High Response Rates and Promising Outcomes of Patients with Relapsed Ewing Sarcoma,Especially in Adolescents and Young Adults Treated on a Novel Hybrid Salvage Chemotherapy Regimen

Abstract

Purpose:

About 30%–35% of nonmetastatic and 60%–80% of metastatic Ewing Sarcoma (ES) will relapse post-treatment and outcomes after relapse continue to be poor over last several decades. Prognostic factors affecting survival after relapse of ES are also not robustly known. We present outcomes using a novel hybrid salvage protocol of four active chemotherapeutic agents in our cohort of patients after relapse of ES.

Methods:

This is a retrospective analysis of all consecutive relapsed ES patients treated with curative intent over 4 years (January 2012 to December 2015). All received 12-cycles of hybrid chemotherapy regimen with surgery/radiotherapy done after first 4 cycles. Event-free survival (EFS)/overall survival (OS) estimates were analyzed by Kaplan–Meier product-limit estimator. Cox regression analysis was performed to identify prognostic factors predicting outcome in relapsed ES.

Results:

Salvage regimen was given to 53/108 relapsed ES patients with the rest having opted for palliation upfront. Median age of the treated patients was 19 years (range: 4–40); male:female ratio was 2.7:1. Median time to first relapse was 18.8 months (range: 2.2–91). While 41/53 patients (77%) completed salvage therapy, 6 (11.3%) progressed and 6 (11.3%) abandoned treatment. Median follow-up of the study cohort is 31 months (range: 4–81). Of the analyzable cohort (n = 47), 30 (64%) had a second relapse or progression on salvage treatment. At last follow-up, 31 patients had died (including one due to toxicity and rest due to disease) and 16 patients were alive (14 with no active disease and 2 with disease). The 4-year EFS and OS are 28% and 37%, respectively, for the entire cohort. While adolescents and young adult patients (AYA) had a better survival (p-0.041), relapsed ES patients with shorter disease-free interval (DFI) (<24 months) had a poorer survival (p-0.004). The type of relapse (local or metastatic or combined) after primary treatment did not affect outcome after salvage therapy.

Conclusions:

We have used a novel hybrid chemotherapy protocol using four active agents in relapsed ES, which is well tolerated and shows promising results. Older age (≥15 years) and longer DFI (>24 months) portend better survival post-relapse. In our cohort of relapsed ES, AYAs fared better than others and type of relapse after primary treatment did not affect outcome after salvage therapy.

Introduction

Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue with a peak incidence in adolescents and young adults (AYA).¹ Long-term survival in patients with non-metastatic ES with the current multimodal approach is 60%–75%.^2,3 However, salvage after relapse is difficult and survival is poor.^4,5 Localized disease at primary diagnosis, late relapse (after a disease-free interval [DFI] of greater than 2 years), single site of recurrence, and normal LDH are known favorable prognostic factors in the setting of relapsed ES.⁶ Age as a prognostic factor remains inconclusive with some studies suggesting younger patients (<15 years) to have an improved outcome compared to AYAs with relapsed ES.⁷ Whether this is a reflection of disease biology or tolerance to intensive chemotherapy remains unclear.⁸

Various chemotherapeutic agents and combination regimens have been used in patients with relapsed ES, including irinotecan+ temozolomide (ITM),^9–11 topotecan + cyclophosphamide (TC),^12,13 high-dose ifosfamide,¹⁴ combinations of ifosfamide + carboplatin + etoposide (ICE),¹⁵ and gemcitabine + docetaxel (GD),^16,17 with some success, but failure rates are still reported to be high. Thus, there is need for a novel approach for patients with relapsed ES to improve outcomes. This study was done to analyze the outcome of such patients with a novel hybrid salvage chemotherapy regimen combining vincristine/topotecan/cyclophosphamide and irinotecan/temozolomide (VTC+ITM). We also compared the outcome between pediatric versus AYAs using this hybrid regimen in our cohort of patients.

