High-dose chemotherapy with autologous stem cell rescue in children and young adults with high-risk Ewing sarcoma

Abstract

Background:

A combination treatment of surgery, chemotherapy, and radiotherapy can improve the survivals of pediatric patients with Ewing sarcoma (ES). However, prognosis remains poor for patients with metastatic disease at diagnosis or recurrence. Other high-risk (HR) features include large tumor burden, tumors of the axial skeleton, and poor histologic response. Several studies have documented high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) to be effective in such patients. In this retrospective study, we present the results of HDC-ASCR for high-risk ES (HRES) in children and young adults in a single institute.

Methods:

From March 2004 to March 2021, patients with ES, Ewing-like sarcoma, or round cell sarcoma received HDC-ASCR as part of treatment were included. The patients’ characteristics, disease status, stem cell dose, engraftment status, post-transplant complications, and outcomes were analyzed.

Results:

Twenty patients receiving HDC-ASCR at complete response (n = 6), partial response (n = 13), and stable disease (n = 1) were enrolled. The male-to-female ratio was 11:9. Median age at diagnosis and transplant was 15.6 years old (range: 3.3-28.9) and 16.2 (range: 4.2-29.9), respectively. The conditioning regimens included ifosfamide-based in two and melphalan-based in 19. All patients achieved successful engraftment without transplant-related mortality. The 5-year progression-free and overall survival (OS) rate were 35% and 54.5%, respectively. The causes of death (n = 8) were all contributed to disease progression. Patients in the complete response group or with localized HRES exhibited a higher 5-year OS (p = 0.047 and 0.05, respectively). Compared with the historical cohort without HDC-ASCR as part of primary treatment, the current cohort had a significantly better 5-year OS (p = 0.018).

Conclusion:

HDC-ASCR seems promising as an alternative treatment for HRES in improving OS in this retrospective study with a limited case number.

1. INTRODUCTION

The Ewing sarcoma family of tumors (ESFT) are rare malignant diseases that can originate from bone or soft tissue. ESFT mostly affects children, adolescents, and young adults. Among individuals in these age groups, ESFT is the second most common type of bone cancer.^1,2 Standard treatment for ESFT is multimodal therapy comprising surgery, chemotherapy, and radiotherapy. Our previous study reported a very poor 5-year overall survival (OS) of 18.8% in metastatic patients with Ewing sarcoma (ES) and an OS of 61.6% in nonmetastatic patients.³ Studies have identified poor histologic response after neoadjuvant chemotherapy, tumor over the axial site, and a large tumor volume at initial diagnosis as risk factors for prognosis.^4–6 In addition, patients with recurrent ES responded poorly to conventional salvage treatment.⁷ Those patients with any of these poor prognostic features or recurrences were regarded as high-risk Ewing sarcoma (HRES).

The optimal treatment strategy for HRES patients was challenging. High-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) as consolidative treatment has been applied to various solid tumors with success.^8,9 Several studies conducted in Western countries have revealed that HDC with ASCR can improve HRES outcomes.^10,11 Karadurmus et al¹² reviewed the role of HDC-ASCR in the treatment of ES. The conclusion he made was that HDC-ASCR may be beneficial in some subgroups, including children with partial response (PR) to conventional chemotherapy, with poor risk as well as metastatic ES, and it remains as a clinical option.¹² However, few studies have investigated the impact of HDC-ASCR on HRES in Asian countries. In this study, we retrospectively evaluated the safety and the efficacy of HDC-ASCR in ESFT patients at our institute in Taiwan.

2. METHODS

2.1. Patients

From March 2004 to March 2021, we enrolled patients diagnosed with ES, Ewing-like sarcoma, or round cell sarcoma who had received HDC-ASCR as consolidation treatment at the Division of Pediatric Hematology/Oncology of Taipei Veterans General Hospital (TPVGH). The cutoff date for data analyses was June 2024. The study was approved by the Institutional Review Board (IRB) of the study hospital (TPVGH-IRB 2022-11-002BC). A waiver of documentation for signed informed consent was also granted by the IRB.

2.2. Clinical staging and follow-up

We recorded the complete medical history of all enrolled patients at initial diagnosis. Before treatment initiation, during, and after treatment, they received several examinations every 3 months until 2 years after treatment completion. The examinations included magnetic resonance imaging of the primary site to define local conditions; computed tomography of the chest to detect lung metastasis; and diagnostic nuclear medicine imaging, either bone scintigraphy, Gallium-67 tumor survey, or whole-body positron emission tomography, to identify any bone or soft tissue metastasis. All patients underwent pathological confirmation.

