Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149925 (small cell lung cancer)
 6,491 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At Indiana University, we began clinical trials with ifosfamide in 1981. Although our initial efforts were in a variety of tumor types, including pancreatic cancer, we have most recently focused our attention on two tumors that have historically exhibited a higher degree of chemosensitivity--testicular cancer and small cell lung cancer (SCLC). In phase II trials, ifosfamide has proven to have single-agent activity in both diseases. Coupling this data with preclinical observations of synergy with cisplatin and etoposide, we began trials of ifosfamide plus cisplatin with either vinblastine (VeIP) or etoposide (VIP) in patients with recurrent germ cell tumors; we also investigated the use of VIP in SCLC. In third-line or greater therapy for recurrent germ cell tumors, a 36% disease-free status was attained, with 16% of patients continuously free of disease for 5 or more years. Currently, ifosfamide is being evaluated as part of initial therapy in patients with advanced disease. In SCLC, VIP has also been investigated as part of initial therapy in patients with extensive disease. The complete response rate of 38% achieved in 37 evaluable patients has spurred the Hoosier Oncology Group to compare the VIP regimen to cisplatin/etoposide in patients with extensive-disease SCLC. Ifosfamide has the broad range of clinical activity, but its ultimate role as part of initial therapy remains to be discerned.
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PMID:Clinical trials with ifosfamide: the Indiana University experience. 132 10

Ifosfamide, an analogue of the alkylating agent cyclophosphamide, is one of the most active agents in the treatment of small cell lung cancer (SCLC). As a single agent, the drug produces a greater than 50% objective response rate. Recent studies using ifosfamide in combination with other active agents, ie, cisplatin, carboplatin, and etoposide, In the treatment of limited-stage and extensive-stage SCLC have achieved high overall response rates and complete responses (CRs). However, the CR rate is higher in limited-disease patients. Additional studies are needed with the various ifosfamide-containing regimens to precisely define their role in the treatment of SCLC in both limited-disease and extensive-disease patients.
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PMID:Overview of ifosfamide in small cell lung cancer. 132 14

The combination of etoposide and cisplatin has become one of the standard treatments for small cell lung cancer. Ifosfamide, an analogue of cyclophosphamide, has demonstrated single-agent antitumor activity comparable with that of the most active agents used to treat small cell lung cancer. Because ifosfamide is relatively nonmyelosuppressive and its principal dose-limiting toxicity, urotoxicity, has largely been eliminated with the introduction of the uroprotective agent mesna, we undertook a phase II study of the combination of all three agents (etoposide/ifosfamide/cisplatin) in good-performance-status, extensive-disease patients 70 years of age or younger. Twenty-five patients (17 men and eight women; median age, 58 years) were treated with 75 mg/m2 etoposide, 20 mg/m2 cisplatin, and 1.0 g/m2/d ifosfamide administered intravenously for 5 days. Mesna (200 mg/m2) was given as a bolus prior to the first day of chemotherapy and then daily by continuous infusion (900 mg/m2 over 24 hours) between administrations of chemotherapy. Mesna was continued for 12 hours after the last dose of ifosfamide. Treatment cycles were planned every 4 weeks for four cycles. Due to severe toxicities in the first eight patients, subsequent patients received only 4 days of treatment (20% dose reduction). Of the 25 extensive-disease patients studied, 23 are evaluable for response. Seven (30%) achieved a complete response and 10 (43%) had a partial response (overall response rate, 73%). Five patients (22%) had stable disease (< 50% decrease and no evidence of disease progression for at least 4 weeks), and disease progressed in 1 patient (4%). The median survival time was 42 weeks (range, 2 to 160+ weeks). Granulocytopenia was dose-limiting: median granulocyte count was 0.486 x 10(9)/L, 21% of cycles had a granulocyte nadir below 0.2 x 10(9)/L, and four patients died of sepsis. Three patients required platelet transfusion and nine needed blood transfusion. Microscopic hematuria occurred in eight patients (11% of treatment cycles) but was reversible in all cases. A number of central nervous system symptoms were reported but could not be definitely attributed to ifosfamide/mesna. Gastrointestinal toxicity was generally mild, which is attributed to the use of an aggressive antiemetic program. The etoposide/ifosfamide/cisplatin regimen is active and produced a complete response rate of 30% in extensive small cell lung cancer; the duration of response and survival appears similar to that of other standard regimens. The 5-day schedule produced excessive toxicity in this patient population, necessitating a 20% dose reduction (by using a 4-day schedule). The method of administration required a minimum of 5 hospital days per cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A phase II study of ifosfamide in combination with etoposide and cisplatin in the treatment of extensive small cell lung cancer. 133 22

