Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
Statistical Analysis
3. Results
3.1. Population
3.2. Toxicity Analysis
3.2.1. Acute and Subacute (<6 Months) Toxicities
3.2.2. Hematological Toxicity
3.2.3. Preliminary Data on Neuroendocrine Toxicities
3.2.4. Preliminary Data on Ototoxicity
3.2.5. Preliminary Data on Late Toxicities
3.3. Preliminary Data on Disease Control and Survival
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patient Characteristics and Radiation | Total Cohort (n = 43) | HR Group (n = 26) | SR Group (n = 14) | Ex-Infant (n = 3) | ||||
---|---|---|---|---|---|---|---|---|
Sex | No. | % | No. | % | No. | % | No. | % |
Male | 23 | 53.5% | 18 | 69.2% | 4 | 26.7% | 1 | 33.3% |
Female | 20 | 46.5% | 8 | 30.8% | 10 | 73.3% | 2 | 66.7% |
Histological subtype | ||||||||
Classic | 31 | 72.1% | 18 | 69.2% | 12 | 85.7% | 1 | 33.3% |
Desmoplastic | 3 | 7.0% | 1 | 3.8% | 1 | 7.1% | 1 | 33.3% |
Large cell/Anaplastic | 7 | 16.3% | 7 | 27.0% | - | - | - | - |
Extensive nodularity | 1 | 2.3% | - | - | - | - | 1 | 33.3% |
NOS | 1 | 2.3% | - | - | 1 | 7.1% | - | - |
Molecular subgroup | ||||||||
Non-WNT/Non-SHH | 29 | 67.4% | 21 | 80.8% | 7 | 50.0% | 1 | 33.3% |
SHH | 8 | 18.6% | 4 | 15.4% | 2 | 14.3% | 2 | 66.7% |
WNT | 3 | 7.0% | - | - | 3 | 21.4% | - | - |
Unavailable | 3 | 7.0% | 1 | 3.8% | 2 | 14.3% | - | - |
MYC amplification | 2 | 4.7% | 2 | 7.7% | - | - | - | - |
Chang Stage at PT | ||||||||
M0 | 28 | 65.1% | 12 | 46.2% | 14 | 100.0% | 2 | 66.7% |
M1 | 2 | 4.7% | 2 | 7.7% | - | - | - | - |
M2 | 2 | 4.7% | 2 | 7.7% | - | - | - | - |
M3 | 11 | 25.6% | 10 | 38.4% | - | - | 1 | 33.3% |
M4 | - | - | - | - | - | - | - | - |
Median (IQR) | Min–Max | Median (IQR) | Min–Max | Median (IQR) | Min–Max | Median (IQR) | Min–Max | |
CSI dose, GyRBE | 36 (12.6) | 23.4–39.6 | 36.0 (0.0) | 24.0 *–39.6 | 23.4 (0.0) | 23.4–25.2 | 36 (6.3) | 23.4–36.0 |
Total TB dose, GyRBE | 54.0 (0.0) | 54.0–55.8 | 54.0 (0.0) | 54.0–55.8 | 54.0 (0.0) | 54.0–55.8 | 54.0 (0.0) | 54.0–54.0 |
Boost on mets, GyRBE | 12.6 (9.0) | 9.0–18.0 | 14.4 (9.0) | 9.0–18.0 | - | - | 9.0 (0.0) | 9.0–9.0 |
Age at diagnosis, years | 8.7 (6.6) | 1.8–18.6 | 10.1 (7.2) | 2.5–18.6 | 6.6 (4.0) | 4.0–17.8 | 1.9 (0.1) | 1.8–2.1 |
Age at PT start, years | 8.9 (6.8) | 3.0–19.0 | 10.3 (7.3) | 3.0–19.0 | 6.7 (3.9) | 4.1–18.0 | 3.8 (0.1) | 3.6–3.8 |
Treatment Characteristics, Response and Follow-Up | Total Sample (n = 43) | HR Group (n = 26) | SR Group (n = 14) | Ex-Infant (n = 3) | ||||
---|---|---|---|---|---|---|---|---|
Extent of resection | ||||||||
Partial | 20 (46.5%) | 15 (57.7%) | 2 (14.3%) | 3 (100.0%) | ||||
Near-total | 2 (4.7%) | - | 2 (14.3%) | - | ||||
Gross-total | 21 (48.8%) | 11 (42.3%) | 10 (71.4%) | - | ||||
HD-CHT with aHSCT prior to PT | 14 (32.6%) | 11 (42.3%) | - | 3 (100.0%) | ||||
Concomitant CHT to PT | 18 (41.9%) | 13 (50.0%) | 5 (35.7%) | - | ||||
