INT. J. HYPERTHERMIA,
1990,
VOL.
6,
NO.
6, 963-969
Effectiveness of intrathoracic chemothermotherapy for malignant pleurisy due to Ewing’s sarcoma: a case report 0. DOIT, K. KODAMAt, M. TATSUTAt, M. HIGASHIYAMAT, Y. AOKI$§, K. KURIYAMAS and R. TATEISHIS
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
Departments of ?Thoracic Surgery, $.Orthopedics and Diagnostic Radiology, and gpathology, Center for Adult Diseases, Osaka, Japan (Received 11 December 1989; revision received 2 February 1990;accepted 5 February
I 9w) This paper describes a case of malignant pleurisy which showed evidence of the effectiveness of a new mode of cancer treatment, intrathoracic chemothermotherapy (ICT). ICT consisted of a bolus intrathoracic injection of 50 mg cisdiamminedichloroplatinum (CDDP) and local heating using 8 MHz radiofrequency waves for 60 min. A patient with multiple lung metastases and malignant pleurisy on both sides due to Ewing’s sanxma was treated on the right side with ICT, along with concomitant systemic .. admmstmtion of 50 mg CDDP. Intrathoracictemperatureswere monitored by insertion of thermocouple temprature sensors,and temperatures of 43°C or over were successfully maintained for about 40 min during each of three treatments. Although the patient died 3 months later of advanced metastases in the left lung and malignant pleurisy on the left side, lung metastases in the right lung were stable on radiographs, and autopsy results showed no cancerous lesions in the right thoracic cavity, which had been treated with ICT. Since no effective response had been obtained clinically or histologically before starting ICT, despite frequent administration of anti-cancer drugs, we conclude that heat acted synergistically with CDDP on drug-resistant cells in this case. Key words: hyperthermia, malignant pleurisy, Ewing’s sarcoma.
1. Introduction Malignant pleurisy often develops in patients with lung or breast cancer as the end stage of the disease (Martini et al. 1975, Chernow and Sahn 1977). Large quantities of effusion cause cardiorespiratory insufficiency and malnutrition, thus hastening the death of the patient. The average survival period of such patients is 6 months or less. Treatment usually consists of drainage of pleural effusions with or without drug instillation and, occasionally, surgical resection of the pleura (Martini et al. 1975). However, none of these measures is sufficiently effective (Chernow and Sahn 1977). It is known that heat potentiates the effect of anti-cancer agents in vitro (Barlogie et al. 1980, Murthy eta’. 1985, Wallner and Li 1987, Cohen and Robins 1987) and in animals (Marmor 1979), and considerable clinical success has been achieved not only in patients with superficial cancer (Kim et al. 1982, Scott et al. 1983) but also in those with deepseated cancer (Abeer ul. 1986, Hiraoka et al. 1987). Recently we reported the development of an extremely effective treatment for local control of malignant pleurisy due to lung cancer, namely intrathoracic chemothemotherapy (ICT) (Kodama et al. 1989). Here we report the excellent local response to ICT in the treatment of a patient with malignant pleurisy due to Ewinig’s sarcoma.
Address correspondence to: Osamu Doi, MD, Department of Thoracic Surgery, The Center for Adult Diseases, 3 Nakiunichi, 1-chome, Higashinari-ku, Osaka 537, Japan. 0256-6736/90$3.00 01990 Taylor & Francis Ltd.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
