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Current Articles | Archives | Search Hand-Foot Syndrome (HFS) blowes posted on August 13, 2010 01:00 Background Hand-foot syndrome (HFS; also known as palmar-plantar erythrodysesthesia [PPE]) is a cutaneous complication associated with continuous fluorouracil therapy and oral capecitabine (therapies used in the treatment of CRC) and is seen with several other agents used in the treatment of various cancers. First reported in 1974, this complication was noted in patients receiving antimetabolites and some chemotherapy antibiotics.1 The median time to onset of HFS with capecitabine is approximately 79 days, ranging from 11 to 360 days. In patients with CRC, HFS is the most frequently reported side effect of oral capecitabine (> 50% of patients) and is the dose-limiting side effect for this agent.2,3 Pathobiology Although the exact mechanism of action is not known, some researchers have theorized that HFS may be related to the crushing of deep capillaries in the soles of the feet and palms of the hands, which may cause drug extravasation into those same capillaries, causing the symptoms of this condition. Another report, by Lin et al,4 describes a different mechanism of action, in which HFS is a consequence of an inflammatory reaction that may result from overexpression of COX-2. These researchers note that COX-2 is upregulated with chemotherapy administration, possibly leading to a COX inflammatory-type reaction.3 Because the condition primarily affects the palms of the hands and the soles of the feet, researchers have also postulated a theory that HFS is caused by the accumulation of drug in the eccrine sweat or the eccrine sweat glands of the hands and feet, causing the damage characteristic of this toxicity.1 Histologically, changes in keratinocytes and vacuolar degeneration of the basal layer are seen, with scattered necrotic areas noted.5 Dilated blood vessels and papillary edema may also appear. However, more research is needed to determine the complete mechanism of action of this common cutaneous side effect. Physical Presentation Symptoms may include Numbness Tingling Swelling Dryness, cracking, edema Erythema Pain, blistering, or even desquamation (Figure 1) Skin reactions may not be noted until the second week of therapy. To control or relieve symptoms, dose reduction or temporary drug cessation may be required (Table 2). Figure 1. Toxicity Grading Scale*: HFS Images courtesy of Susan Moore, RN, MSN, ANP, AOCN. *Data from the National Cancer Institute Cancer Therapy Evaluation Program (page 15).6 Few randomized clinical trial data look at the prevention and management of HFS. Table 1 - Selected trials of treatments for HFS Study Author Study Design Results Recommendations Lauman et al7 Retrospective study in which patients were evaluated in 3 arms: capecitbine alone, pyridixoine prophylaxis with capecitabine, and pyridoxine to alleviate symptoms of HFS Patients who took pyridoxine > 200 mg/d had better symptom control of their HFS than patients who took less than that amount Patients may need higher doses of pyridoxine to ameliorate the symptoms of HFS Fabian et al8 Phase 2 trial of metastatic CRC patients receiving continuous 5-FU; 5 of 25 patients with HFS received pyridoxine 50 or 150 mg/d when moderate HFS noted 4 of 5 patients who received pyridoxine had reversal of HFS without interruption of the 5-FU, and no adverse effect on clinical response was noted Large, controlled trials are needed Karo et al9 Small trial of 5 patients with metastatic breast cancer treated with docetaxel and capecitabine; all patients developed grade 2-3 HFS. Vitamin E therapy 300 mg/d PO was given without dose reduction of therapy After 1 week, HFS symptoms began to disappear It could be of interest to consider vitamin E as a preventive drug with HFS-associated agents Yamamoto et al10 Patients on capecitabine were followed for HFS symptoms; 42 episodes of grade 2 toxicity were identified; all patients received oral vitamin E BID during chemotherapy Reduction in desquamation, pain, and comfort level of all the patients improved; neurologic symptoms improved as well. All patients were able to complete chemotherapy without interruption or delay; 38 of 42 did not develop cutaneous manifestation, and 4 had grade 1 toxicity Vitamin E minimized drug delays and schedule interruptions and maintained the dose density of therapy Cin et al11 13 patients with HFS used bag balm topically in a nonblinded study 12 of 13 reported improvement of symptoms after bag balm; 55% were able to continue chemotherapy without dose delay or reduction Large placebo-controlled trials are needed to determine the effectiveness of bag balm Lopez et al12 Topical DMSO was given to 2 patients undergoing chemotherapy with liposomal doxorubicin who developed grade 3 HFS With topical DMSO 4 times daily for 14 days, HFS resolved over a period of 1-3 weeks Small study; patients must be treated in a prospective trial to definitively document