Anti-Tumour TreatmentCisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer
Introduction
Lung cancer is the most common cancer worldwide [1]. It is the leading cause of cancer-related death [1] and is seen most frequently in developing countries [2]. It is also the most common cancer in men worldwide with 1.2 million cases, accounting for 16.7% of the total cancer burden [2]. Most cases are non-small cell lung cancer (NSCLC) related to tobacco-driven carcinogenesis [2]. Early stage lung cancer can be treated with curative intent, largely surgery [3]. However, the majority of patients present with incurable advanced NSCLC stage IIIB or IV [4], or relapse after curative intent surgery, which reflects the aggressive nature of the disease and poor prognosis [4]. The economic impact falls not only on the health service but on society, because premature deaths, time off work and unpaid care by family and friends also contribute to cancer costs [5].
The genetic heterogeneity of advanced NSCLC has become more apparent over the last decade [6]. Current classification of advanced NSCLC includes histological and molecular subtypes, and classification of NSCLC using these characteristics now influences therapeutic decisions [7]. In addition, genetic drivers that are key oncogenic events have been identified in NSCLC. The incidence of epidermal growth factor receptor (EGFR) mutations in the Caucasian population is approximately 10%, but it is higher in never-smokers, patients with adenocarcinomas, those who are women and those who are East-Asian [8]. The EML4-ALK fusion gene is present in approximately 4% of lung cancers and is encountered more frequently in never-smokers, younger patients and those with adenocarcinomas [8], [9], [10]. Thus, only a small proportion of the total population of patients with advanced NSCLC are presently candidates for molecular-targeted therapies.
For patients with NSCLC who do not have drug-targetable driver mutations (approximately 85–90%), platinum-based chemotherapy remains the unchallenged standard of care. Furthermore, cisplatin is the more active platinum agent for patients with advanced NSCLC and for patients with early-stage disease requiring induction/adjuvant therapy [11]. This review examines the evidence for the use of cisplatin in first-line combination regimens for NSCLC, the issues surrounding the use of cisplatin in this context and the advances that are being made in attempts to optimise therapy. Other platinum agents are mentioned where relevant.
Section snippets
Discovery and initial clinical use of cisplatin
The compound cis-[Pt(NH3)2(Cl)2] was first described by Michele Peyrone [12] in the 1840s and was originally known as Peyrone’s salt (Table 1). In 1965, Rosenberg et al. [13] described electrolysis of platinum electrodes generating a soluble platinum complex, which inhibited binary fission in Escherichia coli. In 1968, cis-diamminedichloroplatinum (II) (cisplatin) was administered intraperitoneally to mice bearing a standard murine transplantable tumour of the day, sarcoma-180, and was shown to
Evolution of cisplatin-based chemotherapy in advanced NSCLC
There has been a concerted effort over the years to define, and refine, the use of cisplatin in the treatment of NSCLC (Table 1; also reviewed elsewhere [22], [23]). In 1995, a meta-analysis of 11 randomised trials first identified the benefit of cisplatin in patients with advanced NSCLC [24]. Cisplatin-based chemotherapy reduced the risk of death by 27%, improved 1-year survival by 10% and increased median survival by 1.5 months compared with supportive care. However, this meta-analysis
Avoiding nephrotoxicity
The first step in avoiding platinum-associated nephrotoxicity is to select patients with an appropriate glomerular filtration rate (GFR) of >60 ml/min. Numerous methods can be used to estimate GFR, the detailed evaluation of which is beyond the scope of this review. The gold standard is chromium-51 labelled ethylene-diamine-tetra-acetic acid (51Cr-EDTA) clearance, but because this is a threshold measurement, if Cockcroft–Gault is >60 ml/min then many physicians would accept this as a measure of
Avoiding emesis
To manage the potentially dose-limiting toxicity of emesis, clinicians have traditionally relied upon serotonin receptor-3 (5-HT3) antagonists and corticosteroids [43], [44]. Since the introduction of the oral neurokinin-1 (NK-1) receptor antagonist aprepitant in 2003 for highly emetogenic chemotherapy [45], this agent has been part of the standard of care for patients receiving cisplatin. When used in combination with a 5-HT3 receptor antagonist and dexamethasone, it increases the rate of
Avoiding neurotoxicity
Peripheral neurotoxicity is the most common dose-limiting problem associated with cisplatin therapy [48]. Cisplatin neurotoxicity is first characterised by paraesthesias and numbness, which typically occur during the first few drug cycles. Loss of vibration sense, paraesthesia and ataxia can become apparent after several treatment cycles. Peripheral neuropathic changes may begin after completion of the chemotherapy course and progress for 2.5–5.5 months after stopping cisplatin [49]. Ototoxicity
Major vascular events
Venous and arterial thromboembolic events (TEE) are increased by 4.1-fold in cancer patients, and the use of chemotherapy heightens this risk to 6.5-fold [55]. In patients with NSCLC treated with cisplatin, the incidence of TEE is even higher (up to 17.6%) [56]. In these studies, deep venous thrombosis and pulmonary emboli were the most common events; however, arterial events including limb ischaemia, myocardial infarction and cerebrovascular accidents account for a substantial proportion of
New drugs in randomised trials in the new millennium
One way to improve outcomes for patients treated with cisplatin doublets in the first-line setting is to add a new biological therapy. The non-selective application of EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib has not proven to be effective. Indeed more than 14,000 patients have been entered into studies with these and other targeted agents without measurable gain in OS (Table 3). All the trials had scientific rationales, for example, targeting cell surface receptors such
Cisplatin resistance
Platinum-based chemotherapy for advanced NSCLC is not curative, and in neo-adjuvant chemotherapy trials pathological complete RRs are approximately 10% [61]. This reflects either de novo or acquired resistance to chemotherapy and represents one of the most significant barriers to improving long-term outcomes [62]. Most of the studies to elucidate mechanisms of resistance to platinum agents have been conducted in cell lines [63]. Multiple mechanisms seem to be at play, and these studies have
The future: new platinums on the horizon
The limitations of cisplatin have led to the development of newer agents with the aims of reducing toxicity and overcoming resistance [93]. By the 1990s, cisplatin and carboplatin were established marketed agents. Although many other new platinum agents had entered development, fewer than 1% of the great number of platinum complexes tested preclinically reached clinical trials [93] and none (until recently) provided the significant benefit that cisplatin or carboplatin offered [63] in NSCLC.
Conclusions
For those patients with NSCLC who do not have a drug-targetable driver (approximately 85–90%), platinum-based chemotherapy remains the first-line treatment, which confers the most clinical benefit for patients with advanced NSCLC. Platinum-based therapy is also the principal approach following targeted therapy. Within the group of chemotherapeutic options available, cisplatin-based doublet therapy at a cisplatin dose of 75–80 mg/m2 every 3 weeks for up to 4–6 cycles remains the mainstay of
Conflicts of interest statement
M. Das, F. Maxwell, C. Visseren-Grul and D. Ferry are employees of Eli Lilly & Company.
J. Cadranel is a primary investigator of several Lilly trials (without financial compensation), participates as an expert in French and international Lilly Advisory Boards (with financial compensation) and has received fees from Eli Lilly to give talks in different academic meetings. T. Benepal, D. Christoph, D. Fennell, R. Lal and Y. Summers have declared no conflicts of interest.
Acknowledgements
The authors acknowledge the editorial support provided by David Peters and Caroline Spencer of Rx Communications, Mold, UK, which was funded by Eli Lilly and Company.
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