Stereotactic Ablative Radiotherapy: A Potentially Curable Approach to Early-Stage Multiple Primary Lung Cancer

Abstract

BACKGROUND

Surgical resection has been the standard treatment for early-stage multiple primary lung cancer (MPLC). However, a significant proportion of patients with MPLC cannot undergo surgery. We explored here the role of stereotactic ablative radiotherapy (SABR) for patients with MPLC.

METHODS

We reviewed MPLC cases treated with SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) for the second tumor. Four-dimensional CT–based planning/volumetric image-guided treatment was used for all patients. Treatment outcomes/toxicities were analyzed.

RESULTS

For the 101 patients treated with SABR, at a median follow-up interval of 36 months and median overall survival of 46 months, 2-year and 4-year in-field local control rates were 97.4% and 95.7%. 2- and 4-year rates of overall survival (OS) were 73.2% and 47.5% and progression-free survival (PFS) were 67.0% and 58.0%. Patients with metachronous tumors had higher OS and PFS than did patients with synchronous tumors (2-year OS 80.6% metachronous vs. 61.5% synchronous; 4-year OS 52.7% vs. 39.7%; p=0.047; 2-year PFS 84.7% vs. 49.4%; 4-year PFS 75.6% vs. 30.4%; p=0.0001). For patients whose index tumor was treated with surgery or SABR, the incidence of grade ≥3 radiation pneumonitis was 3% (2/71), but this increased to 17% (5/30) for patients whose index tumor was treated with conventional radiotherapy. Other grade ≥3 toxicities included grade 3 chest wall pain (3/101, 3%) and grade 3 skin toxicity (1/101, 1%).

CONCLUSIONS

SABR achieves promising long- term tumor control, survival and could be a potential curative treatment of early-stage MPLC.

INTRODUCTION

The incidence of multiple primary lung cancer (MPLC) has been steadily increasing, presumably because of improving patient survival from effective treatment of the first primary lung tumor coupled with earlier detection by multislice spiral computerized tomography (CT) and positron emission tomography (PET) ¹. Currently no guidelines are available on recommended treatments for MPLC. For early-stage tumors, surgical resection has shown encouraging results, with the potential for cure^2–5; however, a significant proportion of patients with MPLC are ineligible for surgery because of limited cardiopulmonary reserves or other medical conditions ⁶. Stereotactic ablative radiotherapy (SABR), also called stereotactic body radiotherapy (SBRT), has emerged as a novel radiation modality with significant applications for early-stage lung cancer. The feasibility, safety, and efficacy of SABR for this purpose have been established by retrospective and prospective studies published over the past decade^7–10, and this technique has become a new standard of care for patients with medically inoperable stage I non-small cell lung cancer (NSCLC). However the application of SABR for multiple early-stage primary lung tumors has been only rarely described.^11–13 We sought here to explore the role of SABR for patients with MPLC.

MATERIALS AND METHODS

Diagnostic Criteria and Patient Selection

We used criteria modified from Martini and Melamed¹⁴ (Table 1) to define MPLC, which included both synchronous MPLC and metachronous MPLC. All patients with NSCLC treated with SABR at our institution between October 2004 and December 2010 had been prospectively registered and were retrospectively reviewed. All eligible patients based on the definition of MPLC were identified and analyzed. The diagnosis of MPLC was originally made when two dominate lung nodules had been identified per patient. For patients with synchronous MPLC, the tumor that was most advanced based on clinical TNM stage was denoted the “index” tumor; for patients with metachronous MPLC, the first tumor detected was the index tumor, and the others were called the second tumors. The histology of both the index and second tumors had to be confirmed pathologically; all second tumors had to have been treated with SABR regardless of how the index tumor had been treated, and the biological effective doses (BEDs) of SABR had to be >100 Gy using LQ model with alpha-beta ratio of 10¹⁰. This study was approved by the institutional review board.

Table 1.

