Jmwnal of Photochemistry and Photobiology, B: Biology, 7 (1990) 87-92
87
RJZVIEW OF PHOTODYNAMIC THERAPY FOR GASTROINTESTINAL TUMOURS IN THE PAST 6 YEARS IN CHINA M. L. JIN, B. Q. YANG, W. ZHANG and P. REN Gastric Diseases Research Unit, Be@ng Institute for Cancer Research, Da-Hong-LmoChang Street, Western District (China] (Received October 5, 1989; accepted February 1, 1990)
Keyword-s. Photodynamic therapy, gastrointestinal tumour, haematoporphyrin derivative, estimated energy dose, chemotherapy.
Patients (142) with advanced gastrointestinal (GI) cancers were treated by photodynamic therapy (PDT) from September 1982 to December 1988. Haematoporphyrin derivative (HpD) (5 mg kg’) was intravenously given 48-72 h prior to PDT. The light source was an argon dye laser emitting at 630 run. The entire tumour was irradiated with a light dose of loo-250 J cme2. Fifteen patients (10.6%) showed complete response (CR), 53 (37.3%) showed partial response (PR) and 32 (22.5%) showed mild response (MR). The clinical results show that the estimated energy dose (EED) of 200-250 J cmm2is appropriate. All patients were treated by PDT and adjuvant chemotherapy showing good results with a follow-up of l-5 years; 13 out of 15 patients in the CR group are alive (86.7%); 12 patients survived more than 2 years (8.8%).
1. Introduction Gastrointestinal (GI) cancer is a common disease in many areas of China. It is a condition associated with a poor prognosis and considerable morbidity. The stage of the disease at the time of treatment influences prognosis [ 1] and the poor prognosis of GI cancer is related to late diagnosis. In advanced cancer (e.g. inoperable or recurrent cases), chemotherapy, radiotherapy and photodynamic therapy represent important clinical techniques. Extensive studies have been carried out with photosensitizers, such as haematoporphyrin derivative (HpD), which are retained by tumours longer than by normal tissues and allow for selective tumour destruction when exposed to light of specific wavelengths (630 run) (most reliably transmitted via a laser system). loll-1344/90/$3.50
0 Elsevier Sequoia/Printed in The Netherlands
88
The application of photodynamic therapy (PDT) in GI cancers was first reported by Hayata et al. [2]. In China, the Cooperative Group on GIPDT has reported the use of laser PDT with HpD for the treatment of GI tumours in 264 cases [3] (Table 1). During a 6 year period, we have treated 142 patients with advanced GI cancers by PDT. This paper reports the results, analyses the effect of estimated energy dose and evaluates the follow-up survey. 2. Materials
and methods
2.1. Photosensitizer HpD (B-HpD and Y-HpD) was used as photosensitizer. B-HpD is derived from ox blood and Y-HpD from pig blood. B-HpD was provided by the Beijing Institute of Medicine and Y-HpD was obtained from Yangzhou Pharmaceuticals Ltd. Skin sensitivity tests were performed before intravenous injection of HpD to avoid anaphylactic reaction. HpD (5 mg kg’ body weight) was given by slow intravenous injection.
2.2. Laser equipment For therapeutic procedures, an argon dye laser was used as the source of excitation light. The laser equipment was made by the Beijing Institute of Opto-Electronic Technology and the Naming Electronic Tube Factory. Tumour localization by fluorescence was carried out using an argon ion laser (514.5 run) set to deliver 50 mW of power. Red light (630 nm) from an argon dye laser was delivered to the tumour through a quartz fibre passed through the biopsy channel of a fibrescope. Two types of quartz fibre were used: a flat-cut bare fibre and a cylindrical fibre. 2.3. Procedure HpD was injected 48-72 h before scanning for fluorescence detection or therapy. The flat-cut bare fibre tip was positioned 10-20 mm away from superficial lesions. Exophytic areas of oesophageal, cardiac and rectal cancer TABLE 1 PDT of GI tumours
in China Number
M. Y. M. Z. S. Y. S.
120 35 29 24 22 20 14
73.3 94.3 69.0 54.2 63.6 100.0 7.1
264
71.6
L. Jin C. Huang L. Chen H. Li C. Li sun D. Xiao
Total
of cases
Response
Author
rate
(%)
89
were treated interstitially using the 30 mm cylindrical fibre. The power output was adjusted to 100-300 mW at the fibre tip. The treatment time was about 20 min and the entire tumour received an estimated energy dose (EED) of loo-250 J cme2. In our experience, the best results were obtained when the tumour received an EED of 200-250 J cmm2. 2.4. Evaluation of therapeutic results of PDT Tumour response was evaluated on the basis of complete response (CR) (no visible abnormality, negative biopsy and cytology), partial response (PR) (degree of obstruction or size of tumour reduced over 509/o), mild response (MR) (degree of obstruction or size of tumour reduced by 25%-50%), no response (NR) (tumour reduced by less than 25%, increased or progression).
