Research ArticleClinical Studies

The Feasibility and Efficacy of Stereotactic Body Radiotherapy for Centrally-located Lung Tumors

WATARU TAKAHASHI, HIDEOMI YAMASHITA, MAMI OMORI, MAYUKA KITAGUCHI, SHINO SHIBATA-KOBAYASHI, AKIRA SAKUMI and KEIICHI NAKAGAWA
Anticancer Research November 2013, 33 (11) 4959-4964;

Abstract

Aim: To investigate the toxicity and outcome of stereotactic body radiotherapy (SBRT) for centrally-located lung tumors. Patients and Methods: A retrospective review was conducted in 45 consecutive patients with centrally-located lung tumors who underwent SBRT. The incidence rate of adverse events (AEs) and outcome after SBRT for primary (32 patients), metastatic and recurrent (13 patients) lung tumors were evaluated. Results: The median follow-up period was 21.2 months. Except for one patient who had grade 4 gastrointestinal toxicity, no patient exhibited any grade 4-5 AE. The 2-year overall survival of patients with primary non-small cell lung cancer (NSCLC) was significantly better than that of those with metastatic and recurrent tumors of 69.4% vs. 46.9% (p=0.04). The local control rates at two years, for patients in the NSCLC and the metastatic/recurrent groups were 70.9% and 100%, respectively (p=0.98). Conclusion: SBRT provided effective treatment for centrally-located lung tumors with tolerable toxicity.

Stereotactic body radiation therapy (SBRT) has become a therapeutic option for early-stage non-small cell lung cancer (NSCLC) and metastatic lung tumors in patients with inoperable disease or for those refusing surgery. SBRT has the advantage of being a minimally invasive procedure, as well as having a relatively short duration in the course of treatment. In addition, SBRT continues to show much better outcomes than conventional radiotherapy (RT) (1-4). However, SBRT for centrally-located lung tumors remains a challenge because the central thoracic structures are considered to include organs at risk. For normal tissues, the use of a high dose per fraction rather than a conventional fractionated dose can increase the risk of late complications if the same volume were irradiated (5). To date, only a few studies have reported on the safety and efficacy of treating centrally-located lung tumors with SBRT (6-8). In a group of 63 patients with centrally-located lung tumors, Haasbeek et al. reported that a total of seven patients developed grade 3 acute or late toxicity after undergoing eight fractions of 7.5 Gy (9). Rowe et al. also reported the results of SBRT for 47 patients with centrally-located tumors. In their series, a total of five patients (10.6%) experienced grade 3-5 pulmonary toxicity (10).

In the present study, a retrospective review was conducted in 45 consecutive patients treated for centrally-located lung tumor with SBRT in our institution between 2003 and 2011. The dose and fractionation employed in this study was different from the two studies mentioned above. The principal aims of this study were: to evaluate the severity of toxicities correlated with this treatment; and to investigate treatment outcomes of centrally-located lung tumors treated with SBRT.

Patients and Methods

From March 2003 to July 2011, SBRT was performed on 148 consecutive patients with lung tumors (primary or recurrent NSCLC and metastatic lung tumor) at the University of Tokyo Hospital. A centrally-located tumor was defined as being within 2 cm of the bronchial tree, major vessels, esophagus, heart, trachea, pericardium, brachial plexus, or vertebral body. As for patients with primary NSCLC patients, complete staging procedures were carried out including computed tomography (CT) of the chest and 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) CT scan. All patients enrolled in this study satisfied the following eligibility criteria: a) solitary lung tumor; b) maximum tumor diameter <50 mm; c) no evidence of lymph node metastasis; d) serum Krebs von den Lungen-6 (KL-6) <500.0 U/ml; e) forced expiratory volume in 1 second (FEV1) ≥750 ml; f) no shadow of interstitial pneumonitis on CT image; g) no history of previous lung or mediastinal RT; and i) no additional concomitant or adjuvant anti-neoplastic therapy (including chemotherapy or fractionated RT) except at disease progression.