Treatment response | ||||||||
CR | 35 (81.4%) | 20 (76.9%) | 12 (85.7%) | 3 | 100.0% | |||
SD | 3 (7.0%) | 3 (11.5%) | - | - | - | |||
PD | 5 (11.6%) | 3 (11.5%) | 2 (14.2%) | - | - | |||
Survival at latest FU | ||||||||
Alive | 41 (95.3%) | 24 (92.3%) | 14 (100.0%) | 3 | 100.0% | |||
Dead | 2 (4.7%) | 2 (7.7%) | - | - | - | |||
Median (IQR) | Min–Max | Median (IQR) | Min–Max | Median (IQR) | Min–Max | Median (IQR) | Min–Max | |
FU duration, months | 26.0 (30.5) | 2.0–67.0 | 20.0 (31.3) | 5.0–67.0 | 28.5 (22.8) | 2.0–66.0 | 24.0 (21.5) | 3.0–46.0 |
Type of Toxicity | Total Sample (n = 43) | High-Dose CSI (n = 27) | Standard-Dose CSI (n = 16) | |||
---|---|---|---|---|---|---|
G1–G2 | G3 | G1–G2 | G3 | G1–G2 | G3 | |
Radiation dermatitis | 28 (65.1%) | 1 (2.3%) | 17 (63.0%) | 1 (3.7%) | 11 (68.8%) | - |
Pharyngeal mucositis | 22 (51.2%) | 2 (4.7%) | 15 (55.6%) | 1 (3.7%) | 7 (43.8%) | 1 (6.3%) |
Nausea/Vomiting | 18 (41.9%) | 1 (2.3%) | 10 (37.0%) | - | 8 (50.0%) | 1 (6.3%) |
Alopecia | 17 * (94.4%) | - | 3 (100%) | - | 14 (93.3%) | - |
Anorexia | 16 (37.2%) | 1 (2.3%) | 8 (29.6%) | - | 8 (50.0%) | 1 (6.3%) |
Fatigue | 15 (34.9%) | - | 8 (29.6%) | - | 7 (43.8%) | - |
Herpes Zoster | 7 (16.3%) | - | 4 (14.8%) | 3 (18.8%) | ||
Headache | 5 (11.6%) | 1 (2.3%) | 2 (7.4%) | 1 (3.7%) | 3 (18.8%) | - |
Upper airway infection | 3 (7.0%) | - | 2 (7.4%) | - | 1 (6.3%) | - |
Insomnia | 2 (4.7%) | - | 1 (3.7%) | - | 1 (6.3%) | - |
Fever | 3 (7.0%) | - | 1 (3.7%) | - | 2 (12.5%) | - |
Cough | 1 (2.3%) | - | - | - | 1 (6.3%) | - |
Diarrhea | 1 (2.3%) | - | - | - | 1 (6.3%) | - |
Myalgia | 1 (2.3%) | - | - | - | 1 (6.3%) | - |
PRES | - | 1 (2.3%) | - | 1 (3.7%) | - | - |
Cavernoma | 1 (2.3%) | - | 1 (3.7%) | - | - | - |
Comparison of High-Dose vs. Standard-Dose CSI | High-Dose CSI (n = 27) | Standard-Dose CSI (n = 16) | Difference (SE) | 95% CI | p |
---|---|---|---|---|---|
Leukocyte Count (Cells/mm³) | Mean (SD) | Mean (SD) | |||
Week 1 | 3339 (1587) | 6679 (3393) | 3340 (932) | 1382–5298 | <0.00 |
Week 2 | 1997 (698) | 3118 (1655) | 1121 (463) | 140–2103 | 0.03 |
Week 3 | 1972 (879) | 3463 (2411) | 1492 (648) | 119–2865 | 0.04 |
Week 4 | 2117 (738) | 3107 (2804) | 990 (738) | −584–2564 | 0.20 |
Week 5 | 2814 (1484) | 4022 (2157) | 1208 (561) | 74–2342 | 0.04 |
Week 6 | 3468 (3641) | 3856 (1548) | 388 (831) | −1299–2074 | 0.64 |
Hemoglobin value (g/dL) | |||||
Week 1 | 11.0 (1.0) | 11.6 (1.6) | 0.5 (0.5) | −0.4–1.5 | 0.25 |
Week 2 | 11.1 (1.2) | 11.3 (1.6) | 0.2 (0.5) | −0.7–1.1 | 0.63 |
Week 3 | 11.0 (1.3) | 11.2 (1.6) | 0.2 (0.5) | −0.7–1.2 | 0.65 |
Week 4 | 11.1 (1.0) | 11.2 (1.6) | 0.1 (0.5) | −0.9–1.1 | 0.87 |
Week 5 | 11.2 (1.0) | 11.2 (1.7) | 0.1 (0.5) | −0.9–1.0 | 0.92 |
Week 6 | 11.2 (0.7) | 11.2 (1.5) | -0.1 (0.4) | −0.9–0.8 | 0.92 |
Platelet count (cells/mm³) | |||||
