Cycles Of Ifosfamide Research Articles

Undifferentiated Pleomorphic Sarcoma of Larynx: A Rare Entity with Review of Literature

Sarcomas of the larynx are rare neoplasms that constitute less than 1% of laryngeal malignancies. We describe a rare case of undifferentiated pleomorphic sarcoma of larynx of a 62-year- old male who presented with hoarseness of voice. Laryngoscope showed growth over glottic region of larynx and biopsy revealed poorly differentiated carcinoma. Patient was treated with radical radiotherapy (RT). After 3 months of completion of RT, laryngoscopy and CECT revealed residual lesion. Cordectomy was done. Post- cordectomy histopathology report (HPR) and review of pre RT biopsy specimen showed tumour composed of highly pleomorphic spindle cells with moderate eosinophilic cytoplasm, vesicular nuclei with prominent eosinophilic nucleoli, frequent mitoses and occasional multinucleate cells. IHC showed tumour cells were positive for vimentin and focal positive for smooth muscle actin but were negative for Pan-CK, CK- 5/6, S-100, CD-34 and desmin. The overall features were consistent with undifferentiated pleomorphic sarcoma. Postcordectomy PET-CT showed metastatic disease. Patient was further managed with 6 cycles of Ifosfamide and Epirubicin based palliative chemotherapy (CT) and after 6 months of CT completion, patient is symptomatically better. The characteristic clinical, histopathological features and management of this rare case are described with a literature review.

Risk factors of ifosfamide-related encephalopathy in adult patients with cancer: A retrospective analysis.

Ifosfamide, a widely used chemotherapeutic agent, has been frequently associated with encephalopathy. A larger-scale study was conducted to identify risk factors of ifosfamide-related encephalopathy, including hepatic function. Adult patients who had completed at least one cycle of ifosfamide between January 2008 and December 2010 were included. Those with renal failure or liver failure were excluded. Data were collected through chart review. Patients with encephalopathy and patients without encephalopathy were compared on age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), baseline serum creatinine (SCr) level, albumin level, white blood cell count, liver function, brain metastasis, and dosage of ifosfamide. Chi-square test or Fisher's exact test, Student t test, and univariate and multivariate logistic regressions were used for analysis. This study enrolled 337 patients. Thirty-eight patients (11%) had ifosfamide-related encephalopathy. They had poorer ECOG PS; higher SCr level, white blood cell count, and aspartate aminotransferase level; and lower serum albumin level compared with patients without encephalopathy. Ifosfamide dosage, brain metastasis, and age were not significant risk factors. Multivariate analysis indicated that only ECOG PS, SCr level, and albumin level contributed significantly to the risk. To date, this is the largest-scale study to have analyzed the risk factors of ifosfamide-related encephalopathy. This study confirms that an ECOG PS of 2-4 and increased SCr level are significant risk factors of ifosfamide-related encephalopathy, whereas increased albumin level decreases the risk, consistent with previous reports. Higher aspartate aminotransferase levels have no significant impact. In contrast to previous studies, ifosfamide dosage and brain metastasis are not significant contributing factors.

Hypopharyngeal Epithelioid Malignant Schwannoma Following Treatment of Hodgkin’s Lymphoma

The objective of this study is to present a patient with hypopharyngeal epithelioid malignant schwannoma as a secondary malignant neoplasm following treatment with MOPP and radiotherapy. The patient, presently a 43 year-old man, was diagnosed at clinical stage III Hodgkin’s lymphoma (HL) with mixed cellularity histopathology at the age of thirteen. He had received 40 Gy radiotherapy to the neck region and MOPP + maintenance MOPP (a total 10 cycles), while malignant schwannoma developed 30 years after the treatment. Although the patient further received four cycles of ifosfamide + adriamycin combination chemotherapy, he died with progression of his malignant schwannoma six months after diagnosis.

Chemotherapy, Irradiation, and Surgery for Function-preserving Curative Therapy of Primary Extremity Soft Tissue Sarcomas

To determine if aerosol granulocyte macrophage-colony-stimulating factor (GM-CSF) decreases the 2-year pulmonary metastasis rate for soft tissue sarcoma. Patients with high-grade soft tissue sarcomas were treated with 2 cycles of ifosfamide, mitomycin, doxorubicin, and cisplatin plus GM-CSF subcutaneous followed by 45 Gy irradiation with concurrent 2 cycles of mitomycin, doxorubicin, and cisplatin followed by surgery +/- intraoperative radiation or brachytherapy. Aerosol GM-CSF (250 mcg twice a day) was administered for 1 week every other week 3× during neoadjuvant therapy and beginning 4 weeks postoperatively every other week 5×. A total of 39 patients were enrolled between November 2001 and April 2006. The median age was 51 years (range, 19 to 65 y). The median lesion size was 9 cm (range, 2.3 to 26.7 cm). Seventy-six percent experienced grade 3-4 hematologic toxicity. Twenty-four of the first 35 evaluable patients (69%; 95% CI, 41%-84%) were free of pulmonary metastasis at 2 years. A total of 82% (95% CI, 70%-95%) of patients were still alive after 3 years, with a median follow-up of 5.5 years (range, 3.4 to 7.6 y). A total of 58% (95% CI, 44%-76%) of patients remained progression free after 3 years. The addition of aerosol GM-CSF to combined chemotherapy, irradiation, and surgery for soft tissue sarcomas did not achieve the study endpoint to decrease the 2-year pulmonary metastasis rate.

