Ifosfamide Etoposide Research Articles

Progression before local control in osteosarcoma: Outcome and prognosis-predictive factors.

The prognosis and impact of early disease progression in patients with osteosarcoma prior to local control (LC), and the potential therapeutic benefits of ifosfamide/etoposide (IE) remain underexplored in the medical literature. A retrospective study was conducted on pediatric patients (≤18years) with osteosarcoma who presented to King Hussein Cancer Center between June 2006 and March 2022. We studied patients with disease progression before LC. Among 195 patients, 31 (17males) exhibited disease progression before LC. The median age at diagnosis was 14.1years, and patients were followed for a median of 23.1months (range: 5.8-94.7). The majority of tumors were located in the extremities (n=28). Ten patients (48%) had lung-only metastasis. Twenty-five patients showed progression at the local site only, and six showed progression both at local/metastatic sites. For the 25 patients with local-site-only progression, the decision for 24 was immediate LC via LSS (n=9), amputation (n=10), hemimandibulectomy (n=1), and radiation therapy (n=1). Three families refused amputation. Among the six patients with combined local/metastatic site progression, the decision was for two to intensify chemotherapy by adding IE, while the other four were recommended immediate LC. However, two of them refused surgery. In total, five patients received IE as intensification for progression, all of whom subsequently progressed. The 5-year event-free survival and overall survival were 27.2% and 31.3%, respectively. Our findings suggest that early disease progression before LC in patients with osteosarcoma is associated with poor prognosis. However, patients initially diagnosed with localized disease and who later exhibited local-disease-only progression appeared to have better outcomes. The potential role of IE in the treatment of patients exhibiting early progression merits further investigation in a larger study cohort.

A clinical case of immune-mediated pneumonitis after nivolumab in a patient with Burkitt lymphoma

Immunotherapy is a promising method in the treatment of cancer. PD-1 (programmed cell death protein 1) receptor and its ligand, which contribute to the reactivation of T-cells exerting their cytotoxic function against the tumor, are one of the targets of antitumor drugs. The effectiveness of immune checkpoint inhibitors has been demonstrated in the treatment of melanoma and non-small cell lung cancer. The spectrum of side effects of antitumor immune drugs differs from the classical ones observed in the cytostatics treatment. Immune-mediated adverse events can affect multiple organs, including skin, gastrointestinal tract, endocrine and nervous systems, and lungs. Pneumonitis is a potentially life-threatening complication and often requires immediate administration of corticosteroids. This article presents the case of a patient with relapsed Burkitt lymphoma treated with nivolumab and R-ICE (rituximab, ifosfamide etoposide, carboplatin) scheme. The therapy was effective, but complicated by immune-mediated pneumonitis. Corticosteroids administration resolved this complication and anti-cancer treatment was completed. The following nivolumab administrations were free of side effects.

Extracranial rhabdoid tumours: Results of a SFCE series of patients treated with a dose compression strategy according to European Paediatric Soft tissue sarcoma Study Group recommendations

Background and aimsExtracranial malignant rhabdoid tumours are tumours that mainly affect young children and have a poor prognosis. In 2014, the European Paediatric Soft-tissue sarcoma Study Group developed treatment recommendations consisting in intensive dose chemotherapy every 2 weeks using vincristine-doxorubicin-cyclophosphamide (VDCy) and ifosfamide-etoposide (IE) associated with early surgery and irradiation of tumour sites. MethodsA retrospective study was conducted on children treated in France by these new recommendations up to January 2019. ResultsThirty-five patients were identified. The primary tumour was in miscellaneous soft parts for 18 patients, in the kidney for 11 and in the liver for six. The median age at diagnosis was 17.5 months (range 1.2–198.2). Distant locations (metastatic or synchronous tumours) were present in 37.1% at diagnosis. SMARCB1 germline pathogenic variant was detected in 17.1% of patients. Overall tolerance was good, with 87–97% of theoretical chemotherapy cumulative doses actually delivered. The median interval between two courses was 18 days. Surgical resection was performed in 83% (19 R0, 7 R1 and 3 R2) and local radiotherapy in 49% of patients. After a median follow-up of 50.4 months (range 16.5–134.1), the 2-year overall and event-free survivals were 47.6% (95% confidence interval [CI] 30.2–63.1) and 42.9% (95% [CI] 26.5–58.3), respectively. On univariate analyses, localised disease and gross total resection were significantly associated with favourable outcomes. ConclusionsIntensive dose chemotherapy with VDCy/IE can be administrated with no remarkable short-term toxicity, including in infants. However, the outcome remains poor for patients without gross total resection and with metastatic or multifocal disease. These patients could be stratified into a high-risk group that requires a new immediate therapeutic approach such as targeted agents combined with multimodal therapy.

