postradiation recurrence for cancer of the esophagus. When X ray film shows only stiffness and irregularly narrowed lumen with smooth wall (Fig. 6) it should be considered as fibrotic constriction resulting from irradiation rather than cancerous recurrence. Even when ulcer, niche (Fig. 7), or filling defect are present, it is better to do an esophagoendoscopy and biopsy, if possible, for confirmation and
Fig. 7. After irradiation of 7000 rad. an ulcer, niche and narrow lumen were observed at the original site of the lesion in the esophageal wall on the X ray film (Fig. 7). Microscopic section shows a large area of extensive necrosis and granulation tissue formation at the original site of the lesion in the esophageal wall. Metastatic cancer was found in the left gastric lymph node. which was outside the irradiation field (Fig. 2. H.E. 1200).
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differentiation. Because the noncancerous ulcer is similar to cancer recurrence on the X ray film, but their pathogenesis and management are totally different. Surgery or re-radiation should be considered for recurrence, but conservation management is indicated for the non-cancerous ulcer. The mechanism of formation of the noncancerous ulcer may be the hampered repair by the “overdose” or trauma after healing. Once infection sets in, local necrosis would deepen and enlarge the ulcer into a crater, i.e., niche. This would bring about a series of symptoms, such as dysphagia and pain in the chest and
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back. The changes on the X ray film may simulate very much a local recurrence. If further irradiation were delivered, the odds would be all for the worse and perforation be imminent. There may be a rapid and fatal outcome. Therefore, the principle of management of the non-cancerous ulcer should always be energetic control of the infection and local cleansing in the form of frequent ingestion of warm and thin fluids and avoidance of local trauma by hot or tough foods to facilitate healing. Operation may also be considered if the above management fails and the patient’s condition permits.
REFERENCES 1. Fu-sheng, L.: Pathologic studies ofesophageal carcinomaA report on 858 cases. Cancer Ptwcw. Trcal. 4: 13-16. 1977. 2. Wei-bo, Y.. Li-jun, Z., Zong-yi. Y., Yan-jun, M., Zihao,
Y., Zhi-xian, Z., Cheng-hai, Z..
Mei.
W.: An analysis
of
3798 cases ofesophageal cancer treated by radiation. C’hinesc~ J. Oncol. 2: 2 16-220, 1980.
0360-3016/R4 $0300 + W 6 1084 Pcrgamon Press Lid
??Original Contribution
DISAPPEARANCE OF LOCAL TUMOR OF ESOPHAGEAL CARCINOMA AFTER IRRADIATION ZONG-YI
YANG,*
Dept. Radiation
HUA-Yu
Hu,?
JIE-HUA
YAN*
AND
XIAN-ZHI
Gut
Oncology, Cancer Institute. Chinese Academy of Medical Sciences. Beijing. China
The range of doses which may lead to disappearance of local tumor after radiation treatment of esophageal carcinoma is extensive. Its possibility may reach 33% if the dose exceeds 5000 rad. However, the sensitivity of this cancer varies greatly in different patients. In clinical practice, the total dose should be decided according to the response of the tumor. Disappearance of local tumor signified better prognosis than otherwise. Radiation ulcer can be easily mistaken as local recurrence. Based upon clinical symptoms and X ray film, the possibility of misdiagnosing ulceration as local recurrence after radiotherapy of more than 6000 rad was as high as 29% (12/ 42) in our experience. The pathogenesis and management of radiation ulcer in the esophagus are discussed. Esophageal cancer, Radiotherapy. INTRODUCI’ION
by irradiation. Of them, 279 patients had undergone planned preoperative irradiation (planned group). Fifty patients had had radical irradiation but received surgery because of local residual tumor or recurrence (radical group). Two patients received surgery for severe stricture in the esophagus after radical irradiation. All of the resected specimens were examined pathologically, and in 47 patients no local residual tumor was found in the esophagus.”