OT-02 * PEDIATRIC ANAPLASTIC MENINGIOMA: A CASE REPORT SUCCESSFULLY TREATED WITH COMBINED CHEMOTHERAPY FOR SOFT TISSUE SARCOMAS AND RADIOTHERAPY

A 2 year-old child with motor deficits and headache was referred to our Hospital with an history of speech difficulties and walking difficulties. A brain MRI scan evidenced a giant tumor of the right hemisphere with diffuse contrast enhancement, hydrocephalus and mass effect. After diagnosis, he immediately underwent neurosurgery and a massive debulking of the lesion was performed. The histological diagnosis was anaplastic meningioma (WHO-grade III). Despite radical surgery, after one-month evidence of disease progression was documented by MRI (relapse on surgical margins) and lumbar puncture (neoplastic cells in liquor sample). Rapid progression, young age and absence of successful therapeutic alternatives determined the decision to start chemotherapy with a protocol for soft tissue sarcomas (EpSSG NRSSTS 2005 protocol). The treatment was started in December 2011 and ended in April 2012, and consisted in 3 cycles of Ifosfamide (3 g/m2/day for 3 days) plus Doxorubucin (37.5 mg/m2/day for 2 days) every 21 days. The cycles were followed by Ifosfamide (3 g/m2/day for 3 days ) concomitant with radiotherapy (54 Gy on tumor primary site). A last cycle of Ifosfamide plus Doxorubicin was after performed. In the last 2 cycles, Doxorubicin dose was reduced of 50% to avoid toxicity. End therapy evaluation showed stable disease at brain MRI and absence of tumor cells in liquor sample. Nonetheless, considering risk of disease progression and of late chemotherapy side effects, a strict follow-up was started. After 3 years from diagnosis the patient showed good clinical conditions, with no evidence of disease progression. Anaplastic meningioma is the most undifferentiated, invasive and aggressive type of meningioma (approximately 1-4%). Surgery and radiotherapy are the most effective therapeutic options, while chemotherapy is usually useless. This case represents a successful management of an anaplastic meningioma with chemotherapy in a pediatric patient.

Acute Pancreatitis Following Brentuximab Vedotin Therapy for Refractory Hodgkin Lymphoma: A Case Report

Brentuximab vedotin is an antibody drug conjugate recently approved for the treatment of adult patients with relapsed or refractory Hodgkin lymphoma. Here, we present a patient with brentuximab vedotin-associated pancreatitis diagnosed on the basis of clinical and radiologic findings and laboratory data. To our knowledge there have been no published reports of pancreatitis occurring with this medication. A 65 year old white man was diagnosed in December 2011 with Hodgkin lymphoma, mixed cellularity subtype, stage IIa, non-bulky disease involving abdominal sites, without retroperitoneal lymph node involvement. The patient denied a personal or family history of gastrointestinal disease, smoking, or alcohol abuse and was not obese. From January to July 2012, the patient received six standard cycles of adriamycin, bleomycin, vinblastine, and dacarbazine treatment and, because of lymphoma refractoriness, from November to January 2013 four cycles of ifosfamide, gemcitabine, vinorelbine, and prednisone salvage therapy, without experiencing any gastrointestinal disorder. Unfortunately, post-chemotherapy computed tomography, positron emission tomography, and inguinal lymph node biopsy showed disease progression. Therefore, on April 2013, the patient began treatment with 1.8 mg/kg brentuximab vedotin total dose 150 mg, intravenously once every 3 weeks. The patient did not receive premedication. Laboratory tests after the first administration showed an increase in aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl transferase levels that normalized within a few days. A few days after the second brentuximab vedotin infusion, the patient developed nausea, stypsis, and epigastric pain. He was hospitalized 7 days after the second administration of brentuximab with persistent nausea, abdominal tenderness, dehydration, and acute constant pain in the epigastric area that gradually worsened. He was afebrile and his only medication was lansoprazole. Abdomen ultrasound examination was negative for gallstones. Additional findings were severe neutropenia (absolute neutrophil count 100/μL) and a significant increase in amylase and lipase levels of 206 and 429 U/L, respectively (amylase upper limit of normal values 52 U/L and lipase upper limit of normal values 61 U/L), (Fig. 1). Amylase elevation was consistent with grade 3 toxicity, whereas serum lipase was consistent with grade 4 (MedDRA code 10040139). Bilirubin and transaminase levels were from two to three times higher than normal levels. A diagnosis of drug-induced acute pancreatitis was made supported by serum amylase levels three times above the upper limit of normal, as reported in the literature [1]. Moreover, abdomen computed tomography showed limited iliac-inguinal nodes with lymphoma involvement, excluding pancreas lymphoma infiltration as the cause of the pancreatitis. The patient was given intravenous fluids, antibiotics, and granulocyte colony-stimulating factor until resolution of neutropenia. Fig. 1 Serum amylase and lipase levels during brentuximab vedotin therapy Pancreas enzymes returned to within normal levels in 3 weeks and the third cycle of brentuximab vedotin was given at the same dose at 50 days from the second infusion and at 30 days from the onset of acute pancreatitis. Administration of subsequent chemotherapy cycles was decided based on improvement of clinical conditions, normalization of amylase and lipase values, and partial reduction of abdominal nodes (abdominal US). After every brentuximab vedotin administration, the patient required subcutaneous granulocyte colony-stimulating factor for 4 days to prevent neutropenia but did not present with any other severe adverse event. No recurrence of pancreatitis or any other side effect was recorded. At the time of writing, after six cycles of treatment with brentuximab vedotin, the patient experienced disease progression. According to Naranjo’s algorithm [2], the causal relationship between medication and acute pancreatitis is probable (score = 5), although this potential adverse event is rare and no other increase in amylase and lipase levels was reported after brentuximab re-challenge. Acute pancreatitis is a reversible inflammatory process of the pancreas. Although the disease process may be limited to pancreatic tissue, it can also involve peripancreatic tissues or more distant organ sites [3]. Although drug-induced acute pancreatitis is considered a rare diagnosis with an estimated incidence of 0.1–2 % [4], many other antineoplastic drugs have been associated with pancreatitis [5, 6]. An extensive review of the literature does not reveal other cases of brentuximab vedotin-induced pancreatitis. As the number of clinical studies is increasing with this new promising drug (37 open studies, http://www.clinicaltrials.gov), we suggest amylase and lipase levels determination when a patient experiences prolonged nausea and/or vomiting and abdominal pain. Moreover, in light of the seriousness of the disease, hematologists should be alert to the possibility of such an adverse reaction. This case has been reported to the Italian Health Authority (AIFA) registered as number 212194 on July 2013 and to the manufacturer of the drug (Takeda).

