Reviewers: John Han-Chih Chang, MD
Source: Journal of Clinical Oncology 1999, Volume 17 (Number 1): pages 409 ? 422
Platinum complexes were stumbled upon as anti-proliferative agents back in the mid-1960's in experiments utilizing bacteria. In vitro (laboratory ? petri dishes, tissue culture, etc?) experiments with tumor models found that cisplatin was the most active agent. Cisplatin has been the backbone of many anti-cancer regimens in testicular, ovarian, lung, head and neck, esophagus, bladder, cervix and endometrial malignancies. Toxicity is not insignificant with regard to causing severe nephrotoxicity, neurotoxicity (ototoxic), and emetogenic (nausea and vomiting). Attempts have now turned to finding an alternative with the same efficacy. Carboplatin has been brought into the fold to provide that answer (initiated into clinical trials in the early 1980's). The attempt in this review article was to detail the differences in pharmacology, toxicity and clinical effectiveness. The article is directed mainly at clinicians of all specialties, but may also be helpful to those of the lay public to understand the decisions that are made in chemotherapy treatment.
Mechanism of Action
Both agents are platinum (II) complexes that target DNA primarily. Cisplatin is activated by H2O. In vitro studies have demonstrated that cisplatin binds more readily to RNA than DNA, but DNA more than proteins. In intact DNA, preferential binding occurs at the N-7 position of guanine and adenine. The cytotoxicity is due to the interstrand crosslinks and intrastrand bifunctional N-7 adducts. The actual mechanism in vivo (in humans or animals) is unclear at this time. It seems that in invitro experiments, carboplatin requires a higher concentration and longer incubation times to reach the same results as cisplatin.
Mechanism of Resistance
Resistance to the effects of platinum agents is related to decreased concentration inside the cell, inactivation of the drug or increased DNA repair mechanism. Any or all of these factors play a role in the eventual resistance of cells (malignant or normal) to any drug. Most of the studies pertain to cisplatin, but the concepts probably apply to both since mechanism and to a lesser degree molecular structure are similar.
The transport mechanisms are not quite clear, but there are obviously 2 ways in which cells can decrease the concentration of drug inside the cell ? increase efflux (expelling) or decrease influx (intake) of the drug. What predominates has not been elucidated though support can be found for each argument in invitro experiments and even in some clinical trials.
Inactivation of cisplatin intracellularly has been detailed in experiments with thiol-containing compounds. Glutathione and metallothioneins are the most notable and can inactivate platinum compounds such that they cannot bind to DNA. Recent clinical trials in esophageal and urothelial malignancies have borne out such drug resistance.
Some cells have enhanced DNA repair mechanisms, which confer resistance on the cell line. There have been various agents given in conjunction with cisplatin and carboplatin in order to circumvent this problem. These DNA repair inhibitors such as etoposide act in synergy with the platinum-containing agents to kill the rapidly proliferating cells.
For cisplatin, an IV bolus injection of 100mg/m2 will lead to an immediate peak of 6mg/mL and a decrease to 2mg/mL within 2 hours. Half life of cisplatin is 43 minutes with approximately 1/4th being eliminated within the first 24 hours (90% renal clearance).
For carboplatin, IV bolus injection of 375mg/m2 leads to 39mg/mL concentration of drug initially, which declines to 9 mg/mL after 2 hours. Carboplatin is excreted in the urine, but not from the renal tubules. Thus, renal clearance is determined by the glomerular filtration rate (GFR). The rest of the drug binds to proteins. The half life of the drug is 116 minutes. As for dosing, the article details the calculation for area under the concentration-time curve (AUC). AUC is defined as the ratio of the amount of drug that reaches the systemic circulation and the clearance of the drug. The Calvert formula embodies this ratio: Dose (mg) = Target AUC (mg-min/mL) x [GFR (mL/min) + 25]. Targeted AUC's have been 5 ? 7 for single agent treatment and perhaps lower for combined chemotherapy.