Materials and Methods

Patients

This is a retrospective analysis of prospectively treated consecutive patients with relapsed ES, with a curative intent, in a single institute, from January 2012 to December 2015. Patients with poor performance status (deemed incapable of tolerating salvage chemotherapy) and those who refused curative intent and opted for palliative supportive care only were excluded from the analysis. Age at presentation, gender, site of metastatic disease, location and extent of recurrence (localized, metastatic, or combined), response to salvage therapy, toxicities, and survival were analyzed for patients treated with the novel hybrid salvage chemotherapy regimen. The outcomes were evaluated to study differences between AYAs and non-AYAs. This study was approved by Institutional Ethics Committee.

Chemotherapy regimen

The hybrid salvage chemotherapy regimen consisted of 11 weeks of induction with 2 cycles of vincristine, topotecan, and cyclophosphamide (VTC) and 2 cycles of ITM (Fig. 1). Post-induction, patients underwent definitive therapy with surgery (limb salvage, amputation, and lung metastasectomy) and/or radiotherapy as per multidisciplinary team's decision. Maintenance therapy consisted of 4 cycles of VTC and 4 cycles of ITM over 23 weeks. Cefpodoxime prophylaxis (10 mg/kg/day, in two divided doses, starting 1 day prior and continued till 3 days after irinotecan infusions) was given to prevent irinotecan-induced diarrhea.^9,18

FIG. 1.

Treatment schema used in the study protocol.

Response assessment and toxicity

Response assessment was done before local therapy (after week 10 of neoadjuvant induction chemotherapy) with computed tomography (CT) or magnetic resonance imaging (MRI) and/or positron emission tomography (PET-CT) scans tailored to individual patients. Best response before any local therapy was measured according to World Health Organization (WHO) criteria.⁹ Complete response (CR) was defined as complete disappearance of all clinically detectable malignant disease. Partial response (PR) was defined as 50% decrease in the size of all measurable lesions, no progression of any evaluable lesions, and no new lesions. It was deemed as progressive disease (PD) if there was 25% or more increase in tumor size, reappearance of any lesion that had previously disappeared, or appearance of any new lesion. Stable disease (SD) was defined as the absence of CR, PR, or PD. Response to salvage regimen was defined as characterized in the medical record or radiographic reports. The original radiographic images were not reviewed to confirm the classification of response. Toxicity data were reviewed as per the clinical notes from the day of the start of salvage therapy and graded according to CTCAE version 5.¹⁹

Statistical analysis

For survival analysis, an event was defined as second progression or death due to any cause. Event-free survival (EFS) was calculated from the date of start of the salvage chemotherapy regimen to event or last follow-up. Overall survival (OS) was calculated from date of start of salvage chemotherapy regimen to death due to any cause or date of last follow-up. Estimates of survival were computed using the Kaplan–Meier method. The hazard ratios (HR) and significance associated with patient characteristics were assessed in a Cox proportional hazard regression model to derive prognostic impact. Confidence Intervals (CI) for HRs were derived from the regression model. Comparison of proportions was assessed using the χ² test or Fisher's exact test. Statistical analysis was performed using SPSS version 21.0.

Results

Between January 2012 and December 2015, 108 patients were diagnosed with relapsed ES. Of these, 55 (51%) did not receive salvage therapy (21 patients opted for palliation, 11 refused any further treatment, 5 had poor performance status, and in 18 patients, adequate details were not available for analysis). Among the 53 patients who were started on hybrid salvage chemotherapy regimen, 6 patients abandoned treatment before completion (reasons not known). The demographic profile of the 47 patients who underwent salvage therapy is given in Table 1. The study cohort had male predominance (M:F-2.7:1). Median age at commencement of salvage chemotherapy was 19 years (range 4–40 years). In this relapsed ES cohort, 13/47 (28%) belonged to pediatric age group (4–14 years) and rest 34/47(72%) were adolescent and young adults (15–40 years). Site of involvement at primary diagnosis was osseous in 36/47 (77%) and extraosseous in 11/47 (23%). The most common osseous primary site was femur, 6/36 (17%), followed by ribs and pelvis, 5/36 (14%) each. Of the 47 patients, 35 (75%) had nonmetastatic disease, 12 (25%) had metastatic disease at primary diagnosis. All patients were treated according to institutional EFT-2001 chemotherapy regimen at primary diagnosis. On this regimen, patients received vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, in addition to surgery and/or irradiation for local control. In the study cohort of 47 patients, 42 had relapsed after first-line treatment and 5 patients had progressed on first-line therapy. Of the 42 patients with relapsed ES, 20 (43%) had metastatic relapse, 16 (34%) had local relapse, and 6 (13%) had combined local and metastatic relapse. Median time to first relapse was 18.8 months (range 2.2–91 months). Early relapse (defined as DFI <2 years) was documented in 15 (32%) patients and late relapse (DFI >2 years) in 27 (68%) patients. In pediatric group, median DFI was 25 months (range 13–97 months), and in AYA group, it was 32 months (range 12–101 months) (p-0.481).

