Scontre VA, Martins JC, de Melo Sete CV, et al. Curcuma longa (turmeric) for prevention of capecitabine-induced hand-foot syndrome: a pilot study. J Diet Suppl. 2017:1-7.
Pilot, uncontrolled clinical trial.
To assess whether oral curcumin supplementation prevents hand-foot syndrome (HFS), a common side effect of capecitabine.
Forty patients diagnosed with either gastrointestinal malignancy (47.5%) or breast cancer (52%), with no previous exposure to capecitabine. Average age was 62 years and most (80%) were female.
Study Medication and Dosage
Patients received turmeric capsules (GNC “extra strength” turmeric), which consisted of 95% curcuminoids (1,050 mg/capsule) and piperine (10 mg/capsule). The total dose of curcuminoids was approximately 4 grams per day starting at the beginning of capecitabine treatment, taken for a total of 6 weeks. Turmeric dosing was divided into 2 capsules twice a day, taken 12 hours apart. Participants received capecitabine at doses above or equal to 1 g/m2 by mouth twice a day for 14 days of a 21-day cycle or, if combined with radiation therapy, continuously at a dose of 1.650 g/m2; 40% of patients were in the latter group.
Dermatologic toxicity assessments were conducted after 3 weeks and at 6 weeks. Assessments were made via quality of life (QoL) questionnaires (European Organization for Research and Treatment of Cancer [EORTC QLQ-C30] and the Dermatological Quality of Life Questionnaire [DLQI]) and serum inflammatory markers (interleukin [IL]-6, tumor necrosis factor alpha [TNF-a], C-reactive protein (CRP), and albumin). Photographs of hands and feet were also taken at 3 and 6 weeks. The Common Terminology Criteria for Adverse Events (CTCAE) was used to assess the intensity of HFS. The CTCAE scale rates the intensity of HFS as follows: grade 1=minimal skin changes of dermatitis without pain; grade 2=skin changes such as bleeding, peeling, blisters, and edema without pain; and grade 3=skin changes with pain interfering with daily function.
When compared to previous clinical trials that assessed the incidence of HFS in patients receiving capecitabine vs those receiving placebo, investigators found that turmeric combined with capecitabine was associated with a lower than expected incidence and severity of HFS. After the first cycle of capecitabine (at 3 weeks), 11 out of 40 patients developed HFS and 4 of those patients developed HFS equal to or greater than grade 2. On second cycle analysis (at 6 weeks), 10 of 29 patients developed HFS of any grade with 3 patients developing HFS of grade 2 or higher. Overall, 10% of participants had grade 2 or higher HFS in this trial as opposed to previous placebo-controlled trials citing rates of grade 2 or higher HFS of approximately 50%. There was no correlation in inflammatory markers (IL-6, TNF-a, CRP, and albumin) and HFS severity at the 3-week or 6-week analysis. Furthermore, there was no correlation between HFS severity and EORTC QoL scores; however, there was a positive correlation with DLQI scores. The latter is a dermatologic-specific QoL assessment.
Turmeric may not only help manage HFS but may also improve dermatologic quality of life.
Hand-foot syndrome (HFS), more precisely known as palmar-plantar erythrodyesthesia (PPE), is a significant side effect associated with several chemotherapy drugs. Capecitabine (Xeloda), an oral chemotherapy agent, frequently causes this dermatologic toxicity. Several other chemotherapy agents such as 5-fluorouracil (5-FU), pegylated-liposomal doxorubicin, docetaxel, vinorelbine, gemcitabine, and multikinase inhibitors can also cause HFS.1 Hand-foot syndrome is a clinical diagnosis, and is typically heralded by dysesthesia followed by a painful palmar and/or plantar erythematous rash that may be associated with edema.2 The rash may become bullous, ulcerative, and severely painful, resulting in interference with activities of daily living (ADL).3 This may necessitate dose reduction of chemotherapy. Although the development of HFS is not life-threatening, it significantly affects QoL in 90% of those with a grade 3 manifestation.3
The pathophysiology of HFS remains unclear. Skin biopsies in humans have demonstrated a higher epidermal basal cell proliferation rate (per Ki-67 staining) in the palm versus the dorsum of the hand. Furthermore, the 5-FU metabolizing enzymes thymidine phosphorylase (TP) and dihydropyridine dehydrogenase (DPD) were also concentrated in palmar tissue. This is important because capecitabine is actually a pro-drug that is metabolized to 5-FU.4 Taken together, this could explain the preferential toxicity to palmar-plantar surfaces. Additional factors implicated in the development of HFS include gravitational forces, vascular anatomy unique to those areas with associated temperature gradients, and increased drug concentration in the eccrine glands of the palms and soles.1 Whatever the case, the frequency of HFS occurrence and its dose-limiting nature make it imperative to develop management and, most importantly, preventive strategies. These strategies must not interfere with the therapeutic efficacy of the given cytotoxic therapies.
