Practical Radiation Oncology (2015) 5, e355-e363
www.practicalradonc.org
Original Report
Definitive dose thoracic radiation therapy in oligometastatic non-small cell lung cancer: A hypothesis-generating study Eric P. Xanthopoulos MD, JD a, b , Elizabeth Handorf PhD c, d , Charles B. Simone II MD a , Surbhi Grover MD, MPH a , Annemarie T. Fernandes MD a , Sonam Sharma MD a , Michael N. Corradetti MD, PhD a, e , Tracey L. Evans MD f , Corey J. Langer MD f , Nandita Mitra PhD c , Anand Shah MD, MPH a, b , Smith Apisarnthanarax MD a , Lilie L. Lin MD a , Ramesh Rengan MD, PhD a, g,⁎ a
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Currently at Department of Radiation Oncology, Columbia University Medical Center, New York, New York c Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania d Currently at Biostatistics and Bioinformatics Facility, Fox Chase Cancer Research Center, Philadelphia, Pennsylvania e Currently at Department of Radiation Oncology, Brigham and Women’s Hospital/Dana Farber Cancer Institute, Boston, Massachusetts f Department of Internal Medicine, Division of Hematology and Medical Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania g Currently at Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington b
Received 29 September 2014; revised 31 October 2014; accepted 19 November 2014
Abstract Purpose: A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor treatment. We report comparative outcomes in oligometastatic non-small cell lung cancer (NSCLC) treated with and without definitive, conventionally fractionated thoracic radiation therapy. Methods and materials: We identified consecutive patients with stage IV NSCLC who had an Eastern Cooperative Oncology Group performance status ≤ 2 and ≤ 4 total sites of metastatic disease and who had been prescribed ≥ 50 Gy of thoracic radiation. Results: Twenty-nine patients with oligometastatic NSCLC were identified between January 2004 and August 2010. Median survival was 22 months from diagnosis. Four patients (14%) experienced pneumonitis greater than or equal to grade 3; 6 (21%) had esophagitis greater than or equal to grade 3. Local control was associated with improved survival (P = .02). In matched subset analysis, median survival was 9 months (P b .01) in patients who received chemotherapy alone. Median time to local failure was 18 versus 6 months (P = .01). On multivariable analysis, radiation (P b .01; odds ratio [OR], 0.33), fewer metastases (P b .01; OR, 2.14), and female sex (P b .01; OR, 0.41) were associated with
Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation Oncology, University of Washington School of Medicine, 1959 NE Pacific St, Seattle, WA 98195. E-mail address: [email protected] (R. Rengan). http://dx.doi.org/10.1016/j.prro.2014.11.006 1879-8500/© 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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improved survival. Conclusions: Definitive dose radiation therapy may improve survival in a select subset of patients with minimal extrathoracic disease in whom local progression is of primary concern. Prospective trials are needed to further evaluate the role of local control in oligometastatic NSCLC. © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction Approximately 40% to 50% of patients with non-small cell lung cancer (NSCLC) present with stage IV disease. 1 These patients have a poor prognosis; expected median survival is 10 to 12 months. 2-4 Platinum-based doublets remain the standard of care for patients with good performance status with stage IV NSCLC who are not candidates for targeted therapy. 1,5 Physicians use low-dose radiation for palliation in this population, a practice validated in at least 1 randomized series. A number of randomized controlled trials have suggested that higher-dose palliative radiation may improve survival, particularly in patients with good performance status. 6,7 Although a quarter or more of stage IV patients succumb to primary tumor progression, these studies have not investigated the role of radiation delivered with a goal of tumor control in these patients. Additionally, none of these studies examined the use of higher-than-palliative dose radiation in oligometastatic patients. Our clinical practice has been to deliver definitive thoracic radiation therapy with a primary intent of tumor control in a subset of patients with good performance status and oligometastatic stage IV NSCLC. The rationale for this therapeutic approach is that local progression can be a cause of significant morbidity and mortality, even in the setting of metastatic disease. The driving hypothesis, therefore, is that the provision of local control of disease can provide clinical benefit in this subset of patients. 8-11 In this report, we examine the clinical outcome of patients treated with this approach with respect to local control, adverse events, and overall survival. Additionally, we performed a matched cohort analysis of these patients with patients matched to similar patients who received chemotherapy alone without thoracic radiation therapy.
Methods Patient inclusion criteria With Institutional Review Board approval, we identified patients with stage IV metastatic NSCLC from a retrospectively updated database from institutional medical records of all patients with NSCLC who received treatment at our institution from January 2004 through August 2010. All patients had stage IV metastatic NSCLC per the American Joint Committee on Cancer’s Cancer Staging Manual (7th edition), Eastern Cooperative Oncology Group
(ECOG) performance status ≤ 2, 4 or fewer metastases documented by imaging or pathology (each lesion was counted separately independent of organ location), no prior radiation of the primary tumor site, radiation prescription ≥ 50 Gy, and no prior resection of the primary tumor. All intrathoracic disease must have been amenable to definitive radiation therapy. Of note, patients may have received either radiation therapy alone, sequential chemotherapy followed by radiation therapy, or concurrent chemoradiation therapy with a platin doublet.
Patient diagnosis and follow-up All patients underwent complete history, physical examination, and computed tomography (CT) or F-18 fluoro-2-deoxyglucose-positron emission tomography (PET) scan at diagnosis. All patients had pathologically confirmed NSCLC. Reflex mutational testing was not performed at the time of this study, and therefore, mutational status was unknown. Patients were followed up at regular intervals, approximately every 3 months for the first 1 to 3 years after treatment and then every 6 to 12 months after 3 years. All patients had a minimum of 6 months of follow-up after radiation. Patients were retrospectively scored for radiation pneumonitis and esophagitis toxicity using the joint Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer acute radiation morbidity scoring criteria. 12
Treatment techniques and parameters All patients were immobilized in a supine position with their arms raised in a customized Alpha Cradle Mold. CT simulation techniques were used to define the target volume. For each patient, a gross tumor volume for the primary tumor (GTV-primary) was delineated that consisted of the primary lung tumor, and a nodal GTV (GTV-nodal) was delineated that encompassed all involved nodal disease. Critical normal tissue structures were contoured by the physician or by the treatment planner. For patients who underwent 4-dimensional CT (4D-CT) planning, internal gross tumor volumes (IGTVs) were generated based on respiratory correlated data sets for both the primary tumor (IGTV-primary) and involved nodes (IGTV-nodal). Clinical target volumes (CTV-primary and CTV-nodal) were generated by use of an expansion of 0.8 cm to the IGTV-primary and 0.3 cm to the IGTV-nodal to encompass microscopic extension of the tumor. For patients who did not
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undergo 4D-CT planning, the CTVs were generated directly from the corresponding GTVs using the corresponding margins, and then the CTV-primary was expanded by 1.5 cm for lower lobe tumors and by 1.0 cm for upper lobe tumors to generate the planning target volume (PTV)-primary, accounting for setup error and tumor motion; the PTV-nodal was generated from the CTV-nodal using a uniform PTV expansion of 0.5 cm. For patients who underwent a 4D-CT, a uniform PTV expansion of 0.5 cm was then applied to the CTV-primary and CTV-nodal to generate the corresponding PTVs. The PTV-primary and PTV-nodal were then unified into a single PTV for planning. Megavoltage linear accelerator x-rays of ≥ 6 MV energy were used for treatment delivery. Doses were prescribed to the maximum isodose level that encompassed the PTV. Patients were treated with conventional fractionation, without a treatment break. Extrathoracic metastatic disease was not included in the thoracic radiation portals. Brain metastases were treated with either whole brain radiation therapy or gamma knife radiosurgery. All patients included in this analysis received definitive dose radiation therapy of at least 50 Gy. We delivered the maximally safe dose to the PTV while constraining the lung to the following parameters: V20 ≤ 35%, V5 ≤ 60%, and mean lung dose ≤20 Gy, consistent with institutional and QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) guidelines. 13 The final prescription was based on several factors, including dosimetric constraints, whether or not the patient was receiving concurrent chemotherapy, performance status, and volume of extrathoracic residual disease. Patients who received concurrent chemoradiation therapy were generally treated with 1.8 Gy per fraction to a maximum dose of 72 Gy. Patients receiving either radiation therapy alone or sequential chemoradiation therapy were generally treated with 2 Gy per fraction to a maximum dose of 80 Gy, on the basis of previously published reports using this dosing regimen. 14
Chemotherapy All patients received at least 1 cycle of either concurrent or sequential cytotoxic chemotherapy. Patients most commonly received cisplatin or carboplatin in combination with other chemotherapeutic agents. Patients were planned to receive definitive therapy upfront based on the clinical criteria outlined above. All patients were reviewed in a multidisciplinary setting. The decision to deliver concurrent or sequential chemoradiation therapy was determined by the multidisciplinary team after review and included a number of factors, including suitability for chemotherapy, physician preference, and performance status of the patient.