964
0. Doi et al.
2. Casereport The patient, a 19-year-old female, was admitted to our hospital in December 1986 with the complaint of weight loss and a mass in the right hip. Palpation revealed a well demarcated osseous tumour 20 cm X 15 cm in diameter in the right hip; loss of sensation and muscular weakness in the L3-S3 region of the right leg were also noted. Chest radiographs disclosed multiple metastases in both lung fields. Bone scans using %Tclabelled phosphate showed radioactivity in the right ilium, the left humerus and the cranium. CT scans of the lower abdomen revealed destruction of the ilium and sacrum by tumours. The hip mass was biopsied and diagnosed as Ewing’s sarcoma. The patient was given two treatments of intra-arterial chemotherapy, each consisting of 125 mg of cis-diamminedichloroplatinum(CDDP) and 60 mg of adriamycin (ADR), administered through the right lumbar artery and the right internal iliac artery, in addition to systemic chemotherapy which included ADR (80 mg), methotrexate (MTX) (90 mg), vindesin (VDS) (6 mg), and ifomide (2 g). After this course of therapy the patient underwent surgery in March 1987 for resection of the right ilium and the L4,5, S1-3 vertebral arches and centrum, and skin flap transplantation. The histological findings of the resected lesions revealed no significant response to the drugs, such as degeneration of tumour cells or necrosis. The patient then received systemic chemotherapy intermittently until February 1988. The total amounts of chemotherapeuticagents given post-operatively are as follows: ADR, 200 mg; aclarubicin (ACR), 120 mg; VDS, 33 mg; MTX, 2300 mg; ifomide, 17 g; peplomycin, 150 mg; and actinomycin D (ACT-D), 5 mg. During this period the primary lesion was well controlled, but the lung metastases gradually grew larger. The patient started expectorating large quantities of blood. Chest radiographs taken at this time showed a tumour 7 cm x6 cm in the right middle lobe (Figure 1). Bronchoscopic findings confirmed haemorrhaging of the bronchus of the middle lobe.
Figure 1. Re-operative chest radiograph showing multiple metastases and a large mass in the right middle lobe.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
Intrathoracic chenwthennotherapy for malignant pleurisy
965
In an attempt to relieve the patient’s symptoms a right thoracotomy by median incision of the sternum was performed on 1 March 1988. In addition to multiple lung metastases, numerous lesions were found on the surfaces of the p u l m o ~ r yand parietal pleura, and the diaphragm, with a small amount of haemorrhagic pleural effusion. Lobectomy of the middle lobe was pefiormed, and two porous silicon tubes were put into the anterior and posterior spaces of the right thoracic cavity. ICT was performed a total of three times at 1-week intervals starting in the second week after surgery. A bolus of 50 mg of CDDP was infused into the pleural cavity through the two silicon tubes. Immediately thereafter, radiofrequency heating using 8 -00MHz (Thermotron RF 8) was applied to the right chest wall for 60 min with a pair of electrodes (25 cm in diameter). A temperature-controlled bolus (overlay bolus) was placed between the electrode and the skin to avoid excessive heating of the subcutaneousfat. Proper surface cooling was achieved by a bolus temperature of 10-15°C. During each treatment, intrathoracic temperatures were monitored by inserting a thermocouple temperature sensor into each of the above-mentioned tubes. No significant difference of temperatures was found between the two sensors. Temperatures of 43°C or over could be maintained for about 40 min at an output power of 800 W without difficulty (Figure 2). Systemic administration of 50 mg of CDDP by drip infusion was performed during this period. After completion of the therapy the CDDP was removed as completely as possible from the pleural cavity to minimize CDDP toxicity. There were no side-effects which interfered with the completion of the therapy, such as pain, dyspnoea, palpitation or nephrotoxicity. Post-lherapy chest radiographs showed almost no increase in the size of the lung metastases and no accumulation of pleural effusion on the right, in contrast to continued growth of the lesions and substantial accumulation of pleural effusion on the left (Figure 3). Three months later the patient died of respiratory insufficiency. Autopsy findings revealed apparently viable metastases in both lungs. However, though the pleural dissemination in the left thoracic cavity was extensive, that in the right thoracic cavity GRAPHIC DISPLAY
PAT1:ENT NN.
g 1500
-a
5
ID NO. : 1008-501
300
600
DATE 1988/03/14 1200
900
1200
600
300 50 h
.v U
48
34
10
20
30
40
50
60
70
80
TIME (MIN.)
Figure 2. Intrathoracic temperature curves. Temperatures of 43°C or over were maintained for about 4 0 min at an output power of 800 W. * Skin temperature.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
