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Radiation therapy for roentogenographically occult lung cancer by external beam irradiation and endobronchial high dose rate brachytherapy
Lung Cancer 25 (1999) 183 – 189 www.elsevier.nl/locate/lungcan
Radiation therapy for roentogenographically occult lung cancer by external beam irradiation and endobronchial high dose rate brachytherapy Masaya Furuta a,*, Iwao Tsukiyama a, Tatsuya Ohno a, Susumu Katano a, Kohei Yokoi b, Makoto Sawafuji b, Kiyoshi Mori b, Keigo Tominaga b b
a Di6ision of Radiation Therapy, Tochigi Cancer Center, 4 -9 -13 Yohnan, Utsunomiya, Tochigi, 320 -0834, Japan Di6ision of Thoracic Diseases, Tochigi Cancer Center, 4 -9 -13 Yonan, Utsunomiya, Tochigi, 320 -0835, 320 -0835, Japan
Received 12 February 1999; received in revised form 10 May 1999; accepted 11 May 1999
Abstract Purpose: We investigated the clinical usefulness of radiation therapy by external beam irradiation and endobronchial brachytherapy for the treatment of roentogenographically occult lung cancer. Patients and methods: From 1995 to 1996, five patients were treated with radiation therapy. We analyzed their treatment outcomes. The follow-up period varied from 3.0 to 3.8 years or until death. External beam radiation (40 Gy/20 fractions/4 weeks) was delivered to the tumor site alone, and not prophylactically given to the mediastinum. Endobronchial brachytherapy using high dose rate iridium (Ir)-192 was concurrently administered principally to a total dose of 18 Gy on the bronchial mucosa in three weekly fractions of 6 Gy each. Results: Complete remission was obtained in all patients. Two patients died of intercurrent diseases at 12 and 21 months without any evidence of recurrence. The disease has been also controlled in the other three cases. With the above doses, three small tumors B 1 cm were controlled without adverse effect. In two tumors, the dose reference points were set 2–7 mm beneath the mucosa, and larger doses were administered by brachytherapy. An applicator acting as a spacer was not used in these cases. The tumors were controlled, although the irradiated bronchi showed severe stenosis in 6 months following the treatment. However, the patients were asymptomatic and did not need further intervention. Conclusion: External beam irradiation combined with endobronchial brachytherapy was useful for the treatment of roentogenographically occult lung cancer as an alternative to surgery. Further investigation is needed to determine the optimal doses of radiation therapy. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Roentogenographically occult lung cancer; Radiation therapy; Endobronchial brachytherapy; Iridium-192; High dose rate
* Corresponding author. Present address: Department of Radiology, Koshigaya Hospital, Dokkyo University School of Medicine, 2-1-50 Minami-Koshigaya, Koshigaya, Saitama, 343-8555, Japan. Tel.: +81-489-651111; fax: + 81-489-651127. 0169-5002/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 9 ) 0 0 0 5 9 - 8
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1. Introduction Recent mass screenings, including sputum cytology, provide a better chance of detecting roentogenographically occult lung cancer in Japan. Surgery is the first choice of treatment for the disease [1,5]. However, some patients have coexistent diseases, such as pulmonary and cardiac disorders, and some may be too old to have surgery, or may have multiple cancers in the lung or in other organs. In these patients, the disease is treated with non-surgical modalities, such as radiation therapy and photodynamic therapy [12]. Recently, brachytherapy with high dose rate (HDR) iridium (Ir)-192 has been widely used in radiation therapy for cancer. Many papers were published on palliative irradiation to airway obstructing diseases using the HDR treatment system [6]. However, no definitive radiation therapy using HDR endobronchial brachytherapy for roentogenographically occult lung cancer has been established yet [8,9,11,13,14]. We experienced five cases of roentogenographically occult lung cancer treated with a combination of external beam irradiation and HDR brachytherapy, and herein report the treatment outcomes.
