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  • 1
    Electronic Resource
    Electronic Resource
    Phase I study of high-dose cisplatin, ifosfamide, and etoposide (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 331-334 
    Details
    ISSN: 1432-0843
    Keywords: Cisplatin ; Ifosfamide ; Phase I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To test the feasibility of a regimen of high-dose cisplatin, ifosfamide, and etoposide (VP-16; VIPP regimen), we registered 15 patients with advanced non-small-cell lung cancer in a phase I trial of the Northern California Oncology Group. One cycle of treatment consisted of high-dose cisplatin given at 100 mg/m2 i.v. on days 1 and 8, VP-16 given at 60–75 mg/m2 i.v. on days 1–3, plus ifosfamide given at 1.0–1.2 g/m2 i.v. on days 1–3; cycles were repeated every 28 days. There were 13 men and 2 women; the median age was 59 years (range, 47–72 years). The median Karnofsky performance status (KPS) was 90 (range, 70–100). All patients were assessable for toxicity and response. The median number of cycles delivered per patient was two (range, one to four). Hematologic toxicity was dose-limiting and required de-escalation of the ifosfamide and VP-16 doses. Ten patients developed a white blood count of 〈1000/mm3 and seven patients developed a platelet count of 〈50,000/mm3. The duration of cytopenia increased progressively with each subsequent cycle of therapy. Two patients required antibiotics for neutropenic fever with documented infections (pneumonia, bacteremia). Seven patients received red blood cell transfusions for a hemoglobin level of 〈8 gm/dl. Grade III or IV non-hematologic toxicities were uncommon and involved one patient each with grade 3 ototoxicity and grade 3 neurotoxicity. Five patients developed laboratory evidence of renal salt wasting. The overall response rate was 33% (5/15) with a complete response being achieved by two patients (13%) and a partial response being attained by three (20%). The overall median survival was 44 weeks. We conclude that although this regimen demonstrated activity, hematologic toxicity limited its use in the palliative treatment of non-small-cell lung cancer. Using hemopoietic growth-factor support to permit dose escalation, this schedule of VIPP may be of interest in a number of different chemotherapy-sensitive tumor types.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686041
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  • 2
    Electronic Resource
    Electronic Resource
    High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: targeted plasma levels are achievable clinically (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. 504-508 
    Details
    ISSN: 1432-0843
    Keywords: Key words Lung cancer ; Toremifene ; Cisplatin ; Protein kinase C ; Phase II trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally ≥5 μM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment consisted of toremifene, 600 mg orally on days 1–7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. Results: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (±8.6) μM and 9.8 (±4.4) μM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. Conclusions: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050852
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  • 3
    Electronic Resource
    Electronic Resource
    Treatment of poor-prognosis extensive disease small-cell lung cancer with an all-oral regimen of etoposide and cyclophosphamide – a Southwest Oncology Group clinical and pharmacokinetic study (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 461-468 
    Details
    ISSN: 1432-0843
    Keywords: Key words Etoposide ; Cyclophosphamide ; Oral chemotherapy ; Pharmacodynamics ; Small-cell lung cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: An all-oral regimen of etoposide and cyclophosphamide was developed for use in poor-prognosis extensive disease small-cell lung cancer. Limited pharmacokinetic sampling was used to derive a pharmacodynamic model predictive of myelosuppression early in the course of therapy. Patients and methods: Eligible patients were chemotherapy-naive and had extensive disease small-cell lung cancer with either SWOG performance status 2 or serum albumin 〈3.5 g/dl. The first cohort (n = 18) received etoposide orally at 50 mg daily and cyclophosphamide orally at 50 mg daily days 1–14 every 28 days. Due to good hematologic tolerance, the second cohort (n = 39) received both agents orally at 50 mg twice daily days 1–14 every 28 days. Plasma etoposide levels were determined in samples drawn at baseline, and at 1 h, 2 h, and 23.5 h (trough) after the first dose. Linear regression analysis was used to determine pharmacokinetic and demographic parameters predictive of