It is well known that a certain percentage of esophageal cancer can be eradicated by radiation, but the relationship between the dose and the disappearance of the tumor is unclear. In clinical practice, the dose to be given is actually decided on empirical basis as, at present, we could hardly know the optimum dose of each individual lesion. For example, a dose of 7000 rad/7 wk is often delivered to patients with moderate or advanced lesions of esophageal cancer in China. This should suffice for some patients, but it may not do so for others. The cancer will recur if the dose is less than what is required; on the other hand, if the dose exceeds what is tolerable, ulceration and perforation of the esophagus may occur. For this reason, we have analyzed 329 patients admitted from December 1959 to August 1974 with esophageal cancers who were irradiated with various doses before surgery in our hospital. Of them, 47 patients were found to have no residual tumor locally. These 47 patients were studied with special reference to the dose, the X ray findings leading to the misdiagnosis of recurrence, and their final outcome.
METHODS
Diagnosis
Thirty patients belonged to the “planned group” and 17 to the “radical group”. Apart from esophagography, they were diagnosed by the following methods: 7 by biopsy through esophagoscope, 4 by cytology before radiation, IO by pathology of metastatic lymph node in the resected specimens (Fig. I and 2), and 6 by clinical detection of lymph node metastasis or/and distant spread during follow-up. In the other 20 patients, although biopsy had never been done, the diagnosis was established by indirect microscopic evidence observed in the resected specimens. By indirect evidence, we mean in sifu observation of degenerated cancerous tissue, such as traces of Cancer nests, keratinized material in the muscular layer of the esophageal wall, or a limited number of dead but recognizable cancer cells, so called “ghost cells” (Fig. 3, 4 and 5). This
AND MATERIALS
Three hundred and twenty-nine patients with esophageal cancer received surgery after having been treated
Acknowledgement-The
Visiting Radiotherapist. t Associate Professor, Deputy Head of Dept. $ Professor, Head of Dept. Reprint requests to: Zong-yi Yang, Dept. of Radiation Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Pan jia Yao, Zuo An Men Wai, Chao Yang District. Beijing,
authors wish lo extend their thanks to Associate Professors Dr. Fu-sheng Liu and Dr. Jing-xian Li for reviewing the histopathologic slides and illustrations of the photomicrograms. Accepted for publication 6 June 1984. * Routine pathologic but not serial sections were done on the resected specimens.
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Fig. 1. 2900 rad given before operation, section shows no residual cancer cell. Only traces of cancer nests and foreign giant cell reaction in the esophageal wall (Fig. 3, H.E. 300). In the same resected specimen, metastatic cancer was observed in a para-esophageal lymph node, which was outside irradiation (Fig I. H.E. 300).
shows that there has been genuine cancer which has disappeared upon irradiation. Radiation techniques Radiation source. 6oCo was used in 261 patients; high energy electron beam in 60 and orthovoltage X ray in 8 patients. Porfal: the length of the portal was decided by the length of the lesion while the width was set at 6 cm. Portals of 6 X 12 cm* or 6 X 15 cm* were commonly used. Number of Portals. In planned group, double anterior and posterior portals were used. For the radical group, three portals were usually used, one perpendicular portal in front and two oblique ones in the back, all converging at the esophagus. Dose and jiiaclionation. in the planned group, a total dose of less than 5000 rad was delivered to all except 4 patients. Fractionation of 1000 rad/l wk was often adopted. However, when the total dose was less than 1500 rad, the fraction was 1000 to 1500 rad/3 to 5 fractions/3 to 7 days. In radical group, all patients were given
a total dose of more than 5000 rad, on the rate of 1000 rad/5 fractions/ 1 wk. Intervalbetween the end ofradiation and the operalion. In the planned group, the interval was 2 to 12 days in the lOOO-rad group, 4 to I8 days in the 2000%rad group, 7 to 22 days in the 3000-rad group and 14 days to 1 month or more in the 4000~rad and 5000-rad groups. In radical group, the interval was less than 6 months in 38 patients, 6 to 12 months in 1 1 patients, and 8 years in 1 patient.
RESULTS Relation between irradiation dose and disappearance of local tumor: Forty-seven of 329 patients ( 14%) had no local residual cancer. If the irradiation dose exceeded 5000 rad, this rate could be as high as 33% ( 18/54) or 25% (l/4) in the planned group and 35% (17/50) in the radical group (Table 1). It is observed from Table 1 that the dose leading to the disappearance of local tumor varies greatly, i.e., from 1500 to 8200 rad. However, 2 other
‘069
Disappearance of local tumor 0 Z.-Y. YANG PI al.
