Skip metastases in appendicular Ewing sarcoma: relationship to distant metastases at diagnosis, chemotherapy response and overall survival.

OBJECTIVE: To identify in appendicular Ewing sarcoma (ES), if skip metastases (SM) are associated with distant metastases at presentation, response to neoadjuvant chemotherapy and overall outcome. MATERIALS AND METHOD: Patients with appendicular ES from 2007 to 2021 who had whole-bone MRI to identify SM were included in the study. Patient demographics included age/gender, bone involved, the presence of SM, longitudinal tumour length, presence of extra-osseous disease and its axial depth if present from whole-bone MRI and lung metastases and distant bone metastases from staging studies. Response to neoadjuvant chemotherapy from resection specimens and overall survival were noted. Comparison of these factors between patients with and without SM was undertaken. RESULTS: Ninety-five patients (66 males; 29 females: mean age 15.8 years; range 5-48 years) were included. On whole-bone MRI, 80 (84.2%) patients had no SM and 15 (15.8%) patients had one or more SM. Of patients without a SM, lung metastases were present in 16 (21%), distant bone metastases in 7 (11%), while 51 (75%) had a good response to chemotherapy compared with 7 (50%), 3 (27%), and 10 (77%), respectively, in patients with a SM. SM were significantly associated with lung metastases (p = 0.02), but not with distant skeletal metastases (p = 0.13), chemotherapy response (p = 0.88), tumour length (p = 0.47), presence of (p = 0.15) or axial depth of extra-osseous disease (p = 0.4). SM were associated with a significantly poorer survival (p = 0.007) and three times greater risk of death during follow-up. CONCLUSIONS: In appendicular ES, the identification of a SM is associated with the presence of lung metastases at presentation and poorer survival.

Survival after high-dose chemotherapy for refractory and recurrent Ewing sarcoma.

BACKGROUND: outcome of primary refractory or recurrent Ewing sarcoma (RRES) is poor and the role of high-dose therapy (HDT) remains uncertain. We retrospectively reviewed all patients treated for RRES in the London Sarcoma Service (LSS) over a 22-year period with the aim of adding to the current literature and developing a prognostic risk score to aid clinical decision-making. METHODS AND RESULTS: One hundred and ninety-six patients were included; 64 patients received HDT, 98 standard non-HDT chemotherapy and 34 no systemic therapy. At RRES, median age was 20 years and seventy-four per cent of patients had progressed or relapsed within 24 months. Median overall survival for HDT and non-HDT patients was 76 months (95% CI 34.8-117.2) and 10.5 months (95% CI 8.9-12.1), respectively. Two and five-year post-relapse survival (PRS) for HDT patients was 67.9% (SE 5.9) and 52.7% (SE 6.5), and for non-HDT patients, 20.5% (SE 4.2) and 2% (SE 1.5). Four prognostic factors significant on multivariate analysis were assigned a score of one point each, creating good (score 0), intermediate (score 1-2) and poor (score 3-4) prognosis groups. The increased score was significantly associated with reduced PRS. CONCLUSION: Our study demonstrates that in RRES, HDT is associated with superior outcomes compared with non-HDT chemotherapy. RRES patients can be risk-stratified according to a predictive prognostic index we have developed, with the potential benefit of HDT observed even in patients with poor prognostic scores.

Is It Time to Call Time on Bone Marrow Biopsy for Staging Ewing Sarcoma (ES)?

Primary malignant bone sarcomas are rare and Ewing sarcoma (ES), along with osteosarcoma, predominates in teenagers and young adults. The well-established multimodality treatment incorporates systemic chemotherapy with local control in the form of surgery, with or without radiation. The presence and extent of metastases at diagnosis remains the most important prognostic factor in determining patient outcome; patients with skeletal metastases or bone marrow infiltration having a significantly worse outcome than those with lung metastases alone. There is, however, no accepted staging algorithm for ES. Large cooperative groups and national guidelines continue to advocate bone marrow biopsy (BMB) for staging but functional imaging techniques, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) with computerised tomography (CT) have been increasingly used for staging cancers and whole-body magnetic resonance imaging (WB-MRI) for staging skeletal metastases. This review outlines the current literature, from which we conclude that BMB is no longer required for the staging of ES as it does not influence the standard of care management. BMB may, however, provide prognostic information and insights into the biology of ES in selected patients on prospective clinical trials.

