Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies
Introduction
Since the serendipitous discovery of the anti-neoplastic activity of cisplatin (cis-diammine-dichloroplatinum(II)) over 30 years ago (Alderden et al., 2006), this agent alongside subsequent analogues (i.e. carboplatin, oxliplatin, satraplatin) has become integral to the gold standard chemotherapeutic management of a myriad of malignancies including gynaecological, germ cell, head and neck, lung and bladder cancers. Cisplatin is the oldest member of this family with a well-recognised toxicity profile including emesis, renal dysfunction, neurotoxicity and ototoxicty. Carboplatin (cis-diammine-cyclobutanedicarboxylato-platinum(II)) was initially believed to have “comparable” therapeutic activity with cisplatin but is associated with significant myelotoxicity (particularly thrombocytopenia) but less nephrotoxicity and neurological sequelae. The mechanism key to their activity lies within the formation of DNA crosslinks which interrupts cellular DNA functioning and subsequently induces apoptosis (Reed et al., 1996).
Furthermore, they form covalent DNA adducts with other subcellular components such as proteins, lipids, RNA and mitochondrial RNA (Hermann et al., 2013). As the nomenclature infers, platinum is the core element of these two agents, with the key molecular difference centred on the leaving groups from the respective parent compounds; namely the chloride group for cisplatin and the cyclobutane-decarboxylate group for carboplatin (Reed, 1998).
The platinum(II) molecules exist in a planar structure in with the two amine groups and the two reactive “leaving” chloride (cisplatin) and cyclobutane-decarboxylate (carboplatin) groups existing in the same configuration (Fig. 1) (Reed, 1998). Moreover, the leaving groups are fixed in space in relation to the platinum core molecule and covalently bind DNA in an inflexible state. This DNA-platinum adduct can only be repaired by the nucleotide excision (NER) pathway (Reed, 1998). The leaving groups also confer significant pharmacokinetic effects; with the cisplatin chloride groups readily dissociating in physiological pH conditions and the carboplatin cyclobutane-decarboxylate groups requiring active cleavage by an esterase during intracellular dissociation. Hence, there are inherent differences in the intratumoural concentrations achieved with these drugs (Hall et al., 2008).
Indeed, previous in vitro studies with cisplatin treated hepatoma and transitional cell cancer cell lines highlighted that drug accumulation correlated with increasing resistance, which is consequently determined by the activity of membrane drug transporters which mediate either active and passive influx of platinum ions (Hall et al., 2008). Active influx of cisplatin appears to be ATP-ase dependent. Andrews et al. demonstrated up to 50% decrease of cisplatin uptake in both sensitive and resistant cells when these cells were pre-incubated with Na+/K+-ATPase-specific inhibitor (Andrews et al., 1991). Interestingly, both renal and cochlea cells, which are particularly susceptible to platinum induced trauma, express high levels of Na+/K+-ATPase. Multiple active uptake pathways, which facilitate the influx of platinum agents, have been identified in cells exhibiting platinum resistance. CTR1 (copper transporter 1, SLC31A1) is a 197 amino acids protein ubiquitously expressed transmembrane transporter involved in intracelleular copper regulation. The extracellular terminus of the CTRI transporter contains a methionine- and histidine-rich domain and CTR1 gene deletion has been shown to lower the intracelleular platinum accumulation which inevitably promotes resistance (Ishida et al., 2002).
Passive transporters have also been implicated in the cellular influx of cisplatin and carboplatin. The solute carrier (SLC) gene encodes a large family of passive transporters predominated by ion-coupled transporters and exchangers. These include the organic cation transporters (OCT) which are highly expressed in the proximal tubules of kidney and appear integral to the development of cisplatin-induced renal injury (Hall et al., 2008). Interestingly, although OCT is a principal cisplatin transporter, it appears to have negligible effects with carboplatin influx (Fig. 2).
Inevitably, the net intracellular concentration of platinum is also determined by passive and active cellular efflux. Arguably the most significant membrane transporters in this realm include the ATP-binding cassette family (ABC) members (also known as multiple drug resistant protein 2; MRP2/P-glycoprotein), which orchestrate the regulation of cisplatin elimination and ensuing resistance (Sprowl et al., 2013). It follows that cancer cells with decreased ABC transcript levels correlate with heightened platinum sensitivity. Other examples include the ATP7A/7B calcium and the glutathione conjugated (GS-X) efflux transporters, the latter of which is a component of the multiple drug resistant 1 (MDR1) family and down-regulation of these genes had been shown to cause intracellular cisplatin retention and subsequent resensitisation (Ikuta et al., 2005). With respect to intracelleular drug trafficking, preliminary studies using nucleic acid labelling and fluorescein-conjugated platinum complexes with elemental spectroscopies indicated that the platinum-compound concentration in cytoplasm appeared to be co-localised in vesicles such as lysosomes and melanosomes (Hall et al., 2008). However, the mechanism of movement of the compound into the nucleus where the DNA damage takes place is unknown.
