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SIDE
EFFECTS OF ANTICANCER CHEMOTHERAPY REGIMENS USED IN COLORECTAL
CANCER
Muzikraviæ
Lj.
Institute
of Oncology Sremska Kamenica, Sremska Kamenica, Serbia
and Montenegro
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ABSTRACT
The
use of various 5-fluorouracil (5-FU) schedules has been a standard
medical treatment of colorectal cancer during passed half century.
For a long time the most frequently used was Ansfield's protocol,
also called Mayo clinic protocol. It comprises of a daily dose of
12mg of 5-FU per kg, given intravenously during five successive
days, and repeated every month (1,2). This schedule was created
in late 50s by Ansfield (1), soon after 5-FU synthesis by Duschinsky
and Heidelberger in 1957(3). Common side effect of this treatment
is myelosuppression manifested as neutropenia, rarely as thromboicytopenia,
and very rarely as anemia. The onset of neutropenia is 8 to 10 days
after the start of chemotherapy, and in most cases with spontaneous
recovery. Mucositis can sometimes appear 3 to 5 days after the start
of chemotherapy, most often manifested as stomatitis, and very rarely
as pharyngitis and esophagitis. Diarrheic syndrome is common, in
most cases mild and spontaneously cured. Nausea and vomiting are
also mild and well tolerated with standard antiemetic therapy (4,5).
Cardiotoxicity, manifested as myocardial ischemia, is a rare side
effect (6). Poor results of therapy with 5-FU given as bolus have
induced trials with different modes of 5-FU application. Sullivan
in 1960, Krant in 1961 and Staley in 1962 conducted trials with
infusion application (7,8), but it was not accepted widely. The
interest for infusion application was renewed by Seifert in 1975
(9), and Lokich definitely confirmed advantages of this approach
(10,11). The response rate was higher and myelotoxicty lower, but
severe mucositis emerged as a main side effect. Protracted infusion
therapy also caused a new side effect, hand-foot syndrome (12,13),
manifested in 25-30% of patients (14). Poor results of 5-FU monotherapy
induced the use of combined chemotherapy, adding nitrosourea compounds
(mainly methyl-CCNU) to 5-FU, but this combination was compromised
by higher myelotoxicity, without better therapeutic response (15).
Combination of 5-fluorouracil with biomodulators
Modulation of 5-FU is widely used to enhance its therapeutic activity.
The most commonly used modulator is leucovorin (calcium folinate).
The improvement in response rate is not followed by markedly enhanced
toxicity, especially considering nausea and vomiting. There was
some increase of diarrhea onset, associated with regimens using
high-dose leucovorin (16). Mucositis appears in higher percentage
than in 5-FU monotherapy, severe (grades 3 and 4) in 22% of patients.
Other approaches are reduction of nucleotide pool by Phosphonoacetyl-L-Aspartate
(PALA), not widely accepted because of strong toxicity, including
cerebellar ataxia, hypoalbuminemia, etc. (16). Combinations with
methotrexate or with interferon are only slightly more effective,
but with additional toxicity (16).
Capecitabin
Capecitabin is a new orally administrable fluoropirimidine. Schedules
with chronic dosing are designed to mimic continuous infusion of
5-FU, so the treatment-related adverse events are similar to these
caused by protracted infusion therapy. Hand-foot syndrome appears
in 40-50% of patients, diarrhea in 40%, nausea in 35%, vomiting
in 20%, and mucositis in 25% of patients (17).
Tomudex
This thymidilate synthesis inhibitor provoked enthusiasm in last
decade as efficient and low-toxic drug, but was not accepted widely
in colorectal cancer treatment (18).
Irinotecan
In standard dosage of 350mg/m2 this drug causes common but also
some specific adverse reactions (19). Myelotoxicity is in 80% patients
manifested as neutropenia, median on day 5 after chemotherapy. Severe
neutropenia of grade 4 was noticed in about 40% patients sometimes
manifested as febrile neutropenia. Anemia was registered in 60%
pts, mainly of mild degree. Thrombocitopenia is a rare side effect,
appearing in 7% of patients. Side effect specific for irinotecan
and present in 83% of patients is acute cholinergic syndrome, manifested
as sweating, salivation, lachrymation, myosis, and abdominal cramping.
Caution is important in patients with bronchial asthma. Prophylaxis
of the acute cholinergic syndrome is quite simple with 0.25mg Atropine
sulfate given subcutaneously before treatment. Delayed diarrhea
(appearing more than 24 h after drug administration; median time
of onset is on day 5) is also characteristic of irinotectan treatment,
manifested in 85% pts, and as severe presentation in 30-40%. At
high risk are pts who had previous abdominal or pelvic irradiation.
This drug is contraindicated in patients with chronic inflammatory
bowel disease and with bowel obstruction. Treatment is simple, but
often it should be conducted in hospital: rehydration, and Loperamid
2 mg every 2 hours. Severe adverse reactions - vomiting, diarrhea,
neutropenia and fever can sometimes be associated and life threatening,
demanding urgent treatment in intensive care unit. Nausea and vomiting
(85%) are common, but are not as big problem as mentioned reactions
are. Hepatotoxicity must be avoided and therefore the manufacturer
suggests very crude assessment of liver function; patients with
bilirubin levels 1.5 above normal values should be excluded Alopecia
is very common, appearing in 85% of patients. Asthenia (75%) and
some other rare side effects were also described (19).
Oxaliplatin
This platinum compound is chemically DACH-oxalato platinum. 1,2-diammino-cyclohexane
(DACH) as part of the drug molecule takes merit for activity in
colorectal cancer, but also is responsible for characteristic sensory
neuropathy. This disturbance can appear in two forms. Soon after
drug administration tingling of the limbs and sometimes of the face
can start, usually disappearing within a few days. Peripheral neuropathy
affects the extremities and increases with repeated cycles of chemotherapy.
The symptoms are more pronounced and of greater duration with continuous
treatment, but can reverse 6 to 8 months after drug cessation. Other
side effects are nausea and vomiting, well controlled with 5-HT
antagonists. Myelosuppression, ototoxicity and nephrotoxicity are
uncommon. There were noticed cold dysesthesia, and laryngopharingeal
spasm, which can be ameliorated by prolonging the duration of infusion
(20).
Combined therapy Expecting synergism or additivity between drugs
with different mechanisms of action, there are in use some combinations
of cytostatics mentioned above. Better response rate could be achieved
with tolerable toxicity, due to their different dose limiting toxicities
(21).
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Oncol 2002; 20:4006-14. |
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Keywords:
Colorectal cancer, Chemotherapy, Side effect |
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