Commentary (Livingston): Coming to Grips With Hand-Foot Syndrome

August 1, 2004

Scheithauer and Blum have madean important contribution to thediscussion of hand-foot syndrome,an increasingly common disorder.They emphasize the occurrenceof hand-foot syndrome in the contextof therapy with capecitabine (Xeloda),a prodrug for fluorouracil (5-FU)that in many ways mimics the continuousinfusion of that compound. Theauthors point out that the only provenmethod for managing hand-foot syndromeis interruption and/or reductionin the dose of the administeredtreatment, and they cite retrospectivedata from completed trials in colorectalcancer to support the hypothesisthat such a policy does not impair treatmentefficacy. We feel that severalpoints deserve further amplification.

Scheithauer and Blum have made an important contribution to the discussion of hand-foot syndrome, an increasingly common disorder. They emphasize the occurrence of hand-foot syndrome in the context of therapy with capecitabine (Xeloda), a prodrug for fluorouracil (5-FU) that in many ways mimics the continuous infusion of that compound. The authors point out that the only proven method for managing hand-foot syndrome is interruption and/or reduction in the dose of the administered treatment, and they cite retrospective data from completed trials in colorectal cancer to support the hypothesis that such a policy does not impair treatment efficacy. We feel that several points deserve further amplification.

Clues to Pathogenesis

Our understanding of the pathogenesis of this syndrome is woefully inadequate at the molecular level, with no specific pathologic findings to define it. There are, however, some hints: We know that pyridoxine (vitamin B6) is essential for normal membrane function and stability, and pyridoxine is widely used, without benefit of human controlled trials, as "prophylaxis" or treatment of hand-foot syndrome. Some data show that antagonism of the P2X purinergic receptor accelerates repair of the skin barrier after its disruption, and also prevents epithelial hyperplasia-adenosine triphosphate (ATP) is an agonist of this receptor and pyridoxal phosphate an antagonist.[1] Other data indicate that pyridoxine antagonists have a detrimental effect on the structure and function of endothelial cells in the foot pads of mice.[2]

The most impressive data from a controlled trial, cited by the authors, are those that show the ability of pyridoxine to ameliorate cutaneous toxicity from liposomal doxorubicin (Doxil) in a canine model, where both the onset and severity of hand-foot syndrome were favorably affected.[3] It is intriguing that liposomal doxoru- bicin also represents a sustainedrelease formulation of a compound whose administration is associated with a much higher incidence of handfoot syndrome than intermittent, bolus administration of the native drug, and shorter dosing intervals lead to increased frequency and severity of skin complications.[4]

In the context of anthracyclines, administration of doxorubicin on a weekly basis, in a dose-dense manner, is associated with a higher incidence of hand-foot syndrome, very possibly related to the fact that such a schedule of administration results in exposure of potentially sensitive cells to cytotoxic concentrations for a substantial fraction of each week. In our own experience with such a dosedense approach in the adjuvant treatment of breast cancer, we found that, when 5-FU on a weekly schedule was combined with this method of doxorubicin administration, the incidence of grade 2 hand-foot syndrome exceeded 50% (much higher than when weekly doxorubicin was given without that agent).[5] The authors cite what may be an analogous experience with docetaxel (Taxotere)-an agent with a known propensity for skin toxicity-in combination with capecitabine vs capecitabine alone.

Underreported Effect

It is important to recognize that hand-foot syndrome is often underreported. Even the grading system is of very recent origin, and the difference between grade 2 and grade 3 is not sharply defined. The authors state that the palms are more frequently affected by blistering (grade 3) than the soles, but this has not been our experience, dealing largely with breast cancer patients who are fully ambulatory at the outset of treatment. We have found that pain with walking is the most common single side effect that limits the daily activities of a patient, and such a side effect may be coded as grade 2 or 3, depending on the eye of the beholder.

Most Effective Approach

We strongly concur that dose interruption, usually followed by a 25% dose reduction at the resumption of therapy, is the most effective approach to diagnosed, symptomatic hand-foot syndrome. It is usually possible to resume therapy within 1 week. We routinely provide pyridoxine as "prophylaxis" at 100 mg tid and continue its administration through the course of hand-foot syndrome, but freely admit that a randomized trial is needed to determine whether this approach is truly efficacious.

Like the authors, we are intrigued by the report that celecoxib (Celebrex) may be effective,[6] and wonder if its efficacy may be mediated through the ability of the drug to inhibit angiogenesis[7]-thus, like nicotine, reducing effective blood supply to an area where injury may induce neovascularization)-as well as its anti-inflammatory properties. As with pyridoxine, we feel that a randomized, controlled trial will be necessary to assess the efficacy of celecoxib.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.



Denda M, Inoue K, Fuziwara S, et al: P2Xpurinergic receptor antagonist accelerates skinbarrier repair and prevents epidermal hyperplasiainduced by skin barrier disruption. J InvestDermatol 119:1034-1040, 2002.


Chang SJ: Vitamin B6 antagonists alterthe function and ultrastructure of mice endothelialcells. J Nutr Sci Vitaminol (Tokyo)46:149-153, 2000.


Vail DM, Chun R, Thamm DH, et al: Efficacyof pyridoxine to ameliorate the cutaneoustoxicity associated with doxorubicin containingpegylated (Stealth) liposomes: A randomized,double-blind clinical trial using acanine model. Clin Cancer Res 4:1567-1571,1998.


Lyass O, Uziely B, Ben-Yosef, et al: Correlationof toxicity with pharmacokinetics ofpegylated liposomal doxorubicin (Doxil) inmetastatic breast carcinoma. Cancer 89:1037-1047, 2000.


Ellis GK, Livingston RB, Gralow JR, etal: Dose-dense anthracycline-based chemotherapyfor node-positive breast cancer. J ClinOncol 20:3637-3643, 2002.


Lin E, Morris JS, Ayers GD: Effect ofCelecoxib on capecitabine-induced hand-footsyndrome and anitumor activity. Oncology16(suppl 14):S31-S37, 2002.


Masferrer JL, Leahy KM, Koki AT, et al:Antiangiogenic and antitumor activities ofcyclooxygenase-2 inhibitors. Cancer Res60:1306-1311, 2000.