Criteria for Diagnosis of Second Primary Lung Tumor

Criteria	No. of Patients
Synchronous tumors (diagnosed within 6 months)	39
Different histology	10
Same histology;* second tumor in different lobe or lung	29
Metachronous tumors (diagnosed >6 months apart)	62
Different histology	23
Same histology*	49
1. Second tumor in different lobe or lung	27
2. Tumor-free interval of at least 4 years	12

^*No patient had extrapulmonary or common lymphatic carcinoma at the time of diagnosis.

Table reproduced, with modifications, from Martini N, Melamed M. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975; 70:606–612.

SABR Treatment Planning

Techniques for patient immobilization and SABR treatment planning have been described in detail in our previous reports.^{9, 15–17} Briefly, four-dimensional (4D) CT images were obtained to take tumor motion into consideration. Dose was prescribed to planning target volume and >95% coverage is intended if normal tissue constraints are met. Patients were treated with 6 to 12 coplanar or non-coplanar 6-MV photon beams using Pinnacle calculation algorithms with heterogeneity correction.

For patients who received prior radiotherapy to chest, markings on prior tattoos were used to identify the areas of prior previous radiotherapy and fused simulation images were used to generate composite plan. If possible, SABR beam angles should avoid previously irradiated areas (except for ipisilateral peripheral lung) particularly for esophagus, bronchial tree, brachial plexus, major vessels, heart, spinal cord and chest wall. The dose-volume constraints used for critical structures were consistent with our previously published guidelines.^{9, 15–17} No violation of constraints for the spinal cord, esophagus, and brachial plexus were allowed; constraints for other normal tissues were judged on the basis of PTV coverage. Typically, when the tumor was close to a critical structure, a compromise in PTV coverage was considered acceptable but internal GTV coverage had to be maintained. Patients with lesions that were very close to or abutting critical structures and whose normal tissue dose volume constraints for 50 Gy in 4 fractions could not be met even with compromise of PTV coverage were treated with 70 Gy in 10 fractions. For the patients who had received radiotherapy (conventional radiotherapy or SABR) for the previous lung tumor, composite plans were generated, ^16–17 and adjustments of SABR planning were made to limit the radiation dose to critical structures on an individual basis. When both the index and the second tumors were treated with SABR, composite plan should still meet with dose volume constraints for single SABR. ⁹ Because there is no practical approach to convert and calculate cumulative BED with different radiotherapy fractionations, BEDs with different fractionations were not taken into consideration when prior radiotherapy was treated with conventional fractionation and the composite plans were generated. ¹⁷ However, both SABR and composite plans were reviewed and compared separately. In general, SABR plan itself needs to meet with dose volume constraints of SABR. ^{9, 15} Composite plan should meet with dose volume constraints of conventional fractionation as we published previously ¹⁸. When these guidelines can’t be met, the case should be presented to a quality assurance meeting for discussion before the treatment plan is finalized. When evaluating the potential chance of radiation pneumonitis for combined conventional fractionation and SABR, predicting model was developed and applied¹⁷. Patients were positioned each day by using either CT-on-rails or cone-beam CT systems. Treatments were delivered on contiguous days but not on Saturdays or Sundays.

Follow-Up

Patients underwent chest CT scanning every 3 months for 2 years after the SABR and then every 6 months for another 3 years. PET scans were recommended at 3–12 months after SABR. Toxic effects were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Effects version 4. Tumor control was evaluated based on findings from both PET and CT images. Local recurrence, defined as progressive CT soft-tissue abnormalities over time that corresponded to avid areas on PET/CT more than 6 months after SABR with SUVmax > 5 as we described before¹⁹ or positive biopsy findings anywhere in the involved lobe, was scored in one of two ways: as either an “in-field failure” (occurring in the area inside the PTV) or an “involved lobe failure” (within the involved lobe but outside the PTV).

