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. Author manuscript; available in PMC: 2022 May 1.
Published in final edited form as: Clin Lung Cancer. 2020 Jun 2;22(3):e342–e359. doi: 10.1016/j.cllc.2020.05.024

Impact of lung parenchymal-only failure on overall survival in early stage lung cancer patients treated with stereotactic ablative radiation therapy

May Elbanna 1, Kevin Shiue 1, Donna Edwards 1, Alberto Cerra-Franco 1, Namita Agrawal 1, Jason Hinton 1, Todd Mereniuk 1, Christina Huang 1, Joshua L Ryan 2, Jessica Smith 2, Vasantha D Aaron 2, Heather Burney 3, Yong Zang 3, Jordan Holmes 1, Mark Langer 1, Richard Zellars 1, Tim Lautenschlaeger 1
PMCID: PMC7708512  NIHMSID: NIHMS1600144  PMID: 32736936

Abstract

Introduction

The impact of lung parenchymal-only failure on patient survival after stereotactic ablative body radiotherapy (SABR) for early stage non-small cell lung cancer (NSCLC) remains unclear.

Methods

The study population included 481 patients with early stage NSC LC who were treated with 3 to 5 fraction SABR between 2000 and 2016. The primary study objective was to assess the impact of out-of-field lung parenchymal-only failure (OLPF) on overall survival (OS).

Results

At a median follow-up of 5.9 years, the median OS was 2.7 years for all patients. Patients with (OLPF) did not have a significantly different OS compared to patients who never failed (p=0.0952, median OS 4.1 years with failure vs. 2.6 years never failure). Analysis in a 1:1 propensity score-matched cohort for KPS, co-morbidity score, and smoking status showed no differences in OS between patients that never failed and those with OLPF (p=0.8). In subgroup analyses exploring impact of time of failure on OS, patients with OLPF 6 months or more after diagnosis did not have significantly different OS compared to those who never failed, when accounting for immortal time bias (p= 0.3, median OS 4.3 years vs 3.5 years never failure). Only seven patients in our dataset failed within 6 months of treatment, of which only four were confirmed to be true failures; therefore, limited data is available in our cohort on the impact of OLPF in ≤6 months on OS.

Conclusions

OLPF after SABR for early stage NSCLC does not appear to adversely affect OS, especially if occurring at least 6 months after SABR. More studies are needed to understand if OLPF within 6 months of SABR is associated with adverse OS. These data are useful when discussing prognosis of lung parenchymal failures after initial SABR.

Keywords: SBRT, SABR, NSCLC

Micro-abstract

The impact of lung parenchymal-only failure on patient survival after stereotactic body radiotherapy (SABR) for early stage non-small cell lung cancer remains unclear. Using database of 481 patients who were treated with SABR between 2000-2016, we showed that lung-only failure after SABR does not adversely impact OS. These data are useful when discussing prognosis with patients after initial SABR.

Introduction

Lung cancer represents 14% of all new cancer cases but disproportionately 25% of all cancer related deaths in the United States, making it the 2nd most common cancer overall and the leading cause of cancer-related deaths [1]. Non-small cell lung cancer (NSCLC) makes up the majority of lung cancer cases, and stereotactic ablative radiation therapy (SABR) is a well-accepted treatment option for patients with medically inoperable early-stage NSCLC [2-7]. Clinical trials are currently underway comparing SABR to surgical management (NCT02468024 (STABLE-MATES), NCT02629458 (SABRTooth), NCT01753414 and NCT02984761 (VALOR study)).

After treatment with SABR, the predominant pattern of failure is distant and/or regional nodal recurrence, but local failures, including within the treated lesion and the involved lobe, occur in up to 20% of patients at 5 years [3, 8-14]. Interestingly, recent data has suggested that patients with isolated local recurrence in the treated lesion or the involved lobe who received salvage treatment had no difference in 5-year overall survival (OS) compared to patients who never had a failure [15]. However, the impact of an isolated out-of-radiation-field lung parenchymal-only failure (OLPF) on survival remains unclear.