966
0. Doi et al.
Figure 3. (a) Post-operative chest radiograph. Two silicon tubes were left in place in the right thoracic cavity (arrows); @) chest. radiograph at 1 month after ICT; (c) chest radiograph just before the patient’s death. had almost completely disappeared and the previously damaged tissue had been replaced by smooth pleura (Figure 4). 3. Discussion Recently, dramatic advances have been made in the treatment of Ewing’s sarcoma (Jurgens el al. 1988, Rosen 1988, Bacci er al. 1989), largely due to the development of effective chemotherapy, but survival after the development of metastases remains poor (Rosen 1988). In the case described here, the patient had multiple pulmonary and bone metastases at the time of diagnosis. Despite frequent treatment with anti-cancer drugs the metastases continued to grow, and malignant pleurisy was found on thoracotomy. It has been well documented that heat potentiates the effects of certain kinds of anticancer drugs. Recently, radiofrequency (RF) waves have been used not only for the treatment of superficial tumours (Kim er al. 1982) but also for that of deep-seated tumours (Abe er ul. 1986, Hiraoka et al. 1987). In general it has been considered difficult to obtain sufficiently high temperatures in the lungs or air-containing body spaces to achieve
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
Intratlioracic chemothemtherapy for malignant pleurisy
967
Figure 4. Photograph of the thoracic cavity at autopsy showing smooth pleura on the right side in contrast to the bulky mass in the lefi side. therapeutic results with RF hyperthermia because of wave distortion and the cooling effect of respiration and circulation. However, we assumed that in the vicinity of the pleura, consisting of the border between the chest wall and the lung, heat might accumulate as a result of the wave distortions, producing a so-called ‘hot spot’. This theory was supported by our experience with precise measurement of the temperature in patients treated with ICT (Kodama et al. 1!389). In the case described here, intracavitary temperatures of 43°C or over were also easily and safely achieved using RF heating. No severe side-effects were found. Autopsy findings confirmed that lesions disseminated throughout the right pleura had almost completdy disappeared. Wallner et al. (1986) reported that heat acts synergistically with CDDP on CDDP-resistant cells in vitro. Although our patient had received two treatments with intra-arterial chemotherapy, each consisting of 125 mg of CDDP and 60 mg of ADR, no response to the drugs was found on histological examination of the resected material. Thus we conclude that the disappearance of pleural lesions in the right side treated by chemothermotherapy is attributable not just to the direct contact of a high concentration of CDDP with the malignant cells, but to the combination of the direct antitumour effect of heat and the heat-potentiated effect of CDDP. The effectiveness of hyperthermia is further attested by the following fact in the case described here. At autopsy, apparently viable cancer cells were found in the pulmonary metastases in both lungs. Chest radiographs taken throughout the patient’s clinical course showed enlargement of the metastases of the untreated left side despite systemic treatment with CDDP, in contrast to the nearly stable condition of the treated right side. The effect of ICT was not great enough to shrink the lesions, probably because of the moderate amounts of anti-cancer drugs given and because of the greater difficulty in achieving effective heating of intrapulmonary lesioris compared with intrathoracic lesions. Nevertheless, these results indicate that the cell cycle of the cancer cells was disrupted by ICT, thus inhibiting their growth. As an intracavitary heating method, perfusion with warm water is used in cancer of
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
968
0. Doi et al.
the bladder (Hall et al. 1974, Kubota e f al. 1984). Recently this method has also been used for the treatment of peritoneal dissemination in stomach cancer (Koga et al. 1988, Fujimoto et al. 1988). However, warm-water perfusion may be inferior to RF heating in several respects: complexity of procedure, leakage of protein, dilution of drugs, and inability to heat adhered parts and the deeper parts of the cavity. The entire thoracic cavity cannot be heated simultaneouslywith RF heat applied to the body surface, but approximately uniform intrathoracic temperatures can be achieved by the dissemination of the introduced heated anti-cancer solution via respiratory movement during the treatment. Furthermore, overheating of fatty tissue near the surface of the body can be reduced considerably by precooling using a temperature-controlled bolus (overlay bolus). In conclusion, the excellent local response obtained in the case described here suggests a potential role for ICT in the treatment of malignant pleurisy due to tumours other than Ewing’s sarcoma as well.
