Toxic effects and their management: daily clinical challenges in the treatment of colorectal cancer.

Average: 5 (1 vote)
Nat Rev Clin Oncol. 2009 Apr;6(4):207-18.

Toxic effects and their management: daily clinical challenges in the treatment of colorectal cancer.


Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Among the many chemotherapeutic options for metastatic colorectal cancer, none has shown clear superiority in efficacy. All pharmacologic agents in current use have been associated with adverse events. Frequently reported adverse events associated with the chemotherapeutic agents oxaliplatin, irinotecan, 5-fluorouracil, and capecitabine include acute and chronic neuropathy, hypersensitivity reactions, diarrhea, neutropenia, and hand-foot syndrome. Although biologic agents are seemingly less toxic, toxic effects can also arise with their use; antiangiogenic agents result in hypertension, and EGFR inhibitors can cause severe hypersensitivity, paronychial infections, and more commonly, dermatologic rash. Furthermore, a correlation has been reported for the efficacy of anti-EGFR agents and development of rash. Data indicate that elderly patients with colorectal cancer who have adequate function and performance status, who may previously have been dissuaded from pursuing active therapy solely on the basis of age, should receive the same treatment as younger patients. To enhance the survival of patients with metastatic colorectal cancer, many therapies are administered. Recognition of treatment-emergent toxic effects will, therefore, aid the design and implementation of management strategies that minimize treatment interruption and/or discontinuation, and enhance quality of life for patients.


Mikael Nordfors's picture

Calcium and magnesium

Dichlorodiaminocyclohexanemplatinum and oxalate are known metabolites of oxaliplatin and potent Ca and mg chelators. the acute cold neuropathy associated with oxaliplatin, which is capable of altering the voltagegated sodium channels, might be linked to chelation of Ca by the oxaliplatininduced oxalate. Chronic neuropathy might be due to the decreased cellular metabolism resulting from accumulation of oxaliplatin in the
dorsalroot ganglia cells.34 a retrospective, cohort study in 161 patients who received FolFoX concluded that patients who received Ca–mg preoxaliplatin and postoxaliplatin (n = 96) had a lower incidence and intensity of any grade acute and chronic oxaliplatinrelated neuropathy compared with those who did not receive Ca–mg (n = 65).35 Ca–mg use was widely adopted to decrease doselimitingm neuropathy owing to its conveni ence and minimal expense. two prospective analyzes of Ca–mg (the n04C7 adjuvant FolFoX study,36 and the ConcePt trial,37 which accrued only 102 and 139 patients, respectively) closed prematurely because of data that suggested decreased efficacy for Ca–mg compared
with placebo.36,37 the n04C7 investigators observed no decline in therapeutic efficacy and concluded that Ca–mg might decrease some symptoms, for example, muscle contractions (P = 0.012) and chronic numbness (P = 0.021).36 the ConcePt trial randomly assigned patients to Ca–mg and also to intermittent or continuous FolFoX. any benefit with Ca–mg in this trial was difficult to ascertain owing to the small number of patients in each arm.37



Xaliproden is an orally active, nonpeptide neurotrophic and neuroprotective 5Ht1areceptor agonist that increases the expression of neurotrophins such as nervegrowth factor, brainderived neurotrophic factor, and neurotrophin 3, and acts on the development and repair of neurons. in a prospective, randomized, doubleblind, placebocontrolled, phase iii study in 649 patients with mCrC who received FolFoX4 and xaliproden
(1 mg/day) or placebo, the development of grade 3 or 4 peripheral sensory neuropathy was significantly reduced in patients who received xaliproden (hazard ratio, 0.61; P = 0.02).38 no difference in efficacy was noted. major limitations of this trial included inability to continue xaliproden after discontinuation of FolFoX4 and failure to acknowledge the difficulties of grade 2 neuropathy (that is, persistent neuropathy that does not affect daily activities). the rate of severe grade 3 or 4 toxic effects with a greater than 2% difference reported between the placebo and xaliproden arms was as follows: diarrhea, 10.9% versus 13.0%; pulmo nary embolism, 0.9% versus 3.1%; fatigue, 3.7% versus 1.5%; neutropenia, 43.0%
versus 37.8%.38



in 86 patients with mCrC who received oral glutamine 15 g twice daily (n = 42) or placebo (n = 44) for seven consecutive days every 2 weeks, patients who received glutamine experienced a lower incidence of grade 1 or 2 peripheral neuropathy after two treatment cycles (16.7% versus 38.6%, respectively; P = 0.04).39 Patients also reported a significantly lower incidence of grade 3 or 4 neuropathy after four (4.8% versus 18.2%, respectively; P = 0.05) and six cycles (11.9% versus 31.8%, respectively; P = 0.04). these results suggest that glutamine supplementation might confer a neuroprotective effect in patients who receive oxaliplatin. no significant differences were observed between groups in terms of response to chemotherapy or survival.39 Glutamine is relatively inexpensive and might improve the thera peutic index of oxaliplatin. an overview of existing literature regarding the use of gluta mine for oxaliplatin chemotherapyinduced peripheral neuropathy is limited butsuggests decreased dose reductions were possible when glutamine was used. 40 Further analysis in large trials is clearly warranted.


Other therapies

other treatment approaches include the antiepileptic medications carbamazepine and gabapentin, but neither has shown clear benefit.

medications currently being investigated include pregabalin and alphalipoic acid, both of which are used in diabetic neuropathy with variable results.