Srikar Vema

1/15/16
Pd 5 and 6
Intern Mentor
Intern Mentor Synthesis Paper
Cisplatin is the most common antineoplastic drug used for the therapy of solid tumors.
Discovered by Dr. Barnette Rosenburg in 1977, Cisplatin is a platinum based chemotherapy drug
that has proved to be an effective combatant against solid tumors. As a result, patients diagnosed
with solid tumors are usually prescribed Cisplatin first. Cisplatin is administered intraveinously
(IV) in that it enters the body directly through the blood stream. The dosage is determined by the
severity of the tumor, if it is malignant or benign, and what stage the tumor is in. Although
studies as well as observation of this drug have provided convincing evidence of the drugs
capabilities, the success that is demonstrated by Cisplatin is only temporary for it possesses draw
backs. Like most drugs, the use of Cisplatin results in significant side effects and these side
effects increase in intensity as the dosage of Cisplatin increases. Arguably the most prominent of
these adverse effects are neurotoxicity, ototoxicity, and nephrotoxicity.And these side effects can
alter the life style of the patient in a negative way, for long periods of time.
The nervous system is categorized into two parts: the Central Nervous System (CNS),
and the Peripheral Nervous System (PNS). The Central nervous system is comprised of the brain
and spinal cord. The spinal cord serves to relay signals between the brain and the rest of the
body while the brain is responsible for deciphering the messages it receives from the spinal cord
and sending messages back that induce reactions to the information it receives from the

environment. The brain also manages the involuntary bodily functions such as breathing, heart
beats, and homeostasis. The Peripheral Nervous system consists of all of the nerves and nerve
cells outside of the CNS. Cisplatin affects the PNS more than any other part of the body.
According to Amptoulach and Tsavaris (2011) Toxicity to the peripheral nervous system is the
major dose-limiting toxicity of at least some of the platinum drugs of clinical interest. (p. 1)
including Cisplatin. The peripheral nerves that are affected by cisplatin are located in the
epidermis, on the tongue, and optical nerves. As a result, the patient will experience impairment
in taste, touch, and vision. Most often, the patients receiving cisplatin are diagnosed with
Peripheral Neuropathy which is the damage of peripheral nerves that leads to weakness,
numbness and pain in the affected area, often the hands and feet area. The nerve endings that are
located in our hands and our feet are part of the PNS and allow us to detect different textures,
and temperatures. Quatoff and Hartung state that In general, the peripheral nervous system
(PNS) has a great capacity of regeneration in response to injury. For regeneration to occur, the
cell body needs to be spared and a long period without damage following the drug administration
allowed so that the PNS has sufficient time to accomplish repair. (1). This means that the
patient cannot receive further treatment after their nerve cells are damaged but if the medication
is stopped, then there is a greater risk that the rate of tumor growth will begin to increase. This
brings an important dilemma into light: Should the medication be terminated to prevent long
lasting damage to the nervous system or should the medication be continued to possibly cure the
save the patient despite the fact that the patients nervous system is deteriorating? To make a
decision, the stage of the tumor, the degree of damage to the nervous system, and the sensitivity
of the patient to cisplatin all have to be taken into consideration before coming to a conclusion.
The curability of Peripheral Neuropathy, or Chemotherapy-induced neuropathy depends on the

dosage of Cisplatin the patient receives. According to Quasthoff and Hartung, Depending on
dosage and agent used, symptoms resolve completely in some cases. Unfortunately, in most
instances, the chemotherapy-induced neuropathy (CIN) is only partly reversible and in the worst
cases damage is completely irreversible. CIN therefore represents an important and persistent
limitation of quality of life even when the tumor has been successfully treated by the drugs. (1).
One type of toxicity that is linked to neurotoxicity is ototoxicity. Cisplatin not only
effects the peripheral nervous system but also the nerves in the ear. the antitumor efficacy of
cisplatincomes at the cost of ototoxicity, which affects at least 60% of pediatric patients.
(Langer et al. 2013). Ototoxicity is the property of being toxic to the ear. Most often, ototoxicity
affects the cochlea or the vestibular system. The cochlea is the spiral cavity located in the inner
ear which produces nerve impulses that are generated as a result of sound waves that reach the
eardrum. The vestibular system is located mostly in the inner ear and is responsible for sensory
information about motion, balance, spatial orientation, and is composed of three separate organs
in each ear; the semicircular duct and the otoliths are the most important in this discussion.
Patients who suffer from ototoxicity experience dizziness and nausea and this is caused by the
impairment of the vestibular system. The nerves that send signals to the brain from the vestibular
system are damaged by the cisplatin so the messages that the brain receives from these damaged
nerve cells are disarranged. The brain receives these messages but because these messages about
the patients position in space the patient experiences nausea and dizziness. The brain is
deciphering the damaged information so the patients perception of special position is altered.
Ototoxicity also causes hearing lass as a result of the same reason for dizziness and nausea.
However, this time, the cochlea is in the spotlight. The nerves that relay messages to the brain
from the cochlea are also impaired by the cisplatin so the brain cannot decipher the signals

properly. This results in hearing loss and if not treated immediately, the hearing loss could be
germinant. Ototoxicity effects children receiving the medication more frequently than adults and
once clinically significant toxicity is observed on audiologic monitoring, current practice