3. Results and discussion Patients (142) with advanced GI cancers were treated by PDT from September 1982 to December 1988 (122 males and 20 females; age range 39-91 years). The clinical diagnosis was coniirmed by endoscopic biopsy and histological examination. X-ray examination (double contrast radiography), ultrasonography and computed tomography (CT) can be used to establish the size and extent of the tumour; ultrasonography and CT are also important imaging methods for dete rmining infiltration or metastasis of the tumour; these examinations may be of help in assessing the clinical state and choosing PDT as the treatment modality. Squamous carcinomas (27 tumours) and adenocarcinomas (the rest) were treated by PDT; 87 patients were inoperable and 55 patients had postoperative recurrence. All patients with oesophageal and cardiac cancer had initial dysphagia. The results of treatment by PDT are given in Table 2. Endoscopy revealed that complete remission was obtained in 15 patients (10.69/o), partial remission was obtained in 53 patients (37.3%) and mild remission was obtained in 32 patients (22.5%); 100 patients (70.4%) showed response to PDT. TABLE
2
Therapeutic Location tuwwur
of
effect of PDT Therapeutic
Total
effect
CR
PR
MR
NR
0esophagu.v Stomach Rectum
3 11 1
5 41 7
4 28 0
14 26 2
26 106 10
Total
15
53
32
42
142
90
The Chinese Cooperative Group on PDT has determined a power output of 200-300 mW cm-’ for clinical use; the EED is 200-250 J cm’-‘. The experiments illustrate that, for equal light doses, better results are obtained using high dose rates. When the power output is lower than 80 mW cm-‘, the photoinduced necrosis is insufficient. However, as the dose increases over 300 J cmm2,it may cause dehydration of the skin and coagulation of proteins, leading to eschar formation which will prevent the penetration of the laser beam and lower the photodynamic effect. Therefore a power output of 200-300 mW cme2 is appropriate for practical use. Results in a series of patients with cardiac cancer of the stomach further illustrate this problem (Table 3). Two patients were irradiated with a power density lower than 100 mW cme2 and an EED lower than 100 J cmm2,with no response to PDT. The response rate of the patients irradiated with 10 l-200 mW cme2 and a dose between 101 and 300 J cmm2was 40.7%. When a power density of 201-300 mW cme2 (EED 101-300 J cme2) was used, the response rate was 64.3%. However, when the patients were irradiated with a power density of higher than 300 mW cmV2 and an EED higher than 201-300 J cmw2, the response rate was 40.0%. These results suggest that a power density of 201-300 mW cmm2and an EED of 101-300 J cmm2are appropriate for clinical use. Cardiac cancer accounted for 82 out of 106 cases of gastric cancer (in China, the incidence and mortality of cardiac cancer are much higher than in other countries). All patients with advanced cardiac cancer have initial dysphagia. Roentgen and endoscopic examinations are used for diagnosis at this stage. Through the use of ultrasonography or CT, the morphology, size and intrinsic structure of the tumour can be observed in detail. In addition, any infiltration or metastasis (such as liver metastases or lymph node metastases) may be detected. Ultrasonography and CT can aid in the assessment of the clinical stage and the choice of treatment in cardiac cancer. Most advanced patients with cardiac cancer cannot be treated by operation [4].
