(P 020) DEFINITIVE RADIATION THERAPY FOR EWING SARCOMA: TREATMENT AND TOXICITY OUTCOMES IN PATIENTS TREATED WITH DOSE ESCALATION APPROACHES

Author(s)

Taylor Weiskittlel, M.S. (she/her/hers)

MD PhD Candidate
Mayo Clinic
Rochester, Minnesota, United States

Co-Author(s)

WH

William S. Harmsen, N/A, M.S.

Principal Biostatistician
Mayo Clinic
Rochester, Minnesota, United States
AM

Anita Mahajan, MD (she/her/hers)

Professor - Department of Radiation Oncology
Mayo Clinic
Rochester, Minnesota, United States
Ivy A. Petersen, MD

Professor of Radiation Oncology
Mayo Clinic
Rochester, Minnesota, United States
Michael G. Haddock, MD

Consultant, Radiation Oncology
Mayo Clinic
Rochester, Minnesota, United States
Wendy Allen-Rhoades, MD, PhD

Assistant Professor
Mayo Clinic
Rochester, Minnesota, United States
SR

Steven I. Robinson, MBBS

Associate Professor of Oncology
Mayo Clinic
Rochester, Minnesota, United States
Nadia N. Laack, MD

Professor and Chair - Department of Radiation Oncology
Mayo Clinic
Rochester, Minnesota, United States
Safia K. Ahmed, MD

Assistant Professor - Department of Radiation Oncology
Mayo Clinic
Phoenix, Arizona, United States

Objective: Recent studies have demonstrated dose escalation for definitive radiation therapy (DE-RT) in Ewing sarcoma (ES) is associated with a lower risk of local recurrence. These studies used conventionally fractionated doses of 64.8 Gy to 70.2 Gy delivered over 7-8 weeks. Hypofractionation offers shorter treatment courses which is beneficial for patients. However, treatment and toxicity outcomes with hypofractionation in the setting of DE-RT for ES have not been described. We report treatment and toxicity outcomes in a cohort of ES patients treated with DE-RT, including hypofractionated DE-RT approaches.

Methods: A retrospective review of ES patients treated with RT to doses ≥55.8 Gy at Mayo Clinic between 2010 and 2018 was performed. Clinical and treatment data related to patient demographics, disease burden, overall treatment course, disease response, treatment plan parameters, and treatment-associated toxicities were abstracted. Overall survival (OS) was defined as standard and assessed using the Kaplan-Meier method. The cumulative incidence of local failure (LF) with death as a competing risk was calculated.

Results: The cohort consisted of 39 patients. Eighteen patients (46%) had metastatic disease at diagnosis. Median age was 23 years (range: 3-65). The most common primary tumor site was pelvis (46%) followed by axial skeleton (44%). Median greatest tumor dimension at diagnosis was 8.3 cm (range: 1.4-15.2). Nearly all patients (97%) received VDC/IE chemotherapy. Twenty-three patients (59%) received DE-RT, of which 17 received conventional fractionation and 6 hypofractionation. Proton therapy was utilized in 46% of patients. The median dose in non-DE-RT patients was 55.8 Gy delivered in 33 fractions (fx). For DE-RT, the median dose was 59.4 Gy (range: 56-62) with standard fractionation (median: 30 fx, range: 28-33), and 61.6 Gy (range: 56.2-66) with hypofractionation (median: 29 fx, range: 27-30 fx).With a median follow-up of 3.1 years (range: 0.4-9.7 years), the 5-year OS and LF for the entire cohort was 60.4% (95% CI, 40.8%-83.8%) and 20.9 (95% CI, 10.2-42.8), respectively. No factors correlated with OS or LF on univariate analysis except for metastases at diagnosis. The 5-year OS was 85.15% (95% CI, 64.96-100.0) and 35.02% (95% CI 12.80-76.36) for localized and metastatic patients respectively (p=0.0165). The cumulative incidence of local failure at 5 years was 6.25% (95% CI, 0.94-41.69) and 38.67% (95% CI, 19.45-76.86) for localized and metastatic patients (p=0.0654) (Fig 1). Though statistically not significant, the 5-year cumulative incidence LF was lower in patients treated with DE-RT at 13.1% (95% CI, 3.6%-47.6%) versus 31.0% for non-DE-RT (95% CI, 13.7%-69.8%, p=0.20). The 5-year OS was 46.0% (95% CI, 21.8%-89.6%) for non-DE-RT patients and 71.5% (95% CI, 47.1-100.0) for DE-RT patients (p=0.13). Target volume coverage, BED, and EQD2 was acceptable across all approaches (Table 1). Neither conventionally nor hypofractionated DE-RT approaches resulted in excessively high doses to organs at risk (Table 2). The toxicities were similar across radiation approaches (Table 3).