Local control evaluation Two physicians reviewed patient records (films, imaging reports, and, if available, pathology) for intrathoracic disease progression after completion of radiation therapy. The reviewers scored tumor burden and response using the
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RECIST criteria (Response Evaluation Criteria in Solid Tumors), version 1.1. Irradiated lesions were also evaluated with RECIST criteria; however, isolated progression within the irradiated field was evaluated by additional confirmatory studies, including PET/CT or biopsy as clinically indicated to confirm progression. 15
Adverse events For the toxicity assessment, we reviewed patient records from the Hospital of the University of Pennsylvania and affiliated institutions. Patient visits to the emergency department and hospital admissions after the start of treatment were categorized as treatment or disease related by at least 2 oncologists. Treatment-related visits consisted of admissions for toxicity to chemotherapy or radiation. Visits were disease related if they were directly related to cancer sequelae or progression.
Statistical analysis Overall survival was computed from the date of diagnosis by imaging (or date of first treatment for a parallel analysis) until death or date of last follow-up when they were censored. Kaplan-Meier and log-rank testing were used to compare unadjusted survival profiles. Cox proportional hazards regression controlled for potential confounders. Any variable with a P value ≤ .10 in the univariate model was eligible for multivariable Cox modeling. A threshold P value ≤ .05 established significance in multivariable models.
Matched cohort analysis We performed a matched cohort comparison of patients with stage IV NSCLC who were treated with and without definitive thoracic radiation therapy. From a comprehensive database of patients with stage IV NSCLC treated with chemotherapy alone during the same time interval, we identified a matched set of 97 patients who satisfied the criteria used to identify our original cohort of 29 patients treated with definitive radiation therapy (ECOG performance status ≤2, ≤4 metastases, no primary tumor surgery or radiation, and no known targetable driver mutation). We then used an exact-matching algorithm with the statistical computing program R (version 12.2) that identified control subjects with matching covariate values. Using this program, we randomly grouped thoracic radiation therapy patients with 2 chemotherapy patients randomly selected by matching them on 4 factors using an exact-matching approach at diagnosis: (1) median age; (2) ECOG performance score; (3) number of involved organs; and (4) specific organ involved. Chemoradiation patients were only included in this exploratory analysis if they could be matched with at least 2 chemotherapy-only patients. Pearson χ 2, Fisher exact test, or nonparametric equality of medians tests were used to
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Patient characteristics Definitive radiation Chemotherapy P value therapy (n = 25) (n = 50)
Patient characteristic Median age, y (range) Race (all), % (n) White Black Other/unknown Female, % (n) ECOG (all), % (n) 1 2 Patients staged by PET, % (n) Organs, % (n) Adrenal Bone Brain Effusion Lung, contralateral Node, extrathoracic Other No. of metastatic organs, % (n) 1 2 3 4 No. of metastatic sites (counting multiple sites within a single organ separately), % (n) 1 2 3 4 At least 1 organ with 2 or more metastases, % (n) Median dose, Gy (range) Median chemotherapy, cycles (range) Patients with multiple chemotherapy regimens, % (n) Concurrent chemotherapy, % (n) Sequential, % (n), median lag Chemotherapy regimen, % (n) Carboplatin
59 (45-79)
58 (30-78)
52 (13) 40 (10) 8 (2) 56 (14)
60 30 10 40
68 (17) 32 (8) 91 (21)
68 (34) 32 (16) 78 (25)
12 (3) 44 (11) 32 (8) 4 (1) 12 (3) 32 (8) 8 (2)
10 (5) 44 (22) 32 (16) 12 (6) 12 (6) 20 (10) 8 (4)
68 (17) 24 (6) 4 (1) 4 (1)
68 26 6 0
52 (13) 32 (8) 4 (1) 12 (3) 28 (7) 68 (50-80) 6.5 (1-24) 56 (14) 52 (13) 48 (12), 4 mo
46 (23) 28 (14) 18 (9) 8 (4) 34 (17) — 6 (1-40) 64 (32) — —
.40 .62 .72 — — .60 — .73 .50 — —
88 (22)
94 (47)
—
(30) (15) (5) (20)
(34) (13) (3) (0)
.87 .43 .51 .39 — .19 1.00 1.00 1.00 .19 .79 1.00 1.00 .26 1.00 .25 1.00 .54 1.00 .85 —
ECOG, Eastern Cooperative Oncology Group; PET, positron emission tomography.
compare the distribution of patient characteristics between the 2 treatment groups. Statistical analyses were performed with STATA/IC (version 11.0 for Mac OS X; StataCorp, College Station, Texas).
Results Characteristics From 430 NSCLC patients consecutively treated from January 2004 through August 2010, we identified 29 patients who met our inclusion criteria. The 29 thoracic radiation therapy patients had a median age of 57 years
(range, 43-79 years). Seventy-two percent had ECOG performance status 1 (range, 1-2). Ninety-one percent were staged with PET in addition to CT imaging. A median dose of 67 Gy (range, 50-83 Gy) was delivered with a median of 7 cycles (range, 1-24) of chemotherapy, with systemic therapy delivered concurrently (55%) or sequentially (45%) with radiation. The median time to chemotherapy or chemoradiation treatment from diagnosis (by imaging) was 2 months; 72% of patients received chemotherapy or chemoradiation treatment within 3 months of diagnosis. Table 1 summarizes the patient characteristics of the thoracic radiation therapy patients and the chemotherapy patients they were matched against. Four radiation therapy patients could not be matched to 2 chemotherapy control subjects and were excluded from the matched-cohort analysis. Patient characteristics were well balanced across
Practical Radiation Oncology: July-August 2015 Table 2
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Toxicity and adverse events, as measured by hospital and ED visits
Toxicity grade Esophagitis, % (n) Pneumonitis, % (n) No. of visits Treatment-related visits, % (n) a Disease-related visits, % (n) a 1 2 3 4 5
10 (3) 45 (13) 21 (6) 0 (0) 0 (0)
17 (5) 14 (4) 14 (4) 0 (0) 0 (0)
0 1 2 3 4 5 ≥6
63 (n = 17) 11 (3) 11 (3) 7 (2) 4 (1) 4 (1) 0 (0)
41 (n = 11) 15 (4) 15 (4) 19 (5) 7 (2) 0 (0) 4 (1)
ED, emergency department. a Total n = 27.
the treatment groups, especially with respect to the number of involved organs, the specific organ involved, and the number of total metastases (counting multiple sites within the same organ separately) (Table 1). We did not find an imbalance in the number of involved organs between the 2 groups. Both the treatment group and the matched control subjects had 1 involved organ in 68% of cases (P = 1.00). For the thoracic radiation therapy versus chemotherapy-only patients, 24% versus 26% had 2 involved organs (P = .85); 4% versus 6% had 3; and 4% versus 0% had 4. Although the number of involved organs remained significantly associated with poorer survival on multivariable analysis (P b .01; odds ratio [OR], 2.14), the groups were well matched. We also did not identify a difference in the specific organ involved with metastasis between the 2 groups. Both arms were exactly matched for bone, brain, contralateral lung, and other metastatic organ involvement (P = 1.00 for each). They also had similar adrenal, pleural effusion, and extrathoracic nodal involvement (P = .79, .26, and .25, respectively).
