Reappraisal of Bronchial Arterial Infusion Therapy for Advanced Lung Cancer Yoh WATANABE*,Junzo SHIMIZU*,Shinya MURAKAMI*,Masayuki YOSHIDA*, Makoto TSUBOTA*,Takashi IWA*,Masanobu KITAGAWA**, Yuji MIZUKAMI**,Akitaka NONOMURA** and Fujitsugu MATSUBARA** ABSTRACT: As preoperative adjuvant therapy for advanced lung cancer, bronchial arterial infusion (BAI) of a chemotherapeutic agent was administered to patients with stage IIIa and IIIb hilar lung cancer. The infusion modality was changed for each term, from a single drug infusion, to a two drug infusion and then a three drug infusion, and the combination of infused drugs was selected in accordance with cell types. A significant radiographic shrinkage was observed after BAI therapy by the single, two and three drug infusions, being noted as 40.7 per cent, 61.8 per cent and 83.9 per cent, respectively. The effect on squamous cell carcinoma was more prominent than on other cell types. Upon microscopic examination of the resected specimens, significant histo-pathological effects were observed in 57.7 per cent of the patients who received single or two drug infusions, while the rate increased to as high as 92.2 per cent in the patients who received the three drug infusion. The histological effects of BAI therapy were also most marked in squamous cell carcinoma. It is of special interest that 5 of the 10 patients who received the three drug infusion of Carboquone (CQ) + Mitomycin C (MMC) + Nimustine-HCL (ACNU) for squamous cell carcinoma, showed complete disappearance of viable cancer cells at the tumor site; something which was never observed after the single and two drug infusions. It was therefore concluded that BAI therapy for advanced lung cancer should be reappraised through the modification of infusion methods. KEY WORDS: infusion chemotherapy, bronchial artery, lung cancer, neoadjuvant therapy, epiderrnoid carcinoma
INTRODUCTION
The clinical value of preoperative adjuvant therapy such as systemic chemotherapy or *The Departments of Surgery and **the Clinical Pathology, Kanazawa University School of Medicine, Kanazawa, Japan Reprint requests to: Yoh Watanabe, MD, The Department of Surgery, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920,Japan
radiation therapy, is controversial. As preoperative adjuvant therapy for lung cancer, we have long been using local infusion therapy of chemotherapeutic agents through the bronchial artery (BAI).1 The radiological and histological effects of BAI therapy have confirmed that two drug infusion is always superior to single drug infusion,2 and that preoperative BAI therapy definitely contributes to an improvement in the resectability rate of advanced lung cancer. Nevertheless,
JAPANESEJoumqALOFSURGERY,VOL.20, No. 1 pp. 27-35, 1990
28
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Watanabe et al.
there is no apparent evidence of an improvement in the postoperative survival rates of these patients) Thus, in order to improve both the resection rate and the survival rate o f patients with advanced lung cancer, we have begun using three drug infusion. Although the results are still only preliminary, they are already more favorable than those achieved with the conventional two drug infusion. In this report, the clinical and the pathological effects of BAI therapy given at various infusion regimes are compared, and the current state and future prospects of this adjuvant therapy are discussed.
~++++
~++++
0
MATERIALS AND METHODS
The candidates for this preoperative treatment were selected from patients with stage IIIA and IIIB lung cancer with hila r involvement in whom histological diagnosis of cell type had been determined by a bronchoscopical biopsy. Using Seldinger's technique, a catheter was introduced into the thoracic aorta. The catheter tip was then wedged into the orifice of the bronchial artery and a bronchial arteriography (BAG) using 10 ml of contrast medium was performed. If the feeding vessel to the tumor site was seen by BAG, chemotherapeutic drugs diluted in a saline solution were infused in accordance with the cell type o f the lung cancer. The infused drugs selected for each cell type are shown in Table 1. Prior to 1975, single drug infusion was performed as follows: 0.1 mg/Kg of Carboquone (CQ) was infused for squamous cell carcinoma, while 0.3 mg/Kg of Mitomycin-C (MMC) was infused for adenocarcinoma, large cell carcinoma, small cell and other cell types of cancer. Between 1975 and 1982, two drug infusion was performed as follows: CQ 6 mg + MMC 8 mg for squamous cell carcinoma, Adriamycin (ADM) 40 m g + MMC 8 mg for adenocarcinoma, ADM 40 mg § CQ 6 mg for large cell carcinoma, and ADM 40 m g + MMC 8 mg for small cell and
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Volume 20 Number 1
Bronchial artery infusion therapy
other cell types of carcinoma. T h r e e drug infusion was started in 1983 using NimustineHCL (ACNU) in addition to the above mentioned combination of two drugs. During BAI therapy, these drugs are diluted in a saline solution o f more than 100 ml, and infused over no less than ten minutes to prevent major complications, such as injury to the spinal cord or esophageal perforation. Evaluation o f the BAI therapy was based on radiological and histopathological findings. For the radiologicaljudgement, a chest X-ray film taken before BAI therapy (control film) was c o m p a r e d with a n o t h e r film taken after BAI therapy and if a 50 p e r cent or greater reduction in the area o f bidimensional diameters was observed, that case was designated as one on which BAI therapy had been radiologically effective, In order to classify the histopathological effects o f BAI therapy, the criteria for the histological j u d g e m e n t o f the effects o f treatment proposed by the J a p a n Lung Cancer Society were used. T h e criteria for the effects (Ef.) are summarized as follows: Ef. 0; no effect g r o u p = n o recognizable morphological effect such as degeneration, necrosis o f other signs, on cancer cells or cancer tissue. Es la; least effected g r o u p = m o r e than two thirds o f the cancer tissue is occupied by presumably viable cancer cells. Es lb; slight effect g r o u p = m o r e than one third but less than two thirds o f the cancer tissue is occupied by presumably viable cancer cells. Ef. 2; moderate effect g r o u p = p r e s u m a b l y viable cancer cells still remain, but they do not exceed one third o f the cancer tissue. Ef. 3; marked effect g r o u p = t h e complete disappearance o f cancer cells or presumably nonviable cancer cells only exist. RESULTS No mortality or any major complications were encountered as a result of the therapy with the exception o f a 47 year old male with epidermoid carcinoma in w h o m C Q and MMC were infused in a routine m a n n e r .
