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Prognosis of non-small cell lung cancer patients with bone oligometastases treated concurrently with thoracic three-dimensional radiotherapy and chemotherapy

Prognosis of non-small cell lung cancer patients with bone oligometastases treated concurrently... Background: To evaluate the efficacy of three-dimensional radiotherapy for non-small cell lung cancer (NSCLC) patients with bone metastases. Methods: Clinical data for 95 NSCLC patients with bone metastases were collected and prognostic factors were analyzed. All patients received radiation to their thoracic primary tumor and ≥2 cycles of chemotherapy. Results: Of these 95 patients, 47 patients had only bone metastases and 48 had both bone metastases and other organ metastases. Univariate analysis showed that factors that statistically significantly contributed to patients having longer overall survival (OS) included receiving a radiation dose to the primary tumor ≥63 Gy, responding to treatment and receiving ≥4 cycles of chemotherapy (p = 0.001, p = 0.037 and p = 0.009, respectively). A radiation dose to the primary tumor ≥63 Gy remained significant for patients with bone metastases only as well as those with bone and other organ metastases when they were analyzed separately (p = 0.045 and p = 0.012, respectively). For patients with bone metastases only, those with T1-2 tumors had longer OS than those with T3-4 (p = 0.048); and patients who received ≥4 cycles chemotherapy compared with those who received <4 cycles had similar OS (p = 0.385). On multivariate analysis, only a radiation dose ≥63 Gy (p = 0.028) and having only bone metastases (p = 0.006) were independent prognostic factors for better OS. Conclusions: A radiation dose to the primary tumor ≥63 Gy and having only bone metastases were associated with better OS in NSCLC patients with bone metastases. For patients with bone metastases only, besides radiation dose, T status was also correlated with OS, whereas the number of chemotherapy cycles was not. Therefore, aggressive thoracic radiation may play an important role in improving OS. Keywords: Non-small Cell Lung Cancer, Bone Metastases, Thoracic Radiotherapy, Chemotherapy Introduction produces a median survival time (MST) of 8–10 months Approximately 55% of patients newly diagnosed with [2,3]. Moreover, the survival duration has not obviously non-small cell lung cancer (NSCLC) have distant metas- increased with chemotherapy treatment for stage IV tases [1]. System chemotherapy is the main treatment NSCLC patients over the past 10–15 years [4]. Different modality for stage IV NSCLC. The response rate to third-generation chemotherapy regimens have similar ef- platinum-based doublet chemotherapy for stage IV ficacy, indicating that the efficacy of a chemotherapeutic NSCLC is approximately 30–40%, and this treatment approach has reached a plateau. However, the metastatic status of NSCLC patients shows variability, and how to treat stage IV NSCLC patients with radiation therapy is * Correspondence: lbgymaaaa@sohu.com not well defined. Equal contributors We investigated clinical metastases features in 546 pa- Department of Thoracic Oncology, Affiliated Hospital of Guiyang Medical College, and Guizhou Cancer Hospital, 1 Beijing Road West, Guizhou, tients with stage IV NSCLC and 53.8% (294/546) of Guiyang, China © 2014 Ouyang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ouyang et al. Radiation Oncology 2014, 9:147 Page 2 of 7 http://www.ro-journal.com/content/9/1/147 Table 1 Clinical characteristics of 95 NSCLC patients with patients had bone metastases, bone being the most com- bone metastases mon metastatic site [5]. Patients with lung cancer who Characteristic Whole Only bone metastases Bone with develop bone metastases have a poor prognosis; the group other organ MST ranges from 7.0 to 8.0 months [6,7]. Recent publi- Metastases Metastases metastases to 1–2 sites to ≥2sites cations also have reported that radiation of the primary Gender tumor may prolong survival time in certain patients with stage IV NSCLC [8-10]. In this context, we performed Male 68 18 18 32 this study to investigate outcomes and prognostic factors Female 27 2 9 16 for NSCLC patients with bone oligometastases at diag- Age (years) nosis, who received radiation therapy for their thoracic Range (median) 30 ~ 78(59) 40 ~ 78(62) 41 ~ 72(59) 30 ~ 76(58) primary tumor. <60 50 9 14 27 ≥60 45 11 13 21 Methods Patient selection and pretreatment evaluation Pathological type Ninety-five patients who came to the hospital from Squamous 31 7 10 14 January 2003 to July 2010 with stage IV NSCLC and Non-squamous 64 13 17 34 who fulfilled all of the following criteria were included T stage in this study. (1) Pathologically or cytologically con- T 36 11 10 15 1–2 firmed diagnosis of NSCLC; (2) newly diagnosed stage T 59 9 17 33 IV disease according to the staging system of the 2002 3–4 American Joint Committee on Cancer; (3) aged between N stage 18–80 years; (4) Karnofsky Performance Status (KPS) N 14 3 4 7 0–1 score ≥70%, as well as a weight loss of no more than N 81 17 23 41 2–3 10% during the 6 months prior to therapy; (5) bone me- GTV 95 17 ~ 489 28 ~ 604 28 ~ 628 tastases at ≤5 sites; (6) adequate bone marrow, liver and (142) (147) (179) renal function; (7) no radiotherapy or chemotherapy KPS contraindications; (8) thoracic radiotherapy using either 70 39 5 9 25 three-dimensional conformal radiation therapy (3D-CRT) >70 56 15 18 23 or intensity-modulated radiation therapy (IMRT); and (9) treatment with at least two cycles of chemotherapy. Prescribed dose Exclusion criteria were as follows: (1) history of a thor- Range (median) 9 ~ 76(63) 23 ~ 76(63) 9 ~ 72(63) 9 ~ 68(58) acic operation, radiotherapy or chemotherapy; (2) preg- <63 Gy 47 10 8 29 nant or