Toxicity and adverse events All patients tolerated radiation therapy well. Twenty-one percent of patients experienced acute esophagitis greater than or equal to grade 3 and 45% experienced greater than or equal to grade 2 esophagitis during treatment. Fourteen percent of patients developed pneumonitis greater than or equal to grade 3 and 28% had pneumonitis greater than or equal to grade 2 at 1 to 6 months after completion of radiation treatment. Sixty-three percent of patients did not have any treatment-related hospital visits related to adverse events (Table 2). Three months after treatment, patients treated by definitive radiation therapy had no median change in ECOG performance score, compared with a median deterioration of 0.5 points seen in chemotherapy recipients (P = .02).
Local control and survival Overall median survival for all patients was 22 months (95% confidence interval [CI], 15-42 months) from diagnosis or 19 months (95% CI, 11-40 months) from
first treatment. Survival rates from diagnosis were 76% (95% CI, 56%-88%) at 1 year and 49% (95% CI, 29%-66%) at 3 years. Median follow-up was 22 months in the 8 surviving patients. The median time to local failure was not reached (95% CI, ≥ 8 months). Median survival in locally controlled patients was 39 months (95% CI, ≥ 15 months) versus 19 months (95% CI, 7-42 months) from diagnosis in patients with local failure. Local control was associated with survival (P = .01). Outcomes based on sites of metastases were analyzed. Patients with adrenal metastases had a median survival of 12 months versus 39 months in those who did not have adrenal metastases (P b .01); in bone, 15 versus 41 months (P = .02); and with pleural effusions, 7 versus 39 months (P b .01). Other sites of metastases, including brain, contralateral lung, and extrathoracic lymph nodes, did not affect outcomes (all P N .05). The number of involved organs, but not the number of discrete metastases, was associated with survival (P b .01). For example, a patient with a single metastasis in each of 3 organs tended to have worse prognosis than a patient with 3 metastases in a single organ.
Thoracic radiation therapy outcomes compared with matched cohort of chemotherapy-only patients We performed an exploratory analysis comparing the outcomes of patients who received definitive thoracic radiation therapy to those of patients receiving chemotherapy alone. A 1-to-2 match was performed based on age, performance status, number of organs involved, and the specific organ involved. As noted previously, 4 radiation therapy patients could not be matched to 2 chemotherapy control subjects and were excluded. Definitive radiation therapy and survival From diagnosis, patients who received definitive radiation therapy versus chemotherapy alone had a median survival of 22 months (95% CI, 15-42 months) versus 9 months (95% CI, 7-16 months; P b .01) (Fig 1A). From first treatment, patients who received definitive radiation therapy versus chemotherapy had a median survival of 19
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months (95% CI, 11-40 months) versus 8 months (95% CI, 5-14 months; P = .01). Survival rates from diagnosis were 76% versus 41% at 12 months and 49% versus 12% at 36 months, respectively. Median follow-up was 21 months in the 6 living patients who received definitive radiation therapy and 25 months (range, 7-41 months) in the 9 surviving chemotherapy-only recipients (P = .75).
OR, 0.41) were associated with survival (Table 3). Although the number of involved organs was associated with survival on multivariable regression (P b .01), the number of total metastases (counting multiple sites within the same organ separately) was not (P = .28).
Definitive radiation therapy and local control Patients who received definitive radiation therapy had a median time to local failure of 18 months (95% CI, ≥ 7 months) versus 6 months (95% CI, 4-8 months) with chemotherapy (P = .03) (Fig 1B).
Discussion
Local control and survival At last follow-up, locally controlled patients had a median survival from diagnosis of 39 months (95% CI, ≥ 8 months) versus 13 months (95% CI, 10-19 months) in patients with a local failure (P = .06). On multivariable analysis, only thoracic radiation therapy (P b .01; OR, 0.33), number of metastatic organs at diagnosis (P b .01; OR, 2.14), and female sex (P b .01;
Figure 1 (A) Kaplan-Meier overall survival from diagnosis, by treatment (P b .01). (B) Kaplan-Meier time to local failure from any first therapy, by treatment (P = .03).
Definitive dose thoracic radiation in a subset of favorable stage IV NSCLC patients is well tolerated, with modest toxicity. In selected patients, it may improve clinical outcomes, perhaps because of improved primary tumor control. With optimal care, median survival of 1 year or more is possible in stage IV patients. 2-4 Yet this prognostic estimate comes from a heterogeneous source, including patients with poor performance status and widely metastatic disease and those with good status and oligometastatic disease. 2-4 There is a broad range to survival in stage IV disease, from weeks to years. 2-4 The driving hypothesis of this report is that local control is of clinical importance in a select subset of patients with limited disseminated disease, and therefore, high-dose thoracic radiation therapy may improve outcome In this analysis, we identified several factors that were associated with overall survival in these stage IV patients. Echoing previous publications, a greater number of involved organs at diagnosis was associated with poorer survival (P b .01; OR, 2.14). Also, consistent with prior studies, female sex (P = .05; OR, 0.41) predicted improved outcomes. 3,16,17 We performed a matched cohort comparison of these patients to a subset of stage IV patients who received chemotherapy alone and identified the patients who received definitive thoracic radiation therapy as having improved local control and overall survival compared with patients who did not. However, there are several weaknesses to such an analysis, including selection bias and the potential impact of confounders. In an attempt to address these potential weaknesses, we performed a matched cohort comparison with 2:1 matching using median age, ECOG performance score, number of involved organs, and the specific organ involved as covariates and confirmed the robustness of our matching algorithm with respect to these covariates. However, one factor that was not accounted for as a separate covariate was the total number of metastatic sites (counting multiple sites within the same organ separately). Comparing the thoracic radiation therapy and chemotherapy-only groups, there was no significant difference in the number of patients harboring 1, 2, 3, or 4 sites of metastatic disease (Table 1). To summarize, an imbalance in the number of metastatic sites between the 2 groups did not appear to contribute to the observed survival difference.
Practical Radiation Oncology: July-August 2015 Table 3
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Univariate and multivariable Cox survival analysis
Radiation therapy (yes/no) White (yes/no) Black (yes/no) Female (yes/no) Adrenal metastases only (yes/no) Bone metastases only (yes/no) Brain metastases only (yes/no) Effusion metastases only (yes/no) Node metastases only (yes/no) Other metastases only (yes/no) No. of metastatic organs (continuous) No. of total metastases (counting multiple sites within a single organ separately) (continuous) At least 1 organ with N 2 metastases (yes/no) Local failure (yes/no)
Univariate P value (HR)
Multivariable P value (HR)
b .01 (0.38) .47 (1.22) .57 (0.85) .02 (0.52) .30 (1.86) .99 (1.00) .23 (0.66) .61 (1.70) .89 (0.94) .08 (3.60) .09 (1.40) .28 (1.15) .95 (1.02) .07 (1.68)
b .01 — — b .01 — — — — — .72 b .01 — — .59
(0.33)
(0.41)
(1.44) (2.14)
(1.18)
HR, hazard ratio.