2. Patients and methods From May 1995 to August 1996, five patients with roentogenographically occult lung cancer were treated with external beam irradiation and endobronchial brachytherapy. Patient age varied from 65 to 83 years (average, 73 years). All patients were male and had clinical stage T1N0M0 of squamous cell carcinoma (Table 1). All were smokers. The cancers were discovered by sputum cytology in three patients and incidentally detected by fiberoptic bronchoscopy for other pulmonary diseases in two patients. Two patients had synchronous double lung cancer in the ipsilateral (Case 5) and contralateral lung (Case 2). The larger tumor of the two was surgically resected, and the smaller one was treated with radiation therapy (Table 1). Radiation therapy was administered by a concurrent combination of external beam irradiation
and endobronchial brachytherapy. External beam irradiation was administered to a total dose of 40 Gy in 4 weeks using a conventional fractionation of 2 Gy per day. The primary site alone was irradiated using small antero-posterior opposed portals (5 × 5–6× 6 cm2). Tumor localization for the external beam irradiation was determined under fluoroscopy using the tip of fiberoptic bronchoscope. Prophylactic irradiation to the mediastinum was not given. Endobronchial brachytherapy was performed according to the procedure reported by Nomoto et al. [8]. Briefly, a bronchoscopically guided guide wire was inserted into the targeted site of the bronchus. The fiberoptic bronchoscope was replaced under fluoroscopy by a flexible applicator with expandable wings. Then the guide wire was removed, and a source transfer tube through which the radioactive source stepped was inserted through the applicator. Finally, the fiberoptic bronchoscope was inserted again to ascertain the position of the applicator and source transfer tube, and then the wings of the applicator were expanded to act as a spacer. During the treatment, the position of the applicator was monitored by fluoroscopy. Tracheostomy was not performed in any of the patients. Radiation dose of the brachytherapy was principally 18 Gy in three fractions in 3 weeks. Reference points (to which a prescribed dose was given) were set at 3–10 mm from the central axis of the radiation source according to the tumor size and radius of the bronchus (Table 2). For small tumors (Cases 1–3), the dose reference points were set on the bronchial mucosa (Table 2). In Case 5 (the first patient treated with this combined radiotherapy in our hospital), the reference point was set 10 mm from the central axis of the radioactive source, or 7 mm beneath the bronchial mucosa. For a large tumor almost stenosing the segmental bronchus and extending proximally to the spur of the left upper and lower lobe bronchi (Case 4), the reference point was set 7 mm from the axis, or 4 mm (at the orifice of the superior segmental bronchus of the left lower lobe) to 2 mm (at the spur of the upper and lower lobe bronchi) beneath the mucosa. In these cases, the dose on the bronchial mucosa increased according to the reference point settings. The length
Case
Age
Gender
Histology
TNM
Site
Bronchoscopic findings before RT
Reason for nonsurgical treatment
1 2
76 67
m m
T1N0M0 T1N0M0
Patient refusal Multiple lung cancer
73 73
m m
Tiny nodule Stenosis of bronchus
Poor pulmonary function Brain infarction
5
83
m
Orifice of super. seg. bronchus of RLLa Spur of lt. upper and lower lobe bronchi Orifice of super. seg. bronchus of LLLb Spur of lt. Upper and lower lobe bronchi Orifice of super. seg. bronchus of RLL
Slight redness Thickened spur
3 4
Squamous Mod. diff. squamous Squamous Mod. diff. squamous Mod. diff. squamous
Thickened spur
Eldery, multiple lung cancer
a b
T1N0M0 T1N0M0 T1N0M0
Superior segmental bronchus of right lower lobe. Superior segmental bronchus of left lower lobe.
M. Furuta et al. / Lung Cancer 25 (1999) 183–189
Table 1 Patient characteristics
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186
of 40 Gy by external beam irradiation and 18 Gy (on the mucosa) by endobronchial brachytherapy. Bronchoscopically, the irradiated bronchi showed only slight atrophy, and no moderate or severe adverse effects were noted in the follow-up periods. In Cases 4 and 5 (the cases in which the reference points were set 2–7 mm beneath the mucosa and larger doses of brachytherapy were administered), the tumors were controlled. However, the irradiated bronchi showed severe stenosis with the mucosa coated with white fur in 6 months following treatment. An applicator acting as a spacer was not used in these patients. The patients were asymptomatic and did not need further intervention. The estimated doses on the mucosa were 9–17 Gy/fraction in Case 4 and 26 Gy/fraction in Case 5.
of the bronchus irradiated was principally determined to cover the tumor with margin of 1 – 2 cm, and total lengths of the bronchus treated were 3 – 6 cm. All patients were followed up for a range of 36 – 45 months or until death. As a follow-up study, fiberoptic bronchoscopy was performed 1, 3, and 6 months after the treatment, and then repeated at 6-month intervals, and cytological examination by brushing was performed if necessary. Sputum cytology was also repeatedly examined.
3. Results
3.1. Local control and sur6i6al Complete remission was obtained in all five cases at the completion of the treatment. One patient died of another cancer in the ipsilateral lung at 13 months (synchronous double lung cancer, Case 5). Autopsy proved that the tumor treated with this combined radiotherapy was controlled. Another patient died of cerebral hemorrhage 21 months after the treatment without any evidence of recurrence (Case 1). The disease has been controlled in the remaining three cases Table 3.
4. Discussion Many papers have been published on the treatment results of surgical resection for roentogenographically occult lung cancer. Martini et al. reported 27 patients treated by resection with none showing recurrence during observation periods of up to 20 years [5]. Cortese et al. showed that the 5-year survival rate in 44 patients with Tis and T1 diseases was 91% [1]. Treatment outcome of roentogenographically occult lung cancer by a combination of external beam irradiation and endobronchial brachyther-
3.2. Radiation dose and fiberoptic bronchoscopy findings following treatment Small tumors B1 cm (Cases 1, 2, and 3) were controlled by combined radiation therapy at a dose
Table 2 Radiation therapy Case
1 2 3 4 5 a
External RT
Endobronchial brachytherapy
Total dose (Gy)
Total dose (Gy)
No. of fractions
Reference point (mm)a
Total dose at 1 cm from source (Gy)
Use of spacer
40 40 40 40 40
18 18 18 12 18
3 3 3 2 3
3 5 7 7 10
2 4.5 9 6 18
Yes Yes Yes No No
Distance from central axis of radioactive source.
