Safety of Oxaliplatin in the Treatment of Colorectal Cancer

ABSTRACT: The new platinum compound oxaliplatin (Eloxatin) appears tohave activity, either alone or in combination, as both first- and second-linetherapy for advanced colorectal cancer. Unlike other platinum derivatives, it isnot associated with significant nephrotoxicity or ototoxicity. The addition ofoxaliplatin at 85 mg/m2 to afluorouracil/leucovorin-based regimen administered every 2 weeks is welltolerated. The incidence of diarrhea and stomatitis increases with the additionof oxaliplatin, but can be managed by adjusting the dose. There is also asignificantly higher incidence of grade 3 or 4 neutropenia with oxaliplatin.Neutropenic febrile complications are rare. The occurrence of other hematologic,hepatic, or renal toxicities does not increase when oxaliplatin is added tofluorouracil-based regimens. Unlike other agents used for the treatment ofcolorectal cancer, oxaliplatin causes acute and chronic neurosensory symptoms.These acute symptoms are managed by taking precautions (eg, avoid colddrinks/food for a few days following treatment). Cumulative neurotoxicity is thedose-limiting toxicity associated with oxaliplatin treatment. This toxicityappears reversible with discontinuation of the drug and typically occurs wellafter the onset of tumor response. [ONCOLOGY14(Suppl 11):15-20, 2000]

Introduction

Standard treatment for advanced colorectalcancer has long been comprised of fluorouracil (5-FU)-based chemotherapyregimens, administered typically by bolus techniques. Despite the modestsurvival benefit associated with the use[1-3] of 5-FU-based regimens, thoseadministered by continuous infusion are well tolerated, with reducedmyelosuppression.[4] The ongoing search for new agents with improved activityand acceptable tolerability has resulted in the availability of promising newagents that are effective against advanced colorectal cancer. These agentsinclude irinotecan (CPT-11, Camptosar) and oxaliplatin (Eloxatin).

Oxaliplatin, a platinum compound, has a novel mechanism ofaction that appears to have activity as both first- and second-linetherapy.[5-12] It has demonstrated synergistic antitumor activity in combinationwith 5-FU and leucovorin both in vitro and in vivo.[13,14] In patients,tolerability of oxaliplatin, either alone or in combination with5-FU/leucovorin, is acceptable. The purpose of this article is to presenttoxicity data from the principal phase II and III clinical trials of oxaliplatinalone and in combination with 5-FU/leucovorin as first- and second-linetreatment of patients with advanced colorectal cancer.

Overviewof Toxicity With Oxaliplatin Therapy

Two multicenter phase II clinical trials (EFC 2960, EFC 2963)assessed oxaliplatin monotherapy in a total of 63 previously untreated patientswith advanced colorectal cancer.[7,8] The oxaliplatin dose was 130 mg/m²every 3 weeks. Among the most common toxicities seen in these trials weregastrointestinal side effects such as nausea, vomiting, or diarrhea, andhematologic toxicities such as neutropenia and thrombocytopenia. Thesetoxicities also occur commonly with other chemotherapeutic agents typically usedto treat colorectal cancer.

One unique toxicity characteristic of oxaliplatin, but not otheragents used to treat colorectal cancer, was paresthesia. This will be discussedin more detail in the section on neurotoxicity. Oxaliplatin monotherapy did notcause significant alopecia, renal toxicity, or ototoxicity, thus distinguishingit from platinum analogs and the other chemotherapy agents used in the treatmentof colorectal cancer.

The multicenter phase III pivotal trial (EFC 2962) ofoxaliplatin as first-line therapy in patients with metastatic colorectal cancerprovided information on the safety of oxaliplatin that is representative acrossother clinical trials.[9] In this randomized trial of 420 previously untreatedpatients, the study arms received either 5-FU/leucovorin alone (n = 207)according to the de Gramont bimonthly schedule of 5-FU/leucovorin plusoxaliplatin at 85 mg/m² every 2 weeks (n =209). The total number of cycles of therapy administered was 2,431 in the5-FU/leucovorin group (median, 11 cycles; range, 1 to 40) and 2,591 in the5-FU/leucovorin plus oxaliplatin group (median, 12 cycles; range, 1 to 35). Thisrepresents an extensive exposure to oxaliplatin therapy for purposes of toxicityanalyses, both acute and chronic.

