Japanese Journal of Clinical Oncology Advance Access originally published online on August 22, 2008
Japanese Journal of Clinical Oncology 2008 38(9):581-588; doi:10.1093/jjco/hyn077
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© The Author (2008). Published by Oxford University Press. All rights reserved
Long-term Observation of 64 Patients with Roentgenographically Occult Lung Cancer Treated with External Irradiation and Intraluminal Irradiation Using Low-dose-rate Iridium
1 Department of Radiation Oncology, Southern Tohoku Proton Center, Fukushima
2 Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya
3 Division of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
For reprints and all correspondence: Nobukazu Fuwa, 7-115, Hachiyamada, 963-8563 Koriyama, Japan. E-mail: nobufuwa{at}nifty.com
Received July 9, 2008; accepted July 17, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: Therapeutic results of intraluminal irradiation were analyzed in 64 patients with roentgenographically occult lung cancer (ROLC).
Methods: The subjects were 64 patients who underwent intraluminal irradiation between 1987 and 2003. Radiotherapy was performed by combining external irradiation with intraluminal irradiation using low-dose-rate iridium (four 370-MBq wires) through a catheter with a spacer. The doses of radiation were 0–70 Gy (median value 46 Gy) by external irradiation and 10–60 Gy (median value 29.3 Gy) by intraluminal irradiation.
Results: The therapeutic effect was CR in 63 patients and PR in 1 patient, and local recurrence was observed in a PR case and in seven of the 63 patients who showed CR. The 5-year overall and relapse-free survival rates were 56 (95% CI, 43–69%) and 55% (95% CI, 43–68%), respectively. Fatal pulmonary hemorrhage was observed in one case.
Conclusions: Considering the facts that ROLC often occurs as multiple cancers and that many patients with ROLC have reduced lung function, radiation therapy by a combination of intraluminal and external irradiation may replace surgery as the first choice for the treatment of this disease.
Key Words: roentgenographically occult lung cancer • intraluminal irradiation • external irradiation • iridium thin wire
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Intraluminal irradiation for lung cancer has come to be used widely in clinical cases only after the advent of the thin and highly flexible iridium sources. However, the primary objective of intraluminal irradiation has been alleviation of symptoms such as cough, bloody sputum and dyspnea caused by tumors in the bronchi, and the procedure has been regarded as a palliative approach (1–12). Reports of intraluminal irradiation as a radical treatment have been limited (13–21), and its role as a radical treatment has not been sufficiently evaluated.
One of the reasons for this condition was that the dose distribution on the bronchial mucous membrane was apt to be uneven with the formerly used conventional bronchial intraluminal irradiation catheter. Part of the bronchial mucous membrane received a low dose of irradiation and tended to develop local recurrence, and part of it received an excessive dosage that sometimes caused a severe problem, i.e. fatal pulmonary hemorrhage (FPH). Therefore, in 1987, we developed an intraluminal irradiation catheter specialized for bronchi with a built-in device, which would make the dose distribution on the bronchial mucous membrane homogeneous (13). The results of roentgenographically occult lung cancer (ROLC) treatment with this catheter were far better for the therapeutic effects and adverse effects as compared with the reports from other researchers (19–21). We have shown that it has an important role as a radical treatment of bronchial intraluminal irradiation.
In this paper, we report the therapeutic and adverse effects of 64 cases of ROLC with more than 3 years of long-term observation, and evaluate the role of intraluminal irradiation in ROLC.
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PATIENTS AND METHODS |
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Patient Characteristics
The subjects were 64 patients who underwent intraluminal irradiation at the Department of Radiation Oncology, Aichi Cancer Center, between May 1987 and May 2003 (Table 1). The lesions were confirmed by bronchoscopic biopsy in all patients. Bronchoscopy was performed due to bloody sputum in 24 patients, abnormal cytology of sputum on screening in 14, persistent cough and sputum in six and for other reasons in 21.
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Whether the tumor invaded outside the bronchial wall was examined by thin slice CT, contrast-enhanced CT was used to see if it had metastasized to the hilar or mediastinal lymph nodes, and whether it had distant metastases was examined by bone scintigraphy, hepatic CT or ultrasonography, and brain CT or MRI.
Surgery was not performed for the following reasons. In 40 patients, surgery was considered to be inappropriate due to the poor general conditions resulting from pulmonary insufficiency, old age and multiple cancers. Although surgery was possible, the other 24 patients refused that option, and selected radiation therapy.