M. Furuta et al. / Lung Cancer 25 (1999) 183–189
187
Table 3 Treatment results Case
Bronchoscopic findings after RT
Local recurrence Follow-up period (month)
Remarks
1 2 3 4 5
Atrophic membrane Atrophic membrane Atrophic membrane Severe stenosis Severe stenosis
No No No No No
Died of cerebral hemorrhage No evidence of disease No evidence of disease No evidence of disease Died of another lung cancer
apy using low dose rate (LDR) Ir-192 was reported by Fuwa et al. in 1991 [3]. They treated eight patients with external beam irradiation (33 – 66 Gy) and endobronchial brachytherapy (10 – 24 Gy/2–5 fraction). The dose reference points (to which the prescribed dose was given) were set on the bronchial mucosa, or 3 – 10 mm from the central axis of the radioactive source according to the diameter of the bronchus. No patients died of disease during the follow-up period of 5 – 20 months and no patient had any adverse late injury. Saito et al. reported the treatment results of as many as 41 patients treated with the same combined modality using doses of 40 Gy by external beam irradiation and 25 Gy in five fractions by LDR endobronchial brachytherapy [10]. Recurrence occurred in only two patients, showing that the disease can be cured with radiation therapy combined with LDR endobronchial brachytherapy as well as surgical resection. Several papers have been published on the treatment results of the HDR endobronchial brachytherapy for the disease [8,9,11,13,14]. Sutedja et al. first reported the therapeutic results of 2 patients with T1 disease in 1993 [11]. They used endobronchial brachytherapy alone at a dose of 10 Gy at 1 cm from the source axis, and repeated the procedure 2 or 3 times. Tre´daniel et al. reported the treatment outcomes of 29 patients with small tumors limited to the bronchial wall [14]. They also administered HDR endobronchial brachytherapy as the sole treatment. This may have had to do with the fact that most of the patients (26 patients) had been previously treated by surgery, external beam radiotherapy, and chemotherapy. Nomoto et al. in 1997 reported the radiotherapeutic outcomes of three patients with
21 36 43 44 13
Tis and T1 lung cancers treated by a combinati on of external beam irradiation (40–60 Gy) and HDR brachytherapy (18 Gy/3 fractions/3 weeks) with the dose reference points set on the mucosa [8]. Pe´rol et al. conducted a dose escalation study in patients with small endobronchial carcinoma treated exclusively with HDR brachytherapy [9]. They treated two patients with three fractions of 7 Gy with the reference point at 1 cm from the source axis, four patients with four fractions of 7 Gy, and 13 with five fractions. Complete response was not achieved in one patient in the 21 Gy protocol and another patient in the 24 Gy regime, and the 2-year disease control rate of all 19 patients was 75%. Two patients of 13 who received 35 Gy developed severe necrosis of the bronchial wall, and the authors warned of a high incidence of late complications with this dose of brachytherapy. Taulelle et al. reported treatment results of endobronchial brachytherapy in 189 patients, including 22 patients with small endobronchial carcinoma [13]. Local control rate of the early disease was 92% in follow-up periods of 5–68 months, although the late toxicity in these patients was not specified. Our treatment method for roentogenographically occult lung cancer is to treat the disease with external beam irradiation and endobronchial brachytherapy as a boost for the following reasons. First, the vertical extent of the disease (the thickness of the tumor) cannot be accurately assessed by fiberoptic bronchoscopy [12]. Since the radiation dose delivered by brachytherapy steeply decreases as the distance from the radioactive source increases, the delivered dose can be decreased in the most deeply invaded part of the tumor when the disease is treated with endo-
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bronchial brachytherapy alone. Thus, external beam irradiation that covers the tumor with a homogeneous dose distribution should be administered first to extinguish the macroscopic disease, and endobronchial brachytherapy to the residual microscopic tumor on the mucosa. This is the reason why we set the dose reference point on the mucosa. Second, the tolerance dose of the normal bronchus may not be much higher than the treatment doses administered in the reported endobronchial brachytherapy. If the dose of brachytherapy is insufficient, local recurrence may occur [9,13]. Excessive doses, however, could result in late severe toxicity of the bronchial mucosa that were not negligible [9]. When brachytherapy is the only method of treatment used, it should be performed in a more fractionated manner using lower doses per fraction, to avoid severe late injury [6]. However, frequent bronchoscopic treatment would decrease the compliance of the treatment. Otherwise, external beam irradiation should be combined with brachytherapy as in the present study. Irradiation to the hilum to a total dose of 40 Gy in conventional fractionation of 2 Gy per day can be safely administered to most patients without causing severe late injury of the lung when delivered with small portals. External beam irradiation in small portals, in fact, caused no late effect that required medication or hospitalization in our