(Chest. 2004;125:340-344.)
© 2004
American College of Chest Physicians
Serum Levels of KL-6 for Predicting the Occurrence of Radiation Pneumonitis After Stereotactic Radiotherapy for Lung Tumors*
Ryusuke Hara, MD;
Jun Itami, MD;
Takafumi Komiyama, MD;
Daiki Katoh, MD and
Tatsuya Kondo, MD
* Department of Radiation Therapy and Oncology, International Medical Center of Japan, Tokyo, Japan.
Correspondence to: Jun Itami, MD, Department of Radiation Therapy and Oncology, International Medical Center of Japan, Toyama 1-21-1 Shinjyuku-ku, Tokyo, Japan 162-8655; e-mail: jitami{at}imcj.hosp.go.jp
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Abstract
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To determine the usefulness of serum KL-6 levels for predicting the occurrence of radiation pneumonitis (RP) after the application of single high-dose stereotactic radiation therapy for lung tumors, the serum KL-6 levels were measured in 16 patients before irradiation and every 1 or 2 months thereafter. Three of the 16 patients experienced RP of grade 3 severity according to the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group toxicity criteria. RP occurred 3 months after the completion of radiation therapy in two patients, and 4 months after completion in one patient. RP occurred at significantly increased frequencies in patients with primary lung cancer (p = 0.01) and adenocarcinoma (p = 0.01), and in those undergoing the concurrent irinotecan therapy (p = 0.02). In all 16 patients, the lactate dehydrogenase level remained normal during the follow-up period. In all three of the patients with RP, KL-6 levels increased by > 1.5-fold compared to the pretreatment value and over the cutoff level of 500 IU. The ratio of the increase in serum KL-6 values 2 months after the patient had undergone irradiation showed a significant correlation with the occurrence of RP (p = 0.04). In conclusion, KL-6 is a useful marker for prediction of the occurrence of RP after single, fractional, high-dose stereotactic irradiation of lung tumors.
Key Words: KL-6 • lung tumor • radiation pneumonitis • stereotactic radiotherapy
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Introduction
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We have developed a microtron-based system for the stereotactic irradiation of body tumors that delivers radiation at a predetermined respiratory phase.1
Using this system, patients with lung tumors have been treated by single fractional irradiation. The preliminary results of this treatment regimen have been reported elsewhere.2
A few patients undergoing single high-dose stereotactic radiotherapy experienced radiation pneumonitis (RP), which was treated by the administration of steroids. The serum level of KL-6 was reported to be a useful marker of RP.3
4
We examined the usefulness of serum KL-6 levels for predicting the occurrence of RP after single high-dose stereotactic radiation therapy.
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Materials and Methods
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The single, fractional, high-dose stereotactic radiation therapy procedure was described in detail elsewhere. Briefly, the patient is fixed noninvasively in a custom-made bed, and CT images at the end-expiratory phase are obtained about 20 cm caudally and rostrally from the tumor with the patient lying in the custom-made bed. Isocentric, multiportal, three-dimensional, converging radiotherapy is planned, and a single dose of radiation therapy is delivered only at the end-expiratory phase using 6-mV x-rays. The subjects in the present study were 16 patients with lung tumors who were undergoing single, fractional, high-dose, stereotactic radiation therapy with sequential measurements of serum KL-6 (Table 1
). None of the tumors were treated by fractionated radiation. Eight patients had metastatic lesions from various primary sites, and six patients had primary lung cancer. The remaining two patients had a solitary lung tumor of unknown histology, although the accumulation of fluorodeoxyglucose in positron emission tomography strongly suggested diagnoses of primary lung cancer. There were six squamous cell carcinomas and six adenocarcinomas. The patients ranged in age from 53 to 90 years, with a median of 73 years. The female/male ratio was 6:10. Circular fields of the following diameters were used for stereotactic irradiation: 50 mm in seven patients; 40 mm in five patients; and 30 mm in four patients. The minimum dose of the gross tumor volume was 35 Gy in 2 patients, 30 Gy in 12 patients, and 20 Gy in 2 patients. The volume irradiated > 8 Gy was defined as V8, because single-fraction irradiation at this dose was reported previously5
as causing RP in humans at a significant rate. V8 ranged from 28 to 306 mL, with a mean of 132 mL. Three patients underwent concurrent chemotherapy with irinotecan (CPT-11). Five patients had chronic lung disorders. Three patients had emphysema, and two patients had chronic bronchitis. The length of follow-up ranged from 2 to 20 months, with a mean of 6 months. During the follow-up period, 14 tumors remained stable, while 2 showed local regrowth. Serum levels of KL-6 were measured by a modified sandwich-type enzyme-linked immunosorbent assay.3
6
7
Serum levels of KL-6 were measured before irradiation and every 1 or 2 months after irradiation, as shown in Figure 1 . The cutoff level of KL-6 was 500 IU. Differences between groups were tested by t test or 
2 test, and p values of < 0.05 were considered to indicate significance.
