British Journal of Radiology 74 (2001),709-714 © 2001 The British Institute of Radiology
Therapeutic effects of simultaneous intraluminal irradiation and intraluminal hyperthermia on oesophageal carcinoma
N Fuwa, MD
1
Y Nomoto, MD
2
K Shouji, MD
2
T Kodaira, MD
1
M Kamata, MD
1 and
Y Ito, MD
1
1Department of Radiation Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusaku, Nagoya 464-0021 and 2Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan
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Abstract
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An applicator enabling simultaneous intraluminal radiotherapy and intraluminal hyperthermia delivery was developed to improve the treatment results for locally advanced oesophageal carcinoma. Eight inoperable cases were treated by this method. Six cases received 40 Gy external irradiation followed by simultaneous intraluminal hyperthermia and radiotherapy (3 Gy and 4 Gy in three cases each) once weekly for 3 weeks; the remaining two cases received 50 Gy external irradiation followed by simultaneous intraluminal hyperthermia and radiotherapy (4 Gy) once weekly for 2 weeks. Hyperthermia was delivered by a radiofrequency current thermotherapy instrument for 30 min at an output that raised the oesophageal mucosal surface temperature to 42–43 °C. Intraluminal radiotherapy was delivered with a microSelectron to a submucosal depth of 5 mm after the first 15 min of hyperthermia. Four cases achieved complete response, with all demonstrating local control. Partial response was obtained in four cases, and three of these patients died of local recurrence. There were no significant adverse side effects apart from fistula in one case. In conclusion, simultaneous intraluminal radiotherapy and hyperthermia may improve the current treatment results for locally advanced oesophageal carcinoma.
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Introduction
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Combined external and intraluminal radiotherapy has been reported to yield good results for early oesophageal carcinoma [1–4], however the treatment results in locally advanced oesophageal carcinoma have been unsatisfactory [1, 5]. The radiation dose reaching the deep submucosal area with intraluminal radiotherapy is greatly reduced compared with that at the oesophageal mucosal surface. In locally advanced oesophageal carcinoma, a radiation dose adequate for tumour control cannot be achieved throughout the whole tumour.
To improve the treatment results of locally advanced oesophageal carcinoma, Sugimachi andcolleagues [6–10] used intraluminal radiofrequency current (RFC) hyperthermia in addition to external irradiation and chemotherapy to treat inoperable cases and reported good therapeutic results. Compared with microwave hyperthermia, RFC hyperthermia has a superior tissue penetrating ability and may be useful in improving the treatment results for locally advanced cases.
Combined radiotherapy and hyperthermia achieve the maximal anti-tumour effect when delivered simultaneously [11–13], however there are many technical problems regarding simultaneous delivery of radiotherapy and hyperthermia, and this method has only been evaluated in a limited number of clinical cases [14–18].
To improve further the results of treatment for locally advanced oesophageal cancer, we devised an applicator that simultaneously delivered an intraluminal high dose of iridium (HDR Ir) irradiation and intraluminal RFC hyperthermia [18]. This method was used clinically and we report the treatment results.
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Hyperthermia delivery
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An RFC hyperthermia instrument (Endoradiotherm 100-A; Olympus Corp., Tokyo, Japan) was used for hyperthermia delivery. Details of this instrument have been reported elsewhere [6–10]. A high dose rate remote afterloading system (microSelectron; Nucletron Oldreft Corp., Columbia, MD) was used for intraluminal radiotherapy. Two types of applicators were devised. The centre of the applicator had a cavity for the insertion of a microSelectron radiation source tube. The Type 1 applicator could accommodate a 5 F radiation source tube, and the Type 2 applicator a 6 F radiation source tube (Figure 1
). The applicator also allowed insertion of a 2.2 mm multipurpose endoscope (PF-22; Olympus Corp.), enabling observation of applicator position and the tumour (Figure 1).