Despite matched pair analysis, confounding selection or hidden biases from unmeasured confounders may explain the potentially worse survival in patients treated with chemotherapy alone. For example, although most patients in both groups received carboplatin, it was not possible to exactly match chemotherapy regimens across the 2 groups. These biases mean that interpretation of our data should be viewed as hypothesis generating. Nevertheless, our findings suggest that patients with oligometastatic stage IV NSCLC treated with thoracic radiation therapy may have improved survival when compared to similar patients who receive chemotherapy alone. Selection bias and unmeasured confounders are inherent limitations in all retrospective reviews. This study supports further investigation with larger prospective studies to assess survival, disease control, and quality of life in this highly selected subset of patients. Aggressive local radiation therapy to sites of intracranial metastases for patients with oligometastatic NSCLC or to sites of lung parenchymal metastases for patients with or without primary lung cancers have been reported previously, but few previous data exist defining the utility of aggressive, nonpalliative local radiation therapy to the primary tumor and regional lymph nodes in NSCLC patients with extrathoracic oligometastatic disease. 18,19 This study is consistent with recently reported results from Sheu et al., 20 who examined outcomes in patients with good performance status and oligometastatic disease who received chemotherapy followed by comprehensive local therapy (either radiation or surgery). They observed that patients who received comprehensive local therapy had improved overall survival and progression-free survival compared with propensity-score matched control subjects. 20 Another approach that has been reported in the setting of oligometastatic disease is the delivery of definitive locally ablative therapy to all sites of disease in select patients with oligometastatic disease either with or without
systemic therapy and surgery. Khan et al 21 reported on 23 patients with 1 to 2 sites of oligometastatic NSCLC treated with systemic therapy, with aggressive local and regional radiation therapy, and with or without surgery. Radiation therapy was delivered to a median dose of 60 Gy in nonsurgically treated patients and 40 Gy when administered as neoadjuvant therapy. Although treatment was very heterogenous across this cohort, at a median follow-up of 17 months, the median time to recurrence for the cohort was 12 months, and the median survival was 20 months, with 22% surviving 3 years. 21 Similarly, Hasselle et al 22 reported a promising median overall survival of 22.7 months in 25 patients treated with high-dose image-guided radiation therapy to all sites of metastases. Cheruvu et al 23 reported a comparative analysis of patients receiving “curative” intent radiation therapy with stage III disease, oligometastatic stage IV disease (b 8 lesions), and oligometastatic recurrent disease. They reported a promising 5-year overall survival rate of 14% in the patients with oligometastatic disease and 27% in those with recurrent oligometastatic disease from the date of diagnosis. Surprisingly, they only reported a 7% 5-year overall survival rate for stage III patients receiving definitive radiation therapy. The largest prospective trial to date in oligometastatic NSCLC was reported by De Ruysscher and colleagues, 24 who treated patients in a prospective phase 2 trial. Forty patients were enrolled, 35 of whom had a solitary site of metastasis. Patients received radical local therapy to all sites of disease (either surgery or radiation). They reported a median overall survival of 13.5 months. On subgroup analysis, they did not identify any patient or tumor parameter that was associated with overall survival. Our results are consistent with recent reports from other institutions. Parikh et al 25 found that definitive local therapy to the primary tumor was associated with prolonged survival in a subset of 186 patients with
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oligometastatic disease treated over a 10-year period at their institution. Similarly, Lopez Guerra et al 26 reported a series of 78 oligometastatic patients (b 5 metastases) receiving definitive chemoradiation therapy, of whom 44 also received ablative therapy to the metastases, and found that a higher dose to the primary tumor was associated with improved overall survival. In a smaller series, Jabbour et al 11 reported favorable outcomes in 9 patients with stage IV NSCLC treated with definitive dose thoracic radiation therapy to only the primary site. That series, however, did not comment on adverse events in these patients. The North Central Cancer Treatment Group initiated the N0724 trial to address this topic. 27 In that trial, patients with 3 or fewer metastases received chemotherapy and were then randomized to either radiation therapy to all residual cancer or no radiation. 27 The study will also report on adverse events but not on broader patient quality of life. The study has been completed, and results are eagerly anticipated. The University of Chicago group launched a randomized trial of chemotherapy with or without hypofractionated image-guided radiation therapy (Synergistic Metastases Annihilation With Radiotherapy and Docetaxel (Taxotere) [SMART]), which unfortunately closed because of lack of accrual (ClinicalTrials.gov identifier NCCT00887315). MD Anderson Cancer Center has also launched a randomized phase 2 trial of chemotherapy with or without aggressive local therapy (surgery or radiation therapy) in oligometastatic NSCLC that is currently accruing patients (ClinicalTrials.gov identifier NCT01725165). Taken together, with continued improvements in imaging and staging techniques that better identify patients with limited-volume extrathoracic disease, there appears to be a subset of patients in whom definitive dose thoracic radiation therapy may add value without worsening quality of life.
Conclusions The combination of definitive dose radiation therapy with chemotherapy in patients with stage IV NSCLC may improve local control without a significant increase in adverse events. Furthermore, our hypothesis-generating results suggest that this improvement in local control may drive an improvement in overall survival in these well-selected patients with a limited metastatic disease burden. Because our study is limited by its retrospective nature and small sample size, further prospective studies with larger cohorts examining not just disease survival and control but also patient quality of life are needed to validate our observations.
References 1. Socinski MA, Crowell R, Hensing TE, et al. American College of Chest Physicians. Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):277S-289S.
Practical Radiation Oncology: July-August 2015 2. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer [published correction appears in N Engl J Med. 2007;356:318]. N Engl J Med. 2006;355(24): 2542-2550. 3. Thatcher N, Ranson M, Lee SM, Niven R, Anderson H. Chemotherapy in non-small cell lung cancer. Ann Oncol. 1995;6(Suppl 1):83-94. 4. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551. 5. Azzoli CG, Baker Jr S, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27(36):6251-6266. 6. Rodrigues G, Videtic GM, Sur R, et al. Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiat Oncol. 2011;1:60-71. 7. Lester JF, Macbeth FR, Toy E, Coles B. Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev. 2006;4:CD002143. 8. Gray PJ, Mak RH, Yeap BY, et al. Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival. Lung Cancer. 2014;85(2):239-244. 9. Ashworth AB, Senan S, Palma DA, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer. 2014;15(5):346-355. 10. Griffioen GH, Toguri D, Dahele M, et al. Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): Patient outcomes and prognostic factors. Lung Cancer. 2013;82(1):95-102. 11. Jabbour SK, Daroui P, Moore D, Licitra E, Gabel M, Aisner J. A novel paradigm in the treatment of oligometastatic non-small cell lung cancer. J Thorac Dis. 2011;3(1):4-9. 12. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31(5):1341-1346. 13. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S70-S76. 14. Rosenzweig KE, Fox JL, Yorke E, et al. Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma. Cancer. 2005;103(10):2118-2127. 15. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 16. Abbasi S, Badheeb A. Prognostic factors in advanced nonsmall-cell lung cancer patients: Patient characteristics and type of chemotherapy. Lung Cancer Int. 2011. Available at: http://dx.doi.org/ 10.4061/2011/152125. Accessed January 12, 2015. 17. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small-cell lung cancer: The Southwest Oncology Group experience. J Clin Oncol. 1991;9(9):1618-1626. 18. Rodrigues G, Eppinga W, Lagerwaard F, et al. A pooled analysis of arc-based image-guided simultaneous integrated boost radiation therapy for oligometastatic brain metastases. Radiother Oncol. 2012;102(2):180-186. 19. Takeda A, Kunieda E, Ohashi T, Aoki Y, Koike N, Takeda T. Stereotactic body radiotherapy (SBRT) for oligometastatic lung tumors from colorectal cancer and other primary cancers in comparison with primary lung cancer. Radiother Oncol. 2011;101(2):255-259. 20. Sheu T, Heymach JV, Swisher SG, et al. Propensity score-matched analysis of comprehensive local therapy for oligometastatic non-small cell lung cancer that did not progress after front-line chemotherapy. Int J Radiat Oncol Biol Phys. 2014;90(4):850-857.
