Lanolin-based dexpanthenol cream, topical hydrocortisone or observation in the prevention of capecitabine-induced hand-foot syndrome: a phase III trial

ABSTRACT

Introduction: The use of capecitabine is associated with hand-foot syndrome (HFS). Since there is anecdotal evidence that lanolin-based creams and topical steroids are useful for the treatment of HFS, we conducted a three- arm phase III trial to compare observation, lanolin-based cream with dexpanthenol (L-D), and topical hydrocortisone in the prevention of HFS.

Material and Methods: Patients with breast or colorectal cancer with indication to use capecitabine as a single agent or in combination were randomized in an open-label fashion to one of the three arms. The initial capecitabine dose was 1,000 or 1,250mg/m², according to the physicians discretion and clinical practice, and dose adjustments followed the local label. The primary endpoint was the frequency of HFS of any grade in the intent-to-treat population, whereas quality of life (QoL), change from baseline in performance status and adverse events were secondary endpoints.

Results: Mean age among the 595 patients randomized was 58 years, and 69% were women. 37% of patients had advanced breast cancer and 63% of patients had colorectal cancer. Capecitabine was used as a single agent in 67% of patients; among the remaining 33% of patients, 82% were treated with oxaliplatin-based combinations. HFS of any grade was seen in 35.6% of patients in the observation group, 24.9% with L-D, and 34.3% with hydrocortisone (p=0.039). The unadjusted odds ratio for the frequency of HFS in the arm treated with L-D was 0.60 (95%CI, 0.39 to 0.92). Only between 2.6% and 9.4% of patients had grade 3 HFS. There were no statistically significant differences in mean change from baseline in any of the QoL scores, the distribution of performance status, or the frequency of adverse events among the three arms.

Conclusion: L-D could be considered a standard strategy in the attempt to prevent capecitabine-induced HFS.

RESUMO

Introdução: O uso de capecitabina está associado à síndrome mão-pé (SMP). Como há poucas evidências sobre a eficácia de cremes à base de lanolina e esteroides tópicos no tratamento da SMP, realizamos um estudo de fase III de três braços para comparar observação, creme à base de lanolina com dexpantenol (L-D) e hidrocortisona tópica na prevenção de SMP.

Material e Métodos: Pacientes com câncer de mama ou colorretal com indicação de uso de capecitabina como agente único ou em combinação foram randomizados de forma aberta para um dos três braços. A dose inicial de capecitabina foi de 1.000 ou 1.250mg/m², conforme critério médico e prática clínica, e os ajustes de dose seguiram a bula local. O endpoint primário foi a frequência de SMP de qualquer grau na população com intenção de tratamento, enquanto a qualidade de vida (QoL), mudanças em performance status em relação ao início do estudo e eventos adversos foram endpoints secundários.

Resultados: A média de idade entre os 595 pacientes randomizados foi de 58 anos, e 69% eram mulheres. 37% dos pacientes tinham câncer de mama avançado, e 63% dos pacientes tinham câncer colorretal. A capecitabina foi usada como agente único em 67% dos pacientes; entre os 33% restantes, 82% foram tratados com combinações à base de oxaliplatina. SMP de qualquer grau foi observada em 35,6% dos pacientes do grupo de observação, 24,9% com L-D e 34,3% com hidrocortisona (p=0,039). A razão de chances (não ajustada) para a frequência de SMP no braço tratado com L-D foi de 0,60 (IC95%, 0,39 a 0,92). Apenas entre 2,6% e 9,4% dos pacientes tiveram SMP de grau 3. Não foram encontradas diferenças estatisticamente significativas na mudança média de nenhum dos escores de QoL em relação ao início do estudo, na distribuição do performance status ou na frequência de eventos adversos entre os três braços.

Conclusão: A L-D pode ser considerada uma estratégia padrão na tentativa de prevenir a SMP induzida pela capecitabina.