Such OLPF cancers after initial SABR can represent metastases from the initial lung cancer or often second primary lung cancers [16]. Management of a 2nd primary cancer in the setting of a cured first lung cancer is usually curative intent treatment, while treatment approaches for metastatic disease are typically not curative. Martini and Melamed proposed three criteria for defining a second primary: (1) histologically distinct from the initial primary lung cancer; (2) histologically similar to the primary tumor but diagnosed at least 2 years after the primary tumor; or (3) histologically similar and occurs within 2 years of the primary tumor but located in different lobes or segments, with no positive intervening lymph nodes and no evidence of metastasis [17]. While these criteria are widely used in the literature, controversy still exists with some proposing incorporating additional criteria such as molecular testing in defining a new primary [18, 19]. Based on analysis of temporal patterns of recurrence and 2nd primary lung cancers others have proposed a more stringent 5 year cut off for defining a 2nd primary [20, 21]. Given that the above criteria remain controversial, patients are routinely offered SABR to new parenchymal lesions occurring at any time after initial SABR in our practice; however, data on outcomes for this scenario supporting an informed discussion with patients are limited [15].

The specific prognostic impact of OLPF for early stage NSCLC patients treated with SABR remains unclear. In this study we aim to determine the impact of OLPF on patient survival using our institution's 16–year experience utilizing SABR for NSCLC.

Materials and Methods

Study population:

This study was approved by our Institutional Review Board. We performed a retrospective analysis of survival outcomes in patients treated with SABR from 2000 to 2016 for early stage NSCLC (AJCC 7eth edition). Patients were identified using medical billing codes and relevant billing information. Eligible patients were ≥ 18 years of age and were diagnosed with early stage NSCLC either histologically or clinically. Clinical diagnosis was based on radiographic suspicion, most often via tumor board consensus, and all patients were either inoperable or refused surgery [10, 11]. Patients were excluded if they had metastatic disease at the time of SABR.

Treatment details:

Details of treatment have been previously reported [8]. In summary, computed tomography (CT) simulation and immobilization were performed in the supine position. Treatment planning and delivery evolved over the 16 year study period; however, most radiation plans were calculated using AAA (Analytical Anisotropic Algorithm, ECLIPSE) with heterogeneity corrections. Most patients were treated with a prescription dose BED10 ≥100Gy prescribed to a planning target volume (PTV) over 3-5 fractions with at least one day between fractions [22]. The most common fractionation schemes overall were 12 Gy x4 fractions, 20 Gy x3, 18 Gy x3, and 10 Gy x5. Centrally located lesions were defined as lesions that were located within 2 cm of the tracheobronchial tree consistent with the RTOG definition. In total, 103 tumors were defined as central in our dataset. Similarly, the most common fractionation regimens used to treat central lesions were 12 Gy x 4 fractions (27%), 10 Gy x 5 fractions (24%), 20 Gyx 3 fractions (19%) and 18 Gy x 3 fractions (15%). A significantly lower number of fractions was used to treat peripheral lesions (314) in comparison to central lesions (103) (p=0.0032). Chi-square test was used to assess the relationship between centrality and number of fractions used to treat. Of note, 36 patients included in this series were treated before 2006 when it was discovered that 3-fraction SBRT is associated with excessive toxicity when use to treat central tumors [23].

Data collection:

The date of diagnosis was defined as the date of histological diagnosis or the date of imaging-based clinical diagnosis. At least 93.5% of lesions were PET staged [24]. Follow-up imaging was performed at the discretion of the treating physician with mostly CT or positron emission tomography (PET). Recurrences were determined by reviewing the patient’s serial imaging (CT, PET/CT) and the clinical judgement of treating physicians. Sites of recurrences were defined as in-field, out-of-field parenchymal-only lung failure (OLPF), nodal, or distant. In-field failure was defined as failure within or abutting the PTV. OLPF included any failure that occurred within the treated lobe (but distant from the PTV), in a different ipsilateral lobe, or in the contralateral lung. Patients who failed in the nodes and/or distantly were considered to be metastatic. OLPF was further divided according to when the failure occurred (within 6 months, 6 - 24 months, or after 24 months).

Statistical analysis:

OS was calculated from the date of the beginning of SABR (to account for interval growth in lesions until treatment is initiated from the date of diagnosis) until death or last follow-up. Patients who were lost to follow-up were censored at their last known follow-up. Time to lung parenchymal failure was defined as time from treatment start to first failure in the treated lobe (distant from the PTV), different ipsilateral lobe, or contralateral lung. One-to-one propensity score matching using KPS, Charlson co-morbidity score, and smoking status (current, former, or never) was performed and OS of the matched cohorts was tested by the log-rank test Patients without OLPF included all patients who did not experience OLPF whether they never failed or failed in sites other than those defined above as OLPF. Patients who never failed were those who truly never experienced any form of failure until death or last follow up date. Separately, multivariate tests using the entire cohort were performed using the Cox proportional hazard model. For multivariate tests including different radiation dose variables, different analyses were performed including only one of the dose parameters as such dose variables are highly correlated (Table 2, Supplementary Tables S1-5). Survival curve was estimated using the Kaplan-Meier method. All statistical tests were two-sided, and p values <0.05 were deemed statistically significant. For pairwise comparisons p-value cutoff was adjusted for the number of comparisons to be made using the Bonferroni correction. SAS version 9.4 (SAS Institute, Cary, North Carolina) was used for all analyses.

