Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol.

Abstract

Between 1984 and 1989, 159 patients presenting with advanced germ cell cancer were entered on a randomized clinical trial comparing the efficacy and toxicity of etoposide and bleomycin and either standard-dose cisplatin (20 mg/m2 daily for 5 days) or high-dose cisplatin (40 mg/m2 daily for 5 days). Of the 159 patients, 153 were assessable for toxicity and response. As expected, patients receiving the high-dose cisplatin regimen experienced significantly more neurotoxicity, ototoxicity, nausea and vomiting, and myelo-suppression. Four patients (3%) died related to therapy. Despite the toxicity encountered, dose intensity was maintained. Overall, 84% of patients in the high-dose arm received 80% or more of the projected dose of cisplatin, etoposide, and bleomycin; and 90% of patients on the standard-dose arm received 80% or more of the projected dose. Of the 76 eligible patients randomized to receive the high-dose cisplatin regimen, 52 (68%) became disease-free with chemotherapy alone or with subsequent resection of residual teratoma or cancer. Of the 77 patients randomized to the standard-dose arm, 56 (73%) became disease-free with chemotherapy alone or with surgery. Median follow-up is now 24 months. Eleven patients (three high-dose and eight standard-dose) relapsed from disease-free status. Overall, 74% of patients receiving the high-dose cisplatin regimen are alive, and 63% are continuously free of disease. Of the patients receiving the standard-dose cisplatin regimen, 74% are alive, and 61% are continuously free of disease. This randomized prospective trial in advanced germ cell cancer achieved dose intensity of the most active single agent in this disease. This dose intensity did not translate into an improved survival or cure. We conclude that dose escalation of cisplatin beyond standard doses results in excess toxicity with no accompanying therapeutic benefit.

Phase I/II study of a short course of weekly cisplatin in patients with advanced solid tumours

“…The patient characteristics are given in Table I (Ozols et al, 1985;Levin et al, 1987;Kaye, 1992) but is controversial in other tumour types. An improvement in treatment outcome with higher than standard cisplatin doses per course was reported for non small cell lung cancer (Gralla et al, 1981;Gandara, 1989), testicular cancer (Samson et al, 1984;Ozols et al, 1988) and head and neck cancer (Forastiere et al, 1987), but randomised studies comparing standard with high cisplatin dosages (in general in day 1-5 or day 1 + 8 schedules) failed to show any benefit for the high dose arms in testicular cancer (Nichols et al, 1991), non small cell lung cancer (Einhorn et al, 1986) and malignant melanoma (Mortimer et al, 1991). Another approach to increase the platinum dose intensity is to increase the frequency of cisplatin administration, or to combine cisplatin with its analogue carboplatin.…”

Baseline and early lymphopenia predict for the risk of febrile neutropenia after chemotherapy

“…The quantification of the individual risk for a given patient remains uneasy in clinical practice. Although the dose of chemotherapy significantly increases the risk of FN, this complication may occur after almost any type of chemotherapy regimen (Miser et al, 1987;Tannock et al, 1988;Velasquez et al, 1988;Coiffier et al, 1989;Elias et al, 1989;Nichols et al, 1991). Individual parameters of the patient contribute, therefore, significantly to the risk of FN, in addition to the type and dose of chemotherapy.…”

“…The risk of FN after administration of chemotherapy not only depends on the type and doses of drugs administered, but also on individual risk factors for each patient, such as performance status (PS), coexisting infections or underlying immunosuppression (Bodey, 1986;Klastersky, 1993;Bodey et al, 1996;Segal et al, 2001). Hence, even after the administration of a dose-intensive chemotherapy regimen, 30 -50% of the patients will not experience FN, while conversely, FN will occur in 2 -15% of the patients who receive chemotherapy regimens with conventional doses of drugs (Miser et al, 1987;Tannock et al, 1988;Velasquez et al, 1988;Coiffier et al, 1989;Elias et al, 1989;Nichols et al, 1991).…”

Current status and future perspectives in the treatment of advanced testicular cancer

“…Nichols and co-workers undertook a randomized trial comparing the BEP regimen with a double dose of CDDP and a standard dose of BEP. 34 This dose intensity did not show a higher response rate or survival benefit. In fact, significantly increased neurotoxicity, ototoxicity, nausea and vomiting, and myelosuppression occurred.…”