lactating; and (3) previous malignancy or other ≥63 Gy 48 10 19 19 concomitant malignant disease. The Institutional Review Treatment Board of the Affiliated Hospital of Guiyang Medical response of College and Guizhou Cancer Hospital China approved primary tumor this study, and the informed consent was obtained from CR + PR 66 15 18 33 all patients. SD + PD 29 5 9 15 Pretreatment evaluation included a complete physical Chemotherapy examination and hematologic and biochemistry profiles. Range (median) 2 ~ 5(4) 2 ~ 4(3) 2 ~ 4(4) 2 ~ 5(4) Fiberoptic bronchoscopy examination and contrast- enhanced computed tomography (CT) of chest were 2-3 cycles 43 10 9 24 performed to accurately evaluate the extent of the pri- ≥4 cycles 52 10 18 24 mary tumor and regional lymph nodes. Bone scintig- Radiation to raphy, contrast-enhanced CT of the abdominal region metastases and magnetic resonance imaging (MRI) of the brain Yes 15 9 3 3 were routinely used to detect distant metastases. If a No 80 11 24 45 PET/CT scan was done, then bone scintigraphy and Note: GTV from a minimum ~ maximal value cm (median). contrast-enhanced CT scans of the abdominal region were not necessary. Additional investigations were per- formed if indicated. Positive PET/CT or bone scan find- Radiotherapy protocol ings for bone metastases also required other additional All patients were immobilized in the supine position radiologic confirmation (e.g., MRI of bone). Clinical with a T bar, wing board and Vac-lock cradle. Images characteristics of the 95 patients are detailed in Table 1. with contrast were obtained from the CT simulator for Ouyang et al. Radiation Oncology 2014, 9:147 Page 3 of 7 http://www.ro-journal.com/content/9/1/147 treatment planning purpose. All patients were scanned Statistical analysis with serial 5-mm slices from the hyoid bone through the The Statistical Package for Social Sciences, version 13.0 third lumbar vertebra. All patient 3D-CRT or IMRT (SPSS, Chicago, IL) was used for statistical analysis. The treatment plans were performed using the ADAC pinna- Kaplan-Meier method was used to calculate overall sur- cle planning system (version 7.4 f) and dose distribu- vival (OS) and compared using the log-rank test. Factors tion was computed with tissue heterogeneity correction. with p <0.1 were included in multivariate analysis. The The gross tumor volume (GTV) included thoracic pri- Cox model was used for multivariate analysis of OS. All mary tumors and hilar or mediastinal lymph nodes with statistical tests were two-sided, and p <0.05 was consid- a short-axis diameter of at least 1 cm on CT, and the ered statistically significant. planning target volume (PTV) was defined as the GTV plus a 1.5-cm margin for setup uncertainty and respira- Results tory motion. Radiation was delivered with a linear accel- The last follow-up was in November 2012. The follow- erator using 6 MV photons. V20 (percentage of the total up periods ranged from 2.0 to 76.0 (median, 11.0) lung volume receiving ≥20 Gy), the maximal point dose months. At the time of the last follow-up, 92 patients of spinal cord and mean esophagus dose were required had died, one patient was lost to follow-up at 20 months to be ≤32%, 50 Gy and ≤35 Gy, respectively, for the indi- after finishing treatment (who was in the group of bone vidual treatment plan. The prescribed dose encompassed and other organ metastases) and two patients were still at least 95% of PTV. Thoracic radiation was delivered in alive with survival times of 47 and 76 months. For all pa- 2 Gy daily fractions (5 days each week) and patients re- tients, the MST was 11.0 months (95% confidence inter- ceived thoracic radiation of at least a dose of 40 Gy in val (CI), 8.5–13.5) and the 1-, 2-, and 3-year OS rates 20 fractions. Thoracic radiation treatment was imple- were 43.6, 16.8 and 8.5%, respectively. The 1-, 2- and mented concurrently with chemotherapy. The fraction- 3-year OS rates were 58.1, 24.8 and 15.8%, respectively ated radiotherapy dose for metastatic tumors ranged for patients with bone metastases only and the MST was from 3 to 10 Gy/fraction with 1 fraction/day, and the 14 months (95% CI, 10.3–17.7). For patients who had total prescribed radiotherapy dose for metastatic lesions bone and other organ metastases, the 1-, 2- and 3-year ranged from 20 to 60 Gy. Radiation to metastatic lesions OS rates were 31.8, 9.8 and 0.0%, respectively and the was implemented concurrently or sequentially with MST was 8 months (95% CI, 5.6–10.4) (χ = 10.092, chemotherapy. p = 0.001). For patients with bone metastases only, the OS for patients with metastases in 1–2 sites was similar Chemotherapy protocol to those with metastases in ≥3sites (χ =0.029, p =0.866). 3 3 All patients received platinum-based doublet chemother- The median GTV was 159 cm (17–628 cm ). The 1-, 2-, apy and the selection of regimens was according to prior and 3-year OS rates for patients with GTV <159 cm studies [3,11]. The commonly used regimens and usage compared with those with GTV ≥159 cm were 54.8 were as follows: 135–175 mg of paclitaxel (P) per square versus 37.5%, 19.4 versus 9.4% and 11.9 versus 3.1%, 2 2 meter of body surface area (mg/m ) or 75 mg/m of do- respectively, and the MST was 14 months (95% CI, cetaxel (D) administered on day 1, followed by 80 mg/ 9.6–18.4) versus 9 months (95% CI, 6.7–11.3), respectively 2 2 m of cisplatinum (C) or carboplatin (Cb) at a dose of (χ =3.281, p = 0.070). The status of the primary tumor 300–350 mg/m administrated on day 2, and vinorelbine and metastatic lesions could be evaluated in 58 of the 92 (V) at a dose of 25 mg/m , administered on days 1 and 8 patients who had died. Of these, six cases had progressive during thoracic radiotherapy given every 21–28 days. disease of the primary tumor without developing any new