Identifying bone sarcoma survivors facing psychosocial challenges. A study of trajectories following treatment.

OBJECTIVE: Bone sarcoma survivors face a number of physical and psychosocial challenges in relation to the late effects they experience following treatment. The present study aimed to identify and explore the different trajectories that bone sarcoma survivors might navigate during follow-up. METHODS: In-depth and semi-structured interviews were conducted, and an inductive thematic analysis was performed. RESULTS: When they were interviewed three to ten years after the primary diagnosis, the eighteen bone cancer survivors were found to be in three different rehabilitation phases that followed fairly distinct trajectories, namely, back to normal, a new normal and still struggling. Only three participants felt that they had returned to a life that was quite similar to the one they had lived prior to having cancer. Fifteen participants considered their lives and their bodies to be significantly altered. CONCLUSION: Sarcoma survivors who undergo life-changing treatment and return to very different lives than they had before should be identified by healthcare professionals and guided through this demanding phase to better cope with their new living conditions. Information on and tailored guidance related to psychosocial challenges may be of particular importance. Active focus on reorientation, as well as possibilities for growth, seems to be important.

Safety and Cost-effectiveness of Outpatient Administration of High-dose Chemotherapy in Children With Ewing Sarcoma.

BACKGROUND: Children with Ewing sarcoma (ES) are subjected to an interval-compressed regimen with cycles of chemotherapy given every 2 weeks, which is nowadays considered to be the standard of care for individuals with such a case. We developed institutional clinical practice guidelines (CPG) applying outpatient administration in regard to this regimen. This study intends to evaluate our institutional experience with this regimen. METHODS: We conducted a retrospective review of patients with ES who were treated using interval-compressed protocol of 14 cycles consisting of alternating cyclophosphamide, doxorubicin, vincristine (VDC) and ifosfamide, etoposide (IE) with a maximum dose of doxorubicin of 375 mg/m. Cycles were subsequently followed by G-CSF administration until count recovery was recorded. Patients treated using our guidelines from June 2013 to June 2015 were eligible for these guidelines. Patients younger than 3 years at the time of diagnosis were not eligible for outpatient administration of chemotherapy. RESULTS: In total 12 patients with localized ES or lung-only metastasis were eligible. By the time of analysis, 153 cycles were administered to these patients. Eight cycles for 6 patients were administered on an inpatient basis while the rest (N=145) were administered in the outpatient chemotherapy unit. The median number of cycles per patient were 14 (with a range of 5 to 14). Ninety cycles (59%) were administered on time per CPG. The median interval between these cycles were 16 days (range, 12 to 36 days). The median interval between induction and consolidation cycles were 14 and 17 days, respectively. Neutropenia was reported at the time of each next cycle for 12 cycles. Transient gross hematuria was reported in 1 patient only. In addition, a cost saving of 21% (approximately US$ 4500) were achieved per patient. CONCLUSIONS: Our study showed that the outpatient administration of interval-compressed regimen is safe and associated with acceptable adherence to this regimen.

Timing of Local Therapy Affects Survival in Ewing Sarcoma.

PURPOSE: We aimed to investigate the relationship between survival and time to local therapy after initiation of up-front chemotherapy in the treatment of patients with localized Ewing sarcoma. METHODS AND MATERIALS: The National Cancer Database was queried for patients with localized Ewing sarcoma treated with primary chemotherapy and subsequent local therapy. Kaplan-Meier survival curves were generated for patients initiating local therapy 6 to 15 weeks and ≥16 weeks after chemotherapy initiation. Multivariable binomial logistic regression was used to identify factors associated with prolonged time to local therapy. A multivariable Cox proportional hazards model was used to identify factors associated with overall survival (OS). RESULTS: The final cohort included 1318 patients. A higher proportion of patients initiating local therapy 6 to 15 weeks after chemotherapy initiation versus ≥16 weeks after chemotherapy initiation were ≤21 years old (79.5% vs 72.0%; P = .004). Age >21 years (P < .001; hazard ratio, 1.65; 95% confidence interval, 1.28-2.12), tumor size >8 cm (P = .016), and time to local therapy ≥16 weeks (P = .005; hazard ratio, 1.41; 95% confidence interval, 1.11-1.80) were associated with reduced OS; after review of margin status, negative margins were associated with improved OS compared with gross disease (P = .029). Patients initiating local therapy at 6 to 15 weeks versus ≥16 weeks had a 5-year OS of 78.7% versus 70.4% and a 10-year OS of 70.3% versus 57.1%, respectively (P < .001). The difference in OS according to time to local therapy was particularly more important in patients receiving radiation therapy alone. Age >21 years and treatment by radiation therapy alone were associated with delayed time (>16 weeks) to local therapy, whereas private insurance and income >$48,000 were less likely to be associated with delayed local therapy. CONCLUSIONS: Delayed time to local therapy ≥16 weeks after chemotherapy initiation was independently associated with worse survival in patients with localized Ewing sarcoma.

