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Cytotoxic and immunosuppressant drugs
See also Alkylating cytostatic agents—nitrosoureas and N -lost derivatives ; Platinum-containing cytostatic drugs
General information
Cytotoxic drugs generally have both anticancer and immunosuppressive properties, while immunosuppressant drugs have more specific immunosuppressive effects, although this is a somewhat arbitrary distinction. Monoclonal antibodies and corticosteroids are not included in the following list.
- A.
Cytotoxic drugs
- 1.
Alkylating drugs
Nitrosoureas : carmustine (BCNU), lomustine (CCNU), nimustine (ACNU), streptozocin.
N-lost derivatives : chlormethine (mechlorethamine, mustine, nitrogen mustard), cyclophosphamide, estramustine.
Others : busulfan, chlorambucil, dacarbazine, ifosfamide, melphalan, mitobronitol, mitomycin, procarbazine, thiotepa, temozolomide, treosulfan.
- 2.
Cytotoxic antibiotics
Anthracyclines [ ]: aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin.
Others : acivicin, amsacrine, bleomycin, dactinomycin (actinomycin D), mitoxantrone.
- 3.
Antimetabolites
Folic acid antagonists : methotrexate, raltitrexed. Purine derivatives: cladribine (2-chlorodeoxyadenosine), fludarabine, mercaptopurine, pentostatin (deoxycoformycin), tioguanine.
Pyrimidine derivatives : capecitabine, cytarabine, fluorouracil [ ], gemcitabine, tegafur.
- 4.
Vinca alkaloids [ ]
Vinblastine, vincristine, vindesine, vinorelbine.
- 5.
Photodynamic drugs
Porfimer, temoporfin.
- 6.
Platinum-containing compounds [ ]
Carboplatin, cisplatin, oxaliplatin.
- 7.
Taxanes
Docetaxel, paclitaxel [ ].
- 8.
Topoisomerase inhibitors [ , ]
Inhibitors of topoisomerase type 1 : irinotecan, topotecan.
Inhibitors of topoisomerase type 2 : etoposide, teniposide.
- 9.
Others
Bexarotene, bortezomib, colaspase and crisantaspase (asparaginases), hydroxycarbamide (hydroxyurea).
- 1.
- B.
Immunosuppressant drugs
- 1.
Antiproliferative immunosuppressants
Azathioprine, mycophenolate mofetil.
- 2.
Calcineurin inhibitors
Ciclosporin, everolimus, pimecrolimus, sirolimus, tacrolimus, temsirolimus.
- 1.
General adverse effects and adverse reactions
There are several types of adverse effects that the cytotoxic drugs have in common. These include hyperuricemia (a feature of the tumor lysis syndrome), bone marrow suppression, oral mucositis, gastrointestinal discomfort, and alopecia. These are dealt with under the relevant headings below. The US National Cancer Institute’s grading of adverse drug reactions, which was originally devised to encompass adverse reactions to anticancer drugs, is described on p. 000.
Individual drugs also have specific adverse effects and cause specific adverse reactions. However, one of the difficulties in attributing adverse reactions to individual cytotoxic and immunosuppressant drugs is the common use of multidrug or multi-intervention studies. A good example of this is the Phase I Study of Foscan-Mediated Photodynamic Therapy and Surgery in Patients with Mesothelioma, in which the authors could not separate the adverse reactions, which included local reactions, cardiotoxicity, and hepatotoxicity, according to causative drug or procedure [ ].
Extravasation of cytotoxic drugs
Extravasation is leakage of intravenous drugs from a vein into the surrounding tissues. This can cause local pain accompanied by burning or stinging, erythema, swelling, and tenderness. Not all cytotoxic drugs are harmful to the tissues after extravasation. The different types of drugs are classified in Table 1 .