therapeutic efficacy In small case reports, treatment with oral corticosteroids (not topical), with COX-2 inhibitors, or sometimes with a nicotine patch has ameliorated HFS symptoms; however, large prospective trials are clearly needed to help refine the optimal therapy of this frequent side effect. Therefore, HFS treatment is largely symptomatic. Patients should be instructed to Avoid immersion in hot water, which could exacerbate symptoms Avoid activities that may increase pressure in affected areas, such as high-impact exercise Avoid tight clothing, vigorous skin rubbing, and sun exposure13 Apply cold compresses, which may help Use topical emollients or other preparations containing urea or lanolin2,3,14 (Table 3) Use protective gloves if needed15 Additional Clinical Information Several case reports have been published recently regarding another complication associated with HFS from capecitabine. In patients with metastatic breast cancer, 2 cases of acquired palmoplantar keratoderma were noted, thought to be a sequela of HFS.16 Another published report described HFS with scleroderma-like changes, also thought to be linked to oral capecitabine, with hyperpigmentation of the palms and soles.17 These cases should be noted as single reports, and more information is needed before these side effects can be conclusively linked to capecitabine. Nurses should continue to be vigilant and report to FDA MedWatch (http://www.fda.gov/medwatch/) all new effects and toxicities thought to be drug related. Drs Saif and Elfiky18 report on differentiating between the presentation of fluoropyrimidine-associated HFS in white and nonwhite patients. Three cases illustrating the disparities between white and nonwhite patients are discussed. The authors suggest a modified grading schema for nonwhite patients. An algorithm outlines pretreatment patient education and monitoring of skin changes during therapy. (See Reference 18 within the reference list for a link to the full-text article without charge.) Nursing Implications HFS can be painful and disruptive to patients’ quality of life. However, the current literature on HFS is limited to identification and treatment, with no existing reports on the effect of HFS on patients’ quality of life (QOL).19 More research on that effect is needed. Oncology nurses should instruct patients regarding the possibility of HFS and the need for early communication of symptoms. Because capecitabine is an oral therapy administered at home, symptom communication is crucial. Early reporting of HSF symptoms can assist nursing and physician staff in appropriate grading of HFS and sooner implementation of care interventions. In most patients, the syndrome is completely reversible.20 However, significant HFS usually requires dose interruption, and if the syndrome persists, dose adjustment becomes necessary.21 Although pyridoxine (50-150 mg/d) has been useful in some patient populations, others receive no benefit from adding this therapy.20 Additionally, because this an oral therapy, adherence may be a concern. Nurses may assess patients’ adherence by suggesting that they bring their medication bottles to clinic visits for pill counts. Table 2. Capecitabine Dose Modification Table Toxicity NCI CTCAE v3.0* During a Course of Therapy Dose Adjustment for Next Treatment Cycle, % of Starting Dose Grade 1 Maintain dose level Maintain dose level Grade 2 1st appearance Interrupt until resolved to grade 0-1 100% 2nd appearance Interrupt until resolved to grade 0-1 75% 3rd appearance Interrupt until resolved to grade 0-1 50% 4th appearance Discontinue treatment permanently Grade 3 1st appearance Interrupt until resolved to grade 0-1 75% 2nd appearance Interrupt until resolved to grade 0-1 50% 3rd appearance Interrupt until resolved to grade 0-1 Grade 4 1st appearance Discontinue permanently or If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 50% Data from Xeloda prescribing information.22 Data from the National Cancer Institute Cancer Therapy Evaluation Program.6 Assessment Tools Polovich et al include a description of HFS under Cutaneous Toxicity in Side Effects of Cancer Therapy.23 Guidelines for coping with HFS skin problems are available here Clinical Practice Guidelines Evidence-based national guidelines do not currently exist. Table 3. Patient Management of Hand-Foot Syndrome: Capecitabine Related Grade Clinical Feature Functional Status Suggested Interventions 1 Numbness, paresthesia, dysesthesia, tingling, painless swelling or erythema of the hands and/or feet Activities of daily living generally unaffected Call nurse or doctor when symptoms first appear. Do not “wait and see.” Skin care: § Reduce friction and pressure: kneeling for long periods of time; leaning on elbows; power walking, jogging, or regular walking for long periods of time; using hand tools; gardening § Wear sunscreen; avoid exposure to heat § Use mild soap to bathe; pat (don’t rub) skin dry § Keep shower and bath water lukewarm to cool; avoid hot tubs and long exposure to hot