International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Thoracic Cancer
Definitive Chemoradiation Therapy Following Surgical Resection or Radiosurgery Plus Whole-Brain Radiation Therapy in Non-Small Cell Lung Cancer Patients With Synchronous Solitary Brain Metastasis: A Curative Approach Cem Parlak, MD,* Hu¨seyin Mertsoylu, MD,y Ozan Cem Gu¨ler, MD,* Cem Onal, MD,* and Erkan Topkan, MD* *Department of Radiation Oncology, Baskent University, Adana Medical Faculty, Adana, Turkey; and yDepartment of Medical Oncology, Baskent University, Adana Medical Faculty, Adana, Turkey Received Nov 5, 2013, and in revised form Dec 11, 2013. Accepted for publication Dec 13, 2013.
Summary This is the first study to evaluate the impact of definitive, concurrent chemoradiation therapy following neurosurgery or radiosurgery and whole-brain radiation therapy in non-small cell lung carcinoma (NSCLC) patients with synchronous solitary brain metastasis (SSBM). We observed improvements in the survival of patients with stage III NSCLC, which may serve as an encouraging basis for future investigations seeking to further improve the outcomes of such highly selected NSCLC patients with SSBM.
Purpose/Objectives: The aim of this study was to evaluate the impact of definitive thoracic chemoradiation therapy following surgery or stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT) on the outcomes of patients with non-small cell lung cancer (NSCLC) with synchronous solitary brain metastasis (SSBM). Methods and Materials: A total of 63 NSCLC patients with SSBM were retrospectively evaluated. Patients were staged using positron emission tomography-computed tomography in addition to conventional staging tools. Thoracic radiation therapy (TRT) with a total dose of 66 Gy in 2 Gy fractions was delivered along with 2 cycles of cisplatin-based chemotherapy following either surgery plus 30 Gy of WBRT (nZ33) or SRS plus 30 Gy of WBRT (nZ30) for BM. Results: Overall, the treatment was well tolerated. All patients received planned TRT, and 57 patients (90.5%) were also able to receive 2 cycles of chemotherapy. At a median follow-up of 25.3 months (7.1-52.1 months), the median months of overall, locoregional progressionfree, neurological progression-free, and progression-free survival were 28.6, 17.7, 26.4, and 14.6, respectively. Both univariate and multivariate analyses revealed that patients with a T1T2 thoracic disease burden (PZ.001), a nodal stage of N0-N1 (PZ.003), and no weight loss (PZ.008) exhibited superior survival. Conclusions: In the present series, surgical and radiosurgical treatments directed toward SSBM in NSCLC patients were equally effective. The similarities between the present survival outcomes and those reported in other studies for locally advanced NSCLC patients indicate the potentially curative role of definitive chemoradiation therapy for highly selected patients with SSBM. Ó 2014 Elsevier Inc.
Reprint requests to: Cem Parlak, MD, Department of Radiation Oncology, Baskent University, Adana Medical Faculty, Kisla Saglik
Int J Radiation Oncol Biol Phys, Vol. 88, No. 4, pp. 885e891, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.12.017
Yerleskesi, 01120 Adana, Turkey. Tel: (90) 5327227977; E-mail: [email protected] Conflict of interest: none.
886
Parlak et al.
Introduction Lung cancer is the leading source of brain metastases (BM); approximately 30% to 50% of patients with non-small cell LC (NSCLC) develop BM (1), and 10% to 20% of these patients present with synchronous BM at the time of NSCLC diagnosis (2, 3). Treatment options for BM in patients with 1 to 3 BM include whole-brain radiation therapy (WBRT), surgery, stereotactic radiosurgery (SRS), chemotherapy, or any combination of these options (4-6). In a retrospective analysis of 916 BM patients treated with WBRT by Lutterbach et al (7), recursive partitioning analysis (RPA) of patients with a single BM, which constitutes a minority of cases (nZ33), had significantly better outcomes than those with multiple BMs (medians Z 13.5 and 8.1 months, respectively). Furthermore, the addition of SRS (8) or surgical resection (5, 9) to WBRT has been demonstrated to result in superior in-brain tumor control (73%-80%) rates compared to WBRT alone, which raises a question about the aggressiveness of the treatment of thoracic primaries, particularly in cases of NSCLC with single BM. Several retrospective series have previously demonstrated encouraging survival outcomes after aggressive treatments of intrathoracic tumors that include surgery, thoracic radiation therapy (TRT), or concurrent chemoradiation therapy (CRT) in patients with synchronous BM (2, 10-17). However, in TRT series, RT doses and intents (palliative or definitive), concomitant use of chemotherapy, number of BMs, and management of BMs vary widely. Lack of randomized trials evaluating the role of definitive TRT or CRT due to the rarity of NSCLC patients with synchronous solitary BM (SSBM) makes it difficult to determine the prognostic groups that might potentially benefit from such aggressive treatment and limits our ability to suggest a standard approach. Therefore, the purpose of the present study was to retrospectively evaluate the impact of surgery or SRS plus WBRT for BM followed by definitive thoracic CRT on outcomes of NSCLC patients with SSBM.
