He et al. BMC Cancer (2016) 16:114 DOI 10.1186/s12885-016-2148-x
RESEARCH ARTICLE
Open Access
Prognostic value of the distance between the primary tumor and brainstem in the patients with locally advanced nasopharyngeal carcinoma Yuxiang He1, Ying Wang1, Lin Shen1, Yajie Zhao1, Pengfei Cao1, Mingjun Lei1, Dengming Chen1, Tubao Yang2, Liangfang Shen1* and Shousong Cao3
Abstract Background: Brainstem dose limitations influence radiation dose reaching to tumor in the patients with locallyadvanced nasopharyngeal cancer (NPC). Methods: A retrospective analysis of the prognostic value of the distance between the primary tumor and brainstem (Dbs) in 358 patients with locally-advanced NPC after intensity-modulated radiation therapy (IMRT). Receiver operating characteristic (ROC) curves were used to identify the cut-off value to analyze the impact of Dbs on tumor dose coverage and prognosis. Results: The three-year overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were 88.8 vs. 78.4 % (P = 0.007), 96.5 vs. 91.1 % (P = 0.018), 87.8 vs. 79.3 % (P = 0.067), and 84.1 vs. 69.6 % (P = 0.002) for the patients with the Dbs > 4.7 vs. ≤ 4.7 mm, respectively. ROC curves revealed Dbs (4.7 mm) combined with American Joint Committee on Cancer (AJCC) T classification had a significantly better prognostic value for OS (P < 0.05). Conclusions: Dbs (≤4.7 mm) is an independent negative prognostic factor for OS/LRFS/DFS and enhances the prognostic value of T classification in the patients with locally-advanced NPC. Keywords: Nasopharyngeal carcinoma, Intensity-modulated radiotherapy, Brainstem, Prognosis, Organs at risk
Background The relationship of clear radiation dose–response has been confirmed for the patients with nasopharyngeal cancer (NPC). For example, Sze et al. [1] found that the risk of local failure increases by 1 % with every 1 cm increase in tumor volume. Additionally, Willner et al. [2] observed a dose–response relationship between the tumor volume and total radiation dose with regards to local control in the patients with NPC, and found that if the tumor volume doubled, an extra 5 Gy was required for achieving equivalent local control, and even a total dose of 72 Gy could not control the tumor with a * Correspondence: [email protected] 1 Department of Oncology, Xiangya Hospital, Central South University, Hunan Province, No. 87, Xiangya Road, Changsha, Hunan Province 410008, PR China Full list of author information is available at the end of the article
volume larger than 64 ml. However, these studies were based on the patients with conventional radiotherapy. A dose–response relationship still exists in the patients with NPC with intensity-modulated radiation therapy (IMRT), even though this new technique has significantly improved tumor dose coverage [3, 4]. However, Ng et al. [5] reported that the negative effect of the primary gross tumor volume (GTV_P) on local failure-free survival (LFFR) and disease-free survival (DFS) was outweighed by the volume of under-dosing due to neighboring neurological structures. In their analysis of 444 patients in whom dose tolerances were maintained for all critical neurological organs at risk (OARs), most patients with T4 disease (some with T3) were under-dosed ( 0 ml) were 87.8 vs. 77.5 % (P = 0.005), 96.5 vs. 89.5 % (P = 0.004), 87.7 vs. 77.9 % (P = 0.047), and 83.3 vs. 66.9 % (P < 0.001), respectively. These were significantly different between the two groups (Fig. 3e-h, Table 5). The rates of 3-year OS, LRFS, DMFS and DFS for the two groups of patients stratified by GTVnx Dmin (≥66Gy or < 66Gy) were 89.6 vs. 77.8 % (P = 0.002), 96.3 vs. 91.7 % (P = 0.03), 89.4 vs. 77.4 % (P = 0.016), and 84.6 vs. 69.5 % (P = 0.002), respectively. These were significantly different between the two groups (Fig. 3i-l, Table 5). The univariate analysis suggests that the factors influencing the 3-year OS are age (P = 0.003), N-stage (P = 0.003), overall stage (P = 0.041), GTVnx Dmin (P = 0.002), and Dbs (P = 0.007), respectively. The factors influencing LFRS are age (P < 0.001), GTVnx Dmin (P = 0.003), and Dbs (P = 0.018), respectively. The factors influencing the 3-year DMFS are N-stage (P < 0.001), T-stage (P = 0.035), overall