Molecular assessment of circulating exosomes toward liquid biopsy diagnosis of Ewing sarcoma family of tumors.

Ewing sarcoma was first described in 1921 in the Proceedings of the New York Pathological Society by an eminent American pathologist from Cornell named James R. Ewing as a "diffuse endothelioma of bone." Since this initial description, more has been discovered regarding Ewing sarcoma and in the 1980's both Ewing sarcoma and peripheral primitive neuroectodermal tumors due to their similar features and shared identical genetic abnormality were grouped into a class of cancers entitled Ewing sarcoma family of tumors (ESFTs). Ewing sarcoma is the second most common pediatric osseous malignancy followed by osteosarcoma, with highest incidence among 10-20 years old. Ewing sarcoma is consistently associated with chromosomal translocation and functional fusion of the EWSR1 gene to any of several structurally related transcription factor genes of the E26 transformation-specific family. These tumor-specific molecular rearrangements are useful for primary diagnosis, may provide prognostic information, and present potential therapeutic targets. Therefore, ways to rapidly and efficiently detect these defining genomic alterations are of clinical relevance. Within the past decade, liquid biopsies including extracellular vesicles (EVs), have emerged as a promising alternative and/or complimentary approach to standard tumor biopsies. It was recently reported that fusion mRNAs from tumor-specific chromosome translocations can be detected in Ewing sarcoma cell-derived exosomes. Within this review, we overview the current advances in Ewing sarcoma and the opportunities and challenges in exploiting circulating exosomes, primarily small bioactive EVs (30-180 nm), as developing sources of biomarkers for diagnosis and therapeutic response monitoring in children and young adult patients with ESFT.

Inadvertently boarding a pirate ship: disease progression in a paediatric patient with relapsed metastatic Ewing sarcoma receiving treatment at a centre for alternative therapy in Mexico.

Complementary and alternative medicine (CAM) therapies are commonly incorporated into the care of patients with paediatric cancer. Many modalities are safe and effective during cancer treatment and have proved beneficial for symptom relief and quality of life. However, situations where alternative therapy is provided without allopathic medical care supportive care resources can pose a safety risk to patients. This report describes the case of a 16-year-old Chinese girl with metastatic Ewing sarcoma who sought treatment with alternative treatment in Mexico. When her disease progressed with an ensuing significant loss of function, the centre personnel were unable to respond to her acute deterioration or provide necessary medical care. This resulted in her being stranded in a foreign country paralysed, isolated, and with large unanticipated financial expenditures.

Validation of prognostic scoring and assessment of clinical benefit for patients with bone sarcomas enrolled in phase I clinical trials.

BACKGROUND: We sought to validate the Royal Marsden Hospital (RMH) and MD Anderson Cancer Center (MDACC) prognostic scoring systems for the selection of bone sarcoma patients for phase I clinical trials and to identify additional risk factors related to survival. PATIENTS AND METHODS: We retrospectively reviewed the baseline characteristics and outcomes of 92 bone sarcoma patients who were referred to MDACC's Phase I Clinical Trials Program. RESULTS: Ninety-two patients with Ewing sarcoma (N = 47), osteosarcoma (N = 22), chondrosarcoma (N = 16), and other tumors (N = 7) were evaluated; 78 were enrolled in at least 1 of 43 different phase I trials. The median overall survival (OS) was 8.8 months (95% confidence interval [CI] = 6.8-13.7 months). Independent factors that predicted shorter survival were male sex, >2 metastatic sites, >3 previous therapies, hemoglobin level <10.5 g/dL, platelet count >200 x103/L, creatinine level ≥1.3 mg/dL, and lactate dehydrogenase level >ULN. Patients with good RMH scores (0-1) had longer OS than patients with poor RMH scores (2-3) (HR = 5.8, 95% CI = 2.9-11.0; P < 0.0001), as did patients with low MDACC scores (0-1) as compared to patients with higher MDACC scores (2-4) (HR = 3.2, 95% CI = 1.9-5.6; P < 0.0001). CONCLUSION: The RMH prognostic score can be used to predict the OS of bone cancer patients referred for phase I trials. The MDACC score added no value to the RMH score and therefore does not have a role in assessment of patients with bone tumors. Patients with advanced bone sarcomas should be considered for phase I trials.

Assessment of histological response of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters.

