This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bardia, A. Articles by Goetz, M. P. Search for Related Content PubMed PubMed Citation Articles by Bardia, A. Articles by Goetz, M. P. Social Bookmarking                            What's this?

Hand-Foot Syndrome After Dose-Dense Adjuvant Chemotherapy for Breast Cancer: A Case Series

Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN

To the Editor:

In 2003, the Cancer and Leukemia Group B (CALGB) trial 9741 published a prospective randomized study which reported that adjuvant chemotherapy delivered in a dose-dense manner (doxorubicin and cyclophosphamide [AC] followed by docetaxel [T], delivered once every 2 weeks) with granulocyte colony-stimulating factor (G-CSF/filgrastim), resulted in a statistically significant decrease in breast cancer recurrence and death as compared with patients who received the same chemotherapy delivered once every 3 weeks, with a similar safety profile.¹ After publication of this study, pegfilgrastim (the pegylated form of filgrastim) became widely incorporated into the dose-dense regimen because pegylation of filgrastim results in a longer half-life, thus allowing more convenient scheduling.²

Hand-Foot syndrome (HFS), also known as acrauding erythema, palmar-plantar erythrodysesthesia, and Burgdof's syndrome, refers to intensely painful bilateral symmetric swelling, erythema, and tenderness over the palms and soles that evolves into desquamation (HFS is also listed in the National Cancer Institute's Common Toxicity Criteria, version 3.0).^3,4,5,6,7 Although HFS was not noted in the original CALGB 9741 trial,¹ our institutional experience suggests that this syndrome may be more prevalent among those patients who receive dose-dense therapy with AC and T along with pegylated G-CSF (pegfilgrastim). We have observed five cases of HFS that have occurred following dose-dense AC or T with pegfilgrastim. Reported in this letter are detailed descriptions of two patients who developed HFS; Table 1 lists details about all of the patients.

Case 2. A 47-year-old woman presented with stage II breast cancer and was treated with AC once every 2 weeks, with pegfilgrastim support on day 2. Following the third dose of AC, the patient developed redness, tenderness, and cracking, involving the palms of her hands. Her symptoms improved spontaneously within 10 days. Because of the severity of her symptoms, the treating physician omitted the last dose of AC and proceeded with paclitaxel. Following the first cycle of T with pegfilgrastim support, she developed redness, cracking, and peeling of her palms. With the second and third cycle of T along with pegfilgrastim support, she continued to have HFS, despite having her hands and feet in ice packs during chemotherapy administration. With the fourth cycle of T, no pegfilgastrim was administered, and no symptoms of HFS were noted by the patient.

Discussion
HFS is a well-known complication of some chemotherapeutic agents, most notably capecitabine,⁵ but has also been noted following cytarabine and doxorubicin.⁶ This current case series (listed in Table 1) clearly suggests that HFS can occur in the setting of dose-dense chemotherapy followed by pegfilgrastim support. In these patients, the syndrome began as a tingling sensation in the palms or soles, followed by characteristic well-defined symmetric swelling, erythema, and desquamation over the next few days. Notably, HFS was observed following both AC and T administration. In all cases, the symptoms occurred 0 to 2 days after pegfilgrastim administration. In four cases, the syndrome resolved after pegfilgrastim was discontinued, despite the fact that chemotherapy administration continued.

The pegylation of filgrastim involves the addition of a polyethylene glycol moiety to a protein, resulting in a longer half-life and enhanced tissue concentrations.² The molecules are generally too large for renal clearance and are primarily cleared through a "self-regulatory mechanism" by neutrophils through a pegfilgrastim receptor.⁹ Given that HFS is characterized histologically by WBC infiltration and vacuolar degeneration of the basal layer,⁴ it is possible that the pegylation of filgrastim augments and prolongs the neutrophil infiltration in some patients, mediating the inflammation observed with HFS. It is notable that patients receiving pegylated chemotherapy such as liposomal doxorubicin are also at higher risk for developing HFS.^10,11

In the CALGB trial 9741, HFS was not described.¹ There are two possible explanations that may account for this discrepancy. First, filgrastim, rather than pegfilgrastim, was used for growth factor support. Second, because HFS was not an expected toxicity at the time the trial was designed, it may have been underreported. Pegfilgrastim became widely incorporated into the dose-dense regimen following the publication of the CALGB trial 9741. However, it was only recently that Burstein et al⁸ published a prospective clinical trial using dose-dense chemotherapy with pegfilgrastim support. Consistent with our findings, Burstein et al noted, in a tabular format, the occurrence of grade 2 or 3 HFS in 4% of their patients. No data were provided regarding the details of this toxicity and whether it altered therapy.

In summary, substantial HFS can occur following the administration of either AC or T, in the setting of pegfilgrastim. Our experience is that this toxicity may lead to treatment delays. The absence of HFS in the CALGB trial 9741¹ in which nonpegylated G-CSF was used suggests that pegylation of filgrastim may contribute to the toxicity observed. However, further studies are needed in patients who receive the AC followed by T dose-dense chemotherapy regimen with filgrastim (with and without pegylation) to confirm this hypothesis, to determine the true frequency of HFS, and to identify potential risk factors that predispose to this toxicity.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported in part by Grant No. CA 90628-03 (M.P.G.).

REFERENCES

1. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 Erratum: 21:2226, 2003

2. Molineux G: The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des 10:1235-1244, 2004[CrossRef][Medline]

3. Burgdorf WH, Gilmore WA, Ganick RG: Peculiar acral erythema secondary to high-dose chemotherapy for acute myelogenous leukemia. Ann Intern Med 97:61-62, 1982[Abstract/Free Full Text]

4. Nagore E, Insa A, Sanmartín O: Antineoplastic therapy-induced palmar plantar erythrodysesthesia ('hand-foot') syndrome incidence, recognition and management. Am J Clin Dermatol 1:225-234, 2000[CrossRef][Medline]

5. Abushullaih S, Saad ED, Munsell M, et al: Incidence and severity of HFS in colorectal cancer patients treated with capecitabine: A single-institution experience. Cancer Invest 20:3-10, 2002[CrossRef][Medline]

6. Baack BR, Burgdorf WH: Chemotherapy-induced acral erythema. J Am Acad Dermatol 24:457-461, 1991[Medline]

7. Lassere Y, Hoff P: Management of hand-foot syndrome in patients treated with capecitabine (Xeloda). Eur J Oncol Nurs 8:S31-S40, 2004 (suppl 1)[CrossRef][Medline]

8. Burstein HJ, Parker LM, Keshaviah A, et al: Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol 23:8340-8347, 2005[Abstract/Free Full Text]

9. Kotto-Kome AC, Fox SE, Lu W, et al: Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model. Pharmacol Res 50:55-58, 2004[CrossRef][Medline]

10. D'Agostino G, Ferrandina G, Ludovisi M, et al: Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer. Br J Cancer 89:1180-1184, 2003[CrossRef][Medline]

11. Keller AM, Mennel RG, Georgoulias VA, et al: Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 22:3893-3901, 2004[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				A. U. Buzdar Adjuvant Chemotherapy for High-Risk Operable Breast Cancer J. Clin. Oncol., May 1, 2007; 25(13): 1642 - 1644. [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bardia, A. Articles by Goetz, M. P. Search for Related Content PubMed PubMed Citation Articles by Bardia, A. Articles by Goetz, M. P. Social Bookmarking                            What's this?