Modified cisplatin, etoposide, and ifosfamide (PEI) salvage therapy for male germ cell tumors: long-term efficacy and safety outcomes

BackgroundSince 1985, we introduced a modified combination of etoposide, ifosfamide, and cisplatin (PEI) as second-line therapy of adult male germ cell tumors with the aim to reduce toxic effect while maintaining efficacy over the original regimen. Patients and MethodsPatients received four cycles of ifosfamide at 2.5 g/m2 on days 1–2, etoposide, and cisplatin at 100 and 33 mg/m2, respectively, on days 3–5 every 21 days, followed by surgery. Results were stratified according to the International Germ Cell Consensus Classification Group-2 (IGCCCG-2). ResultsFrom February 1985 to January 2012, 189 patients were treated. 72.6% were IGCCCG-2 intermediate-to-very high risk. Thirty-five patients (18.5%) had a complete response, 67 (35.4%) a marker normalization (PRm-). Median follow-up was 122.1 months (inter-quartile range [IQR]: 71.4–232.0). Two-year progression-free and 5-year overall survival were 34.3% [95% confidence interval (CI) 28.1% to 41.9%] and 42.1% (95% CI 35.3% to 50.2%), respectively. Survival estimates compared favorably with those obtained by conventional dose chemotherapy (CDCT) regimens in each prognostic category. 70.4% of grade 3–4 neutropenia (25.5% febrile neutropenia), 48.1% thrombocytopenia, 21.2% anemia, 3.2% neurotoxic effect, and no severe renal toxic effect were recorded. ConclusionDose-modified Italian PEI should be considered as an appropriate benchmark for CDCT in the first salvage setting.

SARC006: Phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 (NF1)-associated high-grade malignant peripheral nerve sheath tumors (MPNSTs).

10522 Background: MPNSTs occur in 10% of the NF1 population, and retrospective, pooled analyses have reported worse chemotherapy response for NF1 (9-18%) compared to sporadic MPNSTs (39-55%). Methods: We prospectively evaluated the objective response (OR) rate, [complete responses (CR) and partial responses (PR) WHO criteria] of children and adults with high-grade, unresectable or metastatic chemotherapy naive NF1 associated versus sporadic MPNST after 2 cycles of ifosfamide and doxorubicin (IA) followed by 2 cycles of ifosfamide and etoposide (IE) as primary endpoint. This was followed by surgery and/or radiation for local control and up to 2 more cycles of IA and IE each. Pathology was centrally confirmed. A Simon optimal two-stage design was used with a target response rate of 40% and 17 patients per stratum in the first stage. With 4+/17 ORs, enrollment was to be expanded to 37 patients per stratum, and 11+/37 ORs would be potentially consistent with a 40% OR rate. Results: Both initial stages met criteria for enrollment expansion with 4/17 PRs in NF1 and 4/12 PRs in sporadic MPNSTs, but only 1 additional PR was observed in the expanded NF1 stratum. Of the 9 PRs, 5 were first observed after 2 cycles IA, and additional 4 after 2 cycles IE. Enrollment was slower than expected and the trial was closed before full accrual. Conclusions: While the primary trial objective was not reached due to slow enrollment, with only 5/29 ORs in the NF1 stratum the desired OR rate of 11+/37 would have unlikely been met even if accrual had been completed. We observed a lower OR rate in NF1 compared to sporadic MPNSTs similar to retrospective literature reports. However, our trial was not powered to detect a difference in response rates between the two strata. In addition to PRs after both IA and IE, disease stabilization was achieved in most patients. Novel strategies including the evaluation of targeted agents in combination with chemotherapy should be considered. Clinical trial information: NCT00304083. [Table: see text]

Switching chemotherapy in adult osteosarcoma patients with poor necrosis rates post neoadjuvant methotrexate, cisplatin, and doxorubicin (MAP).