Table 1
Classification of cytostatic drugs according to their ability to cause tissue damage after extravasation
| Vesicants a | Exfoliants b | Irritants c | Inflammatory agents d | Neutral agents e |
|---|---|---|---|---|
| Amsacrine Chlormethine Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Streptozocin Vinca alkaloids |
Aclarubicin Carmustine Cisplatin Dacarbazine Docetaxel Floxuridine Mitoxantrone Oxaliplatin Paclitaxel Topotecan Treosulfan |
Carboplatin Daunorubicin liposomal Doxorubicin liposomal Etoposide Irinotecan Teniposide |
Etoposide phosphate Fluorouracil Methotrexate Raltitrexed |
Asparaginase Bleomycin Cladribine Cyclophosphamide Cytarabine Fludarabine Gemcitabine Ifosfamide Interleukin-2 Melphalan Pentostatin Thiotepa Interferon alfa |
a Vesicants cause pain, inflammation and blistering of the skin and underlying tissues, leading to tissue death and necrosis.
b Exfoliants cause inflammation and shedding of the skin, but are less likely to cause tissue death.
c Irritants cause inflammation and irritation, but rarely cause tissue damage.
d Inflammatory agents cause mild to moderate inflammation and flare in local tissues.
e Neutral agents do not cause inflammation or tissue damage.
The management of extravasation of cytotoxic drugs has been reviewed [ ] and guidelines have been suggested.
Local extravasation
-
Stop administering the drug and explain to the patient that extravasation may have occurred.
-
Put on gloves and goggles.
-
Leave the cannula in place.
-
Attach a 20 ml syringe and try to withdraw residual drug. Give specific antidotes for specific cytotoxic drugs ( Table 2 ).
Table 2Specific antidotes for cytostatic drugs after extravasationDrug Antidote Instructions Comments Anthracyclines Dimethylsulfoxide
DexrazoxaneApply dimethylsulfoxide 99% topically
Give intravenous dexrazoxane; 1000 mg/m 2 on days 1 and 2 and 500 mg/m 2 on day 3; most effective if the first dose is given within 6 hoursApply a cold pack for 15 minutes, four times a day. Inspect after 24 hours and 7 days. If there are signs of erythema or ulceration after 7 days, discuss with a plastic surgeon Chlormethine Sodium thiosulfate Dilute 0.6 ml of sodium thiosulfate 50% with 9.4 ml of water for injection. Inject 4 ml through the cannula, then remove the cannula. Infiltrate with 0.2 ml subcutaneously over and around the affected area Apply a warm pack for 15 minutes, four times a day. Inspect after 24 hours and 7 days. If there are signs of erythema or ulceration after 7 days, discuss with a plastic surgeon Cisplatin a , b Sodium thiosulfate Dilute 0.6 ml of sodium thiosulfate 50% with 9.4 ml of water for injection. Inject 4 ml through the cannula, then remove the cannula. Infiltrate with 0.2 ml subcutaneously over and around the affected area Apply a warm pack for 15 minutes, four times a day. Inspect after 24 hours and 7 days. If there are signs of erythema or ulceration after 7 days, discuss with a plastic surgeon Vinca alkaloids Hyaluronidase Mix 1500 units of hyaluronidase with 1 ml of sodium chloride 0.9% for injection. Inject 0.5 ml through the cannula. Remove the cannula. Infiltrate with 0.2 ml subcutaneously over and around the affected area Apply a warm pack for 15 minutes, four times a day. Inspect after 24 hours and 7 days. If there are signs of erythema or ulceration after 7 days, discuss with a plastic surgeon b Sodium thiosulfate should only be used if a large volume (greater than 20 ml) of concentrated cisplatin (that is a concentration over 0.5 mg/ml) has extravasated.
-
Remove the cannula.
-
Do not apply pressure, which increases the area of extravasation.
-
Apply a thermal pack (for vesicant, exfoliant, and irritant drugs only) ( Table 2 ).
-
Raise the limb for 48 hours for vesicant drugs.
-
Review vesicant extravasation in 24 hours.