Statistical Analysis

Continuous variables were summarized by descriptive statistics. Categorical variables were tabulated by frequency and percentage. The follow-up and survival times were computed from the initiation of local treatment (surgery or radiotherapy) for any of the tumors in synchronous MPLC or the second tumor in metachronous MPLC. Survival functions were calculated using Kaplan-Meier estimates, and the log-rank test was used to assess the equality of the curves. Local control rates of the tumors treated with SABR were calculated from the start date of the SABR for individual tumors, also using Kaplan-Meier method. Probability (p) values <0.05 were considered statistically significant, and statistical tests were based on a two-sided significance level. Statistical analyses were performed with Statistical Package for the Social Sciences (SPSS) software (SPSS, Chicago, IL).

RESULTS

Patient Demographics and Tumor Characteristics

Examinations for staging synchronous MPLC or restaging multiple MPLC included pathologic confirmation by biopsy or cytology and chest CT in all patients, 18F-fluorodeoxyglucose-PET scanning in 98 patients (97%), and brain CT/magnetic resonance imaging in 87 patients (86%). All patients were evaluated by a multidisciplinary thoracic oncology group, which included thoracic surgeons, medical oncologists, radiation oncologists, radiologists, and pathologists. A total of 101 patients with MPLC were eligible and analyzed. In all, 130 tumors (29 index tumors and 101 second tumors) were treated with SABR with dose regimens of 50 Gy in 4 fractions (for 120 tumors) or 70 Gy in 7 fractions (for 10 tumors). Numbers of patients in each diagnostic category are presented in Table 1. The median age at the time of diagnosis of MPLC was 72 years (range 50–90 years). Ages at diagnosis were similar for those with synchronous MPLC (median 72 years, range 50–87 years) and metachronous MPLC (median 72.5 years, range 51–90 years). Slightly more patients were male (n=58) than female (n=43).

The reasons for the use of SABR instead of surgery included concomitant medical problems (79 patients) and patient preference (22 patients). Tumor characteristics are shown in Table 2. The median interval between diagnoses of the two tumors (index and the secondary tumors) for the entire group was 15 months (range 0–210 months), being 1 month (range 0–6) for synchronous MLPCs and 33 months (range 7–210) for metachronous MPLCs. Among all 202 tumors, 188 (93%) were diagnosed as NSCLC and 14 (7%) were neuroendocrine carcinomas (7 small cell carcinomas, 2 large cell neuroendocrine carcinomas, and 5 carcinoids). Tumor histologies were similar for the index and the secondary tumors in 68 patients (67%) and different in 33 patients (33%). Patients with small cell lung cancer as the index tumor were treated with conventional radiotherapy. There was no case of small cell lung cancer histology in the second tumor. The index and the second tumors were both in the ipsilateral lung in 24 patients (24%) and were in both lungs in 77 patients (76%). According to the 7th (2010) edition of the American Joint Committee on Cancer staging system,²⁰ all of the second tumors were stage I; of the index tumors, 71 (70%) were stage I, 16 (16%) stage II, and 14 (14%) stage III. For the index tumors, 47 patients had been treated surgically (lobectomy for 42, wedge resection for 3, sleeve resection for 1, and pneumonectomy for 1); 25 patients had received definitive conventional radiotherapy and 5 patients had received postoperative conventional radiotherapy to a median dose of 63 Gy (range 45–70 Gy); 29 patients had been treated with SABR (50 Gy in 4 fractions for 25 patients or 70 Gy in 10 fractions for 4 patients). Among the 30 patients who had undergone conventional radiotherapy, 13 had stage III index tumors, 9 had stage II index tumors, and 8 had stage I index tumors. All of the second tumors were treated with SABR; most patients (n=95) received 50 Gy in 4 fractions and the other 6 patients received 70 Gy in 10 fractions. Twenty of the 39 patients with synchronous MPLC had had chemotherapy. Of the 62 patients with metachronous MPLC, chemotherapy was used for the index tumor in 28 patients and for the second tumor in only 5 patients.