Practical Radiation Oncology: July-August 2015 21. Khan AJ, Mehta PS, Zusag TW, et al. Long term disease-free survival resulting from combined modality management of patients presenting with oligometastatic, non-small cell lung carcinoma (NSCLC). Radiother Oncol. 2006;81(2):163-167. 22. Hasselle MD, Haraf DJ, Rusthoven KE, et al. Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer. J Thorac Oncol. 2012;7:376-381. 23. Cheruvu P, Metcalfe SK, Metcalfe J, Chen Y, Okunieff P, Milano MT. Comparison of outcomes in patients with stage III versus limited stage IV non-small cell lung cancer. Radiat Oncol. 2011;30:80. 24. De Ruysscher D, Wanders R, van Baardwijk A, et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: Long-term results of a prospective phase II trial (Nct01282450). J Thorac Oncol. 2012;7:1547-1555.
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25. Parikh RB, Cronin AM, Kozono DE, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;89(4):880-887. 26. Lopez Guerra JL, Gomez D, Zhuang Y, et al. Prognostic impact of radiation therapy to the primary tumor in patients with non-small cell lung cancer and oligometastasis at diagnosis. Int J Radiat Oncol Biol Phys. 2012;84(1):e61-e67. 27. Schild SE, Henning GT, Garces YI, Adjei AA, Stella PJ. Randomized phase II study of oligometastatic stage IV non-small cell lung cancer (NSCLC) treated with systemic therapy plus either radiotherapy to all sites of gross residual disease or no radiotherapy: NCCTG status report for study N0724. Available at: http://ncctg.mayo.edu/thebook/Books/Spring_2010/N0724.pdf. Accessed January 12, 2015.
www.practicalradonc.org
Original Report
Definitive dose thoracic radiation therapy in oligometastatic non-small cell lung cancer: A hypothesis-generating study Eric P. Xanthopoulos MD, JD a, b , Elizabeth Handorf PhD c, d , Charles B. Simone II MD a , Surbhi Grover MD, MPH a , Annemarie T. Fernandes MD a , Sonam Sharma MD a , Michael N. Corradetti MD, PhD a, e , Tracey L. Evans MD f , Corey J. Langer MD f , Nandita Mitra PhD c , Anand Shah MD, MPH a, b , Smith Apisarnthanarax MD a , Lilie L. Lin MD a , Ramesh Rengan MD, PhD a, g,⁎ a
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Currently at Department of Radiation Oncology, Columbia University Medical Center, New York, New York c Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania d Currently at Biostatistics and Bioinformatics Facility, Fox Chase Cancer Research Center, Philadelphia, Pennsylvania e Currently at Department of Radiation Oncology, Brigham and Women’s Hospital/Dana Farber Cancer Institute, Boston, Massachusetts f Department of Internal Medicine, Division of Hematology and Medical Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania g Currently at Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington b
Received 29 September 2014; revised 31 October 2014; accepted 19 November 2014
Abstract Purpose: A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor treatment. We report comparative outcomes in oligometastatic non-small cell lung cancer (NSCLC) treated with and without definitive, conventionally fractionated thoracic radiation therapy. Methods and materials: We identified consecutive patients with stage IV NSCLC who had an Eastern Cooperative Oncology Group performance status ≤ 2 and ≤ 4 total sites of metastatic disease and who had been prescribed ≥ 50 Gy of thoracic radiation. Results: Twenty-nine patients with oligometastatic NSCLC were identified between January 2004 and August 2010. Median survival was 22 months from diagnosis. Four patients (14%) experienced pneumonitis greater than or equal to grade 3; 6 (21%) had esophagitis greater than or equal to grade 3. Local control was associated with improved survival (P = .02). In matched subset analysis, median survival was 9 months (P b .01) in patients who received chemotherapy alone. Median time to local failure was 18 versus 6 months (P = .01). On multivariable analysis, radiation (P b .01; odds ratio [OR], 0.33), fewer metastases (P b .01; OR, 2.14), and female sex (P b .01; OR, 0.41) were associated with
Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation Oncology, University of Washington School of Medicine, 1959 NE Pacific St, Seattle, WA 98195. E-mail address: [email protected] (R. Rengan). http://dx.doi.org/10.1016/j.prro.2014.11.006 1879-8500/© 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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improved survival. Conclusions: Definitive dose radiation therapy may improve survival in a select subset of patients with minimal extrathoracic disease in whom local progression is of primary concern. Prospective trials are needed to further evaluate the role of local control in oligometastatic NSCLC. © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction Approximately 40% to 50% of patients with non-small cell lung cancer (NSCLC) present with stage IV disease. 1 These patients have a poor prognosis; expected median survival is 10 to 12 months. 2-4 Platinum-based doublets remain the standard of care for patients with good performance status with stage IV NSCLC who are not candidates for targeted therapy. 1,5 Physicians use low-dose radiation for palliation in this population, a practice validated in at least 1 randomized series. A number of randomized controlled trials have suggested that higher-dose palliative radiation may improve survival, particularly in patients with good performance status. 6,7 Although a quarter or more of stage IV patients succumb to primary tumor progression, these studies have not investigated the role of radiation delivered with a goal of tumor control in these patients. Additionally, none of these studies examined the use of higher-than-palliative dose radiation in oligometastatic patients. Our clinical practice has been to deliver definitive thoracic radiation therapy with a primary intent of tumor control in a subset of patients with good performance status and oligometastatic stage IV NSCLC. The rationale for this therapeutic approach is that local progression can be a cause of significant morbidity and mortality, even in the setting of metastatic disease. The driving hypothesis, therefore, is that the provision of local control of disease can provide clinical benefit in this subset of patients. 8-11 In this report, we examine the clinical outcome of patients treated with this approach with respect to local control, adverse events, and overall survival. Additionally, we performed a matched cohort analysis of these patients with patients matched to similar patients who received chemotherapy alone without thoracic radiation therapy.
Methods Patient inclusion criteria With Institutional Review Board approval, we identified patients with stage IV metastatic NSCLC from a retrospectively updated database from institutional medical records of all patients with NSCLC who received treatment at our institution from January 2004 through August 2010. All patients had stage IV metastatic NSCLC per the American Joint Committee on Cancer’s Cancer Staging Manual (7th edition), Eastern Cooperative Oncology Group
(ECOG) performance status ≤ 2, 4 or fewer metastases documented by imaging or pathology (each lesion was counted separately independent of organ location), no prior radiation of the primary tumor site, radiation prescription ≥ 50 Gy, and no prior resection of the primary tumor. All intrathoracic disease must have been amenable to definitive radiation therapy. Of note, patients may have received either radiation therapy alone, sequential chemotherapy followed by radiation therapy, or concurrent chemoradiation therapy with a platin doublet.
