Toxicity

The administration of a diuretic, such as D-mannitol, along with copius amounts of water before and after treatment, induces frequent passing of water. This reduces the nephrotoxicological effects and ensures that the kidneys are functioning properly. It also makes possible for the administration of larger and more effective doses of cisplatin. Although renal damage is the most serious effect of cisplatin, it actually displays few symptoms, those of which are relatively mild compared to the nausea and vomiting. The mechanism of platinum nephrotoxicity may be similar to that of mercury and may involve depletion of SH groups of the renal tubes. It is therefore, no surprise that nephrotoxicity may also be decreased by pretreatment with a thiol compound.

Another dose-dependent effect of cisplatin is ototoxicity. Again, it is a cumulative and irreversible side effect, that becomes more significant with irradiation therapy. ^‡ The ototoxicity of cisplatin also appears to be most significant in children who may experience loss of balance along with hearing difficulties due to greater sensitivity to the drug. Initial symptoms include tinnitus (ringing in the ears), or some hearing loss or both. These effects usually decrease when the treatment ends, however, many patients experience irreversible hearing loss in the high frequency range (>4kHz). Therefore, audiograms are recommended every two or three cycles to monitor the condition of the inner ear.

The other toxic manifestations of cisplatin are common among antitumour agents. Since most of these drugs exert their major effect by inhibition of DNA synthesis at some time in the cell cycle, normal tissues with a high rate of cellular proliferation will also be affected adversely. These tissues are mainly bone marrow elements, gastrointestinal epithelial cells, hair follicles, and skin:

• The nausea and vomiting caused by cisplatin is extremely severe. It occurs within the first two hours after administration, and will last anywhere from ¼-3 days, (and occasionally up to a week for exceptionally sensitive patients). Standard antiemetic drugs, usually 5-HT3 antagonists with a glucocorticoid, are therefore, prescribed to reduce the severity of the effect. Late persistent nausea with or without vomiting affects a significant minority of patients and may respond to lorazepam, but often requires continued 5-HT3 antagonist therapy. Generally, it is the severity of this effect even with the addition of antiemetics that cause some patients to desist from treatment.

  In addition to the severe nausea and vomiting, patients experience a loss of appetite and taste, and may find it difficult to eat. Consequently, diarrhoea and anorexia is commonly observed. Antidiarrhoeals are often prescribed with plenty of fluids, to reduce the frequency of occurance and replenish water loss. Hydration is therefore, clearly of doubly importance with respect to the use of cisplatin.

• Myelosuppression, the reduction of bone marrow function, is mild relatively to other antineoplastics. However, thrombocytopenia (reduction of platelets and thus ability for blood to clot) and granulocytopenia (reduction of a class of white cells and thus ability to fight off infections), may be observed by days 7-9 and 17-19 after injection, respectively. ^{¤ , ¤} Blood counts fall 1-2 weeks after treatment, therefore, patients may become anaemic, and susceptible to infections, at least temporarily. The extent of blood cell reduction is dependent on the size of the dose and whether other drugs are used in conjunction with cisplatin.

  With increased ease of bruising, prolonged bleeding and reduced immunity, patients are advised to follow certain precautions to minimise potential problems. These include:

  • Maintaining strict personal hygeine, using antibacterial soap for washing;
  • Washing of hands before touching eyes or inside of nose;
  • Being careful while brushing teeth, using dental floss, and using toothpicks;
  • Being careful not to cut oneself accidentally (shaving, using nail clippers,...);
  • Avoiding participation in contact sports;
  • Avoiding individuals with infections, and those having recently received the oral polio vaccine.
  • Not having vaccinations unless approved by a doctor,

  Although bone marrow functionality gradually returns to normal within 21-28 days, patients may require red blood cell and platelet transfusions.

• There are many effects of cisplatin on epidermal and follicle cells, one of which is the commonly known side effect - hair loss. A few others include: ^‡
  • Angioedema
  • Erythema
  • Exfoliative Dermatitis
  • Facial Edema
  • Flushing
  • Hyperhidrosis
  • Rash
  • Alopecia
  • Hypomelanosis
  • Anaphylaxis
  • Gingival Discolouration
  • Injection-site cellulitis
  • Oral Mucosal Lesions

With the application of higher doses, which is a relatively recent feature of chemotherapeutic regimens, other toxic side effects are being reported. At higher or prolonged doses, neurotoxicity becomes a factor. Initial symptoms include numbness and/or tingling in hands or feet. More severe symptoms include, muscle weakness, poor co-ordination and unsteadiness. This may be due to the additional effects of hypomagnesaemia (magnesium deficiency), hypocalcaemia (calcium deficiency), hypokalaemia (potassium deficiency), and hypophosphataemia (phosphorus deficiency). Symptoms are usually reversable, and so disappear slowly over a few months after completion of treatment. Once preventive clinincal interventions to reduce neurotoxicity have been acheived, the major dose-limiting toxicities are considered to be anorexia and peripheral neuropathy, which is the irreversible degradation of the peripheral nerves. The other side effects associated with cisplatin are less common and are rather rare. These include:

• Visual impairment
• Hallucinations
• Conjunctivitis
• Seizures
• Arrhythmias
• Haemolysis
• Headache
• Glucose intolerance
• Pancreatitis
• Hyperuricaemia
• Anaphylactic-like reactions
• Liver damage
• Tetany
• Transient bronchial irritation
• Possible damage to unborn feotuses
• Possible sterilisation
• Allergic reactions - includes itching, dizziness, anxiety, shivering, high temperature and shortness of breath.

In general, the precise mechanisms of action related to the toxic manifestations of cisplatin are unclear. The degree of toxicity associated with cisplatin has motivated the research and development of "second-generation" platinum complexes with increased properties such as new selectivity, including a broader spectrum of activity, especially in cisplatin-resistant tumour lines. These analogues would also have greater clinical effectiveness or reduced toxicity, and modified pharmacological properties such as solubility which would allow for other routes of administration.

A final toxicological aspect of cisplatin that must be mentioned is not to do with side effects, but that of the direct effects towards DNA. As mentioned in the properties page, the carcinogenicity (ability to cause cancer) and mutagenicity (ability to alter DNA) of cisplatin has not been officially determined or ackowledged. ^¤ Many studies have indicated these effects, for example, a study involving the use of mice, ^‡ showed the incidence of lung adenomas and skin papillomas increased in female mice treated with cisplatin. The drug was also shown to induce leukemia in rats of both sexes. No direct evidence of carcinogenicity with respect to humans, however, has yet been shown this to be true. Two other studies examining the mutational specificity of the full range of lesions induced in E. coli DNA treated in vitro and in vivo with cis-DDP, showed that the major mutations caused by cisplatin were transversions at the 5' base of 5'ApG-3' and 5'-GpG-3' sites. ^¤ The mutations at the former site were approximately five times more abundant than those of the latter. The validity of this observed mechanism towards humans however, has not been determined and the mutagenicity of cisplatin remains unresolved.