Table 2.

Univariate and multivariate analysis for parenchymal only lung failure

Parenchymal-only lung failure
UVA MVA (Prescription dose)
HR 95% CI p-value HR 95% CI p-value
Previous NSCLC no vs yes 0.61 0.36 – 1.04 0.0668 0.67 0.37 – 1.21 0.1835
Pathologic vs clinical diagnosis 1.15 0.55 – 2.42 0.7140 1.22 0.49 – 3.04 0.6769
Age 1.01 0.98 – 1.03 0.7043 0.99 0.96 – 1.02 0.6221
Prescription dose‡ 1.00 1.00 – 1.01 0.5349 1.00 1.00 – 1.01 0.5587
Prescription dose‡ ≤105 vs > 105 1.19 0.47 – 2.96 0.7160
Prescription dose‡ ≤110 vs > 110 1.23 0.72 – 2.08 0.4492
Minimum dose‡ to GTV 1.00 1.00 – 1.01 0.5045
Maximum dose‡ to GTV 1.00 1.00 – 1.01 0.4897
Mean dose‡ to GTV 1.00 1.00 – 1.01 0.6706
GTV 1.00 0.98 – 1.02 0.9468 1.01 0.99 – 1.03 0.3466
T stage T1 vs T2 1.08 0.60 – 1.92 0.8016 1.95 0.86 – 4.47 0.1121
Overall histology 0.8455 0.7868
Adeno vs other 0.86 0.48 – 1.56 0.6248 0.86 0.43 – 1.74 0.6765
Adeno vs sqcc 0.86 0.47 – 1.56 0.6091 0.80 0.42 – 1.52 0.4944
Other vs sqcc 0.99 0.55 – 1.81 0.9773 0.93 0.46 – 1.87 0.8324
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Results

Overall, 481 patients met eligibility criteria and were treated with SABR for NSCLC. Demographics and baseline characteristics of patients with OLPF (n=65) vs. patients who never failed (n= 302) and those without OLPF (n=416), which includes patients with nodal and distant failure, are summarized in Table 1 and Supplementary Table S1 respectively. Most patients had T1 tumors (77%). The median follow-up was 5.9 years (0–12.9 years) and median OS was 2.7 years. Patients who experienced OLPF had significantly higher incidence of prior history of NSCLC compared to patients who did not have an OLPF (p=0.048, 30.8% for OLPF patients vs 20% for patients without OLPF) or those who never failed (p= 0.038, 30.8% for OLPF patients vs. 19.2% for patients who never failed). Two out of 65 patients (3.1%) who experienced OLPF had ≥ 2 lung nodules at first presentation. Eight out of 302 (2.6%) patients who never failed presented with ≥ 2 lung nodules. None of the patients who had OLPF within 6 months presented with ≥ 2 lung nodules. Seven patients in our dataset experienced OLPF within 6 months of treatment. Only 4 of those patients were confirmed to be true failures.

Table 1.

Patient and lesion characteristics.

Patient characteristics.
Lung Parenchymal
Failure
(n=65)		 Never Failed
(n=302)		 p-value**
Mean age (standard deviation), yrs.a 72.0 (7.84) 73.5 (9.40) 0.2339
Sex (%).a Female 32 (49.2) 150 (49.7) 0.9489
Lesion characteristics. n (%) n (%)
Prior history of NSCLC Yes 20 (30.8) 58 (19.2) 0.0387
Histology Adenocarcinoma 22 (33.9) 119 (39.4) 0.3647
Squamous cell carcinoma 21 (32.3) 98 (32.5)
NSCLC NOS* 16 (24.6) 48 (15.9)
No pathology 6 (9.2) 37 (12.3)
Location Right upper lobe 23 (35.4) 97 (32.1) 0.7960
Right middle lobe 2 (3.1) 20 (6.6)
Right lower lobe 14 (21.5) 56 (18.5)
Left upper lobe 17 (26.2) 82 (27.2)
Left lower lobe 9 (13.9) 47 (15.6)
Method of diagnosis Imaging/clinical 8 (12.3) 45 (14.9) 0.5895
Stage T1 49 (76.6) 225 (74.5) 0.7301
T2 15 (23.4) 77 (25.5)
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On log-rank test, patients with OLPF did not have a significantly different OS compared to patients who never failed (4.1 years vs. 2.6 years respectively, p= 0.0952) (Figure 1A). However, OS was significantly better in patients with OLPF when compared to those who did not have OLPF (4.1 years vs. 2.4 years respectively, p=0.0397) (Supplementary Figure S1). After propensity score matching, patients with an OLPF did not have a significantly different OS compared to patients who never failed (2.9 years vs. 2.8 years respectively, p=0.8354) (Figure 1B).