10530 Background: Chemotherapy in the treatment of osteosarcoma has improved 5 year overall survival (OS) from 20% with surgery alone to 60-70%. However, poor tumor necrosis following neoadjuvant chemotherapy (NAC) is associated with decreased survival, therefore strategies to improve outcomes are required for these patients. Methods: Records from all adult patients diagnosed with osteosarcoma between 1986 and 2012 were retrospectively reviewed. Patients were stratified according to age at diagnosis (<40yrs and >40yrs), stage (localised or metastatic) and tumor necrosis post NAC (<90% and >90%). All patients received 2 cycles of methotrexate alternating with cisplatin/doxorubicin (MAP) preoperatively. Following surgery, patients with >90% tumor necrosis continued MAP whilst those with <90% necrosis switched to 4 cycles of ifosfamide and etoposide (IE). Results: 105 patients were identified and 98 who received systemic chemotherapy were included. Median age was 23yrs (Range 15-75yrs); 68% of patients were male. Limb sparing surgery was performed in 76% of applicable patients. Of the patients with localised disease (N=85), 5 year OS, with a median follow up of 8 years (1-26 yrs) was 68% (p=0.002). Patients <40 yrs with localised disease had a 5yr OS of 71% (N=73) compared to 40% in those >40 yrs (N=12) (p=0.05). 2/13 patients with metastatic disease at diagnosis are disease free >10 years post diagnosis. 65 of 73 patients with localised disease < 40 yrs had histology reviewed post neoadjuvant MAP. 34/65 (52%) had >90% tumor necrosis and continued on MAP, 5 yr OS 79%, 31 patients (48%) had <90% necrosis and received adjuvant IE, 5 yr OS 68% (P=0.10). Conclusions: Age and stage are important prognostic factors in patients with osteosarcoma treated with chemotherapy and surgery. Historically, patients with <90% tumor necrosis post NAC are considered to have a poorer prognosis. Switching from MAP to IE is an appropriate salvage regimen in such patients and appears to improve long term survival.

Chest Wall Metastasis Resulting from a Primary Extremity Osteosarcoma- a Dramatic Clinical Presentation

Sir, Osteosarcoma is the most common primary malignancy of the bone, with a peak incidence in the second decade and an additional peak in the elderly individuals (seventh and eighth decades) [1]. Improvements in multimodal treatment for osteosarcoma, especially in the use of neoadjuvant and adjuvant chemotherapy have increased the disease-free and the overall survivals. Meanwhile, the prolonged survival of patients has permitted the appearance of new, significant, extra pulmonary targets for metastasis. A 12-year-old boy presented to us with an expansible swelling over the left distal femur, a Jamshidi needle biopsy was suggestive of a high grade osteosarcoma. His initial metastatic work up (CT chest and bone scan) was normal. He received six cycles of ifosfamide, doxorubicin and cisplatin based chemotherapy (4 neoadjuvant and 2 cycles of adjuvant) and a limb salvage surgery with a custom based megaprosthesis. The histopathology of the resected tumor showed residual osteosarcoma with 90 % necrosis. Four months following completion of his adjuvant chemotherapy, he presented to us with a rapidly increasing left anterior chest wall swelling over 2 weeks duration (Fig. 1a). A CT chest revealed an irregular 4 × 2 cm mildly enhancing mass lesion eroding the left 4th rib, the underlying pulmonary parenchyma was however normal (Fig. 1b). His loco-regional disease was clinically under control as was also confirmed by a bone scan. A trucut biopsy from the chest wall swelling was suggestive of metastasis from osteosarcoma (Fig. 2a, b). In view of the short disease free interval and a rapid progression of the chest wall swelling; he was planned for upfront chemotherapy using high dose methotrexate, with a plan to incorporate a surgical resection based on the response. The chest wall lesion unfortunately progressed while the patient was on the second cycle of chemotherapy to a attain a size of 9.3 × 8.4 × 7.7 cm. It was found to infiltrate the pericardium and the thymus; in addition multiple bilateral pleural and sub pleural based nodules were seen in both the lung field, suggestive of lung metastasis as seen in the PET-CT (Fig. 3c, d). The patient refused to accept any additional intensive chemotherapy and was discharged on oral chemotherapy with single agent etoposide. Fig. 1 a Clinical presentation of the rapidly increasing (4 × 2 cm) left anterior chest wall swelling four month following adjuvant chemotherapy. b A CT chest showing an irregular 4 × 2 cm mildly ... Fig. 2 a, b H & Ex20- Section shows tumor fragments composed of sheets of round to oval cells with moderate cytoplasm and vesicular nuclei with prominent nucleoli, occasional tumor giant cells in an osteoid matrix, suggestive of metastatic osteosarcoma ... Fig. 3 a, b Clinical photograph demonstrating the progression of the left anterior chest wall swelling (9 × 8 cm) on salvage chemotherapy. c, d PET-CT showing progression of the chest wall swelling to attain a size of 9.3 × 8.4 × 7.7 cm; ... One-third of patients with osteosarcoma will present with recurrent/metastatic disease during the course of their disease [2]. The lung is the most common site of metastases, with 77 % to 92 % of patients experiencing recurrence at this site and it is reported to be the only site of metastasis in nearly two thirds of the patients. The most common site of the extra pulmonary metastases is bone; the unusual sites of metastasis include the brain, abdominal viscera, lymph nodes, pleura, pericardium and oral cavity. Surgery is an essential component of therapy in the relapse setting; multi-agent chemotherapy may contribute to the improvements in the survival outcomes. A more aggressive clinical behavior seems to be a feature in these patients in whom the prognosis is extremely poor [3, 4], the average survival after recurrence is generally less than a year. In conclusion, considering the dramatic clinical presentation of our patient, extra pulmonary metastasis should be considered as a differential in patient’s previously diagnosed with a primary osteosarcoma.