For all patients, CT images for treatment planning were acquired using Aquillion TMLB (TOSHIBA, Tokyo, Japan) after patients were positioned in a stereotactic body frame (SBF; ELEKTA, Stockholm, Sweden) in the supine position. An SBF-attached template on the patient's abdomen reduced the mobility of the target.

View this table:
Table I.

Patient and tumor characteristics.

From March 2003 to September 2010, CT images were acquired with 1-mm-thick slices around the tumor and 5-mm slices elsewhere using the ‘long scan-time’ technique, which visualized a major part of the trajectory of tumor movement by scanning each slice for a long time (11). Slow CT scan was performed for 4 seconds with abdominal compression. These data were then sent to a treatment planning system (Pinnacle3 v7.4i; Phillips, Andover, MA, USA). The internal target volume (ITV) was delineated using the lung window, and planning target volumes (PTVs) were created by adding 5 mm margins to the ITVs in all directions. The planned dose at the isocenter was 48 Gy in four fractions or 56 Gy in seven fractions, using 6 MV non-coplanar and non-opposing beams. At least eight beams were used.

Since October 2010, volumetric modulated arc therapy (VMAT)-SBRT has been performed with a Synergy linear accelerator (ELEKTA, Stockholm, Sweden). CT images of 2 mm thickness were taken in the treatment position during the expiratory phase. The ITV was contoured as the gross tumor volume (GTV), and an additional 5 mm margin was added to cover the ITV as a PTV. The patients received a dose covering 95% volume (D95) prescription of 50 Gy for PTV in four fractions. The single-arc VMAT with 6 MV was created by SmartArc in the Pinnacle3 (version 9.0i). Dose constraints for normal organs at risk (OAR) for complications were: ipsilateral lung volume receiving 20 Gy (V20) <10% and 5 Gy <25%, contaralateral lung volume receiving 20 Gy (V20) <0% and 5 Gy <15%; and spinal cord volumes receiving 15 Gy (V15) <0%; heart volumes receiving 30 Gy <0%; liver volume receiving 30 Gy <0%. Albeit VMAT-SBRT planning was developed using the optimization constraints above, some cases actually failed to achieve a part of these planning constraints. In all plans, there was an additional 5 mm leaf margin to the PTV in order to make the dose distribution within the PTV more homogeneous.

View this table:
Table II.

Acute and late adverse effects of SBRT for centrally located lung tumors.

After the completion of SBRT, the following evaluations were performed every 2-3 months for 18 months and every six months thereafter: medical history with toxicity evaluation, physical examination, and imaging studies including CT scans of thorax with 3-mm slices. Local control was defined as a situation in which no radiological signs of tumor progression were observed within the radiation portals. Acute and late adverse events (AEs) were graded according to the criteria of the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0 (12). Because tumor was located adjacent to mediastinal structures, the mediastinal dose was evaluated using D2cc (the minimum dose in the most irradiated 2 cc of the mediastinal structures such as major vessels, and the heart).

To evaluate the feasibility and toxicity of SBRT treatment, acute and late toxicities that were grade 2 or more were evaluated. The cumulative probability of AEs was calculated and drawn applying the Kaplan-Meier algorithms with day 1 of treatment as the starting point. The χ2 test was used to evaluate the correlation between toxicity scales and potential risk factors such as histology (NSCLC vs. metastatic and recurrent) and PTV volume. Local control (LCR) and overall survival (OS) rates were calculated from the beginning of SBRT using the Kaplan-Meier method. LCR was calculated to the first local recurrence date, censoring death or last follow-up date. Comparisons of survival between groups were performed with the log-rank test. Confidence intervals (CIs) were calculated by the Cochran-Mantel-Haenszel test. A p-value of less than 0.05 was considered significant.

Figure 1.
Figure 1.

Overall survival and local control of 45 patients with centrally-located lung tumors.

