Prognostic factors for spinal chordomas and chondrosarcomas treated with postoperative pencil-beam scanning proton therapy: a large, single-institution experience.

OBJECTIVE: The aim of this paper was to evaluate the prognostic factors in surgical and adjuvant care for spinal chordomas and chondrosarcomas after surgery followed by high-dose pencil-beam scanning proton therapy (PBS-PT). METHODS: From 1997 to 2016, 155 patients (61 female patients; median age 55 years) with spinal (cervical, n = 61; thoracic, n = 29; lumbar, n = 13; sacral, n = 46; pelvic, n = 6) classic chordomas (n = 116) and chondrosarcomas (n = 39; most were low grade) were treated with maximal safe resection followed by PBS-PT (median dose prescribed: 74 Gy [relative biological effectiveness], range 48.6-77 Gy). The majority of patients (n = 153, 98.7%) had undergone at least 1 resection prior to PBS-PT (median 1, range 0-5; biopsy only, n = 2). Fewer than half (45.1%) of the surgeries were rated as gross-total resections (GTRs) prior to PBS-PT. Surgical stabilization (SS) was present in 39% of all patients (n = 60). Ninety-one patients (59%) presented with macroscopic tumor at the start of PBS-PT. The median follow-up duration was 64.7 months (range 12.2-204.8 months). RESULTS: The 5-year local tumor control, disease-free survival (DFS), and overall survival were 64.9% (95% CI 56.3%-73.5%), 59.4% (95% CI 50.6%-68.2%), and 77.9% (95% CI 70.6%-85.2%), respectively. In total, 63 patients (40.6%) experienced failure during the follow-up period: local only in 32 (20.6%), distal only in 7 (4.5%), local + distal in 19 (12.3%), surgical pathway failure (SPF) only in 2 (1.3%), local + SPF in 2 (1.3%), and distal + SPF in 1 (< 1%). Univariate analysis identified gross residual disease, the presence of SS, and treatment era prior to 2008 as highly significant for worse outcome, with all 3 remaining significant on multivariate analysis. The type of surgery (GTR or subtotal resection/biopsy) and whether GTR was achieved by en bloc or curettage did not show a significant prognostic effect. Surgical complications prior to PBS-PT were present in 42.5% of all surgically treated patients and were seen more commonly in patients with multiple surgical interventions (p = 0.005) and those operated on with the intent of en bloc resection (p = 0.006). CONCLUSIONS: The extent of resection and metallic stabilization substantially influenced clinical outcomes for patients with spinal chordoma or chondrosarcoma despite high-dose adjuvant PBS-PT. Optimal upfront surgical management of these tumors continues to include GTR, as possible, with prompt adjuvant proton therapy.

Long-Term Outcomes and Prognostic Factors After Pencil-Beam Scanning Proton Radiation Therapy for Spinal Chordomas: A Large, Single-Institution Cohort.

PURPOSE: To evaluate the efficacy and safety of high-dose pencil-beam scanning proton therapy (PBS-PT) in the adjuvant treatment of spinal chordomas. METHODS AND MATERIALS: Between 1997 and 2015, 100 patients with spinal chordomas (median age, 56 years; range, 25-81 years) were treated with adjuvant PBS-PT at the Paul Scherrer Institute: cervical (n = 46), thoracic (n = 4), lumbar (n = 12), and sacral (n = 38). The majority (88%) received PBS-PT alone rather than combined photon-proton therapy. The median radiation therapy dose prescribed was 74 Gy (relative biological effectiveness [RBE]) (range, 59.4-77 Gy [RBE]). Thirty-nine patients (39%) had undergone surgical stabilization, primarily with titanium hardware, before radiation therapy. RESULTS: With a median follow-up of 65 months (range, 13-175 months), 5-year local control, disease control, and overall survival rates were 63% (95% confidence interval [CI] 57.7-68.7%; median, 103 months), 57% (95% CI 50.9-62.1%; median, 82 months), and 81% (95% CI 76.8-85.6%; median, 157 months), respectively. On univariate and multivariate analyses, the presence of surgical stabilization was highly prognostic for worsened outcomes. Multivariate analysis also revealed the extent of treatment volumes and presence of gross residual disease to be important in predicting outcomes. High-grade (grade ≥3) toxicities were rare in both the acute (8%) and late (6%) settings. CONCLUSION: For spinal chordomas, PBS-PT remains a highly effective and safe method for delivery of dose-escalated adjuvant radiation therapy. The presence of metallic surgical stabilization prognosticates for worsened outcomes. Further investigation is warranted to characterize ideal treatment volumes and effect of surgical stabilization on therapy for these challenging tumors.