In 1999, the Japan Society of Lung Cancer defined ROLC as shown in Table 2. Among the cases we studied here, 36 cases fitted this definition.
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Radiation Therapy
Details of the catheter for bronchial intraluminal irradiation and the procedure of intraluminal irradiation have been reported previously (13,15,19–21). Iridium thin wires (340 MBq, 5 cm in length and 0.3 mm in diameter) were used as the radiation sources. Four iridium thin wires were inserted into the radiation source tube. The irradiation dose was measured taking the bronchial mucosal surface as the reference point, and a dose of 4–6 Gy per fraction was delivered at 1–2 fractions per week. The distances between the radiation source and the mucosal surface were provisionally standardized at 9 mm for the trachea, 7 mm for the main bronchi, 5 mm for the lobar and segmental bronchi and 3 mm for sub-segmental bronchi. In the case of 5 Gy irradiation for a tumor in the lobar bronchus, the reference point was 5 mm from the radiation source, and
2 Gy/h was delivered. Therefore, the treatment time per session was 2 h 30 min. Intraluminal irradiation was performed after external irradiation until March 1992. Thereafter, however, radiations were performed on the same day. External irradiation was performed by two (AP and PA) opposed portals using a 6 MeV linear accelerator. Gross target volume (GTV) was planned by an X-ray simulator using bronchoscopy.
Planning target volume was intended to add a 2-cm safety margin from the GTV. The dose of external irradiation was 50 Gy or above until 1993; however, it was adjusted thereafter based on the pulmonary function and tumor response, i.e. at 40–50 Gy in those with normal pulmonary function, at 30–40 Gy in patients with reduced pulmonary function (60 mmHg 
PaO2 < 80 mmHg) and no external irradiation in patients with severe pulmonary dysfunction (PaO2 < 60 mmHg). In association, the dose of intraluminal irradiation was increased to 30–50 Gy in patients with reduced pulmonary function and to 20–30 Gy in those with normal pulmonary function.
Patient Assessment
The therapeutic effects were evaluated by bronchoscopy performed within 1 month after the end of the treatment. The effect was considered to be a CR for complete gross disappearance of the tumor and negative cytology, a PR for gross disappearance of the tumor but positive cytology and an NC for gross persistence of the tumor.
The patients had follow-up bronchoscopy every 3 months; chest X ray every 6 months; and chest CT, liver ultrasonography and bone scintigraphy every year.
The overall survival rate, relapse-free survival rate, cause-specific survival and local control rate were calculated by the Kaplan–Meier method (22). Overall survival rate was measured from the first day of the radiation therapy study until death from any cause. Relapse-free survival was measured until recurrence of lung cancer. Time-to-recurrence was measured from the first day of radiation therapy during this study until the date of local and regional recurrence (regrowth) and/or distant metastasis. Patients dying of inter-current disease without evidence of disease were censored at the time of death for time-to-relapse-free survival. Cause-specific survival was measured from the first day of radiation therapy during this study until death resulting from lung cancer. Deaths related to the therapeutic procedures without evidence of disease were regarded as deaths due to lung cancer. The local control rate was measured until local recurrence (regrowth) of treated sites.
This time, we analyzed the three kinds of survival rates mentioned earlier in all the subjects, overall survival rate and local control rate of the cases that met the diagnostic criteria and the cases that are out of the diagnostic criteria of ROLC shown in Table 2, and the overall survival rate and relapse-free survival rate of 24 operable cases.
Statistical analyses were performed using the log-rank test. To assess the prognostic factors for local control, the data were analyzed with respect to age, performance status, tumor size, type of tumor, peripheral visibility, total intraluminal radiation dose and total external beam radiation dose.
On univariate analysis, the log-rank test was used to evaluate the homogeneity of the levels of each prognostic factor on patients' local control. On multivariate analysis, a Cox proportional-hazards model was used to evaluate the adjusted effect of the prognostic factors (23). The prognostic factors here were selected from those significant at level 0.10 on univariate analysis by a stepwise, forward and backward procedure. The significance level for entering a prognostic factor into the Cox model in the stepwise or forward procedure and for removing a prognostic factor from the Cox model in the stepwise or backward, procedure, was 0.15. The proportional-hazards assumption for the Cox model was assessed by the log-minus-log survival plots. The reported P values in the Cox model were based on the Wald test. All reported P values were two-sided. On both of the univariate and multivariate analyses, the hazard ratios and their 95% confidence intervals from the Cox model were also reported. Statistical analyses were performed with the use of the SAS system for Windows, version 8.02 (SAS institute, Cary, NC, USA).