Concurrent thoracic radiation was given within 1 week metastases, and of these six cases, four involved a radi- following the start of chemotherapy. After completion of ation dose <40 Gy, seven cases had progressive disease of thoracic radiotherapy, patients demonstrating a response the primary tumor and initial metastatic lesions, six cases or stable disease continued on chemotherapy for up to had progressive disease of the primary tumor and new 4–6 cycles, whereas patients who experienced progres- metastases, and 39 cases had new metastases in initially sive disease or unacceptable toxicity were transferred to involved or uninvolved organs. second-line therapy. Platinum and taxane-based chemo- The 1-, 2-, and 3-year OS rates for patients who re- therapy were the main regimens used in the current ceived a radiation dose ≥63 Gy to the primary tumor study. PC or PCb regimens were used in 38 cases, DC or compared with those who received a radiation dose DCb regimens in 51 cases and the VC regimen in six <63 Gy were 60.2 versus 26.2%, 21.8 versus 11.9% and cases. In total, 45% of patients received two or three cy- 12.5 versus 4.0%, respectively and the MST was cles of chemotherapy, and 55% of patients received four 15 months (95% CI, 11.9–18.1) versus 9 months (95% or five cycles of chemotherapy. The total number of cy- CI, 6.6–11.4), respectively (χ = 11.038, p = 0.001). There cles was 315 (mean per patient, 3.3). was a significant association between treatment response Ouyang et al. Radiation Oncology 2014, 9:147 Page 4 of 7 http://www.ro-journal.com/content/9/1/147 of the primary tumor and OS; patients who responded 14 months (95% CI, 8.7-19.3) versus 6 months, respect- (complete remission + partial remission) had longer OS ively (95% CI, 3.1–8.9) (χ = 9.706, p = 0.002). However, than those without response (stable disease + progressive this difference was not statistically significant in patients disease) (χ = 4.364, p = 0.037). Radiation to metastatic sites with bone metastases only, and the MST was 14 months was not significantly correlated with OS in patients who (95% CI, 10.3–17.7) versus 12 months (95% CI, 6.8–17.2) 2 2 had both bone and other organ metastases (χ =0.259, (χ =0.756, p = 0.385). Univariate analysis revealed that p = 0.611). However, for patients with bone metastases sex, age, pathology type and N stage were not associ- only and who received radiation to metastatic sites, there ated with OS. Multivariate analysis revealed that a radi- was a trend towards a better OS (χ =2.757, p = 0.097). ation dose ≥63 Gy (p = 0.028) and bone metastases only A radiation dose to primary tumor ≥63 Gy remained (p = 0.006) were independent prognostic factors for bet- significant for OS when patients with only bone metasta- ter OS, and GTV (p = 0.056) and treatment response of ses and those who had bone and other organ metastases the primary tumor (p = 0.084) were marginally corre- were analyzed separately. For patients with bone metas- lated with OS (Table 2). tases only, the 1-, 2- and 3-year OS rates were 68.1, 25.5 and 20.4%, respectively and the MST was 16 months (95% Discussion CI, 14.1–17.9) for those who received radiation ≥63 Gy, This study sought to investigate whether combining sys- and the 1-, 2- and 3-year OS rates were 41.3, 23.6 and temic chemotherapy with radiotherapy in the treatment 7.9%, respectively for those who received radiation <63 of the primary thoracic tumor could further improve Gy and the MST was 10 months (95% CI, 4.8-15.2) survival in NSCLC patients with bone metastases. The (χ =4.012, p = 0.045, Figure 1). For patients who had results of the current study showed that radiotherapy bone both and other organ metastases, the 1-, 2- and ≥63 Gy to the primary tumor, and having only bone 3-year OS rates were 52.1, 17.4 and 0.0%, respectively, and metastatic disease were independent prognostic factors the MST was 14 months (95% CI, 9.6–18.4) for those who for better OS in stage IV NSCLC patients treated with received radiation ≥63 Gy, whereas it was 26.6, 0.0 and concurrent chemoradiotherapy. Radiation dose to the 0.0%, respectively for those who received <63 Gy and primary tumor ≥63 Gy remained significant when pa- the MST was 7 months (95% CI, 4.8–9.2) (χ =6.301, tients with bone metastases only and those with both p = 0.012, Figure 2). bone and other organ metastases were analyzed separ- The 1-, 2- and 3-year OS rates for T1-2 patients com- ately. In accordance with a previous publication [9], our pared with T3-4 were 50.0 versus 39.5%, 27.8 versus results also suggested that aggressive radiation to the 9.3% and 18.5 versus 2.3%, respectively and the MST primary tumor may improve survival in a subset of such was 14 months (95% CI, 9.6–18.4) versus 9 months (95% NSCLC patients with bone metastases. CI, 6.1–11.9), respectively (χ = 3.912, p = 0.048). For pa- Lopez et al. reported that patients who had smaller tients with bone metastases only, patients with T1-2 tumor volumes had longer OS [9]. Our results showed tumors had longer OS than those with T3-4, and the 1-, that patients with a GTV <159 cm tended to have longer 2- and 3-year OS rates were 66.7 versus 46.2%, 38.1 ver- OS than those with a GTV ≥159 cm . On multivariate sus 10.8% and 25.4 versus 5.4%, respectively, and the analysis, GTV was marginally correlated with OS in this MST was 17 months (95% CI, 12.4–21.6) versus 11 months study. Higginson et al. reported that the status of the pri- (95% CI, 7.1–14.9), respectively (χ =3.904, p = 0.048). For mary tumor was associated with OS in NSCLC patients patients who had both bone and other organ metasta- with metastases [12]. For the subset of patients who had ses, T-classification of the primary tumor was not cor- bone metastases only, patients with T1-2 disease had lon- related with OS (χ =0.001, p = 0.962). Patients with a ger OS than those with T3-4. The results from these stud- KPS score >70 showed borderline significantly better OS ies suggest that the status of the primary tumor should be than those with a KPS equal to 70 (χ =2.955, p =0.086). taken under consideration; those with early T-stage and OS was significantly prolonged in patients who re- small volume tumors may obtain more benefit from ag- ceived ≥4 cycles chemotherapy, and the 1-, 2- and 3-year gressive radiation for their primary tumor. Radiation for OS rates were 57.1, 20.3 and 11.6%, respectively, whereas the metastases was not associated with OS in the current the OS rates were 27.2, 12.4 and 4.6% for those who re- study, probably because most of the patients (84%) did ceived <4 cycles, respectively, and the MST was not receive radiotherapy for their metastatic disease, thus 14 months (95% CI, 11.6–16.4) versus 8 months (95% making it difficult to detect an advantage among patients CI, 4.9–11.1) (χ = 6.800, p = 0.009), respectively. Simi- who received radiotherapy for metastatic disease; and for larly, among patients who had both bone and other most of the patients who received radiotherapy for their organ metastases, OS was significantly prolonged in metastatic disease, it was of a palliative nature. those who had received ≥4 cycles of chemotherapy ver- Hellman et al. proposed the notion of oligometastases sus those who had received <4 cycles, and the MST was to indicate the presence of limited metastases and Ouyang et al. Radiation Oncology 2014, 9:147 Page 5 of 7 http://www.ro-journal.com/content/9/1/147 Figure 1 Comparison of overall survival curves at different radiation doses in patients with only bone metastases. suggested the existence of an intermediate clinical state radiation to metastatic sites displayed a trend towards im- between localized disease and widespread disease [13]. proving OS in patients with only bone oligometastases. Aggressive therapy for the primary tumor and metastatic The recommended number of chemotherapy cycles lesions in NSCLC patients with oligometastases may pro- for stage IV NSCLC is 4–6 according to the ASCO duce better OS [9,10,14]. Our results also showed that guideline [15]. We then evaluated patients with and Figure 2 Comparison of overall survival curves at different radiation doses in patients with metastases to both bone and other organs. Ouyang et al. Radiation Oncology 2014, 9:147 Page 6 of 7 http://www.ro-journal.com/content/9/1/147 Table 2 Multivariate analysis of overall survival Second, although patients with only bone metastases Variable HR 95% confidence p-value had better OS than those who had both bone and other interval organ metastases, a higher radiation dose remained sig- lower upper nificant when patients who had only bone metastases T stage (T3-4 vs. T1-2) 1.368 0.863 2.168 0.182 and those who had both bone and other organ metasta- 3 3 ses were analyzed separately. Moreover, for patients who GTV (<159 cm vs. ≥159 cm ) 0.564 0.314 1.014 0.056 had only bone metastases, the T-stage of their primary KPS status (>70 vs. =70) 0.873 0.496 1.437 0.683 tumor was associated with OS. In conclusion, aggressive Thoracic radiation dose 1.649 1.056 2.576 0.028 thoracic radiation plays an important role in improving (<63 Gy vs. ≥63 Gy) OS in NSCLC patients with bone metastases. Response of primary tumor 1.534 0.945 2.492 0.084 (SD + PD vs. CR + PR) Competing interests Chemotherapy (≥4 vs. <4 cycles) 0.804 0.507 1.274 0.353 The authors have no competing interests to declare. Metastatic organ (bone with 1.880 1.203 2.937 0.006 Authors’ contributions other organs vs. bone only) BL designed the study, W-WO, S-FS, ZM, Y-XH, Q-SL, Y-CG and H-QL collected the data. W-WO, S-FS, ZM and BL undertook the data analyses and interpretation, and wrote the report. W-WO and BL carried out the statistical analyses. All without other organ metastases besides bone metastases authors read and approved the final manuscript. separately. Univariate analysis showed that the number Acknowledgements of chemotherapy cycles was not correlated with OS for This study was supported by grants from the Natural Scientists and patients who had bone metastases only. However, the Technical Foundation from the Sci-Tech Office of Guizhou Province, China (No. J2010-2186); and Programs for Science and Technology Development subset of patients who had both bone and other organ of Guizhou Province, China (No. SY2010-3078). metastases, and who had received ≥4 cycles of chemo- therapy, had longer OS. Our findings suggest that the Received: 2 March 2014 Accepted: 21 June 2014 Published: 24 June 2014 status of the metastatic disease may also be used as a criterion to decide the number of chemotherapy cycles References for patients with bone metastases, when they receive ra- 1. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J diation to the primary site. Clin 2013, 63:11–30. 2. Scagliotti GV, Parikh P, Von Pawel J, Biesma B, Vansteenkiste J, Manegold C, There is a limitation of the current study in that the Serwatowski P, Gatzemeier U, Digumarti R, Zukin M: Phase III study imaging data of some patients were not gained to evalu- comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in ate patterns of failure and the relationship between OS chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008, 26:3543–3551. and local control of the primary tumor. Nearly 50% of 3. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, stage IV NSCLC patients experienced local recurrence Johnson DH: Comparison of four chemotherapy regimens for advanced in initially involved sites, and local control and status of non-small-cell lung cancer. N Engl J Med 2002, 346:92–98. 4. 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Prognosis of non-small cell lung cancer patients with bone oligometastases treated concurrently with thoracic three-dimensional radiotherapy and chemotherapy