Fig. 2. After irradiation
of 7000 rad. an ulcer, niche and narrow lumen were observed at the original
site of the
lesion in the esophageal wall
on the X ray film (Fig. 7). Microscopic section shows a large area of extensive necrosis and granulation tissue formation at the original site of the lesion in the esophageal wall. Metastatic cancer was found in the left gastric lymph node, which was outside the irradiation field (Fig. 2. H.E. 1200).
patients who had received more than 9000 rad all had obviously viable cancerous tissues in the specimens.
metastasis and cancer invasion through the wall is listed in Table 3.
Prognosis o$the 47 patients withoutresidual cancer Twenty-three patients are alive and free of disease-a Syear survival rate of 49% and IO-year survival of 47%. In contrast, the prognosis in 282 patients with residual cancer after irradiation is rather poor, the 5- and IO-year survival rates being 28 and 19%, respectively (Table 2). This is statistically significant between differences (p < 0.05, p < 0.01). In 24 patients who died, 9 died of cancer (7 of lymph node metastasis and 2 of blood spread), IO others died of non-cancerous diseases, and 5 patients died of unknown causes.
Factors leading to the disappearance of local cancer The length of lesion was irrelevant to the disappearance of local cancer. In the planned group, the rate of disappearance was 12% (9/78) when the lesion measured less than 5 cm, 10% (21/201) if it was more than 5 cm. In the radical group, the rate of disappearance was 33% (2/6) if the lesion is less than 5 cm and 34% (15/44) if more than 5 cm. In order to study the effect ofthe interval between the radiation and the operation on the rate of disappearance of local cancer, it was necessary to choose a certain group of patients. They had to conform to the criteria of having been treated by similar doses and the group should comprise an adequate number of patients. Consequently, the 4000-rad group was selected as there were more patients in this group than any others. The rate of disappearance of local lesions was I 5% (3/20) with interval of 7 to I3 days, 16% (7/44) with 14 to 20 days, 38% (lO/26) with 2 1 to 27 days, and 12% (3/32) with
Prognosticfactors Tumor size, lymph node metastasis, degree of invasion into the esophageal wall, and dosage in the planned group were analyzed. The results are shown in Table 2. In 249 patients who had received planned preoperative radiation but still had residual cancer, the influence of lymph node
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Fig. 3. 2900 rad given before operation. section shows no residual cancer cell. Only traces of cancer nests and foreign giant cell reaction in the esophageal wall (Fig. 3, H.E. 300). In the same resected specimen, metastatic cancer was observed in a para-esophageal lymph node, which was outside irradiation (Fig. I. H.E. 300).
more than 28 days. There was no evidence to show that the longer the interval, the higher the incidence of disappearance of local cancer. Misdiagnosis
In the radical group, 44 patients were given a dose of more than 6000 rad (Table 1). Apart from 2 patients who underwent surgery for severe stricture, the other 42 patients were clinically considered as local recurrence or cancer uncontrolled before exploration. After resection, there were 12 patients whose lesions showed absence of residual cancer. The rate of misdiagnosed was 29% ( 12142). X rayjindings of lesions misdiagnosed as recurrence The barium esophagogram showed ulcer or niche in 6 patients, marked filling defect in 2 patients, and stiff esophageal wall with irregularly narrowed lumen in 4 patients. In our experience, the presence of ulcer and niche but not filling defect is more likely to be mistaken as recurrence. DISCUSSION In the present series, the 5, IO-, 15- and 20-year survival rates are 3 l%, 23%, 17% and 1 1% respectively. There is
no difference in the survival rates of the planned group and the radical group. However, the prognosis of patients without local residual cancer was better than that of those with residual tumor and statistical significance is noted between their respective survivals (p < 0.05). In the planned group, dose was not relevant to prognosis except in the 2000%rad group. As shown in Table 2, the survival rates of the various dose groups are similar. As most of the patients in the 4000-rad group actually received 4000 rad/4 wks, and it has become traditional in the combined clinic in our chest section (consisting of surgeon and radiotherapist) to set the preoperative dose between 3000 and 4000 rad, we consider 4000 rad or under is acceptable for preoperative radiation. It was believed that the longer lesion, lymph node metastasis, and invasion through the wall were unfavorable prognostic factors. But, as we discovered in the present series, the length of lesion does not influence the survival, although both lymph node metastasis and extension through the wall do exert unfavorable factors which influence the prognosis, especially in the planned group (p < 0.01, Table 2). In the 249 patients who had residual cancer after planned preoperative radiation, the presence of positive nodes seemed more fatal than the invasion through the wall (although y > 0.05, Table 3). The prognosis was worst when both
Disappearance of local tumor 0 Z.-Y. YANG ef d.