Skip metastases in high-grade intramedullary appendicular osteosarcoma: an indicator of more aggressive disease?

OBJECTIVE: To determine whether skip metastases (SM) in high-grade appendicular osteosarcoma (HG-OS) are an indicator of more aggressive disease. MATERIALS AND METHOD: Retrospective review of patients with histologically confirmed diagnosis HG-OS of the long bones from 2007 to 2020, who had whole-bone MRI to identify SM. Data collected included patient age/gender, bone involved, the presence of SM, the presence of lung metastases from chest CT, the presence of distant bone metastases from whole-body bone scintigraphy or whole-body MRI, and chemotherapy response from resection specimen histology. The presence of lung or bone metastases and chemotherapy response were compared between patients without and with SM. RESULTS: The study included 241 patients (146 males; 95 females: mean age 18.2 years; range 4-73 years). Based on whole-bone MRI, 202 (83.8%) patients had no SM and 39 (16.2%) patients had a SM. Of patients without a SM, lung metastases were identified in 44 (22%) and distant bone metastases in 6 (3%) cases, while 80 (43%) had a good chemotherapy response and 105 (57%) had a poor chemotherapy response. Of patients with a SM, lung metastases were identified in 22 (58%) and distant bone metastases in 8 (21%) cases, while 11 (32%) had a good chemotherapy response and 23 (68%) had a poor chemotherapy response. The presence of SM was significantly associated with both lung metastases (p < 0.001) and skeletal metastases (p < 0.001), but not with chemotherapy response (p = 0.24). Patients with SM also had poorer survival (p < 0.001). CONCLUSIONS: The presence of SM in appendicular HG-OS suggests more aggressive disease.

Skeletal staging in Langerhans cell histiocytosis: a multimodality imaging review.

Evaluating the extent of skeletal disease in Langerhans cell histiocytosis (LCH) is a major predictor of patient outcome. Traditionally, whole-body skeletal staging consists of plain radiography and bone scintigraphy. However, more recently whole-body MRI has been shown to be accurate in detecting osseous and extra-osseous lesions, but no large-scale studies analysing its role within the diagnostic algorithm of LCH skeletal staging currently exist. In addition, FDG PET-CT provides useful information regarding disease activity and treatment response, but has an inherent radiation dose which is not ideal in children. Currently, radiographic skeletal survey remains the gold standard with cross-sectional imaging only performed for further characterisation. However, radiographs have shown a wide sensitivity range for skeletal staging and have clear limitations in detecting extra-skeletal disease, a crucial component of stratification in identifying 'at risk' organs. We aim to highlight the various appearances of bony LCH across all the imaging modalities for primary skeletal staging. We will also review the advantages, disadvantages, sensitivity and specificity of each, and establish their role in staging skeletal LCH. Recent studies using whole-body MRI have shown promising results, with radiographs and other modalities playing a more complementary role.

Continuous 14 Day Infusional Ifosfamide for Management of Soft-Tissue and Bone Sarcoma: A Single Centre Retrospective Cohort Analysis.