Toxicities Increased But Incidence of Grade 3/4 Is Low

Although the addition of oxaliplatin to 5-FU/leucovorinchemotherapy was associated with an increase in most toxicities, the incidenceof most was low. The incidence of grade 3/4 National Cancer Institute (NCI)criteria gastrointestinal toxicity was greater in the oxaliplatin group than inthe 5-FU/leucovorin group, reaching statistical significance for nausea,vomiting, diarrhea, and stomatitis (Table 1).[9]An assessment of grade 3/4 gastrointestinal toxicity by cycle showed that theincidence of gastrointestinal toxicities was low, generally occurring in fewerthan 1 of 100 cycles of oxaliplatin therapy (Table1).

The only NCI grade 3/4 hematologic toxicity that occurredsignificantly more often in the group treated with oxaliplatin compared with the5-FU/leucovorin control group was neutropenia (41.7% vs 5.3%; P <.001). However, the incidence of neutropenic fever was similar in both groups (Table2), indicating that neutropenia in the combination was not detrimental. Aswith the gastrointestinal toxicities, the rate of hematologic toxicities was lowwhen assessed by cycle, with neutropenia being the most common (Table2).

Although thrombocytopenia was more common among patients treatedwith oxaliplatin, there were no life-threatening bleeding episodes. There wereno significant differences in NCI grade 3/4 hepatic (SGOT, SGPT, alkalinephosphatase) or renal (creatinine) toxicity between the two groups, whetherassessed by patient or by cycle. In summary, non-neurotoxic side effects withoxaliplatin occur relatively infrequently, are manageable, and are rarely doselimiting.

Neurotoxicity

Neurotoxicity is generally not associated with the chemotherapyagents commonly used to treat colorectal cancer. The neurotoxicity that has beenobserved with oxaliplatin is qualitatively different from that noted withvincristine, cisplatin (Platinol), or paclitaxel (Taxol). The NCI CommonToxicity Scale, which grades the severity of the toxicity, does not accuratelyor adequately capture the neurotoxicity caused by oxaliplatin. Investigators inEurope (where the major clinical trials were conducted), therefore, developed aspecific scale to grade not only the severity, but also the duration of theneuropathy caused by oxaliplatin(Table 3).

Understanding the differences between the scales is importantfor interpretation of the neurotoxicity findings with oxaliplatin. For example,in the NCI grading scale, grade 3 neurotoxicity is severe sensory loss orparesthesia that interferes with function, whereas in the oxaliplatin-specificscale, grade 3 neurotoxicity may have been a milder neuropathy that persistedbetween treatment cycles.

Two Distinct Patterns

There are two distinct patterns of neurosensory toxicity thatoccur with oxaliplatin—acute and cumulative. The unique group of symptoms thatoccur acutely (within hours to days after infusion) can be characterized asaffecting the fingers and toes or the mouth and throat. These symptoms areworsened by exposure to cold. Patients who experience acute neuropathy followingtreatment with oxaliplatin typically relate that picking up a cold drink is likepicking 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-linetherapy (EFC 2962) and in the phase II oxaliplatin second-line therapy trials(EFC 2964, 2917), the overall incidence of cold-related paresthesia of distalextremities was 68% and 78%, respectively (Table4) while prolonged side effects (grade 3 toxicity by theoxaliplatin-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 (Table4).

Pharyngolaryngeal Syndrome

Additionally, a pharyngolaryngeal syndrome has been describedfor which investigators developed a trial-specific grading scale (Table3). When the pharyngolaryngeal syndrome was first noted in patients who feltdyspneic, blood gases were found to be normal, patients were not cyanotic, andwere, in fact, breathing without physiologic compromise. This sensation,described as the pharyngolaryngeal syndrome, is therefore characterized bysubjective dyspnea or dysphagia with normal blood gases and no physical evidenceof obstruction. It is uncommon, occurring in 2.5% of 478 patients enrolled inthe pivotal first- and second-line therapy trials and in 0.3% of 4,477 cycles (Table4).[9,10]

It is typically mild, and develops within hours of theoxaliplatin infusion. True laryngeal spasm, which is probably a hypersensitivityreaction, occurred in only 0.4% of patients or 0.0007% of cycles. It may occurin the first cycle or in subsequent cycles. Severe anaphylactic reactions tooxaliplatin are rare.[15]

Management of the acute neurosensory symptoms that occur withuse of oxaliplatin includes instruction to avoid cold drinks or foods for a fewdays following treatment and to wear gloves if exposure to cold is unavoidable.Patients should also avoid ice chips during 5-FU-based chemotherapy (see Table5). Educating patients about the potential for the pharyngolaryngealsyndrome is important as well.

