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手掌脚掌红肿感觉异常，也称为手足症候群或手至足症候群，是一种不舒服且相对常见的皮肤毒性反应，通常是对某些化学治疗药物；目前对这个症候群仍所知不多，为了厘清这个问题，专家于7月号癌症学志发表了一篇综论性文章，讨论如何处理这个不幸的不良反应。
由来自义大利坎布巴索圣心基督教大学癌症部门Domenica Lorusso领导的作者们表示，手掌脚掌红肿感觉异常，以感觉异常、以及手脚刺痛表现为典型，通常在进行化学治疗后2~12天之间发生，这些症状可能在3~4天后恶化成手掌与脚跟的对称性水肿及红肿。
在手掌、脚跟和其他高压区域的红肿斑块，有紫色以及水肿的片状病灶，通常是轻微且会在1~2周内缓解；然而，若下一次的化学治疗疗程没有延后、或是降低剂量，这个问题可能会恶化成水泡、结痂、溃疡与表皮坏死；作者指出，手掌脚掌红肿感觉异常通常是不舒服的、且可能影响日常生活。
在对这篇综论性文章以电子邮件方式做出评论时（Jaber R等人，Ann Oncol. 2007；于2007年4月1日线上发表），Raja Jaber医师与其来自纽约Stony Brook大学医院的同事称许这是项“出色的”研究，且他们表示对这篇文献非常地感到兴趣；如同Lorusso文章中所整理的，目前仅有的治疗方式是口而相传的，且靠一些好处不明的局部使用药物；典型的来说，最终病患使用较低的剂量、或是延迟后续治疗。他们强调，降低剂量与延后后续治疗，可能降低手足症候群的发生率与减轻症状，目前并没有研究显示，调整过后的疗程在治疗转移性乳癌病患是一样有效的。
Lorusso医师与其同事指出，相较于接受传统doxorubicin的病患，接受聚乙烯二醇化微脂粒doxorubicin者发生手足症候群机率更高；这种新药是一种长效循环剂型，将doxorubicin hydrochloride包覆在聚乙烯二醇化微脂粒中，该药物被核准治疗转移性乳癌、进展性卵巢癌、以及后天免疫不全引起的卡波西氏肉瘤。
在使用目前核准的聚乙烯二醇化微脂粒doxorubicin剂量下，以50 mg/m2 每4周注射一次，作者表示，使用该药物的病患，大约50%会发生手足症候群，且将近20%病患会发生第3级的症状。
研究者表示，评估发生手足症候群，特别是与doxorubicin新剂型有关的，其作用机转未知；然而，数据支持及药物由汗水排除与局部压力有关。
【癌症治疗中令人衰弱的并发症】
Jaber医师与其同事指出，手掌脚掌红肿感觉异常是使用聚乙烯二醇化微脂粒doxorubicin一种令人衰弱的并发症，可能导致延迟、降低或是停止化学治疗；除此之外，使用新的生物多重磷酸酶抑制剂，例如sorafenib与sunitinib，发生这类并发症的机率更高，使得这个问题越来越严重。
作者报告一个使用微脂粒doxorubicin发生第3级手足症候群的病例，且对于治疗反应不佳，但是在短暂使用全身性类固醇后戏剧性地改善。
Stony Brook大学医院的团队表示，如果使用预防性剂量的dexamethasone，仍然手掌脚掌红肿感觉异常，我们认为口服prednisone是值得尝试的；他们附带表示，使用口服prednisolone治疗手掌脚掌红肿感觉异常，其疗效将需要正式的控制组临床试验来获得结论。
同时，Lorusso医师与其同事强调，教育病患早期察觉手足症候群，以减少不适与并发症，是很重要的，他们解释，在每次诊察时，应该仔细询问病患关于接受上一次治疗后发生的病征与症状。
许多药物与非药物治疗已渐使用于手足症候群的预防，非药物介入包括避免过度的压力或是摩擦表皮，以及避免洗热水澡或晒太阳使血管扩张。
相对的，一般认为冰敷可以使血管收缩、减轻药物循环到末端，进而可能减少药物外渗到周边组织，以减少毒性；作者表示，降低温度也可能稳定微脂粒型态，因此降低未受包覆的doxorubicin。
已经被评估用于治疗手足症候群的药物，包括pyridoxine或是维他命B6、dexamethasone、amifostine与COX-2抑制剂，局部用药经常被用于治疗，包括润滑液、芦荟洗剂、以及保水剂，可能可以缓解症状；Lorusso医师与其同事称Bag Balm，一种局部石蜡油－羊毛脂为基质的软膏，具有抗菌成分hydroxyquinoline sulfate；他们的结论是，应该及早治疗，以避免恶化成手掌脚掌红肿感觉异常。
研究者表示无相关资金上往来。
Minimize Chemotherapy-Induced Hand-Foot Syndrome
By Allison Gandey
Medscape Medical News
Palmar-plantar erythrodysesthesia, also called hand-foot syndrome or hand-to-foot syndrome, is an uncomfortable and relatively frequent dermatologic toxic reaction to certain chemotherapeutic agents, and it remains poorly understood. Working to elucidate the problem, experts reporting in a review in the July issue of the Annals of Oncology discuss the challenges of managing this unfortunate adverse event.