There is still no consensus on how to prevent or manage HFS. Clinical trials are lacking for many of the common interventions. To date, the most effective ways to manage HFS are to interrupt treatment and/or reduce the dose of the toxicity-inducing chemical agents. Drugs such as dimethylsulfoxide and oral or topical steroids may ameliorate symptoms; however, they have not been evaluated in randomized clinical trials.1,5-7 In addition, these agents are not without risk.
Urea cream, a lactic acid–based topical keratolytic agent, and Mapisal (Medac), an ointment rich in antioxidants and nourishing oils, are among the few agents that have been assessed in randomized clinical trials. A randomized phase II clinical trial published in 2010 demonstrated that urea and lactic acid–based topical keratolytic agents were no better than placebo in the prevention of capecitabine-induced HFS.8 However, a 2015 phase III clinical trial found a 10% urea cream to be superior to Mapisal, with incidence rates at 39.5% with the Mapisal arm and 22.4% in the urea arm (stratified odds ratio, 2.37; P=0.02).9 Notably, skin-related QoL was significantly worse in the group treated with Mapisal. Since its publication, several controversial points regarding interpretation of this study’s results have been made, including the following:
- No phase II study or exploratory study was performed prior to this phase III clinical study (the latter piece important as it appears Mapisal increased incidence and severity of HFS).
- This trial should not impact clinical practice guidelines as urea cream is not considered a standard and effective treatment in the prevention of HFS per the previously mentioned randomized phase II clinical trial.10
A novel 2015 pilot study evaluated the use of sildenafil on PPE resulting from sunitinib or capecitabine.11 Of the 9 patients who completed the study, 5 reported improvement in foot pain and 3 reported improvement in hand pain. The authors hypothesized that the increase in nitric oxide (NO) concentration would mitigate the mechanisms underlying PPE via improved wound healing. The latter has been demonstrated in preclinical trials.12-16 It is presumed improved wound healing occurs due to upregulation of cyclic guanosine monophosphate (CGMP), which augments the effect of NO. Interestingly, several tyrosine kinase drugs that also cause PPE downregulate NO production,17 thereby decreasing wound healing in the setting of vascular compromise.
Nonpharmaceutical recommendations to manage HFS, often made by nursing staff to patients, include avoiding excessive pressure to the skin, friction, and extreme temperatures.1,7 However, the latter is questionable as some suggest regional cooling to the wrists and ankles may be effective to decrease onset of PPE,18 most commonly during intravenous administration of chemotherapeutics associated with PPE. The theory is that vasoconstriction, due to the cold temperatures, results in less drug accumulation in the distal extremities. Unfortunately, for daily, oral cytotoxic agents such as capecitabine and multityrosine kinase inhibitors, consistent regional cooling is not only impractical, but also painful.