,
Fig. 4. After a dose 4000 rad, stiffness and irregular narrow lumen delivered by a smooth wall was observed on the X ray film (Fig. 6). Only traces of cancer nests, foam ceil and foreign giant cell reaction present in the esophageal wall (Fig. 4. H.E..1000).
factors were present; the prognosis was best if both factors were absent (Table 3). It is generally known that esophageal carcinoma can be eradicated by radical irradiation in a certain percentage of the patients. Yet, up to now, there has been no authentic report ori the relationship between the dose and disappearance of local cancer. In the present series, the dose leading to disappearance of local cancer ranges from 1500 to 8200 rad. This shows that the radiosensitivity of esophageal carcinoma could hardly be considered as constant. However, there is a tendency that the possibility of annihilating the local lesion increases with the dose given. To our surprise, a few lesions completely disappeared when the dose was under 4000 rad. In our series, the lowest doses were 1500 rad/12 days, 2000 rad/15 days, and 2900 rad/26 days. Unfortunately, in the former two treatments, biopsy had never been done. For the latter, histologic proof was obtained from metastasis in the paraesophageal lymph nodes in the resected specimen (Fig. 1). When the dose exceeded 5000 t-ad, 33% of the lesions were eliminated. It should be stressed that it is impossible to rely solely on giving higher doses in the hope of eradicating all the cancer tissue. In Table I, there were two patients who had received more than 9000 rad, still the
cancer tissue presented. It seems that some of the highly sensitive cancer of the esophagus would require only low or moderate dose for elimination while the moderately sensitive cancer would need a higher dose, but those of low sensitivity are not amenable no matter how high dose is administered. Radiation of lower dose (under 5000 tad in 5 weeks) is often considered as palliative in nature. In clinical practice, even if tumor regresses rapidly, the total dose is rarely reduced for fear of tumor regrowth. In fact, some patients treated by such a palliative dose did survive for more than 5 years. We had 7 other patients with esophageal cancer (not included in the present series; in 2 of them the lesion was longer than 8.5 cm) who, for various reasons, received only palliative doses of 4000 rad in 4 weeks to 5000 rad in 5 weeks. They all survived without tumor regrowth for 6 to 17 years. One of them had a very sensitive cancer of 5 cm in length. The tumor regressed rapidly when the dose reached 4900 rad, but the radiation had to be stopped because perforation of the esophageal wall occurred. Surprisingly, this patient is now still living, 17 years after irradiation. This implies that long-term control of tumor is possible for patients with radiosensitive cancers, even though the total dose is re-
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Fig. 5. 6000 rad delivered before operation. Section of the resected specimen shows traces of cancer nests, keratinized material, foreign giant cell reaction and “ghost cell” in the esophageal wall without any viable cancer cell (H.E. 300).
duced. The reason that they been satisfactorily explained. dinary tumor sensitivity may for unexpectedly good local
have lived so long has not Up to the present, extraorbe a reasonable explanation control of long survival of
Table I. Relation between dose and the rate of disappearance of local tumor Planned group
Radical group
NO.
Dose @ad)
looo--group 2000-group 3000-group 4000-group 5000~group 6000-group 7000-group 8000-group 9oc@-group Total
No. treated
without tumor
63 26 70 I16 4
1 2 3 23
279
30
I
% 2 7 4 20 25
II
No. treated
No. without tumor
%
6 14 25 3 2
3 3 9 2 0
50 21 36 60 0
50
17
34
these patients. It is noteworthy that some of the patients with highly sensitive tumors would show an almost normal esophagogram at 4000 rad, but when further irradiated to the planned 7000 rad, serious pain in the back and within the esophagus may ensue. Shortly afterwards, an ulcer may appear in the esophagus which may go to the degree of perforation and bring the patient to death. This is probably a result of early complete regression of the sensitive tumor and the “overdose” causing damage to the tumor bed and the surrounding normal tissues which refuse to heal. If the dose were properly lowered for the sensitive cancers, favorable outcome and longterm survival may be possible. It is sufficient to say that high dose, sometimes although not always, may lead to worse results, so-called supra-lethal dose. For esophageal cancer, the irradiation dose should not be inflexibly set at a constant magnitude, e.g., 7000 rad in 7 weeks. It may be advisable to adjust the total dose according to the response of tumor to radiation. Periodic observation of the cancer during the irradiation can never be overstressed. A range of dose of 5000 rad in 5 weeks to 7000 rad in 7 weeks is clinically practical. For poor or
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Disappearance of local tumor 0 Z.-Y. YANG er a/. Table 2. Survival rate related to the factors S-yearsurvival
Planned group Radical group
No.