TABLE
3
Therapeutic
results of PDT in advanced cardiac cancer
Power (mW cm-‘)
Dose (J cm-‘)
100
100
101-200
101-200 201-300
201300
101-200 201-300
301
201-300
CR
1
1
PR
MR
NR
CR+PR
CR+PR
(%)
1
1
0
4 6
1 9
3 3
5/9 6/X3
55.5 33.3
40.7
2 15
1 5
4
2/3 16/25
66.7 64.0
64.3
2
1
2
2/5
40.0
91
In recent years, protocols of combined PDT and chemotherapy (the UFTM scheme, UFI (FI’-207 + Uracil) + mitomycin C) have been employed. AII patients were re-examined by endoscopy and biopsy at 4 weeks after PDT. Histologic changes observed following treatment were degeneration, necrosis of tumour cehs and infiltration of lymphocytes and plasmacytes into the stroma to different degrees. Tumour necrosis was observed at a depth of about 10 mm. According to our experience, when the average size of tumours is over 50 mmX 50 mm or the deep invasion is over 10 mm, PDT penetration is insufhcient. Best results with PDT were obtained in the series with local recurrence after operation. When no signs of regional and distant metastasis are detected, photodynamic therapy is proposed. When the local recurrence occurs accompanied by distant metastasis, the effect of PDT alone is minimal. A combination of PDT and chemotherapy is more successftd than PDT alone (Table 4). Ten patients showed CR, 17 showed PR and ten showed MR. The contribution of chemotherapy alone to survival is rather poor. The best median survivaI time was around 10 months in responders, and ranged from 4 to 6 months in aII patients receiving chemotherapy; only 0.8% of patients survived more than 2 years [ 5, 61. In this study, aII patients with advanced tumours were treated by a combination of PDT and chemotherapy. AII patients received adjuvant chemotherapy for 1 year. The follow-up survey of this series lasted from 6 to 60 months. Table 5 shows the current status of these patients: the numbers in parentheses indicate patients who are stiII alive; out of 137 cases, 27 patients are alive (19.7%) and 110 patients have died (80.3%); 12 patients (8.8%) survived more than 2 years; six patients have been followed for more than 3 years without signs of recurrence and are stiIIbeing followed. The CR group, which shows good results, was followed for l-5 years; only two patients died at 25 months; 13 out of 15 patients in the CR group are stiII alive (86.7%). The results suggest that combined PDT and chemotherapy may prove to be effective. In ah patients, there were no severe complications, i.e. haemorrhage or perforation; this procedure is harmless to heart, liver, kidneys and bone marrow; 16.9% of patients had mild epigastric pain a few days after treatment; TABLE
4
PDT for local recurrence
after operation
Locatian tumour
Therapeutic
of
Oesophagus Cardia Stomach Rectum Total
eflect
Tota.!
CR
PR
MR
NR
1 7 1 1
1 7 6 3
1 2 7
1 4 6 3
4 20 20 7
10
17
10
14
51
92 TABLE
5
Results of the foIIow-up survey
Results PDT
of
Cases
Obsemation I
CR PR MR NR
15 53 32 42
Total
142
0 30 20 38
(4) (2) (3) (2)
88 (11)
The numbers in parentheses
period
(years)
Lost to follow-up
l-2
2-3
3-5
5
0 (2) 10 (1) 7 (1)
2 (4) 3 (2)
0 (2) 0 (3)
0 (1)
0 2 1 2
17 (4)
5 (6)
0 (5)
0 (1)
5
indicate patients who are stiIi alive.
five patients had slight fever (below 38.5 “C). The side effects even if a combination of PDT and chemotherapy was used.
were slight
References L. Gennari, G. Bonfanti and B. Salvadori, Prognostic factors in gastric cancer, International Congress on Diagnosis and Treatment of Upper Gastrointestinal Tumours, Mainz, 1980, Excerpta Med., Section III (1981) 173-184. Y. Hayata, K. Oho and H. Kato, Applications of lasers in cancer diagnosis and treatment, Med. Image In$ I4 (1982) 19-23. M. L. Jim, B. Q. Yang, R. Li and P. P. Li, Analysis of haematoporphyrin derivative and laser photodynamic therapy of upper gastrointestinal tumours in 52 cases, Laser Med. Sci., 2 (1987) 51-54. J. W. Jackson, D. K. C. Cooper, L. Guvendik and H. Reece-Smith, The surgical management of malIgnant tumours of the oesophagus and cardia: a review of the results in 292 patients treated over a 15-year period (1961-1975), Br. J. Surg., 66 (1979) 98-104. Y. Takano, M. Ogama and J. Inagaki, U.S.-Japan cooperative study of chemotherapy of gastric cancer-The 3rd report, J. Jpn. Sot. Cancer Ther., 15 (1980) 238-240. T. Saito and M. Yokoyama, Healing and recurrence of cancer-from the point of view of cancer chemotherapy, Jpn. J. Cancer Clin., 19 (1973) 285-289.