Given that erythema and swelling are hallmarks of PPE, some postulate that toxic effects of cytotoxic 5-FU may result in activation of inflammatory pathways. This hypothesis makes sense; celecoxib, a cyclooxygenase (COX)-2 inhibitor, has been shown to reduce the rate of grade 2 HFS in 50% of patients when compared to placebo.19 Although celecoxib is seemingly effective in this arena, its consistent use is not without risks, including serious adverse events like gastrointestinal bleeding and perforation.20 These hazards are nonnegotiable in patients with gastrointestinal tumors. It makes great sense to use therapies that do not increase risk of adverse events or interfere with chemotherapeutic agents. Curcumin seems to fit the bill, as it is one of the most studied and well-known natural anti-inflammatory agents and, so far, shows little to no interaction with capecitabine efficacy.21,22
The anti-inflammatory mechanisms of curcumin are multifold.23-27 Clinical trials have demonstrated its ability to downregulate COX-2 activity by modifying nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-KB)-mediated gene activation.28 This makes curcumin an intriguing therapy as a supportive agent in the management and prevention of HFS, given that COX-2 inhibition with celecoxib proved to be protective.
Curcumin or turmeric?
A further point must be made regarding the type of Curcuma longa (turmeric) used in the present study. The authors cite the use of a GNC-formulated extra-strength turmeric formula. While in the abstract the authors state that participants received turmeric, they actually received a standard curcumin concentrate that was 95% curcuminoids that also contained black pepper concentrates intended to enhance absorption. So although this study claims to have used turmeric, the product given was, in fact, curcumin. This is an important point as curcuminoids are those studied in the majority of clinical trials, and their anti-inflammatory and immune-modulating abilities far outweigh those of turmeric alone.28 This study would have been better titled “Curcumin for Prevention of Capecitabine-Induced Hand-Foot Syndrome.” Given this study’s outcomes, curcumin joins a small group of better known and studied natural therapies to mitigate HFS.
Vitamin B6 (pyridoxine) is the most common supplement employed to mitigate the manifestation of capecitabine-induced HFS. Preclinical data and a number of case reports suggest therapeutic efficacy. Case studies have reported on doses up to 800 mg per day.7 A randomized, placebo-controlled trial from 2012 evaluated the use of pyridoxine to avoid capecitabine dose modifications due to intractable PPE.29 Investigators found that pyridoxine, at a dose of 50 mg per day, was associated with fewer capecitabine dose modifications, as well as fewer grade 3/4 HS-related adverse events, compared to placebo. However, these associations were not significant. Since this study, 2 randomized, double-blind trials evaluated the use of pyridoxine to prevent capecitabine-induced PPE.30,31 No benefits were found.
Pyridoxine has and can be used topically as a cream either alone or in conjunction with oral pyridoxine. However, there is no evidence validating the use of topical pyridoxine in the mitigation of PPE in clinical practice.1
The use of henna (Lawsonia inermis) may offer promise as a topical therapeutic for ameliorating PPE. In Arab cultures henna is considered a source of good luck, health, and sensuality. Some even consider it “magic.”32 This herb may also provide antimicrobial, anti-inflammatory, anti-oxidant, analgesic, and wound-healing benefits. An unblinded, nonrandomized trial evaluated the use of topical henna in 6 patients with grade 3 PPE HFS and 2 patients with grade 2 HFS.33 A complete response was reported in 4 of the 6 patients with grade 3 HFS and all of the patients with grade 2 HFS. The remaining 2 patients with grade 3 HFS improved to grade 2 HFS. Furthermore, an observational case study has corroborated its use in the improvement of capecitabine-induced HFS.34 More evidence is certainly needed. The use of topical henna in HFS mitigation may prove to be of high value.
Notably, not all patients develop HFS despite the standard administration of common PPE-inducing agents. Evidence regarding these reasons is coming to light.
A recent (2017) randomized clinical trial compared not only the incidence and time to onset of HFS in patients receiving capecitabine and pyridoxine vs placebo, but also identified biomarker predictors of HFS.35 Investigators corroborated previous evidence that pyridoxine did not significantly delay or prevent the onset of grade 2 or higher HFS. They also found that serum and red blood cell folate levels were independent predictors of HFS. Higher levels of both parameters (every 5 nmol/L increase in serum folate [P=0.001] and every 200 nmol/L increase in red blood cell folate [P=0.003]) were independently and significantly associated with grade 2 or higher HFS. This correlates with mounting evidence from other clinical studies that suggest a relationship between dietary folate intake and fluoropyrimidine toxicity.35 Fluoropyrimidines such as 5-FU, the cytotoxic end product of capecitabine metabolism, depend on the presence of folate to prevent cell division in rapidly dividing cells.36 So, although folate must be available for these drugs to work it may increase their toxicity.