29
Shortly after infusion, he complained o f pain in his right thigh and later developed transient hemiplegia in his right lower extremity which continued for no m o r e than half a day, possibly caused by temporary ischemia o f the spinal cord. However, the symptoms c o m p l e t e l y d i s a p p e a r e d within six months. T h e clinical effects o f BAI therapy as j u d g e d from the radiological findings are shown in Table 2. In most cases, m a x i m u m radiological changes were e n c o u n t e r e d ten to fourteen days after BAI therapy. Single drug BAI produced a rate o f effectiveness of 40.7 p e r cent, or 31 of the 76 cases, as a whole, these effects being most apparent in the cases with epidermoid carcinoma a m o n g the three cell types. Adenocarcinoma was least affected by single drug infusion. W h e n c o m b i n e d infusion of two drugs was used, the rate of effectiveness improved up to 61.8 per cent. In particular, the rate o f effectiveness on a d e n o c a r c i n o m a by two drug infusion using ADM and MMC increased to 58.3 per cent in contrast to 25.0 per cent observed after the single drug infusion of MMC alone. W h e n the effects of single drug infusion were evaluated in comparison with those of two drug infusion, 52 o f the 110 cases, or 47.2 per cent, showed radiological changes of effectiveness. T h e effective rates for epidermoid carcinoma, a d e n o c a r c i n o m a and large cell carcinoma were 54.3 per cent, 35.0 per cent and 53.3 per cent, respectively. In contrast, three drug infusion showed a rate of effectiveness of 83.9 per cent as a whole. In the cases of epidermoid carcinoma, 15 o f 16 cases, or 93.8 p e r cent, showed clinical effectiveness a n d the rate o f effectiveness for a d e n o c a r c i n o m a was 75.,0 p e r cent, or 6 o f 8 cases, which was the highest a m o n g the three infusion modalities o f single, two a n d three drug infusions. T h e h i s t o - p a t h o l o g i c a l effects o f BAI therapy on each cell type by each infusion m e t h o d are shown in Table 3. In practice, the histo-pathological effects o f BAI are e v a l u a t e d as m i c r o s c o p i c a l c h a n g e s o f
Watanabe et al.
30 Table 2.
Jpn. J. Surg. January 1990
Comparison of the Clinical Effects of BAI Therapy verified from Radiological Findings* Epidermoid Carcinoma
Adenocarcinoma
Large Cell Carcinoma
Total
Single drug BAI therapy Two drug BAI therapy
19/36 (52.8) 6/10 (60.0)
7/28 (25.0) 7/12 (58.3)
3/ 7 (42.9) 5/ 8 (62.5)
31/ 76 (40.7) 21/ 34 (61.8)
Single/two drug BAI therapy Three drug BAI therapy
25/46 (54.3) 15/16 (93.8)
14/40 (35.0) 6/ 8 (75.0)
8/15 (53.3) 1/ 2 (50.0)
52/110 (47.2) 26/ 31 (83.9)
40/62 (64.5)
20/48 (41.7)
9/17 (52.9)
78/141 (55.3)
Total
( ):percent * More than a 50 per cent reduction in the area ofbidimensional diameters measured in the chest film. The total number also included cases with miscellaneous cell types other than those of the above three. Table 3. Comparison of the Histo-Pathological Effects of BAI Therapy verified from Resected Specimens El. 0 Single/two drug BAI therapy (n=97) Epidermoid carcinoma (n=47) Adenocarcinoma (n=38) Large cell carcinoma (n----9) Others (n=3) Total Three drug BAI therapy (n=14) Epidermoid carcinoma (n=10) Adenocarcinoma (n=l) Large cell carcinoma (n=0) Others (n=3) Total
:
4 (8.5) 7 (18.4) 0 1 (33.3) 12 (12.4)
Ef. la
El. lb
Ef. 2
Ef. 3
Effective Rate*
8 (17.0) 31 (66.0) 4 (8.5) 15 (39.5) 14 (36.8) 2 (5.3) 4 (44.4) 3 (33.3) 2 (22.2) 2 (66.7) 0 0
0 0 0 0
35/47 (74.5) 16/38 (42.1) 5/ 9 (55.6) 0/ 3 (0)
29 (29.9) 48 (49.5)
0
56/97 (57.7)
8 (8.2)
0 0 0 1 (33.3)
0 0 0 0
2 (20.0) 3 (30.0) 1 (100) 0 0 0 1 (33.3) 1 (33.3)
5 (50.0) 0 0 0
10/10 (100) 1/ 1 (100) 0 2/ 3 (66.7)
1 (7.1)
0
4 (28.6) 4 (28.6)
5 (35.7)
13/14 (92.9)
* Ratio of El. l b, 2, and 3 cases to the total number of cases. greater t h a n El. l b a c c o r d i n g to the aforem e n t i o n e d criteria. T h e r e were 97 resected cases in w h i c h single o r two drugs were infused preoperatively. Twelve cases (12.4 p e r cent) s h o w e d Ef. 0 findings, m e a n i n g n o recognizable c h a n g e s were observed in the t u m o r site after BAI therapy a n d a n o t h e r 29 cases (29.9 p e r cent) were categorized as Ef. l a which could also be classified as a n o n effective group in clinical practice. T h e r e fore, the non-effective rate o f single a n d two d r u g infusions was 42.3 p e r c e n t as a whole. T h e rates o f non-effective cases o f epiderm o i d carcinoma, a d e n o c a r c i n o m a a n d large cell c a r c i n o m a were 25.5 p e r cent, 57.9 p e r cent a n d 44.4 p e r cent, respectively, the least
( ): per cent
effective rate b e i n g observed in a d e n o c a r cinoma. Forty-eight o f the 97 cases, o r 49.5 p e r cent s h o w e d microscopical findings o f Ef. lb, while 8 cases s h o w e d Ef. 2. I f effective cases were c o n f i n e d to those with m o r e t h a n Ef. lb, the effective rate o f the single a n d two drug infusions was 57.7 per c e n t as a whole. However, n o case achieved Ef. 3. T h e rate o f effectiveness o f each cell type was 74.5 per cent for e p i d e r m o i d carcinoma, 42.1 p e r cent for a d e n o c a r c i n o m a , a n d 55.6 p e r cent for large cell carcinoma. W h e n c o m p a r i s o n s were m a d e between single drug infusions a n d two drug infusions for e p i d e r m o i d c a r c i n o m a a n d a d e n o c a r cinoma, the effective rates were 63.6 p e r cent
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Bronchial artery infusion therapy
vs. 73.3 per cent and 40.0 per cent vs. 53.8 per cent, respectively (not shown in Table 3). Although the rate of effectiveness for adenocarcinoma either by single drug infusions or two drug infusions r e m a i n e d low in comparison with that for epidermoid carcinoma, the rate was moderately improved through the combined infusion o f ADM and MMC. Three drug infusions were p e r f o r m e d in 31 cases, 14 of w h o m underwent surgical resection and histo-pathological examinations. Excluding one case o f adenosquamous cell carcinoma, no other case showed microscopical findings o f E s 0 or Ef. l a after three drug infusion. T h e rate o f effectiveness was therefore 92.9 p e r cent, or 13 o f 14 cases as a whole. T h e r e were 4 cases ofEE l b (28.6 per cent), 4 cases of El. 2 (28.6 per cent), a n d 5 cases of El. 3 (35.7 per cent). The three drug infusion o f CQ, MMC a n d ACNU for the cases with epidermoid carcinoma clearly showed a high tumoricydal effect in terms of both the clinical and histopathological effects of BAI therapy. With this infusion method, the effective rate for squamous cell carcinoma increased to 100 per cent. T h o u g h two cases (20 per cent) showed only El. l b effect, three cases (30 per cent) showed El. 2, while five cases (50 per cent) showed EE 3 effect, neither having b e e n observed with the single or two drug infusions. A case of a d e n o c a r c i n o m a showed EE lb, which resulted in a 100 per cent effective rate. O n e case each of mucoepidermoid carcinoma and adenosquamous cell carcinoma showed EE l b and '2, respectively. If we look at the survival period of the patients who underwent surgical resections after the preoperative three drug infusion, to date, there are 6 cases of long-term survival of between 18 months and 5 years, or 37 months on average. T h e cell type o f all these cases was squamous cell carcinoma and 2 o f these cases are briefly presented here. Fig. 1 is a chest X-ray film of a 65 year old male with epidermoid carcinoma. Preoperative BAI therapy using CO__.,MMC and ACNU was p e r f o r m e d twice at 8 day intervals. Fig. 2
31
Fig. 1. Chest X-ray fihn of a 65 year old male with epidermoid carcinoma in the right lower lobe.