water § Keep skin moist; gently apply moisturizing creams or topical emollients. Apply at night and wear loose-fitting cotton gloves; avoid rubber ones (dishwashing gloves), since they retain heat § Put hands and feet in cool water to relieve symptoms Clothing: § Wear comfortable, loose-fitting clothes, shoes, and gloves § Do not go barefoot; wear shoes or slippers when possible 2 Painful erythema and swelling of the hands and/or feet, skin remains intact Activities of daily living more difficult 3 Moist desquamation, ulceration, blistering, or severe pain of the hands and/or feet, tissue breakdown Activities of daily living interrupted: unable to work; difficulty walking and using hands Data from the National Cancer Institute Cancer Therapy Evaluation Program (page 18)6 and Wilkes and Doyle.24 References Clark AS, Vahdat LT. Chemotherapy-induced palmar-plantar erythrodysesthesia syndrome: etiology and emerging therapies. Support Cancer Ther. 2004;1: 213-218. Viale PH, Fung A, Zitella L. Advanced colorectal cancer: current treatment and nursing management with economic considerations. Clin J Oncol Nurs. 2005;9:541-552. Berg D. Capecitabine: a new adjuvant option for colorectal cancer. Clin J Oncol Nurs. 2006;10:479-486. Lin E, Morris JS, Ayers GD. Effect of celecoxib on capectabine-induced hand-foot syndrome and antitumor activity. Oncology (Williston Park). 2002;16 (suppl): 31-37. Nagore E, Insa A, Sanmartin O. Antineoplastic therapy-induced palmar plantar erythrodysesthesia (“hand-foot”) syndrome. Incidence, recognition and management. Am J Clin Dermatol. 2000;1:225-234. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Page 15. Accessed March 19, 2010. Lauman MK, Mortimer J. Effect of pyridoxine on the incidence of palmar plantar erythrodysesthesia (PPE) in patients receiving capecitabine. Proc Am Soc Clin Oncol. 2001;20:392a. Abstract 1565. Fabian CJ, Molina R, Slavik M, et al. Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion. Invest New Drugs. 1990;8:57-63. Karo IO, Sahin B, Erkisi M. Palmar-plantar erythrodysesthesia due to docetaxel-capecitabine therapy is treated with vitamin E without dose reduction. Breast. 2006;5:414-424. Yamamoto D, Yamamoto C, Tanaka K. Novel and effective management of capecitabine induced hand foot syndrome. J Clin Oncol. 2008;26(suppl):734s. Abstract 20615. Cin 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. Proc Am Soc Clin Oncol. 2001;20:409a. Abstract 1632. Lopez A, Wallace L, Dorr R, et al. Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia. Cancer Chemother Pharmacol. 1999;44:303-306. Morse MA. Supportive care in the management of colon cancer. Support Cancer Ther. 2006;3:158-170. Wilkes GM. Therapeutic options in the management of colon cancer: 2005 update. Clin J Oncol Nurs. 2005;9:31-44. Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs. 2006;22:144-151. Do JE, Kim YC. Capecitabine-induced diffuse palmoplantar keratoderma: is it a sequential event of hand-foot syndrome? Clin Exp Dermatol. 2007;32:519-521. Lee SD, Kim HJ, Hwang SJ, et al. Hand-foot syndrome with scleroderma-like change induced by the oral capecitabine: a case report. Korean J Intern Med. 2007;22:109-112. Saif MW, Elfiky AA. Identifying and treating fluoropyrimidine-associated hand-and-foot syndrome in whites and non-white patients. J Support Oncol. 2007;5:337-343. http://www.supportiveoncology.net/journal/articles/0507337.pdf Keating KN, Anderson RT, O’Leary JJ. Hand-foot syndrome: symptom assessment and the impact on quality of life—a review of the peer-reviewed literature. J Clin Oncol. 2008;26(suppl):739s. Abstract 20685. Janusch M, Fischer M, Marsch WCH. et al. The hand-foot syndrome: a frequent secondary manifestation in antineoplastic chemotherapy. Eur J Dermatol. 2006; 16:494-499. Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract. 2006;12:131-141. Xeloda prescribing information. Genentech USA, Inc. 2009. Available here. Accessed March 19, 2010. Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: ONS Publishing Division; 2005:208. Wilkes GM, Doyle D. Palmar-plantar erythrodysesthesia. Clin J Oncol Nurs. 2005;9:103-106. Key Definitions cyclo-oxygenase (COX)—an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and is inactivated by aspirin and other NSAIDs desquamation—peeling off in the form of scales; scaling off, particularly of skin dysesthesia—impairment of sensitivity, especially to touch emollient—agent that softens or soothes the skin erythema—abnormal redness of the skin due to capillary congestion (as in inflammation) erythrodysesthesia—condition caused by continuous infusion therapy or certain oral chemotherapies resulting in a tingling sensation of the palms and soles, progressing to severe pain and tenderness with erythema and edema paresthesia—skin sensation such as burning, prickling, itching, or tingling pyridoxine—vitamin B6, found especially in cereals vacuolar degeneration—formation of nonlipid vacuoles in cytoplasm, most frequently due to accumulation of water by cloudy swelling