Keywords:

Breast neoplasms - Capecitabine - Colorectal neoplasms - Glucocorticoids - Hand-foot syndrome - Dexpanthenol

Descritores:

Neoplasias mamárias - Capecitabina - Neoplasias colorretais - Glicocorticóides - Síndrome mão-pé - Dexpantenol

Publikationsverlauf

Eingereicht: 14. Juni 2022

Angenommen: 19. August 2022

Artikel online veröffentlicht:
13. Dezember 2022

• REFERENCES

• 1 Hof PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M. et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001; Apr; 19 (08) 2282-2292
• 2 O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G. et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline- pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; Jun; 20 (12) 2812-2823
• 3 Twelves C, Wong A, Nowacki MP, Abt M, Burris 3rd H, Carrato A. et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; Jun; 352 (26) 2696-2704
• 4 Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T. et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; Dec; 355 (26) 2733-2743
• 5 Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF. et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007; Nov; 25 (33) 5210-5217
• 6 Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R. et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008; 26 (12) 2006-2012
• 7 Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B. et al. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol 2011; Dec; 29 (34) 4498-4504
• 8 Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; Nov; 367 (19) 1783-1791
• 9 Lassere Y, Hof P. Management of hand-foot syndrome in patients treated with capecitabine (Xeloda). Eur J Oncol Nurs 2004; 8 (Suppl 1): S31-S40
• 10 Kwakman JJM, Elshot YS, Punt CJA, Koopman M. Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncol Rev 2020; Feb; 14 (01) 442-442
• 11 Wolf R. The lanolin paradox. Dermatology 1996; 192 (03) 198-202
• 12 Chin SF, Tchen N, Oza AM. et al. Use of “Bag Balm” as topical treatment of palmar- plantar erythrodysesthesia syndrome (PPES) in patients receiving selected chemotherapeutic agents (abstract 1632). Proc Am Soc Clin Oncol 2001; 20 (Suppl 1): 409a-409a
• 13 Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract 2006; Sep; 12 (03) 131-141
• 14 Huang XZ, Chen Y, Chen WJ, Zhang X, Wu CC, Wang ZN. et al. Clinical evidence of prevention strategies for capecitabine-induced hand-foot syndrome. Int J Cancer 2018; Jun; 142 (12) 2567-2577
• 15 Kang YK, Lee SS, Yoon DH, Lee SY, Chun YJ, Kim MS. et al. Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study. J Clin Oncol 2011; Aug; 28 (24) 3824-3829
• 16 Wolf SL, Qin R, Menon SP, Rowland Junior KM, Thomas S, Delaune R. et al. Placebo- controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5. J Clin Oncol 2010; Dec; 28 (35) 5182-5187
• 17 Yap YS, Kwok LL, Syn N, Chay WY, Chia JWK, Tham CK. et al. Predictors of hand- foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial. JAMA Oncol 2017; Nov; 3 (11) 1538-1545
• 18 Chalermchai T, Tantiphlachiva K, Suwanrusme H, Voravud N, Sriuranpong V. Randomized trial of two different doses of pyridoxine in the prevention of capecitabine- associated palmar-plantar erythrodysesthesia. Asia Pac J Clin Oncol 2010; Sep; 6 (03) 155-160
• 19 Zhang RX, Wu XJ, Lu SX, Pan ZZ, Wan DS, Chen G. The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study. J Cancer Res Clin Oncol 2011; Jun; 137 (06) 953-957
• 20 Corrie PG, Bulusu R, Wilson CB, Armstrong G, Bond S, Hardy R. et al. A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications. Br J Cancer 2012; Aug; 107 (04) 585-587
• 21 Elyasi S, Shojaee FSR, Allahyari A, Karimi G. Topical Silymarin administration for prevention of capecitabine-induced hand-foot syndrome: a randomized, double-blinded, placebo-controlled clinical trial. Phytother Res 2017; Sep; 31 (09) 1323-1329