Fig. 2. Chest X-ray fihn taken 35 days after the second bronchial arterial infusion CQ 6 rag, MMC 8 rag, and ACNU 50 rag. The patient underwent an operation 55 days after the second course of BAI therapy and histological examination of the resected specimen revealed no viable cancer cells at the tumor site. is a chest X-ray film taken 35 days after the second course o f BAI therapy, showing marked decrease o f the tumor shadow. This
32
Watanabe et al.
patient u n d e r w e n t a right lower lobectomy 55 days after the s e c o n d BAI therapy. A histo-pathological examination revealed Ef. 3 effect in which n o c a n c e r cells were seen at the t u m o r site a n d instead, the c a n c e r tissue
Fig. 3. Chest X-ray film of a 66 year old male with epidermoid carcinoma in the left hilum which caused complete atelectasis of the left lung.
Fig. 4. Bronchial arteriography, which identified a tumor in the atelectatic field. A three drug infusion of CQ, MMC and ACNU was performed.
Jpn. J. Surg. January 1990
was completely replaced by necrotic tissue. H e is alive a n d well 41 m o n t h s after the operation. Fig. 3 is a chest X-ray film o f a 66 year old male with e p i d e r m o i d c a r c i n o m a showing
Fig. 5. Chest X-ray film taken i1 days after the first course of BAI therapy. Due to tumor shrinkage, atelectasis of the left lung disappeared.
Fig. 6. Chest X-ray film taken 11 days after the second course of BALItherapy-, performed 39 days after the first course. The patient underwent a left sleeve pneumonectomy 20 days after the second course of BM therapy.
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Bronchial artery infusion therapy
33
Fig. 7. Microscopic views of a preoperative bronchial biopsy (left) and a resected specimen (right) in which preoperative BAI therapy caused the complete disappearance of viable cancer cells. complete atelectasis of the left lung. Fig. 4 shows a bronchial arteriography with a rumor stain within the atelectatic shadow. Three drugs were infused at the time o f arteriography. Fig. 5 is a chest X-ray film taken 11 days after BAI therapy. T h e second course of BAI therapy was done 29 days after the first course of BAI therapy. Fig. 6 is a chest X-ray film taken 11 days after the second course o f BAI therapy, indicating apparent shrinkage of the tumor shadow as a result o f the dual BAI therapy. This patient underwent left sleeve p n e u m o n e c t o m y via a median sternotomy 20 days after the second course of BAI therapy. O n examination o f the resected specimen, no viable cancer cells were found throughout the tumor site. Fig. 7 shows microscopic views of a biopsy taken before BAI therapy and the resected specimen. Following BAI therapy, the cancer cell nests were completely destroyed without any sign of viable cancer cells, and the tumor site completely replaced by necrotic tissue. These findings were compatible with El. 3. H e is alive and well 33 months after the operation. DISCUSSION The main aims of preoperative adjuvant therapy are, firstly, to improve the resectability of lung cancer invading an adjacent structure and, secondly, to p r e v e n t the hematogenous showering of cancer cells
from the operative site by surgical manipulation, both of which are facilitated by the resulting shrinkage of tumor volume. Most of the trials on the effects o f preoperative radiation as adjuvant therapy in that sense have showed negative results? ,~ In 1964, Viamonte et a12 m a d e possible, the selective b r o n c h i a l artery catheterization with the help of Seldinger's technique. T h e authors ~,7 have also b e e n using this type o f anigiography for m a n y years, while at the same time administering an intra-arterial infusion of chemotherapeutic agents as a way to treat advanced lung cancer. T h e advantages o f BAI therapy in the treatment of lung cancer are: @ it can be repeated m a n y times; @ a high density of chemotherapeutics can be infused; @ it can m i n i m i z e the side effects o f a n t i c a n c e r drugs; and @ local side effects such as inflammation, adhesion or fibrosis in the surrounding region of the lung are milder than those which a p p e a r after radiation therapy. Most o f the reported cases of BAI therapy were treated with a single drug infusion. Haller et al. 8 infused 5-fluorouracil or Thio-TEPA; K a h n eL al. 9 reported the continuous infusion of Methotrexate a n d a one shot infusion of Nitrogen mustard; Tare et al. 1~ infused Nitrogen mustard or Cyclophosphamide; and Neyazaki et al. n infused MMC. T h e results of these single drug infusions were mostly discouraging but they
34
Watanabe et al.