PURPOSE: The objective of this study was to evaluate positron emission tomography (PET) using (18)F-fluoro-2-deoxy-D-glucose (FDG) in comparison to volumetry and standardized magnetic resonance imaging (MRI) parameters for the assessment of histological response in paediatric bone sarcoma patients. METHODS: FDG PET and local MRI were performed in 27 paediatric sarcoma patients [Ewing sarcoma family of tumours (EWS), n = 16; osteosarcoma (OS), n = 11] prior to and after neoadjuvant chemotherapy before local tumour resection. Several parameters for assessment of response of the primary tumour to therapy by FDG PET and MRI were evaluated and compared with histopathological regression of the resected tumour as defined by Salzer-Kuntschik. RESULTS: FDG PET significantly discriminated responders from non-responders using the standardized uptake value (SUV) reduction and the absolute post-therapeutic SUV (SUV2) in the entire patient population (SUV, p = 0.005; SUV2, p = 0.011) as well as in the subgroup of OS patients (SUV, p = 0.009; SUV2, p = 0.028), but not in the EWS subgroup. The volume reduction measured by MRI/CT did not significantly discriminate responders from non-responders either in the entire population (p = 0.170) or in both subgroups (EWS, p = 0.950; OS, p = 1.000). The other MRI parameters alone or in combination were unreliable and did not improve the results. Comparing diagnostic parameters of FDG PET and local MRI, metabolic imaging showed high superiority in the subgroup of OS patients, while similar results were observed in the population of EWS. CONCLUSION: FDG PET appears to be a useful tool for non-invasive response assessment in the group of OS patients and is superior to MRI. In EWS patients, however, neither FDG PET nor volumetry or standardized MRI criteria enabled a reliable response assessment to be made after neoadjuvant treatment.

Improving outcomes in difficult bone cancers using multimodality therapy, including radiation: physician and nursing perspectives.

Principles of therapy are similar for Ewing's sarcoma and osteosarcoma. Chemotherapy or surgery alone cures few patients. Multimodality measures are needed for durable response. Quality of life and function are very important short- and long-term considerations. The spine, sacrum, pelvis, ankle, hand, mediastinum, pulmonary hilum, and chest wall are examples of bone cancer locations for which surgery is difficult. Patients with positive margins may need radiation and may experience systemic therapy delay, recurrence, loss of function, or any combination of these. When radiation is used as a means of local control, concomitant chemotherapy can increase its effectiveness. Options for difficult Ewing's sarcoma and osteosarcoma situations and multimodality solutions, including 1 mCi/kg of samarium and proton therapy, are discussed. Combination radiation and chemotherapy regimens are summarized, and organization of patients, caregivers, and medical teams for multimodality therapy is described, along with tools used in our institution that aid in this process.

Impact of whole-body MRI and FDG-PET on staging and assessment of therapy response in a patient with Ewing sarcoma.

In patients with Ewing sarcoma, precise staging is not only crucial for the therapeutic regimen but also for a reliable evaluation of response to therapy. We report on a 15-year-old girl with metastatic spread of a Ewing sarcoma who, apart from conventional staging by bone scan, chest X-ray and CT, was subsidiary examined by FDG-PET and whole-body MRI before and after chemotherapy. Both modalities detected more bone lesions than the bone scan, which led to an altered strategy for radiotherapy. Both examinations might be a great asset to stage-adjusted therapy regimens, ultimately influencing patient outcome.

Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management.

Primitive neuroectodermal tumors are in the Ewing's sarcoma family of tumors and are composed of small round cells. Because of their rare occurrence, optimal therapy is challenging, particularly if they occur in the head and neck. Diagnosis is based on history, immunostaining with at least 2 neural markers, ultrastructural examination, and evidence of an abnormal t(11;22)(q24;q12) translocation as the hallmark for the Ewing's sarcoma family. The prognosis in general is poor because of overt metastasis at the time of diagnosis. Of 27 reported patients with primitive neuroectodermal tumors of the head and neck, 23 were less than 20 years of age. Most patients presented with a tumor in the nasal cavity, paranasal sinuses, or neck. Symptoms developed rapidly (3.6 months, on average), and a lethal outcome occurred in 9 patients. This highly malignant tumor requires an aggressive combination of radical resection, chemotherapy, and radiotherapy. A close follow-up with regular radiographic examination for at least 5 years is mandatory.

Education, employment, insurance, and marital status among 694 survivors of pediatric lower extremity bone tumors: a report from the childhood cancer survivor study.