Acknowledgement This work was supported in part by a Grant-in-Aid for Cancer Research (62-2) from the Ministry of Health and Welfare. References ABE, M., HIRAOKA,M., TAKAHASHI, M., EGAWA, S., MATUSDA,C., ONOYAMA, Y., MORITA,
K., KAKEHI,M., and SUGAHARA, T., 1986, Multi-institutionalstudies on hyperthermia using an 8-MHz radiofrequency capacitive heating device (Thermotron RF-8) in combination with radiation for cancer therapy. Cancer, 58, 1589-1595. BACCI,G., TONI,A., AVELLA,M., MANFRINI,M., SUDANESE, A., CIARONI,D., BORIANI,S . , EMILIANI, E., and CAMPANACCI, M., 1989, Long-term results in 144 localized Ewing’s sarcoma patients treated with combined therapy. Cancer, 63, 1477-1486. BARLOGIE, B., CORRY,P. M., and DREWINKO, B., 1980, In vitro thermochemotherapy of human colon cancer cells with cisdichlorodiammineplatinum(n) and mytomycin C. Cancer Research, 40, 1165-1 168. CHERNOW,B., and SAHN, S . A., 1977, Carcinomatous involvement of the pleura: an analysis of 96 patients. American Journal of Medicine, 63, 695-702. COHEN, J. D., and ROBINS, H. I., 1987, Hyperthermic enhancement of cis-diammine-1, l-cyclobutane dicarboxylateplatinum(n) cytotoxicity in human leukemia cells in vitro. Cancer Research, 47, 4335-4337. FUJIMOTO, S., SHRESTHA,R. D., KOKUBUN, M., OHTA, M., TAKAHASHI, M., KOBAYASHI, K., KIUCHI, S., OKUI, K., MIYOSHI, T., ARIMIZU,N., and TAKAMIZAWA, H., 1988, Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding. Annals of Surgery, 208, 36-41. HALL,R. R., SCHADE,R. O., and SWINNEY, J., 1974, Effects of hyperthermia on bladder cancer. British Medical Journal, 2, 593-594. HIRAOKA,M., Jo, S., AKUTA,K., NISHIMURA,Y., TAKAHASHI, M., and ABE, M., 1987, Radiofrequency capacitive hyperthermia for deep-seated tumors: effects of thennoradiotherapy. Cancer, 60, 128-135. JURGENS,H., EXNER,U., GADNER,H.,HARMS,D., MICHAELIS, J., SAUER,R., TREUNER, J., V O ~ T.,, WINKELMANN, W., WINKLER,K., and GOBEL, U., 1988, Multidisciplinary treatment of primary Ewing’s sarcoma of bone. Cancer, 61, 23-32. KIM, J. H., HAHN,E. W., and ANTICH,P. P., 1982, Radiofrequency hyperthermia for clinical cancer therapy. National Cancer Institute Monograph, 61, 339-342. KODAMA,K.,DOI, O., TATUTA,M., KURIYAMA, K., and TATEISHI,R., 1989, Development of postoperative intrathoracic chemothermotherapy for lung cancer with objective of improving local cure. Cancer, 64, 1422-1428. KOGA,S., HAMAZOE, R., MAETA,M., SHIMIZU,N., MURAKAMI, A., and WAKATSUKI, T., 1988, Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C. Cancer, 61, 232-237. KUBOTA,Y.,SHUIN,T., MIURA,T., NISHIMURA,R., FUKUSHIMA, S., and TAKAI,S., 1984, Treatment of bladder cancer with a combination of hyperthermia, radiation and bleomycin. Cancer, 53, 199-202.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
Intrathoracic chemothennotherapyfor malignant pleurisy
969
MARMOR,J. B., 1979, Interactions of hyperthermia and chemotherapy in animals. Cancer Research, 39, 2269-2276. MARTINI,N . , BAINS, M. S., and BEATTIE,E. J., 1975, Indications for pleurectomy in malignant effusion. Cancer. 35, 734-738. Mmm, M.S., TRAVIS, J. D . , ERICKSON, L. C., KHANDEKAR,J. D . , and SCANLON, E. F., 1985, Combined effect of transdiamminedichloroplatinum(n) and hyperthennia on murine and human tumor cells. Cancer Research, 45, 6232-6237. ROSEN,G., 1988, The current management of malignant bone tumors: where do we go from here? Medical Journal of Australia, 148, 373-377. SCOTT,R. S., JOHNSON,R., KOWAL,H., KrUsHNAMsnn, R. M., STORY, K., and CLAY,L., 1983, Hyperthermia in combination with radiotherapy: a review of five years experience in the treatment of supei-ficialtumors. International J o u m l of Radiation Oncology, Biology, Physics, 9, 1327-1333. WALLNER, K. E., and LI, G. C., 1987, Effect of drug exposure duration and sequencing on hyperthermic polentiation of mytomycin C and cisplatin. Cancer Research, 47, 493-495. WALLNER,K. E., DEGREGORIO,M. W., and Lr, G. C., 1986, Hyperthemic potentiation of cisdiammindchloroplatinum@) cytotoxkity in Chinese hamster ovary cells resistant to the drug. Cancer Research, 46, 6242-6245.