Table 2.

Tumor Characteristics

Characteristics	Synchronous tumors (n=39)		Metachronous tumors (n=62)
	Index tumor	Second tumor	Index tumor	Second tumor
Diagnosis interval, mo. (range)	1 (0–6)		33 (7–210)
Histology
Different	10		23
Similar	29		39
Histologic type
Adenocarcinoma	16	20	22	30
Squamous cell carcinoma	15	9	24	22
Large cell carcinoma	0	0	3	0
Adenosquamous carcinoma	0	0	0	1
NSCLC, NOS	3	9	8	6
Small cell carcinoma	2	1	4	0
Large cell NEC	1	0	0	1
Carcinoid	2	0	1	2
Tumor location
Ipsilateral		5		19
Same lobe		0		6
Different lobe		5		13
Bilateral	3	34		43
Disease stage
I	28	39	43	62
II	8	0	8	0
III	3	0	11	0
Treatment
Surgery	8	0	34	0
SABR	21	39	8	62
Conventional radiotherapy	10	0	15	0
Surgery + PORT	0	0	5	0

NSCLC, non-small cell lung cancer; NOS, not otherwise specified; NEC, neuroendocrine carcinoma; SABR, stereotactic body radiotherapy; PORT, postoperative radiotherapy.

Survival

The median follow-up interval for all patients was 36 months (range 3–80 months), being 48 months (range 21–80 months) for patients who were alive at the time of analysis. When this analysis was undertaken, 31 patients were alive and free of lung cancer and 18 patients were alive with disease. Among the 52 deaths, 28 were related to lung cancer. For all patients, the median survival was 46 months (95% CI: 35–57 months), and 2- and 4-year overall survival (OS) rates were 73.2% (95% CI: 64.6%–81.8%) and 47.5% (95% CI: 36.7%–58.3%) (Fig. 1). The 2-year OS rates were 80.6% for those with metachronous MPLCs and 61.5% for those with synchronous lesions; corresponding 4-year OS rates were 52.7% and 39.7 (p= 0.047) (Fig. 1). The 2- and 4-year progression-free survival (PFS) rates for all patients were 71.3% (95% CI: 62.1%–80.5%) and 58.0% (95% CI: 46.0%–70.0%) (Fig. 2). PFS rates were higher for patients with metachronous tumors than for patients with synchronous tumors (2-year PFS 84.7% metachronous vs. 49.4% synchronous; 4-year PFS 75.6% vs. 30.4%; p=0.0001) (Fig. 2). For patients whose tumors were both of the same histology (meaning that the second lesion could have been a satellite, a metastasis, or a recurrent lesion), the 2-year and 4-year OS rates were 76.4% and 51.2%, which were no different from the OS rates for patients with tumors of different pathology (2-year OS: 66.7% and 4-year OS: 40.5%; p=0.406). The 2- and 4-year OS of patients in whom both tumors were classified as stage I were 76.1% and 55.2%, which was better than the OS rates for the patients whose index tumors were of higher stage (2-year OS 66.7%, 4-year OS 26.6%; p=0.049) (Fig. 3).

Figure 1.

Overall survival for all patients, patients with metachronous multiple primary lung cancer (MPLC), and patients with synchronous MPLC.

Figure 2.

Progression-free survival for all patients, patients with metachronous multiple primary lung cancer (MPLC), and patients with synchronous MPLC.

Figure 3.

Overall survival for patients whose index and second tumors were both stage I and for patients whose index tumors were of higher stage.

Local Control of Tumors Treated with SABR and Patterns of Failure

All of the 130 tumors treated with SABR were stage I. Four of those tumors (3%) had recurred within the PTV (in-field failure), and 4 (3%) recurred within the same lobe but outside the PTV (involved-lobe failure). The 2-year and 4-year in-field local control rates were 97.4% and 95.7%.