The combination of radiotherapy and cytostatic drugs is of interest in the treatment of several solid tumors. In these preclinical investigations we tested whether ifosfamide and ACNU are able to enhance radiation effects. The experiments were performed by using the MTT assay. Two small cell and 2 non small cell lung cancer cell lines were involved. Ifosfamide, ACNU or both drugs together were tested in 6 different concentrations adjusted to the peak blood level. During the 1 hour drug incubation time, the cell lines were either irradiated with a single dose of 4 Gy or not. The main results were that ACNU possessed only little cytostatic activity in the cell lines under examination. In contrast, ifosfamide caused a dose related cytostatic activity in all cell lines. Concentrations of 26 micrograms/ml (NCC-SCLC H 82) or 10-12 micrograms/ml (3 other cell lines) were able to reduce the surviving cell fraction to less than 50% (IC50). While ACNU showed no clear outlined radiosensitizing properties, ifosfamide reinforced the radiation effects in 3 out of 4 cell lines indicating radiosensitizing properties of this drug. Synergistic effects of ifosfamide and ACNU have not been noticed. These preclinical investigations may constitute the basis for combined ifosfamide and irradiation therapy in future clinical trials.
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PMID:Combined chemo- and radiosensitivity testing with ifosfamide and ACNU in human lung cancer cell lines. 166 91

Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is a prodrug metabolised in the liver by cytochrome P450 mixed-function oxidase enzymes to isofosforamide mustard, the active alkylating compound. Mesna, a uroprotective thiol agent, is routinely administered concomitantly with ifosfamide, and has almost eliminated ifosfamide-induced haemorrhagic cystitis and has reduced nephron toxicity. Therapeutic studies, mostly noncomparative in nature, have demonstrated the efficacy of ifosfamide/mesna alone, or more commonly as a component of combination regimens, in a variety of cancers. In patients with relapsed or refractory disseminated nonseminomatous testicular cancer, a salvage regimen of ifosfamide/mesna, cisplatin and either etoposide or vinblastine produced complete response in approximately one-quarter of patients. As a component of both induction and salvage chemotherapeutic regimens, ifosfamide/mesna has produced favourable response rates in small cell lung cancer, paediatric solid tumours, non-Hodgkin's and Hodgkin's lymphoma, and ovarian cancer. Induction therapy with ifosfamide/mesna-containing chemotherapeutic regimens has been encouraging in non-small cell lung cancer, adult soft-tissue sarcomas, and as neoadjuvant therapy in advanced cervical cancer. As salvage therapy, ifosfamide/mesna-containing combinations have a palliative role in advanced breast cancer and advanced cervical cancer. Ifosfamide/mesna can elicit responses in patients refractory to numerous other antineoplastic drugs, including cyclophosphamide. With administration of concomitant mesna to protect against ifosfamide-induced urotoxicity, the principal dose-limiting toxicity of ifosfamide is myelosuppression; leucopenia is generally more severe than thrombocytopenia. Reversible CNS adverse effects ranging from mild somnolence and confusion to severe encephalopathy and coma can occur in approximately 10 to 20% of patients after intravenous infusion, and the incidence of neurotoxicity may be increased to 50% after oral administration because of differences in the preferential route of metabolism between the 2 routes of administration. Other adverse effects of ifosfamide include nephrotoxicity, alopecia, and nausea/vomiting. In general, intravenously administered mesna is associated with a low incidence of adverse effects; however, gastrointestinal disturbances are common following oral administration. Thus, ifosfamide/mesna is an important and worthwhile addition to the currently available range of chemotherapeutic agents. It has a broad spectrum of antineoplastic activity and causes less marked myelosuppression than many other cytotoxic agents. At present, the role of ifosfamide/mesna in refractory germ cell testicular cancer is clearly defined; however, its overall place in the treatment of other forms of cancer awaits delineation in future well-controlled comparative studies.
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PMID:Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. 172 Mar 82