Results

Patients' characteristics. There were centrally-located tumors in 45 out of the 148 patients who were retrospectively analyzed in this study. The patient and tumor characteristics are summarized in Table I. There were 31 males and 14 females, with a median age of 77 years (range=25-92 years). For Karnofsky performance status scale (K-PS), 41 patients (91%) scored more than 80%. Out of the 45 patients, the tumors were classified as follows: primary NSCLC, 32; metastatic lung cancer tumor, 12; and recurrent NSCLC, one. In the cases with metastases, there was a wide variety of primary sites: six of NSCLC, two of esophageal cancer and one each of parotid gland (adenoid cystic carcinoma), cecal cancer, cervical cancer, and lung angiosarcoma. Except for one patient receiving carbon ion therapy for primary parotid gland cancer, 11 patients underwent surgery for the primary site and achieved local control. As for the patient with recurrent NSCLC, he underwent lobectomy with a diagnosis of pT2N0M0 squamous cell carcinoma. The median PTV was 50.8 cc (range=6.4-187.6 cc). The majority (75.6%) of tumors received a dose of 48 Gy or 50 Gy in four fractions (biological equivalent dose (α/β=10) (BED10)=105.6 Gy or 112.5 Gy), and the others (24.4%) received a dose of 56 Gy in seven fractions (BED10=100.8 Gy) at the discretion of each attending radiation oncologist. In most cases treated with 56 Gy in 7 fractions, tumors were located more centrally and were considered as cases at high risk for severe toxicities.

Adverse events. Our SBRT was well-tolerated and all treatments were completed within two weeks. No patients were discontinued due to toxic effects. As shown in Table II, no patient had severe AEs (grades 4-5) except one. Five patients had acute cough (grade 2) and used medication. Radiation pneumonitis (RP) of grades 2 and 3 were observed in three (6.7%) and one patient (2.2%), respectively. The patient with grade 3 RP required steroids and oxygen, and then had remission of oxygen desaturation. The cumulative probability of having AEs of grade 2 or more was 17.2%±6.7% after two years (Figure 2). The median time for showing symptoms was 6.5 months (range=4-10 months). Perforation of gastric tube (grade 4) was observed in one patient. This patient had metastatic lung tumor of esophageal cancer after total esophagectomy with esohageal replacement via the retrosternal route by means of a gastric tube. He had undergone SBRT, consisting of 50 Gy in four fractions in four days. As background, he was a heavy smoker and had an alcohol problem. Two months after SBRT, he developed black stools and abdominal pain. A CT scan and emergency endoscopic examination revealed diffuse mucosal hemorrhage and perforation of the pulled-up gastric tube. No long-term toxicity was observed for the esophagus, heart, and skin.

The PTV had no significant effect on AEs that were grade 2 or more. There was also no difference in the incidence of AEs between patients with NSCLC vs. those with other tumor types.

Figure 2.
Figure 2.

Kaplan-Meier plot of time-to-first occurrence of grades 2-5 toxicity after SBRT.

Figure 3 shows five examples of the dose distributions and D2cc with the ITV (pink line) and PTV (cyan line) in axial view of each case. These cases were the five cases of SBRT with the highest D2cc. Contrary to our expectation, the values of D2cc were not relevant to the severity of AEs.

Clinical outcome. The median follow-up was 21.2 months (range=1.3-55.7 months) for all patients, and 31.9 months (range=7.8-55.7 months) for survivors. At the time of the analysis, 21 patients had died during the follow-up period and the remaining 24 patients were alive. Nine of the 21 deaths were due to cancer. The OS rates at one and two years were 70.4% (95% CI=56.8-83.9%) and 62.1% (47.3-77.0%), respectively (Figure 1). For LCR, from the time of the last follow-up, local failure subsequently occurred in eight patients (17.8%). The median time-to-local failure was 11.7 months (range=2.1-33.4 months). The overall LCRs at one and two years were 89.5% (95% CI=79.6-99.4%) and 77.3% (95% CI=62.0-92.7%), respectively (Figure 1).