Primary esophageal CD30-positive ALK-positive anaplastic large cell lymphoma with MUM1 expression

We report a case of primary esophageal CD30+/ALK+/MUM1+ anaplastic large cell lymphoma (ALCL) and discuss its diagnosis and treatment, specifically in regard to the unusual expression of the B cell marker, MUM1. A 29-year-old Mexican male presented with an esophageal mass with stenosis and dysphagia. Endoscopic samples were sent for hematoxylin–eosin staining and immunohistochemical analysis. Pathologic and immunohistochemical examination resulted in a diagnosis of primary ALCL of the esophagus with CD30+/ALK+/MUM1+ phenotype. This diagnosis was confirmed by molecular analysis [fluorescence in situ hybridization (FISH)]. Initially, two cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy were given, but the patient exhibited progressive disease. Subsequent treatment consisted of four cycles of ifosfamide, carboplatin, and etoposide (ICE). As of the 12-month follow-up examination, the patient is in complete remission. This case suggests that ALCL of the esophagus should be considered in the differential diagnosis of esophageal neoplasms. Biopsy through esophagoscopy or surgical exploration is recommended, and treatment with chemotherapy or radiotherapy can achieve long-term survival.

Long term renal toxicity of ifosfamide in adult patients – 5 year data

Ifosfamide is indicated as first line treatment in a variety of solid tumours in adults. It is known to be nephrotoxic and is often used following therapy with, or as concomitant therapy with other potent nephrotoxins. To date, there are sparse case reports on the incidence of acute kidney injury (AKI) or chronic kidney disease (CKD) in adults exposed to ifosfamide. The available data on the long term renal complications for patients exposed to ifosfamide are thus based entirely on the paediatric population. The aim of this study was to assess the long term effects of ifosfamide exposure on renal function in an adult population and to determine if there are any treatment or patient specific factors that contribute to long term nephrotoxicity. The mean decline in estimated glomerular filtration rate (eGFR) following the first cycle of ifosfamide was 15ml/min/1.73m2. Thereafter, there was a slower but steady decline in eGFR. No patient progressed to end stage renal disease (ESRD). Patient age and concomitant exposure to carboplatin were the only two factors which significantly affected eGFR. This represents the only long term study on the nephrotoxicity of ifosfamide in adults.

Sequential Dose-Dense Doxorubicin and Ifosfamide in Advanced Soft-Tissue Sarcoma Patients in an Out-Patient-Basis Schedule

Aims. This phase II study explored activity/safety of front-line dose-dense chemotherapy in high-grade STS (soft tissue sarcoma) patients and tested ezrin as prognostic factor. Patients and Methods. The protocol consisted of three cycles of doxorubicin (DOXO) 30 mg/m2 on days 1–3 every 2 weeks, followed by three cycles of ifosfamide (IFO) 2.5 g/m2 two hours a day on days 1–5 every 3 weeks, with GCSF support. Ezrin was assessed immunohistochemically. Results. Twenty patients, 13 metastatic and 7 locally advanced, were enrolled. Median age was 39 years (25–60). Median dose intensities were 42 mg/m2/week and 3.6 g/m2/week for DOXO and IFO, respectively. Grade 3/4 toxicities occurred in 18 patients. Response rate was 15% (3 of 20) by RECIST. Patients younger than 45 years with locally advanced disease and synovial histology presented longer survival. A trend towards longer survival was observed among ezrin-positive patients. Conclusions. This dose-dense schedule should not be routinely used due to its high frequency of toxic events; however, a sequential strategy with DOXO and IFO may benefit selected patients and should be further explored with lower doses. The role of ezrin as a prognostic marker should be confirmed in a larger group of patients.

Nonmetastatic osteosarcoma of the extremity: Neoadjuvant chemotherapy with methotrexate (MTX), cisplatin (CDP), doxorubicin (ADM) with or without ifosfamide (IFO)—A randomized trial of the Italian Sarcoma Group (ISG/OS-1).