87
RJZVIEW OF PHOTODYNAMIC THERAPY FOR GASTROINTESTINAL TUMOURS IN THE PAST 6 YEARS IN CHINA M. L. JIN, B. Q. YANG, W. ZHANG and P. REN Gastric Diseases Research Unit, Be@ng Institute for Cancer Research, Da-Hong-LmoChang Street, Western District (China] (Received October 5, 1989; accepted February 1, 1990)
Keyword-s. Photodynamic therapy, gastrointestinal tumour, haematoporphyrin derivative, estimated energy dose, chemotherapy.
Patients (142) with advanced gastrointestinal (GI) cancers were treated by photodynamic therapy (PDT) from September 1982 to December 1988. Haematoporphyrin derivative (HpD) (5 mg kg’) was intravenously given 48-72 h prior to PDT. The light source was an argon dye laser emitting at 630 run. The entire tumour was irradiated with a light dose of loo-250 J cme2. Fifteen patients (10.6%) showed complete response (CR), 53 (37.3%) showed partial response (PR) and 32 (22.5%) showed mild response (MR). The clinical results show that the estimated energy dose (EED) of 200-250 J cmm2is appropriate. All patients were treated by PDT and adjuvant chemotherapy showing good results with a follow-up of l-5 years; 13 out of 15 patients in the CR group are alive (86.7%); 12 patients survived more than 2 years (8.8%).
1. Introduction Gastrointestinal (GI) cancer is a common disease in many areas of China. It is a condition associated with a poor prognosis and considerable morbidity. The stage of the disease at the time of treatment influences prognosis [ 1] and the poor prognosis of GI cancer is related to late diagnosis. In advanced cancer (e.g. inoperable or recurrent cases), chemotherapy, radiotherapy and photodynamic therapy represent important clinical techniques. Extensive studies have been carried out with photosensitizers, such as haematoporphyrin derivative (HpD), which are retained by tumours longer than by normal tissues and allow for selective tumour destruction when exposed to light of specific wavelengths (630 run) (most reliably transmitted via a laser system). loll-1344/90/$3.50
0 Elsevier Sequoia/Printed in The Netherlands
88
The application of photodynamic therapy (PDT) in GI cancers was first reported by Hayata et al. [2]. In China, the Cooperative Group on GIPDT has reported the use of laser PDT with HpD for the treatment of GI tumours in 264 cases [3] (Table 1). During a 6 year period, we have treated 142 patients with advanced GI cancers by PDT. This paper reports the results, analyses the effect of estimated energy dose and evaluates the follow-up survey. 2. Materials
and methods
2.1. Photosensitizer HpD (B-HpD and Y-HpD) was used as photosensitizer. B-HpD is derived from ox blood and Y-HpD from pig blood. B-HpD was provided by the Beijing Institute of Medicine and Y-HpD was obtained from Yangzhou Pharmaceuticals Ltd. Skin sensitivity tests were performed before intravenous injection of HpD to avoid anaphylactic reaction. HpD (5 mg kg’ body weight) was given by slow intravenous injection.
2.2. Laser equipment For therapeutic procedures, an argon dye laser was used as the source of excitation light. The laser equipment was made by the Beijing Institute of Opto-Electronic Technology and the Naming Electronic Tube Factory. Tumour localization by fluorescence was carried out using an argon ion laser (514.5 run) set to deliver 50 mW of power. Red light (630 nm) from an argon dye laser was delivered to the tumour through a quartz fibre passed through the biopsy channel of a fibrescope. Two types of quartz fibre were used: a flat-cut bare fibre and a cylindrical fibre. 2.3. Procedure HpD was injected 48-72 h before scanning for fluorescence detection or therapy. The flat-cut bare fibre tip was positioned 10-20 mm away from superficial lesions. Exophytic areas of oesophageal, cardiac and rectal cancer TABLE 1 PDT of GI tumours
in China Number
M. Y. M. Z. S. Y. S.
120 35 29 24 22 20 14
73.3 94.3 69.0 54.2 63.6 100.0 7.1
264
71.6
L. Jin C. Huang L. Chen H. Li C. Li sun D. Xiao
Total
of cases
Response
Author
rate
(%)
89
were treated interstitially using the 30 mm cylindrical fibre. The power output was adjusted to 100-300 mW at the fibre tip. The treatment time was about 20 min and the entire tumour received an estimated energy dose (EED) of loo-250 J cme2. In our experience, the best results were obtained when the tumour received an EED of 200-250 J cmm2. 2.4. Evaluation of therapeutic results of PDT Tumour response was evaluated on the basis of complete response (CR) (no visible abnormality, negative biopsy and cytology), partial response (PR) (degree of obstruction or size of tumour reduced over 509/o), mild response (MR) (degree of obstruction or size of tumour reduced by 25%-50%), no response (NR) (tumour reduced by less than 25%, increased or progression).