The side effect of nausea and vomiting (emesis) are reduced from nearly 100% of all patients treated with cisplatin to approximately 35% in those receiving carboplatin. This has become less of an issue since the discovery of 3-hydroxytryptamine (5-HT3) receptor inhibitors (Zofran & Kytril) which have reduced the emesis rate 75% by altering the serotonergic pathway.
Nephrotoxicity (kidney damage) used to be dose-limiting in the initial studies, but the use of hydration and induced diuresis has decreased this complication. The mechanism of damage begins with proximal tubular damage leading to decreased reabsorption of sodum and water. Decreased distal tubular reabsorption, renal blood flow and GFR will lead to excretion of enzymes, proteins and other essential molecules. Patients with GFR less than 30 mL/min should not get cisplatin, but those with GFR 50 mL/min or greater can get full dose. Those in between, will need lower than full dose, but will be able to tolerate the drug from a renal standpoint. Those with GFR in the 30 ? 50 mL/min range should get 30% ? 50% of the dose, respectively. Amifostine (WR-2721) has been promising in protecting the kidneys from damage when given as prophalaxis against radiation and chemotherapy induced side effects. Carboplatin, except at very high doses, yield very little if any nephrotoxicity.
Neurotoxicity is now the dose-limiting toxicity for cisplatin. The spectrum of difficulties span peripheral sensory neuropathy, hearing loss, autonomic neuropathy, Lhermitte's sign, seizures, and encephalopathy (happens to 85% at dose over 300 mg/m2). In nearly half, the damage is irreversible. In carboplatin, the incidence of neuropathy is less than 5%.
Myelosuppression is a dose-limiting toxicity for carboplatin. This is especially true for thrombocytopenia (25%), and platelet counts can nadir at 21 days after administration. Cisplatin's myelosuppression is mild, and severe cases occur approximately 5% of the time.
The authors utilized MEDLINE to search for prospective randomized trials in each of 7 sites of malignancy on the comparison of cisplatin versus carboplatin. Twenty-three trials in all were identified as being randomized studies between the two platinum-containing agents. The most were seen in ovarian (12), followed by germ cell (4), head and neck (3), and lung cancers (1 non-small cell and 3 small cell). Most utilized the platinum-containing compound in combination with others agents (ie. cyclophosphamide, Adriamycin, etoposide, bleomycin, 5-fluorouracil, etc...).
To briefly overview, I will summarize what was reported in the authors' review. In ovarian cancer, there seems to be no clinical difference in efficacy in utilizing carboplatin over cisplatin for unresectable or partially resected disease. In completely resected disease, there was one trial where carboplatin was inferior in terms of progression free and overall survival. Relapse free survival is better with cisplatin in germ cell tumors in the 4 randomized studies reviewed. No significant difference was seen in the lung cancer trials comparing the 2 platinum-containing regimens for both response rates and median survival. In three randomized trials for head and neck malignancies, 5-FU and platinum combinations yielded a better complete response rate in two studies and median survival in one study in favor of cisplatin. Otherwise carboplatin was the same. Data from all 23 studies were summarized in tables 3 ? 6.
Phase III randomized trials have not been published in bladder, cervical, endometrial or esophageal cancer, contrasting carboplatin to cisplatin. In bladder cancer, there is some suggestion that carboplatin is inferior, while similar efficacy is likely in cervical and endometrial cancer. Esophageal cancer is NOT a good responder to carboplatin. Cisplatin should always be used over carboplatin in malignancies of the esophagus.
Essentially, this was an abbreviated, but important summary of the differences in the two most commonly used platinum-containing compounds. It presents in a concise and useful fashion the clinical efficacy of several sites in which these platinum compounds are highly utilized. Despite clinical data to suggest outcome equivalence or inferiority and our tremendous improvements in symptom relief strategies, toxicity of treatment must factor into choice of chemotherapeutic agents, especially when multiple medical problems play a role. That is where the greatest benefit of carboplatin lies ? improving toxicity with the least amount of outcome compromise. This has been an excellent reference article.