C Isod oses
PGTVnx
GTVnx
8131 7392 6006 5600 4500 900
SV-PGTVnx Brainstem
Fig. 2 Relationship of the distance between the primary tumor and brainstem (Dbs) and PGTVnx V95 % (a); PGTVnx V95 % (b); and the radiation dose to GTVnx (c) of the patients with locally-advanced NPC. The color-filled areas represent the target volumes: GTVnx (red); PGTVnx (blue); brainstem (yellow); and sacrificed volume of PGTVnx (SV-PGTVnx, orange)
Table 3 D95 % and V95 % of the PGTVnx for the patients with locally-advanced nasopharyngeal carcinoma stratified by the distance from the primary tumor to the brain stem (Dbs) D95 %/V95 %
D95 % (Gy)
Total
V95 % (%)
Total
Dbs ≤ 4.7
Dbs > 4.7
Mean ± SD
69.0 ± 4.9
73.1 ± 2.0
71.5 ± 4.0
Median
70.0
73.7
72.3
95.2
99.8
98.8
Range
49.9–80.5
64.9–81.0
49.9–81.0
84.4–99.8
90–100
84.4–100
Dbs ≤ 4.7
Dbs > 4.7
94.8 ± 3.2
99.1 ± 1.6
97.5 ± 3.2
He et al. BMC Cancer (2016) 16:114
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Table 4 Radiation doses to the PGTVnx and brain stem for the patients with locally-advanced nasopharyngeal carcinoma stratified by T classification and the distance from the primary tumor to the brain stem (Dbs) Dbs ≤ 4.7 mm
Dbs > 4.7 mm
7th AJCC T3
7th AJCC T4
GTV-P (ml)
63.0 (16.5–204.8)
33.6 (5.9–164.0)
25.3 (6.3–73)
49.2 (5.9–204.8)
SV-PGTVnx (ml)
0.52 (0–12.4)
0.002 (0–0.2)
0.02 (0–0.44)
0.24 (0–12.4)
Dmin (Gy)
46.4 (21.9–66.6)
63.1 (21.7–74)
62.5 (38.6–73.6)
55.4 (21.7–74)
Dmean (Gy)
75.4 (65.6–83.9)
75.8 (67.6–84.1)
76.2 (71.0–81.1)
75.6 (65.6–84.1)
Dmax (Gy)
80.3 (69.5–88.7)
79.3 (70.9–88.8)
79.8 (76–84.1)
79.7 (69.5–88.8)
D95 % (Gy)
69.0 (49.9–80.5)
73.1 (64.9–81)
72.8 (57.9–78.4)
71.2 (49.9–81)
V95 % (Gy)
94.8 (84.4–98.8)
99.1 (90–100)
98.8 (90.2–100)
97.2 (84.4–100)
Dmax (Gy)
54.1 (45.1–68.4)
51.8 (41.7–68.8)
50.9 (42.7–56.3)
52.5 (41.7–68.8)
D1 %
49.1 (38.8–59)
46.7 (34.8–58.6)
46.3 (34.8–50.6)
47.9 (36.9–59.9)
D1cc (Gy)
47.6 (36.7–56.7)
45.3 (35.4–52.4)
44.9 (35.4–49.8)
46.4 (35.7–56.7)
D1/3 (Gy)
39.9 (28.7–51.2)
37.2 (22.8–53.8)
37.4 (22.8–53.8)
38.4 (26.1–51.2)
Dmean (Gy)
36.4 (25.8–49.8)
31.6 (19.7–41.7)
31.6 (19.7–37.5)
33.8 (21.1–49.8)
Mean (range) Tumor volume
PGTVnx
Brain stem
SV-PGTVnx: sacrificed volume of the PGTVnx
Fig. 3 Survival curves of the patients with locally-advanced NPC stratified by the distance between the primary tumor and brainstem (Dbs > 4.7 mm or ≤ 4.7 mm, a-d); the sacrificed volume of PGTVnx (SV-PGTVnx ≤ 0 ml or > 0 ml, e-h); and the minimum radiation dose of primary tumor (GTVnx Dmin ≥ 66Gy or < 66 Gy, i-l)
He et al. BMC Cancer (2016) 16:114
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Table 5 Univariate analysis of prognostic factors in the patients with locally-advanced nasopharyngeal carcinoma receiving IMRT Variable
No.# N = 346
3-year OS (%)
Age
p-value
3-year LRFS (%)
0.003
4.7 mm), respectively. The data indicate that appropriate target dose coverage can be achieved in the patients with a large Dbs, but not in the patients with a small Dbs (Table 4). However, the median Dbs was only 3.0 mm in the patients with GTVnx Dmin < 66 Gy, which is much smaller than in the patients with GTVnx Dmin ≥ 66 Gy of 8.6 mm (Fig. 1b and Table 2). Therefore, the Dbs hinders further improvement in radiation dose for IMRT in the patients with locally-advanced NPC.