In the case of acute manifestations of pharyngolaryngealsymptoms, patients should be examined to rule out airway obstruction andreassured or treated with anxiolytics as necessary. For subsequent treatmentcycles, pretreatment with anxiolytics may be helpful, and the length of theoxaliplatin infusion should be increased from 2 hours to 6 hours.

Dose-Limiting Toxicity

The dose-limiting toxicity of oxaliplatin is cumulativeneurosensory toxicity. It worsens with continued exposure to the drug andinitially affects fine sensory motor coordination. Less than 10% of patientsexperience cumulative toxicity before reaching a total cumulative oxaliplatindose of 850 mg/m² (which corresponds to 10 ormore cycles of treatment). It also appears reversible upon cessation oftreatment. In patients who have been prospectively observed, there wasimprovement to a lower grade over a median of 13 weeks.

In the phase III pivotal trial (EFC 2962), the incidence ofgrade 3 cumulative neurologic toxicity was significantly greater withoxaliplatin added to 5-FU/leucovorin than with 5-FU/leucovorin alone regardlessof whether assessed by the NCI neurotoxicity scale (18.2% vs 0%) or theoxaliplatin trial-specific paresthesia scale (16.3% vs 0%) (both P <.001).[9] The impact of the cumulative neurotoxicity with oxaliplatin can beassessed by comparing the time of onset of grade 3 toxicity with the time ofonset of tumor response. With this assessment technique, onset of tumor responseoccurs long before grade 3 cumulative paresthesia is observed (Figure1). Therefore, patients and their physicians can review their desire tocontinue treatment in spite of the side effects, and few nonresponders will beaffected.

WithdrawalsFrom Therapy and Treatment Exposure

Although significantly more patients withdrew from theoxaliplatin treatment arm than from the 5-FU/leucovorin arm in the phase IIIpivotal trial (EFC 2962), overall withdrawals due to toxicity were infrequent(10.6% vs 3.4%; P = .01) (Table 6).[9]The most common reasons for withdrawals related to toxicity were paresthesia,neutropenia, vomiting or diarrhea, patient choice, etc. Treatment-relatedmortality was 1% or less in all studies of oxaliplatin for colorectalcancer,[7-12] as well as in studies for other indications.

The median relative dose intensity for 5-FU was maintained, with(76%) and without (89%) oxaliplatin treatment in the phase III pivotal trial.[9]The median relative dose intensity of oxaliplatin for all cycles was 73%.Reductions in dose and delays in administration were more common because oftoxicities associated with the use of oxaliplatin than with the use of5-FU/leucovorin—66% vs 24% for dose reduction; 86% vs 61% for dose delays,respectively. Evaluated by cycle, 39% of patients required a dose reduction foroxaliplatin compared with 9% for 5-FU/leucovorin, and 29% (oxaliplatin) vs 13%(5-FU/leucovorin) of cycles required a dose delay.

Conclusions

Overall, the addition of oxaliplatin at 85 mg/m²to a 5-FU/leucovorin-based chemotherapy regimen administered on a 2-week cyclefor advanced colorectal cancer is well tolerated. The incidence ofgastrointestinal toxicity is increased with the addition of oxaliplatin, but canbe managed by dose adjustments. Although there is a higher incidence ofneutropenia with oxaliplatin, neutropenic febrile complications are rare. Theoccurrence of other hematologic toxicities, as well as hepatic and renaltoxicities, did not increase when oxaliplatin was added to a 5-FU/leucovorinregimen. The acute neurosensory symptoms that occur uniquely with oxaliplatincan be managed by having patients take simple precautions as described herein.

Cumulative neurotoxicity is the dose-limiting toxicityassociated with oxaliplatin treatment. The cumulative neurotoxicity may bemanaged by alterations in dose schedules, in which initial cycles areadministered every 2 weeks, with subsequent cycles every 3 weeks. It appearsreversible with discontinuation of the drug and occurs well after tumor responseis observed. Overall, the toxicity associated with oxaliplatin treatment ismanageable and rarely limits effective treatment.

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