Figure 1.

Figure 1

Figure 1

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A Overall Survival in Patients with Lung Parenchymal Failure Compared to Patients Who Never Failed

B Overall Survival in Patients with and without Lung Parenchymal Failure after One-to-One Propensity Score Matching

Patients were one-to-one matched on KPS, pack years, and Charlson Comorbidity Index. The matching process yielded 29 matched pairs.

Patients who had OLPF > 2 years after diagnosis (traditionally presumed a second primary lung cancer) lived a median of 5.3 years, which was significantly longer than patients who failed ≤ 2 years who lived a median of 2.2 years (p=0.0093). (Figure 2A)

Figure 2.

Figure 2

Figure 2

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A Overall Survival Comparing Time to Lung Parenchymal Failure

B Overall Survival in Patients with Lung Parenchymal Failure Compared to Patients Who Never Failed (at least 2 years of follow-up)

Patients who failed > 2 years after diagnosis were compared to patients who did not have OLPF or never failed and had at least 2 years of follow up data to adjust for immortal time bias. Patients with a presumed 2nd primary tumor did not have worse OS compared to patients who never failed (p= 0.28, 5.3 years vs 6.0 years respectively, Figure 2B) or those that did not have an OLPF (p=0.709, 5.3 years vs 5.3 years respectively, Supplementary Figure S2).

Accounting for immortal time bias by only analyzing the subgroup of patients with at least 6 months of follow-up, no significant difference in survival between patients who experienced OLPF 6 months or more after diagnosis and those who never failed was seen (p=0.313, 4.3 years vs 3.5 years) (Supplementary Figure S3).

Similarly, there was no difference in OS between patients with OLPF and in-field failure (5.3 years vs. 4.1 years, p=0.502) (Figure 3). However, patients who developed metastatic failure lived a median of 2.0 years, which was significantly shorter than patients with OLPF (4.1 years, vs. 2.0 years, p=0.0003) (Figure 4). None of the analyzed variables was associated with development of OLPF (Table 2, Supplementary Table S1-5).

Figure 3.

Figure 3

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Overall Survival in Patients with In-Field Failure Compared to Patients with Lung Parenchymal Failure

Figure 4.

Figure 4

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Overall Survival Comparing Patients with Lung Parenchymal Failure and Patients with Metastasis

Table 3 summarizes the baseline characteristics and treatment details of patients who had OLPF for exploratory analysis: patients with a unifocal ipsilateral failure (n=28), patients with a unifocal contralateral failure (n=24), and patients who failed with multiple lesions irrespective of location (n=9). There were no significant differences in OS across different patient subgroups. Patients who had single ipsilateral failure lived a median of 4.1 years in comparison to a median of 4.1 years for patients who had a single failure in the contralateral lung, and a median of 4.8 years for patients who failed with multiple lesions irrespective of location (p=0.61) (Supplementary Figure S4).

Table 3.