2.3. Pretransplant treatment

All patients received conventional chemotherapy comprising multiple cycles where vincristine, doxorubicin, and cyclophosphamide (VDC) and ifosfamide and etoposide (IE) are administered alternatively. Informed consent for chemotherapy was obtained from every patient or patient’s legal guardian before treatment. The chemotherapy protocols were reviewed and approved by the Cancer Treatment Quality Monitoring Board of TPVGH.

After neoadjuvant chemotherapy, orthopedic surgeons conducted primary tumor removal with the goal of complete resection in accordance with the recommendations of a multidisciplinary tumor board. Radiotherapy was performed postoperatively over the primary site when the surgical margin was pathologically unclear or considered inadequate by the principal surgeon. The metastasis sites were resected when possible or irradiated lesions made the surgical approach difficult. For recurrent patients, salvage conventional chemotherapy might include (1) cyclophosphamide plus topotecan, (2) irinotecan, temozolomide plus vincristine, (3) docetaxel plus gemcitabine, or (4) ifosfamide, carboplatin plus etoposide for several cycles alternatively, combining local treatment with either maximal surgical resection if possible or/and radiotherapy based on physicians’ decision to achieve second partial or complete response (CR) before HDC.

2.4. HDC with ASCR

Patients who had a diagnosis of HRES through the identification of risk factors such as poor histologic response after neoadjuvant chemotherapy, tumor over axial site, large tumor volume at initial diagnosis and recurrence, were suggested HDC-ASCR as a consolidation treatment. The decision on whether to perform HDC-ASCR was determined through multidisciplinary team discussions that centered on the patient’s willingness for treatment and clinical condition and the eligibility of the treatment for reimbursement under Taiwan’s National Health Insurance System. Before transplant, patients underwent screening for hepatitis B and C serology. Additionally, they underwent baseline assessments including a 24-hour urine creatinine clearance test, pulmonary function test, electrocardiogram, and echocardiogram. We mobilized patients’ peripheral blood stem cells after conventional chemotherapy, either VDC or IE, followed by Granulocyte-colony stimulating factor (G-CSF) at a dose of 6 to 10 µg/kg/d for 3 to 5 days and harvested stem cells on 3 consecutive days once preharvest hematopoietic precursor cell count ≥20/μL and white blood cell (WBC) count ≥3000/μL were achieved.

The conditioning regimens included a melphalan-based regimen with or without total body irradiation or ifosfamide-carboplatin-etoposide. We infused hematopoietic stem cells containing ≥2 × 10⁶ CD34⁺ cells/kg on day 0. During transplant, patients received antibiotic prophylaxis including levofloxacin, micafungin, and metronidazole. They were isolated in a room from day −10 until the date of engraftment. We regularly performed complete cell count monitoring. Neutrophil engraftment is defined as the consecutive occurrence of absolute neutrophil count exceeding 500/µL for 3 consecutive days, and platelet engraftment is determined by the date when the platelet count independently exceeds 20,000/µL for seven consecutive days, regardless of transfusion.

2.5. Data collection

We conducted a retrospective chart review to evaluate patient characteristics, disease status before transplant, stem cell dose, number of transplants, conditioning regimens, engraftment, post-transplant complications, and outcomes.

2.6. Statistics

OS was defined as the time from the transplant (day 0) to either the date of death or final patient contact. Progression-free survival (PFS) was measured from day 0 of the transplant to the occurrence of disease progression, recurrence, death, or final patient contact. The OS and PFS curves were estimated according to the Kaplan–Meier method and compared using the log-rank test. A two-sided p value of <0.05 was defined as statistically significant. SPSS (version 25) software was used for data analyses.