Long-Term Clinical Safety of High-Dose Proton Radiation Therapy Delivered With Pencil Beam Scanning Technique for Extracranial Chordomas and Chondrosarcomas in Adult Patients: Clinical Evidence of Spinal Cord Tolerance.

PURPOSE: To assess the radiation dose tolerance of the spinal cord by reviewing our institutional experience regarding the incidence of radiation-induced spinal cord toxicity after high-dose pencil beam scanning proton therapy (PBSPT). METHODS AND MATERIALS: Seventy-six patients (median age 53 years; range, 23-79 years) treated for spinal chordoma (n=55) or chondrosarcoma (n=21) met the following criteria and were retrospectively analyzed: PBSPT only, no reirradiation or concomitant chemotherapy, maximum dose (Dmax) to the spinal cord of ≥45 Gy(relative biological effectiveness [RBE]), ≥18 years of age, and follow-up of ≥12 months. The delivered dose was 59.4 to 75.2 Gy(RBE) [median 73.9 Gy(RBE)] delivered with conventional fractionation between 2000 and 2014. The Dmax, D2%, and V40-V60 of the surface (sSC) and center (cSC) of the spinal cord were recorded. Toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: Median follow-up was 65.5 months (range, 13-173 months). Patients received a mean Dmax and D2% to the sSC of 59.0 (median 58.7; range, 48.3-75.9) and 55.3 (median 52.7; range, 43.1-73.8) Gy(RBE), respectively. The corresponding values for the cSC were 52.3 (median 52.7; range, 32.3-73.3) and 51.1 (median 52.0; range, 25.3-73.1) Gy(RBE), respectively. Four patients (5%) developed acute radiation-induced neurotoxicity (grade [G] 1, n=1; G2, n=3). Twelve patients (16%) experienced late neurologic toxicities (G1, n=7; G2, n=4; G4, n=1). One patient with a history of pre-PBSPT symptomatic spinal cord compression redeveloped tetraplegia (G4) after receiving a Dmax of 57.8 Gy(RBE) to the sSC and 54.1 Gy(RBE) to the cSC. No significant correlation was found between sSC Dmax and D2%, cSC Dmax and D2%, or the length of CTV and toxicity. CONCLUSIONS: High-dose conformal PBSPT may be delivered safely in close proximity to the spinal cord with minimal neurotoxicity. Dose constraints of 64 Gy(RBE) as D2% for the sSC and 54 Gy(RBE) for the cSC seem appropriate for clinical use.

Long-Term Clinical Outcomes of Pencil Beam Scanning Proton Therapy for Benign and Non-benign Intracranial Meningiomas.

PURPOSE: To assess and report long-term clinical outcomes regarding local control, overall survival, and toxicity-free survival after pencil beam scanning proton therapy for intracranial meningiomas at a single institution. PATIENTS AND METHODS: Ninety-six patients (male/female, 29/67; median age 52.8 years) with intracranial meningiomas (World Health Organization [WHO] grade 1, n=61 [63.5%]; WHO grade 2, n=33 [34.4%]; WHO grade 3, n=2 [2.1%]) were treated with pencil beam scanning proton therapy (n=53 [55.2%] at diagnosis, n=17 [17.7%] at recurrence, and n=26 [27.1%] for tumor progression). Median gross tumor volume before PBSPT was 21.4 cm3 (range, 0.0-546.5 cm3), with a median planning target volume of 123.4 cm3 (range, 4.6-1142.0 cm3). Median duration of follow-up was 56.9 months (range, 12.1-207.2 months). Late toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Thirteen failures (14%) (male/female, 6/7) were observed, of which the majority (n=9, 69%) were of non-benign histology. The 5-year actuarial local control and overall survival were 86.4% and 88.2%, respectively. Five-year grade ≥3 toxicity-free survival was 89.1%. On univariate analysis, local control was worse for patients with higher WHO grade (P≤.001), those treated after at least 1 recurrence (P=.006), those with non-skull base tumor location (P=.014), and males (P=.032). Significant prognosticators for 5-year overall survival were local control (P≤.001), age (P=.002), and timing of proton therapy (initial vs recurrence) (P=.002). CONCLUSIONS: Pencil beam scanning proton therapy is an effective and safe treatment for patients with intracranial meningiomas, resulting in high local control rates with limited toxicity. Up-front radiation likely results in improved outcomes and should be considered, especially for patients with non-benign tumors and/or for those with incomplete resections.

Effect of Anatomic Changes on Pencil Beam Scanned Proton Dose Distributions for Cranial and Extracranial Tumors.