According to the common toxicity criteria version 3, the toxicity was evaluated based on the changes in chest x-p, bronchoscope findings and changes in pulmonary function.
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RESULTS |
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Tumor Response and Clinical Course
Treatments were completed as planned in 63 patients, except for one case (poor general health). The doses were 0–70 Gy (median value 46 Gy) by external irradiation and 10–56 Gy (median value 29.3 Gy) by intraluminal irradiation. The therapeutic effect was a CR in 63 patients and a PR in 1, in whom additional treatments were reserved because of poor general health. Local recurrence was observed in the PR case and seven of the 63 patients who showed CR (follow-up period 3 months to 12 years and 11 months with a median value of 4 years and 10 months). Recurrent sites were inside the primary lesions in two patients and at the periphery of the primary lesions in six patients. Additional therapy for seven patients was segmental resection (1), additional external irradiation (1), additional intraluminal irradiation (1), additional external and intraluminal irradiation (1), additional external irradiation and chemotherapy (2) and chemotherapy (1). Local control was only accomplished in the patient treated surgically, but this patient died due to the distant metastasis 5 years and 6 months after the first treatment.
Survival Rate and Local Control Rate
As of September 2007, 35 patients have died, 10 of them due to lung cancer, and the remaining 25 of other diseases. Figure 1 shows the overall survival and relapse-free survival rate curves for all cases. The 5-year overall survival rate and relapse-free survival rates were 56% (95% CI, 43–69%) and 55% (95% CI, 43–68%), respectively. Figure 2 shows the cause-specific survival rate curve for all cases. The 5-year cause-specific survival rate was 79.5% (95% CI, 68–91%).
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Figure 3 shows overall survival rate curves of the cases that met the diagnostic criteria, and the cases that were out of the diagnostic criteria of ROLC shown in Table 2. The 5-year survival rate of the cases that met the diagnostic criteria, and the cases that were out of the diagnostic criteria, were 57.8% (95% CI, 41–74%) and 52.9% (95% CI, 32–73%), respectively. There was no difference between them (P = 0.63).
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Figure 4 shows local control rate curves of the cases that met the diagnostic criteria, and the cases that were out of the diagnostic criteria. The 5-year local control rate of the cases that met the diagnostic criteria, and the cases that were out of diagnostic criteria, were 96.9% (95% CI, 91–100%) and 71.1% (95% CI, 52–90%), respectively. The local control rate was significantly better in the cases that met the diagnostic criteria (P = 0.0093).
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Figure 5 shows the overall survival and relapse-free survival rate curves in operable cases. The 5-year overall survival rate and relapse-free survival rates were 91.7% (95% CI, 81–100%).
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Factors of Local Control
On univariate analysis, type of tumor and peripheral visibility were found to have a significant impact on local control (Table 3). On multivariate analysis, clearness of peripheral visibility of the lesion was found to have a significant impact on local control (P = 0.026), whereas total dose of external irradiation (
46 Gy) was of borderline significance (P = 0.052) (Table 4).
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Toxicity
There were three treatment-related deaths. Two patients died of respiratory failure due to radiation pneumonitis. Intraluminal irradiation dose was 30.8 Gy in both the cases, and external irradiation doses were 46 and 28 Gy. The other patient died due to bronchial bleeding. This case received 60 Gy of external irradiation and 37 Gy of intraluminal irradiation. Since the post-treatment brushing cytology revealed cancer cells, an additional 16 Gy of re-intraluminal irradiation was given. The bronchial bleeding was caused by the infection from the biopsy done through bronchoscope, which was performed 5 months after this treatment.
There were two other cases of radiation pneumonitis, which needed treatment, and another case of bronchial erosion. Although one of the cases of radiation pneumonitis improved, the other became permanently oxygen dependent. The patient with bronchial erosion had persistent cough and sputum; however, these symptoms were alleviated by conservative treatments.