9506 Background: To compare two chemotherapy protocols with MTX, CDP, ADM and IFO, given according to different schedule, but same cumulative dose in patients with non-metastatic osteosarcoma of the extremity. Methods: Patients aged ≤ 40 years, were randomized to receive two regimens with same cumulative dose (ADM 420mg/m2, MTX 120g/m2, CDP 600 mg/m2, IFO 30g/m2), but different duration (ArmA 44, ArmB 34 weeks). Preoperative treatment. ArmA: Two blocks of MTX (12g/m2), CDP (120mg/m2) and ADM (75mg/m2). Arm B: Two cycles of MTX (12g/m2) and alternating cycles with CDP (120mg/m2)/ADM (70mg/m2), IFO(6g/m2) /CDP(120mg/m2) and IFO(6g/m2)/ ADM (70mg/m2). Postoperative treatment.ArmA: MTX-CDP-ADM were used in good histologic responders [GR (tumor necrosis≥90%)], three cycles of ifosfamide (10/m2) were added in PR. ArmB: CDP/ADM (weeks 12-25), IFO/CDP (week 17), IFO/ADM (weeks 20-30) and MTX (weeks 15-16-23-24-28-29-33-34) were given. Results: From April 2001 to December 2006, 246 patients were enrolled [median age 14 (4-39)] 228 (93%) underwent limb-salvage surgery [ArmA 92%, ArmB 96%, p=0.5]. 109/243 (45%) patients were GR [ArmA 48%, ArmB 42%, p=0.4]. Three (1.2%) patients died as a result of treatment-related toxicity (ArmA 1, ArmB 2) The mean received dose-intensity was 0.82 [ArmA 0.91, ArmB 0.74, p=0.02]. 2,398 cycles were evaluated. Incidence of grade 4 neutropenia was 30% [ArmA 18%, ArmB 43%, p<0.001]. and G4 thrombocytopenia was 21% [ArmA 11%, ArmB 31%, p<0.001].With a median follow-up of 53 months (1-104) 5-year overall (OS) and event-free survival (EFS) were 74 % and 61%. Arm A 5-year OS and EFS: 75% (95%CI 66-83%) and 65% (95%CI 56-74%), Arm B 5-year OS and EFS: 74% (95%CI 65-82%) and 56.5% (95%CI 47-66%). Conclusions: The addition of ifosfamide to MTX, CDP and ADM since the preoperative phase does not improve the GR rate and increases the haematological toxicity. A similar probability of survival can be expected when ifosfamide is added to MTX CDP ADM in all patients or only in a selected population of poor responders to MTX CDP ADM. No significant financial relationships to disclose.

Possible contribution of aprepitant to ifosfamide-induced neurotoxicity

A case of ifosfamide-induced neurotoxicity after the addition of aprepitant to an antiemetic regimen is reported. A 24-year-old white man diagnosed with a malignant peripheral nerve sheath tumor initially in the late 1990s was admitted to the hospital for treatment of a recurrence of the tumor in the supra-clavicular region. In the previous five cycles of ifosfamide, carboplatin, and etoposide, the patient had no problems with the neurotoxic adverse effects associated with ifosfamide use. With the fifth cycle of therapy, the patient suffered severe nausea and vomiting that required his readmission to the hospital. With the initiation of the sixth cycle of chemotherapy, aprepitant was added to the existing antiemetic regimen of ondansetron and dexamethasone. During the sixth cycle, approximately six hours after the infusion of ifosfamide on day 3, the patient exhibited the classic symptoms of ifosfamide-induced neurotoxicity, including visual and auditory hallucinations, obvious sleepiness, confusion, and delirium. Since his symptoms resolved by morning, it was determined that the patient did not require treatment with methylene blue. With the initiation of the seventh cycle of chemotherapy, aprepitant was again added to the standard antiemetic regimen of a corticosteroid and serotonin receptor antagonist. During this hospitalization, around-the-clock methylene blue was added to prevent neurotoxicity. The patient tolerated chemotherapy well without any signs or symptoms of neurotoxicity and was discharged four days later. A 24-year-old patient treated with ifosfamide, carboplatin, and etoposide for a malignant peripheral nerve sheath tumor developed ifosfamide-induced neurotoxicity after the addition of aprepitant to a standard antiemetic regimen consisting of ondansetron and dexamethasone.