PURPOSE: To estimate the frequency and impact of anatomic changes on the delivered dose in pencil beam scanning proton therapy, to assess the need for repeat CT scanning and adaptive replanning. METHODS AND MATERIALS: A total of 730 patients treated at Paul Scherrer Institut between 2007 and 2014 were included in this study, for which the number of patients who had control CT scans and who were replanned as a result of anatomic changes was analyzed. For those that were replanned, the nominal dose distributions (originally optimized on the planning CT scan) were recalculated on the replanning CT scan and differences evaluated using standard dose metrics for planning target volumes and clinical target volumes and organs at risk (OARs). RESULTS: Control CT studies were acquired for 244 patients (33.5%), and replanning was deemed clinically necessary for 40 (16%) of these (5.5% of the total cohort). The OARs and target dose differences between the nominal and recalculated dose distributions were found to be strongly dependent on the subgroup of patients. Nevertheless, dose differences were found to be ≤ 5% for 88% of all analyzed OARs, and planning target volume/clinical target volume V95% was reduced by ≤5% in 87%/90% of cases. CONCLUSIONS: Despite anatomic variations, clinically delivered plans have been found to be robust to anatomic changes, with replanning being deemed necessary in only a small number of cases. However, because the dosimetric effect of such changes can be quite large for some cases, they have to be monitored and evaluated on an individual basis.

Dose to the developing dentition during therapeutic irradiation: organ at risk determination and clinical implications.

PURPOSE: Irradiation of pediatric facial structures can cause severe impairment of permanent teeth later in life. We therefore focused on primary and permanent teeth as organs at risk, investigating the ability to identify individual teeth in children and infants and to correlate dose distributions with subsequent dental toxicity. METHODS AND MATERIALS: We retrospectively reviewed 14 pediatric patients who received a maximum dose >20 Gy(relative biological effectiveness, RBE) to 1 or more primary or permanent teeth between 2003 and 2009. The patients (aged 1-16 years) received spot-scanning proton therapy with 46 to 66 Gy(RBE) in 23 to 33 daily fractions for a variety of tumors, including rhabdomyosarcoma (n=10), sarcoma (n=2), teratoma (n=1), and carcinoma (n=1). Individual teeth were contoured on axial slices from planning computed tomography (CT) scans. Dose-volume histogram data were retrospectively obtained from total calculated delivered treatments. Dental follow-up information was obtained from external care providers. RESULTS: All primary teeth and permanent incisors, canines, premolars, and first and second molars were identifiable on CT scans in all patients as early as 1 year of age. Dose-volume histogram analysis showed wide dose variability, with a median 37 Gy(RBE) per tooth dose range across all individuals, and a median 50 Gy(RBE) intraindividual dose range across all teeth. Dental follow-up revealed absence of significant toxicity in 7 of 10 patients but severe localized toxicity in teeth receiving >20 Gy(RBE) among 3 patients who were all treated at <4 years of age. CONCLUSIONS: CT-based assessment of dose distribution to individual teeth is feasible, although delayed calcification may complicate tooth identification in the youngest patients. Patterns of dental dose exposure vary markedly within and among patients, corresponding to rapid dose falloff with protons. Severe localized dental toxicity was observed in a few patients receiving the largest doses of radiation at the youngest ages; however, multiple factors including concurrent chemotherapy confounded the dose-effect relationship. Further studies with larger cohorts and appropriate controls will be required.

Temporal lobe toxicity analysis after proton radiation therapy for skull base tumors.

PURPOSE: Temporal lobe (TL) parenchyma toxicity constitutes one of the most frequent late adverse event in high-dose proton therapy (PT) for tumors of the skull base. We analyzed clinical events with dosimetric parameters in our patients treated for skull base tumors with spot-scanning PT. METHODS AND MATERIALS: Between 1998 and 2005, a total of 62 patients received PT to a median dose of 71.7 Gy (relative biologic effectiveness [RBE]) (range, 63-74 Gy). The dose-volume histogram of each TL and the entire brain parenchyma (BP) were analyzed according to maximum, mean, and minimum dose as well as doses to 0.5, 1, 2, and 3 cc of brain volume (D(0.5), D(1), D(2), D(3)) and correlated with clinical events. Generalized equivalent uniform dose (gEUD) values were calculated. RESULTS: At a mean follow-up of 38 months (range, 14-92 months), 2 patients had developed symptomatic Grade 3 and 5 patients asymptomatic Grade 1 TL toxicity. Mean doses to a 2-cc volume of BP increased from 71 ± 5 Gy (RBE) for no toxicity to 74 ± 5 Gy (RBE) for Grade 1 and to 76 ± 2 Gy (RBE) for Grade 3 toxicity. TL events occurred in 6 of 7 patients (86%) at or above dose levels of ≥ 64 Gy (RBE) D(3), ≥ 68 Gy (RBE) D(2), ≥ 72 Gy (RBE) D(1), and ≥ 73 Gy (RBE) D(0.5), respectively (p = NS). No statistically significant dose/volume threshold was detected between patients experiencing no toxicity vs. Grade 1 or Grade 3. A strong trend for Grade 1 and 3 events was observed, when the gEUD was 60 Gy. CONCLUSIONS: A statistically significant normal tissue threshold dose for BP has not been successfully defined. However, our data suggest that tolerance of TL and BP to fractionated radiotherapy appears to be correlated with tissue volume included in high-dose regions. Additional follow-up time and patient accrual is likely needed to achieve clinical significance for these dose-volume parameters investigated. Our findings support the importance of establishing an organ-at-risk maximally permissible dose for BP.