Methods and Materials
International Journal of Radiation Oncology Biology Physics emission tomography-CT (FDG-PET-CT), obtained for TRT treatment planning. Eligibility criteria also included age between 18 and 70 years, an Eastern Cooperative Oncology group (ECOG) performance status of 0 to 1, sufficient pulmonary function (forced expiratory volume in 1 second >1200 mL and partial oxygen pressure >60%), and adequate bone marrow reserve and hepatic and renal function. The study protocol was approved by the institutional review board before the collection of any patient information.
Treatment of brain metastasis Patients with SSBM in surgically accessible locations or in need of rapid symptom relief were treated with neurosurgical resection followed by postoperative WBRT (group 1). Patients with lesions in surgically inaccessible locations and those who refused surgery received Gamma Knife (Elekta Inc, Atlanta, GA) or CyberKnife (Accuray Inc, Sunnyvale, CA) SRS followed by WBRT (group 2). For WBRT, whole intracranial content down to the upper border of C2 vertebral body with a margin of at least 1 cm around the bony skull in all directions was treated. Treatment volumes and normal tissues to be spared were defined using customized multileaf collimators, and all patients were treated with a megavoltage linear accelerator with 6 MV photons to a total dose of 30 Gy/10 fractions prescribed to the isodose lines, not “cooler” than 95% and not “hotter” than 107% through 2 laterally opposed fields. Patients received dexamethasone (4-16 mg/day) during WBRT. Because SRS facilities were not available at the time interval in which the patients were treated, all patients received Gamma Knife (nZ13) or CyberKnife-based (nZ17) SRS at other centers. Data obtained from the SRS charts revealed that all patients were suitably immobilized with a stereotactic head frame and underwent gadolinium-enhanced MRI scans for radiosurgical treatment planning. The dose prescriptions to the target volumes (contrastenhancing tumor volume without any margin) were chosen according to maximum diameter of the tumors, as suggested by the RTOG 9005 protocol (ie, 20, 18, and 15 Gy for tumors .05 for each) (Table 3). At a median follow-up time of 25.3 months (range Z 7.1-52.1), 25 patients (39.7%) were alive, and 9 of these patients were free of progression. As shown in Table 3, the most common initial failure was isolated extracranial distant relapses (nZ22; 34.9%). Initial isolated locoregional failures were observed in only 5 patients (7.9%). Overall intracranial control rate was 84.1%, and only 5 patients (7.9%) exhibited isolated intracranial relapse (3 infield [4.8%] and 2 outfield [3.2%]). There were no significant differences between groups in terms of patterns of initial relapses.
Volume 88 Number 4 2014 Table 4
Radically treated metastatic lung cancer Table 5
Results of comparative survival analyses
Survival
Group 1 (nZ33) (95% CI)*
% of OS Median 27.8 (20.8-34.8) (mo) At 2 y 57.1 At 3 y 41.4 % of LRPFS Median 16.4 (10.7-22.1) At 2 y 42.0 At 3 y 34.4 % of NPFS Median 26.3 (13.1-39.5) At 2 y 51.1 At 3 y 39.3 % of PFS Median 14.3 (7.3-21.3) At 2 y 21.2 At 3 y 15.2
Group 2 (nZ30) (95% CI)y
Results of univariate survival analyses
P value Characteristic
28.6 (19.5-37.7)
.91
63.3 41.1 17.7 (4.0-31.4) 46.7 33.4
.77
28.2 (22.9-33.5) 59.8 38.7
.83
15.2 (7.3-23.1) 30.0 16.0
.72
Abbreviations: CI Z confidence interval; LRPFS Z locoregional progression-free survival; NPFS Z neurological progression-free survival; OS Z overall survival; PFS Z progression-free survival. * Group 1 Z neurosurgical resection plus whole-brain radiation therapy. y Group 2 Z stereotactic radiosurgery plus whole-brain radiation therapy.