Ifosfamide is used to treat soft-tissue sarcoma (STS) and bone sarcoma (BS), with improved efficacy at doses above 9 g/m2/cycle. To mitigate treatment-associated toxicity with higher doses, continuous infusional ifosfamide is increasingly used. However, clinical outcome data remain limited. Single-centre retrospective analysis of patients treated with four-weekly infusional ifosfamide (14 g/m2/14d) between August 2012 and February 2019 was conducted. Radiological response, progression-free survival (PFS), overall survival (OS) and toxicity were evaluated. Eighty patients were treated-46 with STS and 34 with BS. Patients received a median of three cycles of infusional ifosfamide (1-24). Overall disease control rate (DCR) in STS was 50% (23 of 46 patients), with a median PFS of 3.8 months, and median OS of 13.0 months. In synovial sarcoma (SS), DCR was 80% (12/15), median PFS 8.1 months and median OS 20.9 months. Overall DCR in BS (34 patients) was 30%, with a median PFS of 2.5 months and median OS of 6.2 months. Five patients (6%) stopped treatment due to toxicity alone within the first two cycles. A further 10 patients stopped treatment due to toxicity during later treatment cycles (12%) and 18 patients (23%) required dose modification. Forty-five patients (56%) experienced grade (G) 3/4 haematological toxicity, with 12 episodes of febrile neutropenia and one treatment-related death. Twenty-seven patients (34%) experienced G3/4 non-haematological toxicity, most commonly nausea and vomiting (10, 13%). In summary, infusional ifosfamide has efficacy in STS, most notable in SS. Benefit appears limited in BS. Treatment is associated with toxicity that requires specialist supportive care.

Screening for Distress in Young People After Treatment for Sarcoma: A Feasibility Study.

Few validated tools are available in childhood cancers settings to assess distress and worry. Twenty-one young people (mean age = 14 years), with an average 4 years since diagnosis, attended a sarcoma follow-up clinic and were asked to complete questionnaires assessing general mood and behavior, quality of life, and distress. All young people completed the Distress Thermometer. However, as the age range was quite wide (9-18 years), different questionnaires were also used with different age groups to assess feasibility and acceptance. In addition, young people were asked for their views about the questionnaires they had completed, asked about previous psychological support, and were asked to rate how useful they had found the medical appointment. Finally, they were asked whether or not they would like a member of the psychology team to contact them to discuss any issues that had been raised by the questionnaires. Patients reported impaired health status and worry about lifestyle, daily activities, and emotional well-being. A health-related quality of life measure (EQ-5D) and an adapted version of the Distress Thermometer were more sensitive than traditional measures and may serve as useful tools to screen for psychological concerns in busy clinical settings.

Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial.

PURPOSE: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. PATIENTS AND METHODS: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 µg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). RESULTS: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. CONCLUSION: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

Interval compressed vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide in patients with advanced Ewing's and other Small Round Cell Sarcomas.

BACKGROUND: To evaluate tolerability and maintenance of dose intensity of 2 weekly treatment with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide (VDC/IE) in patients with advanced small round cell sarcomas including Ewing family tumours (EFT), desmoplastic small round cell tumours (DSRCT) and undifferentiated high grade round cell sarcomas (UHGRCS). METHODS: Retrospective review of 16 patients treated at a single centre with VDC/IE. Dose received, treatment delay, toxicity and clinical outcome were recorded for each cycle up to a maximum of 14 cycles. RESULTS: A total 193 cycles of VDC/IE were administered to 10 patients with EFT, 4 with DSRCT and 2 with UHGRCS. Median age was 22 years with 75% over 18 years. Metastases were present in 14 patients. The mean duration of each cycle was 16.7 days. Febrile neutropenia occurred in 14 % of cycles, and grade 3/4 haematologic toxicity including anaemia and thrombocytopenia in 16 % and 11 % of cycles respectively. Seven patients had a dose reduction. Five patients discontinued VDC/IE early due to toxicity. CONCLUSIONS: This schedule of VDC/IE is feasible in patients with EFT and DSRCT including adults and those with metastases. Its comparison with other standard regimens for these diseases is justified.

A phase I/II study of doxorubicin, ifosfamide, etoposide and interval methotrexate in patients with poor prognosis osteosarcoma.