series. Thus, endobronchial brachytherapy should be administered in combination with external beam irradiation, unless the patient has severe disorders in pulmonary and cardiac function. Another important factor in radiation therapy is tumor volume. The term ‘roentogenographically occult’ lung cancer includes tumors with a wide range in volume, from a faint redness or thickening of the bronchial mucosa to a mass almost obstructing the bronchus [3]. The tumor burden varies widely, and the total dose with which the disease would be controlled increases depending on the volume. Optimal doses of HDR brachytherapy for roentogenographically occult lung cancer have not been established. In our series, three cases (Cases 1 – 3) of small endobronchial tumors were well controlled without moderate or severe adverse
effects. In the study by Nomoto et al., the same doses of external beam irradiation and brachytherapy were administered, and the disease was controlled [8]. As for small endobronchial carcinoma B 1 cm, the dose of 40 Gy by external beam irradiation and 18 Gy (on the mucosa)/3 fractions/3 weeks by endobronchial brachytherapy may be sufficient. If radiation therapy is administered solely by endobronchial brachytherapy, a dose of 35 Gy in five fractions might be too much [10]. For larger tumors and tumors whose distal extent cannot be bronchoscopically confirmed, the radiation dose might be increased. Treatment planning, especially (1) dose reference points and (2) the length of the treatment volume, must be determined carefully. Two cases in which the reference points were set deeply beneath the bronchial mucosa developed severe stenosis of the bronchus. In neither case an applicator was used to act as a spacer. When the dose reference points are set at 1 cm from the source axis, a dose of 6 Gy may be excessive for lesions on the segmental bronchus for which the dose is estimated at 20 Gy or more on the mucosa. In these cases, the dose of the brachytherapy should be specified (1) at a depth below the surface of the bronchial mucosa and (2) on the suface as well. This will be helpful in comparing treatments between different centers. Case 4 had a large tumor stenosing the segmental bronchus. Bronchial stenosis after treatment might be partly attributed to the loss of normal bronchial structure caused by tumor invasion as well as excess dosage [13]. In addition, we strongly recommend using an applicator with expandable wings as a spacer (1) to avoid decentralization of the source in the bronchus [8] and (2) to exclude a target volume from a markedly high dose area around the source [4,10]. Unlike HDR brachytherapy, LDR brachytherapy takes 2–4 h to administer a treatment dose of 5 Gy [10]. Insertion of a tracheostomy tube is necessary for the treatment. HDR brachytherapy takes less than 10 minutes, and it can be performed on outpatients. Moreover, the HDR brachytherapy system has other advantages over LDR brachytherapy: computer-aided optimization of the source placement in the catheters and
M. Furuta et al. / Lung Cancer 25 (1999) 183–189
applicators and easier administration of the radioactive source [7]. The HDR treatment system will be used more widely in the world. As for photodynamic therapy, Furuse et al. reported the treatment outcome of roentogenographically occult lung cancer with a local control rate of 90% [2]. In their analysis, however, tumors larger than 1 cm often failed to be controlled, and the authors concluded that large tumors were not an indication for treatment. Tumors at invisible sites are also a contraindication. Early cases of lung cancer are expected to be increasingly discovered. Among these patients, a sizeable population is referred for non-surgical treatments like radiation therapy. Our results, although from a very small study with a short follow-up period, demonstrated the possibility that external beam irradiation plus endobronchial HDR brachytherapy can be an alternative to surgery for roentogenographically occult lung cancer. An accumulation of cases is needed to determine the optimal dose of brachytherapy.
[4]
[5] [6]
[7]
[8]
[9]
[10]
[11]
References [1] Cortese DA, Pairolero PC, Bergstralh EJ, et al. Roentogenographically occult lung cancer. A ten-year experience. J Thorac Cardiovasc Surg 1980;86:373–80. [2] Furuse K, Fukuoka M, Kato H, et al. A prospective phase II study on photodynamic therapy with Photofrin II for centrally located early stage lung cancer. J Clin Oncol 1993;11:1852 –7. [3] Fuwa N, Morita K, Ito Y, Murao T, Yamada T, Nomoto Y. Treatment results for 17 cases of endobronchial carcinoma with a new applicator of intraluminal irradiation
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[14]