nevertheless clarified that BAI therapy was m u c h m o r e effective on squamous cell carc i n o m a than adenocarcinoma, and that the extent o f t u m o r shrinkage and the long-term survival rates were related to the frequency o f infusion. H From our pilot study done for the purpose of selecting the most effective drug for each cell type, epidermoid carcinoma was found to be most sensitive to CQ, an alkylating agent, 12while adenocarcinoma and large cell carcinoma were more sensitive to MMC. Before 1975, single drug infusion using these drugs was tried andl as shown in Table 2, the effect on a d e n o c a r c i n o m a was mostly poor. To improve the rate of effectiveness on each cell type, especially adenocarcinoma, two drug infusion was started in 1975, after which the rates were moderately improved. Moreover, the short-term effects o f radiological shrinkage o f the tumor, an i m p r o v e m e n t in the resectability rate o f advanced cases and histo-pathological effects were m u c h improved using two drug infusion. However, the effects o n the long-term survival rate o f patients undergoing surgical resections remained obscure because of the retrospective comparison of cases who had u n d e r g o n e BAI therapy preoperatively a n d those who h a d not? These results are in accordance with those of other authors 13,14 and as a result, this treatment modality as a preoperative adjuvant therapy was once abandoned, even by us. In 1983, we started using three drug combination BAI therapy by adding ACNU, an alkylating agent, to the other two drugs for the purpose o f reappraising BAI therapy. T h e reason why we selected ACNU was that this d r u g h a d a marked effect on squamous cell carcinoma in the pilot study of the single infusion of this agent. In fact, with three drug infusion, the clinical as well as histo-pathological effects were most obvious in cases with squamous cell carcinoma. With three drug infusion, 15 of the 16 cases showed a significant shrinkage of the tumor as demonstrated by chest X-ray films. Furthermore, on
Jpn. J. Surg. January 1990
examination o f the resected specimens, it was clarified that all of the cases showed histological changes o f greater than Ef. 2. O f special note is the fact that there were five patients with Ef. 3 changes in which no viable cancer cells n o r even a ghost o f a cancer cell could be observed. Such highly effective r e s p o n s e rates a n d h i g h - g r a d e changes were n e v e r observed with the single or two drug infusion methods. C o n c e r n i n g the effects on other cell types, this could not be clarified because of the small n u m b e r o f patients with other cell types, partly due to the fact that the incidence of a d e n o c a r c i n o m a and large cell carcinoma in the hilar region is not so frequent in comparison with squamous cell carcinoma. By using three drug infusion, the clinical as well as the histo-pathological effects of BAI therapy were m u c h improved. However, greater improvements in b o t h the short-term a n d long-term effects, or the prolongation of survival period can be expected with the help of new anticancer drugs which have b e e n designated as effective for the treatment of lung cancer in systemic use. We have started combination infusions of an immunotherapeutic agent with anticancer drugs following observation of the favourable effects of systemic i m m u n o c h e m o t h e r a p y on lung cancer. 1~-17 Furthermore, we have clearly conducted a pilot study on adoptive immunotherapy via a bronchial artery by an infusion of a lymphokine activated killer (LAK) cells incubated in vitro. We are now employing such multi-modality BAI therapy as neoadjuvant) ~ or preoperative therapy for the surgical resection of stage I I I A and I I I B lung cancers. Thus, various infusions t h r o u g h the b r o n c h i a l arteries should be reappraised, for they can be used in m a n y ways, a n d achieve favorable effects on advanced lung cancer. (Received for publication on Jan. 24, 1989)
Volume 20 Number I
Bronchial artery infusion therapy
REFERENCES 1. Watanabe Y, Yamada T, Ichihashi T, Hashizume Y, Iwa T. Surgical adjuvant therapy for non-small cell lung cancer. Gan to Kagakuryoho (Jap J Cancer Chemother) 1986; 13 (part II): 1534-1546. (English Abst.) 2. Komori Y, Yamada T, Funaki Y, Watanabe Y, Iwa T. Effect of intra-arterial chemotherapy in lung cancer. Gan no Rinsho r Cancer Clin) 1978; 24: 1191-1196. (English Abst.) 3. Collaborative study. Preoperative irradiation of cancer of the lung. Cancer 1975; 36: 914-925. 4. Shields TW, Higgins GA, Lawton R, Lawton R, Heilbrunn A, Keehn RJ. Preoperative X-ray therapy as an adjuvant in the treatment of bronchogenic carcinoma. J Thorac Cardiovasc Surg 1970; 59: 49-61. 5. Viamonte M Jr. Selective bronchial arteriography in man. Preliminary report. Radiology 1964; 83: 830-839. 6, Watanahe Y, Nagai A, Oohashi Y, Yoshida C, Kuroda Y, Bando T. Selective bronchial arteriography for the study of the effect of radiation therapy on tumor vessels of bronchogenic carcinoma. Nihon Kyobu Rinsho (.lap J Chest Clin) 1973; 27: 671-681. (English Abst.) 7. Watanahe Y, Iwa T, Fukatani G, Kuroda Y, Oohashi Y, Yoshida C, Kihara K, Mori A, Sato H, Komori Y. Clinical evaluation of bronchial arteriography for lung disease. Nihon Kyobu Rinsho (Jap J Chest Clin) 1976; 35: 917-922. (English Abst.) 8. HallerJD, Bron KM, Wholey MH, Poller S, Enerson DM. Selective bronchial artery catheterization for diagnostic and physiologic studies and chemotherapy for bronchogenic carcinoma. J Thorac Cardiovasc Surg 1966; 51: 143-152. 9. Kahn PC, Paul RE, Rheinlander HF. Selective bronchial arteriography and intra-arterial chemotherapy in carcinoma of the lung. J Thorac Car-
35
diovasc Surg 1965; 50: 640-647. 10. Tate CF Jr, Viamonte M Jr, AgnewJR. Bronchial arterial perfusion with cytotoxic agents for bronchogenic carcinoma. Preliminary report. Amer Rev Resp Dis 1968; 97: 685-693. 11. Neyazaki T, Ikeda M, Seki Y, Egawa N, Suzuki C. Bronchial artery infusion therapy for lung cancer. Cancer 1969; 24: 912-922. 12. Watanahe Y, Kuroda Y, Sato H, lwa T. Clinical evaluation of Carboquone for treatment of lung cancer with special reference to its effect by bronchial arterial infusion. Gan to Kagakuryoho (JapJ Cancer Chemother) 1976; 3: 85-91. (English Ahst.) 13. Neyazaki T, Hashimoto K, Nakada T, Suzuki C. Long-term results of preoperative bronchial arterial infusion therapy for lung cancer. Kyobu Geka (lap J Thorac Surg) 1975; 28: 838-843. (English Abst.) 14. Ogawa S, Ishihara T, Kikuchi K, Inoue K, Fukai S, Takanami I, Busi A, Ikeda T. Broiachial arterial infusion therapy for inoperable bronchogenic carcinoma, Kyobu Geka (JapJ Thor~/c Surg) 1977; 30: 640-645. (English Ahst.) 15. Watanabe Y, Iwa T. Clinical value of immunotherapy by streptococcal preparation, OK-432, as an adjuvant for lung cancer. Cancer 1984; 53: 248253. 16. Watanabe Y, Iwa T. Immunotberapy of lung cancer: A randomized clinical trial of OK-432 immunotherapy and a review of the literature on nonspecific immunotherapy. Internat J Immunother 1986; 2: 51-67. 17. Watanabe Y, Iwa T. Clinical value of immunotherapy with the Streptococcal preparation OK-432 in non-small cell lung cancer. J Biol Response Modif 1987; 6:169=180 18. Einhorn LH. Neoadjuvant therapy of stage IlI nonsmall cell lung cancer. Ann Thorac Surg 1988; 46: 362-365.
