Patient characteristics
All 23 patients in the study underwent induction chemotherapy and received intrathecal methotrexate for central nervous system (CNS) prophylaxis. Among these, 78% (n=18) were treated according to the MCP-841 protocol, with a dose fractionation of 18 Gy administered in 10 fractions at 1.8 Gy per fraction. The remaining 22% (n=5) followed the BFM-95 protocol, where the dose fractionation was 12.6 Gy in 7 fractions at 1.8 Gy per fraction. In terms of age distribution, 65 % (n=15) of the patients were aged 15 or older, while 35% (n=8) were under the age of 15. Among the participants, 74% (n=18) were male, and 26% (n=5) were female.Regarding the subtype of acute lymphoblastic leukemia (ALL), 22% (n=5) had Pre B ALL, 26% (n=6) had T ALL, and 52% (n=12) had B ALL. The majority of the patients, constituting 78% (n=18), were classified as high-risk individuals.
Dosimetric data
Dosimetric Analysis for ease of convenience, the study population was classified into patients who received a total dose of 18 Gy and 12.6 Gy.
Table 1 – Mean Dose Values of 18 Gy patients
|
Mean
|
Median
|
Std. Deviation
|
DOSAGE
|
18.00
|
18.00
|
0.00
|
LT_LENS
|
1030.65
|
1022.70
|
88.86
|
RT_LENS
|
1021.39
|
1030.65
|
82.64
|
DMEANPTV
|
1894.62
|
1894.20
|
34.69
|
DMEDIANPTV
|
2855.04
|
1899.90
|
4051.62
|
D98PERPTV
|
97.94
|
98.60
|
2.27
|
D98PTV
|
1768.72
|
1775.00
|
31.07
|
D95PTV
|
195.92
|
99.90
|
407.99
|
D2PTV
|
1976.44
|
1968.75
|
52.89
|
D1PTV
|
1986.02
|
1977.50
|
52.66
|
LTHIPPO
|
890.20
|
876.40
|
45.24
|
RTHIPPO
|
908.51
|
894.85
|
39.45
|
HIPPOCOMBO
|
903.76
|
884.55
|
58.82
|
D2HIPPO
|
1260.35
|
1260.35
|
63.13
|
D1HIPPO
|
1867.23
|
1330.85
|
2389.93
|
CONFORMITY
|
0.90
|
0.91
|
0.07
|
HOMOGENEITY
|
0.10
|
0.11
|
0.03
|
DHIPPOMIN
|
6.25
|
6.10
|
0.69
|
DHIPPOMAX
|
15.18
|
15.30
|
1.28
|
DHIPPO20
|
10.15
|
10.20
|
0.32
|
DHIPPO40
|
9.12
|
9.10
|
0.28
|
DHIPPO80
|
7.63
|
7.40
|
0.58
|
For patients treated with 18 Gy the mean dose to PTV was 18.9 Gy ± 0.3 Gy. D98 % PTV 17.6± 0.3 Gy, D2%PTV 19.7± 0.5 Gy. Dose to OARs left lens is 10.3 ± 0.8 Gy,Right lens is 10.2 ± 0.8 Gy.The dose to OAR the Bilateral hippocampus which is the region of interest for this study is 9 ±0.5Gy. Dose to Left Hippocampus 8.9 ±0.4Gy, Right Hippocampus 9±0.3Gy D2 % Hippocampus is 12.6±0.6Gy, Minimal, maximal, D20%, D40%,D50% and D80% doses to the combined hippocampus are also reported for 18Gy dose fractionation. For 18Gy minimal and maximal doses are 6.2Gy and 15.2Gy respectively. D20%, D40%, D50% and D80% are 10.1 Gy, 9.1Gy, 8.9Gy and 7.6 Gy Respectively. The conformity index and homogeneity index were 0.9 and 0.1 respectively (Table 1)
Table 2 – Mean Dose Values of 12 Gy patients
|
Mean
|
Std. Deviation
|
DOSAGE
|
12.00
|
0.00
|
LT_LENS
|
735.64
|
43.90
|
RT_LENS
|
749.22
|
30.69
|
DMEANPTV
|
1330.68
|
22.11
|
DMEDIANPTV
|
1333.86
|
21.46
|
D98PERPTV
|
99.38
|
1.62
|
D98PTV
|
1219.06
|
36.66
|
D95PTV
|
101.40
|
1.57
|
D2PTV
|
1380.74
|
29.46
|
D1PTV
|
1385.70
|
31.02
|
LTHIPPO
|
699.56
|
116.73
|
RTHIPPO
|
714.02
|
64.97
|
HIPPOCOMBO
|
706.88
|
80.79
|
D2HIPPO
|
928.74
|
110.94
|
D1HIPPO
|
949.72
|
112.99
|
CONFORMITY
|
0.91
|
0.02
|
HOMOGENEITY
|
0.12
|
0.03
|
DHIPPOMIN
|
4.88
|
0.75
|
DHIPPOMAX
|
10.34
|
1.35
|
DHIPPO20
|
7.98
|
0.87
|
DHIPPO40
|
7.28
|
0.73
|
DHIPPO80
|
6.06
|
0.90
|
For Patients receiving 12 Gy the mean dose to PTV for was 13.3 Gy ±0.2Gy .D98 % PTV 12.1± 0.3 Gy, D2% PTV 13.8±0.3 Gy. Dose to OARs left lens is 7.3 ± 0.4 Gy, Right lens is 7.4 ± 0.3 Gy. The dose to OAR the Bilateral hippocampus which is the region of interest for this study is 7±0.8Gy. Dose to Left Hippocampus 6.9 ±1Gy, Right Hippocampus 7.1±0.6Gy D2% of Hippocampus is 9.2±1Gy. For 12Gy minimal and maximal doses are 4.8 Gy and 10.3Gy respectively. D20%, D40%,D50% and D80% are 7.9 Gy, 7.2Gy, 7Gy and 6 Gy Respectively. Conformity index and homogeneity index were 0.9 and 0.1 respectively (Table 2).