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using 192Iridium thin wires. J Jpn Soc Ther Radiol Oncol 1991;3:1 – 8. Marinello G, Pierquin B, Grimard L, Barret C. Dosimetry of intraluminal brachytherapy. Radiother Oncol 1992;23:213 – 6. Martini N, Melamed MR. Occult carcinomas of the lung. Ann Thorac Surg 1980;30:215 – 23. Nag S, Abitbol AA, Anderson LL, et al. Consensus guidelines for high dose rate remote brachytherapy in cervical endometrial, and endobronchial tumors. Int J Radiat Oncol Biol Phys 1993;27:1241 – 4. Nickers P, Kunkler I, Scalliet P. Modern brachytherapy: current state and future prospects. Eur J Cancer 1997;33:1747 – 51. Nomoto Y, Shouji K, Toyota S, Sasaoka M, Murashima S, Ooi M, Takeda K, Nakagawa T. High dose rate endobronchial brachytherapy using a new applicator. Radiother Oncol 1997;45:33 – 7. Pe´rol M, Caliandro R, Pommier P, Malet C, Montbarbon X, Carrie C, Ardiet JM. Curative irradiation a of limited endobronchial carcinomas with high-dose rate brachytherapy. Results of a pilot study. Chest 1997;111:1417– 23. Saito M, Yokoyama A, Kurita Y, Uematsu T, Miyao H, Fujimori K. Treatment of roentogenographically occult endobronchial carcinoma with external beam radiotherapy and intraluminal low dose rate brachytherapy. Int J Radiat Oncol Biol Phys 1996;34:1029 – 35. Sutedja G, Baris G, van Zandwijk N, Postmus PE. Highdose rate brachytherapy has a curative potential in patients with intraluminal squamous cell lung cancer. Respiration 1993;61:167 – 8. Sutedja G, Postmus PE. Bronchoscopic treatment of lung cancer. Lung Cancer 1994;11:1 – 17. Taulelle M, Chauvet B, Vincent P, Fe´lix-Faure C, Buciarelli B, Garcia R, Brewer Y, Reboul F. High dose rate endobronchial brachytherapy: results and complications in 189 patients. Eur Respir J 1998;11:162 – 8. Tre´daniel J, Hennequin C, Zalcman G, Walter S, Homasson JP, Maylin C, Hirsh A. Prolonged survival after high-dose rate endobronchial radiation for malignant airway obstruction. Chest 1994;105:767 – 72.
Radiation therapy for roentogenographically occult lung cancer by external beam irradiation and endobronchial high dose rate brachytherapy Masaya Furuta a,*, Iwao Tsukiyama a, Tatsuya Ohno a, Susumu Katano a, Kohei Yokoi b, Makoto Sawafuji b, Kiyoshi Mori b, Keigo Tominaga b b
a Di6ision of Radiation Therapy, Tochigi Cancer Center, 4 -9 -13 Yohnan, Utsunomiya, Tochigi, 320 -0834, Japan Di6ision of Thoracic Diseases, Tochigi Cancer Center, 4 -9 -13 Yonan, Utsunomiya, Tochigi, 320 -0835, 320 -0835, Japan
Received 12 February 1999; received in revised form 10 May 1999; accepted 11 May 1999
Abstract Purpose: We investigated the clinical usefulness of radiation therapy by external beam irradiation and endobronchial brachytherapy for the treatment of roentogenographically occult lung cancer. Patients and methods: From 1995 to 1996, five patients were treated with radiation therapy. We analyzed their treatment outcomes. The follow-up period varied from 3.0 to 3.8 years or until death. External beam radiation (40 Gy/20 fractions/4 weeks) was delivered to the tumor site alone, and not prophylactically given to the mediastinum. Endobronchial brachytherapy using high dose rate iridium (Ir)-192 was concurrently administered principally to a total dose of 18 Gy on the bronchial mucosa in three weekly fractions of 6 Gy each. Results: Complete remission was obtained in all patients. Two patients died of intercurrent diseases at 12 and 21 months without any evidence of recurrence. The disease has been also controlled in the other three cases. With the above doses, three small tumors B 1 cm were controlled without adverse effect. In two tumors, the dose reference points were set 2–7 mm beneath the mucosa, and larger doses were administered by brachytherapy. An applicator acting as a spacer was not used in these cases. The tumors were controlled, although the irradiated bronchi showed severe stenosis in 6 months following the treatment. However, the patients were asymptomatic and did not need further intervention. Conclusion: External beam irradiation combined with endobronchial brachytherapy was useful for the treatment of roentogenographically occult lung cancer as an alternative to surgery. Further investigation is needed to determine the optimal doses of radiation therapy. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Roentogenographically occult lung cancer; Radiation therapy; Endobronchial brachytherapy; Iridium-192; High dose rate
* Corresponding author. Present address: Department of Radiology, Koshigaya Hospital, Dokkyo University School of Medicine, 2-1-50 Minami-Koshigaya, Koshigaya, Saitama, 343-8555, Japan. Tel.: +81-489-651111; fax: + 81-489-651127. 0169-5002/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 9 ) 0 0 0 5 9 - 8
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M. Furuta et al. / Lung Cancer 25 (1999) 183–189
1. Introduction Recent mass screenings, including sputum cytology, provide a better chance of detecting roentogenographically occult lung cancer in Japan. Surgery is the first choice of treatment for the disease [1,5]. However, some patients have coexistent diseases, such as pulmonary and cardiac disorders, and some may be too old to have surgery, or may have multiple cancers in the lung or in other organs. In these patients, the disease is treated with non-surgical modalities, such as radiation therapy and photodynamic therapy [12]. Recently, brachytherapy with high dose rate (HDR) iridium (Ir)-192 has been widely used in radiation therapy for cancer. Many papers were published on palliative irradiation to airway obstructing diseases using the HDR treatment system [6]. However, no definitive radiation therapy using HDR endobronchial brachytherapy for roentogenographically occult lung cancer has been established yet [8,9,11,13,14]. We experienced five cases of roentogenographically occult lung cancer treated with a combination of external beam irradiation and HDR brachytherapy, and herein report the treatment outcomes.