3. Results and discussion Patients (142) with advanced GI cancers were treated by PDT from September 1982 to December 1988 (122 males and 20 females; age range 39-91 years). The clinical diagnosis was coniirmed by endoscopic biopsy and histological examination. X-ray examination (double contrast radiography), ultrasonography and computed tomography (CT) can be used to establish the size and extent of the tumour; ultrasonography and CT are also important imaging methods for dete rmining infiltration or metastasis of the tumour; these examinations may be of help in assessing the clinical state and choosing PDT as the treatment modality. Squamous carcinomas (27 tumours) and adenocarcinomas (the rest) were treated by PDT; 87 patients were inoperable and 55 patients had postoperative recurrence. All patients with oesophageal and cardiac cancer had initial dysphagia. The results of treatment by PDT are given in Table 2. Endoscopy revealed that complete remission was obtained in 15 patients (10.69/o), partial remission was obtained in 53 patients (37.3%) and mild remission was obtained in 32 patients (22.5%); 100 patients (70.4%) showed response to PDT. TABLE
2
Therapeutic Location tuwwur
of
effect of PDT Therapeutic
Total
effect
CR
PR
MR
NR
0esophagu.v Stomach Rectum
3 11 1
5 41 7
4 28 0
14 26 2
26 106 10
Total
15
53
32
42
142
90
The Chinese Cooperative Group on PDT has determined a power output of 200-300 mW cm-’ for clinical use; the EED is 200-250 J cm’-‘. The experiments illustrate that, for equal light doses, better results are obtained using high dose rates. When the power output is lower than 80 mW cm-‘, the photoinduced necrosis is insufficient. However, as the dose increases over 300 J cmm2,it may cause dehydration of the skin and coagulation of proteins, leading to eschar formation which will prevent the penetration of the laser beam and lower the photodynamic effect. Therefore a power output of 200-300 mW cme2 is appropriate for practical use. Results in a series of patients with cardiac cancer of the stomach further illustrate this problem (Table 3). Two patients were irradiated with a power density lower than 100 mW cme2 and an EED lower than 100 J cmm2,with no response to PDT. The response rate of the patients irradiated with 10 l-200 mW cme2 and a dose between 101 and 300 J cmm2was 40.7%. When a power density of 201-300 mW cme2 (EED 101-300 J cme2) was used, the response rate was 64.3%. However, when the patients were irradiated with a power density of higher than 300 mW cmV2 and an EED higher than 201-300 J cmw2, the response rate was 40.0%. These results suggest that a power density of 201-300 mW cmm2and an EED of 101-300 J cmm2are appropriate for clinical use. Cardiac cancer accounted for 82 out of 106 cases of gastric cancer (in China, the incidence and mortality of cardiac cancer are much higher than in other countries). All patients with advanced cardiac cancer have initial dysphagia. Roentgen and endoscopic examinations are used for diagnosis at this stage. Through the use of ultrasonography or CT, the morphology, size and intrinsic structure of the tumour can be observed in detail. In addition, any infiltration or metastasis (such as liver metastases or lymph node metastases) may be detected. Ultrasonography and CT can aid in the assessment of the clinical stage and the choice of treatment in cardiac cancer. Most advanced patients with cardiac cancer cannot be treated by operation [4].