• 22 Macedo LT, Lima JPN, Santos LV, Sasse AD. Prevention strategies for chemotherapy- induced hand-foot syndrome: a systematic review and meta-analysis of prospective randomised trials. Support Care Cancer 2014; Jun; 22 (06) 1585-1593
• 23 Lu W, Huang Z, Chen S, Lv H, Chen X, Lei J. et al. The effectiveness of EVOSKIN^®Palm and sole moisturizing cream in treating capecitabine-associated hand-foot syndrome: a randomized double-blind clinical trial. Ann Palliat Med 2021; Mar; 10 (03) 3009-3017
• 24 U. S. Department of Health and Human Services (HHS-US), National Institutes of Health (NIH), National Cancer Institute (NCI). Cancer therapy evaluation program: common terminology criteria for adverse events, version 3.0 (CTCAE). Washington: HHS-US; 2003
• 25 Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ. et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; Mar; 85 (05) 365-376
• 26 Brabo EP, Paschoal ME, Biasoli I, Nogueira FE, Gomes MC, Gomes IP. et al. Brazilian version of the QLQ-LC13 lung cancer module of the European Organization for Research and Treatment of Cancer: preliminary reliability and validity report. Qual Life Res 2006; Nov; 15 (09) 1519-1524
• 27 Franceschini J, Jardim JR, Fernandes AL, Jamnik S, Santoro IL. Reproducibility of the Brazilian Portuguese version of the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire used in conjunction with its lung cancer-specific module. J Bras Pneumol 2010; Oct; 36 (05) 595-602
• 28 Scheithauer W, McKendrick J, Begbie S, Borner M, Burns WI, Burris HA. et al. Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Ann Oncol 2003; Dec; 14 (12) 1735-1743
• 29 Cassidy J, Twelves C, Van Cutsem E, Hof P, Bajetta E, Boyer M. et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002; Apr; 13 (04) 566-575
• 30 Blum JL, Barrios CH, Feldman N, Verma S, McKenna EF, Lee LF. et al. Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2012; Dec; 136 (03) 777-788
• 31 Lian S, Zhang X, Zhang Y, Zhao Q. Pyridoxine for prevention of hand-foot syndrome caused by chemotherapy agents: a meta-analysis. Clin Exp Dermatol 2021; Jun; 46 (04) 629-635
• 32 Zhang RX, Wu XJ, Wan DS, Lu ZH, Kong LH, Pan ZZ. et al. Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial. Ann Oncol 2012; May; 23 (05) 1348-1353
• 33 Hofheinz RD, Gencer D, Schulz H, Stahl M, Hegewisch-Becker S, Loefer LM. et al. Mapisal versus urea cream as prophylaxis for capecitabine-associated hand-foot syndrome: a randomized phase III trial of the AIO quality of life working group. J Clin Oncol 2015; Aug; 33 (22) 2444-2449
• 34 Zhang RX, Lu ZH, Wan DS, Wu XJ, Ding PR, Kong LH. et al. Neuroprotective effect of neurotropin on chronic oxaliplatin-induced neurotoxicity in stage II and stage III colorectal cancer patients: results from a prospective, randomised, single-centre, pilot clinical trial. Int J Colorectal Dis 2012; Dec; 27 (12) 1645-1650
• 35 Naito M, Yamamoto T, Hara S, Shimamoto C, Miwa Y. Hemoglobin value is the most important factor in the development of hand-foot syndrome under the capecitabine regimen. Chemotherapy 2017; 62 (01) 23-29
• 36 Zhou S, Zhang X, Song Z. Therapeutic effects and toxic side reactions of capecitabine combined with a modified prescription of Fuzheng Jiedusan (resistance strengthening and detoxification granules) on advanced gastric cancer. Biomed Res 2017; 28 (05) 1939-1943
• 37 Scontre VA, Martins JC, Sette CVM, Mutti H, Cubero D, Fonseca F. et al. Curcuma longa (turmeric) for prevention of capecitabine-induced hand-foot syndrome: a pilot study. J Diet Suppl 2017; 15 (05) 606-612
• 38 Hennessy BT, Gauthier AM, Michaud LB, Hortobagyi G, Valero V. Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature. Ann Oncol 2005; Aug; 16 (08) 1289-1296
• 39 Rossi D, Alessandroni P, Catalano V, Giordani P, Fedeli SL, Fedeli A. et al. Safety profile and activity of lower capecitabine dose in patients with metastatic breast cancer. Clin Breast Cancer 2007; Dec; 7 (11) 857-860