SEQUENTIAL SALVAGE CHEMOTHERAPY FOR RECURRENT INTRACRANIAL HEMANGIOPERICYTOMA

Hemangiopericytoma (HPC) is an uncommon primary brain tumor with an almost invariable tendency to recur and metastasize. We undertook a retrospectively collected case series of recurrent intracranial HPCs treated with salvage chemotherapy with the primary objective of evaluating progression-free survival. Fifteen patients, ages 26 to 62 years, with recurrent HPC and who were previously treated with surgery and involved-field radiotherapy were studied. Eight (53%) of these patients had undergone re-resection before study entry. Ten patients (67%) were treated with stereotactic radiotherapy. Chemotherapy was administered to 5 patients at first relapse, 8 at second relapse, and 2 at third relapse (none of these patients were candidates for reoperation or stereotactic radiotherapy). Eight patients developed disseminated disease, all with multifocal intracranial disease (5 with cerebrospinal fluid dissemination, 4 with extraneural metastases). All patients were initially treated with cyclophosphamide, doxorubicin, and vincristine (CAV). After disease progression despite the administration of CAV in clinically appropriate patients, alpha-interferon (alpha-IFN) (9 patients) was administered. Five patients were treated with ifosfamide, cisplatin, and etoposide after they failed to respond to alpha-IFN. Neurological and neuroradiographic evaluations were performed every 8 weeks. All patients were evaluable. A median of 4 cycles of CAV; 8 cycles of alpha-IFN; and 2 cycles of ifosfamide, cisplatin, and etoposide were administered. Chemotherapy-related toxicity included alopecia (100%), anemia (40%), thrombocytopenia (27%), and neutropenia (40%). Best response included 6 patients (40%) with a neuroradiographic partial response (2 with CAV, 4 with alpha-IFN), 14 (93%) had stable disease (9 with CAV, 5 with alpha-IFN), and 9 (60%) had progressive disease (4 with CAV, 5 with ifosfamide, cisplatin, and etoposide). The median overall survival was 14 months (range, 2-24 mo). Salvage chemotherapy demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent surgery- and radiotherapy-refractory intracranial HPC.

Solitary Relapse of Desmoplastic Small Round Cell Tumor Detected by Positron Emission Tomography/Computed Tomography

An 18-year-old male presented with a large pelvic mass and extensive abdominal disease; biopsy showed pathologic and chromosomal findings of desmoplastic small round cell tumor (DSRCT).1 He was in complete remission (CR) after 10 months of aggressive multimodality treatment: six cycles of high-dose cyclophosphamide (4,200 mg/m2) with either doxorubicin (75 mg/m2) -vincristine2 (four cycles) or topotecan (8 mg/m2) -vincristine3 (two cycles), one cycle of high-dose cisplatin (200 mg/m2) -irinotecan (250 mg/m2), two major surgical procedures to resect tumor,4 and whole abdominal-pelvic radiation therapy (3,000 Gy).5 The radiation therapy was delivered in conjunction with irinotecan (250 mg/m2 divided over 5 days) because of that agent's anti-DSRCT activity,6 its radiosensitizing effect,7 and its modest toxicity.8 Autologous peripheral blood stem cells were infused after radiation therapy/irinotecan to minimize myelosuppression. At 26 months from completion of therapy, surveillance computed tomography (CT) revealed a 3.5- × 3.4-cm lesion in the liver, extending to the hepatorenal fossa. Re-treatment consisted of two cycles of irinotecan (250 mg/m2) plus temozolomide (750 mg/m2),8 resection of residual viable DSRCT, and two cycles of ifosfamide (9 g/m2) plus carboplatin (800 mg/m2) plus etoposide (500 mg/m2).9 At 18 months from completion of retrieval therapy, and three months after hybrid [18F]fluorodeoxyglucose (18FDG) –positron emission tomography (PET)/CT showed ongoing CR, another surveillance hybrid PET/CT study unexpectedly revealed 18FDG uptake (standardized uptake value [SUV], 2.3) in the left posterior midthigh along the semitendinosus muscle without a corresponding CT abnormality and considered to be artifactual. Four months later, the same site had increased focal 18FDG uptake (SUV 10.5; Fig 1). The isolated, localized lesion, which measured 2.2 × 2.0 × 2.7 cm, was resected with clean margins (5.5 years from initial diagnosis). It had the striking pathologic appearance that gives DSRCT its name: nests of small round blue cells within abundant desmoplastic stroma (Fig 2). Fig 1. Fig 2. This patient fit the classic clinical picture of DSRCT: peak age in the second and third decades of life, bulky abdominal and pelvic masses, and five to one male predominance. His disease also had the classic biology of DSRCT: a unique chromosomal translocation t(11;22)(p13;q12), which fuses the Ewing sarcoma gene with the Wilms tumor gene (WT1)1; and polyphenotypic differentiation, evidenced by coexpression of epithelial, mesenchymal, and neural markers with immunostaining positive for keratins, desmin, epithelial membrane antigen, vimentin, CD56, CD57, and CD99 (focal), and negative for chromogranin, synaptophysin, leucocyte common antigen, calretinin, and smooth muscle actin.1 Yet, despite the array of clinical and biologic features characteristic of this high-grade sarcoma, thought to arise from serosa, the solitary recurrence was found in the soft tissue of the thigh. That site is not an expected area of relapse of DSCRT and is therefore not targeted for surveillance monitoring of patients with this cancer. The same holds for other soft tissue sarcomas which rarely metastasize to soft tissues in limbs.10,11 Metastatic DSRCT typically involves distant lymph nodes, liver, and lungs; spread to bones and bone marrow is rare. That natural history partly explains why the unexpected finding in this patient of 18FDG uptake in a routine surveillance PET/CT to assess the pelvis, abdomen, and thorax was dismissed as spurious. Falsely positive 18FDG uptake in the lower leg of a patient with sarcoma has in fact been reported.12 Chemotherapy resistance and the massive, nonlocalized tumor burden account for the poor prognosis of DSRCT.1,2,4,5,13-15 High-dose conventional chemotherapy and aggressive surgery can achieve CR, which ought to be consolidated by RT, such that long-term survival or cure is possible.2,16,17 Surgery after chemotherapy shows persistence of peritoneal or omental studding not seen by CT; hence, the need for more sensitive means to evaluate response and confirm remission. For that purpose, we have resorted to hybrid PET/CT. As regards assessing extent of disease, PET/CT has superior overall sensitivity and specificity to PET or CT alone in a variety of adult cancers, with an impact on clinical decisions18; emerging experience strongly suggests the same will apply to pediatric tumors.12,19-21 PET may also yield useful clinical information beyond anatomic localization of disease: PET's depiction of the metabolic state of tumor could correlate with the proliferative or malignant potential of disease and might provide prognostic insights.22,23