BACKGROUND: With increasing numbers of childhood cancer survivors, direct sequelae of cancer therapy and psychosocial outcomes are becoming more important. The authors described psychosocial outcomes (education, employment, health insurance, and marriage) for survivors of pediatric lower extremity bone tumors. METHODS: The long-term follow-up study of the Childhood Cancer Survivor Study is a multiinstitutional cohort study comprising 14,054 individuals who have survived for 5 or more years after treatment for cancer diagnosed during childhood or adolescence. Baseline demographic and medical information were obtained. Six hundred ninety-four survivors had osteosarcoma or Ewing sarcoma of the lower extremity or pelvis and were classified by amputation status and by age at diagnosis. The median age at diagnosis was 14 years old with a median of 16 years of follow up since diagnosis. Demographic characteristics were used to analyze the rates of psychosocial outcomes. RESULTS: Amputation status and age at diagnosis did not significantly influence any of the measured psychosocial outcomes. Education was a significant positive predictor of employment, having health insurance, and being currently in their first marriage. Male gender predicted ever being employed and female gender predicted having health insurance and marriage. When compared with siblings, amputees had significant deficits in education, employment, and health insurance. CONCLUSIONS: Overall, no differences between amputees and nonamputees were found. However, gender and education play a prominent role. When compared with siblings, amputees in this cohort may benefit from additional supports.

The possible cost effectiveness of peripheral blood stem cell mobilization with cyclophosphamide and the late addition of G-CSF.

The purpose of this study was to develop a cost-effective protocol for the mobilization of peripheral blood stem cells (PBSC) in patients with malignancy. Thirty consecutive patients were randomized to mobilize PBSC with the late addition of a standard 250 microg dose of G-CSF (Neutrogen) from day 8 or early addition of the same dose of G-CSF from day 2, following cyclophosphamide (CY) 4 g/m2. The median yield of CD34+ cells from evaluated patients was 7.87 x 10(6)/kg (range, 2.06-27.25), collected in a median of four apheresis (range, 2-9). Target CD34 + cell doses > or = 2.0 x 10(6)/kg were achieved in all patients able to be evaluated. There were no statistically significant differences in CD34+ cell yields or toxicities. Overall engraftment occurred with median days to neutrophils > or = 0.5 x 10(9)/L or platelets > 20 x 10(9)/L of 11 and 17 days, respectively. However, the duration of G-CSF administration was markedly shorter in the late use of G-CSF group than in the early use of G-CSF group, with a median of 9 days compared with 15 days (p<0.001). PBSC harvesting after priming with CY plus delayed use of G-CSF made it a safe and cost-effective procedure.

Qualitative assessment of mixed chimerism after allogeneic bone marrow transplantation with regard to leukemic relapse.

Serial peripheral blood specimen from eight adult patients after sex-mismatched bone marrow transplantation (BMT) for Chronic Myeloid Leukemia (CML) (N = 3). Ewing sarcoma (N = 1), Acute Myeloid Leukemia (AML) in second remission (N = 1), Acute Lymphoid Leukemia (ALL) (N = 1), of multiple myeloma (N = 2) were analyzed by the simultaneous immunophenotypic (moAbs/ APAAP-staining) and genotypic analysis (for X and Y chromosomes) of interphase cells to characterize mixed chimerism, residual host cells, and leukemic relapse. Although a stable donor chimerism for T cells, myelomonocytic cells, and granulocytes was developed in seven of the eight patients at Days +21 to +28 post BMT, 0.5 to 1% host cells of different lineages remained continuously in five of the eight patients post BMT (> day 100). In two patients, one with common ALL and the other with multiple myeloma and long-term stable mixed chimerism, a tumor cell relapse was detected first in a sample at Day +176 and confirmed at Day +294. These malignant cells were genotypically of host origin and presented phenotypes identical to those at diagnosis. In the three patients with CML, residual host cells were identified as CD13 (Patient 3) of CD13/CD34 (Patient 4) positive and in one case as CD4/CD8 positive (Patient 7). Since no exclusive antigenic marker is available for this discrimination in these CML patients, normal host hematopoiesis can interfere with the identification of residual disease. Therefore, the identification of the bcr-abl transcripts by a two-step reverse transcriptase-polymerase chain reaction (RT-PCR) was included in this analysis. Patient 3 was bcr-abl positive at [Days +21, +28, +35, and +311, but negative at Days +121 and +400; Patient 4 was bcr-abl positive at only Day +166 post BMT. These results are interpreted as signaling a continuing risk of relapse. In Patient 7, the bcr-abl RT-PCR was negative at Days +142, +166, and +237. Thus, the combination of the simultaneous immunophenotypic and genotypic analysis and the bcr-abl detection by RT-PCR clearly improves the discrimination between malignant cells and normal residual host cells.