3. RESULTS

3.1. Patient characteristics

Twenty patients received HDC-ASCR treatment between March 2004 and March 2021; their characteristics are listed in Table 1. Among these patients, 11 male and 9 female patients received a diagnosis at the median ages of 15.6 years (range: 3.3-28.9 years) and 16.2 years (range: 4.2-29.9 years), respectively. The median interval between diagnosis to first HDC was 8.7 months (range: 5.7-77.3). Of the patients, 16 (80%) had ES, two (10%) had Ewing-like sarcoma, and two (10%) had round-cell sarcoma. The most common tumor site was the pelvic bone (n = 11). In total, 14 patients (70%) had metastatic disease at diagnosis, and 16 patients (80%) received adjuvant radiotherapy before HDC. CR was achieved before first HDC in six patients (30%); PR in 13 (65%), including four who achieved a second partial response (PR2) after salvage treatment for recurrent disease; and stable disease (SD) in one (5%).

Table 1.

Patient characteristics

Characteristics	Patients (n = 20)
Gender (male:female)	11:9
Median age at diagnosis, y (range)	15.6 (3.3-28.9)
Median age at first HDC, y (range)	16.2 (4.2-29.9)
Interval between diagnosis to first HDC, mo (range)	8.7 (5.7-77.3)
Diagnosis
Ewing sarcoma	16
Ewing-like sarcoma	2
Round cell sarcoma	2
Primary tumor site
Pelvic bone (including sacrum)	11(1)
Bone of extremities	4
Spine or skull	3
Mediastinum	2
Metastases at diagnosis	14
Lung only	6
Bone only	4
Others	4
RT exposure before HDC	16
Disease status before first HDC
Complete response	6
Partial response 1	9
Partial response 2	4
Stable disease	1
Times of transplant
1	19
Tandem	1
Conditioning regimen (n = 21)
Busulfan-melphalan	9
Melphalan-carboplatin-etoposide	6
Total body irradiation-melphalan-etoposide	4
Ifosfamide-carboplatin-etoposide	2
Median follow-up duration, y (range)	3.5 (0.5-13.7)

HDC = high-dose chemotherapy; RT = radiotherapy.

3.2. HSCT details and complications

Nineteen patients received one HDC-ASCR, and the single remaining patient received tandem transplants. Among the 21 transplants, nine cycles of busulfan-melphalan (Bu-Mel), six cycles of melphalan-carboplatin-etoposide, four cycles of total body irradiation-melphalan-etoposide, and two cycles of ifosfamide-carboplatin-etoposide were used as conditioning regimens. Table 2 lists the treatment details of the patients and their outcomes. The median infused CD34⁺ cell dose was 5.2 × 10⁶/kg (range, 0.5-37.3 × 10⁶/kg). There was only one patient receiving the cell dose less than 2 × 10⁶/kg due to clinical decision. The median time for neutrophil engraftment was 11 days (range, 8-19 days), and the median time for platelet engraftment was 16 days (range, 10-31 days). Engraftment was successful in all patients.

Table 2.

