Palmar-Plantar Erythrodysesthesia Syndrome
Palmar-Plantar Erythrodysesthesia Syndrome
The mechanism by which chemotherapy causes PPES is not known precisely. It is speculated that it may be caused by leakage of chemotherapy into small blood vessels in pressure-sensitive areas such as palms and soles. The risk of developing PPES increases with the dosage of chemotherapy. The half-life of liposomal products such as L-DOX increases from 4 minutes to over 3 hours in the first elimination phase and from 8.7 hours to 45 hours in the second elimination phase. During this prolonged exposure, liposomes encapsulating the drug may rupture in microcapillaries in areas receiving pressure (hands, feet), releasing the drug directly into soft tissues and causing damage. In fact, conventional doxorubicin rarely causes PPES, whereas the manufacturer of Doxil states that 37% of patients developed PPES while receiving doxorubicin encapsulated in polyethylene glycol-coated liposomes, of which 16% were of grade III-IV severity.
There is no well-defined treatment for chemotherapy-induced PPES. Dosage reduction, lengthening the rest time between courses, and, ultimately, drug withdrawal are some methods to prevent the syndrome. Pyridoxine 50-150 mg/day was given to postpone the onset and alleviate symptoms of PPES in patients receiving fluorouracil or docetaxel. However, these anecdotal reports reveal that pyridoxine did not completely abolish PPES; rather, it delayed the onset of symptoms and allowed higher dosages to be given. Steroids were administered with variable degree of success. Other reports suggested that topical 99% dimethylsulfoxide might be efficacious in treating PPES induced by L-DOX.
Of interest, L-DNR has not been associated with PPES. Colleagues reported treatment results from a single-agent phase I study of 24 patients with acute leukemia and from another phase I study of an L-DNR-containing regimen of 64 patients with relapsed leukemia. Both were dose-finding studies with dosages of L-DNR from 75-200 mg/m infused daily for 3 days. No PPES occurred in either study. The absence of PPES was confirmed in a retrospective study designed to capture the occurrence of dermatologic toxicity of L-DNR. The 464 patients received cumulative L-DNR doses of 39.6-322.4 mg/m and no PPES was reported.
To our knowledge, this is the first report of PPES associated with L-DNR. Lack of previous reports of this adverse effect may be due to the higher L-DNR dose (100-125 mg/m) and prolonged infusion time (2-6 hrs) in our patients, thus increasing drug exposure. Reports show that cytarabine may be associated with PPES; however, patient number 1 received extensive treatment with cytarabine 2 years earlier and did not report skin toxicity. It is thus likely that PPES was due to L-DNR and not cytarabine. Patient number 2 had not received cytarabine before, so it is not certain whether PPES was related to L-DNR or cytarabine or both. Clinicians should be aware of the potential for PPES in patients receiving high-dose L-DNR.
The mechanism by which chemotherapy causes PPES is not known precisely. It is speculated that it may be caused by leakage of chemotherapy into small blood vessels in pressure-sensitive areas such as palms and soles. The risk of developing PPES increases with the dosage of chemotherapy. The half-life of liposomal products such as L-DOX increases from 4 minutes to over 3 hours in the first elimination phase and from 8.7 hours to 45 hours in the second elimination phase. During this prolonged exposure, liposomes encapsulating the drug may rupture in microcapillaries in areas receiving pressure (hands, feet), releasing the drug directly into soft tissues and causing damage. In fact, conventional doxorubicin rarely causes PPES, whereas the manufacturer of Doxil states that 37% of patients developed PPES while receiving doxorubicin encapsulated in polyethylene glycol-coated liposomes, of which 16% were of grade III-IV severity.
There is no well-defined treatment for chemotherapy-induced PPES. Dosage reduction, lengthening the rest time between courses, and, ultimately, drug withdrawal are some methods to prevent the syndrome. Pyridoxine 50-150 mg/day was given to postpone the onset and alleviate symptoms of PPES in patients receiving fluorouracil or docetaxel. However, these anecdotal reports reveal that pyridoxine did not completely abolish PPES; rather, it delayed the onset of symptoms and allowed higher dosages to be given. Steroids were administered with variable degree of success. Other reports suggested that topical 99% dimethylsulfoxide might be efficacious in treating PPES induced by L-DOX.
Of interest, L-DNR has not been associated with PPES. Colleagues reported treatment results from a single-agent phase I study of 24 patients with acute leukemia and from another phase I study of an L-DNR-containing regimen of 64 patients with relapsed leukemia. Both were dose-finding studies with dosages of L-DNR from 75-200 mg/m infused daily for 3 days. No PPES occurred in either study. The absence of PPES was confirmed in a retrospective study designed to capture the occurrence of dermatologic toxicity of L-DNR. The 464 patients received cumulative L-DNR doses of 39.6-322.4 mg/m and no PPES was reported.
To our knowledge, this is the first report of PPES associated with L-DNR. Lack of previous reports of this adverse effect may be due to the higher L-DNR dose (100-125 mg/m) and prolonged infusion time (2-6 hrs) in our patients, thus increasing drug exposure. Reports show that cytarabine may be associated with PPES; however, patient number 1 received extensive treatment with cytarabine 2 years earlier and did not report skin toxicity. It is thus likely that PPES was due to L-DNR and not cytarabine. Patient number 2 had not received cytarabine before, so it is not certain whether PPES was related to L-DNR or cytarabine or both. Clinicians should be aware of the potential for PPES in patients receiving high-dose L-DNR.
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