1990,
VOL.
6,
NO.
6, 963-969
Effectiveness of intrathoracic chemothermotherapy for malignant pleurisy due to Ewing’s sarcoma: a case report 0. DOIT, K. KODAMAt, M. TATSUTAt, M. HIGASHIYAMAT, Y. AOKI$§, K. KURIYAMAS and R. TATEISHIS
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
Departments of ?Thoracic Surgery, $.Orthopedics and Diagnostic Radiology, and gpathology, Center for Adult Diseases, Osaka, Japan (Received 11 December 1989; revision received 2 February 1990;accepted 5 February
I 9w) This paper describes a case of malignant pleurisy which showed evidence of the effectiveness of a new mode of cancer treatment, intrathoracic chemothermotherapy (ICT). ICT consisted of a bolus intrathoracic injection of 50 mg cisdiamminedichloroplatinum (CDDP) and local heating using 8 MHz radiofrequency waves for 60 min. A patient with multiple lung metastases and malignant pleurisy on both sides due to Ewing’s sanxma was treated on the right side with ICT, along with concomitant systemic .. admmstmtion of 50 mg CDDP. Intrathoracictemperatureswere monitored by insertion of thermocouple temprature sensors,and temperatures of 43°C or over were successfully maintained for about 40 min during each of three treatments. Although the patient died 3 months later of advanced metastases in the left lung and malignant pleurisy on the left side, lung metastases in the right lung were stable on radiographs, and autopsy results showed no cancerous lesions in the right thoracic cavity, which had been treated with ICT. Since no effective response had been obtained clinically or histologically before starting ICT, despite frequent administration of anti-cancer drugs, we conclude that heat acted synergistically with CDDP on drug-resistant cells in this case. Key words: hyperthermia, malignant pleurisy, Ewing’s sarcoma.
1. Introduction Malignant pleurisy often develops in patients with lung or breast cancer as the end stage of the disease (Martini et al. 1975, Chernow and Sahn 1977). Large quantities of effusion cause cardiorespiratory insufficiency and malnutrition, thus hastening the death of the patient. The average survival period of such patients is 6 months or less. Treatment usually consists of drainage of pleural effusions with or without drug instillation and, occasionally, surgical resection of the pleura (Martini et al. 1975). However, none of these measures is sufficiently effective (Chernow and Sahn 1977). It is known that heat potentiates the effect of anti-cancer agents in vitro (Barlogie et al. 1980, Murthy eta’. 1985, Wallner and Li 1987, Cohen and Robins 1987) and in animals (Marmor 1979), and considerable clinical success has been achieved not only in patients with superficial cancer (Kim et al. 1982, Scott et al. 1983) but also in those with deepseated cancer (Abeer ul. 1986, Hiraoka et al. 1987). Recently we reported the development of an extremely effective treatment for local control of malignant pleurisy due to lung cancer, namely intrathoracic chemothemotherapy (ICT) (Kodama et al. 1989). Here we report the excellent local response to ICT in the treatment of a patient with malignant pleurisy due to Ewinig’s sarcoma.
Address correspondence to: Osamu Doi, MD, Department of Thoracic Surgery, The Center for Adult Diseases, 3 Nakiunichi, 1-chome, Higashinari-ku, Osaka 537, Japan. 0256-6736/90$3.00 01990 Taylor & Francis Ltd.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