2. Patients and methods From May 1995 to August 1996, five patients with roentogenographically occult lung cancer were treated with external beam irradiation and endobronchial brachytherapy. Patient age varied from 65 to 83 years (average, 73 years). All patients were male and had clinical stage T1N0M0 of squamous cell carcinoma (Table 1). All were smokers. The cancers were discovered by sputum cytology in three patients and incidentally detected by fiberoptic bronchoscopy for other pulmonary diseases in two patients. Two patients had synchronous double lung cancer in the ipsilateral (Case 5) and contralateral lung (Case 2). The larger tumor of the two was surgically resected, and the smaller one was treated with radiation therapy (Table 1). Radiation therapy was administered by a concurrent combination of external beam irradiation
and endobronchial brachytherapy. External beam irradiation was administered to a total dose of 40 Gy in 4 weeks using a conventional fractionation of 2 Gy per day. The primary site alone was irradiated using small antero-posterior opposed portals (5 × 5–6× 6 cm2). Tumor localization for the external beam irradiation was determined under fluoroscopy using the tip of fiberoptic bronchoscope. Prophylactic irradiation to the mediastinum was not given. Endobronchial brachytherapy was performed according to the procedure reported by Nomoto et al. [8]. Briefly, a bronchoscopically guided guide wire was inserted into the targeted site of the bronchus. The fiberoptic bronchoscope was replaced under fluoroscopy by a flexible applicator with expandable wings. Then the guide wire was removed, and a source transfer tube through which the radioactive source stepped was inserted through the applicator. Finally, the fiberoptic bronchoscope was inserted again to ascertain the position of the applicator and source transfer tube, and then the wings of the applicator were expanded to act as a spacer. During the treatment, the position of the applicator was monitored by fluoroscopy. Tracheostomy was not performed in any of the patients. Radiation dose of the brachytherapy was principally 18 Gy in three fractions in 3 weeks. Reference points (to which a prescribed dose was given) were set at 3–10 mm from the central axis of the radiation source according to the tumor size and radius of the bronchus (Table 2). For small tumors (Cases 1–3), the dose reference points were set on the bronchial mucosa (Table 2). In Case 5 (the first patient treated with this combined radiotherapy in our hospital), the reference point was set 10 mm from the central axis of the radioactive source, or 7 mm beneath the bronchial mucosa. For a large tumor almost stenosing the segmental bronchus and extending proximally to the spur of the left upper and lower lobe bronchi (Case 4), the reference point was set 7 mm from the axis, or 4 mm (at the orifice of the superior segmental bronchus of the left lower lobe) to 2 mm (at the spur of the upper and lower lobe bronchi) beneath the mucosa. In these cases, the dose on the bronchial mucosa increased according to the reference point settings. The length
Case
Age
Gender
Histology
TNM
Site
Bronchoscopic findings before RT
Reason for nonsurgical treatment
1 2
76 67
m m
T1N0M0 T1N0M0
Patient refusal Multiple lung cancer
73 73
m m
Tiny nodule Stenosis of bronchus
Poor pulmonary function Brain infarction
5
83
m
Orifice of super. seg. bronchus of RLLa Spur of lt. upper and lower lobe bronchi Orifice of super. seg. bronchus of LLLb Spur of lt. Upper and lower lobe bronchi Orifice of super. seg. bronchus of RLL
Slight redness Thickened spur
3 4
Squamous Mod. diff. squamous Squamous Mod. diff. squamous Mod. diff. squamous
Thickened spur
Eldery, multiple lung cancer
a b
T1N0M0 T1N0M0 T1N0M0
Superior segmental bronchus of right lower lobe. Superior segmental bronchus of left lower lobe.
M. Furuta et al. / Lung Cancer 25 (1999) 183–189
Table 1 Patient characteristics
185
M. Furuta et al. / Lung Cancer 25 (1999) 183–189
186
of 40 Gy by external beam irradiation and 18 Gy (on the mucosa) by endobronchial brachytherapy. Bronchoscopically, the irradiated bronchi showed only slight atrophy, and no moderate or severe adverse effects were noted in the follow-up periods. In Cases 4 and 5 (the cases in which the reference points were set 2–7 mm beneath the mucosa and larger doses of brachytherapy were administered), the tumors were controlled. However, the irradiated bronchi showed severe stenosis with the mucosa coated with white fur in 6 months following treatment. An applicator acting as a spacer was not used in these patients. The patients were asymptomatic and did not need further intervention. The estimated doses on the mucosa were 9–17 Gy/fraction in Case 4 and 26 Gy/fraction in Case 5.
of the bronchus irradiated was principally determined to cover the tumor with margin of 1 – 2 cm, and total lengths of the bronchus treated were 3 – 6 cm. All patients were followed up for a range of 36 – 45 months or until death. As a follow-up study, fiberoptic bronchoscopy was performed 1, 3, and 6 months after the treatment, and then repeated at 6-month intervals, and cytological examination by brushing was performed if necessary. Sputum cytology was also repeatedly examined.