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Results
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Three of the 16 patients experienced RP of grade 3 according to the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group toxicity criteria.8
All three patients with RP had a cough and continuous fever, and showed infiltrative changes in the irradiated area on chest radiographs. RP occurred 3 months after the completion of radiation therapy in two patients, and 4 months after completion in one patient. In two patients receiving concurrent CPT-11 therapy, pneumonitic changes, as seen on CT images, occurred within the range of an 800-cGy isodose volume. In the other patient, who was not receiving chemotherapy, RP spread out beyond the isodose volume of 800 cGy and reached 300 cGy (Fig 2
). Various clinical as well as therapeutic factors were analyzed for their possible relationships to the incidence of RP (Table 2
). RP occurred at a significantly increased frequency in the patients with primary lung cancer and adenocarcinoma, and in the patients undergoing concurrent CPT-11 therapy. Other factors did not show statistically significant relationships with the occurrence of RP.
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Figure 2.. Top: treatment planning of single fractional, high-dose, stereotactic irradiation for the treatment of primary lung adenocarcinoma. The minimal gross tumor volume dose was 30 Gy. The arrow indicates the 300-cGy isodose line. Top middle: RP 4 months after irradiation. The area of RP corresponds to the 300-cGy isodose line. RP changes were confined and were only minimally observed in the CT scan slices 2.5 cm caudally (bottom middle) and 2.5 cm rostrally (bottom).
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In all 16 patients, lactate dehydrogenase levels remained normal during the follow-up period, while serum KL-6 levels increased above the cutoff level in all 3 patients with RP before and after the diagnosis. In all three patients with RP, KL-6 rose to levels > 1.5-fold greater than the pretreatment value. One patient without RP showed a posttreatment increase of 1.5-fold in KL-6 levels compared to the pretreatment value, although the maximal value lay below the cutoff level (313 IU). Another patient with primary adenocarcinoma of the lung had a pretreatment KL-6 value that was over the cutoff level of 500 IU. However, the value decreased to below the cutoff level after irradiation, and the patient did not experience RP.
The ratios of the increases in KL-6 level at 1 and 2 months after irradiation were analyzed in comparison to the pretreatment level to determine its value in the prediction of the occurrence of RP (Table 3
). The increment ratio of the serum KL-6 value 2 months after irradiation showed a significant correlation with the occurrence of RP. The patients with RP had a mean KL-6 increment ratio of 1.54, while the mean ratio for patients without RP was 1.1.