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Figure 1. The applicator tip for delivering intraluminal hyperthermia. Top: A 6 F radiation source is inserted into the centre of the applicator, which has a 10 mm diameter balloon. Bottom: An endoscope, 2.2 mm in diameter, is inserted into the centre of the applicator, which has a 15 mm diameter balloon.
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For practical clinical application, the hyperthermia conditions were created by setting the temperature of the cooling water to 40 °C, and theoutput was computer-controlled to achieve anoesophageal mucosal surface temperature of 42–43 °C. Figure 2 shows the temperature distribution by thermography in an agar phantom under these conditions. Figure 3 shows the temperature distribution by thermography when the oesophageal mucosal surface temperature remained unchanged at 42–43 °C while the temperature ofthe cooling water was reduced to 20 °C. Compared with Figure 2, the area at 43 °C or higher in Figure 3 penetrates into deeper regions and gives a more suitable hyperthermic distribution for locally advanced cases.
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Figure 2. The temperature distribution by thermography in an agar phantom. The temperature of thecooling water was 40 °C and the output was computer-controlled to achieve an applicator surface temperatureof 42–43 °C. Heating time was 15 min. The temperature of point x was 45.1 °C.
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Figure 3. The temperature distribution by thermography in an agar phantom. The temperature of thecooling water was 20 °C and the output was computer-controlled to achieve an applicator surface temperature of 42–43 °C. Heating time was 15 min. The temperature of point x was 51.9 °C.
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Methods and materials
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Eight patients were treated at Mie University Hospital between January 1995 and September 1998. Table 1 shows the patient characteristics. All patients were male, with ages ranging from 61 years to 81 years (median 73.5 years). Seven patients had squamous cell carcinomas and one patient had an adenocarcinoma.
The clinical stage was determined by plain chestradiography, upper gastrointestinal fluoroscopy, upper gastrointestinal endoscopy, contrast enhanced chest CT, contrast enhanced liver CT or hepatic ultrasound, and bone scintigraphy. The 1997 International Union Against Cancer (UICC) TNM classification was used [19]. The contraindications for surgery were local tumour extent (four patients with T3 tumours), advanced age (one T1 and one T2), liver dysfunction (one T2) and refusal of surgery (one T2).
This treatment was approved by the Ethics Committee of Mie University. Patients were fully informed before treatment of the advantages and possible adverse side effects of this treatment; all gave written informed consent.
Each patient was treated with a dose of 2 Gy daily five times a week using 10 MV X-rays. The first six patients received a total of 40 Gy, while the remaining two patients received 50 Gy (Table 1
). The external irradiation field extended 3 cm above and below the tumour. Patients receiving 40 Gy were irradiated through two anteroposterior opposed fields. In those receiving 50 Gy, an additional 10 Gy was given through two oblique fields, excluding the spinal cord from the irradiation field.
Intraluminal irradiation and intraluminal hyperthermia were administered 1 to 2 weeks after external irradiation. Intraluminal hyperthermia was applied by heating the area for 30 min under the conditions described above, after the temperature of the oesophageal mucosal surface reached 42 °C. Intraluminal irradiation was started 15 min after the temperature of the oesophageal mucosal surface had reached 42 °C.
The field of intraluminal irradiation extended 1.5 cm above and below the tumour. The irradiation dose was estimated at a site 5 mm below the oesophageal mucosa, and the first three patients received 3 Gy once a week, for a total of three fractions (Figure 4). In the following three patients the dose administered per fraction was increased to 4 Gy and a total of 12 Gy was given, but a deep ulcer developed in the oesophageal mucosa in one of these patients, as described below. The number of intraluminal irradiation sessions in the following two patients was therefore decreased to two, and the dose of external irradiation was changed to 50 Gy (Table 1).
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Figure 4. A dummy source tube was inserted into thecentre of the applicator in Case 1. After 40 Gy external beam irradiation, simultaneous intraluminal irradiation and intraluminal hyperthermia was administered once weekly for 3 weeks.