Week 1 | 21,5240 (69,388) | 311,300 (103,713) | 96,060 (27,333) | 40,728–151,392 | <0.00 |
Week 2 | 135,590 (41,774) | 203,750 (55,424) | 68,160 (15,545) | 36,691–99,629 | <0.00 |
Week 3 | 137,353 (50,476) | 192,800 (92,686) | 55,447 (25,974) | 1083–109,810 | 0.04 |
Week 4 | 141,436 (54,175) | 218,267 (96,355) | 76,831 (27,053) | 20,209–133,452 | 0.01 |
Week 5 | 156,385 (54,281) | 278,750 (103,357) | 122,365 (27,946) | 64,070–180,660 | <0.00 |
Week 6 | 161,936 (56,438) | 276,767 (71,235) | 114,831 (20,153) | 74,067–155,595 | <0.00 |
Therapy | Cases | % |
---|---|---|
Any non-preexisting HRT | 6 | 14.0 |
Monotherapy | 4 | 9.3 |
Multi-drug HRT | 2 | 4.7 |
Specific hormones: | ||
Thyroxine | 5 | 11.6 |
Hydrocortisone | 3 | 7.0 |
Desmopressin | 1 | 2.3 |
Testosterone | 1 | 2.3 |
Median | Min–Max | |
Hypothalamic/Pituitary dose, GyRBE | 41.24 | 36.0–55.0 |
Latency to HRT | 9.5 months | 3.0–25.0 months |
Patient | CSI/TB dose (GyRBE) | Grade | Laterality | Cochlear Dmean (GyRBE) | Previous Chemotherapy | |
---|---|---|---|---|---|---|
Right | Left | |||||
1 | 23.4/30.6 | G1 | Bilateral | 35 | 28 | No |
2 | 36.0/18.0 | G2 | Bilateral | 37 | 37 | Yes |
3 | 36.0/18.0 | G2 | Bilateral | 37 | 42 | Yes |
4 | 23.4/30.6 | G2 | Bilateral | 23 | 26 | No |
5 | 36.0/18.0 | G3 | Right | 53 | 36 | Yes |
6 | 23.4/30.6 | G3 | Bilateral | 32 | 31 | No |
7 | 23.4/30.6 | G3 | Right | 35 | 42 | Yes |
Toxicity | High-Dose CSI (n = 27) | Standard-Dose CSI (n = 16) | ||
---|---|---|---|---|
No. of Cases (%) | Grade | No. of Cases (%) | Grade | |
Cavernoma | 8 (29.6%) | G1 | 1 (6.3%) | G1 |
1 (3.7%) | G2 | - | - | |
Intracranial bleeding | 1 (3.7%) | G2 | - | - |
Loss of visual acuity | - | - | 2 (12.5%) | G1 |
Osteoporosis | 1 (3.7%) | G2 | ||
CMV Encephalitis | 1 (3.7%) | G4 | - | - |
Stroke | 1 (3.7%) | G1 | - | - |
RBC Transfusion | 1 (3.7%) | G3 | - | - |
VII CN Paralysis | - | - | 1 (6.3%) | G1 |
Chronic headache | - | - | 1 (6.3%) | G1 |
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Ruggi, A.; Melchionda, F.; Sardi, I.; Pavone, R.; Meneghello, L.; Kitanovski, L.; Zaletel, L.Z.; Farace, P.; Zucchelli, M.; Scagnet, M.; et al. Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study. Cancers 2022, 14, 2747. https://doi.org/10.3390/cancers14112747
Ruggi A, Melchionda F, Sardi I, Pavone R, Meneghello L, Kitanovski L, Zaletel LZ, Farace P, Zucchelli M, Scagnet M, et al. Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study. Cancers. 2022; 14(11):2747. https://doi.org/10.3390/cancers14112747
Chicago/Turabian StyleRuggi, Alessandro, Fraia Melchionda, Iacopo Sardi, Rossana Pavone, Linda Meneghello, Lidija Kitanovski, Lorna Zadravec Zaletel, Paolo Farace, Mino Zucchelli, Mirko Scagnet, and et al. 2022. "Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study" Cancers 14, no. 11: 2747. https://doi.org/10.3390/cancers14112747