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Table 3.. Incidence of RP According to the Increment Ratio of KL-6 Level 1 and 2 Months after Undergoing Single Fractional, High-Dose, Stereotactic Radiation Therapy*
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Discussion
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KL-6 is an antibody against human lung adenocarcinoma,6
the serum titer of which has been reported to be a sensitive marker of active pneumonitis, including RP.9
Goto et al4
reported that in conventional radiation therapy of lung tumors the serum KL-6 level reflected the severity of RP, and that an increase in its level of > 1.5-fold was associated with serious RP that was refractory to steroid therapy. The severity of RP has been reported to be determined mainly by the area irradiated with a dose of > 20 Gy in conventional fractionation.10
11
In contrast, all three of the patients with RP in the present study were treated successfully with steroids despite increases in KL-6 levels of > 1.5-fold compared to the baseline value. In single fractional stereotactic radiation therapy under respiratory gating, the target volume could be reduced to such a degree that the mean volume was only 65 mL and the pneumonitic changes were confined to very small areas in comparison to conventional radiation therapy with anteroposterior opposing fields. Therefore, in the present study, the rise in serum KL-6 levels was induced not by the large volume of a high-dose region, but by a single fractional application of a large dose. A single high dose of radiation confined to a small volume of lung might have evoked marked destruction of lung tissues with the resultant remarkable increase in serum KL-6 levels, even though the RP changes were confined to small volumes. In addition, the increase in the KL-6 level was seen 1 to 2 months before the occurrence of RP symptoms, and the ratio of the increase 2 months after irradiation could predict the occurrence of RP. The levels of lactate dehydrogenase, another marker of RP, did not increase in the three patients with RP. Therefore, KL-6 is very useful in predicting the occurrence of RP after single fractional stereotactic irradiation, although the rise per se does not indicate the severity of RP as seen in the increase in KL-6 after a patient undergoes conventional anteroposterior irradiation.
Anscher et al12
reported that the development of pulmonary injury was associated with persistently elevated levels of plasma transforming growth factor (TGF)-ß levels after high-dose thoracic radiotherapy. Fu et al13
reported that these changes in plasma TGF-ß levels were correlated with the risk of pulmonary injury independent of the volume of lung irradiated. Therefore, TGF-ß also may be useful as a predictor of RP after small-volume thoracic irradiation.
Primary lung carcinoma, adenocarcinoma, and concurrent CPT-11 therapy were found to be significant risk factors for RP after single fractional stereotactic irradiation. Although CPT-11 is a very promising agent for the treatment of non-small cell lung cancer, it has been shown to induce clinically significant pulmonary toxicity.12
13
In the present series, lung tumors that were mainly peripherally located were irradiated, all of the patients with histologically proven lung cancer had adenocarcinomas, and CPT-11 was administered only to those patients with primary lung adenocarcinoma. Therefore, concurrent therapy with CPT-11 was the major cause of RP seen in the present study, although the RP could be successfully alleviated by steroid treatment. Although the concurrent administration of CPT-11 is appealing to enhance the local control rate as well as to improve prognosis in patients with non-small cell lung cancer who are undergoing single fractional stereotactic irradiation, the occurrence and severity of RP must be strictly monitored by checking KL-6 levels and clinical symptoms. RP occurred in the regions included within the 8-Gy dose distribution in two patients, and within the 3-Gy dose distribution in one patient. In a previous study using whole-body irradiation, Wara et al5
demonstrated that 8 Gy is the tolerance dose in the lung in single fractional irradiation. It remains unknown why a single patient showed RP changes reaching the region exposed to the far lower dose of 3 Gy. Some immunologic processes induced by tissue destruction in single fractional high-dose irradiation might be involved in the extension of RP, and further observation of the radiation changes in the lung after single fractional high-dose irradiation is required.
In conclusion, KL-6 is a useful marker for the prediction of the occurrence of RP after single, fractional, high-dose stereotactic irradiation of lung tumors. The extent of RP might reach beyond the tolerance dose of single fractional lung irradiation, and it is necessary to examine the mechanism of RP as well as that of the increment of KL-6 after single, fractional, high-dose stereotactic irradiation.
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Footnotes
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Abbreviations: CPT-11 = irinotecan; RP = radiation pneumonitis; TGF = transforming growth factor; V8 = irradiated volume more than 8 Gy
Received for publication February 26, 2003.
Accepted for publication July 1, 2003.
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References
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- Kohno, N, Akiyama, M, Kyoizumi, S, et al Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma. Jpn J Clin Oncol 1988;18,203-216[Abstract/Free Full Text]
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- Tsujino, K, Hirota, S, Endo, M, et al Predictive value of dose-volume histogram for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys 2003;55,110-115[CrossRef][ISI][Medline]
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- Fu, X, Huang, H, Bentel, G, et al Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biological parameters V30 and transforming growth factor ß. Int J Radiat Oncol Biol Phys 2001;50,899-908[CrossRef][ISI][Medline]
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Abstract
Introduction