"Palmar-plantar erythrodysesthesia typically presents with dysesthesia and tingling in the hands and feet, which usually appear 2 to 12 days after administration of chemotherapy," note the authors led by Domenica Lorusso, MD, from the department of oncology at Catholic University of the Sacred Heart, in Campobasso, Italy. "These symptoms may progress 3 to 4 days later into symmetrical edema and erythema of the palms and soles."
Erythematous plaques with violaceous and edematous patches in the palms, soles, and other high-pressure areas are usually mild and resolve in a week or 2. The problem may, however, evolve into blistering desquamation, crusting, ulceration, and epidermal necrosis if the next chemotherapy cycle is not delayed or the dose reduced. The reviewers point out that palmar-plantar erythrodysesthesia is often uncomfortable and can interfere with the ability to carry out normal activities.
Commenting on the review in an e-letter to the journal (Jaber R et al. Ann Oncol. 2007; published online April 11, 2007), Raja Jaber, MD, and colleagues from Stony Brook University Hospital, in New York, called the work "outstanding," and they report having read it with great interest. "As summarized by the Lorusso review, the only treatments so far are anecdotal and rely on topical agents with unclear benefits. Typically, the patients end up receiving a lowered dosage or have their treatments delayed." They emphasize that while dose reduction and schedule lengthening may decrease the incidence and ameliorate symptoms of hand-foot syndrome, there are no studies demonstrating that these altered schedules are equally effective in treating patients with metastatic breast cancer.
Dr. Lorusso and colleagues report the incidence of hand-foot syndrome is increased in patients receiving pegylated liposomal doxorubicin compared with conventional doxorubicin. The new drug is a long-circulating formulation in which doxorubicin hydrochloride is encapsulated within pegylated liposomes. It is approved to treat patients with metastatic breast cancer, advanced ovarian cancer, and acquired immunodeficiency syndrome–related Kaposi's sarcoma.
In studies that utilized the currently approved dose of pegylated liposomal doxorubicin of 50 mg/m2 every 4 weeks, the reviewers suggest that about 50% of patients receiving the product developed hand-foot syndrome and roughly 20% experienced grade 3 symptoms.
The researchers note that studies evaluating the development of hand-foot syndrome specifically associated with new-formulation doxorubicin have not fully identified the mechanism; however, data support the roles of drug excretion in sweat and local pressure as contributors.
Debilitating Complication of Cancer Therapy
"Palmar-plantar erythrodysesthesia is a debilitating complication of pegylated liposomal doxorubicin that can lead to delay, reduction, or discontinuation of chemotherapy," Dr. Jaber and colleagues write in their letter. "In addition, it will be an increasing problem due to a high incidence associated with new biologic multikinase inhibitors such as sorafenib and sunitinib."
The authors report on a case of liposomal doxorubicin–related persistent grade 3 hand-foot syndrome, refractory to the reported treatments, that responded dramatically to a short course of systemic treatment with oral prednisone.
"We propose oral prednisone as a safe treatment modality worth trying if palmar-plantar erythrodysesthesia occurs despite preventive dosages of dexamethasone, pyridoxine, and cooling of extremities," suggest the team from Stony Brook University Hospital. "Definite conclusions as to the efficacy of oral prednisone in the treatment of palmar-plantar erythrodysesthesia will require formal controlled clinical trials," they add.
In the meantime, Dr. Lorusso and colleagues emphasize the importance of patient education for early detection of hand-foot syndrome to minimize discomfort and complications. "At each visit, the patient should be carefully asked about signs and symptoms following the last dose," they explain.
Several pharmacologic and nonpharmacologic treatments have been used to prevent hand-foot syndrome. Nonpharmacologic interventions include avoiding undue pressure or rubbing of the skin and avoiding blood vessel dilation induced by hot showers or sun exposure.
In contrast, cooling is said to result in vasoconstriction, lessening circulation of drug to distal extremities. This in turn may lead to less drug extravasation into surrounding tissue, resulting in less toxicity. It is also possible that lower temperatures stabilize the liposomal configuration, thereby reducing the concentration of unencapsulated doxorubicin, the reviewers suggest.
Pharmacologic agents that have been evaluated for hand-foot syndrome include pyridoxine or vitamin B6, dexamethasone, amifostine, and COX-2 inhibitors. Topical agents are typically used to treat cases, and nonpharmacologic treatments that may relieve symptoms include emollients, aloe vera lotion, and moisturizing creams. Dr. Lorusso and colleagues name Bag Balm, a topical petroleum-lanolin-based ointment with the antiseptic ingredient hydroxyquinoline sulfate. They conclude, "Treatment measures must be started as soon as possible when necessary to help prevent progression of palmar-plantar erythrodysesthesia."
The researchers report having no significant financial relationships.
Ann Oncol. 2007;18:1159-1164. Abstract