The ability of the cancer cells to repair DNA damage inflicted by cytotoxic agents is also an important factor in platinum sensitivity. Excision repair cross complementation group-1 (ERCC1)-XPF complex is a structure specific endonuclease that has a number of roles in DNA repair mechanisms including nucleotide excision repair, intra-strand crosslink repair and double strand break repair (McNeil, 2012). The role of ERCC1 in platinum resistance mechanism had been established in multiple ovarian cancer cell lines with intrinsic cisplatin resistance (Selvakumaran et al., 2003). Furthermore, ERCC1 mRNA expression may also be utilized to predict response to platinum based regimens in treating non-small cell lung (NSCLC) (Cobo et al., 2007, Lord et al., 2002), gastric (Metzger et al., 1998), cervical (Muallem et al., 2014) and colorectal cancers (Shirota et al., 2001). However, the relationship between ERCC1 and patient outcomes appear less clear as data emanating from these studies either support or refute inverse correlations with ERCC1 expression and survival. Moreover, there is emerging evidence confirming no association between ERCC1 and platinum resistance in numerous tumour types including NSCLC (Booton et al., 2007) and ovarian cancer (Stadlmann et al., 2008). Nevertheless, the relationship between other mediators of DNA repair such as BRCA and response to platinum agents seemingly appears more consistent; whereby upregulation of BRCA1 (which mediates double strand break repair via homologous recombination) also induces platinum resistance (Husain et al., 1998) and conversely, BRCA mutations are a hallmark of platinum sensitivity (Dann et al., 2012). The latter aspect is clearly exemplified by epithelial ovarian cancer in which at least 50% of cases harbour homologous recombination defects (Mukhopadhyay et al., 2012) which underpin the inherent platinum sensitivity of this disease at initial presentation.
In view of the fact that DNA adduct formation enhances radisosensitivity, platinum agents are paramount to a myriad of chemoradiation regimes in several tumour types. Several mechanisms have been postulated as to why platinum-radiation interactions facilitate tumour kill; e.g. inhibition of sublethal damage repair, inhibition of recovery from lethal damage, alterations in cellular kinetics and tumour volume leading to improved blood supply and increased tissue oxygenation (DiSaia and Creasman, 2012)
Taking into consideration the potent apoptotic properties of platinum agents, it is clear to see why these drugs represent the cornerstone of management for numerous malignancies, which are described herein.
Section snippets
Non-small cell lung cancer (NSCLC)
Multiple trials with platinum containing regimens in NSCLC have shown superiority over best supportive care in terms of improving overall survival (NSCLC, 2008). Moreover, in the metastatic setting, 1st line therapy with a platinum doublet remains the gold standard of care (Azzoli et al., 2009). The question regarding the preference of platinum agents has been exhaustively addressed by a Cochrane review comparing the use of cisplatin and carboplatin in combination with third-generation drugs in
Small-cell lung cancer (SCLC)
Carboplatin and cisplatin doublets are established treatment agents in both limited and extensive stage SCLC (Chan and Coward, 2013). A recent meta-analysis of clinical studies based on individual patient data conducted by Rossi et al. (2012) compared the use of these two agents as 1st line treatment demonstrated no difference in efficacy but disparate toxicity profiles, with more myelotoxicity with carboplatin and higher rates of non-haematological toxicities with cisplatin. Four randomised
Malignant mesothelioma
In malignant pleural mesothelioma, the combination of cisplatin and the multi-folate antagonist, pemetrexed, has been the cornerstone of first-line systemic therapy for the past decade (Vogelzang et al., 2003). This regimen proved superior to cisplatin monotherapy in terms of both OS (12.1 months vs 9.3 months) and ORR (41.3% vs 16.7%). Furthermore, phase II studies have demonstrated equivalent survival rates with carboplatin-pemetrexed doublets with (median OS 12.7–14 months) (Katirtozoglou et
Oesophageal and gastric cancer
In 1999, the RTOG 85-01 study established concurrent radiation with cisplatin/5-fluorouracil as definitive treatment for locally advanced oesophageal cancer (Cooper et al., 1999). This regimen demonstrated significant median OS benefit compared to radiation (RT) alone (14 months vs 9 months) and a 5-year survival rate of 27%. However, in terms of neoadjuvant therapy, the role of platinum-based chemoradiation appears controversial. In patients with potentially resectable disease, the CROSS study
Germ cell tumours
