UMLS:C0027651 - FACTA Search

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Recent radiobiological analysis of the radiotherapy results for prostate cancer revealed that prostate carcinoma behaves as a late responding tissue, sharing an alpha/beta ratio lower than 2Gy. These findings suggest that hypofractionation may be more effective. Reduction of the overall treatment time could further increase response by abrogating the effect of rapid tumor repopulation. In the present study we report a conformal technique applied (to pelvis and prostate) for the treatment of high-risk prostate cancer, using hypofractionated and accelerated radiotherapy (3.4Gy x 15 consecutive fractions) supported with high-dose daily amifostine (1000mg subcutaneously) to protect normal tissues against early and late effects. The biological dose delivered to the prostate cancer by this HypoARC (hypofractionated accelerated radiotherapy with cytoprotection) technique is estimated to be 71.4Gy (alpha/beta= 1.5 Gy). The time-adjusted biological dose is estimated to 77-94 Gy. Amifostine tolerance was excellent. All seven patients recruited up to now have accomplished their treatment with grade 0-1 cystitis or diarrhoea (5/7 grade 0). The study is ongoing to assess efficacy and late effects of HypoARC.
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PMID:Conformal hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC) for high risk prostatic carcinoma: rationale, technique and early experience. 1551 Jun 17

Pelvic malignancies, including bladder, prostate, and gynecologic cancers, are typically treated with some form of radiation therapy. Reducing radiation-related toxicities in these patients is important for maintaining good quality of life as survival rates increase and also for directly affecting cure rates by reducing delays in radiotherapy. Amifostine (Ethyol) has been shown to reduce rectal bleeding in patients with prostate cancer treated with radiation therapy, prevent radiation-related dermatitis, and provide widespread mucosal protection without adversely affecting local or distant tumor control.
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PMID:Managing toxicities in pelvic malignancies. 1560 21

Concurrent chemotherapy and radiation has improved the outcome for patients presenting with locally advanced squamous cell carcinomas of the head and neck (SCCHN). These improvements have come at a cost of increased treatment-related toxicities. We previously reported the results of a phase II trial examining the role of concurrent carboplatin, paclitaxel, and daily radiotherapy (RT) in SCCHN. In an attempt to decrease these side effects, we conducted a prospective phase II trial evaluating the role of amifostine (Ethyol, MedImmune Oncology, Inc, Gaithersburg, MD) in patients treated with this concurrent chemoRT scheme. From April 2002 to September 2004, 19 patients with stage III-IV SCCHN were enrolled on a prospective phase II trial. Treatment consisted of daily RT delivered to 70.2 Gy (1.8 Gy/fx) with amifostine 500 mg IV (<1 hour before RT), and concurrent weekly carboplatin (100 mg/m2) and paclitaxel (40 mg/m2). Median age was 58.5 years (range, 48 to 70 years); male to female ratio was, 83%:17%; Caucasian versus other was, 61%/39%. Tumor characteristics based on histology were: primary cancers of the oropharynx (55.6%); supraglottic larynx (16.7%); hypopharynx (16.7%); oral cavity (5.6%); and unknown primaries (5.6%). All patients presented with locally advanced, unresectable disease T4 (50%), T3 (27.8%), and advanced nodal disease (N2b-N3) (78%). Toxicities were measured weekly during treatment and at each follow-up visit. Disease response to therapy was determined 2 months after completion of therapy. Seventeen patients are evaluable for response and survival at 2 months following completion of RT. Eighty-four percent completed the prescribed radiation treatment, and 84% of patients received more than six cycles of chemotherapy. The median number of missed chemotherapy cycles was 1.5 (range, 0 to 5 cycles). Fifty-six percent of patients received more than 90% of prescribed amifostine doses, with chemoRT-related toxicity being the most common reason for withholding the dose (77%). Median doses of missed amifostine were three (range, 0 to 30 doses). Grade 3 toxicities associated with therapy were: mucositis and dysphagia (40% of patients each), dehydration (27%), xerostomia (20%), and dermatitis (20%); 53% of patients experienced grade 3 leukopenia, while grade 3/4 neutropenia developed in 20%/13%. No grade 4/5 nonhematologic toxicities were encountered. Forty percent of patients completed RT without unscheduled treatment breaks secondary to treatment-related toxicity. Median treatment-break time was 5 days (range, 0 to 20 days). Clinical complete response at both the primary site of disease and neck was achieved in 75% of patients 2 months following completion of RT. Weekly carboplatin and paclitaxel administered concurrently with definitive RT and daily amifostine is well tolerated, with over 85% of patients completing therapy with acceptable toxicity. The addition of amifostine appears to decrease treatment-related toxicity without impacting efficacy.
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PMID:The evaluation of amifostine for mucosal protection in patients with advanced loco-regional squamous cell carcinomas of the head and neck (SCCHN) treated with concurrent weekly carboplatin, paclitaxel, and daily radiotherapy (RT). 1572 15