Table 1.

Demographic Characteristics of Patients with Relapsed Ewing Sarcoma

Demographics	n = 47
Age
Median	19 years
Range	4–40 years
Pediatric Age at relapse (4–14 years)	13 (28%)
AYA Age at relapse (15–40 years)	34 (72%)
Sex
Male	35 (74%)
Female	12 (26%)
Primary tumor site
Osseous axial	12 (26%)
Pelvis	5
Chest wall	5
Vertebral	2
Osseous appendicular	24 (51%)
Femur	6
Tibia	4
Humerus	4
Others	10
Extraosseous	11 (23%)
Disease status at primary diagnosis
Nonmetastatic	35 (75%)
Metastatic	12 (25%)
Lung only	8
Lung+node	2
Bone	1
Liver+node	1
Disease status at salvage therapy
Local-only relapse	16 (34%)
Metastatic relapse	20 (43%)
Combined relapse	6 (13%)
Primary progressive (PD)	5 (10%)
Sites of relapse/PD
Local	19 (40%)
Metastatic
Lungs only	7 (15%)
Extrapulmonary	14 (30%)
Combined
Local+ Lung only	3 (6%)
Local+ extrapulmonary	4 (9%)

Tumor response and toxicity

The best response to this hybrid salvage regimen was evaluable in 41/47 patients. The overall objective response rate (ORR) was 75% (CR+PR) (Table 2). Six patients (15%) had achieved CR, and 25 (60%) achieved PR. Six patients (13%) had PD and 4 (10%) patients had SD. The overall ORR was 90% (28/31; CR-10/28, PR-18/28) among AYA group compared to 70% (7/10; CR-2/7, PR-5/7) in pediatric age group (p-0.143). Hematologic toxicity was predominant with grade 4 neutropenia in 15 (32%) patients and grade 4 thrombocytopenia in 5 (11%) patients. Other significant toxicity noticed was grade 4 diarrhea in 4 (8.5%), grade 2 transaminitis in 5 (11%), and grade 2 nephrotoxicity in 3 (6%) patients. One patient expired secondary to Gram-negative septicemia. Three patients had cardiac dysfunction during salvage chemotherapy, which was deemed as a complication of anthracyclines used during the primary treatment.

Table 2.

Treatment Response and Toxicity Summary in Relapsed Ewing Sarcoma with Hybrid Salvage Regimen

Tumor response
Best response achieved		(n = 41)
Complete response (CR)		6 (15%)
Partial response (PR)		25 (60%)
Progressive disease (PD)		6 (15%)
Stable disease (SD)		4 (10%)
Overall objective response (CR+PR) 75%
Toxicity summary
Toxicity (n = 47)	Grade-2	Grade-3	Grade-4
Anemia	4 (8.5%)	7 (15%)	1 (2%)
Neutropenia	3 (6%)	12 (25%)	15 (31%)
Thrombocytopenia	8 (17%)	7 (15%)	5 (10%)
Diarrhea	8 (17%)	5 (10%)	4 (8.5%)
Peripheral Neuropathy	4 (8.5%)	6 (12%)	0
Transaminitis	5 (11%)	0	0
Nephrotoxicity	3 (6%)	0	0

Outcomes and prognostic factors

Of the 47 patients who took treatment per protocol, 6 patients had progression during salvage therapy; of these, 5 had primary progressive refractory disease at the start of salvage therapy. Forty-one patients completed the planned salvage chemotherapy protocol. For local therapy, 16/41 (39%) received definitive radiation, 11/41 (27%) underwent wide surgical excision alone, and 14/41 (34%) required surgical excision along with irradiation.