Alive
%
279 50
84 I8
329
No.
Alive
C
30
169 33
30 5
70
23
202
28 17
I3 8
46 47
22 IO
49
45
21
47\1
32
II
34
3
28 27
232 30
43 6
IS 20
147 23
22 2
I5 9
4
33
70 9
0
8 0
282
79
28 j
262
49
19
170
24
I4
4
7
60 I9 58 2 0
I5 0 I2 0 0
25 0 21 0 0
I4 I2 IO 0 0
2 0 3 0 0
I4 0 30 0 0
II3 59
27 3
24 5
42 I4
S
I
I2 7
24 8
4 I
17 I3
8 0
I 0
I3 0
91 79 21 II
I9 II 5 0
21 I4 24 0
34 22 6 2
5 I I 0
5 5 I7 0
57 II2 4 29
I2 IS I 4
21 I6 25 I4
24 32 2 6
2 4 0 I
8 I3 0 I7
“planned” No residual ca. ,.mdical”
“planned” With residual ca. “radical..
Planned group
1000 Zoo0 3000 4000 5000
No.
Alive
%
30 36
260 47
56 I4
22
102
31
307
30 I7
I4 9
47 53
47
23
249
rad rad rad rad rad
63 26 70 II6 4
20 3 23 38 0
32 I2 33 33 0
“Planned”
node negative node positive
176 103
71 14
40 I2 *
“Radical”
node negative node posirivc
39 II
IS 2
38 I8
confined in extending through confined in extending through
I48 131 32 I8
57 28 I4 3
39 21 + 43 I7
,.Planned..
less than 5 cm more than S cm
..Radical..
less than 5 cm more than 5 cm
78 201 6 44
26 58 3 IS
33 29 50 34
“Planned” “Radical”
20-year survival
I S-year survival
IO-year survival P
CO.05
CO.0 I
<0.05
P
63 26 69 98 4
IS 3 I2 26 0
24 I2 I7 27 0
I65 95
47 9
28 9
31 IO
13 I
35 IO
139 121 31 16
42 I4 I2 2
30 I2 $ 39 I3
75 I85 6 41
I8 38 3 II
24 21 50 27
moderately sensitive lesions, 7000 rad in 7 weeks is needed. If the lesion is highly sensitive, the dose should be lowered accordingly. The idea of bringing down the dose for sensitive cancers is based on the basic premise that the esophageal cancer can be cured and, at the
CO.0 I
CO.0 I
P
No.
Alive
%
I8 I6
56 8
6
II
I
I3
35
I7
64
7
II
8
36
4
3
30
2
2 I
P
same time, the supra-lethal damage in the normal tissues can be avoided. How should we judge on the radiosensitivity of the esophageal cancer and decide on the optimum dose? This problem is not yet solved and needs further studies. Ac-
Table 3. The prognosis related to the combined factors of degree of invasion of tumor (confined or extending through the wall) and-lymph node metastasis (positive or negative) in 249 patients who had received planned preoperative radiation but still had residual cancer
Syear survival No.
Alive
0
80
38
48
I O-year survival P
No.
Alive
%
76
26
34
l5-year survival P
20-year survival
No.
Alive
46
No.