Standard conventional radiation therapy for advanced head and neck tumors typically involves administering high radiation dose to the major salivary glands bilaterally. In most cases, this causes a marked reduction in oral saliva output. Xerostomia is one of the most prevalent late side effects of radiation for head and neck malignancies, and patients cite it as the major cause of decreased quality of life. The degree of xerostomia has been reported to depend on the radiation dose and volume of salivary gland irradiated. Several studies show dose-volume-response relationships in the salivary glands, suggesting the possibility of significant improvement in saliva production postradiation, as well as quality of life, if radiation techniques can spare the salivary glands. A growing body of literature supports the premise that intensity-modulated radiation therapy (IMRT) allows irradiation of tumor targets in the head and neck while sparing substantial portions of salivary glands. Early clinical experience has shown substantial sparing of salivary flow following IMRT, and suggests at least equal tumor control but improved xerostomia compared with patients receiving standard radiation techniques. We hypothesize that the addition of a radiation protector, such as amifostine (Ethyol; Medimmune Inc, Gaithersburg, MD) may further improve salivary function over that obtained with IMRT alone. To test this hypothesis, we have initiated a pilot clinical trial to compare unstimulated and stimulated salivary flow rates 6 months and 1 year after IMRT + amifostine with historic controls treated with IMRT alone. Twenty-seven patients have been accrued onto this trial, and the toxicity and compliance data are reported herein.
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PMID:Toxicity and compliance of subcutaneous amifostine in patients undergoing postoperative intensity-modulated radiation therapy for head and neck cancer. 1572 16

While concurrent delivery of chemotherapy and radiotherapy (RT) has a synergistic effect on tumor control and improves the median and overall survival in patients with locally advanced non-small cell lung cancer, appreciable acute and late morbidity occur to the esophagus and the lung during treatment (ie, acute radiation esophagitis, pulmonary toxicity). Emerging evidence suggests that the volume of normal lung exposed to certain threshold doses of RT might predict for the incidence of pneumonitis. Clinical data also indicate that amifostine (Ethyol; Medimmune Inc, Gaithersburg, MD), an organic thiophosphate, acts as a selective cytoprotective agent for normal tissues against the toxicities of chemotherapy and RT. Moreover, preclinical and clinical data suggest that subcutaneous administration of amifostine may be better tolerated with similar efficacy to that of the intravenous route. We are conducting an open-label trial that is accruing patients with locally advanced non-small cell lung cancer, who will receive concurrent chemoradiotherapy (cisplatin/etoposide or carboplatin/paclitaxel plus RT delivered using 3-dimensional conformal radiotherapy treatment planning) and amifostine 500 mg before RT. Incidence and severity of acute radiation esophagitis, acute radiation pneumonitis, chronic radiation pneumonitis, and changes in pulmonary function will be recorded, as will elements of the RT treatment planning (eg, dose volume histogram data for the lung and esophagus). Pre- and post-therapy pulmonary function is a primary endpoint, and others include general safety assessments of subcutaneous amifostine administration.
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PMID:Open label multicenter trial of subcutaneous amifostine (Ethyol) in the prevention of radiation induced esophagitis and pneumonitis in patients with measurable, unresectable non-small cell lung cancer. 1572 22

Amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) is a cytoprotective and radioprotective agent for normal tissues against the deleterious effects of chemotherapeutic agents and/or ionizing radiation. We have compiled a unique database for meta-analysis that aims to address the controversial concept of the tumor protection. The proposed meta-analysis on survival outcome, which is based on individual patient data, will be more useful than literature-based meta-analyses because of the superiority of reliable, longer follow-up patient data. It will be also possible to study the effect(s) of amifostine in different tumor types.
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PMID:Randomized trials of amifostine and radiotherapy: effect on survival? 1572 26

The influence of amifostine alone and in combination with doxorubicin, cytarabine, and etoposide on the cell growth and on bcl-2, bax and p65 gene expression was investigated in human acute promyelocytic leukemia cell line HL-60. No or very little influence of the exposure of HL-60 cells to amifostine (10(-6) to 10(-2) M) on cell proliferation was shown. Proliferation of HL-60 cells exposed to doxorubicin, cytarabine, or etoposide dropped down with increasing doses of these drugs. Only in the case of doxorubicin, more effective inhibition of HL-60 cell growth was observed when combination of doxorubicin, cytarabine or etoposide with amifostine was used. Cytotoxic effect of cytarabine or etoposide was not reduced by amifostine. The lowering of the cytotoxic index (IC50) was observed only when HL-60 cells were preincubated with amifostine followed by doxorubicin treatment. IC50 was estimated as 2.1 x 10(-7) M and 0.9 x 10(-7) M for doxorubicin and doxorubicin with amifostine, respectively. This effect was accompanied by the induction of caspase 3 activity. HL-60 cells treated with doxorubicin alone showed about 35-fold increase in caspase 3 activity. The enzyme activity was stimulated by combination of doxorubicin with amifostine up to 94 times. Furthermore, the expression of bcl-2 and bax genes involved in apoptosis as well as tumor-associated p65 gene were determined. Semiquantitative reverse transcriptase polymerase chain reaction showed a decrease in bcl-2 and an increase in bax and p65 expression in HL-60 cells treated with doxorubicin in combination with amifostine when compared with the cells treated only with doxorubicin. Amifostine may potentiate doxorubicin therapeutic efficiency in human acute promyelocytic leukemia cells.
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PMID:Induction of caspase 3 activity, bcl-2 bax and p65 gene expression modulation in human acute promyelocytic leukemia HL-60 cells by doxorubicin with amifostine. 1598 19

Anthracyclines are powerful cytotoxic agents, used as first-line treatment of leukemias and many other tumors, but host-tissue toxicity is their main dose-limiting factor. However, their therapeutic effects depend not only on the toxicity, hence on the dose, but also on drug resistance. Among the mechanisms that can account for cell sensitivity to anthracyclines, there is an overexpression of drug transport proteins, like the transmembrane P-glycoprotein (PGP), the multidrug- resistance-related protein (MRP) and the lung-resistance-related protein (LRP). Attempts to reduce the toxicity of chemotherapeutic agents without affecting their efficacy have been made using liposomal anthracyclines or cytoprotective agents, as Amifostine. The aim of this study was to evaluate and compare the toxic effects of Daunorubicin, in normal or liposomal formulation, used in combination with WR1065, the active metabolite of Amifostine, against normal and tumor cells. In conclusion these data show that the preincubation with WR-1065 does not inhibit the drug toxic effect on blast cells and on tumor cell lines, independently by their multidrug resistance phenotype, but has a cytoprotective effect on stem cells causing a drug cytotoxicity reduction of 10-20%. This advantage is even higher using the liposomal formulation of DNR. Therefore, Amifostine can offer a chance of protecting normal cells from the toxicity of anthracyclines, in normal or liposomal formulation. The combination of liposomal anthracyclines with Amifostine can confer further advantages in management of leukemic patients, especially the elderly where treatment toxicity is a main problem. These patients may be candidates for alternative therapeutic strategies and the combination of DNX and Amifostine is an attractive treatment for these cases where a low nonhematological toxicity is required.
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PMID:Effect of amifostine on the cytotoxicity of daunorubicin and daunoxome in tumor and normal cells. 1600 Nov 70