Transitioning ifosfamide chemotherapy regimens to the ambulatory setting: reviewing cost savings and safety profile.

PurposeTo characterize and compare both the outcome and cost of treatment of outpatient (OP) and inpatient (IP) ifosfamide therapy.MethodsA single-center retrospective chart review of patients 18 years and older receiving ifosfamide therapy. The primary endpoint compares and evaluates the side effect profiles of ifosfamide-treated patients in the OP/IP settings. The adverse event grading system was characterized using the CTCAE Version 5.0. The highest grade was documented per cycle. The secondary endpoint of this study compares the costs of OP/IP therapy. It was assumed that the cost of medication was equivalent for IP/OP treatments. The cost saved with OP administration was determined by the average cost of hospital stay for IP admission.ResultsIfosfamide therapy of 86 patients (57 OP, 29 IP) was reviewed. The predominant OP regimens were doxorobucin-ifosfamide-mesna (AIM) with 43.9% and ifosfamide-etoposide (IE) with 29.8%. Grade 4 anemia, thrombocytopenia, and neutropenia were most frequent in IP vs OP therapies (22.9% IP vs 4.3% OP, 21.6% IP vs 9.2% OP, and 22.8% IP vs 19.6% OP respectively). Neutropenic fever (NF) occurred in 20 OP patients which were predominantly treated with AIM or IE and led to average hospital stay of 6 days. Neurotoxicity, treated with methylene blue (MB) occurred in 4 OP patients. OP therapy saved a total of 783 hospital days, leading to a cost savings of $2,103,921.ConclusionsTransitioning ifosfamide to the OP setting is feasible for academic and community infusion centers with the OP administration being safe, well-tolerated, and associated with decreased total cost of care. The current processes allow for safe transition of chemotherapy of chemotherapy under times of COVID.

Transitioning ifosfamide based chemotherapy to the outpatient setting: A model of implementation of transitioning chemotherapy outpatient in a safety net hospital.

1540 Background: Ifosfamide displays clinical activity against germ cell tumors as well as soft-tissue and bone sarcomas. It is used in different oncology regimens and commonly administered inpatient due to patient monitoring and side effect management. Transitioning certain chemotherapy regimens to the outpatient setting provides a novel approach to treating patients while maximizing patient satisfaction and decreasing total patient care costs1. There is limited data and protocol development to transition ifosfamide regimens to the ambulatory setting. This study’s purpose is to characterize a pharmacy managed ambulatory oncology workflow for transitioning ifosfamide based-regimens to the outpatient setting. Methods: A retrospective cohort chart review was conducted at a single center and included patients 18 years and older receiving at least one cycle of ifosfamide therapy between September 1, 2013 and July 31, 2019. The primary outcome was to evaluate the side effect profile and cost of treatment of ifosfamide. The secondary endpoint included number of hospitalizations. The adverse event grading system was defined using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The highest grade observed for adverse effects was documented for every cycle of each patient. The cost was evaluated by labs ordered, drug used, length of stay in the hospital for chemotherapy or adverse reactions. Results: Ifosfamide therapy of 86 patients (57 OP, 29 IP) was reviewed. The predominant OP regimens were adriamycin-ifosfamide-mesna (AIM) with 43.9% and ifosfamide-etoposide (IE) with 29.8%. Grade 4 anemia, thrombocytopenia, and neutropenia were most frequent in IP vs OP therapies (22.9% IP vs 4.3% OP, 21.6% IP vs 9.2% OP, and 22.8% IP vs 19.6% OP respectively). Neutropenic fever (NF) occurred in 20 OP patients which were predominantly treated with AIM or IE, and led to average hospital stay of 6 days. Neurotoxicity, treated with methylene blue (MB), occurred in 4 OP patients. OP therapy saved a total of 783 hospital days, leading to a cost savings of $2,103,921. Conclusions: Transitioning to outpatient therapy is feasible for academic and community infusion centers. Administration of chemotherapy in the outpatient setting has shown to be safe, well-tolerated, and associated with decreased total cost of care, thereby lowering costs under the oncology care model when compared with inpatient chemotherapy costs.