Long-term outcome after static intensity-modulated total body radiotherapy using compensators stratified by pediatric and adult cohorts.

PURPOSE: To report the long-term outcome after total body irradiation with intensity-modulating compensators and allogeneic/autologous transplantation, especially in terms of therapy-related toxicity in pediatric and adult cohorts. METHODS AND MATERIALS: A total of 257 consecutive patients (40 children and 217 adults) have been treated since 1983 with TBI using static intensity-modulated radiotherapy for hematologic malignancies. The total dose of 12 Gy was applied in six fractions within 3 days before allogeneic (n = 174) or autologous (n = 83) transplantation. The median follow-up was 9.2 years. RESULTS: The 5-year overall survival rate was 47.9% (49.8% for the adults and 37.5% for the children, p = 0.171). The 5-year tumor-related mortality rate was 23%, and the 5-year treatment-related mortality rate 29.2% (29.5% in the adults and 27.5% in the pediatric patients). Interstitial pneumonitis developed in 28 (10.9%) of 257 patients and in 12.5% of the pediatric cohort. The interstitial pneumonitis rate was 25% in pediatric patients treated with a 12-Gy lung dose compared with 4.2% for those treated to an 11-Gy lung dose. The overall survival rate stratified by lung dose was 26.7% for 12 Gy and 52.4% for 11 Gy (p = 0.001). The incidence of veno-occlusive disease and cataract was 5.8% and 6.6% in all patients and 12.5% and 15% in the pediatric patients, respectively (p < 0.05). Secondary malignancies were found in 4.3% of all patients, all in the adult cohort at transplantation. CONCLUSION: Static intensity-modulated total body irradiation with a total dose of 12 Gy before allogeneic/autologous transplantation is a successful treatment with good long-term outcome and acceptable therapy-related toxicities. Constraining the lung dose to 11 Gy substantially lowered the actuarial treatment-related mortality. This effect was especially striking in the pediatric patients.

20 years of experience in static intensity-modulated total-body irradiation and lung toxicity. Results in 257 consecutive patients.

PURPOSE: To analyze lung complications after allogeneic or autologous transplantation following total-body irradiation (TBI) with compensators, so-called sIMRT (static intensity-modulated radiotherapy). PATIENTS AND METHODS: Between 1983 and 1998, 257 patients with different hematologic malignancies underwent TBI in six fractions to a total dose of 12 Gy within 3 consecutive days (212 with 11 Gy lung dose) prior to allogeneic (n=174) or autologous (n=83) transplantation. 40 patients were <16 years of age. Minimum follow-up time was 5 years. Median follow-up period was 110 months (13-231 months). RESULTS: 5-year survival rate was 47.9%, 5-year tumor-related mortality 23%, 5-year treatment-related mortality 29.2% (12 Gy lung dose: 53.3%+/-14.6%, 11 Gy: 24.1%+/-5.7%). Interstitial pneumonitis (IP) developed in 28 of 257 patients (10.9% +/- 3.8%). IP incidences in the allogeneic and autologous groups were 14.4% (+/-5.6%) and 3.6% (0-7.6%), respectively. IP incidences with 12/11 Gy lung dose were 22% (+/-12%)/8.5% (+/-3.7%). IP mortality was 9.3% (+/-3.6%). 13 of 28 patients with IP had a cytomegalovirus infection, five an acute graft-versus-host disease grade IV of the lungs. IP incidences with 12/11 Gy lung dose were 25% (9-50%)/4.2% (0.2-19.1%) in patients <16 years, and 20.7% (9.4-37.4%) and 13.3% (+/-6.5%) in older patients after allogeneic transplantation. CONCLUSION: Compensator-generated static intensity-modulated TBI with a total dose of 12 Gy and a lung dose of 11 Gy is a modern and comfortable treatment with moderate lung toxicity, small dose inhomogeneities and little setup failure before transplantation. Especially patients <16 years of age benefit from lung dose reduction.