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Therapeutic effects were evaluated by upper gastrointestinal fluoroscopic and endoscopic findingsobtained within 4 weeks after treatment. Patients showing complete disappearance of thetumour on both images were regarded as having achieved complete response (CR), those demonstrating 50% or more reduction in tumour maximum diameter were evaluated as having achieved partial response (PR) and those demonstrating less than 50% tumour reduction were regarded as having no change.
During follow-up, upper gastrointestinal fluoroscopy and endoscopy were performed once every 3–4 months, and contrast enhanced chest CT and contrast enhanced liver CT or ultrasound were performed once every 6–8 months after treatment.
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Results (Table 1)
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The primary effect of treatment was CR in four patients and PR in four patients. Two of the CR patients have survived without recurrence for 24 months and 41 months after treatment, respectively. The remaining two patients died of distant metastasis without local failure 11 months and 12 months, respectively, after treatment. Three of the four PR patients died of local failure and the remaining patient died of intercurrent disease without local failure 8 months after treatment.
Adverse side effects associated with treatment were noted in only one patient. Although the patient achieved CR, chest pain appeared 6 months after treatment and endoscopy showed a mucosal ulcer around the central part of the primary site. Total oesophagectomy was carried out because conservative treatment for 2 months did not improve the symptoms and local recurrence could not be ruled out. There were no malignant cells in the ulcerated area that had caused concern pre-operatively, and the ulcer had almost healed. However, another deep ulcer extending to the oesophageal adventitia was observed below this site. Because there were no malignant cells in this ulcer, and as it was located within the range of intraluminal irradiation and hyperthermia, the ulcer was considered to have been caused by treatment. This patient has survived without disease for 41 months. There were no other adverse events that caused clinical problems.
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Discussion
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There have been four large-scale randomized controlled trials comparing radiotherapy alone with a combination of radiotherapy and hyperthermia [20–23]. In three of the four studies, the local control rate was significantly higher in the group treated by a combination of radiotherapy and hyperthermia than in the group treated by radiotherapy alone [21–23], and in two of the three studies the survival rate was also significantly higher in the combined treatment group [22, 23]. Kitamura et al [9] performed a randomized controlled trial to compare the combination of intraluminal hyperthermia, chemotherapy and external radiotherapy (HCR group) with the combination of chemotherapy and external radiotherapy (CR group) for pre-operative treatment of oesophageal cancer, although the number of cases was small [9]. Complete disappearance of malignant cells was observed in 8 (25%) of the 32 patients in the HCR group and in 2 (5.9%) of the34 patients in the CR group at the time of surgery. The survival rate was also significantly higher in the group treated with hyperthermia. These results suggested that the combined treatment of hyperthermia with radiotherapy contributed to the improvement in the survival rate as well as local control.
The anti-tumour effect of combined radiotherapy and hyperthermia is maximized when these modalities are administered simultaneously [11–13]. In vivo and in vitro experiments indicate that the effect is augmented 2.5 to 3 times [13]. However, when tumour and normal tissues are irradiated and heated, the normal tissue sensitivity is also increased. The therapeutic gain factor (TGF) becomes 1 and the advantage of simultaneous administration is lost. To increase the TGF in simultaneous radiotherapy and hyperthermia it is necessary to confine irradiation and hyperthermia to the tumour as far as possible. Intraluminal irradiation and hyperthermia is theoretically ideal in this context.
Figure 5 shows a composite figure of the dose distribution during intraluminal irradiation in Case 1; the heat distribution is shown in Figure 2. In this case, the intraluminal radiation dose was 4.5 Gy on the oesophageal mucosal surface, 3 Gy at a submucosal depth of 5 mm and 2.25 Gy at a depth of 1 cm, showing a sharp reduction of radiation dose with submucosal depth. The tumour dose to deeper areas will be greatly reduced for locally invasive tumours extending more than 1 cm below the mucosa. During intraluminal hyperthermia, the temperature was approximately 42 °C at the oesophageal mucosal surface and 44 °C at a submucosal depth of 1–2 cm, with a higher temperature in submucosal regions. Simultaneous radiotherapy and hyperthermia not only augmented the biological anti-tumour effect, but had the additional advantage of complementing regions of diminished radiation dose with hyperthermia. These findings suggest that an increased anti-tumour effect can be expected in those locally advanced cases in which intraluminal radiotherapy alone is unlikely to be effective, and that the external and intraluminal irradiation doses may be decreased in early cases, thus reducing damage to normal tissues.