Patients with Lung Parenchymal Failure

Patient characteristics.
Lung Parenchymal
Failure – Isolated/single
failure
(n=28)		 Lung Parenchymal
Failure – Contralateral
lung only
(n=24)		 Lung Parenchymal
Failure – Multiple
failures
(n=9)
Median age (range), yrs.a 74 (57-88) 71 (62-82) 72 (65-83)
Sex (%).a Female 15 (53.6) 13 (54.2) 3 (33.3)
Lesion characteristics. n (%) n (%) n (%)
Prior history of NSCLC Yes 8 (28.6) 8 (33.3) 3 (33.3)
Histology Adenocarcinoma 7 (25.0) 10 (41.7) 4 (44.4)
Squamous cell carcinoma 12 (42.9) 7 (29.2) 2 (22.2)
NSCLC NOS* 5 (17.9) 5 (20.8) 3 (33.3)
No pathology 4 (14.3) 2 (8.3) 0 (0.0)
Location Right upper lobe 11 (39.3) 5 (20.8) 6 (66.7)
Right middle lobe 2 (7.1) 0 (0.0) 0 (0.0)
Right lower lobe 6 (21.4) 6 (25.0) 2 (22.2)
Left upper lobe 5 (17.9) 9 (37.5) 0 (0.0)
Left lower lobe 4 (14.3) 4 (16.7) 1 (11.1)
Method of diagnosis Imaging/clinical 4 (14.3) 4 (16.7) 0 (0.0)
Stage T1 23 (85.2) 17 (70.8) 7 (77.8)
T2 4 (14.8) 7 (29.2) 2 (22.2)
Median Range Median Range Median Range
Treatment Total Dose GY 60 (48 – 66) 52 (48 – 66) 54 (48 – 60)
Dose/Fraction 20 (12 – 22) 17 (10 – 22) 18 (10 – 20)
BED10 Rx Dose 180 (105.6-211.2) 138 (100- 211.2) 151.2 (100-180)
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Patients who experienced OLPF lived a median of 1.6 years post failure (Supplementary Figure S5) and patients who were considered metastatic lived a median of 0.7 years from the failure event (Supplementary Figure S6).

Discussion

This study represents one of the largest series of NSCLC patients treated with SABR with one of the longest follow-ups. Our data suggest that isolated lung parenchymal-only failure (OLPF) does not adversely impact overall survival in patients treated with SABR for early stage NSCLC, particularly if recurrence occurs after 6 months. In our series, patients with OLPF had a median OS of 4.1 years vs. 2.6 years in patients who never failed and 2.4 years for patients without OLPF. Lack of survival difference remained after controlling for performance status, smoking history and comorbidities. Clinically this finding is useful when discussing prognosis of lung parenchymal failures after initial SABR.

Currently, there is a paucity of data showing the impact of lung recurrence versus new primary on survival outcomes for SABR-treated patients. Criteria for identifying parenchymal lung failure versus second lung primary continue to be an area of active debate [20, 25-27]. Several groups have looked at patterns of recurrence and development of second lung primaries post SABR either by applying Martini and Melamed Criteria [17, 25] or slightly modified cut offs [20, 21]. The Martini and Melamed Criteria define second primaries based on the temporal relationship of the second nodule compared to the primary with a 2 -year cutoff. On the contrary, other reports have proposed a more stringent cut off of 5 years after first diagnosis [20, 21]. Our data show that there was no difference in survival for those that had OLPF vs. those who never failed. Additionally, For patients who had at least 2 years follow-up, patients who experienced OLPF had similar OS to those who never failed (median OS 5.3 years with failure vs. 6 years without, p=0.28).

Although comprehensive genomic profiling has been proposed as a method for identifying recurrences vs new primaries [27-30], it is not yet a standard of care and its prognostic significance remains unclear. Therefore time to recurrence, that we as well as other groups have used to look at patterns of lung recurrence and/or development of new primaries, continues to be the most clinically useful parameter. Although post-SABR local recurrences are rare, they unfortunately do occur [31]. Multiple factors contribute to local failure including: radiation dose, gross tumor volume, fraction size, total dose, and prescription target (for example isocenter versus volumetric). Smoking has also been shown to be associated with significantly increased risk of all-cause mortality and recurrence in early stage NSCLC [32]. Therefore based on our data, salvage therapy, whether in the form of surgery, repeat SABR, external beam radiation therapy (EBRT), or radiofrequency ablation (RFA), are legitimate options to offer to patients [33].

A recent study by Brooks et al. provided a comprehensive analysis of long-term outcomes of local, regional, and distant failure post SABR. Local recurrence was defined as progressive disease in the same lobe as the primary tumor while regional recurrence was defined as failure in the hila or mediastinum. Failure either in previously uninvolved lobes or outside the thorax was considered distant. They found no significant difference in 5-year OS between SABR-treated patients who never failed and patients who had isolated LR and salvage treatment. However, 5-year OS was significantly lower in patients with isolated regional recurrence and salvage treatment [15]. Another study by Hamaji et al. showed that salvage surgery is associated with significantly improved median and 5-year OS in comparison to patients offered best supportive care [34]. Multiple other studies have showed that either modality is associated with good local control [35, 36]. Similarly, RFA was shown as an alternative salvage tool that is associated with good local control irrespective of median tumor size [37].