BACKGROUND: The prognosis for patients with metastatic or axial-skeletal osteosarcoma is poor. A phase I/II study was conducted of intensive chemotherapy with interval methotrexate, to assess the feasibility, response rate and toxicity in this group of patients. PATIENTS AND METHODS: Thirteen patients, median age 18 (range: 8-34), with metastatic or axial-skeletal osteosarcoma were treated with ifosfamide 2.5 g/m(2), etoposide 150 mg/m(2), and doxorubicin 20 mg/m(2) on days 1-3, every 21 days, with interval methotrexate 12 g/m(2) given on day 14, for a maximum of eight cycles. Surgery to the primary was considered after four cycles for those with operable disease, or together with metastatic disease at completion of chemotherapy in those with inoperable tumours. RESULTS: A total of 85 cycles were given, median 6 per patient (range: 4-8). Only 6 of the 13 patients completed all 8 cycles of chemotherapy. Forty-eight cycles (56%) required a dose reduction. The principal toxicity was myelosuppression, with a median nadir neutrophil count of 0.1 (range: 0-4.1). Grade 3 or 4 infection was seen in 41 cycles (48%). Histological response was assessable in seven patients, all of whom achieved a >or=90% necrosis. Radiological response rate, evaluable in seven patients with lung metastases, was 43%. All but one patient has had subsequent disease progression or relapse, with a median event free survival of 13 months (range: 5-53). CONCLUSION: This regimen was associated with responses, but these were not sustained. Substantial toxicity was seen, preventing optimal delivery. More effective, less toxic regimens are needed in this group of patients.

Improving Outcomes After Relapse in Ewing's Sarcoma: Analysis of 114 Patients From a Single Institution.

The outcome for patients with relapsed Ewing's sarcoma is poor. A retrospective analysis was carried out to identify factors associated with improved survival. Between 1992 and 2002, 114 patients presented with relapsed or progressive disease. Median time to progression/relapse was 13 months (range, 2-128). Treatment at relapse included high dose treatment (HDT) in 29 patients, and surgery or definitive radiotherapy in 29. 2 and 5-year post relapse survival (PRS) was 23.5% and 15.2%, respectively. In multivariate analysis, the most significant factors associated with improved survival were disease confined locally or to the lungs (2-year PRS, 40% versus 6%; P < .001), relapse > 18 months from diagnosis (2-year PRS, 53% versus 8%; P < .001), HDT at relapse (2-year PRS, 62% versus 11%; P < .001), and surgery and/or radiotherapy at relapse (2-year PRS, 51% versus 14%; P < .001). First treatment failure in Ewing's sarcoma is mostly fatal. Improved survival can be achieved in selective patients with aggressive treatment. These improvements are confined to those without bone or bone marrow metastases.

Myogenin--a more specific target for RT-PCR detection of rhabdomyosarcoma than MyoD1.

BACKGROUND: MyoD1 and myogenin are differentially expressed in early myogenesis and have been identified in rhabdomyosarcoma (RMS). This study evaluates reverse transcriptase-polymerase chain reaction (RT-PCR) for MyoD1 and myogenin mRNA as diagnostic markers of RMS, and the potential application of this method for the detection of small volume disease in bone marrow (BM) and peripheral blood (PB). PROCEDURE: Expression of MyoD1 and myogenin mRNA was examined by RT-PCR in RMSs (9 alveolar RMS, 10 embryonal RMS, 1 pleomorphic RMS), and 21 other paediatric tumor samples (10 neuroblastoma, 10 Ewing sarcomas, and 1 Sarcoma (not otherwise specified) (S(NOS)). BM (n = 19) and PB (n = 22) samples from the same RMS study population were also examined for MyoD1 and myogenin mRNA expression. RESULTS: Positive expression of both markers was demonstrated in adult muscle, but not in normal PB. Myogenin mRNA was expressed in 16/18 and MyoD1 mRNA in 12/12 RMSs studied. Myogenin was not expressed in 10/10 neuroblastomas, but was present in 2/10 Ewing sarcomas. However, MyoD1 mRNA was detected in 10/10 Ewing sarcomas and 7/10 neuroblastomas. Myogenin mRNA was detected in two BM samples from children with histologically negative BM and in 1/22 PB samples. Detection of MyoD1 mRNA in BM and PB was compromised by the amplification of a similar sized, non-specific product. CONCLUSIONS: Myogenin mRNA is a more specific marker than MyoD1 for the diagnosis of RMS. Myogenin mRNA is potentially a useful target for the assessment of small volume disease in RMS.