Among patients who experienced treatment failure after previous treatment (surgery or radiotherapy) and current SABR, the first site of cumulative failure, was local recurrence in 11.9% (12/101), regional lymph node recurrence in 14.9% (15/101), and distant metastasis in 11.9% (12/101). Interestingly, no difference was found in patterns of failure between patients whose index tumor was stage I and those whose index tumors were of higher stage. Having a third primary tumors seemed more prevalent among the patients whose index tumor was stage I (15.5% vs. 6.7% among those with higher-stage index tumors, data not shown). Among the 13 third primary lung tumors (as defined by our MPLC criteria), 7 were re-treated with SABR, 1 was treated with proton therapy, 1 was treated with systemic therapy, and 4 were not treated at our hospital because of other co-morbidities.

Toxicity

The common SABR-associated toxicities are shown in Table 3. To compare the distribution of toxicities, we classified all the patients into three groups according to the treatment approach used for the index tumor: SABR group (n=29), surgery group (n=42 [excluding the patients who received postoperative radiotherapy]), and conventional radiotherapy group (n= 30 [including patients who received definitive and postoperative conventional radiotherapy]) (Table 3). Interestingly, the incidence of grade 2 radiation pneumonitis (RP) was lower in group that index tumor was treated with SABR as compared with surgery and conventional radiotherapy, indicating lung volume loss caused by surgery or conventional radiotherapy may have negative impact in RP. One patient (3%) in the SABR group, one (2%) in the surgery group, and five (17%) in the conventional radiotherapy group experienced grade ≥3 RP All 5 of the patients with grade ≥3 RP in the conventional radiotherapy group had index tumors that were higher than stage I, suggesting that the large conventional radiotherapy volumes used to treat these higher-stage tumors may have contributed to the higher incidence of RP. The patient who experienced the sole grade 5 event (pneumonitis) had been treated with concurrent chemoradiation therapy plus consolidation chemotherapy for a stage IIIA index tumor, and grade 2 RP had developed after that. Four years later, SABR was given to the contralaterally located second tumor. Two months after the SABR, this patient developed RP and then an overwhelming pneumonia that resulted in respiratory failure and death. Because this event may have been precipitated by the RP and need for prednisone, it was scored as a related event. This patients’ forced expiratory volume in 1 second (FEV1) before SBRT had been 33%, and the composite dose-volume parameters were mean lung dose 22 Gy, lung V₅ 81%, and lung V₂₀ 39%.

Table 3.

Treatment-Related Toxicity

Toxicity	Total Patients (n=101)	Treatment for Index Tumor
		SARB (n=29)	Surgery (n=42)	C-RT (n=30)
Pneumonitis
Grade 1	70 (69.3)	24 (82.8)	29 (69.0)	17 (56.7)
Grade 2	20 (19.8)	3 (10.3)	10 (23.8)	7 (23.3)
Grade 3	6 (14.9)	1 (3.4)	1 (2.4)	4 (13.3)
Grade 4	0	0	0	0
Grade 5	1 (1.0)	0	0	1 (3.3)
Skin toxicity
Grade 1	19 (18.8)	9 (31.0)	6 (14.3)	4 (13.3)
Grade 2	9 (8.9)	3 (10.3)	4 (9.5)	2 (6.7)
Grade 3	1 (1.0)	0	0	1 (3.3)
Chest wall pain
Grade 1	12 (11.9)	6 (20.7)	4 (9.5)	2 (6.7)
Grade 2	22 (21.8)	8 (26.7)	8 (19.0)	6 (20.0)
Grade 3	3 (3.0)	3 (10.3)	0	0
Rib fracture
Grade 1	4 (4.0)	3 (10.3)	1 (2.4)	0
Grade 2	20 (19.8)	12 (41.4)	6 (14.3)	2 (6.7)

Abbreviations: SABR, stereotactic ablative radiotherapy; C-RT, conventional radiotherapy. Data are presented as number of patients (n), with percentages in parentheses.