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Springer Journals
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Copyright © 2014 by Ouyang et al.; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
DOI
10.1186/1748-717X-9-147
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24962716
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Abstract

Background: To evaluate the efficacy of three-dimensional radiotherapy for non-small cell lung cancer (NSCLC) patients with bone metastases. Methods: Clinical data for 95 NSCLC patients with bone metastases were collected and prognostic factors were analyzed. All patients received radiation to their thoracic primary tumor and ≥2 cycles of chemotherapy. Results: Of these 95 patients, 47 patients had only bone metastases and 48 had both bone metastases and other organ metastases. Univariate analysis showed that factors that statistically significantly contributed to patients having longer overall survival (OS) included receiving a radiation dose to the primary tumor ≥63 Gy, responding to treatment and receiving ≥4 cycles of chemotherapy (p = 0.001, p = 0.037 and p = 0.009, respectively). A radiation dose to the primary tumor ≥63 Gy remained significant for patients with bone metastases only as well as those with bone and other organ metastases when they were analyzed separately (p = 0.045 and p = 0.012, respectively). For patients with bone metastases only, those with T1-2 tumors had longer OS than those with T3-4 (p = 0.048); and patients who received ≥4 cycles chemotherapy compared with those who received <4 cycles had similar OS (p = 0.385). On multivariate analysis, only a radiation dose ≥63 Gy (p = 0.028) and having only bone metastases (p = 0.006) were independent prognostic factors for better OS. Conclusions: A radiation dose to the primary tumor ≥63 Gy and having only bone metastases were associated with better OS in NSCLC patients with bone metastases. For patients with bone metastases only, besides radiation dose, T status was also correlated with OS, whereas the number of chemotherapy cycles was not. Therefore, aggressive thoracic radiation may play an important role in improving OS. Keywords: Non-small Cell Lung Cancer, Bone Metastases, Thoracic Radiotherapy, Chemotherapy Introduction produces a median survival time (MST) of 8–10 months Approximately 55% of patients newly diagnosed with [2,3]. Moreover, the survival duration has not obviously non-small cell lung cancer (NSCLC) have distant metas- increased with chemotherapy treatment for stage IV tases [1]. System chemotherapy is the main treatment NSCLC patients over the past 10–15 years [4]. Different modality for stage IV NSCLC. The response rate to third-generation chemotherapy regimens have similar ef- platinum-based doublet chemotherapy for stage IV ficacy, indicating that the efficacy of a chemotherapeutic NSCLC is approximately 30–40%, and this treatment approach has reached a plateau. However, the metastatic status of NSCLC patients shows variability, and how to treat stage IV NSCLC patients with radiation therapy is * Correspondence: lbgymaaaa@sohu.com not well defined. Equal contributors We investigated clinical metastases features in 546 pa- Department of Thoracic Oncology, Affiliated Hospital of Guiyang Medical College, and Guizhou Cancer Hospital, 1 Beijing Road West, Guizhou, tients with stage IV NSCLC and 53.8% (294/546) of Guiyang, China © 2014 Ouyang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ouyang et al. Radiation Oncology 2014, 9:147 Page 2 of 7 http://www.ro-journal.com/content/9/1/147 Table 1 Clinical characteristics of 95 NSCLC patients with patients had bone metastases, bone being the most com- bone metastases mon metastatic site [5]. Patients with lung cancer who Characteristic Whole Only bone metastases Bone with develop bone metastases have a poor prognosis; the group other organ MST ranges from 7.0 to 8.0 months [6,7]. Recent publi- Metastases Metastases metastases to 1–2 sites to ≥2sites cations also have reported that radiation of the primary Gender tumor may prolong survival time in certain patients with stage IV NSCLC [8-10]. In this context, we performed Male 68 18 18 32 this study to investigate outcomes and prognostic factors Female 27 2 9 16 for NSCLC patients with bone oligometastases at diag- Age (years) nosis, who received radiation therapy for their thoracic Range (median) 30 ~ 78(59) 40 ~ 78(62) 41 ~ 72(59) 30 ~ 76(58) primary tumor. <60 50 9 14 27 ≥60 45 11 13 21 Methods Patient selection and pretreatment evaluation Pathological type Ninety-five patients who came to the hospital from Squamous 31 7 10 14 January 2003 to July 2010 with stage IV NSCLC and Non-squamous 64 13 17 34 who fulfilled all of the following criteria were included T stage in this study. (1) Pathologically or cytologically con- T 36 11 10 15 1–2 firmed diagnosis of NSCLC; (2) newly diagnosed stage T 59 9 17 33 IV disease according to the staging system of the 2002 3–4 American Joint Committee on Cancer; (3) aged between N stage 18–80 years; (4) Karnofsky Performance Status (KPS) N 14 3 4 7 0–1 score ≥70%, as well as a weight loss of no more than N 81 17 23 41 2–3 10% during the 6 months prior to therapy; (5) bone me- GTV 95 17 ~ 489 28 ~ 604 28 ~ 628 tastases at ≤5 sites; (6) adequate bone marrow, liver and (142) (147) (179) renal function; (7) no radiotherapy or chemotherapy KPS contraindications; (8) thoracic radiotherapy using either 70 39 5 9 25 three-dimensional conformal radiation therapy (3D-CRT) >70 56 15 18 23 or intensity-modulated radiation therapy (IMRT); and (9) treatment with at least two cycles of chemotherapy. Prescribed dose Exclusion criteria