Dose-response and dose-survival advantage for high versus low-dose cisplatin combined with vinblastine and bleomycin in disseminated testicular cancer a southwest oncology group study

Summary Twenty-five patients with advanced solid tumours were entered in a phase I/II study of six, weekly cycles of cisplatin. Nineteen patients were chemonaive and six were previously treated. The starting dose was 50 mg m-2 week-'. This dose could be escalated without major toxicity to 70 mg m-2 week-'. At a dose of 80 mg m -2 myelosuppression grade 3 occurred as well as grade I nephro-and neurotoxicity. The maximum tolerated dose was 85 mg m-2 with dose limiting thrombocytopenia. Hypertonic saline was effective in preventing nephrotoxicity. Ondansetron was a very effective antiemetic in the first weeks of treatment but its efficacy waned later on. Responses were observed in head and neck cancer, melanoma and mesothelioma. At the dose level of 80 mg m -2 the optimal dose intensity was reached. This schedule will be tested further in phase 11 studies.

Section: Resultsmentioning

confidence: 94%

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

Planting¹,

Burg²,

Boer-Dennert³

et al. 1993

“…However, in a larger study (van Eys, 1989) no difference in outcome was seen for the higher dose arm. Another study (Samson, 1984) revealed that patients with testicular cancer fared better at a higher dose level of cisplatin with an improved CR rate and survival. The dose-response effect of cisplatin in germ cell tumours has recently been confirmed by Ozols (1988), although in this study the waters were muddied by the addition of etoposide in the higher dose arm.…”

Section: Dose Escalating Studiesmentioning

confidence: 99%

Dose intensity in cancer chemotherapy

Dodwell

Gurney²,

Thatcher³

1990

There is substantial evidence that, for the majority of antitumour agents including alkylating agents, anthracycline antibiotics and anti-metabolites, there is a steep dose response curve when these agents are studied in in vitro and in vivo models (Griswold et al., 1963;Bruce et al., 1966;Schabel et al., 1984). It is this dose-response relationship which is often cited in support of high dose chemotherapy with autologous bone marrow rescue as a promising avenue for the treatment of solid tumours. The purpose of this review is to assess the evidence that dose and dose intensity are important determinants of outcome in the treatment of human cancer with cytotoxic chemotherapy. We will review retrospective and prospective studies of dose and dose intensity in a variety of tumour types, and discuss how future clinical studies may be planned and presented to provide a more informed therapeutic rationale for exposing patients to greater doses of cytotoxic drugs in an attempt to improve outcome. Retrospective dose intensity analysis Breast cancerIn 1984 Hryniuk and Bush analysed the complete and partial remission rates and median survival times of 26 published studies using CMF-type regimens in the treatment of advanced breast cancer. For each regimen they also calculated the average relative dose intensity in the following way.The doses of cyclophosphamide, methotrexate and 5-fluorouracil were converted to a standard form of mg m2 per week. The dose intensities of each agent were compared to the dose intensity of a regimen used by Cooper (1969). The dose intensities of the test regimen were expressed as a fraction of the intensities of each drug in the Cooper protocol. The relative dose intensities for each drug in an individual CMF regimen were then averaged to give the average relative dose intensity (ARDI) of CMF-containing therapy for that particular 'test' regimen. They found a linear relationship between response rate and ARDI (Figure 1). The relationship was even more clearcut when doses actually delivered to patients, rather than planned protocol doses, were used to calculate ARDI (Figure 1).When the ARDI of a variety of CAF (cyclophosphamide, doxorubicin and 5-fluorouracil) regimens were calculated in the same way and expressed as a fraction of the ARDI of a dose intensive 'reference' regimen used by Bull and Tormey (1978) again there was a clear positive correlation between ARDI and response rate and again the relationship was clearer when delivered, rather than planned, doses were used. Hryniuk and Bush also extended their observations to median survival time. The median survival time (MST) (of all patients) and the remission rates in these studies (CMF and CAF)

“…Since the nephrotoxicity of DDP seems to be related to peak serum-free platinum levels, DDP bolus doses >100 mg m-2 would be predicted to be more toxic than smaller daily doses such as 20 mg m-2 x 5 days (Reece et al, 1987). On the other hand, reducing DDP to cumulative doses lower than 75 mg m-2 at 3 week intervals results in inferior survival in patients with metastatic germ cell cancer (Samson et al, 1984). Thus, adequate platinum dosing appears to be relevant for maintaining cure rates but may also be associated with a higher incidence of acute and late nephrotoxicity (Osanto et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity

Bokemeyer

Fels²,

Dunn³

et al. 1996

Summary Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by coadministration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10-6 or 7.25 x 10-5 mol 1-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer.