Standard treatment for advanced colorectal cancer has long been comprised of fluorouracil(Drug information on 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(Drug information on irinotecan) (CPT-11, Camptosar) and oxaliplatin(Drug information on 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 1).
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 2).
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 limiting.
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(Drug information on cisplatin) (Platinol), or paclitaxel(Drug information on 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 4).
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 4).[9,10]
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 affected.