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Figure 5. A composite figure of the dose distribution during intraluminal irradiation and the heat distribution in Case 1.
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This treatment provided favourable therapeutic effects, although only eight patients were included in the study. However, such highly effective therapy means that the likelihood of unexpected adverse side effects is also high. The doses of external and intraluminal irradiation were not high in the patient with an oesophageal mucosal ulcer, and enhancement by concurrent use of intraluminal heating and intraluminal irradiation seems to have been one of the causes of the ulceration.
It has been indicated that the combination of conventional external radiotherapy and intraluminal radiotherapy is useful for treatment of oesophageal cancer in the early stages [1–4], while the combination of conventional external radiotherapy and chemotherapy is useful for treatment of advanced oesophageal cancer [24–27]. However, the local control rate of early oesophageal cancer is 60–70%, even with the combination of external and intraluminal radiotherapy, showing that further improvement may be possible. The survival rate in advanced oesophageal cancer has improved slightly with the combination of radiotherapy and chemotherapy, but the local control rate is still poor. Simultaneous intraluminal irradiation and hyperthermia for oesophageal cancer is still under evaluation. The optimal doses of intraluminal and external irradiation, the optimal heating conditions and the indications for this treatment remain to be clarified, but it has the potential to improve the local control rate.
Received for publication September 12, 2000.
Revision received February 22, 2001.
Accepted for publication April 27, 2001.
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References
|
|---|
-
Hishikawa Y, Kurisu K, Taniguchi M, Kamikonya N, Miura T. High-dose-rate intraluminal brachytherapy for esophageal cancer: 10 years experience in Hyogo Collge of Medicine. Radiother Oncol 1991;21:107–14.[Medline]
-
Akagi Y, Hirokawa Y, Kagemoto M, Matsuura K, Ito A, Fujita K, et al. Optimum fractionation for high-dose-rate endoesophageal brachytherapy following external irradiation of early stage esophageal cancer. Int Radiat Oncol Biol Phys 1999;43:525–30.
-
Nishimura Y, Okuno Y, Ono K, Mitsumori M, Nagata Y, Hiraoka M. External beam radiation therapy with or without high-dose-rate intraluminal brachytherapy for patients with superficial esophageal carcinoma. Cancer 1999;86:220–8.[Medline]
-
Maigon P, d'Hombres A, Truc G, Barillot I, Michiels C, Bedenne L, et al. High dose rate brachytherapy for superficial cancer of the esophagus. Int J Radiat Oncol Biol Phys 2000;46:71–6.[Medline]
-
Hyden EC, Langholz B, Tilden T, Lam K, Luxton G, Astrahan M, et al. External beam and intraluminal radiotherapy in the treatment of carcinoma of the esophagus. J Thorac Cardiovasc Surg 1988;96:237–41.[Abstract]
-
Sugimachi K, Inokuchi K. Hyperthermochemoradiotherapy and esophageal carcinoma. Semin Surg Oncol 1986;2:38–44.[Medline]
-
Sugimachi K, Kitamura K, Baba K, Ikebe M, Ikebe M, Morita M, et al. Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus—a prospective randomized trial. Int J Hyperthermia 1992;8:289–95.[Medline]
-
Sugimachi K, Kuwano H, Ide H, Toge T, Saku M, Oshiumi Y. Chemotherapy combined with or with- out hyperthermia for patients with oesophageal carcinoma: a prospective randomized trial. Int J Hyperthermia 1994;10:485–93.[Medline]
-
Kitamura K, Kuwano H, Watanabe M, Nozoe T, Yasuda M, Sumiyoshi K, et al. Prospective randomized study of hyperthermia combined with chemoradiotherapy for esophageal carcinoma. J Surg Oncol 1995;60:55–8.[Medline]
-
Saeki H, Kawaguchi H, Kitamura K, Ohno S, Sugimachi K. Recent advances in preoperative hyperthermochemoradiotherapy for patients with esophageal cancer. J Surg Oncol 1998;69:224–9.[Medline]
-
Joshi DS, Barendsen GW, van der Schueren E. Thermal enhancement of the effectiveness of gamma radiation for induction of reproductive death in cultured mammalian cells. Int J Radiat Oncol Biol Phys 1978;34:233–43.