He et al. BMC Cancer (2016) 16:114
The reason for us to choose Dbs 4.7 mm as the cut-off value is from ROC curve analysis. The determination of ROC cut-off value is always complied with the principle of maximization in the sensitivity plus (1-specificity) or the maximization of the sum of the true positive rate and false negative rate, which is the optimal cut-off value. Therefore, we calculated the cut-off value of Dbs as 4.7 mm by ROC curve analysis. We initially investigated three distances: 1) Dbs > 5 mm ; 2) Dbs > 2 mm but ≤ 5 mm; and 3) Dbs ≤ 2 mm before we chose ROC curve analysis to find the optimal cut-off value. The results showed that the 3-year OS, LRFS, DMFS, and DFS were 88.5 vs 85.6 vs 68.5 % (P = 0.003),96.2 vs 92.5 vs 88.9 % (P = 0.033), 87.5 vs 86.1 vs 68.7 % (P = 0.012), and 84.0 vs 78.6 vs 56.9 % (P < 0.001) for Dbs > 5 mm, Dbs > 2 mm but ≤ 5 mm; and Dbs ≤ 2 mm, respectively. However, there are not the optimal cut-off values for comparison. An insufficient dose of radiation is associated with reduced local control and a poor prognosis. For example, Ng et al. [5] reported that a bulky primary tumor was related to poorer OS; however, if a satisfactory dose of radiation (>70 Gy) was delivered to large tumors, the same treatment outcomes could be achieved similarly to small tumors. In addition, the effect of GTV_P volume on LFFR and DFS was outweighed by the degree of underdosing. In our study, most patients had a prescribed dose of approximately 73.92 Gy and a D95 % of 70.22 Gy. The tumor volume under-dosed ( 4.7 mm than the patients with Dbs ≤ 4.7 mm (P
0 ml (P < 0.05). The results are consistent with the report by Ng et al. [5], which they showed that the 5 year LRFS, DFS, and OS were 90.4 vs 54.3 %, 70.6 vs 26.0 %, and 76.8 vs 53.2 % (p < 0.001) for the patients with GTV-P 66.5 Gy < 3.4 cm3 and the patients with GTV-P 66.5 Gy ≥ 3.4 cm3, respectively. Their results indicate that the volume of tumor under-dosed (
RESEARCH ARTICLE
Open Access
Prognostic value of the distance between the primary tumor and brainstem in the patients with locally advanced nasopharyngeal carcinoma Yuxiang He1, Ying Wang1, Lin Shen1, Yajie Zhao1, Pengfei Cao1, Mingjun Lei1, Dengming Chen1, Tubao Yang2, Liangfang Shen1* and Shousong Cao3
Abstract Background: Brainstem dose limitations influence radiation dose reaching to tumor in the patients with locallyadvanced nasopharyngeal cancer (NPC). Methods: A retrospective analysis of the prognostic value of the distance between the primary tumor and brainstem (Dbs) in 358 patients with locally-advanced NPC after intensity-modulated radiation therapy (IMRT). Receiver operating characteristic (ROC) curves were used to identify the cut-off value to analyze the impact of Dbs on tumor dose coverage and prognosis. Results: The three-year overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were 88.8 vs. 78.4 % (P = 0.007), 96.5 vs. 91.1 % (P = 0.018), 87.8 vs. 79.3 % (P = 0.067), and 84.1 vs. 69.6 % (P = 0.002) for the patients with the Dbs > 4.7 vs. ≤ 4.7 mm, respectively. ROC curves revealed Dbs (4.7 mm) combined with American Joint Committee on Cancer (AJCC) T classification had a significantly better prognostic value for OS (P < 0.05). Conclusions: Dbs (≤4.7 mm) is an independent negative prognostic factor for OS/LRFS/DFS and enhances the prognostic value of T classification in the patients with locally-advanced NPC. Keywords: Nasopharyngeal carcinoma, Intensity-modulated radiotherapy, Brainstem, Prognosis, Organs at risk