myelosuppression. Results: A total of 173 treatment cycles were delivered. Patients on the daily regimen had a 22% response rate (complete and partial), a 22% unconfirmed response rate, and a 5-month median survival, while patients on the twice-daily regimen had a 28% response rate (complete and partial), a 13% unconfirmed response rate, and a 7-month median survival. Granulocytopenia and alopecia were the most common toxicities seen. Significant granulocytopenia could be predicted for the twice-daily regimen according to the formula ln(AGC nadir)=7.80 − 1.88(trough), with an increased incidence of granulocytopenia if the etoposide trough value was ≥1.49 μg/ml. Conclusion: Oral etoposide and oral cyclophosphamide given days 1–14 every 28 days is well tolerated and results in an acceptable response rate and median survival in poor-prognosis (poor performance status or low serum albumin) extensive disease small-cell lung cancer. A trough etoposide level obtained within 24 h of starting therapy can predict severe granulocytopenia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800051119
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  • 4
    Electronic Resource
    Electronic Resource
    High-dose cisplatin with diethyldithiocarbamate (DDTC) rescue therapy: preliminary pharmacologic observations (1989)
    Springer
    Cancer chemotherapy and pharmacology 23 (1989), S. 276-278 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Diethyldithiocarbamate (DDTC), a chelating agent that is a major metabolite of disulfuram, has been proposed as a potential rescue agent to reduce toxicity following high-dose cisplatin (HDCP) therapy. In the present study, we examined the pharmcologic interaction of HDCP and DDTC given as rescue therapy. Total plasma platinum and ultrafiltrate platinum pharmacokinetics and DDTC levels were determined in six patients with advanced malignancies who received a total of 11 cycles of HDCP with DDTC rescue. HDCP therapy (200 mg/m2 per cycle) consisted of 100 mg/m2 reconstituted in 250 cc 3% saline and infused over 3 h on days 1 and 8 of each 28-day cycle. DDTC rescue at a dose of 4 gm/m2 was given by an i.v. infusion (duration 1.5–3.5 h), beginning 45 min after the completion fo cisplatin infusion. Peak total and ultrafiltrate levels and cisplatin pharmacokinetics in this study were indistinguishable from those of previous studies using the same HDCP regimen without DDTC rescue. Ultrafiltrate or unbound plasma platinum was〈10% of total plasma platinum concentrations and demonstrated a biphasic pattern of elimination. Levels of DDTC predicted to be chemoprotective (〉400 μM) were achieved with the dose and schedule used in this study. These data demonstrate that DDTC can be targeted to protective plasma concentrations without significantly altering plasma cisplatin pharmacokinetics and support the potential usefulness of DDTC as a rescue agent following HDCP therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00292403
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  • 5
    Electronic Resource
    Electronic Resource
    Control of high-dose-cisplatin-induced emesis with an all-oral three-drug antiemetic regimen (2000)
    Springer
    Supportive care in cancer 8 (2000), S. 46-48 
    Details
    ISSN: 1433-7339
    Keywords: Key words Antiemetics ; Dexamethasone ; Emesis ; Granisetron ; Prochlorperazine ; Cisplatin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In this pilot trial, the antiemetic efficacy and tolerability of an all-oral antiemetic combination in the prevention of both acute and delayed nausea and vomiting following high-dose cisplatin was evaluated. Fifty-two patients receiving cisplatin (median dose 100 mg/m2) were entered. Patients received (1) 60 min prior to cisplatin: prochlorperazine spansule 15 mg, dexamethasone 20 mg, granisetron 2 mg; (2) 12 h after cisplatin: prochlorperazine spansule 15 mg, dexamethasone 10 mg; (3) on days 2 and 3: prochlorperazine spansule 15 mg b.i.d., dexamethasone 8 mg b.i.d.; (4) on days 4 and 5: dexamethasone 4 mg b.i.d. All antiemetics were administered orally. The study period was the 120 h after cisplatin administration. The primary efficacy end-point was complete control (no vomiting, retching or antiemetic rescue) of delayed emesis (24–120 h after cisplatin). Complete control of delayed emesis was achieved in 26 patients (53%). Nineteen patients (39%) noted no delayed nausea. Complete control of acute emesis (24 h after cisplatin) was attained in 44 patients (86%). The no nausea rate during the first 24 h was 74%. Overall, 39 patients (80%) were satisfied or very satisfied with their outcome. Treatment was well tolerated with infrequent and minor adverse events. In conclusion, an all-oral combination of granisetron, dexamethasone and prochlorperazine is a highly effective and well-tolerated regimen for preventing acute cisplatin-induced emesis. Control of delayed emesis was not better than with current standard treatment, and more effective approaches are needed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005209900077
