Adjuvant and neoadjuvant chemotherapy for Ewing sarcoma family tumors in patients aged between 40 and 60: report of 35 cases and comparison of results with 586 younger patients treated with the same protocols in the same years

BACKGROUND: The clinical and pathologic features of 46 patients 40 to 60 years old with Ewing sarcoma family tumor (ESFT) diagnosed at the authors' institute between 1972 and 2000 were reviewed. METHODS: Ten patients with metastatic tumors at presentation went elsewhere for treatment; 35 of 36 remaining cases with localized disease were treated at the authors' institution according to different chemotherapy protocols activated in successive years. In patients with nonmetastatic tumors local treatment was surgery in 9 patients, radiotherapy in 16, and surgery followed by radiotherapy in 10. RESULTS: At follow-up times ranging from 6 and 34 years (mean, 17.8 years), 15 patients (42.9%) remained continuously disease-free, 19 experienced recurrence, and 1 died of chemotherapy-related toxicity. The 5- and 10-year event-free survivals were 42.9% and 35.2%, respectively, and the 5- and 10-year overall survivals were 46.1% and 42.8%, respectively. Comparing this group of patients with 586 cases of younger patients seen in the same period at Rizzoli, the only difference between the 2 groups was a significantly higher rate of tumors located in the soft tissues with a larger volume in the older group. The results achieved were comparable in the 2 groups, although the older group had a lower chemotherapy dose-intensity and a higher rate of WHO grade 4 hematologic toxicity. CONCLUSIONS: For patients with localized disease treated with adjuvant and neoadjuvant chemotherapy the results were essentially comparable in the 2 groups. It is concluded that patients 40 years or older with ESFT should be treated in the same way as younger patients and included in treatment trials for these tumors.     

Ewing sarcoma outcomes in a country with limited resources: Egypt as an example

As the scarcity of published research that comprehensively and meticulously analyzed the patient, disease, and treatment factors of prognostic significance in Ewing sarcoma (EWS) in Egypt; This study aimed at assessing survival outcomes of EWS in Upper Egypt, delineating factors of prognostic significance in comparison to other leading oncology centers in Egypt and internationally. By retrospectively reviewing medical records of 85 patients with a verified diagnosis of EWS in the period from 2001 to 2015 at Pediatric and Medical Oncology Departments at South Egypt Cancer Institute; We gathered data relevant to the patient, disease, and treatment variables of the study. Survival was estimated using the Kaplan Meier method and differences between various groups were determined by log rank test. Univariable and multivariable analyses were performed using Cox regression. With a median follow-up period of 62.7 months (95% CI 52.2-73.2, SE=5.4) for the study patients, the estimates of event-free survival (EFS) and overall survival (OS) at 3 and 5 years were 42.1% and 50.6%, and 40.8% and 48.5%, respectively. Metastatic disease at initial presentation (HR=8.91, 95% CI, 4.00-19.9; P<0.0001) stood as the most powerful predictor of OS in the multivariable analysis, followed by surgery used as a local modality (HR=0.16, 95% CI, 0.06-0.44; P=0.0004). Response to neoadjuvant chemotherapy (HR=2.61, 95% CI, 1.11-6.13; P=0.028), primary tumor size (HR=2.49, 95% CI, 1.03-6.03; P=0.044) were also shown to be significantly associated with OS. Radiotherapy as a local modality, whose effect, apparently shown to increase the hazard of events occurrence in the univariable analysis, an effect that was reversed to reveal EFS advantage (HR=0.41, 95% CI, 0.18-0.95; P=0.036) after control of other variables. With 5-year OS of 48.5%, our survival results were comparable to those previously published from Egypt; however, differences still exist between centers due to varied representative study samples. However, outcomes in Egypt in general are still inferior to internationally published studies.     

Clinical outcome of children and adults with localized Ewing sarcoma

BACKGROUND:

As Ewing sarcoma (EWS) can affect children and adults, these patients can be treated at either a pediatric or an adult institution. This study investigated whether differences in therapeutic strategy undertaken in pediatric and adult specialty sarcoma centers correlated with clinical outcome.

METHODS:

Data from patients with localized EWS treated between 1990 and 2005 at tertiary care pediatric and adult institutions were reviewed.