It is important to note that salvage surgery can be challenging post SABR due to radiation-induced changes in the lung and surrounding tissue. Potential complications of salvage surgery include fibrosis, adhesions, and decreased lung volumes [38]. Similarly, repeat SABR can be associated with unacceptable grade 4 or 5 toxicities if patients/tumors were not appropriately selected, such as centrally-located failures that are closer to critical structures [39]. Overall, prospective studies are needed for better evaluation of either modality as a salvage option.

Despite good local control associated with initial SBRT as well as different salvage modalities, distant failure is common. Multiple studies looked at predictive factors of distant failure. One study showed only age significantly correlated to the risk of distant failure [40]. However, we previously showed that GTV and radiation dose were significantly associated with metastasis. However, histology, T-stage, centrality, lung parenchymal failures, and previous NSCLC were not [24]. The high rate of distant failure despite good local control warrants the study of adjuvant systemic therapy, which has not been thoroughly investigated in this setting due to medical comorbidities in this population [41]. The advent of immunotherapy could provide a tolerable option in this vulnerable population. Preliminary data suggest that combining SBRT with immune checkpoint inhibitor may provide a clinical benefit [42-44] with better toxicity profile when compared to conventional chemotherapy [45].

In summary, our study provides novel information on the impact of OLPF on survival outcomes in patients treated with SABR despite being limited by the disadvantages that are inherent to retrospective studies, such as selection bias and lack of control on exposures and outcomes, which increases the risk of confounding. For instance, our study does not consider whether OLPF failures are considered recurrences versus second primaries. Although this is a limitation, our findings are more broadly applicable, particularly because the clinical definition of recurrence versus second primary remains controversial and can be difficult to determine in clinical routine practice. Other limitations of our study include the small number of failures that happened within only 6 months of treatment (7 failures, limiting our ability to understand if failure within 6 months might be associated with worse outcomes) and the long time span of the study (16 years) over which treatment protocols evolved.

Despite its limitations, to our knowledge, our study is the first to show that isolated OLPF does not negatively impact OS in NSCLC patients treated with SABR. This novel finding sets the stage for informed decision making when discussing salvage treatment options in patients who experience OLPF after SABR treatment. Our future goal is to investigate the impact of salvage modalities on patient survival in this large cohort of NSCLC patients treated with SABR with extensive follow-up.

Supplementary Material

1

Clinical Practice Points:

  • Stereotactic ablative body radiation (SABR or SBRT) has significantly improved early-stage NSCLC outcomes with good local control, however distant failure is common

  • The impact of out of field lung parenchymal-only failure (OLPF) on overall survival is not known.

  • There is lack of consensus on defining a second primary versus a lung recurrence. Additionally, there is lack of data that could inform the impact of lung recurrence versus new primary on survival outcomes for SABR-treated patients.

  • Our study provides the current best available evidence for the impact of lung parenchymal-only failure on overall survival. Specifically, our data suggests lung parenchymal-only failure after SABR for early stage NSCLC does not adversely affect OS, especially if occurring at least 6 months after SABR, irrespective of performance status, smoking history and comorbidities

  • Our study does not consider whether OLPF failures are considered recurrences versus second primaries. Although this is a limitation, our findings are more broadly applicable, particularly because the clinical definition of recurrence versus second primary remains controversial and can be difficult to determine in clinical routine practice.

  • This data provide the basis for discussing prognosis with patients who experience lung parenchymal failures after initial SABR in an evidence-based approach.

  • Salvage therapy whether in the form of surgery, repeat SABR, external beam radiation therapy (EBRT), or radiofrequency ablation (RFA) have been shown to be safe and effective options for some patients.

  • Despite good local control associated with initial SBRT as well as different salvage modalities, distant failure is common. Emerging data is now suggesting that this vulnerable population could potentially benefit from novel immunotherapies.