From January 1986 through December 1988, 227 patients were included in a multi-institutional pilot study for small cell lung cancer (SCLC). Out of the 211 patients who fully completed the staging procedures, 77 (35%) appeared to have SCLC limited to the thorax. All patients received combination therapy consisting of AVI (Adriamycin, VP-16 and Ifosfamide), except during radiotherapy when the Adriamycin was omitted, plus twice daily fractionated 18 MV radiotherapy. Treatment protocol consisted of 4 initial courses of AVI, followed by 3 courses of radiotherapy alternating with modified chemotherapy (VP-16 and Ifosfamide), completed by 2 courses of initial chemotherapy (AVI). Radiotherapy consisted of 1.5 Gy/fraction, 2 fractions/day, 5 days/week in the first course, and 1.8 Gy/fraction, 2 fractions/day, 5 days/week, in the second and third courses, for a total tumor dose of 51 Gy, felt to be equivalent to 60 Gy at normal fractionation. CT treatment planning was employed to design a treatment consisting of multiport radiotherapy, using AP-PA and laterals or obliques beams. During the first course, the homolateral hemithorax received 9 Gy total dose on days 1, 3, 5. During the third course, 360 degrees arctherapy was generally used to boost the reduced tumor volume to a 51 Gy. Besides chest X ray and CT scan, staging and restaging procedures included fiberoptic bronchoscopy. Response rate after irradiation is 61%, with 46% complete responders and 51% local control. The median survival is 14 months, and disease-free survival 42% at 1 year. Complications consisted of cardiac toxicity in 2 patients, 1 death of acute pulmonary toxicity, and 4 instances of moderate chronic radiation pneumonitis. Thus, high doses of radiation can be delivered combined with chemotherapy using this protocol, with an acceptable toxicity and encouraging results in response rate and local control. A longer follow-up is needed to evaluate the impact of these results on survival.
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PMID:Hyperfractionated radiotherapy alternating with multidrug chemotherapy in the treatment of limited small cell lung cancer (SCLC). Groupe Lyonnais d'Oncologie Thoracique. 216 18

Ifosfamide, an analogue of cyclophosphamide, has been proven to be of value in numerous malignancies, including testicular cancer, sarcoma, and lymphoma. Furthermore, ifosfamide is more suitable for combination chemotherapy than its parent compound because it causes less myelosuppression than cyclophosphamide. There have been only a few studies evaluating single-agent ifosfamide in small cell lung cancer (SCLC). In patients who have had little or no prior chemotherapy, ifosfamide appears as active as any single agent. Combination chemotherapy regimens employing cisplatin (or carboplatin) plus etoposide plus ifosfamide are currently under way on both sides of the Atlantic. A Hoosier Oncology Group (HOG) study will evaluate this three-drug regimen v cisplatin plus etoposide, and this protocol will establish or refute the value of ifosfamide as first-line therapy in extensive SCLC.
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PMID:Ifosfamide in small cell lung cancer. 253 44

