High‐dose ifosfamide in relapsed pediatric osteosarcoma: Therapeutic effects and renal toxicity

Berrak, Su Gülsün; Pearson, Megan; Berberoĝlu, Semha; İnci, İlhan; Jaffe, Norman

doi:10.1002/pbc.20228

Cited by 54 publications

(29 citation statements)

References 33 publications

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“…Chemotherapy protocols have produced survival rates in the 55% to 70% range for nonmetastatic extremity osteosarcoma (37). Ifosfamide and etoposide have proven activity in metastatic osteosarcoma (1,38). Efforts to increase the dose intensity of preoperative or high-risk disease have not improved results (11,39,40).…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma

Anderson

Wiseman

Erlandson

et al. 2005

Clinical Cancer Research

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Osteoblastic metastases and osteosarcoma can avidly concentrate bone-seeking radiopharmaceuticals. We sought to increase effectiveness of high-dose 153 Samarium ethylenediaminetetramethylenephosphonate ( 153 Sm-EDTMP, Quadramet) on osteosarcomas using a radiosensitizer, gemcitabine. Fourteen patients with osteoblastic lesions were treated with 30 mCi/kg 153 Sm-EDTMP. Gemcitabine was administered 1day after samarium infusion. Residual total body radioactivity was within the safe range of <3.6 mCi on day +14 (1.1 F 0.4 mCi; range, 0.67-1.8 mCi).All patients received autologous stem cell reinfusion 2 weeks after 153 Sm to correct expected grade 4 hematopoietic toxicity. Peripheral blood progenitor cells were infused in 11 patients; three patients had marrow infused. Blood count recovery was uneventful after peripheral blood progenitor cells in 11of 11patients. Toxicity from a single infusion of gemcitabine (1,500 mg/m 2 ) in combination with 153 Sm-EDTMP was minimal (pancytopenia). However, toxicity from a daily gemcitabine regimen (250 mg/m 2 /d Â 4-5 days) was excessive (grade 3 mucositis) in one of two patients. There were no reported episodes of hemorrhagic cystitis (hematuria) or nephrotoxicity. At the 6-to 8-week follow-up, there were six partial remissions, two mixed responses, and six patients with progressive disease. In the 12 patients followed >1year, there have been no durable responses. Thus, although high-dose 153 Sm-EDTMP + gemcitabine has moderate palliative activity (improved pain; radiologic responses) in this poor-risk population, additional measures of local and systemic control are required for durable control of relapsed osteosarcoma with osteoblastic lesions. The strategy of radioactive drug binding to a target followed by a radiosensitizer may provide synergy and improved response rate.

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Section: Discussionmentioning

confidence: 99%

Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma

Anderson

Wiseman

Erlandson

et al. 2005

Clinical Cancer Research

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“…Ifosfamide can have serious adverse effects on the kidney despite concurrent use of the uroprotectant mesna. The most common manifestation of ifosfamide‐induced nephrotoxicity is proximal tubular dysfunction, and less often, decreased GFR 8–18. During therapy, acute renal tubular dysfunction often resolves prior to the next course; however, permanent and potentially progressive kidney damage may also occur 16.…”

Section: Introductionmentioning

confidence: 99%

“…A reduction in GFR (defined by serum creatinine levels at or above three times normal) occurred in 25% of patients treated with high dose ifosfamide (14 g/m 2 ) 17. Following administration of more conventional doses, progressive renal insufficiency occurred in 17–50% of ifosfamide‐treated youngsters 19.…”

Section: Introductionmentioning

confidence: 99%

Renal late effects in patients treated for cancer in childhood: A report from the Children's Oncology Group

Jones

Spunt

Green

et al. 2008

Pediatric Blood & Cancer

126

108

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Background Improvements in childhood cancer therapy have led to increasing numbers of long-term survivors. These survivors are at risk for a variety of late effects due to the disease itself, treatment exposures (surgery, chemotherapy, and radiotherapy), underlying medical problems, and health behaviors. The COG LTFU Guidelines are risk-based, exposure-related recommendations for the identification and management of late effects due to therapies utilized in the treatment of childhood cancer, and are designed for asymptomatic survivors presenting for routine medical follow-up two or more years after completion of cancer therapy. Procedure The COG Guidelines Task Force on Urinary Tract Complications conducted an extensive review of the medical literature via MEDLINE. Specific treatment exposures which were reviewed include nephrectomy, chemotherapy regimens known to be nephrotoxic (cisplatin, carboplatin, ifosfamide, and methotrexate) and renal irradiation. Literature sources were ranked according to the strength of evidence and are cited in the review. Conclusions This review summarizes the literature that supported the recommendations for cancer survivors at risk for nephrotoxicity previously outlined in the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers (COG LTFU Guidelines).

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“…Moreover, other factors like the greater cross-linking arm length of IFO and its longer half-life may be contributing to this difference [39]. IFO has shown antitumor activity against a variety of tumors, including small-cell and non-small-cell lung carcinoma [40][41][42][43], breast cancer [44][45][46], ovarian cancer [47,48], bladder cancer [49][50][51], cervical cancer [52], osteosarcoma [53], neuroblastoma [54,55], leukaemia [56,57], multiple myeloma [58], and lymphomas [59,60]. IFO could be used in both single agent and combination therapy with many other cytotoxic agents in clinical practice, such as etoposide, doxorubicin and mitomycin.…”

Section: Pharmacology Of Oxazaphosphorines Antitumor Activity and Mecmentioning

confidence: 99%

Reversal of Resistance to Oxazaphosphorines

Zhang¹,

Tian²,

Zhu³

et al. 2006

CCDT

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The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO) and trofosfamide are one important group of alkylating agents. However, resistance is the major hindrance for success of oxazaphosphorine chemotherapy. The mechanism of resistance to oxazaphosphorines is not fully identified, but recently some novel insights into these aspects have been generated by using sensitive analytical techniques and powerful pharmacogenetic techniques. Potential mechanisms for oxazaphosphorine resistance include decreased activation by cytochrome P450s (e.g. CYP3A4, CYP2C9 and CYP2B6), increased deactivation of the agents by deactivating enzymes such as aldehyde dehydrogenases (ALDHs), increased cellular thiol level, increased DNA repair capacity, and altered cellular apoptotic response to DNA repair, e.g. deficient apoptosis due to lack of cellular mechanisms to result in cell death following DNA damage. In addition, decreased cellular accumulation of cytotoxic species of oxazaphosphorines may also play a role in the resistance. This review highlights the pharmacology of oxazaphosphorine anticancer drugs and possible agents that reverse the resistance to these agents. Possible agents that can overcome oxazaphosphorine resistance include inducers of CYPs, modulators of GSTs and ALDHs, modulators of DNA repair process, antisense oligonucleotides against genes encoding various enzymes and signalling proteins, and novel gene delivery systems. Most of these agents have been investigated in preclinical studies and promising results have been observed. To date, several types of these agents are being evaluated in Phase III trials in cancer patients. Further studies are needed to identify the molecular targets associated with resistance to oxazaphosphorines.

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High‐dose ifosfamide in relapsed pediatric osteosarcoma: Therapeutic effects and renal toxicity

Abstract: HD-IFX is effective in patients who have failed conventional chemotherapy including IFX (9 g/m(2)). Improved disease-free survival was achieved in 30% of patients. However, renal failure constitutes an important life-threatening complication and its development is unpredictable.

Cited by 54 publications

References 33 publications

Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma

Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma

Renal late effects in patients treated for cancer in childhood: A report from the Children's Oncology Group

Reversal of Resistance to Oxazaphosphorines

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