-
Overgaard J. Simultaneous and sequential hyperthermia and radiation treatment of an experimental tumor and its surrounding normal tissue in vivo. Int J Radiat Oncol Biol Phys 1980;6:1507–15.[Medline]
-
Overgaard J, Nielsen OS, Lindegaard JC. Biological basis for rational design of clinical treatment with combined hyperthermia and radiation. NATO ASI Ser E 1987;127:54–79.
-
Kuroda M, Inamura K, Tahara S, Mimura S, Mikami Y, Kawasaki S, et al. Report of a study using phantom materials, and clinical experience with simultaneous radio-hyperthermotherapy. Acta Med Okayama 1992;46:417–26.
-
Ashayeri E, Bonney G, DeWitty RL, Goldson AL, Leffall LD, Thomas JN. Preliminary survivorship report on combined intraoperative radiation and hyperthermia treatments for unresectable pancreatic adenocarcinoma. J Natl Med Assoc 1993;85:36–40.[Medline]
-
Moros EG, Straube WL, Klein EE, Maurath J, Myerson RJ. Clinical system for simultaneous external superficial microwave hyperthermia and cobalt-60 radiation. Int J Hyperthermia 1995;11:11–26.[Medline]
-
Myerson RJ, Straube WL, Moros EG, Emami BN, Lee HK, Perez CA, et al. Simultaneous superficial hyperthermia and external radiotherpy: report of thermal dosimetry and tolerance to treatment. Int J Hyperthermia 1999;15:251–66.[Medline]
-
Fuwa N, Nomoto Y, Shouji K, Nakagawa T, Ito Y, Kikuchi Y. Simultaneous intraluminal irradiation and hyperthermia treatment for esophageal carcinoma. Nippon lgaku Hoshasen Gakkai Zasshi 1995;55:993–5.
-
International Union Against Cancer. TNM classification of malignant tumours (5th edn). Geneva: UICC, 1997.
-
Emami B, Scott C, Perez CA, Asbell S, Swift P, Grigsby P, et al. Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Group. Int J Radiat Oncol Biol Phys 1996;34:1097–104.[Medline]
-
Overgaard J, Gonzalez Gonzalez D, Hulshof MC, Arcangeli G, Dahl O, Mella O, et al. Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology. Int J Hyperthermia 1996;12:3–20.[Medline]
-
Sneed PK, Stauffer PR, McDermott MW, Diederich CJ, Lamborn KR, Prados MD, et al. Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost +/- hyperthermia for glioblastoma multiforme. Int J Hyperthermia 1998;15:287–95.
-
Van der Zee J, Gonzalez Gonzalez D, Van Rhoon GC, Van Dijk JDP, Van Putten WLJ, Hart AAM, et al. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomized, multicentre trial. Lancet 2000;355:1119–25.[Medline]
-
Araujo CM, Souhami L, Gil RA, Carvalho R, Garcia JA, Froimtchuk MJ, et al. A randomized trial comparing radiation therapy versus concomitant radiation therapy and chemotherapy in carcinoma of the thoracic esophagus. Cancer 1991;67:2258–61.[Medline]
-
Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593–8.[Abstract]
-
Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA, Al-Sarraf M, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999;281:1623–7.[Abstract/Free Full Text]
-
Ohtsu A, Boku N, Muro K, Chin K, Muto M, Yoshida S, et al. Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus. J Clin Oncol 1999;17:2915–21.[Abstract/Free Full Text]
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Abstract
Introduction