Local Lung Mass Masquerading a Very Aggressive Extraskeletal Ewing Sarcoma Presenting as Bilateral Paraparesis in a Young Adult

Ewing sarcoma is typically seen in children involving long bones. Although well described, its presentation in extraskeletal tissues is relatively rare and is classified as an Ewing sarcoma family of tumors. They are mostly curable when they occur in children. An extraskeletal Ewing sarcoma in adults is uncommon, limiting the experience in adult oncologists. The biopsy is essential for definitive diagnosis, which shows small round blue cells that must be differentiated from lymphoma, embryonal rhabdomyosarcoma, and small cell carcinoma. Management is multimodal, involving surgery, radiation for local treatment of primary tumor, and systemic chemotherapy. A multidisciplinary approach, coupled with risk-adapted intensive neoadjuvant and adjuvant multi-agent chemotherapies and other modalities such as radiation and surgery for control of the primary site and metastatic disease, is needed. The primary multidrug chemotherapy regimen consists of alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and ifosfamide/etoposide (IE) given every 2 weeks with growth factor support. Prognosis and the 5-year survival rate are better for localized than the metastatic disease, and in metastatic disease, it is better for patients with lung metastasis than other metastatic disease sites. We describe a rare extraskeletal tumor arising from a lung that tested positive for Ewing sarcoma, also known as Askin’s tumor in a young adult. In our case, the tumor rapidly metastasized locally to involve the thoracic spine causing paraparesis. Timely diagnosis and early management are essential to improve outcomes. We also present how treatment can be delayed due to sepsis and emphasize the careful multispecialty approach’s importance. J Med Cases. 2020;11(12):388-393 doi: https://doi.org/10.14740/jmc3582

Local Lung Mass Masquerading a Very Aggressive Extraskeletal Ewing Sarcoma Presenting as Bilateral Paraparesis in a Young Adult

Ewing sarcoma is typically seen in children involving long bones. Although well described, its presentation in extraskeletal tissues is relatively rare and is classified as an Ewing sarcoma family of tumors. They are mostly curable when they occur in children. An extraskeletal Ewing sarcoma in adults is uncommon, limiting the experience in adult oncologists. The biopsy is essential for definitive diagnosis, which shows small round blue cells that must be differentiated from lymphoma, embryonal rhabdomyosarcoma, and small cell carcinoma. Management is multimodal, involving surgery, radiation for local treatment of primary tumor, and systemic chemotherapy. A multidisciplinary approach, coupled with risk-adapted intensive neoadjuvant and adjuvant multi-agent chemotherapies and other modalities such as radiation and surgery for control of the primary site and metastatic disease, is needed. The primary multidrug chemotherapy regimen consists of alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and ifosfamide/etoposide (IE) given every 2 weeks with growth factor support. Prognosis and the 5-year survival rate are better for localized than the metastatic disease, and in metastatic disease, it is better for patients with lung metastasis than other metastatic disease sites. We describe a rare extraskeletal tumor arising from a lung that tested positive for Ewing sarcoma, also known as Askin’s tumor in a young adult. In our case, the tumor rapidly metastasized locally to involve the thoracic spine causing paraparesis. Timely diagnosis and early management are essential to improve outcomes. We also present how treatment can be delayed due to sepsis and emphasize the careful multispecialty approach’s importance.

Methotrexate-Etoposide-Ifosfamide Compared with Doxorubicin-Cisplatin-Ifosfamide Chemotherapy in Osteosarcoma Treatment, Patients Aged 18-25 Years.

