NcXHF

CAVALETTI, ALBERTI, AND MARMIROLI
other neurotoxic drugs, with the same disappointing
results. 32
Conventional chemotherapy has limitations in its effectiveness,
and it is associated with potentially severe side effects
as a result of damage to normal tissues, as shown for
CIPN. To overcome some of these problems, a transition to
rationally designed, molecularly targeted drugs, which aims
at a much more specifıc effect on cancer cells and a sparing of
normal tissues, has occurred in chemotherapy. Several of these
targeted drugs are now used routinely. Different from chemotherapy
with curative intent, cancer-targeted drugs also are used
as continuous administration after treatment response, and
maintenance therapy can be continued in cases of tumor progression
to prevent uncontrolled growth. Although these drugs
are generally considered safer and less toxic than conventional
chemotherapy, off-target toxicities (e.g., neurotoxicity) may
emerge, particularly during prolonged use.
Although the literature evidence is still limited and data are
somewhat inconsistent, PNS toxicity has been described. Moreover,
because cancer-targeted therapies frequently are used after
or in combination with conventional chemotherapy, the possibility
that their use could worsen the toxicity profıle of standard
neurotoxic chemotherapy drugs also should be considered. In
Table 2, examples regarding the possible peripheral neurotoxic
effect of cancer-targeted drugs are reported.
Also, the pathogenesis of cancer-targeted drugs effects on
the PNS is largely unknown. It has been suggested that some
of their neurotoxic effects are a result of the capacity to interact
with the immune system. For instance, fıve of a series of
85 patients treated with alemtuzumab developed a progressive
sensorimotor radiculoneuropathy and/or a myelitis. 33
Moreover, in 2010, another case of acute inflammatory
polyradiculoneuropathy (Guillain-Barré syndrome) was reported
in an alemtuzumab-treated patient. 34 In these cases, it
has been hypothesized that alemtuzumab may trigger an
autoimmune cascade that results from indiscriminate dysregulation
of regulatory T cells or from a molecular mimicry.
In addition to the immune-mediated effect on the PNS,
clinical pictures compatible with classical CIPN also have
been described with cancer-targeted drugs. The administration
of brentuximab vedotin can be associated with a dosedependent
peripheral neuropathy that can limit prolonged
administration of the drug. In phase I studies, cumulative
dose-related peripheral neuropathy, probably associated with
unconjugated microtubule inhibitor monomethyl auristatin E
(i.e., the active part of the molecule acting as the classical chemotherapy
drugs) was clinically relevant; 37% of patients showed
persistent symptoms, which led to drug discontinuation in 25%
of patients. 35 In another study, 73% of patients treated with
brentuximab vedotin developed peripheral neuropathy, mostly
mild to moderate, and similar data were replicated in phase II
studies. 36 However, dramatic motor neuropathy also has been
associated with brentuximab vedotin use. 37
It can be concluded that careful monitoring that is based on
a formal neurologic assessment of the possible PNS toxicity
of all of these new drugs is mandatory to ascertain in prospective
clinical trials their real toxicity profıles, alone or in combination
treatments.
EVIDENCE OF LONG-TERM PERSISTENCE OF
CHEMOTHERAPY-INDUCED PERIPHERAL
NEUROTOXICITY
The previously accepted paradigm that CIPN, in nearly all
cases, is a reversible clinical condition has recently been challenged
by several studies performed mainly in patients with
breast, colorectal, and ovarian cancer, in which the use of
neurotoxic drugs is frequent and survival for greater than 5
years is increasingly frequent.
TABLE 2. Examples of Peripheral Neurotoxicity of Targeted Agents Used in Cancer Therapy
Drug Reported Previous Neurotoxic Treatment Description of Peripheral Nervous System Toxicity
Alemtuzumab None Progressive peripheral sensorimotor radiculoneuropathy and/or myelitis
Brentuximab vedotin Previous chemotherapy (undefined) Peripheral sensory neuropathy: any grade in up to 66%; grade 3 in up to 8%
Peripheral motor neuropathy: any grade in up to 11%, grade 3 in up to 7%
Carfilzomib Lenalidomide or thalidomide Treatment-related neuropathy: any grade in up to 17%; rarely grade 3
Ibritumomab CVP or COP or CHOP Paresthesias: grade 1 in up to 13%
Imatinib Cytarabine “Pain in limbs”: any grade in up to 11%; grades 3-4 in up to 1%
Ipilipumab Carboplatin Guillain-Barré syndrome
Lapatinib Taxanes, vinorelbine “Pain in extremities”: any grade in up to 13%; grade 3 in 1%
Regorafenib Oxaliplatin Sensory neuropathy: any grade in up to 7%; grade 3 in 1%
Rituximab CHOP (first-line), ProMACE CytaBOM (second-line) Guillain-Barré syndrome
None
Guillain-Barré syndrome
Sorafenib Previous chemotherapy (undefined) Treatment-emergent sensory neuropathy: grades 1-2 in up to 20%
Vemurafenib Previous chemotherapy (undefined) Peripheral neuropathy: any grade in up to 10%; grade 3 in 1%
Vorinostat Previous chemotherapy (undefined) Cutaneous polyneuropathy (tingling) was reported as leading to discontinuation
Abbreviations: CVP, cyclophosphamide, vincristine, prednisone; COP, cyclophosphamide, vincristine, prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; ProMACE CytaBOM,
cyclophosphamide, doxorubicin, etoposide cytozar, bleomycin, vincristine, methotrexate, prednisone.
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