International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Definitive Primary Therapy in Patients Presenting With Oligometastatic Non-Small Cell Lung Cancer Ravi B. Parikh, AB,* Angel M. Cronin, MS,y David E. Kozono, MD, PhD,y,z Geoffrey R. Oxnard, MD,y,z Raymond H. Mak, MD,y,z David M. Jackman, MD,y,z Peter C. Lo, MA,y Elizabeth H. Baldini, MD, MPH,y,z Bruce E. Johnson, MD,y,z and Aileen B. Chen, MD, MPPy,z *Harvard Medical School, Boston, Massachusetts; yDana-Farber Cancer Institute, Boston, Massachusetts; and zBrigham and Women’s Hospital, Boston, Massachusetts Received Jan 25, 2014, and in revised form Mar 17, 2014. Accepted for publication Apr 3, 2014.

Summary Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from definitive therapy to the primary tumor. Using an institutional database of patients prospectively enrolled upon diagnosis of stage IV NSCLC between 2002 and 2012, we investigated the effect of definitive primary therapy on overall survival. Definitive primary therapy was associated with prolonged survival in patients with oligometastatic NSCLC. Select characteristics, including good performance status, nonsquamous histology, and limited nodal disease, may predict prolonged survival.

Purpose: Although palliative chemotherapy is the standard of care for patients with diagnoses of stage IV non-small cell lung cancer (NSCLC), patients with a small metastatic burden, “oligometastatic” disease, may benefit from more aggressive local therapy. Methods and Materials: We identified 186 patients (26% of stage IV patients) prospectively enrolled in our institutional database from 2002 to 2012 with oligometastatic disease, which we defined as 5 or fewer distant metastatic lesions at diagnosis. Univariate and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary tumor on overall survival. Results: Median age at diagnosis was 61 years of age; 51% of patients were female; 12% had squamous histology; and 33% had N0-1 disease. On multivariable analysis, Eastern Cooperate Oncology Group performance status 2 (hazard ratio [HR], 2.43), nodal status, N2-3 (HR, 2.16), squamous pathology, and metastases to multiple organs (HR, 2.11) were associated with a greater hazard of death (all P3 cm), nodal spread of disease (N0-1 to N2-3), organ sites with metastatic involvement (brain, bone, adrenal glands, other single organs, multiple organs), pathology (nonsquamous epidermal growth factor receptor [EGFR] wildtype or unknown, nonsquamous EGFR activating mutation, squamous), and number of metastatic lesions (1, 2, or 3-5). Treatment characteristics examined included use of aggressive local therapy to primary and metastatic sites. We defined aggressive local therapy of primary disease as either surgical resection and/or definitive radiation of biological equivalent dose (BED10 without time adjustment) 53 or stereotactic body radiation therapy (SBRT) to the primary tumor. We defined aggressive local therapy of metastatic disease as surgical resection and/or high-dose radiation (BED 53, whole-brain radiation therapy, stereotactic radiation surgery, or SBRT) to all known sites of metastatic disease.

Statistical methods Overall survival rates among patients with diagnoses of oligometastatic versus more extensive disease were compared using univariate Cox proportional hazards regression. Because our institutional database began to enroll all patients with lung cancer diagnoses starting only in 2009 (prior to this date most patients were selectively enrolled for specific projects based on likely genomic characteristics), survival rates among these cohorts were compared only for those with diagnoses in 2009 and after. Among patients whose oligometastatic disease was diagnosed from 2002 to 2012, univariate associations between patient and disease factors with receipt of definitive primary therapy were assessed using the Fisher exact test. Univariate and multivariaable Cox proportional hazards models with backward selection were used to analyze patient and disease factors associated with overall survival. To evaluate the association between definitive primary therapy and overall survival, we prespecified that propensity score methodology would be used to balance the treatment groups with respect to observed confounding variables. Propensity scores analyses were conducted using inverse probability weights to balance measurable confounders between those who did and did not receive definitive treatment; all variables described in Table 1 were used to calculate the patient’s propensity to receive definitive treatment, regardless of statistical significance (21, 22). P values were 2-sided and values of 3.0 cm Nodal status (nZ185) N0-N1 N2-N3 Pathology Nonsquamous, EGFR wild-type or unknown Nonsquamous, EGFR activating Squamous Number of metastatic lesions 1 2 3-5 Metastatic organs Brain only Bone only Adrenal only Other single organ Multiple organs

Overall (%)

No. receiving definitive treatment (%) No

Yes

P Value

186 (100) 133 (100) 53 (100) .065 116 (62) 70 (38)

77 (58) 39 (74) 56 (42) 14 (26)

92 (49) 94 (51)

61 (46) 31 (58) 72 (54) 22 (42)

.144

.507 170 (94) 123 (95) 47 (92) 11 (6) 7 (5) 4 (8) .722 132 (71)

93 (70) 39 (74)

53 (29)

39 (30) 14 (26) .088

162 (87) 112 (84) 50 (94) 24 (13) 21 (16) 3 (6) .643 161 (87) 116 (87) 45 (85) 25 (13) 17 (13) 8 (15) .504

71 (39) 113 (61)

53 (40) 18 (34) 78 (60) 35 (66)

61 (33) 124 (67)

37 (28) 24 (45) 95 (72) 29 (55)

.037

.323 144 (77) 104 (78) 40 (75)

20 (11)

16 (12)

4 (8)

22 (12)

13 (10)

9 (17) .026

97 (52) 40 (22) 49 (26)

63 (47) 34 (64) 28 (21) 12 (23) 42 (32) 7 (13)

54 53 14 28 37

25 45 10 20 33

70 Gy. Patients with fewer metastatic lesions

N = 820

Table 2 Unadjusted association between treatment and overall survival among patients with oligometastatic disease Enrolled within 12 months of diagnosis

Treatment

N = 725 (88%)

No aggressive treatment Yes: to metastatic sites only Yes: to primary tumor only Yes: to both metastatic sites and primary tumor

Oligometastatic

Non-Oligometastatic

N = 186 (26%)

N = 539 (74%)

Fig. 1.

Study cohort.

Number of Hazard patients (%) ratio* 101 (54) 32 (17)

1.00 0.90

16 (9)

0.64

37 (20)

0.59

95% CI

P Value

– 0.571.41 0.331.24 0.370.95

– .647

Abbreviation: CI Z confidence interval. * Hazard ratios >1 represent lower overall survival.

.189 .029

Volume -  Number -  2014

5

Primary therapy in oligometastatic NSCLC

Table 3 Univariate and multivariable Cox proportional hazards regression to determine associations between clinicopathologic characteristics and overall survival, among patients with oligometastatic disease Multivariabley (nZ177)

Univariate Factor Age (years) 10% Radiologic size of primary tumor 3.0 cm >3.0 cm Nodal status N0-N1 N2-N3 Pathology Non-squamous, EGFR wild-type or unknown Non-squamous, EGFR activating mutation Squamous Number of metastatic lesions 1 2 3-5 Number of metastatic organsz 1 2-3

Hazard ratio*

95% CI

P Value

Hazard ratio*

95% CI

Reference 0.76

0.52-1.12

.162

Reference .85

0.59-1.24

.406 .092

Reference .49

0.22-1.12

– –

– –

Reference 2.43

1.39-4.25

– –

– –

– –

– –

– –

– –

Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer.

Although palliative chemotherapy is the standard of care for patients with diagnoses of stage IV non-small cell lung cancer (NSCLC), patients with a s...
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