Current therapeutic approaches for lung cancer favor treatment intensification, with the presumption that dose-intense chemotherapy regimens and/or higher radiation therapy (RT) doses or novel fractionation schemes will result in increased patient survival. Also, the trend for non-operative therapy has favored concurrent over sequential regimens. The incidence of severe acute esophagitis in patients treated for lung cancer with standard (once daily) RT alone is 1.3%, and induction chemotherapy increases the risk of severe acute esophagitis slightly over that of standard RT alone. In contrast, a strong radiosensitizing effect of chemotherapy given concurrently with standard thoracic RT (chemoRT) is associated with an incidence of severe esophagitis of 14% to 49%. Acute esophagitis may be severe and disabling, and result in hospitalization, placement of a feeding tube in the stomach or intravenous feedings, and steady supportive care. Also, RT may need to be halted temporarily to allow for healing of the esophageal lining; treatment breaks in turn decrease survival of patients with unresectable lung cancer. Therefore, esophagitis as a dose-limiting toxicity of chemoRT may have a direct impact on tumor control and survival. Aggressive types of RT fractionation have also been associated with worsening esophagitis grades and duration. Moreover, it is commonly assumed in the radiation oncology clinic that the longer the length of the esophagus segment included in the RT field the higher the probability of esophageal toxicity, although differing opinions are commonly expressed. Recent advances in 3-dimensional conformal RT allow a unique chance to gain volumetric data pertaining to organ damage rather than rely on older estimates based on organ length (eg, esophagus) or portion (ie, lung, spinal cord). The Radiation Therapy Oncology Group (RTOG) conducted a large phase III, randomized study RTOG 98-01 examining chemoRT with or without the amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD), a cyto- and radioprotectant in locally advanced non-small cell lung cancer (n = 243). While amifostine did not significantly reduce severe esophagitis based on National Cancer Institute Common Toxicity Criteria and weekly physician dysphagia logs, swallowing dysfunction over time (based on patient diaries, the equivalent of Esophagitis Index) was significantly lower in the amifostine arm ( P = .03). Therefore, significant progress has been accomplished in our understanding of the basis of esophageal injury resulting from thoracic RT, and future effort may find other effective strategies to either minimize or eliminate esophagitis.
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PMID:Treatment-related esophagitis. 1601 37

Amifostine is a pharmacological antioxidant used as a cytoprotectant in cancer chemotherapy and radiotherapy. It is thought to protect normal tissues relative to tumor tissue against oxidative damage inflicted by cancer therapies by becoming concentrated at higher levels in normal tissues. The degree to which amifostine nevertheless accumulates in tumors and protects them against cancer therapies has been debated. Guidelines have been published that direct its use in chemotherapy and radiation, taking into consideration the concerns of tumor protection. In this article, clinical studies of amifostine appearing since the publication of the most recent set of guidelines are reviewed. Randomized and nonrandomized trials of regimens involving chemo-therapeutic agents (chemotherapy, chemoradiation, conditioning regimens for bone marrow transplant) are discussed. Nineteen studies showed positive effects for amifostine reducing the level of side effects of these regimens, while 9 showed no effect and 1 had a questionable result. Clinically relevant levels of amifostine toxicity were observed in several studies, but subcutaneous administration may reduce such toxicity. Amifostine showed protection against mucositis, esophagitis, neuropathy, and other side effects, although protection against cisplatin-induced ototoxicity was not observed. No evidence of tumor protection was observed. Amifostine may enable populations unable to tolerate conventional cancer therapy to receive treatment of their cancers, even if some degree of tumor protection is eventually discovered. The authors discuss the implications of this research for patient populations seen in integrative cancer care centers and for research on phytochemical antioxidants such as vitamins and carotenoids.
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PMID:Commentary: the pharmacological antioxidant amifostine -- implications of recent research for integrative cancer care. 1646 91

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