A phase II clinical trial of gemcitabine and split dose cisplatin in advanced non-small cell lung cancer in an outpatient setting

Abstract

Abstract. In response to increasing pressure on inpatient services and a meta-analysis indicating that cisplatin (C) is superior to carboplatin, we report a phase II trial of gemcitabine (G) and split-dose C in advanced non-small cell lung cancer (NSCLC) in an outpatient setting. Patients with stage IIIB/IV NSCLC received: G/C 1250/40 mg/m 2 ; G and C were given on day (d) 1 and d8 in a 21d cycle. Patients with performance status 0-2, adequate bone marrow function and calculated glomerular filtration rate (GFR) >50 ml/min were eligible. Forty-two patients were enrolled: 25 male; median age 62 (range 37-78) years. There were 26 patients (62%) with stage IV disease. One hundred and thirty-eight cycles of chemotherapy were delivered. Chemotherapy was well tolerated, allowing maintenance of planned dose intensity (DI) with mean dose delivered of 780.1 mg/m 2 (93%) and 25.6 mg/m 2 (96%) for G and C, respectively. The overall response rate was 43%. Median survival was 12.5 months with a median follow-up of 13.5 months. One year survival rate was 51%. G plus C both given on d1 and d8 (q21d) is a very active, well tolerated and convenient outpatient schedule, which maintains DI. IntroductionPlatinum-based chemotherapy is used for most patients with advanced NSCLC and is superior to best supportive care alone in terms of survival and quality of life (1,2). Gemcitabine plus carboplatin (GCb) is the most widely used regimen in the UK (3). Outpatient administration of GCb is considered more convenient than cisplatin-based regimens that require admission or protracted outpatient visits for hydration and diuresis. Doubt remains over the relative efficacy of carboplatin (Cb) and cisplatin (C) when given in combination with newer chemotherapeutic agents. Several studies making this comparison show superiority for cisplatin over carboplatin (4-7). Furthermore, a meta-analysis of randomised trials comparing cisplatin to carboplatin has indicated a significant survival advantage favouring cisplatin when combined with a new agent (8).It has been reported that the optimal dose intensity of cisplatin for NSCLC is between 21-30 mg/m 2 /week, equating to either 70-80 mg/m 2 q 3-weekly or 100 mg/m 2 q 4-weekly (Raftopoulos H, et al, Proc ASCO 22: abs. 2596. Administration of a cisplatin dose of this magnitude requires an 8-h schedule. Such a regimen poses practical difficulties for chemotherapy outpatient departments and the cost of inpatient care can be prohibitive. An out-patient splitdose gemcitabine plus cisplatin regimen involving two 4-h visits may circumvent these issues and facilitate the use of the more active platinum agent without compromising dose intensity.Experimental data suggest that a combination of gemcitabine and cisplatin given using an appropriate schedule (simultaneous or close proximity exposure) can act synergistically. Synergy may be mediated by inhibition of ribonucleotide reductase by gemcitabine depleting the deoxynucleotide pool required for DNA replication and thereby inhibiting excision repair of cisplatin...

Renal Toxicity Associated with Weekly Cisplatin and Gemcitabine Combination Therapy for Treatment of Advanced Biliary Tract Cancer

“…The treatment successfully reduced the incidence of nausea and vomiting and showed an efficacy similar to the regimen using the standard method of cisplatin [26,27,28,29,30,31]. In these studies as well as the ABC-02 study [6], the total dose of cisplatin was regulated up to 300-500 mg, and the adverse events associated with the cumulative levels of cisplatin were so rare that these seemed to be trivial.…”

“…In weekly regimens, the single-dose intensity of cisplatin could be reduced; however, the total-dose intensity of cisplatin might not. This might be one of the reasons why neurotoxicity was rarely observed in the weekly regimen [26,29,31]. …”

“…The modification is expected to reduce treatment interruption and long hydration periods and to increase the possibility of the treatment in an outpatient setting without reduced dose intensity [25,26,27]. In the reports, which adopted weekly cisplatin for lung cancer and bladder cancer [26,28,29,30,31], the incidences of nausea and vomiting were successfully reduced to 6-9%; however, that of nephropathy was not reduced (5%) even though these studies regulated the total dose of cisplatin up to 280-525 mg. In advanced BTC, past reports [6] on the weekly regimen indicated that the incidences of nephropathy were 3 and 1.5% [any grade and grade 3 from Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0; http://evs.nci.nih.gov/ftp1/CTCAE/About.html)], respectively, which suggested that it was unclear whether or not the regimen always reduced the cumulative toxicity against renal function.…”

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

“…Gemcitabine shows anticancer activity against a variety of solid tumors, including non-small-cell lung (11), pancreatic (12), bladder (13), and breast cancers (14). Gemcitabine is converted intracellularly to the active metabolites difluorodeoxycytidine di-and triphosphates (dFdCDP and dFdCTP).…”

Phase II study of liposomal cisplatin (Lipoplatin™) plus gemcitabine versus cisplatin plus gemcitabine as first line treatment in inoperable (stage IIIB/IV) non-small cell lung cancer

“…A number of chemotherapy regimens have been explored in clinical trials and in medical practice. For example, preferred regimens for first line treatment against NSCLC in EU include gemcitabine and cisplatin [3][4][5] and carboplatin-paclitaxel in USA [6,7]; second line treatments tested include single agents such as docetaxel [8,9], pemetrexed [10] and erlotinib [11] as well as combinations of gemcitabine plus docetaxel [12], gemcitabine and irrinotecan [13], docetaxel-ifosfamide-carboplatin [14].…”