Summary of transplant details and patient outcomes

Patient no.	Age at diagnosis (y)		Gender	Primary site	Interval between Dx to first HDC (mo)	Indication for HDC	Disease and status before first HDC	Conditioning regimen	PFS (y)	OS (y)	Salvage treatment	Response after salvage treatment	Current disease status
1	15.8		M	Pelvis	10.9	Metastasisa	ES/PR1	Ifos-Carbo-VP16	0.2	0.5	TIP, R/T	Refractory	DOD
2	15.8		M	Pelvis	6.2	Metastasisa	ES/CR1	TBI-Mel-VP16	13.7+	13.7+	-	-	NED
3	8.9		F	C spine	6	Axial sitea	ES/PR1	TBI-Mel-VP16	11.7+	11.7+	-	-	NED
4	15.4		F	Pelvis	8	Metastasisa	ES/PR1	Mel-Carbo-VP16	0.4	1.0	Gemcitabine, R/T	Refractory	DOD
5	21.4		F	Pelvis	5.7	Metastasisa	ES/PR1	TBI-Mel-VP16	0.7	2.4	Robatumumab, Temozolomide, R/T, ICE	Refractory	DOD
6	25.1		F	Pelvis	6.1	Metastasisa	ES/SD	TBI-Mel-VP16	0.2	0.6	R/T, TC, GGT, BEP	Refractory	DOD
7	23.3		M	Pelvis	6.4	Metastasisa	ES/CR1	Mel-Carbo-VP16	9.8+	9.8+	-	-	NED
8	4.2		F	Fibula	77.3	Recurrence	ES/PR2	Mel-Carbo-VP16	1.0	3.5	R/T, TC, IE, VI(T), VActDC	Refractory	DOD
9	23.7		M	Sacrum	45.3	Recurrence	ES/PR2	Mel-Carbo-VP16	0.7	4.7	IE, VActDC, VI(T), bevacizumab, TC, GD	Refractory	DOD
10	4.1		F	Pelvis	9.5	Metastasisa	ES/PR1	Mel-Carbo-VP16	2.2	6.3+	OP, R/T, VIT, GGT	CR	NED
11	22.5		M	T spine	13.6	Axial sitea	ES/PR1	Mel-Carbo-VP16	1.0	6.1+	ICE, R/T, OP, TC, GD, pazopanib, VIT, regorafenib, cabozantinib	SD	AWD
12	3.8		F	Femur	50.1	Recurrence	ES/PR2	Bu-Mel	2.5	5.5+	OP, GGT, R/T	CR	NED
13	3.3		M	Pelvis	10.3	Metastasisa	ES/PR1	Bu-Mel	0.2	0.5	R/T, ICE, GGT, TC	Refractory	DOD
14	21.5		M	Pelvis	7.6	Axial sitea	ES/CR1	Bu-Mel	4.1+	4.1+	-	-	NED
15	8.4		M	Radius	23.4	Recurrence	ES/PR2	Bu-Mel	0.3	1.0	IE, GGT, TC, R/T, VIT, pazopanib	Refractory	DOD
16	8.0		M	Mediastinum	6.6	Partial resectiona	RCS/PR1	Bu-Mel	4.1+	4.1+	-	-	NED
17	28.9		F	Femur	11.4	Partial resectiona	ES/CR1	Bu-Mel	3.0+	3.0+	-	-	NED
18b		13.6	M	Mediastinum	8	Metastasisa	ELS/PR1	Bu-Mel→Ifos-Carbo-VP16	2.0	3.6+	OP, TC, VIT, GGT, ICE, cabozantinib	CR	NED
19	8.5		M	Skull	7.7	Partial resectiona	ELS/CR1	Bu-Mel	1.3	3.5+	OP, R/T, VIT	Refractory	AWD
20	18.2		F	Pelvis	9.4	Metastasisa	RCS/CR1	Bu-Mel	3.3+	3.3+	-	-	NED

AWD = alive with disease; BEP = bleomycin-etoposide-cisplatin; Bu-Mel = busulfan-melphalan; CR = complete response; DOD = died of disease; Dx = diagnosis; ELS = Ewing-like sarcoma; ES = Ewing sarcoma; F = female; GD = gemcitabine-dacarbazine; GGT = gemcitabine-taxotere; HDC = high-dose chemotherapy; ICE = ifosfamide-carboplatin-etoposide; IE = ifosfamide-etoposide; Ifos-Carbo-VP16 = ifosfamide-carboplatin-etoposide; M = male; Mel-Carbo-VP16 = melphalan-carboplatin-etoposide; NED = no evidence of disease; OP = operation; OS = overall survival; PFS = progression-free survival; PR = partial response; RCS = round cell sarcoma; R/T = radiotherapy; SD = stable disease; TBI-Mel-VP16 = total body irradiation-melphalan-etoposide; TC = topotecan-cyclophosphamide; TIP = taxotere-ifosfamide-cisplatin; VActDC = vincristine-actinomycin D-cyclophosphamide; VI(T) = vincristine-irinotecan ± temozolomide.

^aPatients received HDC as part of treatment at frontline.

^bThe patient (no. 18) received two times of HDC with stem cell rescue.

Neutropenic fever was noted in 20 of 21 transplants (95%). Other post-transplant complications included mucositis (67%), oral candidiasis (33%), gastritis (14%) (complicated with upper gastrointestinal bleeding in two), diarrhea (10%), transient seizure during busulfan infusion (10%), nasal bleeding (10%), skin rash (5%), gingivostomatitis (5%), esophagitis (5%), pneumonia (5%), cellulitis (5%), hypokalemia (5%), elevated liver function (5%) and hemorrhagic cystitis (5%). No transplant-related mortality was recorded.