The Addition of Ifosfamide/Etoposide to Cisplatin/Teniposide Improves the Survival of Children With Retinoblastoma and Orbital Involvement

This study aimed to determine the impact of the addition of ifosfamide/etoposide to a regimen containing cisplatin/teniposide on the survival of patients with retinoblastoma with orbital involvement. Thirty patients were treated at the A. C. Camargo Hospital, Brazil, from 1986 to 2002. From 1986 to April 1992 (period I, n=12), treatment consisted of 3 cycles of induction chemotherapy with cisplatin and teniposide, followed by maintenance with same drugs alternating with cyclophosphamide, vincristine, and doxorubicin every 21 days for 60 weeks. Since April 1992 (period II, n=18), the treatment consisted of 3 cycles of ifosfamide and etoposide followed by maintenance with same drugs, alternating with cisplatin and teniposide every 21 days for 36 weeks. In both periods, children were submitted to exenteration with eyelid preservation and orbital radiation therapy with 45 cGy, and also received intrathecal therapy with methotrexate plus dexamethasone and cytarabine. Kaplan-Meier method was used for survival analysis. The median age was 31 months. Most patients (86.7%) presented unilateral tumors. The 3-year overall survival was 34.4% and 72.2%, respectively, for patients treated during periods I and II (P=0.061). The addition of ifosfamide/etoposide to chemotherapy with cisplatin/teniposide improves survival in these patients, but further studies are still necessary.

An Eyelid Sialoblastoma-Like Tumor with a Sarcomatoid Myoepithelial Component

Nonround cell tumors are rare in children and often difficult to diagnose. This article describes an 18-month-old child who presented with a mass on the outer aspect of the left eyelid. This mass was incompletely excised. Histologically, the tumor had nests of basaloid and relatively round cells with immature acinar or ductular structures similar to those seen in a conventional sialoblastoma, but these nests were embedded in a malignant spindle cell stroma. This stroma on immunohistochemistry was marked with S-100 and cytokeratin, which, in combination with the pertinent ultrastructural evidence, indicated a myoepithelial differentiation. Overall histologic features suggested a tumor similar to a sialoblastoma with sarcomatoid transformation of the myoepithelial component, hitherto not described in literature. This tumor probably arose from the palpebral lobe of the lacrimal gland. Postsurgery, the patient received chemotherapy (6 cycles of ifosfamide, vincristine, and doxorubicin hydrochloride [Adriamycin]) and local radiotherapy in view of residual disease. Three months after completion of the treatment (1 year after surgery), the patient is well, without any local disease. Awareness of this unusual histology of sialoblastoma will help in avoiding misdiagnosis and also refine treatment-related issues on this rare tumor.

Impact of High-Dose Busulfan Plus Melphalan As Consolidation in Metastatic Ewing Tumors: A Study by the Société Française des Cancers de l'Enfant

To improve the prognosis for patients with metastatic Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) using conventional chemotherapy and consolidation high-dose chemotherapy (HDCT) containing busulfan and melphalan. Ninety-seven unselected patients with newly diagnosed metastatic ES/PNET received induction chemotherapy that included five cycles of cyclophosphamide 150 mg/m2/d for 7 days, doxorubicin 35 mg/m2/d once, followed by two cycles of ifosfamide 1.8 g/m2/d for 5 days, and etoposide 100 mg/m2/d for 5 days. Patients in complete or very good partial remission received HDCT with busulfan total dose 600 mg/m2 and melphalan 140 mg/m2 followed by autologous blood stem cells. Local therapy (surgery and/or radiation therapy) was performed before or after HDCT. Ninety-seven patients were enrolled from 1991 to 1999 (median age, 12.3 years; range, 0.2 to 25 years). Among them, 75 received HDCT. The 5-year event-free survival (EFS) rate for all 97 patients was 37% and the overall survival (OS) rate was 38%. The EFS after HDCT was 47%. The EFS for the 44 patients with lung-only metastases was 52%, whereas it was 36% for patients with bone metastases without bone marrow involvement. Among the 23 patients with bone marrow metastases, only one survived. The multivariate analysis for both EFS and for OS identified three independent prognostic factors: age, fever at diagnosis, and bone marrow involvement. Compared with conventional chemotherapy, HDCT may yield benefits for patients with lung-only metastases or bone metastases. These results warrant confirmation in a randomized trial and provide part of the background data for the ongoing Euro-Ewing study.