Standard treatment for advanced colorectal
cancer has long been comprised of fluorouracil (5-FU)-based chemotherapy
regimens, administered typically by bolus techniques. Despite the modest
survival benefit associated with the use[1-3] of 5-FU-based regimens, those
administered by continuous infusion are well tolerated, with reduced
myelosuppression. The ongoing search for new agents with improved activity
and acceptable tolerability has resulted in the availability of promising new
agents that are effective against advanced colorectal cancer. These agents
include irinotecan (CPT-11, Camptosar) and oxaliplatin (Eloxatin).
Oxaliplatin, a platinum compound, has a novel mechanism of
action that appears to have activity as both first- and second-line
therapy.[5-12] It has demonstrated synergistic antitumor activity in combination
with 5-FU and leucovorin both in vitro and in vivo.[13,14] In patients,
tolerability of oxaliplatin, either alone or in combination with
5-FU/leucovorin, is acceptable. The purpose of this article is to present
toxicity data from the principal phase II and III clinical trials of oxaliplatin
alone and in combination with 5-FU/leucovorin as first- and second-line
treatment of patients with advanced colorectal cancer.
Two multicenter phase II clinical trials (EFC 2960, EFC 2963)
assessed oxaliplatin monotherapy in a total of 63 previously untreated patients
with advanced colorectal cancer.[7,8] The oxaliplatin dose was 130 mg/m2
every 3 weeks. Among the most common toxicities seen in these trials were
gastrointestinal side effects such as nausea, vomiting, or diarrhea, and
hematologic toxicities such as neutropenia and thrombocytopenia. These
toxicities also occur commonly with other chemotherapeutic agents typically used
to treat colorectal cancer.
One unique toxicity characteristic of oxaliplatin, but not other
agents used to treat colorectal cancer, was paresthesia. This will be discussed
in more detail in the section on neurotoxicity. Oxaliplatin monotherapy did not
cause significant alopecia, renal toxicity, or ototoxicity, thus distinguishing
it from platinum analogs and the other chemotherapy agents used in the treatment
of colorectal cancer.
The multicenter phase III pivotal trial (EFC 2962) of
oxaliplatin as first-line therapy in patients with metastatic colorectal cancer
provided information on the safety of oxaliplatin that is representative across
other clinical trials. In this randomized trial of 420 previously untreated
patients, the study arms received either 5-FU/leucovorin alone (n = 207)
according to the de Gramont bimonthly schedule of 5-FU/leucovorin plus
oxaliplatin at 85 mg/m2 every 2 weeks (n =
209). The total number of cycles of therapy administered was 2,431 in the
5-FU/leucovorin group (median, 11 cycles; range, 1 to 40) and 2,591 in the
5-FU/leucovorin plus oxaliplatin group (median, 12 cycles; range, 1 to 35). This
represents an extensive exposure to oxaliplatin therapy for purposes of toxicity
analyses, both acute and chronic.
Toxicities Increased But Incidence of Grade 3/4 Is Low
Although the addition of oxaliplatin to 5-FU/leucovorin
chemotherapy was associated with an increase in most toxicities, the incidence
of most was low. The incidence of grade 3/4 National Cancer Institute (NCI)
criteria gastrointestinal toxicity was greater in the oxaliplatin group than in
the 5-FU/leucovorin group, reaching statistical significance for nausea,
vomiting, diarrhea, and stomatitis (Table 1).
An assessment of grade 3/4 gastrointestinal toxicity by cycle showed that the
incidence of gastrointestinal toxicities was low, generally occurring in fewer
than 1 of 100 cycles of oxaliplatin therapy (Table
The only NCI grade 3/4 hematologic toxicity that occurred
significantly more often in the group treated with oxaliplatin compared with the
5-FU/leucovorin control group was neutropenia (41.7% vs 5.3%; P <
.001). However, the incidence of neutropenic fever was similar in both groups (Table
2), indicating that neutropenia in the combination was not detrimental. As
with the gastrointestinal toxicities, the rate of hematologic toxicities was low
when assessed by cycle, with neutropenia being the most common (Table
Although thrombocytopenia was more common among patients treated
with oxaliplatin, there were no life-threatening bleeding episodes. There were
no significant differences in NCI grade 3/4 hepatic (SGOT, SGPT, alkaline
phosphatase) or renal (creatinine) toxicity between the two groups, whether
assessed by patient or by cycle. In summary, non-neurotoxic side effects with
oxaliplatin occur relatively infrequently, are manageable, and are rarely dose
Neurotoxicity is generally not associated with the chemotherapy
agents commonly used to treat colorectal cancer. The neurotoxicity that has been
observed with oxaliplatin is qualitatively different from that noted with
vincristine, cisplatin (Platinol), or paclitaxel (Taxol). The NCI Common
Toxicity Scale, which grades the severity of the toxicity, does not accurately
or adequately capture the neurotoxicity caused by oxaliplatin. Investigators in
Europe (where the major clinical trials were conducted), therefore, developed a
specific scale to grade not only the severity, but also the duration of the
neuropathy caused by oxaliplatin(Table 3).