Figure 6 is a scattergram plotting the doses of intraluminal and external irradiation in each patient, along the horizontal and vertical axes, respectively. The two cases that developed problems in the bronchial mucous membrane received over 45 Gy of intraluminal irradiation doses.
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Multiple Primary Cancer
We confirmed a total of 20 cases of double cancer: four cases before the treatment, six cases simultaneously, six cases after the treatment and four cases before and after the treatment. There were four cases of triple or more primary cancer. There were 12 cases of lung cancer, nine cases of head and neck cancer, four cases of esophageal cancer and one case of stomach cancer.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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There are two requirements dictating the use of intraluminal radiotherapy for ROLC. One is irradiation at a sufficient dose for complete control of the tumor, and the other is the avoidance of overdosing normal tissues, to minimize late injury (chronic injury) in long-term survivors. To mitigate this problem, overdosing of the bronchial mucosa must be avoided by making the dose distribution in the bronchial mucosa as even as possible. For this purpose, devices to equalize the dose distribution, such as the catheter with a spacer that we developed, (13) which holds the radiation source in the center of the bronchus, are needed.
FPH is the greatest problem that may be caused by intraluminal irradiation (1,6). Overdosing of the bronchial wall is considered to be one of its causes, and equalization of the dose distribution of the bronchial mucosa is important for the prevention of FPH.
Unfortunately, we experienced one case of FPH. A possible reason was overdose with 60 Gy of external irradiation and 56 Gy of intraluminal irradiation. Another possibility was the infection from the post-treatment biopsy, which led to the bleeding. Great care should be used in performing the post-treatment biopsy.
Next, the depth of dose prescription was evaluated. In many reports, the dose was prescribed at 5 or 10 mm from the source. To deliver the dose theoretically to the surface of the bronchial mucosa, we assumed that it was 9 mm from the source in the trachea, 7 mm from the source in the main bronchus, 5 mm from the source in the lobar to segmental bronchi and 3 mm from the source in the subsegmental bronchi. Since the diameter of the tracheal bronchial tree varies widely, we considered that the monitoring point should be changed depending on the treated region.
Treatment results of intraluminal irradiation for ROLC are shown in Table 5. The method of Saito et al. (19) was similar to our's. Both methods showed better treatment results compared with other reports and there was only one case of FPH. We believe that this suggested the correctness of the method we presented.
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What, then, would be the optimal doses of intraluminal and external irradiation for ROLC? ROLC may vary from small superficial lesions a few millimeters in diameter to lesions exceeding 2 cm in diameter, so that the application of a uniform optimal dose to all lesions is inappropriate. The dose of external irradiation should be determined on the basis of the pulmonary function. Presently, we perform external irradiation at <40 Gy with intraluminal irradiation at 30 Gy or higher in patients with reduced pulmonary function. In patients with normal pulmonary function, we tentatively adjust the dose of external irradiation depending on the tumor size and the responses of the tumor in a range of 40–50 Gy with intraluminal irradiation at 20–30 Gy.
In case the tumor diameter is over 2 cm, metastasis to hilar lymph nodes is possible (24,25). Combination with chemotherapy, or if pulmonary function is normal, inclusion of the hilar of the lung in the radiation field should be considered.
Surgery is the standard treatment for ROLC, and ROLC often develops in heavy smokers, many of whom have reduced pulmonary function. Also, 20% or more of the patients with ROLC have multiple cancers (26). Therefore, surgery should be avoided as much as possible in patients with this disease (26,27). Though non-surgical therapies for ROLC include photodynamic therapy (PDT), PDT is inapplicable depending on the site of the tumor, and is generally indicated for the tumors <1 cm in diameter (28–30). Intraluminal irradiation is considered to have a wider range of indications than PDT.
Table 2 shows the definition of ROLC according to the Japan Society of Lung Cancer. In our treatment results, local control rate of the cases that met the diagnostic criteria, shown in Table 2, was good. The treatment result of operable cases was also very good in our study. This suggested that radiation therapy with intraluminal irradiation as the main therapy could be the first choice for cases meeting the diagnostic criteria.
Intraluminal irradiation using high-dose-rate iridium as the source is expected to spread worldwide, and ROLC will be included in its indications. Therefore, when intraluminal irradiation with high-dose-rate iridium is applied to ROLC, an applicator with a spacer as utilized in this study should be used, and a very careful dose escalation study is necessary.
Conflict of interest statement
None declared.
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