The incidence of chest wall pain and rib fracture was higher in the group that index tumor was treated by SABR as compared with surgery and conventional radiotherapy (Table 3). However, this data was cumulative incidence from two courses of SABR for the index and the secondary tumor. We did not count the rib fracture caused by surgery procedures. There was a correlation between rib fracture and chest wall pain: 20/24 patients with rib fracture developed grade 1/2 (n=18) or grade 3 (n=2) chest wall pain.

DISCUSSION

In the present study, 130 stage I MPLC tumors were treated with SABR. The 4-year in-field local control rate of 95.7% was satisfactory and consistent with previous reports of SABR for stage I single primary lung cancers.^7–10 As reported before, radiation dose is crucial for local tumor control, and a BED of >100 Gy to the target volume is needed to achieve optimal local control.¹⁰ In our study, all tumors had received SABR with a BED >100 Gy (112.5 Gy for 50 Gy in 4 fractions and 119 Gy for 70 Gy in 10 fractions). There was one MPLC patient treated with 40 Gy in 4 fractions (BED=80 Gy) who was not included in present study but was reported previously¹⁵. This patient did encounter in-field local recurrence and we have not used this regimen since our previous publication. Most importantly, rates of OS and PFS at 4 years were 47.5% and 58.0% for all patients, and 52.7% (OS) and 75.6% (PFS) for patients with metachronous lesions. These findings suggest that SABR may be able to cure up to 58% for all MPLC and 75.6% for metachronous MPLC patients.

The diagnosis of MPLC in routine practice is usually not easy and there is possible conflict between diagnosis of MPLC and oligometastasis. A difference in histology in the primary and secondary tumors is considered a reliable indicator of MPLC, but if the two tumors are of the same or similar histology, it can be difficult to distinguish a second primary carcinoma from a recurrent, metastatic, or satellite lesion arising from the first tumor. Clinically, patients who have tumors meeting the MPLC criteria in Table 1 are often considered to have metastatic disease and are offered palliative therapy such as chemotherapy, which would be expected to negatively affect outcomes. In our study, no difference in survival was found between the patients with tumors of same or different histologies. Thus at least some of our second tumors of the same histology as the first were real secondary primary carcinomas and as such warrant active local treatment with curative intent.²¹

For patients with stage I NSCLC, similar outcomes after SABR and surgery treatments have been reported by several groups,^22–25 although none of those studies involved data from randomized clinical trials. For MPLC treated by surgical resection, Dr. Aziz reported median overall survival of 40 months and 5 years survival of 38%.² Dr. Rice analyzed a cohort of prospective study and showed that even both the index and the second tumors were stage I, the median survival after surgical resection was 49.2 months. ⁴ With a median OS of 46 months and OS rates of 47.5% at 4 years (estimated 37.9% at 5 years) in our study, effectiveness of SABR appears comparable to that of surgery for early MPLC.^2–5 However, more detail analysis such as case control or propensity matched study should be performed to validate our observation. Interestingly, the OS for patients in whom both index and secondary primary tumors were stage I was similar to the OS for patients with pure stage I single primary lung cancer.²⁰ These results further suggest that MPLC should be treated with curative intent rather than palliation as metastatic disease. Considering that many patients with MPLC have other significant medical issues that may preclude surgery, SABR provides an attractive alternative approach for a potentially curative treatment.