Background The relationship of clear radiation dose–response has been confirmed for the patients with nasopharyngeal cancer (NPC). For example, Sze et al. [1] found that the risk of local failure increases by 1 % with every 1 cm increase in tumor volume. Additionally, Willner et al. [2] observed a dose–response relationship between the tumor volume and total radiation dose with regards to local control in the patients with NPC, and found that if the tumor volume doubled, an extra 5 Gy was required for achieving equivalent local control, and even a total dose of 72 Gy could not control the tumor with a * Correspondence: [email protected] 1 Department of Oncology, Xiangya Hospital, Central South University, Hunan Province, No. 87, Xiangya Road, Changsha, Hunan Province 410008, PR China Full list of author information is available at the end of the article
volume larger than 64 ml. However, these studies were based on the patients with conventional radiotherapy. A dose–response relationship still exists in the patients with NPC with intensity-modulated radiation therapy (IMRT), even though this new technique has significantly improved tumor dose coverage [3, 4]. However, Ng et al. [5] reported that the negative effect of the primary gross tumor volume (GTV_P) on local failure-free survival (LFFR) and disease-free survival (DFS) was outweighed by the volume of under-dosing due to neighboring neurological structures. In their analysis of 444 patients in whom dose tolerances were maintained for all critical neurological organs at risk (OARs), most patients with T4 disease (some with T3) were under-dosed ( 0 ml) were 87.8 vs. 77.5 % (P = 0.005), 96.5 vs. 89.5 % (P = 0.004), 87.7 vs. 77.9 % (P = 0.047), and 83.3 vs. 66.9 % (P < 0.001), respectively. These were significantly different between the two groups (Fig. 3e-h, Table 5). The rates of 3-year OS, LRFS, DMFS and DFS for the two groups of patients stratified by GTVnx Dmin (≥66Gy or < 66Gy) were 89.6 vs. 77.8 % (P = 0.002), 96.3 vs. 91.7 % (P = 0.03), 89.4 vs. 77.4 % (P = 0.016), and 84.6 vs. 69.5 % (P = 0.002), respectively. These were significantly different between the two groups (Fig. 3i-l, Table 5). The univariate analysis suggests that the factors influencing the 3-year OS are age (P = 0.003), N-stage (P = 0.003), overall stage (P = 0.041), GTVnx Dmin (P = 0.002), and Dbs (P = 0.007), respectively. The factors influencing LFRS are age (P < 0.001), GTVnx Dmin (P = 0.003), and Dbs (P = 0.018), respectively. The factors influencing the 3-year DMFS are N-stage (P < 0.001), T-stage (P = 0.035), overall
C Isod oses
PGTVnx
GTVnx
8131 7392 6006 5600 4500 900
SV-PGTVnx Brainstem
Fig. 2 Relationship of the distance between the primary tumor and brainstem (Dbs) and PGTVnx V95 % (a); PGTVnx V95 % (b); and the radiation dose to GTVnx (c) of the patients with locally-advanced NPC. The color-filled areas represent the target volumes: GTVnx (red); PGTVnx (blue); brainstem (yellow); and sacrificed volume of PGTVnx (SV-PGTVnx, orange)
Table 3 D95 % and V95 % of the PGTVnx for the patients with locally-advanced nasopharyngeal carcinoma stratified by the distance from the primary tumor to the brain stem (Dbs) D95 %/V95 %
D95 % (Gy)
Total
V95 % (%)
Total
Dbs ≤ 4.7
Dbs > 4.7
Mean ± SD
69.0 ± 4.9
73.1 ± 2.0
71.5 ± 4.0
Median
70.0
73.7
72.3
95.2
99.8
98.8
Range
49.9–80.5
64.9–81.0
49.9–81.0
84.4–99.8
90–100
84.4–100
Dbs ≤ 4.7
Dbs > 4.7
94.8 ± 3.2
99.1 ± 1.6
97.5 ± 3.2
He et al. BMC Cancer (2016) 16:114
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Table 4 Radiation doses to the PGTVnx and brain stem for the patients with locally-advanced nasopharyngeal carcinoma stratified by T classification and the distance from the primary tumor to the brain stem (Dbs) Dbs ≤ 4.7 mm
Dbs > 4.7 mm
7th AJCC T3
7th AJCC T4
GTV-P (ml)
63.0 (16.5–204.8)
33.6 (5.9–164.0)
25.3 (6.3–73)
49.2 (5.9–204.8)
SV-PGTVnx (ml)
0.52 (0–12.4)
0.002 (0–0.2)
0.02 (0–0.44)
0.24 (0–12.4)
Dmin (Gy)
46.4 (21.9–66.6)
63.1 (21.7–74)
62.5 (38.6–73.6)
55.4 (21.7–74)