Conclusion: Though statistically not significant, DE-RT was associated with a lower LF incidence in our cohort (13.1%) compared to non-DE-RT (31.0%). Both conventionally fractionated and hypofractionated DE-RT approaches were associated with a similar toxicity profile as non-DE-RT without compromise in target volume coverage. This suggests DE-RT, including hypofractionated approaches, are safe and efficacious for ES patients treated with definitive radiation therapy and warrant further investigation.

	Non-dose Escalated	Dose Escalated Conventionally Fractionated	Dose Escalated Hypofractionated
GTV
Min. Dose (Gy)	48.09 (29.19-55.11)	51.08 (33.63-61.83)	51.42 (49.79-55.92)
V95% (%)	100 (97.7-100)	100 (99.9-100)	100 (96.8-100)
V99% (%)	100 (96.8-100)	100 (91.6-100)	99.2 (96.100)
V100% (%)	100 (95.8-100)	100 (78.1-100)	98.4 (95.9-99.99)

GTV Boost
Min. Dose (Gy)	53.77 (26.21-59.91)	54.69 (46.99-61.25)	59.96 (55.13-63.2)
V95% (%)	100 (100-100)	100 (95.5-100)	100 (100-100)
V99% (%)	100 (92.07-100)	100 (92-100)	100 (98-100)
V100% (%)	99.7 (88.2-100)	99.8 (90.1-100)	98.4 (96.4-100)
CTV
Min. Dose (Gy)	44.01 (24.24-50.62)	49.94 (36.84-56.35)	46.03 (27.96-52.35)
V95% (%)	100 (99.33-100)	100 (97.8-100)	99.99 (99.7-100)
V99% (%)	100 (98.87-100)	99.5 (84.1-100)	99.95 (88.7-100)
V100% (%)	100 (98.4-100)	99.3 (78-100)	99.67 (79.7-100)
CTV Boost
Min. Dose (Gy)	50.78 (36.86-59.9)	52.95 (45.21-61.25)	55.92 (51.04-59.96)
V95% (%)	100 (91.4-100)	100 (91.4-100)	100 (99.8-100)
V99% (%)	97.75 (84.5-100)	99.9 (66.5-100)	99.2 (98.8-100)
V100% (%)	96.56 (79.1-100)	99.3 (52.4-100)	98.4 (95-100)
PTV
Min. Dose (Gy)	45.19 (42.53-46.85)	44.16 (30.93-52.73)	40.48 (30.93-50.46)
V95% (%)	100 (97-100)	100 (97.5-100)	99.76 (99.39-99.93)
V99% (%)	99.5 (98.52-100)	99.44 (93-100)	98.74 (98.2-99.92)
V100% (%)	97.4 (92.8-100)	97.86 (92.7-100)	97.86 (96.54-99.07)
PTV Boost
Min. Dose (Gy)	49.20 (44.44-57.99)	52.92 (31.16-59.81)	53.46 (51.81-57.09)
V95% (%)	100 (97.2-100)	100 (88.5-100)	99.9 (99.8-100)
V99% (%)	99.3 (94.71-99.8)	99.31 (78.7-100)	97.3 (95.8-99.6)
V100% (%)	97.02 (90.9-98.7)	98.15 (74.6-100)	95 (89.8-98.2)
EQD2 (α/β =10) i.e. acute effects	57.82 (54-58.77)	58.41 (56-62)	62.24 (56.53-67.1)
BED (α/β =10) i.e. acute effects	69.38 (64.8-70.52)	70.09 (67.2-74.4)	74.69 (67.84-80.52)
EQD2 (α/β =3) i.e. late effects	56.45 (54-58.72)	57.72 (55.15-62)	63.14 (57.06-68.64)
BED (α/β =3) i.e. late effects	94.08 (90-97.86)	96.2 (91.92-103.33)	105.22 (95.1-114.4)