RESULTS:

Fifty‐three patients (24 adult and 29 pediatric) were treated. Pediatric patients received a median of 16 cycles of chemotherapy comprised of doxorubicin, vincristine, cyclophosphamide, ifosfamide, and etoposide. Adult patients received a median of 10 cycles of treatment, and a significantly lower total cumulative dose of ifosfamide and cyclophosphamide (P < .0001). There was no difference noted with regard to the total dose of doxorubicin, or in the type of local therapy offered (surgery or radiotherapy, vs both). However, local therapy occurred earlier in pediatric patients compared with adults (3.7 months vs 7.4 months; P = .0003). The 3‐year event‐free survival (EFS) rate in pediatric and adult patients was 70% ± 9% and 43% ± 13% (P = 0.1), respectively. The 3‐year overall survival rate was 81% ± 7.7% and 59% ± 12% (P = .02) for pediatric and adult patients, respectively. Factors found to be significantly associated with EFS on univariate analysis included pelvic site, cyclophosphamide dose, and time to local therapy. On multivariate analysis, only pelvic disease (hazard ratio [HR] 4.26; P = .018) and time to local therapy (HR, 1.19; P = .002) were found to be significant.

CONCLUSIONS:

Adults with localized EWS have an inferior outcome compared with pediatric patients. This difference may be related to lower doses of alkylating agents and the timing of local therapy. Cancer 2010. © 2010 American Cancer Society.     

Ethnic and racial differences in patients with Ewing sarcoma

BACKGROUND:

Ewing sarcoma (ES) was a malignant tumor of bone or soft tissue. One of the few risk factors for developing ES is race, with a higher incidence noted in populations of European rather than African or Asian ancestry. The goal of the current study was to evaluate racial and ethnic differences in presentation and overall survival (OS) among patients diagnosed with ES before age 40 years.

METHODS:

Data from the Surveillance, Epidemiology, and End Results database identified 1715 patients aged <40 years who were diagnosed with ES between 1973 and 2005. Racial and ethnic group differences were compared using chi‐square tests. OS was estimated by Kaplan‐Meier analysis and compared using log‐rank tests and Cox models.

RESULTS:

Black patients had significantly more soft‐tissue tumors compared with white non‐Hispanic patients (P <.0001). Asian and white Hispanic patients were found to have an intermediate frequency of soft‐tissue tumors that also differed from white non‐Hispanic patients (P <.0001). White Hispanic patients presented with a higher proportion of larger tumors compared with white non‐Hispanic patients (P = .042). Black patients tended to be older than white non‐Hispanic patients (P = .012). Sex, frequency of pelvic tumors, and metastatic status did not appear to differ by ethnicity or race. OS was found to differ according to race and ethnicity. Even after controlling for known confounders, OS was significantly worse for black, Asian, and white Hispanic patients compared with white non‐Hispanic patients (P = .0031, P = .0182, and P = .0051, respectively).

CONCLUSIONS:

Ethnic and racial differences in characteristics and outcomes of patients with ES do exist. Understanding the etiology of these differences will require further study. Cancer 2010. © 2010 American Cancer Society.     

Malignant primary cardiac tumors: review of a single institution experience

BACKGROUND.

Primary cardiac sarcomas are uncommon. The authors undertook to review the Mayo Clinic's experience with primary cardiac sarcomas consisting of 34 patients seen over a 32‐year period.

METHODS.

The patient database at the Mayo Clinic was searched to identify patients with malignant tumors of the heart seen during the 32‐year period between 1975 and 2007. Thirty‐four patients with primary cardiac sarcomas were identified and their medical records reviewed for details pertaining to presenting symptoms, staging modalities, treatment approaches, and outcomes.

RESULTS.

Of the 34 patients, 17 were men and 17 were women. The median age was 44 years. The mean duration of symptoms at the time of diagnosis was 3.6 months. The most common histologic type was angiosarcoma (41%). The median follow‐up for the entire group was 12 months (range, 0‐61 months). The median survival for those who underwent a complete surgical excision was 17 months compared with 6 months for those in whom a surgical complete remission could not be achieved (P = .01). Patients with angiosarcoma had a lower survival compared with patients with other histologies (5 months vs 17 months; P = .01). The median survival of patients with metastatic disease was 5 months versus 15 months in patients without metastatic disease (P = .03 by the log‐rank test).

CONCLUSIONS.

Cardiac sarcomas remain a rare but lethal disease. Compared with extracardiac sarcomas, the prognosis for patients with cardiac sarcomas remains very poor. A complete surgical excision should be performed if possible. Innovative treatment strategies are required. Cancer 2008. © 2008 American Cancer Society.     