Modern cisplatin based chemotherapy for metastatic germ cell tumours (GCT) in males has resulted in cure rates exceeding 80% (Mead and Stenning, 1997). Numerous attempts have been made to reduce treatment-associated toxicity of cisplatin-based regimens in these patients with excellent long-term prognosis. Hence, there has been a wealth of comparative studies aiming to investigate any potential non-inferiority with carboplatin. Horwich et al. conducted the largest of such studies in metastatic
Bladder cancer
There is emerging evidence supporting the use of neoadjuvant cisplatin-based chemotherapy for locally advanced bladder carcinoma. A meta-analysis comparing this regimen followed by local treatment vs local treatment alone pooled 3005 patients from 11 randomised controlled trials (Collaboration ABCAM-a, 2005). This confirmed a significant OS advantage (HR = 0.86, 95% CI 0.77–0.95, p = 0.003) equivalent to 5% absolute improvement in survival at 5 years with cisplatin-based therapy. There is a paucity
Cancer of unknown primary (CUP)
As platinum salts exhibit a broad spectrum of activity in numerous solid malignancies, it appears fitting they represent the core of systemic management for carcinomas of unknown primary (CUP). The treatment of poorly differentiated CUP centres on carboplatin-based regimens including carboplatin-gemcitabine, carboplatin-paclitaxel and carboplatin-docetaxel (Briasoulis et al., 2000, El-Rayes et al., 2005, Huebner et al., 2009). The carboplatin-paclitaxel doublet appears to be effective in
Gynaecological cancers
In contrast to most other tumour types reviewed herein, carboplatin-doublets now represent the gold-standard of chemotherapeutic regimens for epithelial ovarian cancer (EOC) in neoadjuvant, adjuvant and palliative settings (Berek et al., 2000). A number of pivotal studies have facilitated the establishment of this treatment paradigm. The largest of these was a non-inferiority phase III Gynaecologic Oncology Group (GOG) study (n = 792) comparing carboplatin-paclitaxel with the then standard
Head and neck cancers
Concurrent treatment with high dose cisplatin and radiotherapy represents the definitive adjuvant treatment for high risk head and neck squamous cell carcinoma (Adelstein et al., 2003, Bernier et al., 2005); with an associated complete response rate of 40% and median OS of 19.1 months. In comparison to radiation alone, the results from the two large phase III adjuvant studies confirm that the addition of cisplatin improves locoregional and disease free survival with mixed results on overall
Conclusions
Although platinum salts remain the principal constituent amongst chemotherapeutic schedules for solid tumours, the landscape in managing these diseases has changed dramatically in the last decade. Clearly, this has been driven by the advent of targeted therapies and refinement of dosing regimens particularly in combination with other cytotoxic agents and radiation. Cisplatin and carboplatin remain the most commonly used platinum agents with the broadest spectrum of clinical activity.
Conflict of interest
The authors have no conflict of interests to declare.
Gwo Yaw Ho is a medical oncologist at the Royal Women Hospital, Melbourne and a PhD candidature at Walter & Eliza Hall Institute of Medical Research, Melbourne. His research focuses on novel drug development for the subset of high-grade serous ovarian cancer with poorest clinical outcome.
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Cited by (0)
Gwo Yaw Ho is a medical oncologist at the Royal Women Hospital, Melbourne and a PhD candidature at Walter & Eliza Hall Institute of Medical Research, Melbourne. His research focuses on novel drug development for the subset of high-grade serous ovarian cancer with poorest clinical outcome.
Natasha Woodward is a Senior Consultant Medical Oncologist at Mater Adult Hospital, Brisbane, Australia. She specialises in the treatment of breast and testicular germ cell malignancies.
Jermaine I.G. Coward is a consultant medical oncologist at the Princess Alexandra Hospital, Brisbane. He was appointed as a UK Medical Research Council Clinical Fellow at Barts Cancer Institute, Queen Mary, University of London and conducted basic research into the role of IL-6 in ovarian cancer. This included the first translational clinical trial of anti-IL-6 antibody therapy in patients with platinum resistant ovarian cancer and this work culminated in his PhD award in 2010. After completing specialist oncology training at the Royal Marsden Hospital, London, he was appointed as a Senior Research Fellow and Leader of the Inflammation & Cancer Therapeutics Group (2012–2015) at Mater Research housed at the Translational Research Institute, Brisbane, Australia. He is currently the co-lead of the Princess Alexandra Hospital medical oncology Phase I unit and the primary remit of his research revolving around efficient translation of novel bench-side discoveries in cancer related inflammation into combinatorial clinical trials.