Long term neurological sequelae of high dose 3D conformal fractionated combined proton-photon therapy to the cauda equina

Abstract

To report late neurological sequelae and clinical outcomes for patients treated with high dose 3D conformal fractionated combined proton-photon radiation therapy to portions of the cauda equina (L2-coccyx). From 1974 through 1995, 62 patients were treated to fields encompassing portions of the cauda equina (L2-coccyx) with high dose 3D conformal fractionated combined proton-photon radiation therapy. This report describes clinical outcomes and late neurological sequelae in 53 patients with detailed data regarding neurological follow up and dose delivered to the cauda was available. Mean patient age was 43 years (range 6–79 years). 27 patients (51%) were male. Median follow-up was 87 months (range 14–217 months); 39 patients (71%) were followed for at least 5 years. Histology in all patients was reviewed at Massachusetts General Hospital. 66% of patients had either chordomas (18 patients) or another type of sarcoma (17 patients), 3 patients had giant cell tumors, and the other 15 patients had miscellaneous tumor types. Doses were defined in terms of CGE, Cobalt Gray Equivalents (CGE = proton Gy × RBE 1.1). Prescribed GTV doses ranged from 48.4 to 84.2 CGE. Median and mean GTV doses were 69.2 CGE and 69.5 CGE ± 7.64, respectively. Median and mean cauda doses were 67.5 CGE and 64.5 ± 13.3 CGE (38.8–84.2 CGE). Daily fraction size ranged from 1.8–2.24 CGE. Follow-up clinical data regarding tumor status and date of onset of neurological symptoms were obtained from patient charts, referring physicians, or by telephone contact with the patient or their relatives. Neurological symptoms developing in the absence of evident local failure were scored as radiation toxicity. No treatment failures occurred in 27 patients, 25 of whom were alive without evidence of disease (NED) at follow-up times ranging from 50 to 217 months. 26 patients had some type of failure, including 11 with local failure only (LF), 7 with distant failure only (DF), and 8 with both local and distant failure (LFsDF). Only 2, 3, and 3 patients were alive in the groups with LF, DF, or LFsDF respectively. Local recurrence free and disease free survival rates at 5 years were 72 ± 6 % and 75 ± 6 %, and at 10 years were 56 ± 8% and 48 ± 8% respectively. Thirteen patients experienced neurological sequelae in the absence of evident local failure. 10 had pain, numbness, and weakness and 3 had pain only. Using the LENT Scale for Peripheral Nerves, 4 patients had grade 4, 2 patients had grade 3, and 7 patients had grade 2 toxicity. Evident toxicity appeared in 7 patients (54%) at least 60 months after treatment. Median and mean cauda doses in patients with neurological toxicity were 75.4 CGE and 71.9 ± 11.1 CGE, respectively, and were 66 CGE and 62.1 ± 13.2 CGE in the remaining 40 patients without neurological toxicity (p = 0.02). In patients with neither neurological toxicity nor local failure, median cauda dose was 58.7 CGE and mean dose was 57.2 ± 12.3 CGE (p = 0.002). All grade 4 toxicities were associated with cauda doses greater than 75 CGE. The probability of surviving without neurological sequelae (whether from local failure or radiation toxicity) at 5 years was 59 ± 7% at 5 years and 33 ± 7% at 10 years. The probability of surviving without radiation sequelae in patients without local failure was 78 ± 7% at 5 years and 51 ± 11% at 10 years. This study demonstrates that the traditional milestone for defining tolerance at 5 years is not appropriate for the cauda equina, since over half of the late toxicities observed occurred at least that long after treatment. Very long follow-up is required in patients such as those reported here to accurately assess neurologic damage, and then to differentiate that phenomenon from local recurrence. Both local and distant failures remain issues for these patients, even with the radical doses used in this population. Patients treated to cauda doses above 70 CGE were at significantly increased risk of neurological toxicity, and above 75 CGE at risk of Grade 4 toxicity