Patient diagnosis and follow-up All patients underwent complete history, physical examination, and computed tomography (CT) or F-18 fluoro-2-deoxyglucose-positron emission tomography (PET) scan at diagnosis. All patients had pathologically confirmed NSCLC. Reflex mutational testing was not performed at the time of this study, and therefore, mutational status was unknown. Patients were followed up at regular intervals, approximately every 3 months for the first 1 to 3 years after treatment and then every 6 to 12 months after 3 years. All patients had a minimum of 6 months of follow-up after radiation. Patients were retrospectively scored for radiation pneumonitis and esophagitis toxicity using the joint Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer acute radiation morbidity scoring criteria. 12
Treatment techniques and parameters All patients were immobilized in a supine position with their arms raised in a customized Alpha Cradle Mold. CT simulation techniques were used to define the target volume. For each patient, a gross tumor volume for the primary tumor (GTV-primary) was delineated that consisted of the primary lung tumor, and a nodal GTV (GTV-nodal) was delineated that encompassed all involved nodal disease. Critical normal tissue structures were contoured by the physician or by the treatment planner. For patients who underwent 4-dimensional CT (4D-CT) planning, internal gross tumor volumes (IGTVs) were generated based on respiratory correlated data sets for both the primary tumor (IGTV-primary) and involved nodes (IGTV-nodal). Clinical target volumes (CTV-primary and CTV-nodal) were generated by use of an expansion of 0.8 cm to the IGTV-primary and 0.3 cm to the IGTV-nodal to encompass microscopic extension of the tumor. For patients who did not
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undergo 4D-CT planning, the CTVs were generated directly from the corresponding GTVs using the corresponding margins, and then the CTV-primary was expanded by 1.5 cm for lower lobe tumors and by 1.0 cm for upper lobe tumors to generate the planning target volume (PTV)-primary, accounting for setup error and tumor motion; the PTV-nodal was generated from the CTV-nodal using a uniform PTV expansion of 0.5 cm. For patients who underwent a 4D-CT, a uniform PTV expansion of 0.5 cm was then applied to the CTV-primary and CTV-nodal to generate the corresponding PTVs. The PTV-primary and PTV-nodal were then unified into a single PTV for planning. Megavoltage linear accelerator x-rays of ≥ 6 MV energy were used for treatment delivery. Doses were prescribed to the maximum isodose level that encompassed the PTV. Patients were treated with conventional fractionation, without a treatment break. Extrathoracic metastatic disease was not included in the thoracic radiation portals. Brain metastases were treated with either whole brain radiation therapy or gamma knife radiosurgery. All patients included in this analysis received definitive dose radiation therapy of at least 50 Gy. We delivered the maximally safe dose to the PTV while constraining the lung to the following parameters: V20 ≤ 35%, V5 ≤ 60%, and mean lung dose ≤20 Gy, consistent with institutional and QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) guidelines. 13 The final prescription was based on several factors, including dosimetric constraints, whether or not the patient was receiving concurrent chemotherapy, performance status, and volume of extrathoracic residual disease. Patients who received concurrent chemoradiation therapy were generally treated with 1.8 Gy per fraction to a maximum dose of 72 Gy. Patients receiving either radiation therapy alone or sequential chemoradiation therapy were generally treated with 2 Gy per fraction to a maximum dose of 80 Gy, on the basis of previously published reports using this dosing regimen. 14
Chemotherapy All patients received at least 1 cycle of either concurrent or sequential cytotoxic chemotherapy. Patients most commonly received cisplatin or carboplatin in combination with other chemotherapeutic agents. Patients were planned to receive definitive therapy upfront based on the clinical criteria outlined above. All patients were reviewed in a multidisciplinary setting. The decision to deliver concurrent or sequential chemoradiation therapy was determined by the multidisciplinary team after review and included a number of factors, including suitability for chemotherapy, physician preference, and performance status of the patient.
Local control evaluation Two physicians reviewed patient records (films, imaging reports, and, if available, pathology) for intrathoracic disease progression after completion of radiation therapy. The reviewers scored tumor burden and response using the
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RECIST criteria (Response Evaluation Criteria in Solid Tumors), version 1.1. Irradiated lesions were also evaluated with RECIST criteria; however, isolated progression within the irradiated field was evaluated by additional confirmatory studies, including PET/CT or biopsy as clinically indicated to confirm progression. 15
Adverse events For the toxicity assessment, we reviewed patient records from the Hospital of the University of Pennsylvania and affiliated institutions. Patient visits to the emergency department and hospital admissions after the start of treatment were categorized as treatment or disease related by at least 2 oncologists. Treatment-related visits consisted of admissions for toxicity to chemotherapy or radiation. Visits were disease related if they were directly related to cancer sequelae or progression.
Statistical analysis Overall survival was computed from the date of diagnosis by imaging (or date of first treatment for a parallel analysis) until death or date of last follow-up when they were censored. Kaplan-Meier and log-rank testing were used to compare unadjusted survival profiles. Cox proportional hazards regression controlled for potential confounders. Any variable with a P value ≤ .10 in the univariate model was eligible for multivariable Cox modeling. A threshold P value ≤ .05 established significance in multivariable models.
Matched cohort analysis We performed a matched cohort comparison of patients with stage IV NSCLC who were treated with and without definitive thoracic radiation therapy. From a comprehensive database of patients with stage IV NSCLC treated with chemotherapy alone during the same time interval, we identified a matched set of 97 patients who satisfied the criteria used to identify our original cohort of 29 patients treated with definitive radiation therapy (ECOG performance status ≤2, ≤4 metastases, no primary tumor surgery or radiation, and no known targetable driver mutation). We then used an exact-matching algorithm with the statistical computing program R (version 12.2) that identified control subjects with matching covariate values. Using this program, we randomly grouped thoracic radiation therapy patients with 2 chemotherapy patients randomly selected by matching them on 4 factors using an exact-matching approach at diagnosis: (1) median age; (2) ECOG performance score; (3) number of involved organs; and (4) specific organ involved. Chemoradiation patients were only included in this exploratory analysis if they could be matched with at least 2 chemotherapy-only patients. Pearson χ 2, Fisher exact test, or nonparametric equality of medians tests were used to
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Patient characteristics Definitive radiation Chemotherapy P value therapy (n = 25) (n = 50)
Patient characteristic Median age, y (range) Race (all), % (n) White Black Other/unknown Female, % (n) ECOG (all), % (n) 1 2 Patients staged by PET, % (n) Organs, % (n) Adrenal Bone Brain Effusion Lung, contralateral Node, extrathoracic Other No. of metastatic organs, % (n) 1 2 3 4 No. of metastatic sites (counting multiple sites within a single organ separately), % (n) 1 2 3 4 At least 1 organ with 2 or more metastases, % (n) Median dose, Gy (range) Median chemotherapy, cycles (range) Patients with multiple chemotherapy regimens, % (n) Concurrent chemotherapy, % (n) Sequential, % (n), median lag Chemotherapy regimen, % (n) Carboplatin
59 (45-79)
58 (30-78)
52 (13) 40 (10) 8 (2) 56 (14)
60 30 10 40
68 (17) 32 (8) 91 (21)
68 (34) 32 (16) 78 (25)
12 (3) 44 (11) 32 (8) 4 (1) 12 (3) 32 (8) 8 (2)
10 (5) 44 (22) 32 (16) 12 (6) 12 (6) 20 (10) 8 (4)
68 (17) 24 (6) 4 (1) 4 (1)
68 26 6 0
52 (13) 32 (8) 4 (1) 12 (3) 28 (7) 68 (50-80) 6.5 (1-24) 56 (14) 52 (13) 48 (12), 4 mo
46 (23) 28 (14) 18 (9) 8 (4) 34 (17) — 6 (1-40) 64 (32) — —
.40 .62 .72 — — .60 — .73 .50 — —
88 (22)
94 (47)
—
(30) (15) (5) (20)
(34) (13) (3) (0)
.87 .43 .51 .39 — .19 1.00 1.00 1.00 .19 .79 1.00 1.00 .26 1.00 .25 1.00 .54 1.00 .85 —
ECOG, Eastern Cooperative Oncology Group; PET, positron emission tomography.
compare the distribution of patient characteristics between the 2 treatment groups. Statistical analyses were performed with STATA/IC (version 11.0 for Mac OS X; StataCorp, College Station, Texas).