Purpose: The French standard chemotherapy for osteosarcoma combines high-dose methotrexate (HDM) and etoposide-ifosfamide (EI) in children and adolescents, and API-AI (doxorubicin-cisplatin-ifosfamide) in adults. We herein present the results of M-EI and API-AI in 18- to 25-year-old patients. Methods: Patients, 18-25 years old, received either M-EI or API-AI regimens. M-EI comprised seven M and two EI doses preoperatively then M-EI in standard-risk patients (good histological response without metastasis) and five M-AP (methotrexate-doxorubicin-cisplatin) in high-risk patients (poor histological response, metastasis, and/or unresectable primary), postoperatively. API-AI comprised three API and two AI doses preoperatively, then two AI and two PI in standard-risk patients and five EI in high-risk patients, postoperatively. Results: We analyzed 95 patients 18-25 years of age: 55 received M-EI and 40 API-AI. The groups had similar baseline characteristics. Eighty-nine patients (94%) had surgery. Twenty-nine of 55 M-EI patients (60%) and 16/40 API-AI patients (41%) had good histological responses to preoperative chemotherapy. At 5 years, event-free survival was 50% (95% confidence interval [CI]: 39-60) and overall survival was 65% (95% CI: 54-74). Acute toxicity was similar, without treatment-related deaths. Conclusions: Survival outcomes with M-EI and API-AI were not significantly different. Tolerance was acceptable with both regimens. HDM is thus feasible for young adults. However, our study limitations preclude any definitive conclusions.

Primary Ewings Sarcoma/Primitive Neuroectodermal Tumor (PNET) of the Breast: a Rare Tumor

Extra osseous Ewing’s sarcoma (EES) is regarded as a member of Ewing’s sarcoma family of tumors (ESFT). A 16-year-old lady presented to the outpatient department of our institute with awareness of progressively increasing lump in the right breast of 5 months duration. Biopsy from the lump done elsewhere was suggestive of poorly differentiated malignancy. On examination, there was a large mass occupying almost the entire right breast. Computed tomography scan (chest) showed a large well-defined minimally enhancing heterogeneous soft tissue lesion of size 17.3 × 14.6 × 14.4 cm in the right breast. Both lungs were normal. Metastatic work up was within normal limits. Review of the biopsy at our center showed fragmented tissue exhibiting sheets of monotonous population of round cells with dark staining nuclei with mitotic figures and minimal cytoplasm. On immunohistochemical (IHC) analysis, the neoplastic cells exhibited CD99 and Friend leukemia integration 1 (FLI1) positivity whereas they were negative for leucocyte common antigen (LCA), desmin, and myogenin, which was consistent with Ewing’s sarcoma/PNET family of tumor. She received 2 cycles of neoadjuvant chemotherapy with VAC (vincristine, doxorubicin, cyclophosphamide) + IE (ifosfamide, etoposide) alternately following which simple mastectomy with latissimus dorsi myocutaneous flap reconstruction was done. Less than 4 cases of EES of the breast have been documented in Indian literature so far. In this report, we discuss the clinicopathological features of this rare and fascinating tumor with a brief review of literature.

Renal Ewing's sarcoma: A single institute experience of seven patients.

e22538 Background: Renal Ewing’s sarcoma constitutes a rare subset of extraskeletal ewings with aggressive clinical course and dismal outcomes. The purpose of our study was to review our experience in the management of patients with Renal Ewing’s Sarcoma. Methods: We retrospectively analysed patients with Renal Ewing’s Sarcoma who were registered in Sarcoma Medical Oncology Clinic at AIIMS, New Delhi between September 2016 and January 2019. Results: A total of eight patients were registered in the study period, one of which was diagnosed with wilms tumor post nephrectomy and was excluded from our study. Of seven patients included in analysis, five (71.4%) were males. The commonest symptoms were flank pain (57.1%) and hematuria (57.1%). The median age was 28 years (range, 18 to 50 years). The mean Hemoglobin was 10.4 g/dl (range, 6-14 g/dl). The median tumor size was 13 cm (range, 5-25 cm). Four patients (57.1%) were non-metastatic while three (42.9%) had metastases in bone, lung and liver, and peritoneum respectively. Diagnosis was established by an upfront nephrectomy in four patients (57.1%) and biopsy in three patients (42.9%). Translocation for EWSR1 was done in 5 patients of which four (80%) were positive and one patient (20%) were negative. The test was not carried out in two patients due to inadequate tissue sampling. Three patients received neoadjuvant chemotherapy with VAC and the rest (four) received it after surgery. Ifosfamide-etoposide (IE) was added to VAC regimen in first two patients, in one being added post nephrectomy. This patient developed Ifosfamide-induced renal failure resulting in death. Radiotherapy was given in two patients, one pre-operative owing to large inoperable mass, and post operative in the other due to positive margins. At last follow up, three patients (42.9%) are alive and are on chemotherapy after radical nephrectomy. Four patients (57.1%) have died, three due to disease (all metastatic) and one due to chemotoxicity. The median survival was 15 months. Conclusions: Unlike extremity, renal ewings sarcoma more commonly presents in higher age and with advanced disease. Translocation studies are a prerequisite in a suspected case of Renal Ewings Sarcoma, especially due to possibility of discrepancies in pre and post-operative diagnoses. Our institutional protocol does not recommend the use of Ifosfamide in the subset of patients with single kidney, post nephrectomy. Caution must be exercised before instituting the drug and should be given only pre-operatively in absence of renal dysfunction.