3. Results
3.1. Local control and sur6i6al Complete remission was obtained in all five cases at the completion of the treatment. One patient died of another cancer in the ipsilateral lung at 13 months (synchronous double lung cancer, Case 5). Autopsy proved that the tumor treated with this combined radiotherapy was controlled. Another patient died of cerebral hemorrhage 21 months after the treatment without any evidence of recurrence (Case 1). The disease has been controlled in the remaining three cases Table 3.
4. Discussion Many papers have been published on the treatment results of surgical resection for roentogenographically occult lung cancer. Martini et al. reported 27 patients treated by resection with none showing recurrence during observation periods of up to 20 years [5]. Cortese et al. showed that the 5-year survival rate in 44 patients with Tis and T1 diseases was 91% [1]. Treatment outcome of roentogenographically occult lung cancer by a combination of external beam irradiation and endobronchial brachyther-
3.2. Radiation dose and fiberoptic bronchoscopy findings following treatment Small tumors B1 cm (Cases 1, 2, and 3) were controlled by combined radiation therapy at a dose
Table 2 Radiation therapy Case
1 2 3 4 5 a
External RT
Endobronchial brachytherapy
Total dose (Gy)
Total dose (Gy)
No. of fractions
Reference point (mm)a
Total dose at 1 cm from source (Gy)
Use of spacer
40 40 40 40 40
18 18 18 12 18
3 3 3 2 3
3 5 7 7 10
2 4.5 9 6 18
Yes Yes Yes No No
Distance from central axis of radioactive source.
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187
Table 3 Treatment results Case
Bronchoscopic findings after RT
Local recurrence Follow-up period (month)
Remarks
1 2 3 4 5
Atrophic membrane Atrophic membrane Atrophic membrane Severe stenosis Severe stenosis
No No No No No
Died of cerebral hemorrhage No evidence of disease No evidence of disease No evidence of disease Died of another lung cancer
apy using low dose rate (LDR) Ir-192 was reported by Fuwa et al. in 1991 [3]. They treated eight patients with external beam irradiation (33 – 66 Gy) and endobronchial brachytherapy (10 – 24 Gy/2–5 fraction). The dose reference points (to which the prescribed dose was given) were set on the bronchial mucosa, or 3 – 10 mm from the central axis of the radioactive source according to the diameter of the bronchus. No patients died of disease during the follow-up period of 5 – 20 months and no patient had any adverse late injury. Saito et al. reported the treatment results of as many as 41 patients treated with the same combined modality using doses of 40 Gy by external beam irradiation and 25 Gy in five fractions by LDR endobronchial brachytherapy [10]. Recurrence occurred in only two patients, showing that the disease can be cured with radiation therapy combined with LDR endobronchial brachytherapy as well as surgical resection. Several papers have been published on the treatment results of the HDR endobronchial brachytherapy for the disease [8,9,11,13,14]. Sutedja et al. first reported the therapeutic results of 2 patients with T1 disease in 1993 [11]. They used endobronchial brachytherapy alone at a dose of 10 Gy at 1 cm from the source axis, and repeated the procedure 2 or 3 times. Tre´daniel et al. reported the treatment outcomes of 29 patients with small tumors limited to the bronchial wall [14]. They also administered HDR endobronchial brachytherapy as the sole treatment. This may have had to do with the fact that most of the patients (26 patients) had been previously treated by surgery, external beam radiotherapy, and chemotherapy. Nomoto et al. in 1997 reported the radiotherapeutic outcomes of three patients with
21 36 43 44 13
Tis and T1 lung cancers treated by a combinati on of external beam irradiation (40–60 Gy) and HDR brachytherapy (18 Gy/3 fractions/3 weeks) with the dose reference points set on the mucosa [8]. Pe´rol et al. conducted a dose escalation study in patients with small endobronchial carcinoma treated exclusively with HDR brachytherapy [9]. They treated two patients with three fractions of 7 Gy with the reference point at 1 cm from the source axis, four patients with four fractions of 7 Gy, and 13 with five fractions. Complete response was not achieved in one patient in the 21 Gy protocol and another patient in the 24 Gy regime, and the 2-year disease control rate of all 19 patients was 75%. Two patients of 13 who received 35 Gy developed severe necrosis of the bronchial wall, and the authors warned of a high incidence of late complications with this dose of brachytherapy. Taulelle et al. reported treatment results of endobronchial brachytherapy in 189 patients, including 22 patients with small endobronchial carcinoma [13]. Local control rate of the early disease was 92% in follow-up periods of 5–68 months, although the late toxicity in these patients was not specified. Our treatment method for roentogenographically occult lung cancer is to treat the disease with external beam irradiation and endobronchial brachytherapy as a boost for the following reasons. First, the vertical extent of the disease (the thickness of the tumor) cannot be accurately assessed by fiberoptic bronchoscopy [12]. Since the radiation dose delivered by brachytherapy steeply decreases as the distance from the radioactive source increases, the delivered dose can be decreased in the most deeply invaded part of the tumor when the disease is treated with endo-