Footnotes

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References

  • 1.Howlader N, et al. , SEER cancer statistics review, 1975-2012, National Cancer Institute. Bethesda, MD, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. 2015. [Google Scholar]
  • 2.Siegel RL, Miller KD, and Jemal A, Cancer statistics, 2020. CA: A Cancer Journal for Clinicians, 2020. 70(1): p. 7–30. [DOI] [PubMed] [Google Scholar]
  • 3.Onishi H, et al. , Stereotactic body radiotherapy (SBRT) for operable stage I non–small-cell lung cancer: can SBRT be comparable to surgery? International Journal of Radiation Oncology* Biology* Physics, 2011. 81(5): p. 1352–1358. [DOI] [PubMed] [Google Scholar]
  • 4.Lagerwaard FJ, et al. , Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer. International Journal of Radiation Oncology* Biology* Physics, 2012. 83(1): p. 348–353. [DOI] [PubMed] [Google Scholar]
  • 5.Nagata Y, et al. , Prospective trial of stereotactic body radiation therapy for both operable and inoperable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group Study JCOG0403. International Journal of Radiation Oncology* Biology* Physics, 2015. 93(5): p. 989–996. [DOI] [PubMed] [Google Scholar]
  • 6.Nyman J, et al. , SPACE–a randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC. Radiotherapy and Oncology, 2016. 121(1): p. 1–8. [DOI] [PubMed] [Google Scholar]
  • 7.Louie AV, et al. , Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: controversies, insights, and changing horizons. Radiotherapy and Oncology, 2015. 114(2): p. 138–147. [DOI] [PubMed] [Google Scholar]
  • 8.Shiue K, et al. , Histology, tumor volume, and radiation dose predict outcomes in NSCLC patients after stereotactic ablative radiotherapy. Journal of Thoracic Oncology, 2018. 13(10): p. 1549–1559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Timmerman RD, et al. , Stereotactic body radiation therapy for operable early-stage lung cancer: findings from the NRG Oncology RTOG 0618 Trial. JAMA oncology, 2018. 4(9): p. 1263–1266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Robinson CG, et al. , Patterns of failure after stereotactic body radiation therapy or lobar resection for clinical stage I non–small-cell lung cancer. Journal of Thoracic Oncology, 2013. 8(2): p. 192–201. [DOI] [PubMed] [Google Scholar]
  • 11.Crabtree TD, et al. , Analysis of first recurrence and survival in patients with stage I non–small cell lung cancer treated with surgical resection or stereotactic radiation therapy. The Journal of thoracic and cardiovascular surgery, 2014. 147(4): p. 1183–1192. e10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Lee A, et al. , Local control after stereotactic body radiation therapy for early-stage non-small cell lung cancer: a tale of 2 schedules? International Journal of Radiation Oncolog• Biolog• Physics, 2016. 96(2): p. E483–E484. [Google Scholar]
  • 13.Woody NM, et al. , A histologic basis for the efficacy of SBRT to the lung. Journal of Thoracic Oncology, 2017. 12(3): p. 510–519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Senthi S, et al. , Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. The lancet oncology, 2012. 13(8): p. 802–809. [DOI] [PubMed] [Google Scholar]
  • 15.Brooks ED, et al. , Association of long-term outcomes and survival with multidisciplinary salvage treatment for local and regional recurrence after stereotactic ablative radiotherapy for early-stage lung cancer. JAMA network open, 2018. 1(4): p. e181390–e181390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Surapaneni R, et al. , Stage I lung cancer survivorship: risk of second malignancies and need for individualized care plan. Journal of Thoracic Oncology, 2012. 7(8): p. 1252–1256. [DOI] [PubMed] [Google Scholar]
  • 17.Martini N and Melamed MR, Multiple primary lung cancers. The Journal of thoracic and cardiovascular surgery, 1975. 70(4): p. 606–612. [PubMed] [Google Scholar]
  • 18.Xue X, et al. , Diagnosis of multiple primary lung cancer: a systematic review. Journal of international medical research, 2013. 41(6): p. 1779–1787. [DOI] [PubMed] [Google Scholar]
  • 19.Team NLSTR, Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine, 2011. 365(5): p. 395–409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Thakur MK, et al. , Risk of second lung cancer in patients with previously treated lung cancer: analysis of Surveillance, Epidemiology, and End Results (SEER) Data. Journal of Thoracic Oncology, 2018. 13(1): p. 46–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Han SS, et al. , Risk stratification for second primary lung cancer. Journal of Clinical Oncology, 2017. 35(25): p. 2893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Onishi H, et al. , Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. Journal of thoracic oncology, 2007. 2(7): p. S94–S100. [DOI] [PubMed] [Google Scholar]
  • 23.Timmerman R, et al. , Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. Journal of clinical oncology, 2006. 24(30): p. 4833–4839. [DOI] [PubMed] [Google Scholar]