were as follows: (1) history of a thor- Range (median) 9 ~ 76(63) 23 ~ 76(63) 9 ~ 72(63) 9 ~ 68(58) acic operation, radiotherapy or chemotherapy; (2) preg- <63 Gy 47 10 8 29 nant or lactating; and (3) previous malignancy or other ≥63 Gy 48 10 19 19 concomitant malignant disease. The Institutional Review Treatment Board of the Affiliated Hospital of Guiyang Medical response of College and Guizhou Cancer Hospital China approved primary tumor this study, and the informed consent was obtained from CR + PR 66 15 18 33 all patients. SD + PD 29 5 9 15 Pretreatment evaluation included a complete physical Chemotherapy examination and hematologic and biochemistry profiles. Range (median) 2 ~ 5(4) 2 ~ 4(3) 2 ~ 4(4) 2 ~ 5(4) Fiberoptic bronchoscopy examination and contrast- enhanced computed tomography (CT) of chest were 2-3 cycles 43 10 9 24 performed to accurately evaluate the extent of the pri- ≥4 cycles 52 10 18 24 mary tumor and regional lymph nodes. Bone scintig- Radiation to raphy, contrast-enhanced CT of the abdominal region metastases and magnetic resonance imaging (MRI) of the brain Yes 15 9 3 3 were routinely used to detect distant metastases. If a No 80 11 24 45 PET/CT scan was done, then bone scintigraphy and Note: GTV from a minimum ~ maximal value cm (median). contrast-enhanced CT scans of the abdominal region were not necessary. Additional investigations were per- formed if indicated. Positive PET/CT or bone scan find- Radiotherapy protocol ings for bone metastases also required other additional All patients were immobilized in the supine position radiologic confirmation (e.g., MRI of bone). Clinical with a T bar, wing board and Vac-lock cradle. Images characteristics of the 95 patients are detailed in Table 1. with contrast were obtained from the CT simulator for Ouyang et al. Radiation Oncology 2014, 9:147 Page 3 of 7 http://www.ro-journal.com/content/9/1/147 treatment planning purpose. All patients were scanned Statistical analysis with serial 5-mm slices from the hyoid bone through the The Statistical Package for Social Sciences, version 13.0 third lumbar vertebra. All patient 3D-CRT or IMRT (SPSS, Chicago, IL) was used for statistical analysis. The treatment plans were performed using the ADAC pinna- Kaplan-Meier method was used to calculate overall sur- cle planning system (version 7.4 f) and dose distribu- vival (OS) and compared using the log-rank test. Factors tion was computed with tissue heterogeneity correction. with p <0.1 were included in multivariate analysis. The The gross tumor volume (GTV) included thoracic pri- Cox model was used for multivariate analysis of OS. All mary tumors and hilar or mediastinal lymph nodes with statistical tests were two-sided, and p <0.05 was consid- a short-axis diameter of at least 1 cm on CT, and the ered statistically significant. planning target volume (PTV) was defined as the GTV plus a 1.5-cm margin for setup uncertainty and respira- Results tory motion. Radiation was delivered with a linear accel- The last follow-up was in November 2012. The follow- erator using 6 MV photons. V20 (percentage of the total up periods ranged from 2.0 to 76.0 (median, 11.0) lung volume receiving ≥20 Gy), the maximal point dose months. At the time of the last follow-up, 92 patients of spinal cord and mean esophagus dose were required had died, one patient was lost to follow-up at 20 months to be ≤32%, 50 Gy and ≤35 Gy, respectively, for the indi- after finishing treatment (who was in the group of bone vidual treatment plan. The prescribed dose encompassed and other organ metastases) and two patients were still at least 95% of PTV. Thoracic radiation was delivered in alive with survival times of 47 and 76 months. For all pa- 2 Gy daily fractions (5 days each week) and patients re- tients, the MST was 11.0 months (95% confidence inter- ceived thoracic radiation of at least a dose of 40 Gy in val (CI), 8.5–13.5) and the 1-, 2-, and 3-year OS rates 20 fractions. Thoracic radiation treatment was imple- were 43.6, 16.8 and 8.5%, respectively. The 1-, 2- and mented concurrently with chemotherapy. The fraction- 3-year OS rates were 58.1, 24.8 and 15.8%, respectively ated radiotherapy dose for metastatic tumors ranged for patients with bone metastases only and the MST was from 3 to 10 Gy/fraction with 1 fraction/day, and the 14 months (95% CI, 10.3–17.7). For patients who had total prescribed radiotherapy dose for metastatic lesions bone and other organ metastases, the 1-, 2- and 3-year ranged from 20 to 60 Gy. Radiation to metastatic lesions OS rates were 31.8, 9.8 and 0.0%, respectively and the was implemented concurrently or sequentially with MST was 8 months (95% CI, 5.6–10.4) (χ = 10.092, chemotherapy. p = 0.001). For patients with bone metastases only, the OS for patients with metastases in 1–2 sites was similar Chemotherapy protocol to those with metastases in ≥3sites (χ =0.029, p =0.866). 3 3 All patients received platinum-based doublet chemother- The median GTV was 159 cm (17–628 cm ). The 1-, 2-, apy and the selection of regimens was according to prior and 3-year OS rates for patients with GTV <159 cm studies [3,11]. The commonly used regimens and usage compared with those with GTV ≥159 cm were 54.8 were as follows: 135–175 mg of paclitaxel (P) per square versus 37.5%, 19.4 versus 9.4% and 11.9 versus 3.1%, 2 2 meter of body surface area (mg/m ) or 75 mg/m of do- respectively, and the MST was 14 months (95% CI, cetaxel (D) administered on day 1, followed by 80 mg/ 9.6–18.4) versus 9 months (95% CI, 6.7–11.3), respectively 2 2 m of cisplatinum (C) or carboplatin (Cb) at a dose of (χ =3.281, p = 0.070). The status of the primary tumor 300–350 mg/m administrated on day 2, and vinorelbine and metastatic lesions could be evaluated in 58 of the 92 (V) at a dose of 25 mg/m , administered on