Alive
90
49
1I
22
24
3
13
Node positive plus extending through Node positive plus confined in Node negative plus extending through Node negative plus confined in
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cording to our experience, the following three points are worth mentioning: 1) The sensitivity of esophageal cancer may be estimated by the rate of cancer resolution in relation to the dose increment. The rate shrinkage is observed by weekly barium meal screening or bi-weekly esophagography. A speedy shrinkage by a lower dose implies that the cancer is sensitive to irradiation and only a low or moderate total dose is needed. Otherwise, a higher total dose should be delivered. Although it is generally believed that the poorly differentiated cancer also readily responds to radiation, they are uncommon in esophageal cancer. Our material shows only 8.7% (36/417) belonged to this type.’ In the present group of irradiated patients who showed no local residual cancer, 7 of them had been biopsied before radiotherapy and none of them had
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poorly differentiated cancer. Instead, all of them show squamous cell carcinoma grade 2. Three of these 7 patients received doses of only 3000, 4000, and 4000 rad respectively. It is obvious that the response could be explained not only by intrinsic radiosensitivity but also by poor pathologic differentiation. 2) According to our serial esophagograms taken at weekly intervals, i.e. every 1000 rad, those taken at 4000 rad have the critical significance. The sensitive lesions often completely or nearly disappear at 4000 rad. 3) In typing of the lesions as shown on esophagogram before irradiation, the small fungating and intralumenal types are usually highly sensitive to irradiation. The clinical reduction of tumor seen on the X ray film usually conforms well with the degeneration observed under the microscope and both are closely related to the prognosis.
Fig. 6. After a dose 4000 rad, stiffness and irregular narrow lumen delivered by a smooth wall was observed on the X ray film (Fig. 6). Only traces of cancer nests, foam cell and foreign giant cell reaction present in the esophageal wall (Fig. 4, H.E. 1000).
Disappearance of local tumor ??Z.-Y. YANG t’/ (I/.
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The 5-year survival rate is 19.7% 4 3.6% if the lesion on the X ray film “disappears” after irradiation. “Marked reduction” would give a 5-year survival of 10% + 2% while the “fair reduction”, 7.3% +- 290 and “no change”, 0.6% rt 0.5%.2 The findings on the X ray film of local recurrence after irradiation were mainly filling defect, narrowing of the lumen and ulcer or niche on the esophageal wall. Whenever these signs appeared on the X ray film, they were almost invariably diagnosed as local recurrence. However,
this diagnosis carried a 29% error on patients who had received more than 6000 rad. Consequently, it is necessary to keep this in mind when diagnosing a postradiation recurrence for cancer of the esophagus. When X ray film shows only stiffness and irregularly narrowed lumen with smooth wall (Fig. 6) it should be considered as fibrotic constriction resulting from irradiation rather than cancerous recurrence. Even when ulcer, niche (Fig. 7), or filling defect are present, it is better to do an esophagoendoscopy and biopsy, if possible, for confirmation and
Fig. 7. After irradiation of 7000 rad. an ulcer, niche and narrow lumen were observed at the original site of the lesion in the esophageal wall on the X ray film (Fig. 7). Microscopic section shows a large area of extensive necrosis and granulation tissue formation at the original site of the lesion in the esophageal wall. Metastatic cancer was found in the left gastric lymph node. which was outside the irradiation field (Fig. 2. H.E. 1200).
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differentiation. Because the noncancerous ulcer is similar to cancer recurrence on the X ray film, but their pathogenesis and management are totally different. Surgery or re-radiation should be considered for recurrence, but conservation management is indicated for the non-cancerous ulcer. The mechanism of formation of the noncancerous ulcer may be the hampered repair by the “overdose” or trauma after healing. Once infection sets in, local necrosis would deepen and enlarge the ulcer into a crater, i.e., niche. This would bring about a series of symptoms, such as dysphagia and pain in the chest and
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back. The changes on the X ray film may simulate very much a local recurrence. If further irradiation were delivered, the odds would be all for the worse and perforation be imminent. There may be a rapid and fatal outcome. Therefore, the principle of management of the non-cancerous ulcer should always be energetic control of the infection and local cleansing in the form of frequent ingestion of warm and thin fluids and avoidance of local trauma by hot or tough foods to facilitate healing. Operation may also be considered if the above management fails and the patient’s condition permits.
REFERENCES 1. Fu-sheng, L.: Pathologic studies ofesophageal carcinomaA report on 858 cases. Cancer Ptwcw. Trcal. 4: 13-16. 1977. 2. Wei-bo, Y.. Li-jun, Z., Zong-yi. Y., Yan-jun, M., Zihao,
Y., Zhi-xian, Z., Cheng-hai, Z..
Mei.
W.: An analysis
of
3798 cases ofesophageal cancer treated by radiation. C’hinesc~ J. Oncol. 2: 2 16-220, 1980.