Genetic-targeted therapy of thyroid cancer: a real promise | Medicine & Health > Diseases & Disorders from AllBusiness.com

Genetic-targeted therapy of thyroid cancer: a real promise | Medicine & Health > Diseases & Disorders from AllBusiness.com: "- Sent using Google Toolbar"

Targeted Therapy for Thyroid Cancer

Composition comprising hemp oil for treating topical diseases, especially hand-foot syndrome - Patent application

Composition comprising hemp oil for treating topical diseases, especially hand-foot syndrome - Patent application

News - Sunitinib Offers Favourable Outcomes for Patients With Refractory Thyroid Cancers - a Summary from the UK

News - Sunitinib Offers Favourable Outcomes for Patients With Refractory Thyroid Cancers: Presented at WCTC

Sunitinib Offers Favourable Outcomes for Patients With Refractory Thyroid Cancers: Presented at WCTC

By Cameron Johnston

TORONTO -- August 11, 2009 -- Patients with thyroid cancers who are refractory to radioactive iodine therapy, and/or have progressed following surgical resection of the thyroid seem to show favourable responses when treated with sunitinib, according to a study presented here at the World Congress on Thyroid Cancer (WCTC).

Ezra Cohen, MD, University of Chicago, Chicago, Illinois, presented the preliminary results of a phase 2 study at an oral presentation on August 8.

The study results included only patients with differentiated cancers; the results from a second cohort of patients with medullary carcinomas were not presented.

Patients in the study had either papillary (n = 18), follicular (n = 8), Hurthle cell (n = 10), or insular (n = 2) thyroid cancer.