The mean volume of the bilateral contoured hippocampus is 4.5 cc(3.11-5.8). The average treatment time in our study was 5.5 min, which is less than the treatment time when delivered through IMRT in a study by Tomas K. et al (Tomas k, 2014).
Survival Outcomes
Among the 23 persons who were followed up for a total of 1291 person-months, there were 8 deaths and 5 lost to follow up. The incidence rate of deaths among the sample of persons diagnosed with ALL was 5.7 deaths per 1000 person-months (95% CI: 2.9, 11.5) of follow-up from the date of diagnosis. In 46 months from the time of diagnosis, about 75% of the sample of patients were alive. The median duration of survival for this sample of patients was 63 months. No CNS relapses and no patient died of CNS relapse. (Fig 4)
Neurocognitive analysis
Base line Neurocognitive assessment pre RT was done for 22 patients out of 23, post RT 6 months and 1 year evaluation was done for 17 patients to see any early decline in neurocognitive functions 4 year assessment was done for 3 patients .For neurocognitive assessment, study participants were classified into two groups based on Age and neurocognitive test. A group of 6-15 and another group 16-25.
For patients aged < 15 years, neurocognitive assessment was performed using the Malin Intelligence scale for Indian children (MISIC). Mean verbal scores at baseline, 6 months post-RT, and 1 year post-RT and 4 year post-RT were 93, 98, 99 and 93.5 respectively, and the difference was statistically significant (p =0.001). The mean performance scores at baseline, 6 months post-RT, and 1 year post-RT and 4 year post-RT were 92, 98,102 and 99 respectively, and the difference was statistically significant (p = 0.001). The Mean AVLT delayed recall scores at baseline, 6 months post-RT, and 1 year post-RT were 61, 76,91 and 96 respectively, and the difference was statistically significant (p = 0.001). The composite score of all verbal and performance tests gave a total full-scale IQ (FSIQ) at a baseline of 93 at the end line (6 months post treatment) was 98 at the end of one year 101 and at end of 4 year 95 with a statistically significant difference (p=0.001)(Table 3).
Neurocognitive assessment of patients aged 16–25 years was performed using the Wallis Adult performance test (WAPIS–PR). Mean immediate recall scores at baseline, 6 months post-RT, and 1 year post-RT and 4 year post-RT were 47, 56, 60 and 95 respectively, and the difference was statistically significant (p = 0.01). Mean delayed recall scores at baseline, 6 months post-RT, and 1 year post-RT and 4 year post-RT were 55, 67, 70 and 95 respectively, and the differences were not statistically significant (p = 0.23). The composite score of all tests gave a total full-scale IQ (IQ) at a baseline of 92 (6), at the end of 6 months post-treatment was 99 (6), at the end of 1 year was 102(6), and at the end of 4 year was 109 and the difference was statistically significant (p=0.03) (Table 3).
Table 3- Neurocognitive assessment results
Scores
|
Mean (standard deviation)
|
p-value for within patients change
|
Adults Group (n=6)
|
|
Baseline
(n=6)
|
At 6-months follow-up
(n=6)
|
At 1-year follow-up
(n=6)
|
At 4-year follow-up (n=1)
|
|
Immediate recall (IR)
|
47.5 (±33.6)
|
56.7 (±27.9)
|
60.0 (±26.6)
|
95.0 (±0)
|
0.01*
|
Delayed
Recall (DR)
|
55.8 (±37.1)
|
67.5 (±23.4)
|
70.0 (±21.0)
|
95.0 (±0)
|
0.23
|
Intelligent quotient (IQ)
|
92.0 (±10.2)
|
99.5 (±9.3)
|
102.5 (±9.3)
|
109.0 (±0)
|
0.03*
|
Paediatrics Group (n=11)
|
|
Baseline
(n=11)
|
At 6-months follow-up
(n=11)
|
At 1-year follow-up
(n=11)
|
At 4-year follow-up (n=2)
|
|
Verbal quotient (VQ)
|
93.5 (±8.8)
|
98.7 (±9.5)
|
99.9 (±9.2)
|
93.5 (±0.7)
|
<0.001*
|
Performance quotient
(PQ)
|
92.6 (±10.9)
|
98.4 (±9.6)
|
102.1 (±7.8)
|
99.0 (±0)
|
<0.001*
|
Delayed recall
(DR)
|
61.8 (±20.4)
|
76.8 (±19.1)
|
91.8 (±6.0)
|
96.5 (±0.7)
|
<0.001*
|
Full Scale (IQ)
|
93.4 (±8.6)
|
98.4 (±8.0)
|
101.8 (±7.9)
|
95.0 (±0)
|
<0.001*
|