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

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. 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. 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. Our study showed that the outpatient administration of interval-compressed regimen is safe and associated with acceptable adherence to this regimen.

The addition of cycles of irinotecan/temozolomide (i/T) to cycles of vincristine, doxorubicin, cyclophosphamide (VDC) and cycles of ifosfamide, etoposide (IE) for the treatment of Ewing sarcoma (ES).

10533Background: Treatment for ES in North America has evolved to include cycles of VDC and IE. A regimen including these 5 agents with interval dose compression has achieved 5 year EFS of 73% for ...

Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study

BackgroundIn most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014. MethodsTreatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate. Results409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7–24.5), with 55 patients aged 18–25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51–62%) and overall survival 71% (66–76%). ConclusionM-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.

1523P - Efficacy of second line treatment with etoposide and ifosfamide in adult patients with advanced Ewing Sarcoma family tumors

Background: Ewing Sarcoma family tumors (ES) are rare subtypes of sarcomas, and even less common in adult patients. For those not amenable to treatment with curative intent, sequential therapy with multi-agent combinations is the standard of care, usually followed by ifosfamide/etoposide (IE) at the time of progression, largely based on protocols that included pediatric patients. Nevertheless, less is known about the efficacy of this approach for adult patients with ES refractory to first-line therapy. Methods: We assembled a retrospective cohort of patients aged 18 or older diagnosed with metastatic/inoperable ES refractory to first-line combinations, treated with IE between 2010 and 2016. Patient´s characteristics, tumor variables, treatment outcomes and toxicity data were evaluated. Kaplan-Meier method was used to estimate overall survival and uni/multivariate analysis were carried out to identify factors associated with survival. Results: Among 18 adult patients, the mean age of diagnosis was 22 years, 73% were male and 84% had an ECOG of 0-1 at commencement of IE. Pelvis and thorax were the most common primary sites. The mean number of cycles of IE was 4. The disease control rate was 27%, with partial responses occurring in 16% of the patients (there were no complete responses). The median OS was 4,8 months (IC 95% 0,7-8,8). Toxicities ³ grade 3 occurred in 61% of the patient, including two treatment-related deaths. The main grade 4 toxicity was febrile neutropenia. Hospitalization were required in 55% of the cases. Conclusions: IE has limited efficacy and significant toxicity when used in the second-line setting for adult patients with advanced ES, and different approaches should be investigated for these patients. Legal entity responsible for the study: Instituto do Câncer do Estado de São Paulo Funding: None Disclosure: All authors have declared no conflicts of interest.

Disseminated Cerebrospinal Embryonal Tumor in the Adult.

Introduction. According to the 2016 World Health Organization classification of Tumors of the Central Nervous System, the term Primitive Neuroectodermal Tumor has been replaced by the term Embryonal Tumor (ET). We present a case of disseminated cerebrospinal ET presenting in an adult patient. Illustrative Case. A 49-year-old male presenting with low back pain, dysuria, and hypoesthesia of the lower extremities referred to our emergency department. Brain and whole spine contrast-enhanced MRI documented a diffusively disseminated heterogeneous neoplasm with intradural extra- and intramedullary involvement of the cervicothoracic tract and cauda equina. A primary biopsy of the lumbosacral localization was performed through L5 bilateral laminectomy. Histologic diagnosis was Embryonal Tumor Not Otherwise Specified. The patient underwent chemotherapy with postoperative adjuvant alternating Vincristine-Doxorubicin-Ifosfamide (VAI) and Ifosfamide-Etoposide (IE). Discussion. Spinal ETs are exceedingly rare especially when presenting in the adult patient. Neurosurgical and oncologic management is still unclear. When feasible, surgical removal should always be performed to obtain a histologic diagnosis. Postoperative adjuvant therapy might entail both chemo- and radiotherapy; however a consensus on this matter is still lacking.

Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group

The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

Metastatic Malignant Transformation of Teratoma to Primitive Neuroectodermal Tumor (PNET)

Metastatic germ cell cancers are highly chemosensitive and have 80% cure rate with cisplatin-based chemotherapy. Postchemotherapy teratoma can usually be surgically resected. However, teratoma, which is pluripotent tissue, can undergo malignant transformation along mesodermal elements to primitive neuroectodermal tumor (PNET). Unlike teratoma, PNET can metastasize and render a patient unresectable and incurable. We report the results of treatment of patients with malignant transformation to PNET with cyclophosphamide+doxorubicin+vincristine (CAV) alternating with ifosfamide+etoposide (IE). We reviewed 86 patients with histologically confirmed PNET transformed from testicular teratoma at Indiana University from 1998 to 2012. We identified 18 patients who were treated with chemotherapy comprising cyclophosphamide (1000 to 1200 mg/m), doxorubicin (50 to 75 mg/m), and vincristine (2 mg) alternating with ifosfamide (1.8 g/m) plus etoposide (100 mg/m) for 5 consecutive days. Treatment was given every 3 weeks with a maximum of 6 cycles or until progression or undue toxicity. Hematopoietic growth factors were usually incorporated. The remaining 68 patients underwent surgical resection. Twelve patients had unresectable disease and 6 were treated in an adjuvant setting. Median age was 29 years (range, 20 to 53 y). Nine of the 12 metastatic patients achieved objective response by RECIST criteria. Six of those were rendered with no evidence of disease (NED) with further surgery. Although 4 of the 6 patients subsequently relapsed, 1 patient remains alive and NED at 78 months. The 6 patients who received adjuvant treatment are alive with NED at 9 to 90 months with a median duration of 32.7 months. CAV and IE alternating chemotherapy has high objective response rate for PNET transformed from teratoma and results in occasional long-term disease-free survival when combined with subsequent resection. We recommend adjuvant CAV alternating with IE chemotherapy for patients with PNET after RPLND due to the high probability of recurrent disease and their high chemosensitivity to this regimen.

Treatment outcome and patterns of failure in patients of non-pineal supratentorial primitive neuroectodermal tumor: review of literature and clinical experience form a regional cancer center in north India.

Supra-tentorial primitive neuroectodermal tumors (SPNET) are high-grade, hemispheric tumors, which account for around 2-3 % of pediatric brain tumors. We herein intend to report the clinical features and treatment outcome of patients with nonpineal SPNET treated at our institute. Clinical data were collected by retrospective chart review from 2006 to 2012. Histopathology slides were reviewed, and relevant immunohistochemistry stains were done. Overall survival (OS), recurrence-free survival (RFS) and event-free survival (EFS) were analyzed by the Kaplan-Meier product-limit method. Fifteen patients met the study criterion (male: female = 2:1). Median age at presentation was 11 years (range 3-49 years). Surgical resection was gross total in 6 (40%) and subtotal in 8 (53.33%) patients. At presentation, two patients had leptomeningeal dissemination. Radiation therapy was delivered in 11 (73.33%) patients: craniospinal irradiation in 8 (36 Gy/20 fractions/4 weeks to the craniospinal axis followed by a local boost of 20 Gy/10 fractions/2 weeks) and focal RT in 3 patients. Systemic chemotherapy (median 6 cycles; range 1-16 cycles), given in 13 (86.67%) patients, included the VAC regimen (vincristine, adriamycin, cyclophosphamide) alternating with IE (ifosfamide,etoposide). After a median follow-up of 22.6 months (mean, 24.47 months), complete response and progressive disease were noted in 8 (53.33%) and 7 (46.67%) patients, respectively. Median OS was not reached, and estimated median EFS was noted to be 4.12 years (actuarial rate of EFS at 2 years, 55.2%). Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with 6-12 cycles of an alternating regimen of VAC and IE is a reasonable treatment strategy in patients with nonpineal SPNET.