  • 24.Cerra-Franco A, et al. , Predictors of Nodal and Metastatic Failure in Early Stage Non–small-cell Lung Cancer After Stereotactic Body Radiation Therapy. Clinical lung cancer, 2019. 20(3): p. 186–193. e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Spratt DE, et al. , Recurrence patterns and second primary lung cancers after stereotactic body radiation therapy for early-stage non–small-cell lung cancer: implications for surveillance. Clinical lung cancer, 2016. 17(3): p. 177–183. e2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Huang K, et al. , High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer. Radiotherapy and Oncology, 2013. 109(1): p.51–57. [DOI] [PubMed] [Google Scholar]
  • 27.Klempner SJ, et al. , The clinical use of genomic profiling to distinguish intrapulmonary metastases from synchronous primaries in non–small-cell lung cancer: a mini-review. Clinical lung cancer, 2015. 16(5): p. 334–339. e1. [DOI] [PubMed] [Google Scholar]
  • 28.Thunnissen E, SC02. 01 Multiple Primary Lung Cancers Versus Lung Metastases: Pathological Differential Diagnosis. Journal of Thoracic Oncology, 2017. 12(1): p. S75–S77. [Google Scholar]
  • 29.de Bruin EC, et al. , Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science, 2014. 346(6206): p. 251–256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Cassidy RJ, et al. , Next - generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy. Cancer, 2017. 123(19): p.3681–3690. [DOI] [PubMed] [Google Scholar]
  • 31.Timmerman RD, et al. , Long-Term results of stereotactic body radiation therapy in medically inoperable stage I Non–Small cell lung cancer. JAMA oncology, 2018. 4(9): p. 1287–1288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Parsons A, et al. , Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. Bmj, 2010. 340: p. b5569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Kumar SS and McGarry RC, Management of local recurrences and regional failure in early stage non-small cell lung cancer after stereotactic body radiation therapy. Translational lung cancer research, 2019. 8(Suppl 2): p. S213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Hamaji M, et al. , Treatment and prognosis of isolated local relapse after stereotactic body radiotherapy for clinical stage I non-small-cell lung cancer: importance of salvage surgery. Journal of Thoracic Oncology, 2015. 10(11): p. 1616–1624. [DOI] [PubMed] [Google Scholar]
  • 35.Ogawa Y, et al. , Repeat stereotactic body radiotherapy (SBRT) for local recurrence of non-small cell lung cancer and lung metastasis after first SBRT. Radiation Oncology, 2018. 13(1): p. 136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Antonoff MB, et al. , Salvage pulmonary resection after stereotactic body radiotherapy: a feasible and safe option for local failure in selected patients. The Journal of thoracic and cardiovascular surgery, 2017. 154(2): p. 689–699. [DOI] [PubMed] [Google Scholar]
  • 37.Hinduja RH, et al. , P2. 16–19 Feasibility and Outcomes of Radiofrequency Ablation as Salvage Modality After Hypofractionated Radiation/SBRT for Early NSCLC. Journal of Thoracic Oncology, 2018. 13(10): p. S838. [Google Scholar]
  • 38.Dickhoff C, et al. , Salvage surgery for local recurrence after stereotactic body radiotherapy for early stage non-small cell lung cancer: a systematic review. Therapeutic advances in medical oncology, 2018. 10: p. 1758835918787989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Peulen H, et al. , Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy. Radiotherapy and Oncology, 2011. 101(2): p. 260–266. [DOI] [PubMed] [Google Scholar]
  • 40.Miller CJ, et al. , Predictors of Distant Failure After Stereotactic Body Radiation Therapy for Stages I to IIA Non–Small-Cell Lung Cancer. Clinical lung cancer, 2019. 20(1): p. 37–42. [DOI] [PubMed] [Google Scholar]
  • 41.Juloori A, et al. , An Externally Validated Nomogram for Predicting Distant Metastasis after Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: Implications for Adjuvant Systemic Therapy. International Journal of Radiation Oncolog• Biolog• Physics, 2018. 102(3): p. S11. [Google Scholar]
  • 42.Shaverdian N, et al. , Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. The Lancet Oncology, 2017. 18(7): p. 895–903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Tang C, et al. , Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral T cells. Clinical Cancer Research, 2017. 23(6): p. 1388–1396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Welsh J, et al. , Phase 2 5-arm trial of ipilimumab plus lung or liver stereotactic radiation for patients with advanced malignancies. International Journal of Radiation Oncolog• Biolog• Physics, 2017. 99(5): p. 1315. [Google Scholar]
  • 45.Verma V, et al. , Safety of combined immunotherapy and thoracic radiation therapy: analysis of 3 single-institutional phase I/II trials. International Journal of Radiation Oncology* Biology* Physics, 2018. 101(5): p. 1141–1148. [DOI] [PubMed] [Google Scholar]

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