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  • 6
    Electronic Resource
    Electronic Resource
    Chemotherapy of metastatic testicular cancer: Current status and future prospects (1990)
    Springer
    World journal of urology 8 (1990), S. 20-26 
    Details
    ISSN: 1433-8726
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Introduction of the chemotherapeutic agent cisplatin in 1974 initiated 15 years of progress in the management of metastatic testicular cancer at a pace virtually unprecedented in the history of medical oncology. With current cisplatin- and etoposide-based regimens, longterm survival of 80% is consistently achieved. Recently completed clinical trials have defined several prognostic variables that disthinguish good- and poor-prognosis subsets of patients. Since the great majority of patients with good-prognosis disease achieve complete remission and long-term survival, the current focus of research in this patient population has shifted to means of reducing treatment-related toxicity. By comparison, in poor-prognosis patients the cure rate remains an unacceptable 40%–50%. Clinical research in this population has focused primarily on methods of intensifying treatment, such as alternating non-cross-resistant drug combinations, increasing the dose intensity of cisplatin, and investigating new active agents such as ifosfamide. Even in the setting of relapsed or resistant disease, high-dose chemotherapy with or without autologous bone marrow transplant offers the potential for long-term remission in some patients. Future prospects for improving the therapeutic index may include colony-stimulating-factor support to circumvent chemotherapy-related myelosuppression, the use of chemosensitizers to reverse drug resistance, or the introduction of biologic response modifiers into the therapeutic armamentarium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01576273
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  • 7
    Electronic Resource
    Electronic Resource
    Topical dimethylsulfoxide may prevent tissue damage from anthracycline extravasation (1989)
    Springer
    Cancer chemotherapy and pharmacology 23 (1989), S. 316-318 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The optimal management of anthracycline extravasation remains unclear. Traditional topical measures to reduce local tissue damage, including corticosteroids, sodium bicarbonate, and ice applications, have not consistently demonstrated beneficial effects. This report describes our experience with four adult patients who suffered anthracycline extravasation and were treated with a regimen of ice, local glucocorticoid injection, and dimethylsulfoxide (DMSO) 55%–99% applied topically every 2–4h after extravasation for a minimum of 3 days. In all four cases, pain and erythema resolved within 2 days; in no case did tissue necrosis or skin ulceration occur. Topical DMSO is a safe, inexpensive agent that appears to reduce the risk of anthracycline-induced tissue damage. Further studies are needed to determine the optimal dose and schedule of DMSO application and to assess its efficacy in extravasation injuries from other vesicants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00292411
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  • 8
    Electronic Resource
    Electronic Resource
    Phase I trial of a 5-day infusion ofL-leucovorin plus daily bolus 5-fluorouracil in patients with advanced gastrointestinal malignancies (1993)
    Springer
    Cancer chemotherapy and pharmacology 32 (1993), S. 215-220 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The combination of leucovorin [(6d,l)-5-formyltetrahydrofolate] and 5-fluorouracil (5-FU) has increased efficacy compared to 5-FU alone as treatment of advanced colorectal cancer. Leucovorin is metabolized to methylene tetrahydrofolate, which potentiates the antitumor actions of 5-FU by forming a ternary complex of thymidylate synthase, fluorodeoxyuridine and methylene tetrahydrofolate. Onlyl-leucovorin is metabolized to methylene tetrahydrofolate and forms this ternary complex. However,d-leucovorin may not be inert.d-Leucovorin may impair cellular uptake and metabolism ofl-leucovorin, thereby inhibiting the actions ofl-leucovorin. Because of this possible limitation to the effectiveness of racemic leucovorin, we have begun to explore the effects of the pure, biologically active isomer,l-leucovorin. In this phase I trial, patients with advanced