Results Characteristics From 430 NSCLC patients consecutively treated from January 2004 through August 2010, we identified 29 patients who met our inclusion criteria. The 29 thoracic radiation therapy patients had a median age of 57 years
(range, 43-79 years). Seventy-two percent had ECOG performance status 1 (range, 1-2). Ninety-one percent were staged with PET in addition to CT imaging. A median dose of 67 Gy (range, 50-83 Gy) was delivered with a median of 7 cycles (range, 1-24) of chemotherapy, with systemic therapy delivered concurrently (55%) or sequentially (45%) with radiation. The median time to chemotherapy or chemoradiation treatment from diagnosis (by imaging) was 2 months; 72% of patients received chemotherapy or chemoradiation treatment within 3 months of diagnosis. Table 1 summarizes the patient characteristics of the thoracic radiation therapy patients and the chemotherapy patients they were matched against. Four radiation therapy patients could not be matched to 2 chemotherapy control subjects and were excluded from the matched-cohort analysis. Patient characteristics were well balanced across
Practical Radiation Oncology: July-August 2015 Table 2
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Toxicity and adverse events, as measured by hospital and ED visits
Toxicity grade Esophagitis, % (n) Pneumonitis, % (n) No. of visits Treatment-related visits, % (n) a Disease-related visits, % (n) a 1 2 3 4 5
10 (3) 45 (13) 21 (6) 0 (0) 0 (0)
17 (5) 14 (4) 14 (4) 0 (0) 0 (0)
0 1 2 3 4 5 ≥6
63 (n = 17) 11 (3) 11 (3) 7 (2) 4 (1) 4 (1) 0 (0)
41 (n = 11) 15 (4) 15 (4) 19 (5) 7 (2) 0 (0) 4 (1)
ED, emergency department. a Total n = 27.
the treatment groups, especially with respect to the number of involved organs, the specific organ involved, and the number of total metastases (counting multiple sites within the same organ separately) (Table 1). We did not find an imbalance in the number of involved organs between the 2 groups. Both the treatment group and the matched control subjects had 1 involved organ in 68% of cases (P = 1.00). For the thoracic radiation therapy versus chemotherapy-only patients, 24% versus 26% had 2 involved organs (P = .85); 4% versus 6% had 3; and 4% versus 0% had 4. Although the number of involved organs remained significantly associated with poorer survival on multivariable analysis (P b .01; odds ratio [OR], 2.14), the groups were well matched. We also did not identify a difference in the specific organ involved with metastasis between the 2 groups. Both arms were exactly matched for bone, brain, contralateral lung, and other metastatic organ involvement (P = 1.00 for each). They also had similar adrenal, pleural effusion, and extrathoracic nodal involvement (P = .79, .26, and .25, respectively).
Toxicity and adverse events All patients tolerated radiation therapy well. Twenty-one percent of patients experienced acute esophagitis greater than or equal to grade 3 and 45% experienced greater than or equal to grade 2 esophagitis during treatment. Fourteen percent of patients developed pneumonitis greater than or equal to grade 3 and 28% had pneumonitis greater than or equal to grade 2 at 1 to 6 months after completion of radiation treatment. Sixty-three percent of patients did not have any treatment-related hospital visits related to adverse events (Table 2). Three months after treatment, patients treated by definitive radiation therapy had no median change in ECOG performance score, compared with a median deterioration of 0.5 points seen in chemotherapy recipients (P = .02).
Local control and survival Overall median survival for all patients was 22 months (95% confidence interval [CI], 15-42 months) from diagnosis or 19 months (95% CI, 11-40 months) from
first treatment. Survival rates from diagnosis were 76% (95% CI, 56%-88%) at 1 year and 49% (95% CI, 29%-66%) at 3 years. Median follow-up was 22 months in the 8 surviving patients. The median time to local failure was not reached (95% CI, ≥ 8 months). Median survival in locally controlled patients was 39 months (95% CI, ≥ 15 months) versus 19 months (95% CI, 7-42 months) from diagnosis in patients with local failure. Local control was associated with survival (P = .01). Outcomes based on sites of metastases were analyzed. Patients with adrenal metastases had a median survival of 12 months versus 39 months in those who did not have adrenal metastases (P b .01); in bone, 15 versus 41 months (P = .02); and with pleural effusions, 7 versus 39 months (P b .01). Other sites of metastases, including brain, contralateral lung, and extrathoracic lymph nodes, did not affect outcomes (all P N .05). The number of involved organs, but not the number of discrete metastases, was associated with survival (P b .01). For example, a patient with a single metastasis in each of 3 organs tended to have worse prognosis than a patient with 3 metastases in a single organ.
Thoracic radiation therapy outcomes compared with matched cohort of chemotherapy-only patients We performed an exploratory analysis comparing the outcomes of patients who received definitive thoracic radiation therapy to those of patients receiving chemotherapy alone. A 1-to-2 match was performed based on age, performance status, number of organs involved, and the specific organ involved. As noted previously, 4 radiation therapy patients could not be matched to 2 chemotherapy control subjects and were excluded. Definitive radiation therapy and survival From diagnosis, patients who received definitive radiation therapy versus chemotherapy alone had a median survival of 22 months (95% CI, 15-42 months) versus 9 months (95% CI, 7-16 months; P b .01) (Fig 1A). From first treatment, patients who received definitive radiation therapy versus chemotherapy had a median survival of 19
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months (95% CI, 11-40 months) versus 8 months (95% CI, 5-14 months; P = .01). Survival rates from diagnosis were 76% versus 41% at 12 months and 49% versus 12% at 36 months, respectively. Median follow-up was 21 months in the 6 living patients who received definitive radiation therapy and 25 months (range, 7-41 months) in the 9 surviving chemotherapy-only recipients (P = .75).
OR, 0.41) were associated with survival (Table 3). Although the number of involved organs was associated with survival on multivariable regression (P b .01), the number of total metastases (counting multiple sites within the same organ separately) was not (P = .28).
Definitive radiation therapy and local control Patients who received definitive radiation therapy had a median time to local failure of 18 months (95% CI, ≥ 7 months) versus 6 months (95% CI, 4-8 months) with chemotherapy (P = .03) (Fig 1B).
Discussion
Local control and survival At last follow-up, locally controlled patients had a median survival from diagnosis of 39 months (95% CI, ≥ 8 months) versus 13 months (95% CI, 10-19 months) in patients with a local failure (P = .06). On multivariable analysis, only thoracic radiation therapy (P b .01; OR, 0.33), number of metastatic organs at diagnosis (P b .01; OR, 2.14), and female sex (P b .01;
Figure 1 (A) Kaplan-Meier overall survival from diagnosis, by treatment (P b .01). (B) Kaplan-Meier time to local failure from any first therapy, by treatment (P = .03).