The United States has one of the poorest safety profiles in regards to these drugs due to its folate fortification guidelines in common food sources.37 It therefore behooves us, as practitioners, to make sure that patients are not getting additional forms of supplemental folate either in single form or as part of a mixed supplement, a multivitamin being the most common source. One could even go so far as to suggest patients decrease their consumption of food sources of folate during treatment with fluoropyrimidines. Serum and RBC folate measurements may provide, as noted, accurate parameters of risk assessment. However, guidelines regarding just what those parameters are remain undefined and their use in clinical practice possibly premature.
We must also consider that some patients metabolize folate as well as fluoropyrimidines differently per unique genetic blueprints. A growing body of evidence suggests that germline single nucleotide polymorphisms (SNPs) in candidate genes, such as those that code for folate metabolism, molecular targets of the drug, and enzymes and/or transporters, are involved in its metabolism and excretion.38 Most SNP analysis of capecitabine and its toxicities has focused on thymidylate synthase and dihydropyrimidine dehydrogenase (DPD), the former its target and the latter a player in the drug’s catabolism.39 Dihydropyrimidine dehydrogenase deficiency is a life-threatening condition for patients on these drugs, while DPD overexpression may result in not only reduced toxicity but also lower clinical efficacy.40 In conjunction, methyltetrahydrofolate reductase (MTHFR) and its variants are the SNPs most commonly associated with folate metabolism. A 2013 clinical study concluded that a homozygous variant of MTHFR predicted HFS.41 Bottom line, the assessment of germline mutations may provide guidance as to the least toxic and most effective capecitabine dose and help identify patients who are at greatest risk. In the future, these mutations may provide targets for specific therapies. Greater knowledge and broader application of these mutations may change the way disease is treated. Until then, it is imperative to continually identify the best therapies to mitigate and, most importantly, prevent the occurrence of PPE.
This study by Scontre et al is the first to evaluate the use of curcumin for prevention of HFS with capecitabine use, and it appears this intervention may hold promise. However, the data are weak; the trial was not randomized, blinded, or placebo-controlled. As noted, the authors failed to find positive correlation between inflammatory parameters and HFS severity. Furthermore, although global QoL assessment was not associated with severity of HFS, QoL from dermatologic toxicity was associated with severity of HFS. Turmeric may not only help manage HFS but may also improve dermatologic QoL.
This study did not assess any outcome data regarding the efficacy of the capecitabine treatment. As with any agent that appears to lessen a side effect of a cytotoxic therapy, it is essential that the efficacy of the given treatment be validated to ensure there is no loss of drug function. As a single-arm pilot study, it’s impossible to compare outcomes in those receiving curcumin against those not receiving it. However, going forward, it is essential to track drug efficacy along with HFS development.
Clinical evidence will always provide the best guide. When evidence is scarce, ultimately clinical practice must first be safe, resting on a foundation of knowledge, understanding, and experience to best help our patients. This is unquestionably true in the practice of naturopathic medicine.
As we better understand the pathophysiology of certain conditions; more randomized, double-blind, placebo-controlled trials are completed; epigenetic evaluations are standardized; and our continued efforts to help our patients from an integrated standpoint grows, clinical experience, without neglect for growing evidence, remains the best roadmap.
The present study by Scontre et al sheds light on turmeric in the treatment of HFS. Topical henna and NO-inducing agents may also have value. Might we also apply curcumin topically to address capecitabine-induced skin damage? How effective might it be locally if its oral use appears to offer some promise? Would a topical mixture of curcumin and henna offer a synergistic partnership and overall greater management of HFS? These questions offer areas in need of further study. It is possible that topical applications may provide greater benefit for patients who are already taxed from oral medications and have side effects from capecitabine, which may include nausea and gastrointestinal unease.
Overall, there remains no clear consensus as to the best and most validated tool for mitigating PPE. The use of curcumin for the mitigation of PPE is a case in point.