For the 32 patients with primary NSCLC, the median survival time (MST) was 40.5 months, and the 2-year OS was 69.4% (95% CI=52.6-86.3%). On the other hand, for patients with metastatic and recurrent tumors, the MST was 9.2 months, and 2-year OS was 46.9% (95% CI=17.4-76.3%). There was a significant difference in the rates of OS between patients with NSCLC vs. those with the other tumor types (p=0.04). In addition, the LCR at two years among patients in the NSCLC and the metastatic/recurrent groups were 70.9% (95% CI=52.1-89.7%) and 100%, respectively. There was also no difference in the LCRs between patients with NSCLC vs. those with the other tumor types (p=0.98).

Discussion

Even currently, the optimal dose of SBRT has not been determined for centrally-located lung tumor but has been investigated in a few clinical studies (13-14). One such study reported good control rates and the safety of SBRT with a BED ≥100 Gy (15). Therefore, the SBRT doses of 48 Gy or 50 Gy in four fractions and 56 Gy in seven fractions which were used in the current study were consistent with previously reported studies. As a result, our retrospective study also demonstrated that SBRT for centrally-located lung tumor resulted in excellent local tumor control. The 2-year LCR of 77.3% compared favorably with other rates reported in the literature. As for the 2-year OS, there was a significant difference between primary NSCLC and pulmonary metastasis (69.4% vs. 46.9%, p=0.04). Since new metastases occur frequently in patients with lung metastases, they might carry a poor prognosis after the first SBRT is delivered successfully.

At present, one of the most controversial topics in SBRT is toxicity after treating mediastinal tumors. Timmerman et al. reported that SBRT for centrally-located tumors was a strong predictor of severe complications (16). Since results from only a few small series have been published that describe SBRT in this location (6-10), it is difficult to accurately estimate the incidence of complications. We report here the results of a retrospective, single-institution feasibility study of SBRT for centrally located lung tumors. Although grade 1-2 acute non-hematological toxicities, such as cough or fatigue, were observed in the current study, all patients did complete the planned SBRT. Grade 2-3 RP was noted in four patients (8.9%), which was similar to the findings of earlier studies. Grade 3 and 4 severe toxicities were observed in two patients (4.4%). Out of these, one patient developed RP (grade 3) six months after completion of SBRT. The other patient developed a perforation of a pulled-up gastric tube (grade 4) two months after completing the treatment. Although it is likely that the perforation may have been caused mainly by radiation to the gastric tube, smoking and poor nutrition might also have partly contributed to this event. There are reports that deterioration due to smoking and poor nutritional status during RT could be associated with poorer short-term treatment outcomes and severe toxicity (17, 18).

Figures 3.
Figures 3.

CT images showing dose distributions of the patients with top five cases of the minimum doses in the most irradiated 2 cc of the mediastinal structures (D2cc). Cyan, Internal target volume (ITV); pink, planning target volume (PTV).

Several limitations of the current study warrant mentioning. Firstly, this was a retrospective review with a limited number of cases and relatively short follow-up. Secondly, we treated heterogeneous cases that included NSCLC and metastatic lung tumor from various primary sites. Thirdly, three different fractionations were chosen for SBRT. These limitations can be overcome by further prospective studies that include long-term results, as well as data on local control and late complications. A phase I/II study (RTOG 0813) is evaluating the escalation of doses delivered for centrally-located tumors. Such an ongoing study may provide with additional information about the optimal dose and schedule for SBRT.

In summary, our use of SBRT for centrally-located lung tumors showed a lower incidence of complications and a satisfactory local tumor control using 48 Gy/4 fr, 50Gy/4 fr or 56 Gy/7 fr.

  • Received September 9, 2013.
  • Revision received October 12, 2013.
  • Accepted October 14, 2013.

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The Feasibility and Efficacy of Stereotactic Body Radiotherapy for Centrally-located Lung Tumors
WATARU TAKAHASHI, HIDEOMI YAMASHITA, MAMI OMORI, MAYUKA KITAGUCHI, SHINO SHIBATA-KOBAYASHI, AKIRA SAKUMI, KEIICHI NAKAGAWA
Anticancer Research Nov 2013, 33 (11) 4959-4964;
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