Among the 41 patients who completed the salvage therapy, 24 (58%) had second relapse. Median time to second relapse was 15 months (range: 2–38 months). At the time of last follow-up, 16 patients were alive, 14 without any evidence of disease, and 2 patients were alive with disease. Thirty-one patients expired, of which 30 were secondary to disease progression and second relapse. One patient died due to sepsis and febrile neutropenia following chemotherapy. At the time of censoring (1st April 2020), the median follow-up of the study cohort is 31 months (range: 4–81 months). The estimated 4-year EFS was 28.4% ± 7% and OS was 37.2% ± 7% (Figs. 2 and 3). On univariate analysis, AYAs (p-0.028) and late relapses (p-0.008) showed better outcome. We did not find significant difference in EFS (p-0.520) or OS (p-0.475), whether the relapse was localized, metastatic, or combined. Gender, baseline metastatic status, site of primary tumor, and site of recurrence also had no statistically significant association with survival after relapse (Table 3). Multivariate analysis by Cox regression showed patients with shorter DFI (<2 years) had 3.4 times (95% CI: 1.3–8.6) greater chance of having an event (p-0.012) and 4.7 times (95% CI: 1.3–16.2) greater chance of death (p-0.013).

FIG. 2.

Event-free survival at 4 years is 28.4%. Color images are available online.

FIG. 3.

Overall survival at 4 years is 37.2%. Color images are available online.

Table 3.

Univariate Analysis of Factors Predicting Outcome in Relapsed Ewing Sarcoma

Prognostic variables (n)	4-year EFS (%)	p-value	4-year OS (%)	p-value
Gender
Men (35)	30.70	0.728	38.90	0.326
Women (12)	21.40	0.728	42.90	0.326
Site of the tumor
Osseous Axial (12)	16.70	0.140	25.00	0.317
Osseous Appendicular (24)	41.40		44.50
Extra-osseous (11)	11.90		16.20
Baseline metastatic disease
Yes (12)	47.60	0.145	55.60	0.095
No (35)	22.20	0.145	30.80	0.095
Type of relapse
Local (16)	22.00	0.520	29.40	0.475
Combined (6)	16.70		22.20
Metastatic (20)	37.20		52.80
Site of recurrence
Local only (16)	22.00	0.261	29.40	0.338
Lung only (6)	66.70		66.70
Lung plus local (3)	33.30		50.00
Extrapulmonary (17)	18.9		37.50
Age group at starting salvage
Pediatric (4–14 years)	15.40	0.041	15.40	0.034
AYA (15–40 years)	33.60	0.041	31.50	0.034
Disease free interval after primary treatment (months)
<24 months (15)	8.40	0.004	8.30	0.001
>24 months (27)	40.40	0.004	56.20	0.001
Total Cohort	28.40%		37.20%

Bold indicates statistically significant p values.

EFS, event-free survival; OS, overall survival.

Discussion

Relapsed ES continues to be a clinical challenge and there are no universally acceptable standard of care guidelines. Available evidence is only from retrospective studies. Optimally selected combination of multiagent chemotherapy and local control modality with surgery and/or radiotherapy are the preferred treatment approaches. Role of high-dose (HD) chemotherapy with stem cell rescue in relapsed ES is still controversial^20–22 and data on biological agents are evolving.^23–25 Casey et al. showed an ORR of 63% with 8.3 months of median progression-free survival using irinotecan/temozolamide combination.⁹ Hunold et al. used topotecan/cyclophosphamide in their patients with relapsed ES and achieved 35% CR with a 1-year OS of 61%.¹² In our cohort, hybrid combination achieved an ORR (CR+PR) of 75%, which is better than the previously reported series. The long-term outcome of patients with recurrent ES remains poor with 5-year OS ranging from 8% to 23% in different series.^5,6,26–28 With a median follow-up of 31 months, our study cohort had a 4-year EFS and OS of 28.4% ± 7% and 37.2% ± 7%, respectively, which is promising.