3.3. OS and PFS

The 5-year OS and PFS were 54.5% ± 12.7% and 35% ± 10.7%, respectively (Fig. 1A). Among the 20 patients, 13 patients (65%) had tumor progression or recurrence at a median interval of 8.4 months (range, 2.0-30.1 months) after HDC-ASCR, and eight patients (40%) died of disease progression. Among the 13 patients with disease progression, four patients who underwent transplantation due to disease recurrence still had tumor progression despite HDC-ASCR treatment, and seven patients presented with initial metastatic disease. In terms of disease condition before transplant, patients in the CR group exhibited a favorable 5-year OS of 100%, and patients in the PR or SD group had 5-year OS rate of 40.0% ± 13.9% (Fig. 1B), showing a statistical significance (p = 0.047). No difference in OS was observed between Bu-Mel and the other conditioning regimens (p = 0.353, Fig. 1C). The 3-year OS in the Bu-Mel group was 77.8% ± 13.9%, and the 5-year OS in patients receiving other conditioning regimens was 45.5% ± 15.0%. Among the 16 patients who received HDC-ASCR as part of primary treatment, a 5-year OS of 100% was noted in patients with localized high-risk disease (n = 6) to 50% ± 15.8% in patients with metastases (n = 10) (Fig. 1D). This difference in outcome approached statistical significance (p = 0.064).

Fig. 1.

Survival rates in this study group. A, Five-year PFS and OS in 20 patients with ESFT receiving HDC-ASCR. B, Five-year OS in patients achieving CR or PR/SD before first HDC-ASCR. C, Three- and 5-y OS in patients receiving busulfan-melphalan regimen or others. D, Five-year OS in patients with localized high risk or metastasis as indication of HDC-ASCR. CR = complete response; ESFT = Ewing sarcoma family of tumors; HDC-ASCR = high-dose chemotherapy-autologous stem cell rescue; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease.

3.4. Comparison with our historical cohort with HRES who did not receive HDC-ASCR

We compared these 16 patients, who received HDC-ASCR as a part of primary treatment, with a previous cohort of 19 patients at our hospital who did not receive HDC-ASCR for their high-risk disease. The patients’ characteristics and follow-up period are listed in Table 3. For direct comparison outcome differences between the two cohorts, OS and PFS were calculated from diagnosis date, instead of day 0 used in HDC-ASCR setting. The 5-year OS and PFS in patients receiving HDC-ASCR were 68.8% ± 11.6% and 43.8% ± 12.4%, respectively. The 5-year OS and PFS in patients not receiving HDC-ASCR were both 31.6% ± 10.7% (Fig. 2A, B). However, the difference was only significant in OS, not PFS (p = 0.018 for OS, 0.104 for PFS).

Table 3.

Patients’ characteristics of children and young adults with HRES receiving HDC-ASCR or not as a part of primary treatment

Characteristics	HDC-ASCR (n = 16)	No HDC-ASCR (n = 19)3	p
Diagnosis year range	2003-2020	1994-2014
Gender (male:female)	9:7	8:11	0.404
Median age at diagnosis, y (range)	15.8 (3.3-28.9)	17.5 (3.4-44)	0.465
Primary tumor site			0.307
Pelvic bone	10	6
Bone of extremities	1	2
Spine or skull	3	5
Mediastinum	2	2
Others	0	4 (1 rib, 1 clavicle, 1 retroperitoneum, and 1 scapula)
Metastases at diagnosis	10	12	0.921
Lung only	4	4
Bone only	4	4
Others	2	4
Median follow-up (after diagnosis), y (range)	4.2 (1.1-14.2)	1.8 (0.6-14.8)	0.381
Median follow-up (after HDC), y (range)	3.5 (0.4-13.7)	NA

HDC-ASCR = high-dose chemotherapy-autologous stem cell rescue; HRES = high-risk Ewing sarcoma; NA = not applicable.

Fig. 2.

Comparison of survival rates between this cohort (n=16) and our previous cohort without HDC-ASCR at frontline (n=19). A, Five-year OS in patients with HRES receiving HDC-ASCR or not as a part of primary treatment at frontline. B, Five-year PFS in patients with HRES receiving HDC-ASCR or not as a part of primary treatment at frontline. HDC-ASCR = high-dose chemotherapy-autologous stem cell rescue; HRES = high-risk Ewing sarcoma; OS = overall survival; PFS = progression-free survival.

4. DISCUSSION

Our retrospective study demonstrated encouraging potential for the application of HDC-ASCR therapy in patients with HRES in Asia. The 5-year OS and PFS were 54.5% ± 12.7 % and 35% ± 10.7%, respectively, in all patients. Successful engraftment was achieved in all patients with a limited toxicity profile. The 5-year OS of patients with localized high-risk, metastases, and recurrent diseases was 100%, 50% ± 15.8%, and 25%, respectively. Patients with recurrent diseases had the worst outcome. In this study, all six patients with localized high-risk disease survived, and only one among them had disease progression.

In a randomized study by Whelan et al,¹⁰ HDC with ASCR improved survival rate (8-year OS 64.5% vs 55.6%) in patients with localized HRES. Yamada et al¹³ examined 14 cases of ESFT in patients aged between 15 and 35 years. These patients underwent HDC with ASCR as consolidation therapy, with results showing a 3-year failure-free survival rate of 50%.¹³ Increasing evidence supports the role of HDC with ASCR as a primary treatment approach for HRES. The disease status before HDC has been identified as a significant prognosis factor for patients’ outcomes.¹⁴ Patients who achieved CR and underwent consolidation with HDC-ASCR had superior outcomes relative to those transplanted in PR.¹⁵ Drabko et al¹¹ demonstrated that patients who achieved CR had a 5-year OS of 92%, but patients in PR had a significantly lower 5-year OS of 27%. Our findings align with previous studies, indicating that survival rate in the CR group was superior than that in the PR group. We observed an impressive 5-year survival rate of 100% (n = 6) with statistical significance. How to achieve CR before HDC-ASCR is of the utmost importance. Further studies to investigate the integration of modalities such as chemotherapy, irradiation, or novel targeted therapies to improve disease control before consolidation are urgently required. The optimal timing for initiating HDC-ASCR in patients with PR remains uncertain, and further investigation is warranted.

In our previous cohort,³ patients with metastases who received conventional treatment had a 5-year OS of 16.7%. In this study, 10 patients with metastasis at the time of initial diagnosis who underwent HDC with ASCR as their primary treatment had a 5-year OS of 50%. We also compared the outcome differences in HRES group with (current cohort) or without HDC-ASCR (historical cohort) as a part of primary treatment at frontline. The basic patients’ characteristics and follow-up period between two groups were similar, except for the year of diagnosis. Patients who did not receive HDC-ASCR were diagnosed during 1994-2014 and patients who received HDC-ASCR during 2003-2020. Both 5-year OS and PFS were better in patients receiving HDC-ASCR, but statistical significance was noted only in OS, not PFS, which probably was related to the limited case numbers. Because the two cohorts were treated in different eras, the better OS might also derive from effective salvage treatment, improved supportive care, and better local treatment, including surgical technique, perioperative extracorporeal high-dose irradiation/cryotherapy, and localization for radiotherapy.

In the previous decade, the survival rate of ESFT improved. However, a high prevalence of disease recurrence with a poor 5-year OS rate of <20% has been noted.¹⁶ Effective therapy for recurrent disease is crucial, and several studies have been conducted to investigate this issue.^17-19 Some studies have demonstrated the potential of HDC-ASCR as a salvage treatment option for recurrent disease.^18,19 Rasper et al’s¹⁸ study revealed a 5-year OS of 40% in the HDC group but only a 10% OS in the conventional second-line chemotherapy group. In Tenneti et al’s²⁰ focused literature review of HDC-ASCR for children and young adults with relapsed ES, potential survival benefit in chemosensitive patients was observed in patients receiving HDC-ASCR compared with conventional chemotherapy. Our study had four patients with recurrence. Before transplant, second PR was achieved in some patients through salvage chemotherapy with or without radiotherapy. The salvage chemotherapy regimens included cyclophosphamide plus topotecan, irinotecan, temozolomide plus vincristine, docetaxel plus gemcitabine, or ifosfamide, carboplatin plus etoposide for several cycles alternatively based on physicians’ decision. This was followed by HDC-ASCR. No challenges were encountered in harvesting sufficient stem cells despite extensive previous treatment. Despite a 5-year OS of 25%, all four patients experienced disease progression. HDC-ASCR did not prevent further progression or recurrence. Thus, long-term disease remission in patients following HDC-ASCR treatment remains a significant concern. Currently, several studies using multi-kinase inhibitors, that is, Regorafenib (phase II, NCT04055220) or Cabozantinib (phase II, NCT05135975), as maintenance therapy for patients with ES or patients with solid tumors, respectively, are recruiting, hopefully bring benefit on relapse-free survival in those patients in the future.