-
Consult a plastic surgeon if necessary.
Extravasation from a central venous catheter
If the patient complains of altered sensation, pain, burning, or swelling at the central venous catheter site or in the ipsilateral chest, or if there is a change in intravenous flow rate, extravasation may have occurred.
-
Stop administering the drug and explain to the patient that extravasation may have occurred.
-
Put on gloves and goggles.
-
Attach a 20 ml syringe and try to withdraw residual drug from the line.
-
If the reason for extravasation is needle dislodgement, and if aspiration through the needle was unsuccessful, remove the needle and try to aspirate subcutaneously in the pocket and surrounding tissues.
-
Give specific antidotes for specific cytotoxic drugs ( Table 2 ).
-
If a needle is still in situ it should be removed after instillation of the antidote; the antidote can also be injected into the surrounding tissues if needed.
-
Do not apply pressure, which increases the area of extravasation.
-
Apply a thermal pack (for vesicant, exfoliant, and irritant drugs only) ( Table 2 ).
-
Review vesicant extravasation in 24 hours.
-
Extravasation in the deep part of a central venous catheter will require referral to a plastic surgeon.
Organs and systems
Nervous system
Neurological symptoms occur in more than 20% of patients with cancer and can be increased by cytotoxic drugs. Acute and late neurotoxic syndromes involve a number of cytotoxic agents ( Table 3 ).
Table 3
Neurotoxic effects of cytostatic drugs
| Drug | Neurotoxicity |
|---|---|
| Asparaginase | Acute encephalopathy |
| Bortezomib | Peripheral neuropathy |
| Busulfan | Seizures |
| Carmustine | Brain damage in conventional doses when combined with radiation |
| Chlorambucil | Disorientation, cognitive dysfunction |
| Chlormethine | Rare encephalopathy following high doses |
| Cisplatin | Peripheral neuropathy, deafness, cerebral cortical blindness, seizures |
| Cytarabine | Cerebellar ataxia in high doses |
| Fluorouracil | Cerebellar ataxia in high doses |
| Ifosfamide | Mild memory disturbances |
| Methotrexate | Acute meningitis; acute fatal cerebral dysfunction; chronic leukoencephalopathy |
| Oxaliplatin | Acute and chronic sensory neuropathy |
| Taxanes | Peripheral neuropathy |
| Vinblastine | Jaw pain, myopathy, inappropriate ADH secretion |
| Vincristine | Peripheral neuropathy, abdominal pain, constipation |
| Vindesine | Overdose or accidental intrathecal injection is usually fatal |
| Vinorelbine | Sensorimotor distal symmetrical axonal neuropathy |
The late nervous system effects in survivors 7 years after treatment for childhood acute lymphoblastic leukemia include impaired concentration, attention, and memory [ ].
The late effect of chemotherapy and radiotherapy for nervous system lymphoma has been studied in 15 patients; 10 had severe symptomatic diffuse changes in the white matter within 8 months of completing treatment [ ].
Endocrine
Combined cytotoxic drug therapy for Hodgkin’s disease in childhood often results in abnormal endocrine function, particularly increases in follicle-stimulating hormone, prolactin, and thyroid-stimulating hormone [ ].
Metabolism
Hyperglycemia was reported in 21 of 56 patients who received weekly paclitaxel with oral estramustine and carboplatin (4-weekly); under 10% required pharmacological intervention [ ]. There was mild hyperphosphatemia in 24.
There was fasting hypoglycemia in 19 of 35 children with acute lymphoblastic leukemia receiving maintenance therapy of daily oral mercaptopurine and weekly oral methotrexate; all the children improved on withdrawal of chemotherapy and 10 of 15 normalized [ ].
There have been cases of acute tumor lysis syndrome in patients with melanoma [ ] and light-chain amyloidosis [ ]. The authors reviewed the incidence of acute tumor lysis syndrome in these diseases, which are less typically associated with it.
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