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bronchial brachytherapy alone. Thus, external beam irradiation that covers the tumor with a homogeneous dose distribution should be administered first to extinguish the macroscopic disease, and endobronchial brachytherapy to the residual microscopic tumor on the mucosa. This is the reason why we set the dose reference point on the mucosa. Second, the tolerance dose of the normal bronchus may not be much higher than the treatment doses administered in the reported endobronchial brachytherapy. If the dose of brachytherapy is insufficient, local recurrence may occur [9,13]. Excessive doses, however, could result in late severe toxicity of the bronchial mucosa that were not negligible [9]. When brachytherapy is the only method of treatment used, it should be performed in a more fractionated manner using lower doses per fraction, to avoid severe late injury [6]. However, frequent bronchoscopic treatment would decrease the compliance of the treatment. Otherwise, external beam irradiation should be combined with brachytherapy as in the present study. Irradiation to the hilum to a total dose of 40 Gy in conventional fractionation of 2 Gy per day can be safely administered to most patients without causing severe late injury of the lung when delivered with small portals. External beam irradiation in small portals, in fact, caused no late effect that required medication or hospitalization in our series. Thus, endobronchial brachytherapy should be administered in combination with external beam irradiation, unless the patient has severe disorders in pulmonary and cardiac function. Another important factor in radiation therapy is tumor volume. The term ‘roentogenographically occult’ lung cancer includes tumors with a wide range in volume, from a faint redness or thickening of the bronchial mucosa to a mass almost obstructing the bronchus [3]. The tumor burden varies widely, and the total dose with which the disease would be controlled increases depending on the volume. Optimal doses of HDR brachytherapy for roentogenographically occult lung cancer have not been established. In our series, three cases (Cases 1 – 3) of small endobronchial tumors were well controlled without moderate or severe adverse
effects. In the study by Nomoto et al., the same doses of external beam irradiation and brachytherapy were administered, and the disease was controlled [8]. As for small endobronchial carcinoma B 1 cm, the dose of 40 Gy by external beam irradiation and 18 Gy (on the mucosa)/3 fractions/3 weeks by endobronchial brachytherapy may be sufficient. If radiation therapy is administered solely by endobronchial brachytherapy, a dose of 35 Gy in five fractions might be too much [10]. For larger tumors and tumors whose distal extent cannot be bronchoscopically confirmed, the radiation dose might be increased. Treatment planning, especially (1) dose reference points and (2) the length of the treatment volume, must be determined carefully. Two cases in which the reference points were set deeply beneath the bronchial mucosa developed severe stenosis of the bronchus. In neither case an applicator was used to act as a spacer. When the dose reference points are set at 1 cm from the source axis, a dose of 6 Gy may be excessive for lesions on the segmental bronchus for which the dose is estimated at 20 Gy or more on the mucosa. In these cases, the dose of the brachytherapy should be specified (1) at a depth below the surface of the bronchial mucosa and (2) on the suface as well. This will be helpful in comparing treatments between different centers. Case 4 had a large tumor stenosing the segmental bronchus. Bronchial stenosis after treatment might be partly attributed to the loss of normal bronchial structure caused by tumor invasion as well as excess dosage [13]. In addition, we strongly recommend using an applicator with expandable wings as a spacer (1) to avoid decentralization of the source in the bronchus [8] and (2) to exclude a target volume from a markedly high dose area around the source [4,10]. Unlike HDR brachytherapy, LDR brachytherapy takes 2–4 h to administer a treatment dose of 5 Gy [10]. Insertion of a tracheostomy tube is necessary for the treatment. HDR brachytherapy takes less than 10 minutes, and it can be performed on outpatients. Moreover, the HDR brachytherapy system has other advantages over LDR brachytherapy: computer-aided optimization of the source placement in the catheters and
M. Furuta et al. / Lung Cancer 25 (1999) 183–189
applicators and easier administration of the radioactive source [7]. The HDR treatment system will be used more widely in the world. As for photodynamic therapy, Furuse et al. reported the treatment outcome of roentogenographically occult lung cancer with a local control rate of 90% [2]. In their analysis, however, tumors larger than 1 cm often failed to be controlled, and the authors concluded that large tumors were not an indication for treatment. Tumors at invisible sites are also a contraindication. Early cases of lung cancer are expected to be increasingly discovered. Among these patients, a sizeable population is referred for non-surgical treatments like radiation therapy. Our results, although from a very small study with a short follow-up period, demonstrated the possibility that external beam irradiation plus endobronchial HDR brachytherapy can be an alternative to surgery for roentogenographically occult lung cancer. An accumulation of cases is needed to determine the optimal dose of brachytherapy.
[4]
[5] [6]
[7]
[8]
[9]
[10]
[11]
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