days 1 and 8 patients who had died. Of these, six cases had progressive during thoracic radiotherapy given every 21–28 days. disease of the primary tumor without developing any new Concurrent thoracic radiation was given within 1 week metastases, and of these six cases, four involved a radi- following the start of chemotherapy. After completion of ation dose <40 Gy, seven cases had progressive disease of thoracic radiotherapy, patients demonstrating a response the primary tumor and initial metastatic lesions, six cases or stable disease continued on chemotherapy for up to had progressive disease of the primary tumor and new 4–6 cycles, whereas patients who experienced progres- metastases, and 39 cases had new metastases in initially sive disease or unacceptable toxicity were transferred to involved or uninvolved organs. second-line therapy. Platinum and taxane-based chemo- The 1-, 2-, and 3-year OS rates for patients who re- therapy were the main regimens used in the current ceived a radiation dose ≥63 Gy to the primary tumor study. PC or PCb regimens were used in 38 cases, DC or compared with those who received a radiation dose DCb regimens in 51 cases and the VC regimen in six <63 Gy were 60.2 versus 26.2%, 21.8 versus 11.9% and cases. In total, 45% of patients received two or three cy- 12.5 versus 4.0%, respectively and the MST was cles of chemotherapy, and 55% of patients received four 15 months (95% CI, 11.9–18.1) versus 9 months (95% or five cycles of chemotherapy. The total number of cy- CI, 6.6–11.4), respectively (χ = 11.038, p = 0.001). There cles was 315 (mean per patient, 3.3). was a significant association between treatment response Ouyang et al. Radiation Oncology 2014, 9:147 Page 4 of 7 http://www.ro-journal.com/content/9/1/147 of the primary tumor and OS; patients who responded 14 months (95% CI, 8.7-19.3) versus 6 months, respect- (complete remission + partial remission) had longer OS ively (95% CI, 3.1–8.9) (χ = 9.706, p = 0.002). However, than those without response (stable disease + progressive this difference was not statistically significant in patients disease) (χ = 4.364, p = 0.037). Radiation to metastatic sites with bone metastases only, and the MST was 14 months was not significantly correlated with OS in patients who (95% CI, 10.3–17.7) versus 12 months (95% CI, 6.8–17.2) 2 2 had both bone and other organ metastases (χ =0.259, (χ =0.756, p = 0.385). Univariate analysis revealed that p = 0.611). However, for patients with bone metastases sex, age, pathology type and N stage were not associ- only and who received radiation to metastatic sites, there ated with OS. Multivariate analysis revealed that a radi- was a trend towards a better OS (χ =2.757, p = 0.097). ation dose ≥63 Gy (p = 0.028) and bone metastases only A radiation dose to primary tumor ≥63 Gy remained (p = 0.006) were independent prognostic factors for bet- significant for OS when patients with only bone metasta- ter OS, and GTV (p = 0.056) and treatment response of ses and those who had bone and other organ metastases the primary tumor (p = 0.084) were marginally corre- were analyzed separately. For patients with bone metas- lated with OS (Table 2). tases only, the 1-, 2- and 3-year OS rates were 68.1, 25.5 and 20.4%, respectively and the MST was 16 months (95% Discussion CI, 14.1–17.9) for those who received radiation ≥63 Gy, This study sought to investigate whether combining sys- and the 1-, 2- and 3-year OS rates were 41.3, 23.6 and temic chemotherapy with radiotherapy in the treatment 7.9%, respectively for those who received radiation <63 of the primary thoracic tumor could further improve Gy and the MST was 10 months (95% CI, 4.8-15.2) survival in NSCLC patients with bone metastases. The (χ =4.012, p = 0.045, Figure 1). For patients who had results of the current study showed that radiotherapy bone both and other organ metastases, the 1-, 2- and ≥63 Gy to the primary tumor, and having only bone 3-year OS rates were 52.1, 17.4 and 0.0%, respectively, and metastatic disease were independent prognostic factors the MST was 14 months (95% CI, 9.6–18.4) for those who for better OS in stage IV NSCLC patients treated with received radiation ≥63 Gy, whereas it was 26.6, 0.0 and concurrent chemoradiotherapy. Radiation dose to the 0.0%, respectively for those who received <63 Gy and primary tumor ≥63 Gy remained significant when pa- the MST was 7 months (95% CI, 4.8–9.2) (χ =6.301, tients with bone metastases only and those with both p = 0.012, Figure 2). bone and other organ metastases were analyzed separ- The 1-, 2- and 3-year OS rates for T1-2 patients com- ately. In accordance with a previous publication [9], our pared with T3-4 were 50.0 versus 39.5%, 27.8 versus results also suggested that aggressive radiation to the 9.3% and 18.5 versus 2.3%, respectively and the MST primary tumor may improve survival in a subset of such was 14 months (95% CI, 9.6–18.4) versus 9 months (95% NSCLC patients with bone metastases. CI, 6.1–11.9), respectively (χ = 3.912, p = 0.048). For pa- Lopez et al. reported that patients who had smaller tients with bone metastases only, patients with T1-2 tumor volumes had longer OS [9]. Our results showed tumors had longer OS than those with T3-4, and the 1-, that patients with a GTV <159 cm tended to have longer 2- and 3-year OS rates were 66.7 versus 46.2%, 38.1 ver- OS than those with a GTV ≥159 cm . On multivariate sus 10.8% and 25.4 versus 5.4%, respectively, and the analysis, GTV was marginally correlated with OS in this MST was 17 months (95% CI, 12.4–21.6) versus 11 months study. Higginson et al. reported that the status of the pri- (95% CI, 7.1–14.9), respectively (χ =3.904, p = 0.048). For mary tumor was associated with OS in NSCLC patients patients who had both bone and other organ metasta- with metastases [12]. For the subset of patients who had ses, T-classification of the primary tumor was not cor- bone metastases only, patients with T1-2 disease had lon- related with OS (χ =0.001, p = 0.962). Patients with a ger OS than those with T3-4. The results from these stud- KPS score >70 showed borderline significantly better OS ies suggest that the status of the primary tumor should be than those with a KPS equal to 70 (χ =2.955, p =0.086). taken under consideration; those with early T-stage and OS was significantly prolonged in patients who re- small volume tumors may obtain more benefit from ag- ceived ≥4 cycles chemotherapy, and the 1-, 2- and 3-year gressive radiation for their primary tumor. Radiation for OS rates were 57.1, 20.3 and 11.6%, respectively, whereas the metastases was not associated with OS in the current the OS rates were 27.2, 12.4 and 4.6% for those who re- study, probably because most of the patients (84%) did ceived <4 cycles, respectively, and the MST was not receive radiotherapy for their metastatic disease, thus 14 months (95% CI, 11.6–16.4) versus 8 months (95% making it difficult to detect an advantage among patients CI, 4.9–11.1) (χ = 6.800, p = 0.009), respectively. Simi- who received radiotherapy for metastatic disease; and for larly, among patients who had both bone and other most of the patients who received radiotherapy for their organ metastases, OS was significantly prolonged in metastatic disease, it was of a palliative nature. those who had received ≥4 cycles of chemotherapy ver- Hellman et al. proposed the notion of oligometastases sus those who had received <4 cycles, and the MST was to indicate the presence of limited metastases and Ouyang et al. Radiation Oncology 2014, 9:147 Page 5 of 7 http://www.ro-journal.com/content/9/1/147 Figure 1 Comparison of overall survival curves at different radiation doses in patients with only bone metastases. suggested the existence of an intermediate clinical state radiation to metastatic sites displayed a trend towards im- between localized disease and widespread disease [13]. proving OS in patients with only bone oligometastases. Aggressive therapy for the primary tumor and metastatic The recommended number of chemotherapy cycles lesions in NSCLC patients with oligometastases may pro- for stage IV NSCLC is 4–6 according to the ASCO duce better OS [9,10,14]. Our results also showed that guideline [15]. We then evaluated patients with and Figure 2 Comparison of overall survival curves at different radiation doses in patients with metastases to both bone and other organs. Ouyang et al. Radiation Oncology 2014, 9:147 Page 6 of 7 http://www.ro-journal.com/content/9/1/147 Table 2 Multivariate analysis of overall survival Second, although patients with only bone metastases Variable HR 95% confidence p-value had better OS than those who had both bone and other interval organ metastases, a higher radiation dose remained sig- lower upper nificant when patients who had only bone metastases T stage (T3-4 vs. T1-2) 1.368 0.863 2.168 0.182 and those who had both bone and other organ metasta- 3 3 ses were analyzed separately. Moreover, for patients who GTV (<159 cm vs. ≥159 cm ) 0.564 0.314 1.014 0.056 had only bone metastases, the T-stage of their primary KPS status (>70 vs. =70) 0.873 0.496 1.437 0.683 tumor was associated with OS. In conclusion, aggressive Thoracic radiation dose 1.649 1.056 2.576 0.028 thoracic radiation plays an important role in improving (<63 Gy vs. ≥63 Gy) OS in NSCLC patients with bone metastases. Response of primary tumor 1.534 0.945 2.492 0.084 (SD + PD vs. CR + PR) Competing interests Chemotherapy (≥4 vs. <4 cycles) 0.804 0.507 1.274 0.353 The authors have no competing interests to declare. Metastatic organ (bone with 1.880 1.203 2.937 0.006 Authors’ contributions other organs vs. bone only) BL designed the study, W-WO, S-FS, ZM, Y-XH, Q-SL, Y-CG and H-QL collected the data. W-WO, S-FS, ZM and BL undertook the data analyses and interpretation, and wrote the report. W-WO and BL carried out the statistical analyses. All without other organ metastases besides bone metastases authors read and approved the final manuscript. separately. Univariate analysis showed that the number Acknowledgements of chemotherapy cycles was not correlated with OS for This study was supported by grants from the Natural Scientists and patients who had bone metastases only. However, the Technical Foundation from the Sci-Tech Office of Guizhou Province, China (No. J2010-2186); and Programs for Science and Technology Development subset of patients who had both bone and other organ of Guizhou Province, China (No. SY2010-3078). metastases, and who had received ≥4 cycles of chemo- therapy, had longer OS. Our findings suggest that the Received: 2 March 2014 Accepted: 21 June 2014 Published: 24 June 2014 status of the metastatic disease may also be used as a criterion to decide the number of chemotherapy cycles References for patients with bone metastases, when they receive ra- 1. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J diation to the primary site. Clin 2013, 63:11–30. 2. 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Kong FM, Ten Haken RK, Schipper MJ, Sullivan MA, Chen M, Lopez C, Kalemkerian GP, Hayman JA: High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 2005, 63:324–333. doi:10.1186/1748-717X-9-147 Cite this article as: Ouyang et al.: Prognosis of non-small cell lung cancer patients with bone oligometastases treated concurrently with thoracic three-dimensional radiotherapy and chemotherapy. Radiation Oncology 2014 9:147. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

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Radiation OncologySpringer Journals

Published: Jun 24, 2014

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