INTRODUCTION
The clinical value of preoperative adjuvant therapy such as systemic chemotherapy or *The Departments of Surgery and **the Clinical Pathology, Kanazawa University School of Medicine, Kanazawa, Japan Reprint requests to: Yoh Watanabe, MD, The Department of Surgery, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920,Japan
radiation therapy, is controversial. As preoperative adjuvant therapy for lung cancer, we have long been using local infusion therapy of chemotherapeutic agents through the bronchial artery (BAI).1 The radiological and histological effects of BAI therapy have confirmed that two drug infusion is always superior to single drug infusion,2 and that preoperative BAI therapy definitely contributes to an improvement in the resectability rate of advanced lung cancer. Nevertheless,
JAPANESEJoumqALOFSURGERY,VOL.20, No. 1 pp. 27-35, 1990
28
Jpn. J. Surg. January 1990
Watanabe et al.
there is no apparent evidence of an improvement in the postoperative survival rates of these patients) Thus, in order to improve both the resection rate and the survival rate o f patients with advanced lung cancer, we have begun using three drug infusion. Although the results are still only preliminary, they are already more favorable than those achieved with the conventional two drug infusion. In this report, the clinical and the pathological effects of BAI therapy given at various infusion regimes are compared, and the current state and future prospects of this adjuvant therapy are discussed.
~++++
~++++
0
MATERIALS AND METHODS
The candidates for this preoperative treatment were selected from patients with stage IIIA and IIIB lung cancer with hila r involvement in whom histological diagnosis of cell type had been determined by a bronchoscopical biopsy. Using Seldinger's technique, a catheter was introduced into the thoracic aorta. The catheter tip was then wedged into the orifice of the bronchial artery and a bronchial arteriography (BAG) using 10 ml of contrast medium was performed. If the feeding vessel to the tumor site was seen by BAG, chemotherapeutic drugs diluted in a saline solution were infused in accordance with the cell type o f the lung cancer. The infused drugs selected for each cell type are shown in Table 1. Prior to 1975, single drug infusion was performed as follows: 0.1 mg/Kg of Carboquone (CQ) was infused for squamous cell carcinoma, while 0.3 mg/Kg of Mitomycin-C (MMC) was infused for adenocarcinoma, large cell carcinoma, small cell and other cell types of cancer. Between 1975 and 1982, two drug infusion was performed as follows: CQ 6 mg + MMC 8 mg for squamous cell carcinoma, Adriamycin (ADM) 40 m g + MMC 8 mg for adenocarcinoma, ADM 40 mg § CQ 6 mg for large cell carcinoma, and ADM 40 m g + MMC 8 mg for small cell and
# ~N ++++ ~J 9
0 x 0
,< 0
E
E
9
~5 o5 9 0
e
Volume 20 Number 1
Bronchial artery infusion therapy
other cell types of carcinoma. T h r e e drug infusion was started in 1983 using NimustineHCL (ACNU) in addition to the above mentioned combination of two drugs. During BAI therapy, these drugs are diluted in a saline solution o f more than 100 ml, and infused over no less than ten minutes to prevent major complications, such as injury to the spinal cord or esophageal perforation. Evaluation o f the BAI therapy was based on radiological and histopathological findings. For the radiologicaljudgement, a chest X-ray film taken before BAI therapy (control film) was c o m p a r e d with a n o t h e r film taken after BAI therapy and if a 50 p e r cent or greater reduction in the area o f bidimensional diameters was observed, that case was designated as one on which BAI therapy had been radiologically effective, In order to classify the histopathological effects o f BAI therapy, the criteria for the histological j u d g e m e n t o f the effects o f treatment proposed by the J a p a n Lung Cancer Society were used. T h e criteria for the effects (Ef.) are summarized as follows: Ef. 0; no effect g r o u p = n o recognizable morphological effect such as degeneration, necrosis o f other signs, on cancer cells or cancer tissue. Es la; least effected g r o u p = m o r e than two thirds o f the cancer tissue is occupied by presumably viable cancer cells. Es lb; slight effect g r o u p = m o r e than one third but less than two thirds o f the cancer tissue is occupied by presumably viable cancer cells. Ef. 2; moderate effect g r o u p = p r e s u m a b l y viable cancer cells still remain, but they do not exceed one third o f the cancer tissue. Ef. 3; marked effect g r o u p = t h e complete disappearance o f cancer cells or presumably nonviable cancer cells only exist. RESULTS No mortality or any major complications were encountered as a result of the therapy with the exception o f a 47 year old male with epidermoid carcinoma in w h o m C Q and MMC were infused in a routine m a n n e r .
29
Shortly after infusion, he complained o f pain in his right thigh and later developed transient hemiplegia in his right lower extremity which continued for no m o r e than half a day, possibly caused by temporary ischemia o f the spinal cord. However, the symptoms c o m p l e t e l y d i s a p p e a r e d within six months. T h e clinical effects o f BAI therapy as j u d g e d from the radiological findings are shown in Table 2. In most cases, m a x i m u m radiological changes were e n c o u n t e r e d ten to fourteen days after BAI therapy. Single drug BAI produced a rate o f effectiveness of 40.7 p e r cent, or 31 of the 76 cases, as a whole, these effects being most apparent in the cases with epidermoid carcinoma a m o n g the three cell types. Adenocarcinoma was least affected by single drug infusion. W h e n c o m b i n e d infusion of two drugs was used, the rate of effectiveness improved up to 61.8 per cent. In particular, the rate o f effectiveness on a d e n o c a r c i n o m a by two drug infusion using ADM and MMC increased to 58.3 per cent in contrast to 25.0 per cent observed after the single drug infusion of MMC alone. W h e n the effects of single drug infusion were evaluated in comparison with those of two drug infusion, 52 o f the 110 cases, or 47.2 per cent, showed radiological changes of effectiveness. T h e effective rates for epidermoid carcinoma, a d e n o c a r c i n o m a and large cell carcinoma were 54.3 per cent, 35.0 per cent and 53.3 per cent, respectively. In contrast, three drug infusion showed a rate of effectiveness of 83.9 per cent as a whole. In the cases of epidermoid carcinoma, 15 o f 16 cases, or 93.8 p e r cent, showed clinical effectiveness a n d the rate o f effectiveness for a d e n o c a r c i n o m a was 75.,0 p e r cent, or 6 o f 8 cases, which was the highest a m o n g the three infusion modalities o f single, two a n d three drug infusions. T h e h i s t o - p a t h o l o g i c a l effects o f BAI therapy on each cell type by each infusion m e t h o d are shown in Table 3. In practice, the histo-pathological effects o f BAI are e v a l u a t e d as m i c r o s c o p i c a l c h a n g e s o f
Watanabe et al.