Median OS, LRPFS, NPFS, and PFS for the entire study population were 28.6 months (95% confidence interval [CI]: 24.732.5 months), 17.7 months (95% CI: 13.9-21.5), 26.4 months (95% CI: 21.4-31.4 months), and 14.6 months (95% CI: 9.919.3 months), respectively (Fig. 1). Survival comparisons according to the management of SSBM revealed no significant differences between 2 groups at any survival endpoint. The corresponding medians, 2- and 3-year OS rates, and LRPFS, NPFS, and PFS rates for groups 1 and 2 are given in Table 4. Univariate analyses revealed that T1-T2 thoracic disease burden (PZ.001), N0-N1 nodal stage (PZ.003), and the absence of weight loss exceeding 5% (PZ.008) were associated with improved survival (Table 5, Fig. 1). Multivariate analysis of the factors that were significantly associated with OS in the univariate analyses demonstrated that all of these factors retained their independent prognostic values. Hazard ratios for T stage, N stage, and weight loss status were 0.34 (95% CI: 0.15-0.79; PZ.01), 0.44 (95% CI: 0.17-0.96; PZ.04), and 0.34 (95% CI: 0.15-0.76; PZ.009), respectively.
Discussion The results of this retrospective investigation demonstrated that definitive CRT following WBRT and surgical (27.8 months) or radiosurgical (28.4 months) intervention for SSBM in selected oligometastatic patients yielded survival outcomes within the range that has recently been reported for stage 3 NSCLC patients, regardless of the SSBM management technique used (22). Considering the poor survival rates, WBRT alone is the most widely accepted treatment for patients with multiple BMs (>3). However, in the era of more sophisticated staging techniques,
889
Age
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Thoracic Cancer
Definitive Chemoradiation Therapy Following Surgical Resection or Radiosurgery Plus Whole-Brain Radiation Therapy in Non-Small Cell Lung Cancer Patients With Synchronous Solitary Brain Metastasis: A Curative Approach Cem Parlak, MD,* Hu¨seyin Mertsoylu, MD,y Ozan Cem Gu¨ler, MD,* Cem Onal, MD,* and Erkan Topkan, MD* *Department of Radiation Oncology, Baskent University, Adana Medical Faculty, Adana, Turkey; and yDepartment of Medical Oncology, Baskent University, Adana Medical Faculty, Adana, Turkey Received Nov 5, 2013, and in revised form Dec 11, 2013. Accepted for publication Dec 13, 2013.
Summary This is the first study to evaluate the impact of definitive, concurrent chemoradiation therapy following neurosurgery or radiosurgery and whole-brain radiation therapy in non-small cell lung carcinoma (NSCLC) patients with synchronous solitary brain metastasis (SSBM). We observed improvements in the survival of patients with stage III NSCLC, which may serve as an encouraging basis for future investigations seeking to further improve the outcomes of such highly selected NSCLC patients with SSBM.
Purpose/Objectives: The aim of this study was to evaluate the impact of definitive thoracic chemoradiation therapy following surgery or stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT) on the outcomes of patients with non-small cell lung cancer (NSCLC) with synchronous solitary brain metastasis (SSBM). Methods and Materials: A total of 63 NSCLC patients with SSBM were retrospectively evaluated. Patients were staged using positron emission tomography-computed tomography in addition to conventional staging tools. Thoracic radiation therapy (TRT) with a total dose of 66 Gy in 2 Gy fractions was delivered along with 2 cycles of cisplatin-based chemotherapy following either surgery plus 30 Gy of WBRT (nZ33) or SRS plus 30 Gy of WBRT (nZ30) for BM. Results: Overall, the treatment was well tolerated. All patients received planned TRT, and 57 patients (90.5%) were also able to receive 2 cycles of chemotherapy. At a median follow-up of 25.3 months (7.1-52.1 months), the median months of overall, locoregional progressionfree, neurological progression-free, and progression-free survival were 28.6, 17.7, 26.4, and 14.6, respectively. Both univariate and multivariate analyses revealed that patients with a T1T2 thoracic disease burden (PZ.001), a nodal stage of N0-N1 (PZ.003), and no weight loss (PZ.008) exhibited superior survival. Conclusions: In the present series, surgical and radiosurgical treatments directed toward SSBM in NSCLC patients were equally effective. The similarities between the present survival outcomes and those reported in other studies for locally advanced NSCLC patients indicate the potentially curative role of definitive chemoradiation therapy for highly selected patients with SSBM. Ó 2014 Elsevier Inc.