gastrointestinal malignancies were treated with a 5-day continuous infusion ofl-leucovorin and daily intravenous boluses of 5-FU at 370 mg/m2. The dose ofl-leucovorin was escalated in groups of three patients at four doses, 200 mg/m2 per day, 400 mg/m2 per day, 700 mg/m2 per day and 1000 mg/m2 per day. Treatment was repeated every 28 days. Seventeen patients with advanced gastrointestinal cancers entered the trial. Sixteen patients were evaluable for toxicity. Toxicity was similar to that expected for leucovorin plus 5-FU. The most common severe toxicities (and the number of patients affected) were: diarrhea (2), mucositis (2), nausea/vomiting (1), and abdominal/rectal pain (2). The maximum tolerated dose ofl-leucovorin was 700 mg/m2 per day. Twelve patients were evaluable for response. One complete, one partial and one minor response were observed. All responses occurred among the nine patients with colorectal carcinomas. The combination ofl-leucovorin and 5-FU is well tolerated by patients and appears active for treatment of advanced colorectal carcinomas. Additional clinical trials are necessary to determine ifl-leucovorin is more effective thand,l-leucovorin for modulating the effectiveness of 5-FU.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685838
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of cisplatin in patients receiving interleukin-2-containing treatment regimens (1989)
    Springer
    Cancer chemotherapy and pharmacology 24 (1989), S. 135-136 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Plasma cisplatin pharmacokinetics were determined in 6 patients enrolled in a phase I trial of combined high-dose cisplatin and Interleukin-2 (IL-2) therapy. Cisplatin (100 mg/m2) was given in 3% saline as a 3-h infusion on days 1 and 8 of each 28-day cycle; IL-2(2-4×106 units/m2) was given as an i.v. bolus on days 15–19 in a dose escalation trial. Peak total and ultrafiltrate plasma platinum concentrations were 1.15 and 0.172 μg/ml for cycle 1 and 1.2 and 0.124 μg/ml for cycle 3, respectively. The AUCs for total and ultrafiltrate plasma platinum were 7.33 and 0.965 μg/ml per hour for cycle 1 and 8.48 and 0.924 μg/ml per hour for cycle 3, respectively. Total body clearances for total and ultrafiltrate platinum were 0.051 and 0.525 ml/h for cycle 1 and 0.042 and 0.443 ml/h for cycle 3, respectively. These data demonstrate no significant effects of IL-2 on the plasma pharmacokinetics of cisplatin in the dose schedule given and support the feasibility of this combined modality therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00263136
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  • 10
    Electronic Resource
    Electronic Resource
    High-dose cisplatin and mitomycin C in advanced non-small cell lung cancer: a phase II study of the Northern California Oncology Group (1990)
    Springer
    Cancer chemotherapy and pharmacology 27 (1990), S. 243-247 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To investigate chemotherapeutic dose intensity in advanced non-small-cell lung cancer (NSCLC), we evaluated a pharmacokinetically designed schedule of high-dose cisplatin (200 mg/m2 per 28-day cycle) plus mitomycin C. Between March 1987 and March 1989, 62 patients were registered for a phase II study of the Northern California Oncology Group (NCOG). The treatment schedule consisted of cisplatin in hypertonic saline given on a divided days 1 and 8 schedule (100 mg/m2 on each day) plus mitomycin C given at a dose of 8 mg/m2 on day 1 of each cycle. In 61 patients evaluable for response analysis, the overall response rate was 39% (24/61), with a complete response being achieved in 6% (4/61) of cases and a partial response, in 33% (20/61). The response according to reviewed histologic subtype included squamous, 53% of patients (10/19); large cell, 31% (4/13); and adenocarcinoma, 34% (10/29). The median survival for all patients was 19.3 weeks. The mean cisplatin and mitomycin C delivered dose intensities in this study were 45 mg/m2 per week (90% of the projected dose) and 1.5 mg/m2 per week (75%). The toxicity of this combination regimen in the 62 enrolled patients was significant but manageable. Leukopenia (WBC, 〈1,000/mm3) and thrombocytopenia (platelets, 〈25,000/mm3) occurred in 3# and 8% of patients treated, respectively. Dose-limiting renal toxicity and clinically significant ototoxicity developed in 8 patients each (13%), and a peripheral sensory neuropathy was observed in 17 cases (27%). Whether this type of dose-intensive therapy results in an improved therapeutic index in NSCLC is currently being evaluated in a randomized comparative trial versus standard-dose cisplatin therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685721
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