30 Table 2.
Jpn. J. Surg. January 1990
Comparison of the Clinical Effects of BAI Therapy verified from Radiological Findings* Epidermoid Carcinoma
Adenocarcinoma
Large Cell Carcinoma
Total
Single drug BAI therapy Two drug BAI therapy
19/36 (52.8) 6/10 (60.0)
7/28 (25.0) 7/12 (58.3)
3/ 7 (42.9) 5/ 8 (62.5)
31/ 76 (40.7) 21/ 34 (61.8)
Single/two drug BAI therapy Three drug BAI therapy
25/46 (54.3) 15/16 (93.8)
14/40 (35.0) 6/ 8 (75.0)
8/15 (53.3) 1/ 2 (50.0)
52/110 (47.2) 26/ 31 (83.9)
40/62 (64.5)
20/48 (41.7)
9/17 (52.9)
78/141 (55.3)
Total
( ):percent * More than a 50 per cent reduction in the area ofbidimensional diameters measured in the chest film. The total number also included cases with miscellaneous cell types other than those of the above three. Table 3. Comparison of the Histo-Pathological Effects of BAI Therapy verified from Resected Specimens El. 0 Single/two drug BAI therapy (n=97) Epidermoid carcinoma (n=47) Adenocarcinoma (n=38) Large cell carcinoma (n----9) Others (n=3) Total Three drug BAI therapy (n=14) Epidermoid carcinoma (n=10) Adenocarcinoma (n=l) Large cell carcinoma (n=0) Others (n=3) Total
:
4 (8.5) 7 (18.4) 0 1 (33.3) 12 (12.4)
Ef. la
El. lb
Ef. 2
Ef. 3
Effective Rate*
8 (17.0) 31 (66.0) 4 (8.5) 15 (39.5) 14 (36.8) 2 (5.3) 4 (44.4) 3 (33.3) 2 (22.2) 2 (66.7) 0 0
0 0 0 0
35/47 (74.5) 16/38 (42.1) 5/ 9 (55.6) 0/ 3 (0)
29 (29.9) 48 (49.5)
0
56/97 (57.7)
8 (8.2)
0 0 0 1 (33.3)
0 0 0 0
2 (20.0) 3 (30.0) 1 (100) 0 0 0 1 (33.3) 1 (33.3)
5 (50.0) 0 0 0
10/10 (100) 1/ 1 (100) 0 2/ 3 (66.7)
1 (7.1)
0
4 (28.6) 4 (28.6)
5 (35.7)
13/14 (92.9)
* Ratio of El. l b, 2, and 3 cases to the total number of cases. greater t h a n El. l b a c c o r d i n g to the aforem e n t i o n e d criteria. T h e r e were 97 resected cases in w h i c h single o r two drugs were infused preoperatively. Twelve cases (12.4 p e r cent) s h o w e d Ef. 0 findings, m e a n i n g n o recognizable c h a n g e s were observed in the t u m o r site after BAI therapy a n d a n o t h e r 29 cases (29.9 p e r cent) were categorized as Ef. l a which could also be classified as a n o n effective group in clinical practice. T h e r e fore, the non-effective rate o f single a n d two d r u g infusions was 42.3 p e r c e n t as a whole. T h e rates o f non-effective cases o f epiderm o i d carcinoma, a d e n o c a r c i n o m a a n d large cell c a r c i n o m a were 25.5 p e r cent, 57.9 p e r cent a n d 44.4 p e r cent, respectively, the least
( ): per cent
effective rate b e i n g observed in a d e n o c a r cinoma. Forty-eight o f the 97 cases, o r 49.5 p e r cent s h o w e d microscopical findings o f Ef. lb, while 8 cases s h o w e d Ef. 2. I f effective cases were c o n f i n e d to those with m o r e t h a n Ef. lb, the effective rate o f the single a n d two drug infusions was 57.7 per c e n t as a whole. However, n o case achieved Ef. 3. T h e rate o f effectiveness o f each cell type was 74.5 per cent for e p i d e r m o i d carcinoma, 42.1 p e r cent for a d e n o c a r c i n o m a , a n d 55.6 p e r cent for large cell carcinoma. W h e n c o m p a r i s o n s were m a d e between single drug infusions a n d two drug infusions for e p i d e r m o i d c a r c i n o m a a n d a d e n o c a r cinoma, the effective rates were 63.6 p e r cent
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Bronchial artery infusion therapy
vs. 73.3 per cent and 40.0 per cent vs. 53.8 per cent, respectively (not shown in Table 3). Although the rate of effectiveness for adenocarcinoma either by single drug infusions or two drug infusions r e m a i n e d low in comparison with that for epidermoid carcinoma, the rate was moderately improved through the combined infusion o f ADM and MMC. Three drug infusions were p e r f o r m e d in 31 cases, 14 of w h o m underwent surgical resection and histo-pathological examinations. Excluding one case o f adenosquamous cell carcinoma, no other case showed microscopical findings o f E s 0 or Ef. l a after three drug infusion. T h e rate o f effectiveness was therefore 92.9 p e r cent, or 13 o f 14 cases as a whole. T h e r e were 4 cases ofEE l b (28.6 per cent), 4 cases of El. 2 (28.6 per cent), a n d 5 cases of El. 3 (35.7 per cent). The three drug infusion o f CQ, MMC a n d ACNU for the cases with epidermoid carcinoma clearly showed a high tumoricydal effect in terms of both the clinical and histopathological effects of BAI therapy. With this infusion method, the effective rate for squamous cell carcinoma increased to 100 per cent. T h o u g h two cases (20 per cent) showed only El. l b effect, three cases (30 per cent) showed El. 2, while five cases (50 per cent) showed EE 3 effect, neither having b e e n observed with the single or two drug infusions. A case of a d e n o c a r c i n o m a showed EE lb, which resulted in a 100 per cent effective rate. O n e case each of mucoepidermoid carcinoma and adenosquamous cell carcinoma showed EE l b and '2, respectively. If we look at the survival period of the patients who underwent surgical resections after the preoperative three drug infusion, to date, there are 6 cases of long-term survival of between 18 months and 5 years, or 37 months on average. T h e cell type o f all these cases was squamous cell carcinoma and 2 o f these cases are briefly presented here. Fig. 1 is a chest X-ray film of a 65 year old male with epidermoid carcinoma. Preoperative BAI therapy using CO__.,MMC and ACNU was p e r f o r m e d twice at 8 day intervals. Fig. 2
31
Fig. 1. Chest X-ray fihn of a 65 year old male with epidermoid carcinoma in the right lower lobe.