For the first time in a clinical study oral Ifosfamide was used: 65 elderly or unfit patients with small cell lung cancer (SCLC) were treated as outpatients with fractionated oral Ifosfamide and Etoposide. Forty patients (62%) had extensive stage (ED) disease. The median age of the patients was 66 years. In the 60 patients evaluable for response the objective response rate was 90% with a complete response (CR) rate of 32% and a partial response (PR) rate of 58%. The overall median survival of all 65 patients was 11 months (13 months for LD, 9.5 months for ED). In those patients with LD achieving a CR or a PR radiotherapy was given to the mediastinum. No prophylactic cranial irradiation was given. There was a rapid improvement in the responding patients' performance status and symptoms generally with the first treatment cycle. Overall haematological toxicity was mild, with intravenous antibiotics only being required in 4% of the courses and with only one treatment-related death from septicaemia. A higher than expected rate of CNS toxicity was seen (30%). This was generally mild and always fully reversible and consisted mainly of forgetfulness, occasionally hallucinations, nightmares and somnolence. In only one case did encephalopathy necessitate early termination of treatment. This raises the question of whether Ifosfamide metabolism differs quantitatively or qualitatively when given by the oral route as opposed to the usual intravenous route. We conclude that this simple outpatient based treatment gives a high response rate with rapid improvement in symptoms.
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PMID:A simple outpatient treatment with oral ifosfamide and oral etoposide for patients with small cell lung cancer (SCLC). 254 60

Eight-eight previously untreated patients with small cell lung cancer were treated with a combination of VP16, adriamycin and vincristine (VPAV) for three courses. Resistance to these drugs is associated with the multidrug resistance (MDR) membrane glycoprotein in cell lines in vitro. The clinical relevance of this mechanism of resistance was assessed by using a second line treatment with intravenous infusions of ifosfamide/mesna 5 g/m2 every 3 weeks in patients with only partial responses or non-responders. Cross-resistance to alkylating agents is rare in the MDR. Ifosfamide produced partial responses in six (43%) of 14 patients unresponsive to prior therapy. Intravenously infused ifosfamide/mesna was also used in consolidation therapy with only minor bone marrow or urinary tract toxicity. This did not prevent CNS relapse. The overall response rate to VPAV was 69% and for all treatment modalities, 75%. Median survival for all patients ws 39.5 weeks and 59 weeks for all patients attaining complete response. The addition of large fraction chest irradiation given with the final course of induction chemotherapy to those with good chemotherapy responses produced a further response in 44% of assessable patients. Combined modality treatment resulted in moderate and reversible toxicity. The lack of improved survival with ifosfamide and the resistance of the majority of patients to salvage with ifosfamide/mesna suggested that the MDR is not the major mechanism of resistance in the clinic, since cross-resistance to alkylating agents of this type is not a feature of MDR cells.
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PMID:The multidrug resistant phenotype in clinical practice; evaluation of cross resistance to ifosfamide and mesna after VP16-213, doxorubicin and vincristine (VPAV) for small cell lung cancer. 283 98

Ifosfamide has been found to have antineoplastic activity in a variety of solid tumors. In germ cell tumors, the substitution of ifosfamide for bleomycin in the standard combination bleomycin/etoposide/cisplatin (BEP) did not improve efficacy and caused significantly more toxicity than BEP. This regimen (VIP), however, has shown promise when used with high-dose carboplatin/etoposide as salvage therapy in patients with germ cell tumors not responding to first-line BEP. It is unclear whether the addition of ifosfamide to the carboplatin/etoposide regimen results in an improved therapeutic outcome in patients with multiple recurrent germ cell tumors. In such patients, as well as in those with poor-risk germ cell cancer, high-dose chemotherapy given with hematopoietic growth factors and bone marrow rescue may have a role. In small cell lung cancer, single-agent ifosfamide has produced response rates of 48% to 76%. Currently, the role of ifosfamide is being defined in untreated and recurrent small cell lung cancer.
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PMID:The role of ifosfamide in germ cell tumors and small cell lung cancer. 761 Mar 94


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