Site	Non-dose Escalated	Dose Escalated	Dose Escalated Hypofractionated
Bladder
Mean (cGy)	1215.2 (0-4556.1)	1056.5 (0.5-3038)	386.3 (0.5-2704.9)
Max (cGy)	4790.5 (0-6059.7)	3924.7 (338.6-5901.9)	1187.25 (29-5549.3)
Rectum
Mean (cGy)	2439.9 (1010.7-4818.2)	1289.65 (410.7-3641.8)	1796 (1698.2-1893.8)
Max (cGy)	5677.2 (4431.3-6069.7)	5490.3 (3012.9-6247.2)	5885.7 (5729.7-6041.7)
Colon
Mean (cGy)	854.6 (0.3-1854)	2205.15 (266.2-3197.3)	1632.3 (12.8-2412.5)
Max (cGy)	4766 (65.9-5879.6)	5947 (2257.6-6541.7)	5388.5 (3540.8-6610.1)
Spinal Cord
Mean (cGy)	715.6 (12.6-3884.9)	4584 (78.4-5136.6)	1059.6 (821.9-1297.3)
Max (cGy)	3480 (10-5373.8)	5614.9 (0-5879.9)	2629.8 (1787.5-3472.1)
Femoral Head
Mean (cGy)	892.6 (0-5537.9)	730.9 (0.3-2780)	455.2 (0-1011)
Max (cGy)	3383.4 (0-5344.4)	3197.1 (38.1-5578)	1047.2 (0-5002.2)
Sacral Plexus
Mean (cGy)	2723.9^*	2112.55 (74.3-4150.8)	3517.4^*
Max (cGy)	5615.6^*	6029.5 (2219.7-6112)	6452.5^*
Brachial Plexus
Mean (cGy)	3426.55 (1033.3-5393.1)	5514.3^*	2935.9^*
Max (cGy)	5286.5 (3364.2-5903.5)	6006.8 (5793-6220.6)	5947.3^*
Small Bowel
Mean (cGy)	477.6 (0-2527.2)	1458.55 (1.2-1720.3)	1930.9 (0-2725.2)
Max (cGy)	4722.6 (0-5597)	4928.9 (726.1-5896)	5301.6 (0-5743.4)
v50 Gy (cc)	0 (0-37.0174)	0.9554 (0-38.1339)	1.33245 (0-9.8225)
v52 Gy (cc)	0 (0-23.4306)	0 (0-33.3595)	0.01345 (0-3.6749)
v54 Gy (cc)	0 (0-9.8822)	0 (0-27.3472)	0 (0-1.0948)

Grade	Event	Age	Location	Size, cm	Radiation Dose (Gy)	Fraction Size	Fraction Number
II	Dermatitis	8	Infratemporal Region	8.3	55.8	1.8	31
II	Dermatitis	31	Cervical Spine	4.8	55.8	1.8	31
II	Oral Mucositis	9	Infratemporal Region	8.3	55.8	1.8	31
II	Oral Mucositis	65	Maxillary Sinus	4	55.8	1.8	31
II	Esophagitis	18	Scapula	NA	55.8	1.8	31
II	Esophagitis	31	Cervical Spine	4.8	55.8	1.8	31
II	Diarrhea	30	Low Pelvis	10.1	55.8	1.8	31
II	Dermatitis	16	Pubis and Ischium	8.7	56	2	28
II	Dermatitis	19	Sacrum	NA	59.4	1.8	33
II	Dermatitis	45	Calf	3.4	60	2	30
II	Diarrhea	28	Sacrum	10.5	56	2	28
II	Diarrhea	37	Retroperitoneal Pelvis	8.3	60	2	30
II	Diarrhea	57	Sacrum	4.7	66	2.2	30
III	Osteonecrosis	31	Ilium	NA	60.2	2.15	28
IV	Acute Myeloid Leukemia	31	Paraspinal	4.6	55.8	1.8	31
IV	Myelodysplastic Syndrome	17	Pubis and Ischium	8.7	56	2	28