The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy

PURPOSE: To evaluate the importance of surgical margins for local and systemic control of Ewing's sarcoma family tumors (ESFT). METHODS AND MATERIALS: Between 1979 and 1999, 512 patients with ESFTs entered 4 different adjuvant and neoadjuvant studies performed at a single institution. Of these patients, 335 were treated with surgery alone (196) or surgery followed by radiotherapy at doses of 44.8 Gy (139). We compared their outcome with that of the 177 patients who were locally treated by radiotherapy at 60 Gy. RESULTS: Local control (88.8% vs. 80.2%, p < 0.009) and 5-year disease-free survival (63.8% vs. 47.6%, p < 0.0007) were significantly better in patients treated with surgery and, among them, in those with adequate surgical margins (96.6% vs. 71,7%, p < 0.0008, and 69.6% vs. 46.3%, p < 0.0002). Nonetheless, better results were observed only in extremity tumors. CONCLUSIONS: Surgery is better than radiotherapy in cases of extremity ESFT with achievable adequate surgical margins, and in cases of inadequate surgical margins, adjuvant reduced-dose radiotherapy is ineffective. Therefore, when inadequate margins are expected, patients are better treated with full-dose radiotherapy from the start.     

Clinical outcome of patients with Ewing sarcoma family of tumors of bone in Japan: the Japanese Musculoskeletal Oncology Group cooperative study

BACKGROUND: Ewing sarcoma family of tumors (ESFT) of bone is extremely rare in Japan. The objectives of the current study were to assess the clinical outcome and prognostic factors of patients with ESFT of bone in Japan and to compare them between Euro-American and Japanese populations. METHODS: The authors conducted a retrospective analysis of 243 patients who were treated for ESFT of bone in Japan between 1981 and 2003. Local therapy was surgery in 35% of patients, surgery combined with radiotherapy in 40% of patients, radiotherapy alone in 22% of patients, and no local treatment in 3% of patients. All but 3 patients received various regimens of multidrug chemotherapy. RESULTS: The median patient age was 16 years. The primary disease sites were the trunk in 53% of patients and the extremities in 47% of patients. Forty-one patients had metastases at presentation. The median follow-up was 66 months. A univariate survival analysis demonstrated that patients who had metastases at presentation, primary site in the trunk, age >or=16 years, tumor size >or=10 cm, tumor that responded poorly to induction chemotherapy, and local treatment with radiotherapy alone had a significantly worse event-free survival (EFS). A multivariate analysis further verified that the former 3 factors were significant adverse prognostic factors. Of 201 patients with localized disease, 45 patients who received current chemotherapy regimens that included ifosfamide and etoposide had a significantly better 5-year EFS rate (67.6%) compared with other patients. CONCLUSIONS: The clinical outcome of patients with localized ESFT of bone in Japan has improved markedly with the use of current chemotherapy regimens that include ifosfamide and etoposide and has become comparable to the outcomes observed in other major series of Euro-American patients. The prognostic factors are also almost identical.     

Second cancers in patients with the Ewing sarcoma family of tumours

BackgroundPatients are at risk of second malignancies (SM) after treatment for Ewing sarcoma family of tumours (ESFT).MethodsWe performed a retrospective review of 237 patients with ESFT treated at our institution from September 1979 through to February 2004. Cumulative incidence (CI) of SM by the type of malignancy and treatment was estimated.ResultsTwelve patients with SM were identified. Secondary leukaemia (SL) developed in 8 patients (2 ALL, 6 MDS/AML), a median 2.6 years (range 1.4–19.6 years) after diagnosis of ESFT. Four patients had secondary solid tumours, a median 8.0 years (range 7.4–9.4 years) after the ESFT diagnosis. Five- and 10-year estimates of the CI of SM were 3.0 ± 1.1% and 4.7 ± 1.5%, respectively. Patients treated on recent protocols with higher cumulative doses or an increased dose intensity of alkylators and epipodophyllotoxins and the use of G-CSF had a higher estimated CI of SL than those in earlier studies (5-year CI 6.4 ± 2.4% versus 0.0 ± 0.0%, respectively, P = 0.004).ConclusionsPatients with ESFT are at risk for SM after treatment. The cumulative incidence of SM is higher with the current treatment protocols and may be related to the intensification of chemotherapeutic agents.     

Modulating sphingosine-1-phosphate receptors to improve chemotherapy efficacy against Ewing sarcoma

Tumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper-permeability promotes chemotherapy delivery primarily to a tumor's periphery. Here, we identify a method for enhancing chemotherapy efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein-coupled Sphinosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper-permeability can be reversed. In our study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE-013 caused more organized, mature and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved antitumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.     