The optimal conditioning regimen of HDC remains unclear. In our clinical practice, we initially used melphalan-based conditioning regimens. However, we exercised caution in using total body irradiation in combination with other agents, especially in cases where previous radiation exposure was identified. This approach aimed to minimize the risk of additional radiotherapy-related toxicity in long-term periods, particularly among pediatric patients. Drabko et al’s¹¹ retrospective study demonstrated that the use of HDC with Bu-Mel as consolidation therapy in patients with HRES led to improved treatment outcomes. Following the promising results of Whelan et al’s¹⁰ randomized study in 2018, our hospital transitioned from using melphalan-based conditioning regimens to using Bu-Mel regimen for HDC in patients with HRES. In our study, the 3-year OS in Bu-Mel group was 77.8%, although this finding did not reach statistical significance. This could be attributed to a limited number of cases and the relatively short follow-up period for patients who received the Bu-Mel regimen. Further investigation with a longer follow-up period and collaboration among multiple institutions are necessary to obtain more comprehensive results. A study that used thiotepa-etoposide-carboplatin as a conditioning regimen for HRES also demonstrated a promising outcome, with 5-year event-free survival of 73% in a CR1 group with 10 patients.²¹ Further randomized studies are required to identify the optimal conditioning regimens for patients with HRES.

After the benefits of HDC-ASCR were confirmed, additional studies investigated the efficacy of tandem transplant.^15,22 Our study had one patient receiving tandem transplant as consolidation treatment. Jahnukainen et al’s²¹ study showed long-term survival (15 and 9 years) in two cases following tandem transplant. However, Loschi et al’s²² study found that use of tandem transplant with HD-thiotepa followed by Bu-Mel in 13 primary disseminated multifocal ES patients did not lead to improved outcomes. In Rosenthal et al’s¹⁵ study, 13 patients with poor prognosis ESFT were treated with tandem HDC. The treatment was well tolerated with acceptable toxicity, and the treatment-related mortality was 5%. The study reported a 3-year survival of 58%.¹⁵

Our study had two patients with round-cell sarcoma. Their pathological features were similar to ES, but they did not have typical genetic translocation. The role of HDC in round cell sarcoma is still unclear. HDC-ASCR may afford patients longer OS, but further case enrollment and longer-term follow-ups are required to substantiate our findings.

With regard to transplant-related complications, the previous study reported two treatment-related deaths in 93 patients from myelopathy induced by radiotherapy and respiratory distress syndrome, and it also identified the most common toxicities were in the hematological and gastrointestinal systems.¹⁰ Other studies showed hematological toxicity was consistent with fevers of unknown origin.²² In our experience, all patients achieved successful engraftment and no transplant-related mortality was noted. Nevertheless, neutropenic fever was the leading complication, followed by mucositis. Appropriate antibiotics prophylaxis, prompt management for neutropenic fever, and oral hygiene maintenance were imperative during peritransplant period.

This study has several limitations, including its retrospective design and use of patient data from a single institute, which may restrict the generalizability of the results. Additionally, the limited number of cases, heterogeneity of patients and relatively short follow-up period prevent a solid conclusion in the impact and prognostic analyses of HDC-ASCR on treatment outcomes in patients with HRES.

In conclusion, with successful engraftment and limited toxicity, the role of HDC with ASCR in children and young adults with HRES seems promising as an alternative treatment in the Asian population. This is the first study in Taiwan to evaluate the efficacy of HDC-ASCR with results consistent with Western literature. In our study, comparison in HRES group between with HDC-ASCR (current cohort) and without HDC-ASCR (historical cohort) as a part of primary treatment showed only statistical significance in OS, not PFS, which probably was related to the limited number of patients. Given its retrospective nature and the inclusion of a relatively small sample size over a limited observation period, prospective and randomized studies on a nationwide and multi-institutional scale are required. Such a study would provide more conclusive evidence regarding the efficacy of HDC-ASCR on pediatric patients with HRES in Taiwan.

ACKNOWLEDGMENTS

This study was supported by grants to Dr. Hsiu-Ju Yen from the Ministry of Health and Welfare, Taiwan (MOHW112-TDU-B-222-124017) and from Taipei Veterans General Hospital, Taiwan (V112D68-003-MY3-1).