TABLE
3
Therapeutic
results of PDT in advanced cardiac cancer
Power (mW cm-‘)
Dose (J cm-‘)
100
100
101-200
101-200 201-300
201300
101-200 201-300
301
201-300
CR
1
1
PR
MR
NR
CR+PR
CR+PR
(%)
1
1
0
4 6
1 9
3 3
5/9 6/X3
55.5 33.3
40.7
2 15
1 5
4
2/3 16/25
66.7 64.0
64.3
2
1
2
2/5
40.0
91
In recent years, protocols of combined PDT and chemotherapy (the UFTM scheme, UFI (FI’-207 + Uracil) + mitomycin C) have been employed. AII patients were re-examined by endoscopy and biopsy at 4 weeks after PDT. Histologic changes observed following treatment were degeneration, necrosis of tumour cehs and infiltration of lymphocytes and plasmacytes into the stroma to different degrees. Tumour necrosis was observed at a depth of about 10 mm. According to our experience, when the average size of tumours is over 50 mmX 50 mm or the deep invasion is over 10 mm, PDT penetration is insufhcient. Best results with PDT were obtained in the series with local recurrence after operation. When no signs of regional and distant metastasis are detected, photodynamic therapy is proposed. When the local recurrence occurs accompanied by distant metastasis, the effect of PDT alone is minimal. A combination of PDT and chemotherapy is more successftd than PDT alone (Table 4). Ten patients showed CR, 17 showed PR and ten showed MR. The contribution of chemotherapy alone to survival is rather poor. The best median survivaI time was around 10 months in responders, and ranged from 4 to 6 months in aII patients receiving chemotherapy; only 0.8% of patients survived more than 2 years [ 5, 61. In this study, aII patients with advanced tumours were treated by a combination of PDT and chemotherapy. AII patients received adjuvant chemotherapy for 1 year. The follow-up survey of this series lasted from 6 to 60 months. Table 5 shows the current status of these patients: the numbers in parentheses indicate patients who are stiII alive; out of 137 cases, 27 patients are alive (19.7%) and 110 patients have died (80.3%); 12 patients (8.8%) survived more than 2 years; six patients have been followed for more than 3 years without signs of recurrence and are stiIIbeing followed. The CR group, which shows good results, was followed for l-5 years; only two patients died at 25 months; 13 out of 15 patients in the CR group are stiII alive (86.7%). The results suggest that combined PDT and chemotherapy may prove to be effective. In ah patients, there were no severe complications, i.e. haemorrhage or perforation; this procedure is harmless to heart, liver, kidneys and bone marrow; 16.9% of patients had mild epigastric pain a few days after treatment; TABLE
4
PDT for local recurrence
after operation
Locatian tumour
Therapeutic
of
Oesophagus Cardia Stomach Rectum Total
eflect
Tota.!
CR
PR
MR
NR
1 7 1 1
1 7 6 3
1 2 7
1 4 6 3
4 20 20 7
10
17
10
14
51
92 TABLE
5
Results of the foIIow-up survey
Results PDT
of
Cases
Obsemation I
CR PR MR NR
15 53 32 42
Total
142
0 30 20 38
(4) (2) (3) (2)
88 (11)
The numbers in parentheses
period
(years)
Lost to follow-up
l-2
2-3
3-5
5
0 (2) 10 (1) 7 (1)
2 (4) 3 (2)
0 (2) 0 (3)
0 (1)
0 2 1 2
17 (4)
5 (6)
0 (5)
0 (1)
5
indicate patients who are stiIi alive.
five patients had slight fever (below 38.5 “C). The side effects even if a combination of PDT and chemotherapy was used.
were slight
References L. Gennari, G. Bonfanti and B. Salvadori, Prognostic factors in gastric cancer, International Congress on Diagnosis and Treatment of Upper Gastrointestinal Tumours, Mainz, 1980, Excerpta Med., Section III (1981) 173-184. Y. Hayata, K. Oho and H. Kato, Applications of lasers in cancer diagnosis and treatment, Med. Image In$ I4 (1982) 19-23. M. L. Jim, B. Q. Yang, R. Li and P. P. Li, Analysis of haematoporphyrin derivative and laser photodynamic therapy of upper gastrointestinal tumours in 52 cases, Laser Med. Sci., 2 (1987) 51-54. J. W. Jackson, D. K. C. Cooper, L. Guvendik and H. Reece-Smith, The surgical management of malIgnant tumours of the oesophagus and cardia: a review of the results in 292 patients treated over a 15-year period (1961-1975), Br. J. Surg., 66 (1979) 98-104. Y. Takano, M. Ogama and J. Inagaki, U.S.-Japan cooperative study of chemotherapy of gastric cancer-The 3rd report, J. Jpn. Sot. Cancer Ther., 15 (1980) 238-240. T. Saito and M. Yokoyama, Healing and recurrence of cancer-from the point of view of cancer chemotherapy, Jpn. J. Cancer Clin., 19 (1973) 285-289.