Understanding the differences between the scales is important
for interpretation of the neurotoxicity findings with oxaliplatin. For example,
in the NCI grading scale, grade 3 neurotoxicity is severe sensory loss or
paresthesia that interferes with function, whereas in the oxaliplatin-specific
scale, grade 3 neurotoxicity may have been a milder neuropathy that persisted
between treatment cycles.
Two Distinct Patterns
There are two distinct patterns of neurosensory toxicity that
occur with oxaliplatinacute and cumulative. The unique group of symptoms that
occur acutely (within hours to days after infusion) can be characterized as
affecting the fingers and toes or the mouth and throat. These symptoms are
worsened by exposure to cold. Patients who experience acute neuropathy following
treatment with oxaliplatin typically relate that picking up a cold drink is like
picking up dry ice, while drinking a cold drink feels like drinking crushed ice.
This type of acute neuropathy is not disabling for most patients.
In the phase III pivotal trial of oxaliplatin as first-line
therapy (EFC 2962) and in the phase II oxaliplatin second-line therapy trials
(EFC 2964, 2917), the overall incidence of cold-related paresthesia of distal
extremities was 68% and 78%, respectively (Table
4) while prolonged side effects (grade 3 toxicity by the
oxaliplatin-specific grading scale) were uncommon (0.5% and 2.6%).[9,10]
Cold-related paresthesias of the pharyngolaryngeal area were less common (23%
and 19% for all grades) than those of the distal area (Table
Additionally, a pharyngolaryngeal syndrome has been described
for which investigators developed a trial-specific grading scale (Table
3). When the pharyngolaryngeal syndrome was first noted in patients who felt
dyspneic, blood gases were found to be normal, patients were not cyanotic, and
were, in fact, breathing without physiologic compromise. This sensation,
described as the pharyngolaryngeal syndrome, is therefore characterized by
subjective dyspnea or dysphagia with normal blood gases and no physical evidence
of obstruction. It is uncommon, occurring in 2.5% of 478 patients enrolled in
the pivotal first- and second-line therapy trials and in 0.3% of 4,477 cycles (Table
It is typically mild, and develops within hours of the
oxaliplatin infusion. True laryngeal spasm, which is probably a hypersensitivity
reaction, occurred in only 0.4% of patients or 0.0007% of cycles. It may occur
in the first cycle or in subsequent cycles. Severe anaphylactic reactions to
oxaliplatin are rare.
Management of the acute neurosensory symptoms that occur with
use of oxaliplatin includes instruction to avoid cold drinks or foods for a few
days following treatment and to wear gloves if exposure to cold is unavoidable.
Patients should also avoid ice chips during 5-FU-based chemotherapy (see Table
5). Educating patients about the potential for the pharyngolaryngeal
syndrome is important as well.
In the case of acute manifestations of pharyngolaryngeal
symptoms, patients should be examined to rule out airway obstruction and
reassured or treated with anxiolytics as necessary. For subsequent treatment
cycles, pretreatment with anxiolytics may be helpful, and the length of the
oxaliplatin infusion should be increased from 2 hours to 6 hours.
The dose-limiting toxicity of oxaliplatin is cumulative
neurosensory toxicity. It worsens with continued exposure to the drug and
initially affects fine sensory motor coordination. Less than 10% of patients
experience cumulative toxicity before reaching a total cumulative oxaliplatin
dose of 850 mg/m2 (which corresponds to 10 or
more cycles of treatment). It also appears reversible upon cessation of
treatment. In patients who have been prospectively observed, there was
improvement to a lower grade over a median of 13 weeks.
In the phase III pivotal trial (EFC 2962), the incidence of
grade 3 cumulative neurologic toxicity was significantly greater with
oxaliplatin added to 5-FU/leucovorin than with 5-FU/leucovorin alone regardless
of whether assessed by the NCI neurotoxicity scale (18.2% vs 0%) or the
oxaliplatin trial-specific paresthesia scale (16.3% vs 0%) (both P <
.001). The impact of the cumulative neurotoxicity with oxaliplatin can be
assessed by comparing the time of onset of grade 3 toxicity with the time of
onset of tumor response. With this assessment technique, onset of tumor response
occurs long before grade 3 cumulative paresthesia is observed (Figure
1). Therefore, patients and their physicians can review their desire to
continue treatment in spite of the side effects, and few nonresponders will be
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