Reprint requests to: Cem Parlak, MD, Department of Radiation Oncology, Baskent University, Adana Medical Faculty, Kisla Saglik
Int J Radiation Oncol Biol Phys, Vol. 88, No. 4, pp. 885e891, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.12.017
Yerleskesi, 01120 Adana, Turkey. Tel: (90) 5327227977; E-mail: [email protected] Conflict of interest: none.
886
Parlak et al.
Introduction Lung cancer is the leading source of brain metastases (BM); approximately 30% to 50% of patients with non-small cell LC (NSCLC) develop BM (1), and 10% to 20% of these patients present with synchronous BM at the time of NSCLC diagnosis (2, 3). Treatment options for BM in patients with 1 to 3 BM include whole-brain radiation therapy (WBRT), surgery, stereotactic radiosurgery (SRS), chemotherapy, or any combination of these options (4-6). In a retrospective analysis of 916 BM patients treated with WBRT by Lutterbach et al (7), recursive partitioning analysis (RPA) of patients with a single BM, which constitutes a minority of cases (nZ33), had significantly better outcomes than those with multiple BMs (medians Z 13.5 and 8.1 months, respectively). Furthermore, the addition of SRS (8) or surgical resection (5, 9) to WBRT has been demonstrated to result in superior in-brain tumor control (73%-80%) rates compared to WBRT alone, which raises a question about the aggressiveness of the treatment of thoracic primaries, particularly in cases of NSCLC with single BM. Several retrospective series have previously demonstrated encouraging survival outcomes after aggressive treatments of intrathoracic tumors that include surgery, thoracic radiation therapy (TRT), or concurrent chemoradiation therapy (CRT) in patients with synchronous BM (2, 10-17). However, in TRT series, RT doses and intents (palliative or definitive), concomitant use of chemotherapy, number of BMs, and management of BMs vary widely. Lack of randomized trials evaluating the role of definitive TRT or CRT due to the rarity of NSCLC patients with synchronous solitary BM (SSBM) makes it difficult to determine the prognostic groups that might potentially benefit from such aggressive treatment and limits our ability to suggest a standard approach. Therefore, the purpose of the present study was to retrospectively evaluate the impact of surgery or SRS plus WBRT for BM followed by definitive thoracic CRT on outcomes of NSCLC patients with SSBM.
Methods and Materials
International Journal of Radiation Oncology Biology Physics emission tomography-CT (FDG-PET-CT), obtained for TRT treatment planning. Eligibility criteria also included age between 18 and 70 years, an Eastern Cooperative Oncology group (ECOG) performance status of 0 to 1, sufficient pulmonary function (forced expiratory volume in 1 second >1200 mL and partial oxygen pressure >60%), and adequate bone marrow reserve and hepatic and renal function. The study protocol was approved by the institutional review board before the collection of any patient information.