In our study, patients with synchronous disease experienced significantly reduced survival compared with those with metachronous disease, a finding similar to those in other published reports. ^26–28 Although the possible explanation for this difference might lie in the impact of the stage of the index tumor on survival, in our cohort, the proportion of higher-stage (II and III) index tumors was almost same for those with synchronous and those with metachronous disease. The median interval between diagnosis of the index tumor and the second tumors in those with metachronous disease was 33 months as compared with 1 month in synchronous disease; this means more than half of the index tumors had been controlled for more than 33 months, indicating the inherently favorable nature of the disease. In addition, some of the synchronous MPLCs may have been metastatic disease from the index tumor. Interestingly, no significant difference in pattern of failure was found between patients whose index tumor was stage I and those with higher-stage index tumors, indicating that some index tumors had been cured even when those tumors were stage >I. The incidence of third primary tumors appearing seemed higher among patients with stage I index tumors (p=n.s.), which may indicate that patients with stage I index tumors have the highest chance of curative treatment, the longest survival, or both.

RP was the most common SABR-associated toxicity in this study. However, most of the grade ≥3 RP occurred in patients whose index tumors had been treated with conventional radiotherapy (5/30 patients, or 17%), a rate similar to that in our previous studies of SABR for patients previously treated with conventional thoracic radiotherapy and predictive model of RP has been reported.^{14,15,16–17} All 5 of the patients who had received conventional radiotherapy and developed grade ≥3 RP had had index tumors of stage higher than I (a total of 22 patients), and none of the patients with stage I index tumors treated with conventional radiotherapy (8 patients) experienced grade ≥3 RP. Treatment volumes were not available for all of the patients in our study, because some had been treated at outside hospitals several years before. However, considering the correlation between treatment volume and tumor stage, we assume that the larger treatment volumes could have contributed to the development of these side effects in addition to use of conventional radiotherapy techniques. The rate of grade ≥3 RP in patients whose index tumors were treated with SABR or surgery (<3%) was similar to that of patients treated with SABR for single tumors.^7–9 These findings suggest that careful attention should be paid to patients with MPLC who have more advanced tumors and have received both SABR and conventional radiotherapy.

The rates and severity of other toxicities were considered acceptable and comparable with those in other studies of SABR for single lung tumors. Three patients in our study (3%) experienced grade 3 chest wall pain, a rate similar to that in the largest analysis of chest wall toxicity after SABR for stage I NSCLC to date, in which severe chest wall pain was observed in 2.2% of patients.^29–31 All 3 of the patients in the present study had been treated with SABR for both tumors, and all 6 of their tumors were located close to the chest wall, which probably contributed to the development of severe chest wall pain. However, the pain in those patients probably was not related to dose overlap of the SABR fields on the chest wall because the two tumors in these patients were located bilaterally. Factors predicting the occurrence of chest wall pain have been explored in previous studies.^29–31

To our knowledge, our current study involves the largest number of patients with MPLC and the longest follow-up time for MPLC treated with SABR. To date, only a few studies^11–13 have been done to evaluate the use of SABR for MPLC. Creach et al.¹¹ retrospectively analyzed 63 MPLC patients in whom SABR was used for at least one tumor. The 2-year OS was 58.5% and no grade ≥3 toxicities were experienced. Another two studies^12–13 each included only 10 patients, and all of the lung tumors in these patients had been treated with SABR. Favorable therapeutic effects and minimal toxicity were reported. It is difficult to compare these studies with ours because of differences in patient selection criteria and follow-up times. However, the promising treatment outcomes and the acceptable toxicity profile in reports from us and from others lead us to believe that SABR can be an effective alternative to surgery for early-stage MPLC tumors.

This study did have some limitations. First, the results are based on a group of patients retrospectively selected from our SABR program according to the criteria listed in Table 1. Second, we did not conduct more detail comparison between surgery and SABR to adjust other variables. Finally, this study focused mostly on patients with only two tumors, which may limit the generalizability of our findings to MPLCs that include more tumors.

Summary

1. SABR achieves an excellent long-term tumor control and promising PFS and OS in early-stage MPLC.

2. Toxicity could happen but within the scope of SABR in stage I disease.

3. Caution should be taken integrating SABR with prior comprehensive radiotherapy for stage II/III disease.