Prognostic factors for local and distant control in Ewing sarcoma family of tumors.

BACKGROUND: Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. The individual contributions of each treatment component cannot be analyzed separately; improvements in local and systemic control can influence each other. PATIENTS AND METHODS: We reviewed the records of 220 patients treated on institutional protocols from 1979 to 2004. Factors predictive of local and distant recurrence were analyzed. RESULTS: The median age at diagnosis was 13.7 years. Ninety-five patients relapsed at a median of 1.6 years. The 5-year overall survival estimate was 63.5% +/- 3.5%. The estimated 5-year cumulative incidence (CI) of local failure was 25.1% +/- 3.0%. Local failure was associated with treatment era (P < 0.001), tumor size (P = 0.037) and type of local control (P = 0.021). Systemic treatment intensification improved local control. The estimated 5-year CI of distant recurrence was 22.5% +/- 2.9%. Patients with localized disease (P < 0.001), smaller tumors (P = 0.018) and those who received surgery +/- radiation for local control (P = 0.023) had lower CI of distant failure. CONCLUSIONS: Successful treatment of ESFT requires optimal systemic and local therapy. Both treatment modalities are intertwined and the control of both local and distant disease is the result of the combined approach.     

92例初治尤文氏肉瘤家族肿瘤综合治疗疗效和生存分析

背景和目的：尤文氏肉瘤家族肿瘤（Ewing’ssarcomafamilyoftumor,ESFF）恶性度高、进展快,其最佳治疗方法目前仍在探讨中。本研究旨在分析ESFF的临床特点和探讨其治疗方法。方法：回顾性分析1995年1月至2008年4月中山大学肿瘤防治中心收治的92例初治ESFF。结果：骨尤文氏肉瘤（Ewing’ssarcomaofbone,ETB）23例,骨外尤文氏肉瘤（extraosseousEwing’Ssarcoma,EOE）21例,外周性原始神经外胚叶瘤（peripheralprimitiveBeuroectodermaltumor,PNET）43例,Askin瘤5例。中位随访时间31．5个月（10～137个月）。局限期综合治疗38例,单一治疗19例,两组3年生存（overallsurvival,OS）率分别为63％、20％,3年无事件生存（events．freesurvival,EFS）率分别为46％、18％,两组问生存差异具有统计学意义（P均〈0．001）。局限期综合治疗患者在全身化疗的基础上加用手术加或不加放疗组远期生存均优于化疗＋放疗组（x2=7．591、9．212,P=0．006、0．002）。CAV／IE交替方案对局限期接受综合治疗患者延长了无事件生存期,但其总生存时间差异无统计学意义（X2=6．950、3．530,P=0．008、0．06）。多因素生存分析显示治疗模式以及疗效是独立的预后因素。结论：综合治疗能明显改善局限期ESFT患者疗效和生存．手术加化疗加或不加放疗的治疗模式在疗效和生存方面优于化疗加放疗治疗模式。治疗模式和近期疗效是独立的预后因素。     

根治性放疗同步化疗治疗局部晚期尤文氏肉瘤家族肿瘤的临床效果#br#

目的评价根治性放疗同步化疗治疗局部晚期尤文氏肉瘤家族肿瘤的临床效果。方法回顾性分析2012年6月至2015年12月新疆医科大学附属肿瘤医院收治的24例局部晚期尤文氏肉瘤家族肿瘤行根治性放疗同步化疗患者的临床资料,男15例,女9例;骨病变12例,骨外病变12例;腰椎3例,骶骨3例,小腿6例,上臂3例,肩胛骨3例,锁骨3例,腰大肌3例;24例均无法广泛切除。先行4周期化疗,方案：长春新碱+阿霉素+环磷酰胺/异环磷酰胺+依托泊苷（VAC/IE）交替方案各2周期,每3周重复1次,再行调强放疗,处方剂量：56 Gy/28f,2 Gy/次,5次/周,6周完成;放疗过程中原方案同步化疗2周期,再按原方案化疗10个周期;治疗过程中,每2周期化疗后根据实体肿瘤疗效评价标准（RECIST）评估原发病灶局部情况;治疗结束后,通过定期复查进行随访。结果同步放化疗后,全组24例患者中6例完全缓解（CR）,12例部分缓解（PR）,6例疾病稳定（SD）;总有效率（CR+PR+SD）为100%。5年无进展生存率（RFS）为58.3%,5年总生存率（OS）为62.5%。放化疗后发生Ⅰ～Ⅱ度骨髓抑制15例,Ⅲ～Ⅳ度骨髓抑制9例;Ⅰ～Ⅱ度胃肠道反应24例,1～2级急性放射性皮炎24例。结论根治性放疗同步化疗治疗局部晚期尤文氏肉瘤家族肿瘤的效果确切,耐受性良好,对于不能手术保肢或肿瘤不可切除的患者可选择该治疗方案。     

