“Decadose” Effects of Cisplatin on Squamous Cell Carcinoma of the Upper Aerodigestive Tract. II. Clinical Studies

Abstract

There is evidence that solid tumors rapidly acquire cellular resistance to cisplatin. This resistance is usually mild to moderate and could be circumvented with higher concentrations of drug exposure if ancillary methods were available to avoid systemic cytotoxicity. The purpose of this study was to determine whether a tenfold increase in dose (decadose) would overcome cisplatin resistance. In a clinical trial, response effects of cisplatin at dose intensities ranging from 32.5 to 200 mg/m2 per week, which were delivered by highly selective intra-arterial infusions with a simultaneously administered intravenous neutralizing agent, were measured in 31 patients with squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT). The overall response rate (complete response [CR] and partial response [PR] to cisplatin therapy at dose intensity intervals of 0 to 74, 75 to 149, and 150 to 200 mg/m2 per week were 45.5%, 72.7%, and 100%, respectively. The average received dose intensities for nonresponders and responders (CR and PR) were 57.8 and 120.7 mg/m2 per week, respectively (P = .031). The results indicate that resistance to standard doses of cisplatin by SCC of the UADT, both previously untreated and recurrent, can be substantially overcome with "decadose" cisplatin therapy. Progress toward improving survival of patients with head and neck cancer, and possibly other site-specific malignancies, may be achieved by incorporating decadose cisplatin therapy into a multimodality treatment plan.

Cisplatin and Radiotherapy in the Treatment of Locally Advanced Head and Neck Cancer

“…Robbins et al (44) clinically investigated whether a drugresistant tumour remains resistant even for high doses of cisplatin through a tenfold increase in the administered dose. The doses used in this trial ranged from 32.5 to 200 mg/m 2 per week, and to overcome toxicity, cisplatin was delivered by intra-arterial infusion with simultaneous intravenous administration of sodium thiosulphate as a neutralizing agent.…”

Intraarterial cisplatin with intravenous paclitaxel and ifosfamide as an organ‐preservation approach in patients with paranasal sinus carcinoma

“…The same group went on to expand their observations suggesting that resistance to standard doses of cisplatin could be overcome substantially with supradose cisplatin therapy delivered interarterially. 35 High-dose IA cisplatin subsequently was incorporated into a multimodality treatment plan with concomitant RT 36 ; the CR rate was 80% at the level of the primary tumor and 61% regionally, the projected 5-year OS rate was 39%, and the diseaserelated survival rate was 54%. This approach was adopted by the Radiation Therapy Oncology Group, with a reported CR rate of 86% at the primary site and 89% regionally; and, with a median follow-up of 18.4 months, the 2-year local control rate was of 62% and the survival rate was 58%.…”

RADPLAT: An Alternative to Surgery?

“…The observed response rates in that study suggested that acquired tumor resistance to cisplatin may be overcome through the use of these very high concentrations, with an 86% response in previously untreated patients (CR rate, 45%; partial response [PR] rate, 41%) and a 63% response rate in patients with recurrent disease (CR rate, 25%, PR rate, 38%). The patients who responded to treatment were subsequently found to have received a significantly higher average dose intensity than nonresponders (120.7 vs. 57.8 mg/m 2 per week; p = .031), suggesting that high tumor response rates can be achieved through the incorporation of decadose cisplatin therapy into multimodality treatment plans [8].…”

“…It was previously demonstrated in vitro [7] and in vivo [8] that resistance may be overcome through the use of higher concentrations of cisplatin. However, in human subjects, the higher concentrations required could lead to devastating systemic toxicity-already a major problem with chemoradiation protocols, which also appear to aggravate radiation-induced mucositis [23].…”

“…This "neutralization" of cisplatin effectively increases the drug's plasma clearance, allowing very high doses to be administered directly into the tumor tissue while minimizing systemic toxicity. Using the RAD-PLAT procedure, dose intensities up to 10 times those used in standard chemotherapy protocols may be administered [7,8].…”