Treatment of brain metastasis Patients with SSBM in surgically accessible locations or in need of rapid symptom relief were treated with neurosurgical resection followed by postoperative WBRT (group 1). Patients with lesions in surgically inaccessible locations and those who refused surgery received Gamma Knife (Elekta Inc, Atlanta, GA) or CyberKnife (Accuray Inc, Sunnyvale, CA) SRS followed by WBRT (group 2). For WBRT, whole intracranial content down to the upper border of C2 vertebral body with a margin of at least 1 cm around the bony skull in all directions was treated. Treatment volumes and normal tissues to be spared were defined using customized multileaf collimators, and all patients were treated with a megavoltage linear accelerator with 6 MV photons to a total dose of 30 Gy/10 fractions prescribed to the isodose lines, not “cooler” than 95% and not “hotter” than 107% through 2 laterally opposed fields. Patients received dexamethasone (4-16 mg/day) during WBRT. Because SRS facilities were not available at the time interval in which the patients were treated, all patients received Gamma Knife (nZ13) or CyberKnife-based (nZ17) SRS at other centers. Data obtained from the SRS charts revealed that all patients were suitably immobilized with a stereotactic head frame and underwent gadolinium-enhanced MRI scans for radiosurgical treatment planning. The dose prescriptions to the target volumes (contrastenhancing tumor volume without any margin) were chosen according to maximum diameter of the tumors, as suggested by the RTOG 9005 protocol (ie, 20, 18, and 15 Gy for tumors .05 for each) (Table 3). At a median follow-up time of 25.3 months (range Z 7.1-52.1), 25 patients (39.7%) were alive, and 9 of these patients were free of progression. As shown in Table 3, the most common initial failure was isolated extracranial distant relapses (nZ22; 34.9%). Initial isolated locoregional failures were observed in only 5 patients (7.9%). Overall intracranial control rate was 84.1%, and only 5 patients (7.9%) exhibited isolated intracranial relapse (3 infield [4.8%] and 2 outfield [3.2%]). There were no significant differences between groups in terms of patterns of initial relapses.
Volume 88 Number 4 2014 Table 4
Radically treated metastatic lung cancer Table 5
Results of comparative survival analyses
Survival
Group 1 (nZ33) (95% CI)*
% of OS Median 27.8 (20.8-34.8) (mo) At 2 y 57.1 At 3 y 41.4 % of LRPFS Median 16.4 (10.7-22.1) At 2 y 42.0 At 3 y 34.4 % of NPFS Median 26.3 (13.1-39.5) At 2 y 51.1 At 3 y 39.3 % of PFS Median 14.3 (7.3-21.3) At 2 y 21.2 At 3 y 15.2
Group 2 (nZ30) (95% CI)y
Results of univariate survival analyses
P value Characteristic
28.6 (19.5-37.7)
.91
63.3 41.1 17.7 (4.0-31.4) 46.7 33.4
.77
28.2 (22.9-33.5) 59.8 38.7
.83
15.2 (7.3-23.1) 30.0 16.0
.72
Abbreviations: CI Z confidence interval; LRPFS Z locoregional progression-free survival; NPFS Z neurological progression-free survival; OS Z overall survival; PFS Z progression-free survival. * Group 1 Z neurosurgical resection plus whole-brain radiation therapy. y Group 2 Z stereotactic radiosurgery plus whole-brain radiation therapy.
Median OS, LRPFS, NPFS, and PFS for the entire study population were 28.6 months (95% confidence interval [CI]: 24.732.5 months), 17.7 months (95% CI: 13.9-21.5), 26.4 months (95% CI: 21.4-31.4 months), and 14.6 months (95% CI: 9.919.3 months), respectively (Fig. 1). Survival comparisons according to the management of SSBM revealed no significant differences between 2 groups at any survival endpoint. The corresponding medians, 2- and 3-year OS rates, and LRPFS, NPFS, and PFS rates for groups 1 and 2 are given in Table 4. Univariate analyses revealed that T1-T2 thoracic disease burden (PZ.001), N0-N1 nodal stage (PZ.003), and the absence of weight loss exceeding 5% (PZ.008) were associated with improved survival (Table 5, Fig. 1). Multivariate analysis of the factors that were significantly associated with OS in the univariate analyses demonstrated that all of these factors retained their independent prognostic values. Hazard ratios for T stage, N stage, and weight loss status were 0.34 (95% CI: 0.15-0.79; PZ.01), 0.44 (95% CI: 0.17-0.96; PZ.04), and 0.34 (95% CI: 0.15-0.76; PZ.009), respectively.
Discussion The results of this retrospective investigation demonstrated that definitive CRT following WBRT and surgical (27.8 months) or radiosurgical (28.4 months) intervention for SSBM in selected oligometastatic patients yielded survival outcomes within the range that has recently been reported for stage 3 NSCLC patients, regardless of the SSBM management technique used (22). Considering the poor survival rates, WBRT alone is the most widely accepted treatment for patients with multiple BMs (>3). However, in the era of more sophisticated staging techniques,
889
Age