Fig. 2. Chest X-ray fihn taken 35 days after the second bronchial arterial infusion CQ 6 rag, MMC 8 rag, and ACNU 50 rag. The patient underwent an operation 55 days after the second course of BAI therapy and histological examination of the resected specimen revealed no viable cancer cells at the tumor site. is a chest X-ray film taken 35 days after the second course o f BAI therapy, showing marked decrease o f the tumor shadow. This
32
Watanabe et al.
patient u n d e r w e n t a right lower lobectomy 55 days after the s e c o n d BAI therapy. A histo-pathological examination revealed Ef. 3 effect in which n o c a n c e r cells were seen at the t u m o r site a n d instead, the c a n c e r tissue
Fig. 3. Chest X-ray film of a 66 year old male with epidermoid carcinoma in the left hilum which caused complete atelectasis of the left lung.
Fig. 4. Bronchial arteriography, which identified a tumor in the atelectatic field. A three drug infusion of CQ, MMC and ACNU was performed.
Jpn. J. Surg. January 1990
was completely replaced by necrotic tissue. H e is alive a n d well 41 m o n t h s after the operation. Fig. 3 is a chest X-ray film o f a 66 year old male with e p i d e r m o i d c a r c i n o m a showing
Fig. 5. Chest X-ray film taken i1 days after the first course of BAI therapy. Due to tumor shrinkage, atelectasis of the left lung disappeared.
Fig. 6. Chest X-ray film taken 11 days after the second course of BALItherapy-, performed 39 days after the first course. The patient underwent a left sleeve pneumonectomy 20 days after the second course of BM therapy.
Volume 20 Number 1
Bronchial artery infusion therapy
33
Fig. 7. Microscopic views of a preoperative bronchial biopsy (left) and a resected specimen (right) in which preoperative BAI therapy caused the complete disappearance of viable cancer cells. complete atelectasis of the left lung. Fig. 4 shows a bronchial arteriography with a rumor stain within the atelectatic shadow. Three drugs were infused at the time o f arteriography. Fig. 5 is a chest X-ray film taken 11 days after BAI therapy. T h e second course of BAI therapy was done 29 days after the first course of BAI therapy. Fig. 6 is a chest X-ray film taken 11 days after the second course o f BAI therapy, indicating apparent shrinkage of the tumor shadow as a result o f the dual BAI therapy. This patient underwent left sleeve p n e u m o n e c t o m y via a median sternotomy 20 days after the second course of BAI therapy. O n examination o f the resected specimen, no viable cancer cells were found throughout the tumor site. Fig. 7 shows microscopic views of a biopsy taken before BAI therapy and the resected specimen. Following BAI therapy, the cancer cell nests were completely destroyed without any sign of viable cancer cells, and the tumor site completely replaced by necrotic tissue. These findings were compatible with El. 3. H e is alive and well 33 months after the operation. DISCUSSION The main aims of preoperative adjuvant therapy are, firstly, to improve the resectability of lung cancer invading an adjacent structure and, secondly, to p r e v e n t the hematogenous showering of cancer cells
from the operative site by surgical manipulation, both of which are facilitated by the resulting shrinkage of tumor volume. Most of the trials on the effects o f preoperative radiation as adjuvant therapy in that sense have showed negative results? ,~ In 1964, Viamonte et a12 m a d e possible, the selective b r o n c h i a l artery catheterization with the help of Seldinger's technique. T h e authors ~,7 have also b e e n using this type o f anigiography for m a n y years, while at the same time administering an intra-arterial infusion of chemotherapeutic agents as a way to treat advanced lung cancer. T h e advantages o f BAI therapy in the treatment of lung cancer are: @ it can be repeated m a n y times; @ a high density of chemotherapeutics can be infused; @ it can m i n i m i z e the side effects o f a n t i c a n c e r drugs; and @ local side effects such as inflammation, adhesion or fibrosis in the surrounding region of the lung are milder than those which a p p e a r after radiation therapy. Most o f the reported cases of BAI therapy were treated with a single drug infusion. Haller et al. 8 infused 5-fluorouracil or Thio-TEPA; K a h n eL al. 9 reported the continuous infusion of Methotrexate a n d a one shot infusion of Nitrogen mustard; Tare et al. 1~ infused Nitrogen mustard or Cyclophosphamide; and Neyazaki et al. n infused MMC. T h e results of these single drug infusions were mostly discouraging but they
34
Watanabe et al.