suggests dose reductions or omissions, potentially reducing cure, but the ototoxic damage is
already done and the hearing loss is permanent.
The kidneys play an important role in the excretory system and are composed of over one
million microtubules called nephrons each. The nephrons filter the blood by separating excess
nutrients and metabolic waste from the blood and sending the clean blood back into circulation.
The waste filtered out by the nephrons include excess electrolytes, nitrogen, urea and creatine. If
the nephrons do not properly filter the blood, the waste will re-enter the blood stream and the
patient will essentially be poisoned. Another prominent side effect of Cisplatin is nephrotoxicity
which effects the nephrons. According to Arnay Safirstein, one of (cisplatins) chief doselimiting side effect is nephrotoxicity, which evolves slowly and predictably after initial and
repeated exposure.. Because all of the blood in the body must flow through the kidneys and
cisplatin is added directly into the blood stream, The kidney accumulates and retains platinum
to a greater degree than other organs and is the principal excretory organ for injected cisplatin
(460). As a result, the nephrons of patients receiving Cisplatin are continually exposed to the
platinum base of Cisplatin and deteriorate over time. According to Hanigan and Devrajan,
Cisplatin is toxic to the renal proximal tubules. The severity of toxicity in early clinical trials
called into question the use of cisplatin as a chemotherapy agent . Hydration protocols were
developed that reduced the nephrotoxicity and allowed dose escalation to therapeutic levels.
However, even with vigilant hydration, approximately one-third of patients treated with cisplatin
have transient elevation of blood urea nitrogen levels or other evidence of kidney damage in the

days following cisplatin treatment. (48). Renal Proximal Tubules are an essential portion of the
nephron that plays a role in filtration. After the filtrate passes through the Tubules, it continues
towards the bladder. The severity of nephrotoxicity increases as the dosage of Cisplatin
increases. Cisplatin caused dose-dependent inhibition of QO2, which was delayed in onset. The
concentration of cisplatin required for inhibition decreased as the duration of exposure was
increased [40-min exposure, threshold concentration of 10(-4) M, inhibitor constant (Ki) of 10(3) M; 4-h exposure, threshold concentration of 3 X 10(-5) M, Ki of 10(-4) M]. Both ouabainsensitive and ouabain-insensitive QO2 were reduced, indicating inhibition of all
adenosinetriphosphatases, including Na(+)- K(+)-ATPase activity. (Brady et al. 1990) where
QO2 is Oxygen consumption of the test subject. The cells that make up the renal tubules become
more and more inactive as the dosage of cisplatin varied and the amount of time the cells were
exposed to Cisplatin increased. The cells oxygen consumption decreased resulting in the
decelerated performance of the renal tubules. As a result, an increase in electrolytes such as
Potassium (K+),and Sodium (Na+), in the blood stream. The study was performed in vivo
meaning cisplatin was administered to a live organism. Due to this, we cannot determine
causation. When a study is performed in vivo, the changes that are measured could be a result of
the many complicated and interrelated processes that occur in the organism. For example, the
reduced oxygen consumption and increase in the concentration of electrolytes may have several
reasons for its occurrence but we are sure that the kidneys are effected by Cisplatin. The
Cisplatin essentially weakens the mitochondria in the nephron cells which impede the
performance of the nephrons. The nephrons, now working at slower rates than normal, cannot
filter the blood of the excess electrolytes, urea and water that is carried to the kidneys via the
blood stream. As a result, the waste products re-enter the bloodstream and cause the patients own

blood to become toxic. Although this is a very serious problem, It is does not cause long term
problems. Nephrotoxicity usually shows signs very quickly. Kidney failure is possibly, usually
leading to death but there are very few of such cases. Unlike the nervous System, the kidneys are
able to heal themselves over shorter time periods so the damage is almost never long term.
Cisplatin is an extremely effective drug that is often used as a first defense in battling
tumors. However, with the advantages of cisplatin also comes significant disadvantages. These
disadvantages can affect the patient so much that it can change the patients lifestyle completely.
The most considerable side effects are Neurotoxicity, Ototoxicity, and Nephrotoxicity and all of
these side effects become worse as the dosage of cisplatin increases. As of now, preventive
measures being applied in pediatric practice to reduce or stop the progression of these side
effects is to reduce the dosage of Cisplatin. Although this method may curtail the damage done
by the side effects, it also restrains the curing of the tumors. The required dosage of cisplatin is
not met and the tumor may grow. As a result, reducing the dosage of cisplatin essential slows the
growth of the tumor but does not eradicate it completely causing the patient to pay more money
for the treatment and also to suffer the pain that comes with cancer. Collaborative clinical trails
are taking place to increase our knowledge about the side effect of cisplatin and how to reduce
theses adverse effects while treating the tumors effectively. There is still much to learn before we
can find the cure for cancer but at least we can make the lives of cancer patients and their
families easier.

Works Cited

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Arany, I., & Safirstein, R. L. (2003, September). Cisplatin nephrotoxicity. InSeminars in

dddddnephrology (Vol. 23, No. 5, pp. 460-464). WB Saunders.

Quasthoff, S., & Hartung, H. P. (2002). Chemotherapy-induced peripheral neuropathy. Journal

dddddof neurology, 249(1), 9-17.
Brady, H. R., Kone, B. C., Stromski, M. E., Zeidel, M. L., Giebisch, G. E. R. H. A. R. D., &
dddddGullans, S. R. (1990). Mitochondrial injury: an early event in cisplatin toxicity to renal
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Hanigan, M. H., & Devarajan, P. (2003). Cisplatin nephrotoxicity: molecular
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Langer, T., am Zehnhoff-Dinnesen, A., Radtke, S., Meitert, J., & Zolk, O. (2013). Understanding
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Brock, P. R., Knight, K. R., Freyer, D. R., Campbell, K. C., Steyger, P. S., Blakley, B. W., ... &
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dddddmechanisms, predisposition, and protection, including a new International Society of
dddddPediatric Oncology Boston ototoxicity scale. Journal of Clinical Oncology, 30(19), 2408ddddd2417.