Histological response to neoadjuvant chemotherapy in localized Ewing sarcoma of the bone: A retrospective analysis of available scoring tools

AimThe aim is to evaluate which of the existing scoring systems of histological response to neoadjuvant chemotherapy best stratifies the clinical outcome of patients with localized Ewing sarcoma of bone.Methods474 patients with diagnosis of localized Ewing sarcoma of bone were included. The median follow-up was 13.5 years.ResultsThe overall survival and the disease-free survival (DFS) were 70.8% and 63.9% at 5 years. The percentage of histological response to neoadjuvant chemotherapy ranged between 5% and 100% (mean 83%). The agreement between Bologna System and the different percentual cut-offs of histological response to neoadjuvant chemotherapy was high, with kappa statistics of 0.83 for a cut-off of ≥90%; 0.86 for a cut-off of ≥95%; 0.79 for a cut-off of ≥96% and 0.61 for a cut-off of 100%. Statistically higher DFS rates for good responders compared to poor responders were found when using each given system. Model performance indicators showed that Bologna system had a lower AIC score and a higher c-statistics to predict DFS. When the patients classified as good responders using the different percentual cut-offs of histological response to neoadjuvant chemotherapy, were instead re-classified using the Bologna system, statistical differences were noted in DFS within each specific group.ConclusionsAll scoring tools to evaluate histological response to neoadjuvant chemotherapy offer good predictive value for DFS in localized Ewing’s sarcoma of bone. The Bologna system better stratifies those patients with histological response to neoadjuvant chemotherapy between 90 and 99%, representing a more reliable scoring tool in this subset.     

氨磷汀联合化疗治疗Ewing肉瘤/PNET的临床观察

目的探讨氨磷汀联合化疗治疗Ewing肉瘤/PNET的疗效、不良反应和安全性。方法 32例Ewing肉瘤/PNET患者分为化疗加氨磷汀组(观察组)及单纯化疗组(对照组),观察组12例,对照组20例。行IFO-IFO-DDP-ADM化疗2周期后评价疗效、不良反应。结果观察组完全缓解(CR)及非常好的部分缓解率(VGPR)为91.6%,对照组为90.0%,两组比较差异无统计学意义(P>0.05)。比较两组各种Ⅰ度～Ⅳ度不良反应发生率,差异无统计学意义(P>0.05)。比较两组发生的Ⅳ度不良反应,观察组Ⅳ度白细胞减少为25.0%,对照组为70.0%;观察组Ⅳ度粒细胞减少25.0%,对照组为75.0%,差异均有统计学意义(P<0.05)。结论氨磷汀联合化疗治疗Ewing肉瘤/PNET不改变化疗疗效,不增加各种常见不良反应发生率;可以明显减少化疗后Ⅳ度白细胞及粒细胞减少的发生率,安全性好。     

Persistent psychological distress in long-term survivors of pediatric sarcoma: the experience at a single institution

BACKGROUND: The long-term psychological impact of pediatric sarcoma is largely unknown. As part of a cross-sectional study examining the late effects of pediatric sarcoma therapy, we examined whether psychological distress or posttraumatic stress symptoms are present in an adult cohort of pediatric sarcoma survivors. METHOD: Thirty-four patients participated in the study, an average of 17 years after their treatment ended, each completing the SCID module for Posttraumatic Stress Disorder, Impact of Events Scale, Brief Symptom Inventory (BSI) and a questionnaire assessing sociodemographic variables and psychosocial issues. RESULTS: Significant persistent psychological distress characterized this cohort of patients. Seventy-seven percent scored in the clinical range on the BSI. Twelve percent met diagnostic criteria for PTSD. Current psychological distress was associated with intrusive thoughts and avoidant behaviors, male gender, employment, difficulty readjusting to work/school after treatment, and enduring worries about health. No differences were found based on age, presence of metastatic disease or time since diagnosis. CONCLUSIONS: This is the first report of a clinical evaluation of psychological distress in a cohort of pediatric sarcoma survivors treated with intensive multimodal cancer therapy. The results suggest that survivors of pediatric sarcoma might be at high risk for adverse psychological outcomes. Appropriate interventions are proposed.