nevertheless clarified that BAI therapy was m u c h m o r e effective on squamous cell carc i n o m a than adenocarcinoma, and that the extent o f t u m o r shrinkage and the long-term survival rates were related to the frequency o f infusion. H From our pilot study done for the purpose of selecting the most effective drug for each cell type, epidermoid carcinoma was found to be most sensitive to CQ, an alkylating agent, 12while adenocarcinoma and large cell carcinoma were more sensitive to MMC. Before 1975, single drug infusion using these drugs was tried andl as shown in Table 2, the effect on a d e n o c a r c i n o m a was mostly poor. To improve the rate of effectiveness on each cell type, especially adenocarcinoma, two drug infusion was started in 1975, after which the rates were moderately improved. Moreover, the short-term effects o f radiological shrinkage o f the tumor, an i m p r o v e m e n t in the resectability rate o f advanced cases and histo-pathological effects were m u c h improved using two drug infusion. However, the effects o n the long-term survival rate o f patients undergoing surgical resections remained obscure because of the retrospective comparison of cases who had u n d e r g o n e BAI therapy preoperatively a n d those who h a d not? These results are in accordance with those of other authors 13,14 and as a result, this treatment modality as a preoperative adjuvant therapy was once abandoned, even by us. In 1983, we started using three drug combination BAI therapy by adding ACNU, an alkylating agent, to the other two drugs for the purpose o f reappraising BAI therapy. T h e reason why we selected ACNU was that this d r u g h a d a marked effect on squamous cell carcinoma in the pilot study of the single infusion of this agent. In fact, with three drug infusion, the clinical as well as histo-pathological effects were most obvious in cases with squamous cell carcinoma. With three drug infusion, 15 of the 16 cases showed a significant shrinkage of the tumor as demonstrated by chest X-ray films. Furthermore, on
Jpn. J. Surg. January 1990
examination o f the resected specimens, it was clarified that all of the cases showed histological changes o f greater than Ef. 2. O f special note is the fact that there were five patients with Ef. 3 changes in which no viable cancer cells n o r even a ghost o f a cancer cell could be observed. Such highly effective r e s p o n s e rates a n d h i g h - g r a d e changes were n e v e r observed with the single or two drug infusion methods. C o n c e r n i n g the effects on other cell types, this could not be clarified because of the small n u m b e r o f patients with other cell types, partly due to the fact that the incidence of a d e n o c a r c i n o m a and large cell carcinoma in the hilar region is not so frequent in comparison with squamous cell carcinoma. By using three drug infusion, the clinical as well as the histo-pathological effects of BAI therapy were m u c h improved. However, greater improvements in b o t h the short-term a n d long-term effects, or the prolongation of survival period can be expected with the help of new anticancer drugs which have b e e n designated as effective for the treatment of lung cancer in systemic use. We have started combination infusions of an immunotherapeutic agent with anticancer drugs following observation of the favourable effects of systemic i m m u n o c h e m o t h e r a p y on lung cancer. 1~-17 Furthermore, we have clearly conducted a pilot study on adoptive immunotherapy via a bronchial artery by an infusion of a lymphokine activated killer (LAK) cells incubated in vitro. We are now employing such multi-modality BAI therapy as neoadjuvant) ~ or preoperative therapy for the surgical resection of stage I I I A and I I I B lung cancers. Thus, various infusions t h r o u g h the b r o n c h i a l arteries should be reappraised, for they can be used in m a n y ways, a n d achieve favorable effects on advanced lung cancer. (Received for publication on Jan. 24, 1989)
Volume 20 Number I
Bronchial artery infusion therapy
REFERENCES 1. Watanabe Y, Yamada T, Ichihashi T, Hashizume Y, Iwa T. Surgical adjuvant therapy for non-small cell lung cancer. Gan to Kagakuryoho (Jap J Cancer Chemother) 1986; 13 (part II): 1534-1546. (English Abst.) 2. Komori Y, Yamada T, Funaki Y, Watanabe Y, Iwa T. Effect of intra-arterial chemotherapy in lung cancer. Gan no Rinsho r Cancer Clin) 1978; 24: 1191-1196. (English Abst.) 3. Collaborative study. Preoperative irradiation of cancer of the lung. Cancer 1975; 36: 914-925. 4. Shields TW, Higgins GA, Lawton R, Lawton R, Heilbrunn A, Keehn RJ. Preoperative X-ray therapy as an adjuvant in the treatment of bronchogenic carcinoma. J Thorac Cardiovasc Surg 1970; 59: 49-61. 5. Viamonte M Jr. Selective bronchial arteriography in man. Preliminary report. Radiology 1964; 83: 830-839. 6, Watanahe Y, Nagai A, Oohashi Y, Yoshida C, Kuroda Y, Bando T. Selective bronchial arteriography for the study of the effect of radiation therapy on tumor vessels of bronchogenic carcinoma. Nihon Kyobu Rinsho (.lap J Chest Clin) 1973; 27: 671-681. (English Abst.) 7. Watanahe Y, Iwa T, Fukatani G, Kuroda Y, Oohashi Y, Yoshida C, Kihara K, Mori A, Sato H, Komori Y. Clinical evaluation of bronchial arteriography for lung disease. Nihon Kyobu Rinsho (Jap J Chest Clin) 1976; 35: 917-922. (English Abst.) 8. HallerJD, Bron KM, Wholey MH, Poller S, Enerson DM. Selective bronchial artery catheterization for diagnostic and physiologic studies and chemotherapy for bronchogenic carcinoma. J Thorac Cardiovasc Surg 1966; 51: 143-152. 9. Kahn PC, Paul RE, Rheinlander HF. Selective bronchial arteriography and intra-arterial chemotherapy in carcinoma of the lung. J Thorac Car-
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diovasc Surg 1965; 50: 640-647. 10. Tate CF Jr, Viamonte M Jr, AgnewJR. Bronchial arterial perfusion with cytotoxic agents for bronchogenic carcinoma. Preliminary report. Amer Rev Resp Dis 1968; 97: 685-693. 11. Neyazaki T, Ikeda M, Seki Y, Egawa N, Suzuki C. Bronchial artery infusion therapy for lung cancer. Cancer 1969; 24: 912-922. 12. Watanahe Y, Kuroda Y, Sato H, lwa T. Clinical evaluation of Carboquone for treatment of lung cancer with special reference to its effect by bronchial arterial infusion. Gan to Kagakuryoho (JapJ Cancer Chemother) 1976; 3: 85-91. (English Ahst.) 13. Neyazaki T, Hashimoto K, Nakada T, Suzuki C. Long-term results of preoperative bronchial arterial infusion therapy for lung cancer. Kyobu Geka (lap J Thorac Surg) 1975; 28: 838-843. (English Abst.) 14. Ogawa S, Ishihara T, Kikuchi K, Inoue K, Fukai S, Takanami I, Busi A, Ikeda T. Broiachial arterial infusion therapy for inoperable bronchogenic carcinoma, Kyobu Geka (JapJ Thor~/c Surg) 1977; 30: 640-645. (English Ahst.) 15. Watanabe Y, Iwa T. Clinical value of immunotherapy by streptococcal preparation, OK-432, as an adjuvant for lung cancer. Cancer 1984; 53: 248253. 16. Watanabe Y, Iwa T. Immunotberapy of lung cancer: A randomized clinical trial of OK-432 immunotherapy and a review of the literature on nonspecific immunotherapy. Internat J Immunother 1986; 2: 51-67. 17. Watanabe Y, Iwa T. Clinical value of immunotherapy with the Streptococcal preparation OK-432 in non-small cell lung cancer. J Biol Response Modif 1987; 6:169=180 18. Einhorn LH. Neoadjuvant therapy of stage IlI nonsmall cell lung cancer. Ann Thorac Surg 1988; 46: 362-365.