Intra-patient dose escalation in Ewing’s sarcoma treated with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide: a retrospective review

BackgroundData suggests that males experience less toxicity and poorer survival than females treated for Ewing’s sarcoma. We instituted an intra-patient dose escalation (DE) policy with Vincristine/Doxorubicin/Cyclophosphamide (VDC) alternating with Ifosfamide/Etoposide (IE) based on hematological nadirs and report its feasibility and safety.MethodsA retrospective review of adherence to DE guidelines and toxicities was conducted for patients who received DE with VDC/IE over 3 years at a single cancer center. Absolute neutrophil counts (ANC) was collected on days 8, 12 and 15 for cycles 1–6. DE of 10%/cycle was applied if ANC > 1.5×109/L and platelet > 100×109/L on all blood results. The primary endpoint was the proportion of patients who received appropriate DE. The secondary endpoint was to assess morbidity, changes in hematologic nadirs between gender and age and a comparison with a prior cohort of ESFT patients who did not receive DE. Gender comparisons were assessed via independent 2-sample t-tests assuming unequal variances. Within cycle changes in hematologic nadirs were assessed using repeated measures ANOVA. Relapse free survival and overall survival (OS) curves were estimated using the Kaplan-Meier method.Results23 patients were identified (mean age: 27; range 17–54). 91 decisions for DE were made (1 decision excluded because of progressive disease) with 90% concordance with guidelines. No adverse outcomes occurred as a result of the inappropriate escalation. Grade 3/4 febrile neutropenia (FN) during VDC and IE was 26.1% (6/23 patients) and 17.4% respectively with no difference for those who were DE. Males were less neutropenic after C1 and C3 of VDC compared to females (P-value C1 = 0.003; C3 = 0.005). VDC was associated with greater neutropenia on day 8 whereas IE had greater neutropenia on day 12 (P-value <0.001). During VDC, a non statistical difference in neutropenia was seen for individuals aged 15–25 (n = 13) compared with older individuals (P-value = 0.09). OS comparison for those with localized disease with a prior cohort who were not DE showed similar outcomes (P-value = 0.37).ConclusionsDE is deliverable without increased adverse outcomes. Males have less myelosuppression during VDC, and should be especially considered for DE.

Metastatic malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Results with PNET-based chemotherapy.

4598 Background: Metastatic germ cell cancers are highly chemosensitive and have 80% cure rate with cisplatin based chemotherapy. Post-chemotherapy teratoma can usually be surgically resected. However, teratoma, which is pleuripotent tissue, can undergo malignant transformation along mesodermal elements to PNET. Unlike teratoma, PNET can metastasize and render a patient unresectable and incurable. We report the results of treatment of patients with PNET with cyclophosphamide + doxorubicin + vincristine (CAV) alternating with ifosfamide + etoposide (IE). Methods: We reviewed 81 patients with histologically confirmed PNET transformed from testicular teratoma at Indiana University from 1998 to 2011. We identified 13 cases who were treated with chemotherapy comprising cyclophosphamide 1000-1200 mg/m2, doxorubicin 50-75 mg/m2, and vincristine 2 mg alternating with ifosfamide 1.8 grams/m2 plus etoposide 100 mg/m2 for 5 days. Treatment was given every 3 weeks with a maximum of 6 cycles or until progression or undue toxicity. Hematopoeitic growth factors were usually incorporated. The remaining 68 patients underwent surgical resection. Results: Ten patients had unresectable disease and 3 were treated in an adjuvant setting. Median age was 31 years (range 20-53). Ten of 13 patients had received prior platinum based chemotherapy. Eight of 10 evaluable patients achieved objective response. Five of those were rendered with no evidence of disease(NED) with further surgery. Although 4 of the 5 patients subsequently relapsed, 1 patient remains alive with NED at 69 months. The 3 patients who received adjuvant treatment after retroperitoneal lymph node dissection (RPLND) are alive with NED at 1, 4 and 8 years. Conclusions: CAV and IE alternating chemotherapy has high objective response rate for PNET transformed from teratoma and results in occasional long term disease free survival when combined with subsequent resection. We recommend adjuvant CAV alternating with IE chemotherapy for patients with PNET after RPLND due to the high probability of recurrent disease and their high chemosensitivity to this regimen.