The hybrid chemotherapy regimen of VTC + ITM was well tolerated in our patients, as shown in Table 2. Even though this hybrid salvage regimen had lesser dose of irinotecan (10–20 mg/m²/day), we observed slightly higher gastrointestinal toxicities in our patients than previously reported in other studies.^9–11,29 Hematological toxicity was similar to those observed with studies that used topotecan and cyclophosphamide combination for relapsed ES.^12,30 Although not supported with data in our cohort, hematological toxicities followed TC courses, whereas diarrhea followed ITM courses, as would be expected from the toxicity profile of individual agents. Overall, the toxicities were manageable considering the balance of expected low survivals and intensities of therapy, with one death attributable to toxicity due to Gram-negative septicemia.

In our cohort, there was no significant difference in outcomes between patients with local relapse versus systemic or combined relapses. However, on univariate analysis, metastatic relapse showed a trend toward better outcome compared to local relapse without statistical significance (4-year OS of 52.8% vs. 29.4%, p-0.389). This is contrary to previous reports that predicted worse outcomes after systemic relapses.^4,6 We do not have evidence to explain this phenomenon conclusively, but recent unpublished analysis of the Euro-Ewing 99 trials also has shown local relapses to be only a harbinger of further systemic failures and thus poor outcomes. We could theorize that local relapses are caused by inherently resistant tumor biology.

In relapsed ES, younger age has been shown to be associated with improved outcome in some case series.³¹ Overall inferior outcomes of AYA with sarcomas compared to younger patients may be attributed to broader challenges faced by AYAs, which include limited clinical trial participation, the unmet needs for additional age-specific psychosocial and supportive care, and the importance of an enhanced focus on survivorship and late effects.³² However, Palmerini et al. observed slightly better progression-free survival and OS in relapsed ES patients ≥18 years compared to <18 years.³³ In our study, we report that AYA patients (15–40 years) had a higher chance of salvage compared to pediatric age group at relapse (4-year EFS 39.6% vs. 15.4%, p-0.028). Better acceptability and tolerance to further intensive treatments after failure of primary treatment may be a factor, but the small patient cohort limits our ability to analyze the age factor adequately. On multivariate Cox regression analysis, DFI remains the most important prognostic factor affecting outcome in our cohort, similar to previous studies.^4,6,34

The rEECur study, under Euro Ewing Consortium, is an ongoing trial to establish the superiority of chemotherapy regimens in relapsed ES through a multiarm randomization of four best established salvage regimens, (1) cyclophosphamide/topotecan (TC), (2) gemcitabine/docetaxel (GD), (3) high-dose ifosfamide (IFOS), and (4) irinotecan/temozolomide (ITM).³¹ First interim analysis of rEECur has shown GD to be less effective than TC, ITM, or IFOS in reducing tumor burden or prolonging PFS in relapsed ES.³⁵ Our study attempted to improve the outcome of patients with relapsed ES by using a hybrid salvage chemotherapy regimen combining vincristine/topotecan/cyclophosphamide with irinotecan/temozolamide (VTC+ITM). To best of our knowledge, this is first report of such combination (VTC+ITM) in patients with relapsed ES. The hybrid salvage regimen was well tolerated and produced good overall ORR. However, these responses were not sustained and many patients eventually progressed after salvage therapy also. Hence, the need to study out-of-box approaches like prolonged maintenance metronomic chemotherapy after induction of best responses with conventional HD chemotherapy regimens may be a future option. Another unresolved area of research would be HD chemotherapy in patients with CR post-salvage regimen, although tolerance to HD chemotherapy after intensive first-line and salvage chemotherapy to achieve CR is a matter of concern. Ours is a retrospective analysis of prospectively treated patients of relapsed ES, but so is most available literature in this setting. Also, nearly 50% of patients in our cohort were not treated with curative intent after relapse. This may reflect logistical and economic limitations rather than disease biology.

Conclusions

The hybrid combination chemotherapy regimen using VTC and ITM can be used in patients with relapsed ES with acceptable toxicity. In this report, AYAs fared better than pediatric patients post-salvage. Patients with a longer DFI (>24 months) had a better outcome. There was no difference in outcomes between patients of ES with local and systemic relapses post-salvage chemotherapy.

Footnotes

Acknowledgment

The authors thank the patients and their families for consenting to report the outcomes.

Disclaimer

These data were presented as Oral Article in “Nollenberg Award Session for Bone tumors” in SIOP-2017 conference, Washington-DC, USA.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this study.

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