964
0. Doi et al.
2. Casereport The patient, a 19-year-old female, was admitted to our hospital in December 1986 with the complaint of weight loss and a mass in the right hip. Palpation revealed a well demarcated osseous tumour 20 cm X 15 cm in diameter in the right hip; loss of sensation and muscular weakness in the L3-S3 region of the right leg were also noted. Chest radiographs disclosed multiple metastases in both lung fields. Bone scans using %Tclabelled phosphate showed radioactivity in the right ilium, the left humerus and the cranium. CT scans of the lower abdomen revealed destruction of the ilium and sacrum by tumours. The hip mass was biopsied and diagnosed as Ewing’s sarcoma. The patient was given two treatments of intra-arterial chemotherapy, each consisting of 125 mg of cis-diamminedichloroplatinum(CDDP) and 60 mg of adriamycin (ADR), administered through the right lumbar artery and the right internal iliac artery, in addition to systemic chemotherapy which included ADR (80 mg), methotrexate (MTX) (90 mg), vindesin (VDS) (6 mg), and ifomide (2 g). After this course of therapy the patient underwent surgery in March 1987 for resection of the right ilium and the L4,5, S1-3 vertebral arches and centrum, and skin flap transplantation. The histological findings of the resected lesions revealed no significant response to the drugs, such as degeneration of tumour cells or necrosis. The patient then received systemic chemotherapy intermittently until February 1988. The total amounts of chemotherapeuticagents given post-operatively are as follows: ADR, 200 mg; aclarubicin (ACR), 120 mg; VDS, 33 mg; MTX, 2300 mg; ifomide, 17 g; peplomycin, 150 mg; and actinomycin D (ACT-D), 5 mg. During this period the primary lesion was well controlled, but the lung metastases gradually grew larger. The patient started expectorating large quantities of blood. Chest radiographs taken at this time showed a tumour 7 cm x6 cm in the right middle lobe (Figure 1). Bronchoscopic findings confirmed haemorrhaging of the bronchus of the middle lobe.
Figure 1. Re-operative chest radiograph showing multiple metastases and a large mass in the right middle lobe.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
Intrathoracic chenwthennotherapy for malignant pleurisy
965
In an attempt to relieve the patient’s symptoms a right thoracotomy by median incision of the sternum was performed on 1 March 1988. In addition to multiple lung metastases, numerous lesions were found on the surfaces of the p u l m o ~ r yand parietal pleura, and the diaphragm, with a small amount of haemorrhagic pleural effusion. Lobectomy of the middle lobe was pefiormed, and two porous silicon tubes were put into the anterior and posterior spaces of the right thoracic cavity. ICT was performed a total of three times at 1-week intervals starting in the second week after surgery. A bolus of 50 mg of CDDP was infused into the pleural cavity through the two silicon tubes. Immediately thereafter, radiofrequency heating using 8 -00MHz (Thermotron RF 8) was applied to the right chest wall for 60 min with a pair of electrodes (25 cm in diameter). A temperature-controlled bolus (overlay bolus) was placed between the electrode and the skin to avoid excessive heating of the subcutaneousfat. Proper surface cooling was achieved by a bolus temperature of 10-15°C. During each treatment, intrathoracic temperatures were monitored by inserting a thermocouple temperature sensor into each of the above-mentioned tubes. No significant difference of temperatures was found between the two sensors. Temperatures of 43°C or over could be maintained for about 40 min at an output power of 800 W without difficulty (Figure 2). Systemic administration of 50 mg of CDDP by drip infusion was performed during this period. After completion of the therapy the CDDP was removed as completely as possible from the pleural cavity to minimize CDDP toxicity. There were no side-effects which interfered with the completion of the therapy, such as pain, dyspnoea, palpitation or nephrotoxicity. Post-lherapy chest radiographs showed almost no increase in the size of the lung metastases and no accumulation of pleural effusion on the right, in contrast to continued growth of the lesions and substantial accumulation of pleural effusion on the left (Figure 3). Three months later the patient died of respiratory insufficiency. Autopsy findings revealed apparently viable metastases in both lungs. However, though the pleural dissemination in the left thoracic cavity was extensive, that in the right thoracic cavity GRAPHIC DISPLAY
PAT1:ENT NN.
g 1500
-a
5
ID NO. : 1008-501
300
600
DATE 1988/03/14 1200
900
1200
600
300 50 h
.v U
48
34
10
20
30
40
50
60
70
80
TIME (MIN.)