Of the 38 who were enrolled, 37 had been treated with radioactive iodine, 35 had had prior surgery, 15 had had external beam radiation therapy (EBRT), and 6 had had systemic chemotherapy. Many had a combination of therapies.

All patients had shown signs of progressive disease within the previous 6 months before being enrolled in the study. Thirty-one patients had distant metastases at the time of enrolment.

Patients were treated with sunitinib 50 mg/day on a 4-week-on/2-week-off cycle.

Overall, 26 patients (68%) had stable disease and 7 (18%) had a partial response. Progression-free survival was 57% and 34% at 1 and 2 years respectively. Overall survival was 76% and 70% at 1 and 2 years respectively.

Treatment response was determined according to modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria as well as by the patient's decrease in thyroglobulin levels.

Adverse events were very common in this study group, although according to Dr. Cohen, they were not unexpected and were comparable to what had been seen in other studies when sunitinib was used to treat renal cell carcinoma.

A total of 5 patients discontinued the study due to adverse events, which included fatigue (79%), diarrhoea (56%), and hand-foot syndrome (53%). There were also 3 toxic deaths, which were felt to be related to the sunitinib (1 case of sepsis, 1 of liver failure, and 1 of left ventricular failure).

Half of the patients (19/38) had to undergo dose reductions as a result of the aggressive toxicity profile.

Nonetheless, Dr. Cohen said sunitinib is an active agent, showing an 87% response rate among patients whose thyroid carcinomas were refractory to virtually all other available treatments.

[Presentation title: Sunitinib in Patients With Radioactive Iodine Refractory and Progressive Differentiated Thyroid Cancer: A Phase 2 Study. Abstract O51]

Phase 2 study of sunitinib in refractory thyroid cancer. - This is my clinical trial

Phase 2 study of sunitinib in refractory thyroid cancer. - ASCO

New drug coming for thyroid cancer??? from XL 184 | The Haystack

June 21st, 2010

BMS Bails on Exelixis

Exelixis has lost a second big pharma partner for its most advanced compound in development. Bristol-Myers Squibb is giving back the rights to XL184, a MET inhibitor in several Phase II and III trials in cancer, less than two years after buying into the program for $195 million. GlaxoSmithKline had already given up rights to the drug in October 2008.
As part of the termination agreement, BMS will shell out $17 million, a figure that would have covered its financial contribution to the drug’s development over the next three months. The South San Francisco-based biotech said in a conference call this morning that despite the loss of about $20 million in expected revenues this year from the collaboration, it will still end the year with a higher cash balance than in 2009.
However, that healthier balance sheet has more to do with cost-cutting than milestone payments from partners. In March, the company underwent a major restructuring in order to help support the development of the drug candidate, cutting 40% of staff, or 270 jobs. The move was meant to save the company $90 million through 2011, and help fund the development of XL 184, arguably the most critical compound in the Exelixis pipeline.
XL184 blocks three protein kinases, MET, VEGFR2, and RET, and is being studied to treat thyroid cancer, glioblastoma, and a variety of other cancers. If an ongoing Phase III trial in thyroid cancer yields positive results, Exelixis expects to ask FDA for approval in 2011. The biotech also plans a Phase III in glioblastoma towards the end of this year.
“We could not agree with BMS on the prioritization of XL184, the speed, the scope of the program,” George Scangos said this morning.
So what’s next for Exelixis and XL 184? The biotech firm is clearly on the lookout for partner number three. Scangos told analysts he expected even more suitors at the company’s doorstep, as the data for the compound is more robust than when it was negotiating with BMS in 2008.
XL 184 was being watched as one of several drugs in development that block MET, a protein implicated in cancer metastasis. ArQule is developing ARQ197, which recently offered up solid Phase II data in lung cancer. Pfizer’s Crizotinib, which blocks MET and ALK, is also in Phase III trials in lung cancer. GlaxoSmithKline, Exelixis’ previous partner for XL 184, continues to develop XL880, which blocks MET and VEGFR2.