Mucocutaneous toxicity induced by pegylated liposomal doxorubicin: a single‐institution, retrospective case series

Dear Editor, Pegylated liposomal doxorubicin (PLD), a chemotherapeutic agent that belongs to the class of anthracyclines, is widely used for treatment of multiple malignancies, including breast cancer, ovarian cancer and Kaposi sarcoma.1,2,3,4 Liposomal encapsulation of doxorubicin offers many advantages compared with the soluble, free form of the drug. PLD is characterized by dose‐limiting mucocutaneous toxicity, mild myelosuppression, minimal alopecia and a lack of apparent cardiac toxicity.5,6 Common dermatological adverse reactions include palmar‐plantar erythrodysaesthesia (PPE), maculopapular and vesicobullous rash, stomatitis and/or mucositis.7 The most accredited hypothesis of the pathogenesis of skin toxicity, is that PLD is preferentially accumulated in tissue with increased microvascular permeability, including tumour and normal tissue such as skin and mucosae, particularly in sites subjected to pressure, friction and repeated trauma (hands and feet).8 On the basis of the above scenario regarding PLD safety, we performed a single‐institution, retrospective study to evaluate the incidence of skin toxicity in patients with solid malignancies treated with PLD from 2010 to 2014. We collected medical records from all patients, which included information regarding age, comorbidities, known history of allergy, stage of disease, prior treatments, the number of cycles of PLD and all adverse events experienced by patients during treatment with this drug. In the present analysis, we included all those patients who had received at least one cycle of PLD. Skin toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. If patients exhibited skin toxicity ≥ grade 2, the treatment with PLD was delayed until the toxicity had resolved and the dosage was reduced by 25% for subsequent cycles. Further dosage reductions were allowed in case of additional episodes of skin toxicity. If a case was clinically judged to be of significant toxicity and persisted for more than 6 weeks, then therapy was withdrawn. A total of 41 patients who had received PLD for metastatic or recurrent disease were included in the present analysis. The median age of patients was 61 years (range 43–80). There were 20 cases of breast cancer, 16 cases of ovarian cancer, three cases of cholangiocarcinoma and two cases of Kaposi sarcoma. In total, 22 patients (54%) received PLD as part of a combined chemotherapy regimen and 19 patients (46%) received PLD as a single agent. The dose range for PLD was 20–50 mg m−2 and patients received a median of three cycles (range 1–20) of treatment. Overall, 39% of patients (16 of 41) had skin toxicity and five of these 16 had more than one reaction during the entire course of treatment. In total, nine patients had PPE (grade 1, 2 and 3) (Fig. 1a–c), four patients had a diffuse follicular rash (three grade 1 and one grade 2) (Fig. 1d–f), four patients had intertrigo‐like eruptions (one grade 2 and three grade 3) (Fig. 2), five patients had hair and nail alterations, and three patients had mucositis with painful erosions and ulcerations. No grade 4 skin toxicities were reported. All cases of skin toxicity occurred within 1–3 cycles of treatment. Five patients with grade 2 and grade 3 PPE required dose delay and one dosage reduction. After dosage reduction, these patients continued to receive treatment. PLD treatment was interrupted in two patients owing to persistent skin toxicity. (a–f) Hand‐foot syndrome. Grade 1 with erythematous sensitive reaction; grade 3 with erythematous‐oedematous plaques and patches, erosions and flat bullae. Diffuse follicular rush. Widespread scaly erythematous accentuation of the hair follicle is evident. (a–d) Intertrigo‐like eruption involving abdomen, groin and waist; flat brown macules on the trunk and axillae. Intertrigo‐like eruption with erythematous patches over skinfolds. Hand‐foot syndrome with oedematous erythema, flat bullae and erosions. Palmar‐plantar erythrodysaesthesia is the most common cumulative toxicity experienced by patients treated with PLD and appears to be dose‐interval related. It is characterized by dysaesthesia and tingling, with symmetrical painful erythema and swelling of the palms and soles followed by desquamation and exfoliation; in severe cases, patients may experience blister formation, especially on the feet, with considerable functional impairment. The development of PPE is both dosage‐ and schedule‐dependent, and the reaction tends to recur with increasing intensity on re‐exposure.9,10,11 The second most frequent adverse reaction in our study was diffuse follicular rash. It consists of a widespread scaly erythematous accentuation of the hair follicles along the lateral parts of the limbs and, sometimes, over the trunk. Diffuse follicular rash can be underdiagnosed because it generally presents as a grade 1 toxicity and does not affect patient's quality of life significantly.9,10,11 Intertrigo‐like eruption was observed in four patients. This eruption consists of erythematous patches developing over skinfolds (e.g. axillae, belt region). The skin involved in areas of friction may become painful and erosive. Generally, PLD dosage reduction is required in these cases.9,10,11 Hair and nail modifications (diffuse alopecia with alteration of hair growth, onycholysis, onychomadesis and periungual pyogenic granuloma‐like lesions) were detected in five patients (12%). To our knowledge, this is the first time that these kinds of alterations have been described as occurring with such a high frequency. In our case series, mucositis developed in four of 41 patients (10%). Dose‐limiting toxicities occurred as stomatitis or PPE in 12 of 41 patients (29%) with recurrent advanced stage ovarian cancer or endometrial carcinoma. A frequency of 6% has been reported in patients with AIDS‐related Kaposi sarcoma. The same study showed that one‐third of patients developed stomatitis with doses > 60 mg m−2.12 The dose range for PLD in our study was 20–50 mg m−2 and patients received a median of three cycles. In about 10% of patients, PLD dosage was reduced and treatment was delayed. In another study 34% of 35 patients who received PLD required either a dosage reduction or treatment delay.13 In conclusion, skin toxicity related to PLD is not to be underestimated. According to our data, it can affect almost half of patients treated with this drug formulation. On the basis of this high frequency, both physicians and patients should be aware of this occurrence. Generally, skin toxicity related to PLD is considered to be dose dependent; however, we did not observe a dose‐limiting effect in the group of adverse reactions reported in this study. Funding sources: none. Conflicts of interest: none declared. M.V. and M.S. contributed equally.