Definitive dose thoracic radiation in a subset of favorable stage IV NSCLC patients is well tolerated, with modest toxicity. In selected patients, it may improve clinical outcomes, perhaps because of improved primary tumor control. With optimal care, median survival of 1 year or more is possible in stage IV patients. 2-4 Yet this prognostic estimate comes from a heterogeneous source, including patients with poor performance status and widely metastatic disease and those with good status and oligometastatic disease. 2-4 There is a broad range to survival in stage IV disease, from weeks to years. 2-4 The driving hypothesis of this report is that local control is of clinical importance in a select subset of patients with limited disseminated disease, and therefore, high-dose thoracic radiation therapy may improve outcome In this analysis, we identified several factors that were associated with overall survival in these stage IV patients. Echoing previous publications, a greater number of involved organs at diagnosis was associated with poorer survival (P b .01; OR, 2.14). Also, consistent with prior studies, female sex (P = .05; OR, 0.41) predicted improved outcomes. 3,16,17 We performed a matched cohort comparison of these patients to a subset of stage IV patients who received chemotherapy alone and identified the patients who received definitive thoracic radiation therapy as having improved local control and overall survival compared with patients who did not. However, there are several weaknesses to such an analysis, including selection bias and the potential impact of confounders. In an attempt to address these potential weaknesses, we performed a matched cohort comparison with 2:1 matching using median age, ECOG performance score, number of involved organs, and the specific organ involved as covariates and confirmed the robustness of our matching algorithm with respect to these covariates. However, one factor that was not accounted for as a separate covariate was the total number of metastatic sites (counting multiple sites within the same organ separately). Comparing the thoracic radiation therapy and chemotherapy-only groups, there was no significant difference in the number of patients harboring 1, 2, 3, or 4 sites of metastatic disease (Table 1). To summarize, an imbalance in the number of metastatic sites between the 2 groups did not appear to contribute to the observed survival difference.
Practical Radiation Oncology: July-August 2015 Table 3
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Univariate and multivariable Cox survival analysis
Radiation therapy (yes/no) White (yes/no) Black (yes/no) Female (yes/no) Adrenal metastases only (yes/no) Bone metastases only (yes/no) Brain metastases only (yes/no) Effusion metastases only (yes/no) Node metastases only (yes/no) Other metastases only (yes/no) No. of metastatic organs (continuous) No. of total metastases (counting multiple sites within a single organ separately) (continuous) At least 1 organ with N 2 metastases (yes/no) Local failure (yes/no)
Univariate P value (HR)
Multivariable P value (HR)
b .01 (0.38) .47 (1.22) .57 (0.85) .02 (0.52) .30 (1.86) .99 (1.00) .23 (0.66) .61 (1.70) .89 (0.94) .08 (3.60) .09 (1.40) .28 (1.15) .95 (1.02) .07 (1.68)
b .01 — — b .01 — — — — — .72 b .01 — — .59
(0.33)
(0.41)
(1.44) (2.14)
(1.18)
HR, hazard ratio.
Despite matched pair analysis, confounding selection or hidden biases from unmeasured confounders may explain the potentially worse survival in patients treated with chemotherapy alone. For example, although most patients in both groups received carboplatin, it was not possible to exactly match chemotherapy regimens across the 2 groups. These biases mean that interpretation of our data should be viewed as hypothesis generating. Nevertheless, our findings suggest that patients with oligometastatic stage IV NSCLC treated with thoracic radiation therapy may have improved survival when compared to similar patients who receive chemotherapy alone. Selection bias and unmeasured confounders are inherent limitations in all retrospective reviews. This study supports further investigation with larger prospective studies to assess survival, disease control, and quality of life in this highly selected subset of patients. Aggressive local radiation therapy to sites of intracranial metastases for patients with oligometastatic NSCLC or to sites of lung parenchymal metastases for patients with or without primary lung cancers have been reported previously, but few previous data exist defining the utility of aggressive, nonpalliative local radiation therapy to the primary tumor and regional lymph nodes in NSCLC patients with extrathoracic oligometastatic disease. 18,19 This study is consistent with recently reported results from Sheu et al., 20 who examined outcomes in patients with good performance status and oligometastatic disease who received chemotherapy followed by comprehensive local therapy (either radiation or surgery). They observed that patients who received comprehensive local therapy had improved overall survival and progression-free survival compared with propensity-score matched control subjects. 20 Another approach that has been reported in the setting of oligometastatic disease is the delivery of definitive locally ablative therapy to all sites of disease in select patients with oligometastatic disease either with or without
systemic therapy and surgery. Khan et al 21 reported on 23 patients with 1 to 2 sites of oligometastatic NSCLC treated with systemic therapy, with aggressive local and regional radiation therapy, and with or without surgery. Radiation therapy was delivered to a median dose of 60 Gy in nonsurgically treated patients and 40 Gy when administered as neoadjuvant therapy. Although treatment was very heterogenous across this cohort, at a median follow-up of 17 months, the median time to recurrence for the cohort was 12 months, and the median survival was 20 months, with 22% surviving 3 years. 21 Similarly, Hasselle et al 22 reported a promising median overall survival of 22.7 months in 25 patients treated with high-dose image-guided radiation therapy to all sites of metastases. Cheruvu et al 23 reported a comparative analysis of patients receiving “curative” intent radiation therapy with stage III disease, oligometastatic stage IV disease (b 8 lesions), and oligometastatic recurrent disease. They reported a promising 5-year overall survival rate of 14% in the patients with oligometastatic disease and 27% in those with recurrent oligometastatic disease from the date of diagnosis. Surprisingly, they only reported a 7% 5-year overall survival rate for stage III patients receiving definitive radiation therapy. The largest prospective trial to date in oligometastatic NSCLC was reported by De Ruysscher and colleagues, 24 who treated patients in a prospective phase 2 trial. Forty patients were enrolled, 35 of whom had a solitary site of metastasis. Patients received radical local therapy to all sites of disease (either surgery or radiation). They reported a median overall survival of 13.5 months. On subgroup analysis, they did not identify any patient or tumor parameter that was associated with overall survival. Our results are consistent with recent reports from other institutions. Parikh et al 25 found that definitive local therapy to the primary tumor was associated with prolonged survival in a subset of 186 patients with
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oligometastatic disease treated over a 10-year period at their institution. Similarly, Lopez Guerra et al 26 reported a series of 78 oligometastatic patients (b 5 metastases) receiving definitive chemoradiation therapy, of whom 44 also received ablative therapy to the metastases, and found that a higher dose to the primary tumor was associated with improved overall survival. In a smaller series, Jabbour et al 11 reported favorable outcomes in 9 patients with stage IV NSCLC treated with definitive dose thoracic radiation therapy to only the primary site. That series, however, did not comment on adverse events in these patients. The North Central Cancer Treatment Group initiated the N0724 trial to address this topic. 27 In that trial, patients with 3 or fewer metastases received chemotherapy and were then randomized to either radiation therapy to all residual cancer or no radiation. 27 The study will also report on adverse events but not on broader patient quality of life. The study has been completed, and results are eagerly anticipated. The University of Chicago group launched a randomized trial of chemotherapy with or without hypofractionated image-guided radiation therapy (Synergistic Metastases Annihilation With Radiotherapy and Docetaxel (Taxotere) [SMART]), which unfortunately closed because of lack of accrual (ClinicalTrials.gov identifier NCCT00887315). MD Anderson Cancer Center has also launched a randomized phase 2 trial of chemotherapy with or without aggressive local therapy (surgery or radiation therapy) in oligometastatic NSCLC that is currently accruing patients (ClinicalTrials.gov identifier NCT01725165). Taken together, with continued improvements in imaging and staging techniques that better identify patients with limited-volume extrathoracic disease, there appears to be a subset of patients in whom definitive dose thoracic radiation therapy may add value without worsening quality of life.
Conclusions The combination of definitive dose radiation therapy with chemotherapy in patients with stage IV NSCLC may improve local control without a significant increase in adverse events. Furthermore, our hypothesis-generating results suggest that this improvement in local control may drive an improvement in overall survival in these well-selected patients with a limited metastatic disease burden. Because our study is limited by its retrospective nature and small sample size, further prospective studies with larger cohorts examining not just disease survival and control but also patient quality of life are needed to validate our observations.
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