Figure 2. Intrathoracic temperature curves. Temperatures of 43°C or over were maintained for about 4 0 min at an output power of 800 W. * Skin temperature.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
966
0. Doi et al.
Figure 3. (a) Post-operative chest radiograph. Two silicon tubes were left in place in the right thoracic cavity (arrows); @) chest. radiograph at 1 month after ICT; (c) chest radiograph just before the patient’s death. had almost completely disappeared and the previously damaged tissue had been replaced by smooth pleura (Figure 4). 3. Discussion Recently, dramatic advances have been made in the treatment of Ewing’s sarcoma (Jurgens el al. 1988, Rosen 1988, Bacci er al. 1989), largely due to the development of effective chemotherapy, but survival after the development of metastases remains poor (Rosen 1988). In the case described here, the patient had multiple pulmonary and bone metastases at the time of diagnosis. Despite frequent treatment with anti-cancer drugs the metastases continued to grow, and malignant pleurisy was found on thoracotomy. It has been well documented that heat potentiates the effects of certain kinds of anticancer drugs. Recently, radiofrequency (RF) waves have been used not only for the treatment of superficial tumours (Kim er al. 1982) but also for that of deep-seated tumours (Abe er ul. 1986, Hiraoka et al. 1987). In general it has been considered difficult to obtain sufficiently high temperatures in the lungs or air-containing body spaces to achieve
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
Intratlioracic chemothemtherapy for malignant pleurisy
967
Figure 4. Photograph of the thoracic cavity at autopsy showing smooth pleura on the right side in contrast to the bulky mass in the lefi side. therapeutic results with RF hyperthermia because of wave distortion and the cooling effect of respiration and circulation. However, we assumed that in the vicinity of the pleura, consisting of the border between the chest wall and the lung, heat might accumulate as a result of the wave distortions, producing a so-called ‘hot spot’. This theory was supported by our experience with precise measurement of the temperature in patients treated with ICT (Kodama et al. 1!389). In the case described here, intracavitary temperatures of 43°C or over were also easily and safely achieved using RF heating. No severe side-effects were found. Autopsy findings confirmed that lesions disseminated throughout the right pleura had almost completdy disappeared. Wallner et al. (1986) reported that heat acts synergistically with CDDP on CDDP-resistant cells in vitro. Although our patient had received two treatments with intra-arterial chemotherapy, each consisting of 125 mg of CDDP and 60 mg of ADR, no response to the drugs was found on histological examination of the resected material. Thus we conclude that the disappearance of pleural lesions in the right side treated by chemothermotherapy is attributable not just to the direct contact of a high concentration of CDDP with the malignant cells, but to the combination of the direct antitumour effect of heat and the heat-potentiated effect of CDDP. The effectiveness of hyperthermia is further attested by the following fact in the case described here. At autopsy, apparently viable cancer cells were found in the pulmonary metastases in both lungs. Chest radiographs taken throughout the patient’s clinical course showed enlargement of the metastases of the untreated left side despite systemic treatment with CDDP, in contrast to the nearly stable condition of the treated right side. The effect of ICT was not great enough to shrink the lesions, probably because of the moderate amounts of anti-cancer drugs given and because of the greater difficulty in achieving effective heating of intrapulmonary lesioris compared with intrathoracic lesions. Nevertheless, these results indicate that the cell cycle of the cancer cells was disrupted by ICT, thus inhibiting their growth. As an intracavitary heating method, perfusion with warm water is used in cancer of
Int J Hyperthermia Downloaded from informahealthcare.com by University of Toronto on 01/13/15 For personal use only.
968
0. Doi et al.
the bladder (Hall et al. 1974, Kubota e f al. 1984). Recently this method has also been used for the treatment of peritoneal dissemination in stomach cancer (Koga et al. 1988, Fujimoto et al. 1988). However, warm-water perfusion may be inferior to RF heating in several respects: complexity of procedure, leakage of protein, dilution of drugs, and inability to heat adhered parts and the deeper parts of the cavity. The entire thoracic cavity cannot be heated simultaneouslywith RF heat applied to the body surface, but approximately uniform intrathoracic temperatures can be achieved by the dissemination of the introduced heated anti-cancer solution via respiratory movement during the treatment. Furthermore, overheating of fatty tissue near the surface of the body can be reduced considerably by precooling using a temperature-controlled bolus (overlay bolus). In conclusion, the excellent local response obtained in the case described here suggests a potential role for ICT in the treatment of malignant pleurisy due to tumours other than Ewing’s sarcoma as well.
Acknowledgement This work was supported in part by a Grant-in-Aid for Cancer Research (62-2) from the Ministry of Health and Welfare. References ABE, M., HIRAOKA,M., TAKAHASHI, M., EGAWA, S., MATUSDA,C., ONOYAMA, Y., MORITA,
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