Dmean (Gy)
75.4 (65.6–83.9)
75.8 (67.6–84.1)
76.2 (71.0–81.1)
75.6 (65.6–84.1)
Dmax (Gy)
80.3 (69.5–88.7)
79.3 (70.9–88.8)
79.8 (76–84.1)
79.7 (69.5–88.8)
D95 % (Gy)
69.0 (49.9–80.5)
73.1 (64.9–81)
72.8 (57.9–78.4)
71.2 (49.9–81)
V95 % (Gy)
94.8 (84.4–98.8)
99.1 (90–100)
98.8 (90.2–100)
97.2 (84.4–100)
Dmax (Gy)
54.1 (45.1–68.4)
51.8 (41.7–68.8)
50.9 (42.7–56.3)
52.5 (41.7–68.8)
D1 %
49.1 (38.8–59)
46.7 (34.8–58.6)
46.3 (34.8–50.6)
47.9 (36.9–59.9)
D1cc (Gy)
47.6 (36.7–56.7)
45.3 (35.4–52.4)
44.9 (35.4–49.8)
46.4 (35.7–56.7)
D1/3 (Gy)
39.9 (28.7–51.2)
37.2 (22.8–53.8)
37.4 (22.8–53.8)
38.4 (26.1–51.2)
Dmean (Gy)
36.4 (25.8–49.8)
31.6 (19.7–41.7)
31.6 (19.7–37.5)
33.8 (21.1–49.8)
Mean (range) Tumor volume
PGTVnx
Brain stem
SV-PGTVnx: sacrificed volume of the PGTVnx
Fig. 3 Survival curves of the patients with locally-advanced NPC stratified by the distance between the primary tumor and brainstem (Dbs > 4.7 mm or ≤ 4.7 mm, a-d); the sacrificed volume of PGTVnx (SV-PGTVnx ≤ 0 ml or > 0 ml, e-h); and the minimum radiation dose of primary tumor (GTVnx Dmin ≥ 66Gy or < 66 Gy, i-l)
He et al. BMC Cancer (2016) 16:114
Page 7 of 11
Table 5 Univariate analysis of prognostic factors in the patients with locally-advanced nasopharyngeal carcinoma receiving IMRT Variable
No.# N = 346
3-year OS (%)
Age
p-value
3-year LRFS (%)
0.003
4.7 mm), respectively. The data indicate that appropriate target dose coverage can be achieved in the patients with a large Dbs, but not in the patients with a small Dbs (Table 4). However, the median Dbs was only 3.0 mm in the patients with GTVnx Dmin < 66 Gy, which is much smaller than in the patients with GTVnx Dmin ≥ 66 Gy of 8.6 mm (Fig. 1b and Table 2). Therefore, the Dbs hinders further improvement in radiation dose for IMRT in the patients with locally-advanced NPC.
He et al. BMC Cancer (2016) 16:114
The reason for us to choose Dbs 4.7 mm as the cut-off value is from ROC curve analysis. The determination of ROC cut-off value is always complied with the principle of maximization in the sensitivity plus (1-specificity) or the maximization of the sum of the true positive rate and false negative rate, which is the optimal cut-off value. Therefore, we calculated the cut-off value of Dbs as 4.7 mm by ROC curve analysis. We initially investigated three distances: 1) Dbs > 5 mm ; 2) Dbs > 2 mm but ≤ 5 mm; and 3) Dbs ≤ 2 mm before we chose ROC curve analysis to find the optimal cut-off value. The results showed that the 3-year OS, LRFS, DMFS, and DFS were 88.5 vs 85.6 vs 68.5 % (P = 0.003),96.2 vs 92.5 vs 88.9 % (P = 0.033), 87.5 vs 86.1 vs 68.7 % (P = 0.012), and 84.0 vs 78.6 vs 56.9 % (P < 0.001) for Dbs > 5 mm, Dbs > 2 mm but ≤ 5 mm; and Dbs ≤ 2 mm, respectively. However, there are not the optimal cut-off values for comparison. An insufficient dose of radiation is associated with reduced local control and a poor prognosis. For example, Ng et al. [5] reported that a bulky primary tumor was related to poorer OS; however, if a satisfactory dose of radiation (>70 Gy) was delivered to large tumors, the same treatment outcomes could be achieved similarly to small tumors. In addition, the effect of GTV_P volume on LFFR and DFS was outweighed by the degree of underdosing. In our study, most patients had a prescribed dose of approximately 73.92 Gy and a D95 % of 70.22 Gy. The tumor volume under-dosed ( 4.7 mm than the patients with Dbs ≤ 4.7 mm (P
0 ml (P < 0.05). The results are consistent with the report by Ng et al. [5], which they showed that the 5 year LRFS, DFS, and OS were 90.4 vs 54.3 %, 70.6 vs 26.0 %, and 76.8 vs 53.2 % (p < 0.001) for the patients with GTV-P 66.5 Gy < 3.4 cm3 and the patients with GTV-P 66.5 Gy ≥ 3.4 cm3, respectively. Their results indicate that the volume of tumor under-dosed (
